{
"claim": "Hypothesis: Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging",
"timestamp": "2026-08-05T18:42:20.197Z",
"settings": {
"mode": "Social",
"library": "PubMed",
"format": "Preprint",
"length": "Standard",
"rigor": "Strict",
"tagCloud": "on",
"breadth": 50,
"depth": 3,
"runs": 2,
"evalsPerRun": 1,
"autoExplore": false,
"smartFollowUp": true
},
"prompt_settings": {
"research_veridical_check": {
"name": "Research Veridical Verification",
"purpose": "Audits the final research response after quotes pass to ensure absolute veridicality, logical consistency, and zero hallucinated external knowledge.",
"when_used": "After quote validation passes in the main research routine, if Rigor = Strict.",
"content": "You are a strict QA Audit AI. Your job is to verify the RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"assistant_veridical_check": {
"name": "Assistant Veridical Verification",
"purpose": "Audits the assistant's response to ensure absolute veridicality and rule adherence.",
"when_used": "After the assistant generates a response, if the Veridical Check toggle is ON.",
"content": "You are a strict QA Audit AI. Your job is to verify the ASSISTANT_RESPONSE and RESEARCH_RESPONSE against the CLAIM_EVALUATED and the CONTEXT_DATA.\n\nCRITICAL RULES FOR EVALUATION:\n1. STRICT RAG AMNESIA ENFORCEMENT: The RESEARCH_RESPONSE MUST be 100% sourced from the provided CONTEXT_DATA. Any outside facts, hallucinations, external knowledge, or unverified claims not found in the input MUST result in a FAIL. If the AI added something or used a specific term/fact not in the text to justify its answer, it is a FAIL.\n2. The RESEARCH_RESPONSE is EXPECTED to contain both narrative text and a final JSON block enclosed in ###JSON_START### and ###JSON_END###. Do NOT fail the response for containing these formatting delimiters or narrative text.\n3. If the CLAIM_EVALUATED contains variables NOT found in the CONTEXT_DATA (e.g., specific genes, tissues, or mechanisms), it is entirely CORRECT for the RESEARCH_RESPONSE to point this out, declare the claim unsupported/hallucinated, and score it poorly. This is a successful evaluation and MUST be scored as a PASS.\n4. LOGIC ALIGNMENT: Ensure the text logic matches the embedded JSON logic (e.g., if the text says the claim is false, the Alignment score should be low).\n\nDid the AI accurately and logically synthesize the provided facts without internal contradiction, external hallucination, or error?\n\nReturn ONLY a valid JSON object. Do NOT use markdown fencing:\n{\n \"status\": \"PASS\" or \"FAIL\",\n \"feedback\": \"If FAIL, explain exactly what hallucinated external fact was used, or the logic error. If PASS, leave empty.\"\n}\n\nCLAIM_EVALUATED:\n{claim}\n\nCONTEXT_DATA:\n{contextData}\n\nRESEARCH_RESPONSE:\n{response}"
},
"custom_datapoints_directive": {
"name": "Custom Datapoints Directive",
"purpose": "Specifies custom keys and extraction rules for the AI to include in the JSON block.",
"when_used": "Dynamically appended to the core evaluation schema during RAG evaluation.",
"content": "### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n- \"lung_microbiome_axis\": Investigate how commensal metabolites like indole-3-acetaldehyde influence tissue-resident macrophage phagocytic efficiency in aged lung tissue.\n- \"systemic_crosstalk\": Test if restoring alveolar macrophage efferocytic function in the lung creates a systemic dampening of age-related inflammatory markers in distal organs like the liver or heart.\n- \"metabolic_checkpoint\": Examine if NRF2 signaling enhancement (via indole-3-acetaldehyde/PXR pathway) can rescue age-related mitochondrial fitness deficits in tissue-resident macrophages.\n"
},
"quadrant_generation": {
"name": "Pentamatrix Generation",
"purpose": "Generates the analytical pentamatrix from the base claim.",
"when_used": "Beginning of the Semmelweis mode workflow.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes\n\nINITIAL EVALUATION: CLAIM vs. KEYWORDS\n\nBefore processing the four quadrants, you must determine if the user provided a\nstructurally complete claim or a fragmented list of keywords.\n\n - If Full Claim: Act as a strict transcription engine.\n - If Keyword List / Fragment: Act as a Speculative Synthesis Engine.\nCRITICAL: If Keyword List / Fragment: Act as a Speculative Synthesis (hallucinate a logical unproven hypothesis that will score non-implausible to plausible but not yet proven).\n\nQUADRANT CONSTRAINTS\n\n0. RAW USER TEXT\n1. ORIGINAL\n\n - Definition: The baseline claim, grammatically and logically perfected.\n - Rule for Full Claims: Transcribe exactly as stated. Your ONLY modification\n is to fix spelling, punctuation, and grammar. If the input is a question,\n convert it into a declarative claim.\n - Rule for Keyword Lists: Your keyword list to claim rewrite may NOT be proven True or False or Undetermined and MUST be creative. You MUST NOT summarize the keywords. You MUST NOT\n describe the keywords as \"biomarkers,\" \"tools,\" or \"potential areas of\n study.\" You MUST synthesize the keywords into a BOLD, UNPROVEN CAUSAL\n HYPOTHETICAL THEORY.\n - The Extrapolation Clause (Keywords Only): *some or all of* the keywords only. novel idea. \n\n2. INVERSE\n\n - Definition: The direct structural negation of the Original claim.\n - Rule: Directly negate the primary relationship. Do NOT introduce new\n variables. Flip the boolean state of the primary verb (e.g., \"promotes\"\n becomes \"does not promote\").\n\n3. ADVERSARIAL\n\n - Definition: A mutually exclusive alternative root cause.\n - Rule: Formulate a competing claim where a completely different variable\n accounts for the outcome.\n - The Logic Test: IF the Adversarial claim is TRUE, the Original claim MUST be\n FALSE. It must represent a conflict of causality.\n\n4. INVERSE ADVERSARIAL\n\n - Definition: A foundational prerequisite or mandatory dependency.\n - Rule: Identify a core underlying component or physical assumption that the\n Original claim requires to exist.\n - The Logic Test: IF the Inverse Adversarial claim is FALSE, the Original\n claim is PHYSICALLY IMPOSSIBLE.\n\nOUTPUT FORMAT\n\nReturn ONLY valid JSON. Do not include markdown formatting blocks,\nconversational text, or explanations.\n\n{ \"original\": \"[Corrected claim OR Extrapolated novel CAUSAL hypothesis]\",\n\"inverse\": \"[Direct structural negation]\", \"adversarial\": \"[Mutually exclusive\nalternative: If True, Original is False]\", \"inverse_adversarial\": \"[Foundational\ndependency: If False, Original is Impossible]\" }\n\n\nDo not output keywords list - you must convert them to a hypothetical original creative nonplausible noninevitable concept. Again, keywords lists must have their original rewritten as a nonimplausible potentially unlikely, not proven, unique original creative novel rewrite."
},
"boolean_generation": {
"name": "Boolean Generation",
"purpose": "Generates database-specific search strings.",
"when_used": "Stage 1 of each pentamatrix's evaluation loop.",
"content": "You are an expert librarian and systematic reviewer. Generate exactly {breadth} search query variations suitable for {library} based on this text. \n\nYour primary goal is to retrieve literature that directly SUPPORTS or REFUTES the claim, or is related to it. Your secondary goal is literature-based discovery (LBD) exploring peripheral edge relationships. Use OR to discover edges and overlooked abstracts.\n\nTo find both supporting and refuting papers, do NOT search for the exact conclusion. Instead, search for the intersection of the core variables (e.g., Variable A AND Variable B). USE \"OR\" for edge discovery.\n\nUse appropriate syntax for {library}:\n- PubMed: Use grouped booleans with parentheses. Group synonyms using OR (e.g., (\"Term 1\" OR \"Synonym 1\")). Connect distinct core concepts using AND. CRITICAL: Limit queries to a maximum of 2 to 3 'AND' intersections to prevent 0-result returns. Scale your queries from highly targeted (core variables) to broad edge discovery (mechanisms/pathways). Include MeSH terms.\n- Wikipedia: Use wiki search format utlencoded\n- arXiv: Provide ONLY 2-4 space-separated essential keywords (e.g., polar bear, skin, color). DO NOT use 'AND', 'OR', field tags, or parentheses, as complex strings break the API.\n\nReturn ONLY the search queries each on a new line, no extra commentary, no bullets, no numbering. \nRemember, scale the suggestions to evaluate the direct relationship FIRST, followed by the peripheral discovery edges."
},
"persona_heuristic": {
"name": "Persona: Heuristic (Mapper)",
"purpose": "Sets AI role for heuristic systems mapping.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Heuristic).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a heuristic logic mapper and researcher. You play the role of a Systems Architecht.\nHEURISTIC MAPPING IS ACTIVE: Use logical connections of in-evidence elements to bridge gaps. Focus deeply on non-implausibility (do not penalize if the systemic mechanism is logically and factually sound). Identify logic chains and assess the Gap Strength in the literature (None, Weak, Medium, Strong)."
},
"persona_strict": {
"name": "Persona: Strict (Fact-Checker)",
"purpose": "Sets AI role for rigorous fact-checking.",
"when_used": "Stage 4 RAG evaluation (if Rigor = Strict).",
"content": "You are a strict, rigorous scientific fact-checker.\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes."
},
"format_preprint": {
"name": "Format: Preprint",
"purpose": "Defines the academic output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Preprint).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations. You must actually use the quotes you select within the conext of the preprint publication you write."
},
"format_clinical": {
"name": "Format: Clinical",
"purpose": "Defines the medical output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Clinical).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a clinical, medical-professional tone.\nFormat your readable response using these exact clinical headers:\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [CLINICAL BOTTOM-LINE / REWRITTEN CLAIM]\n(Scientific synthesis)\n### [RISK VS REWARD & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [PATIENT APPLICATION: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"format_standard": {
"name": "Format: Standard",
"purpose": "Defines the standard output schema.",
"when_used": "Stage 4 RAG evaluation (if Format = Standard).",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nIf the user asked a question, you must first provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nThen use a friendly and appropriate tone and answer their intent based solely on the research provided.\nFormat your readable response using these exact standard headers:\n[ANSWER TO USER] (if they asked a question)\n###[CLAIM EVALUATED]\n(Exact wording of the claim evaluated)\n### [REWRITTEN CLAIM/PATHWAY]\n(Scientific synthesis based on evidence)\n### [JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [HIGHLIGHTS: NOVEL & OVERLOOKED]\n(3-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"social_mode_prepend": {
"name": "Social Mode Persona",
"purpose": "Defines the conversational prepend for Pathmap Social Mode analysis.",
"when_used": "When Analysis Mode = 'Pathmap Social' in Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###[FRIENDLY ANSWER TO USER INTENT]\nAddress the user intent directly at the very top. Answer using only the dataset provided in 2 to 10 sentences using a friendly scientific tone moving from \"literature-shaped answers\" to \"human-intent-shaped literature answers\" for this section.\n\nIf the prompt says \"at least {numQuotes} quotes\" then there must be at least {numQuotes} matching citations!"
},
"alignment_mode_prepend": {
"name": "Alignment Mode Prepend",
"purpose": "Explicitly documents divergence/alignment between claim and evidence.",
"when_used": "When Analysis Mode = 'Alignment Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes. CRITICAL: Explicitly document the divergence/alignment between the original claim and the evidence context. Note any contradictions or supporting facts clearly."
},
"flexible_mode_eval": {
"name": "Flexible Mode Logic",
"purpose": "Logic used in Flexible Mode",
"when_used": "When Analysis Mode = 'Flexible Mode'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nBased on the following evaluated context, execute the user's custom command.\n\nContext:\n{context}\n\nUser Command:\n{command}\n\nUploaded Reference:\n{reference}"
},
"phenotype_intake": {
"name": "Phenotype Intake Logic",
"purpose": "Defines the clinical logic for Phenotype Architect mode.",
"when_used": "When Analysis Mode = 'Phenotype Architect'.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nYou are a clinical Phenotype Architect. Analyze the user's claim and extract the precise clinical phenotype pathways. Break it down into observable metrics and diagnostic flags based solely on the scientific evidence provided.\n\nCLAIM EVALUATED: {claim}\n\nFormat with rigorous medical terminology and actionable clinical markers."
},
"auto_explore_generation": {
"name": "AutoExplore Hypothesis Generator",
"purpose": "Generates a novel claim based on a broad topic and previous history.",
"when_used": "Beginning of each loop when AutoExplore is enabled.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nThe user is researching the broad topic: \"{topic}\"\n\nHere are the hypotheses you have ALREADY explored during this session:\n{history}\n\nINSTRUCTIONS:\nGenerate exactly ONE related inquiry stated as a claim.\n- It MUST be formatted as a declarative statement.\n- DO NOT wrap it in quotes.\n- DO NOT include conversational text or explanations.\n- Just return the simple claim."
},
"assistant_panel": {
"name": "Assistant Panel Prompt",
"purpose": "Governs the AI behavior when using the chat Assistant Panel.",
"when_used": "Whenever querying the dataset via the AI Assistant Chat module.",
"content": "You are an expert Data Scientist and Visualization Architect. Answer the user directly and truthfully. Do not introduce yourself.\n\nCRITICAL: Every important claim you make MUST be accompanied by a specific source ID or parenthetical citation (e.g., [ID: 12345]) if it is derived from the context.\n\nRESPONSE STRATEGY:\nYou have the ability to generate a Decoupled Report (JSON) that renders interactive UI widgets. Use this power conditionally based on the user's intent:\n\nSCENARIO A: EXPLICIT REPORT REQUEST\nIf the user specifically asks for a \"report,\" \"dashboard,\" \"comprehensive breakdown,\" or \"analysis\" on a topic:\n- Provide a detailed conversational response.\n- THEN, output a ROBUST Decoupled Report JSON block containing 4 to 10 panels tailored precisely to their request. (Include \"synthesis\" and \"pathmap\" as mandatory selections).\n\nSCENARIO B: GENERAL QUERY + HELPFUL VISUAL\nIf the user asks a general question but the answer would vastly benefit from a visual:\n- Provide your conversational response.\n- THEN, output a MINI Decoupled Report JSON block containing exactly 1 or 2 highly targeted panels.\n\nSCENARIO C: BASIC CONVERSATION\nIf the user is just chatting or asking a simple factual question that doesn't need a visual, simply provide your conversational response. Omit the JSON block entirely.\n\n================================================================\nDECOUPLED REPORT PROTOCOL (JSON)\n================================================================\nDo NOT generate raw HTML, CSS, or JS. Output ONLY valid JSON inside the fencing.\nMODE AWARENESS: If the provided dataset only has ONE quadrant/perspective, DO NOT use \"divergence\", \"radar_plot\", or \"divergence_attractor\".\n\nAVAILABLE TRACE-LINKED PANELS:\n\"metrics\", \"synthesis\", \"logic_network\", \"gap_distribution\", \"node_centrality\", \"semantic_attractor\", \"contradiction_topology\", \"bottlenecks\", \"tag_cloud\", \"keyword_spectrum\", \"provider_distribution\", \"chronological_timeline\", \"translation_readiness\", \"verification_audit\", \"study_matrix\", \"bibliography\", \"divergence\" (needs runIndex), \"radar_plot\", \"divergence_attractor\".\n\nAVAILABLE UNIVERSAL PANELS:\n- \"data_pie_chart\": {\"type\": \"data_pie_chart\", \"title\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"data_bar_chart\": {\"type\": \"data_bar_chart\", \"title\": \"...\", \"xAxisLabel\": \"...\", \"data\": [{\"label\": \"A\", \"value\": 10}]}\n- \"event_timeline\": {\"type\": \"event_timeline\", \"title\": \"...\", \"data\": [{\"date\": \"1990\", \"title\": \"...\", \"desc\": \"...\"}]}\n- \"comparison_matrix\": {\"type\": \"comparison_matrix\", \"title\": \"...\", \"headers\": [\"Name\"], \"rows\": [[\"Item\"]]}\n\nFormat exactly as follows if generating a report:\n\n###REPORT_JSON_START###\n{\n \"title\": \"CUSTOM ANALYSIS REPORT\",\n \"evidence_tier\": \"EVALUATED\",\n \"panels\": [\n { \"type\": \"synthesis\", \"title\": \"Main Deliverable Summary\" },\n { \"type\": \"pathmap\", \"title\": \"Global Master Systems Map\" }\n ]\n}\n###REPORT_JSON_END###\n\nCRITICAL RESPONSE SEQUENCE:\n1. First, provide your conversational response.\n2. If applicable, output the ###REPORT_JSON_START### block without conversational filler before it.\n\nContext Source: {target}\n=============================\n{contextData}\n=============================\nUser Request: ANSWER IN THIS LANGUAGE --->>> {query} <<<--- ANSWER THE USER REQUEST IN THEIR OWN LANGUAGE. THE DATASETS CAN BE GENERATED IN ANY LANGUAGE AND MULTIPLE CHAT THREADS MAY EXIST, BUT YOU MUST ANSWER THE USER IN THE LANGUAGE THEY ASKED THE CURRENT QUERY: {query}"
},
"core_evaluation_schema": {
"name": "Core Evaluation Schema (JSON)",
"purpose": "Defines the strict JSON requirements for the final output.",
"when_used": "Appended to every Stage 4 RAG evaluation.",
"content": "RAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42462036\nTitle: Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.\nAbstract: Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.\n\nID: 41924876\nTitle: Impairment of Macrophage Functions by the Senescence-Associated Secretory Phenotype of Vascular Smooth Muscle Cells-Brief Report.\nAbstract: This study aimed to determine the effect of senescent vascular smooth muscle cells (VSMCs) on foam cell formation and macrophage phagocytic activity in atherosclerotic conditions. We measured the capacity of senescent VSMCs for scavenging oxLDL (oxidized low-density lipoprotein), which was impaired in senescent cells compared with proliferating and quiescent cells. Next, we obtained human peripheral blood monocytes from people >60 years old and differentiated them into macrophages using GM-CSF (granulocyte-macrophage colony-stimulating factor). We treated the macrophages with conditioned media derived from proliferating, quiescent, and senescent VSMCs and measured oxLDL uptake, phagocytosis, and efferocytosis. The results demonstrated that macrophages treated with senescent VSMC conditioned media experienced impaired oxLDL uptake, phagocytic activity, and reduced ability to clear senescent cells. Treatment of senescent VSMCs with senomorphic drugs before conditioned media transfer restored macrophage functions, confirming that the SASP (senescence-associated secretory phenotype) is critical for impairing macrophages during atherosclerotic conditions. Our results suggest that the SASP derived from senescent VSMCs prevents foam cell formation and disrupts the homeostatic function of macrophages in atherosclerosis. By suppressing macrophage function, senescent cells seem to evade immune clearance and accumulate, further propagating disease development.\n\nID: 41297051\nTitle: Impaired AMP-Dependent Protein Kinase-Mediated Neutrophil Extracellular Trap Clearance by Aged Macrophages in Sepsis-Induced Liver Injury.\nAbstract: This study investigates the role and mechanism of neutrophil extracellular trap (NET) clearance by aged macrophages during sepsis-induced liver injury, as elderly patients show higher rates of organ damage and mortality in sepsis. A sepsis model was established using cecal ligation and puncture (CLP) in aged (100-week-old) and young mice (8-week-old) to study NET clearance by macrophages, assessing liver injury and inflammatory responses with interventions targeting AMP-dependent protein kinase (AMPK) and phagocytosis pathways. Additionally, the study included 40 sepsis patients, with 25 elderly (65-89 years) and 15 young (31-62 years) individuals, and collected peripheral blood samples from all for in vitro experiments. In aged mice, a significant increase in 7-day mortality was observed (hazard ratio [HR] = 2.50, 95% confidence interval [CI], 1.10-5.65, P = .009), alongside heightened inflammatory response and liver injury (histopathology score: 3.2 \u00b1 0.4 vs 2.4 \u00b1 0.6; P = .021), compared to young mice post-CLP. Hepatic NET accumulation markedly increased (mean difference [MD] = 0.43%, 95% CI, 0.25%-0.61%; P < .001), which was attenuated by DNase I-mediated NET inhibition, reducing hepatic enzymes and inflammatory responses. Consistently, transplantation of young bone marrow into aged recipients significantly reduced NET accumulation (MD = -0.33%, 95% CI, -0.43% to -0.22%; P < .001). Mechanistically, the phosphorylation of AMPK (0.68-fold vs young; P < .001) and Ca 2+ /calmodulin-dependent protein kinase kinase 2 (CaMKK2) was suppressed in aged septic mice. Activation of AMPK via 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) led to a decrease in hepatic NET accumulation (MD = -0.30%, 95% CI, -0.41% to -0.19%; P < .001), improved liver injury (histopathology score: 2.49 \u00b1 0.24 vs 3.07 \u00b1 0.28; P = .006), and reduced 7-day mortality (HR = 0.37, 95% CI, 0.15-0.94, P = .038). Critically, elderly patients exhibited elevated NET-related markers, compounded by suppressed AMPK phosphorylation and impaired NET phagocytosis (MD = -16.34%, 95% CI, -24.31% to -8.37%; P = .002). Aging impairs AMPK-mediated macrophage clearance of NETs in the liver, exacerbating liver inflammatory injury. Focusing on NETs could offer a therapeutic strategy to mitigate liver damage and reduce mortality in elderly sepsis patients.\n\nID: 41151577\nTitle: Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling.\nAbstract: Yolk-sac-derived embryonic cardiac tissue-resident macrophages (TRMPs) colonize the heart early in development and are essential for proper heart development, supporting tissue remodeling, angiogenesis, electrical conduction, efferocytosis, and immune regulation. We present here a human heart-macrophage assembloid (hHMA) model by integrating autologous human pluripotent stem cell (hPSC)-derived embryonic monocytes into heart organoids to generate physiologically relevant TRMPs that persist long-term and contribute to cardiogenesis. Using single-cell transcriptomics, live imaging, and proteomics, we demonstrate that TRMPs modulate cardiac paracrine signaling, perform efferocytosis, and regulate extracellular matrix remodeling and electrical conduction. In a proof-of-concept maturated hHMA model of chronic inflammation, TRMPs adopt pro-inflammatory phenotypes that promote arrhythmogenic activity, consistent with atrial fibrillation through activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. This system enables detailed mechanistic studies of immune-cardiac interactions and provides a powerful in vitro platform for modeling human heart development and inflammation-driven arrhythmias.\n\nID: 40632838\nTitle: Myeloid MAS-driven macrophage efferocytosis promotes resolution in ischemia-stressed mouse and human livers.\nAbstract: Liver ischemia-reperfusion injury (LIRI) is an inevitable detrimental event after liver transplantation. The MAS receptor plays a protective role in various diseases. However, the specific roles of MAS in myeloid cell innate immunity and the maintenance of hepatic tissue homeostasis remain unclear. Here, we showed that mice with systemic, Kupffer cell-specific, or myeloid cell-specific Mas1 deficiency were vulnerable to LIRI. Single-cell RNA sequencing, spatial transcriptomics, and intravital imaging revealed that myeloid deficiency of Mas1 resulted in impaired macrophage efferocytosis by down-regulating MER tyrosine kinase (MERTK), leading to the accumulation of aged neutrophils and exacerbation of inflammation and pathology. Mechanistic studies indicated that the MAS receptor regulated the Kr\u00fcppel-like factor 4 (KLF4)/MERTK axis in macrophages via the protein kinase A (PKA)/cAMP response element-binding protein (CREB) signaling pathway. KLF4 directly bound to the promoter region of MERTK and transcriptionally promoted its expression in macrophages, leading to attenuation of the liver inflammatory response. Macrophage-specific knockout of KLF4 and MERTK in the mice also resulted in impaired macrophage efferocytosis with the accumulation of aged neutrophils. Macrophage-specific overexpression of KLF4 in vivo effectively reversed the phenotype exacerbated by myeloid Mas1 deficiency. In addition, we demonstrated that MAS+MERTK+ macrophages actively migrated toward aged neutrophils in ischemia-stressed human livers, thereby promptly clearing aged neutrophils. In summary, this study documented the regulatory function of the MAS/KLF4/MERTK axis in macrophage efferocytosis via PKA/CREB signaling. This axis may thus serve as a therapeutic target and checkpoint regulator of homeostasis in response to LIRI.\n\nID: 40419113\nTitle: Compromised efferocytosis during aging is related to COVID-19 severity in mice.\nAbstract: Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019 (COVID-19). In older individuals, a dysregulated immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection contributes to disease severity; however, the underlying mechanism remains elusive. In this study, we established an aging mouse model of COVID-19, successfully replicating the development of a relatively severe disease in older adults. Further single-cell transcriptome analysis revealed a distinct immune cell landscape in the infected lungs, accompanied by an over-activated inflammatory response, especially in aging mice. Compared to young mice, aging mice showed extensive neutrophil activation, NETosis, and a dramatic decrease in the number of alveolar macrophages (AMs). Moreover, as important executors of efferocytosis, AMs exhibited a low efferocytotic gene signature and downregulation of multiple efferocytosis receptors in aged mice. Further analysis indicated that the efferocytosis of neutrophils, whether undergoing apoptosis or NETosis, was compromised after SARS-CoV-2 infection. Since efferocytosis is a key process in inflammatory resolution, impaired efferocytosis may contribute to hyperinflammation in aging lungs. Our study reveals the characteristics and role of efferocytosis in aging mice after SARS-CoV-2 infection and provides valuable insights for the potential treatment of COVID-19.\n\nID: 39945065\nTitle: Age-Related Impairments in Immune Cell Efferocytosis and Autophagy Hinder Atherosclerosis Regression.\nAbstract: Aging is a well-established risk factor for the development and progression of atherosclerosis, but the molecular mechanisms underlying this relationship remain poorly defined, and its role in atherosclerosis regression is unknown. To uncover age-related alterations that may impair atherosclerosis regression, we investigated the response of young and old macrophages to atherogenic lipoproteins in vitro and in vivo. Metabolic and proteomic studies were performed in vitro using macrophages differentiated from the bone marrow of young or old mice. To test the role of immune cell aging in atherosclerosis regression, bone marrow from young and old donors was transplanted into irradiated young recipient mice expressing gain-of-function AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9). Following 14 weeks of Western diet feeding, atherosclerosis regression was induced by switching to a standard laboratory diet for 4 weeks. Compared with young macrophages, old macrophages accumulated more lipid droplets upon lipid loading with the pro-atherogenic lipoprotein aggregated LDL (low-density lipoprotein), accompanied by a failure to proportionally induce autophagy and cholesterol efflux. Proteomic analysis of bone marrow-derived macrophages revealed that pathways related to endocytosis, engulfment, and phagocytosis were downregulated in old lipid-loaded macrophages. Functional studies confirmed a reduction in efferocytic capacity in old macrophages. In recipient mice transplanted with old bone marrow, atherosclerosis regression was impaired, as evidenced by inefficient resolution of circulating inflammatory cell levels, reduced activation of plaque autophagy and apoptotic cell clearance, and persistent plaque CD45+ and CD68+ content. Aging impairs macrophage function through reduced efferocytosis and autophagy activation, limiting atherosclerosis regression. These results highlight the need to better define the mechanisms linking aging to atherosclerosis to develop targeted therapies for the aging population.\n\nID: 39938482\nTitle: Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration.\nAbstract: In response to organ injury in adults, macrophages often promote scarring, yet during early life, they are required for tissue regeneration. To elucidate the mechanisms underlying age-associated regeneration, we compared the macrophage injury response in newborn versus adult hearts. Single-cell analysis revealed an accumulation of tissue-resident macrophages in neonates that were selectively polarized for apoptotic cell recognition and uptake (efferocytosis). Ablation of the apoptotic cell recognition receptor Mertk in newborns prevented cardiac regeneration. These findings could be attributed to reprogramming of macrophage gene expression that was required for biosynthesis of the eicosanoid thromboxane A2, which unexpectedly activated parenchymal cell proliferation. Markers of thromboxane A2 production were suppressed in adult macrophages after efferocytosis. Moreover, macrophage-neighboring neonatal cardiomyocytes expressed the thromboxane A2 receptor, whose activation induced a metabolic shift that supported cellular proliferation. Our data reveal a fundamental age-defined macrophage response in which lipid mitogens produced during efferocytosis support receptor-mediated tissue regeneration.\n\nID: 36090969\nTitle: Age-related decline in the resistance of mice to bacterial infection and in LPS/TLR4 pathway-dependent neutrophil responses.\nAbstract: Host defense against bacterial and fungal infections diminishes with age. In humans, impaired neutrophil responses are thought to contribute to this decline. However, it remains unclear whether neutrophil responses are also impaired in old mice. Here, we investigated neutrophil function in old mice, focusing on responses primed by lipopolysaccharide (LPS), an endotoxin released by gram-negative bacteria like E. coli, which signals through toll-like receptor (TLR) 4. We show that old mice have a reduced capacity to clear pathogenic E. coli during septic peritonitis. Neutrophil recruitment was elevated during LPS-induced but not aseptic peritonitis. Neutrophils from old mice showed reduced killing of E. coli. Their reactive oxygen species (ROS) production was impaired upon priming with LPS but not with GM-CSF/TNF\u03b1. Phagocytosis and degranulation were reduced in a partially LPS-dependent manner, whereas impairment of NET release in response to S. aureus was independent of LPS. Unexpectedly, chemotaxis was normal, as were Rac1 and Rac2 GTPase activities. LPS-primed activation of Erk and p38 Mapk was defective. PIP3 production was reduced upon priming with LPS but not with GM-CSF/TNF\u03b1, whereas PIP2 levels were constitutively low. The expression of 5% of neutrophil proteins was dysregulated in old age. Granule proteins, particularly cathepsins and serpins, as well as TLR-pathway proteins and membrane receptors were upregulated, whereas chromatin and RNA regulators were downregulated. The upregulation of CD180 and downregulation of MyD88 likely contribute to the impaired LPS signaling. In summary, all major neutrophil responses except chemotaxis decline with age in mice, particularly upon LPS priming. This LPS/TLR4 pathway dependence resolves previous controversy regarding effects of age on murine neutrophils and confirms that mice are an appropriate model for the decline in human neutrophil function.\n\nID: 35485304\nTitle: Laser-mediated osteoblast ablation triggers a pro-osteogenic inflammatory response regulated by reactive oxygen species and glucocorticoid signaling in zebrafish.\nAbstract: In zebrafish, transgenic labeling approaches, robust regenerative responses and excellent in vivo imaging conditions enable precise characterization of immune cell behavior in response to injury. Here, we monitored osteoblast-immune cell interactions in bone, a tissue which is particularly difficult to in vivo image in tetrapod species. Ablation of individual osteoblasts leads to recruitment of neutrophils and macrophages in varying numbers, depending on the extent of the initial insult, and initiates generation of cathepsin K+ osteoclasts from macrophages. Osteoblast ablation triggers the production of pro-inflammatory cytokines and reactive oxygen species, which are needed for successful macrophage recruitment. Excess glucocorticoid signaling as it occurs during the stress response inhibits macrophage recruitment, maximum speed and changes the macrophage phenotype. Although osteoblast loss is compensated for within a day by contribution of committed osteoblasts, macrophages continue to populate the region. Their presence is required for osteoblasts to fill the lesion site. Our model enables visualization of bone repair after microlesions at single-cell resolution and demonstrates a pro-osteogenic function of tissue-resident macrophages in non-mammalian vertebrates.\n\nID: 34482812\nTitle: Macrophages target Listeria monocytogenes by two discrete non-canonical autophagy pathways.\nAbstract: Non-canonical autophagy pathways decorate single-membrane vesicles with Atg8-family proteins such as MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3). Phagosomes containing the bacterial pathogen Listeria monocytogenes (L.m.) can be targeted by a non-canonical autophagy pathway called LC3-associated phagocytosis (LAP), which substantially contributes to the anti-listerial activity of macrophages and immunity. We here characterized a second non-canonical autophagy pathway targeting L.m.-containing phagosomes, which is induced by damage caused to the phagosomal membrane by the pore-forming toxin of L.m., listeriolysin O. This pore-forming toxin-induced non-canonical autophagy pathway (PINCA) was the only autophagic pathway evoked in tissue macrophages deficient for the NADPH oxidase CYBB/NOX2 that produces the reactive oxygen species (ROS) that are required for LAP induction. Similarly, also bone marrow-derived macrophages (BMDM) exclusively targeted L.m. by PINCA as they completely failed to induce LAP because of insufficient production of ROS through CYBB, in part, due to low expression of some CYBB complex subunits. Priming of BMDM with proinflammatory cytokines such as TNF and IFNG/IFN\u03b3 increased ROS production by CYBB and endowed them with the ability to target L.m. by LAP. Targeting of L.m. by LAP remained relatively rare, though, preventing LAP from substantially contributing to the anti-listerial activity of BMDM. Similar to LAP, the targeting of L.m.-containing phagosomes by PINCA promoted their fusion with lysosomes. Surprisingly, however, this did not substantially contribute to anti-listerial activity of BMDM. Thus, in contrast to LAP, PINCA does not have clear anti-listerial function suggesting that the two different non-canonical autophagy pathways targeting L.m. may have discrete functions.Abbreviations: actA/ActA: actin assembly-inducing protein A; ATG: autophagy-related; BMDM: Bone marrow-derived macrophages; CALCOCO2/NDP52: calcium-binding and coiled-coil domain-containing protein 2; CYBA/p22phox: cytochrome b-245 light chain; CYBB/NOX2: cytochrome b(558) subunit beta; E. coli: Escherichia coli; IFNG/IFN\u03b3: interferon gamma; L.m.: Listeria monocytogenes; LAP: LC3-associated phagocytosis; LGALS: galectin; LLO: listeriolysin O; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; NCF1/p47phox: neutrophil cytosol factor 1; NCF2/p67phox: neutrophil cytosol factor 2; NCF4/p67phox: neutrophil cytosol factor 4; Peritoneal macrophages: PM; PINCA: pore-forming toxin-induced non-canonical autophagy; plc/PLC: 1-phosphatidylinositol phosphodiesterase; PMA: phorbol 12-myristate 13-acetate; RB1CC1/FIP200: RB1-inducible coiled-coil protein 1; ROS: reactive oxygen species; S. aureus: Staphylococcus aureus; S. flexneri: Shigella flexneri; SQSTM1/p62: sequestosome 1; S. typhimurium: Salmonella typhimurium; T3SS: type III secretion system; TNF: tumor necrosis factor; ULK: unc-51 like autophagy activating kinase; PM: peritoneal macrophages; WT: wild type.\n\nID: 32528461\nTitle: Resolvin D1 Reduces Lung Infection and Inflammation Activating Resolution in Cystic Fibrosis.\nAbstract: Non-resolving lung inflammation and Pseudomonas aeruginosa infections are the underlying cause of morbidity and mortality in cystic fibrosis (CF). The endogenous lipid mediator resolvin (Rv) D1 is a potent regulator of resolution, and its roles, actions, and therapeutic potential in CF are of interest. Here, we investigated actions and efficacy of RvD1 in preclinical models of cystic fibrosis. Cftr knockout mice with chronic P. aeruginosa lung infection were treated with RvD1 to assess differences in lung bacterial load, inflammation, and tissue damage. Cells from volunteers with CF were treated with RvD1 during ex vivo infection with P. aeruginosa, and effects on phagocytosis and inflammatory signaling were determined. In CF mice, RvD1 reduced bacterial burden, neutrophil infiltration, and histological signs of lung pathology, improving clinical scores of diseases. Mechanistically, RvD1 increased macrophage-mediated bacterial and leukocyte clearance in vivo. The clinical significance of these findings is supported by actions in primary leukocytes and epithelial cells from volunteers with CF where RvD1 enhanced P. aeruginosa phagocytosis and reduced genes and proteins associated to NF-\u03baB activation and leukocyte infiltration. Concentration of RvD1 in sputum from patients with CF was also inversely correlated to those of cytokines and chemokines involved in CF lung pathology. These findings demonstrate efficacy of RvD1 in enhancing resolution of lung inflammation and infections and provide proof of concept for its potential as a prototypic novel pro-resolutive therapeutic approach for CF.\n\nID: 31998762\nTitle: Metabolic and Immunological Effects of Intermittent Fasting on a Ketogenic Diet Containing Medium-Chain Triglycerides in Healthy Dogs.\nAbstract: In several species, intermittent fasting (IF) has been shown to have beneficial effects, including delayed aging, increased lifespan, increased insulin sensitivity, reduced ischemic tissue damage, delayed onset of neurodegenerative disease and improved neuronal repair following injury. However, the metabolic and immunological effects of IF have not been well-established in dogs. The aim of this study was to examine the effects of a 48 h IF regimen using a low fat and a high fat diet in healthy dogs by quantifying the metabolic, hormonal, and immunological changes. We hypothesized that IF dogs would have higher blood ketone and ghrelin concentrations, lower blood leptin, insulin and glucose concentrations, and signs of immunosuppression compared to dogs eating daily. Ten healthy adult dogs were randomized into three group and underwent three feeding regimes in a 3 \u00d7 3 Latin square design: twice a day feeding on a low fat (23% energy from fat; LF) diet, 48 h fasting on a low fat diet, and 48 h fasting on a high fat enriched with medium-chain triglycerides (68% energy from fat; HF) diet. Body weight, food intake, activity, blood glucose, \u03b2-hydroxybutyrate, leptin, ghrelin, and insulin were measured. Lymphocyte proliferation and neutrophil/macrophage phagocytosis and respiratory burst were measured as markers of immune function. Nuclear magnetic resonance spectroscopy was used to relatively quantify plasma metabolites. When the dogs were IF on a HF diet, they had the highest concentration of blood ketones (mean 0.061 mmol/L, SD 0.024), whereas they had the lowest concentration (mean 0.018 mmol/L, SD 0.004) when fed daily. Blood glucose and insulin concentrations were lower in IF dogs on a HF diet compared to daily feeding or IF on a LF diet. There was an increase in plasma \u03b2-hydroxybutyrate concentrations, and a reduction in glucose and insulin concentrations when dogs were IF on a HF diet. There was only a decline in the immune parameters studied when the dogs were IF on a LF diet, which was not seen when on the HF diet. The results of this study indicate the potential of IF to be further investigated as a potential beneficial feeding regime for dogs.\n\nID: 31540482\nTitle: Glutathione Induced Immune-Stimulatory Activity by Promoting M1-Like Macrophages Polarization via Potential ROS Scavenging Capacity.\nAbstract: The present study investigated the immunomodulatory activity of reduced glutathione (GSH) by assessment of the macrophage polarization (MP)-mediated immune response in RAW 264.7 cells. Furthermore, we identified the signal pathway associated with immune regulation by GSH. The expressions of MP-associated cytokines and chemokines were assessed using cytokine array, nCounter Sprit platform, ELISA and immunoblotting. Phagocytosis activity and intracellular reactive oxygen species (ROS) generation were measured using fluorescence-activated cell sorter. As results of the cytokine array and nCounter gene array, GSH not only up-regulated pro-inflammatory cytokines, including interleukins and tumor necrosis factor-\u03b1, but also overexpressed neutrophil-attracting chemokines. Furthermore, GSH significantly stimulated the production of immune mediators, including nitric oxide and PGE2, as well as phagocytosis activity through nuclear factor kappa B activation. In addition, GSH significantly decreased LPS-induced ROS generation, which was associated with an activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2)/ heme oxygenease-1 (HO-1) signaling pathway. Our results suggest that GSH has potential ROS scavenging capacity via the induction of Nrf2-mediated HO-1, and immune-enhancing activity by regulation of M1-like macrophage polarization, indicating that GSH may be a useful strategy to increase the human defense system.\n\nID: 25597390\nTitle: Attenuated phagocytosis of secondary necrotic neutrophils by macrophages in aged and SMP30 knockout mice.\nAbstract: Secondary necrotic cells generated in\u2009vivo induce inflammatory responses; for example, the production of macrophage inflammatory protein-2 (MIP-2) and subsequent infiltration of neutrophils. The aim of the present study was to elucidate the effect of aging on the phagocytosis of secondary necrotic cells and the inflammatory responses by using either wild-type (WT) young mice, WT aged mice or senescence-accelerated mice (SMP30(-/-) mice). The phagocytosis of secondary necrotic neutrophils with resident macrophage from either WT young mice, WT aged mice or SMP30(-/-) mice was examined by coculturing macrophages with secondary necrotic neutrophils in\u2009vitro. To investigate the inflammatory response induced by secondary necrotic cells, time-dependent infiltration of neutrophils and production of MIP-2 were determined in the peritoneal cavity on the injection of secondary necrotic cells. The phagocytosis of secondary necrotic cells by macrophages from WT aged and SMP30(-/-) mice was significantly reduced as compared with that by macrophages from WT young mice. On peritoneal injection of secondary necrotic cells, the peak time of neutrophil infiltration was earlier in SMP30(-/-) mice than in WT young mice. The number of neutrophils in SMP30(-/-) mice at the peak time was also greater than that in WT young mice. Our findings showed that the phagocytosis of secondary necrotic cells was attenuated in aged mice and SMP30(-/-) mice, and that the MIP-2 production was enhanced and subsequently neutrophil infiltration was exaggerated on peritoneal injection of secondary necrotic cells into those mice.\n\nID: 24681489\nTitle: Effect of silica particle size on macrophage inflammatory responses.\nAbstract: Amorphous silica particles, such as nanoparticles (<100 nm diameter particles), are used in a wide variety of products, including pharmaceuticals, paints, cosmetics, and food. Nevertheless, the immunotoxicity of these particles and the relationship between silica particle size and pro-inflammatory activity are not fully understood. In this study, we addressed the relationship between the size of amorphous silica (particle dose, diameter, number, and surface area) and the inflammatory activity (macrophage phagocytosis, inflammasome activation, IL-1\u03b2 secretion, cell death and lung inflammation). Irrespective of diameter size, silica particles were efficiently internalized by mouse bone marrow-derived macrophages via an actin cytoskeleton-dependent pathway, and induced caspase-1, but not caspase-11, activation. Of note, 30 nm-1000 nm diameter silica particles induced lysosomal destabilization, cell death, and IL-1\u03b2 secretion at markedly higher levels than did 3000 nm-10000 nm silica particles. Consistent with in vitro results, intra-tracheal administration of 30 nm silica particles into mice caused more severe lung inflammation than that of 3000 nm silica particles, as assessed by measurement of pro-inflammatory cytokines and neutrophil infiltration in bronchoalveolar lavage fluid of mice, and by the micro-computed tomography analysis. Taken together, these results suggest that silica particle size impacts immune responses, with submicron amorphous silica particles inducing higher inflammatory responses than silica particles over 1000 nm in size, which is ascribed not only to their ability to induce caspase-1 activation but also to their cytotoxicity.\n\nID: 21562053\nTitle: The innate immune system and the clearance of apoptotic cells.\nAbstract: Removal of unwanted, effete, or damaged cells through apoptosis, an active cell death culminating in phagocytic removal of cell corpses, is an important process throughout the immune system in development, control, and homeostasis. For example, neutrophil apoptosis is central to the resolution of acute inflammation, whereas autoreactive and virus-infected cells are similarly deleted. The AC removal process functions not only to remove cell corpses but further, to control inappropriate immune responses so that ACs are removed in an anti-inflammatory manner. Such \u2033silent\u2033 clearance is mediated by the innate immune system via polarized monocyte/macrophage populations that use a range of PRRs and soluble molecules to promote binding and phagocytosis of ACs. Additionally, attractive signals are released from dying cells to recruit phagocytes to sites of death. Here, we review the molecular mechanisms associated with innate immune removal of and responses to ACs and outline how these may impact on tissue homeostasis and age-associated pathology (e.g., cardiovascular disease). Furthermore, we discuss how an aging innate immune system may contribute to the inflammatory consequences of aging and why the study of an aging immune system may be a useful path to advance characterization of mechanisms mediating effective AC clearance.\n\nID: 18445021\nTitle: Influence of aging on murine neutrophil and macrophage function against Candida albicans.\nAbstract: Previous work by our group showed that aged C57BL/6 mice develop an altered innate and adaptive immune response to Candida albicans and are more susceptible to systemic primary candidiasis. In this work, we used young (2-3 months old) and aged (18-20 months old) C57BL/6 mice to study in vitro the influence of aging on (1) the fungicidal activity of neutrophils and macrophages, (2) the production of cytokines by resident peritoneal macrophages in response to C. albicans, and (3) cell surface Toll-like receptor (TLR) 2 expression on resident peritoneal macrophages. Our results indicate that murine phagocytes have a fungicidal activity well preserved with aging. In vitro production of proinflammatory cytokines (IL-6, IL-1beta, and tumor necrosis factor-alpha and chemokines (MIP-2) by purified (CD11b(+)) peritoneal macrophages in response to yeasts and hyphae of C. albicans was significantly lower in aged mice as compared with young mice. However, the production of IL-10 by macrophages, in response to C. albicans, was similar in both young and aged animals. Moreover, baseline TLR2 surface expression level was lower on aged macrophages than on control macrophages. Taken together, these data indicate that the increased susceptibility to C. albicans disseminated infections in aged mice is correlated with defects in TLR2 expression and in cytokine production, but not with an impaired fungicidal activity.\n\nID: 18387441\nTitle: Aging-related defects are associated with adverse cardiac remodeling in a mouse model of reperfused myocardial infarction.\nAbstract: The purpose of this study was to study aging-associated alterations in the inflammatory and reparative response after myocardial infarction (MI) and their involvement in adverse post-infarction remodeling of the senescent heart. Advanced age is a predictor of death and ventricular dilation in patients with MI; however, the cellular mechanisms responsible for increased remodeling of the infarcted senescent heart remain poorly understood. Histomorphometric, molecular, and echocardiographic end points were compared between young and senescent mice undergoing reperfused infarction protocols. The response of young and senescent mouse cardiac fibroblasts to transforming growth factor (TGF)-beta stimulation was examined. Senescence was associated with decreased and delayed neutrophil and macrophage infiltration, markedly reduced cytokine and chemokine expression in the infarcted myocardium, and impaired phagocytosis of dead cardiomyocytes. Reduced inflammation in senescent mouse infarcts was followed by decreased myofibroblast density and markedly diminished collagen deposition in the scar. The healing defects in senescent animals were associated with enhanced dilative and hypertrophic remodeling and worse systolic dysfunction. Fibroblasts isolated from senescent mouse hearts showed a blunted response to TGF-beta1. Although young mice exhibit a robust post-infarction inflammatory response and form dense collagenous scars, senescent mice show suppressed inflammation, delayed granulation tissue formation, and markedly reduced collagen deposition. These defects might contribute to adverse remodeling. These observations suggest that caution is necessary when attempting to therapeutically target the post-infarction inflammatory response in patients with reperfused MI. The injurious potential of inflammatory mediators might have been overstated, owing to extrapolation of experimental findings from young animals to older human patients.\n\nID: 17336301\nTitle: Effects of aging on triggering receptor expressed on myeloid cells (TREM)-1-induced PMN functions.\nAbstract: Triggering receptor expressed on myeloid cell-1 (TREM-1) is a recently described receptor that has many effects on polymorphonuclear neutrophil (PMN), as the engagement of this receptor on PMN can induce phagocytosis, respiratory burst and degranulation. We studied the effects of aging on TREM-1 engagement in human PMN. PMN from elderly were found to have impaired response following TREM-1 engagement. Notably they were not able to modulate the TREM-1-induced respiratory burst as PMN from young did. TREM-1 engagement could not reverse PMN survival following incubation with LPS or GM-CSF in the elderly whereas it did in the young. The phosphorylation of TREM-1 signal transduction molecules was altered with aging. Finally, TREM-1 engagement could not drive the recruitment of TREM-1 in the lipid-rafts of the elderly explaining in part the altered response. The observed alterations in TREM-1 response are possibly an important contributing factor in the higher incidence of sepsis-related deaths in the elderly population.\n\nID: 12383649\nTitle: Variability of neutrophil and pulmonary alveolar macrophage function in swine.\nAbstract: Neutrophils and alveolar macrophages are essential defence mechanisms against bacterial infection of the lung. The purpose of this study was to evaluate the variability of a panel of neutrophil and alveolar macrophage function assays in swine, and to determine if the function of these leukocytes differed at various stages of production. Measured neutrophil functions included chemotaxis, phagocytosis, oxidative burst, and degranulation. Phagocytosis and oxidative burst were measured in alveolar macrophages isolated from bronchoalveolar lavage fluid (BALF). Both neutrophil and alveolar macrophage functions were highly variable from day-to-day and between pigs. Individual pigs did not have consistently high or low neutrophil and macrophage responses over time when compared to their cohorts. Older grower-finisher pigs had significantly greater neutrophil oxidative burst responses than younger suckling and weaner pigs (P < 0.001). Similarly, alveolar macrophages from suckling and early weaner pigs less than 40 days of age had significantly lower oxidative burst responses than those from older pigs (P = 0.02). Age-related variation in phagocytosis, chemotaxis, or granule secretion were not detected. These results establish baseline data for individual and age-related variation in swine leukocyte function, and form a basis for further evaluation of the contribution of non-infectious factors to development of the porcine respiratory disease complex.\n\nID: 11710909\nTitle: Age-related alterations in the inflammatory response to dermal injury.\nAbstract: Previous studies have documented that the ability to heal wounds declines with age. Although many factors contribute to this age-associated deficit, one variable that has not been carefully examined is leukocyte recruitment and function in wounds. This investigation compares the inflammatory response in excisional wounds of young (age 8 wk) and aged (age 22 mo) mice. In the early inflammatory response, neutrophil content of wounds was similar for both aged and young mice. In contrast, macrophage levels were 56% higher in aged versus young mice (81 +/- 20 vs 52 +/- 13 cells per mm2). In the later inflammatory response, wounds of aged mice exhibited a delay in T cell infiltration, with maximum T cell levels at day 10 in aged mice versus day 7 in young mice. Despite this delay, the eventual peak concentration of T cells was 23% higher in the wounds of aged mice (152 +/- 11 cells per mm2 vs 124 +/- 21cells per mm2). The observed alterations in inflammatory cell content suggested that chemokine production might be altered with age. An elevation of monocyte chemoattractant protein (MCP-1) levels was observed in wounds of aged mice. RNase protection studies, however, revealed that the production of most chemokines, including MIP-2, MIP-1alpha, MIP-1beta, and eotaxin, tended to decline with age. Because optimal wound healing requires both appropriate macrophage infiltration and phagocytic activity, phagocytosis was examined. Compared to young mice, wound macrophages from aged mice exhibited a 37%-43% reduction in phagocytic capacity. Taken together, the data demonstrate age-related shifts in both macrophage and T cell infiltration into wounds, alterations in chemokine content, and a concurrent decline in wound macrophage phagocytic function. These alterations may contribute to the delayed repair response of aging.\n\nID: 9738659\nTitle: Spontaneous and Fas-mediated apoptosis are diminished in umbilical cord blood neutrophils compared with adult neutrophils.\nAbstract: Apoptosis mediates neutrophil (PMN) phagocytosis and is influenced by cytokines and the Fas/Fas ligand pathway. To determine whether apoptosis of cord blood PMN differs from those of adults, cultured PMN were evaluated by morphological analysis, flow cytometry (TUNEL assay), and DNA gel electrophoresis. In addition, we studied the effect of anti-Fas IgM or cycloheximide on induction of PMN apoptosis. Spontaneous apoptosis (24 h) was less in cord blood PMN (mean +/- SD; 29 +/- 9 vs. adults, 56 +/- 14%, P < 0.001). Treatment (6 h) with anti-Fas IgM induced less apoptosis in cord blood PMN (24 +/- 6 vs. adults, 63 +/- 7%, P < 0.001), as did treatment with cycloheximide (13 +/- 10 vs. adults, 55 +/- 16%, P < 0.01). These data suggest the pre-existence of proteins that inhibit apoptosis or the absence of those that promote apoptosis in cord blood PMN.\n\nID: 9152935\nTitle: Relationship between age-dependent changes of bovine neutrophil functions and their intracellular Ca2+ concentrations.\nAbstract: Neutrophil functions and intracellular Ca2+ concentrations ([Ca2+]i) were evaluated in 15 Holstein cattle divided into the following 3 groups: 5 neonatal calves less than 1 week old (group 1), 5 young calves 2 to 4 weeks old (group 2) and 5 cows 2 to 3 years old (group 3). The ability of neutrophils to phagocytose Candida albicans (C. albicans) was significantly higher (p < 0.05) in neonatal and young calves than in cows, whereas the phagocytosis by neutrophils of bovine IgG-coated yeasts (IgG-yeasts) was significantly lower (p < 0.05) in neonatal and young calves than that in cows. The killing activity by neutrophils of C. albicans in neonatal and young calves was significantly lower (p < 0.05) than that in cows. Luminol dependent chemiluminescent (LDCL) responses stimulated with opsonized zymosan (OPZ), heat-aggregated IgG (H-agg.IgG) and phorbol myristate acetate (PMA) were apparently lower in neonatal and young calves than in cows. No clearly different expressions of complement receptor type 3 (CR3) on neutrophils were observed among the 3 groups of cattle, although the values due to the binding of FITC-anti-bovine IgG to neutrophils in neonatal and young calves were lower than those in group 3. The OPZ-induced [Ca2+]i of neutrophils in neonatal and young calves were significantly higher (p < 0.05) than those in cows, but they were lower in neonatal and young calves when stimulated with H-agg.IgG. These results indicate that CR3- and FcR-mediated phagocytic and killing activities of neutrophils in neonatal and young calves are different from those in cows. These phenomena may be associated with age-dependent changes in [Ca2+]i.\n\nID: 7846130\nTitle: Granulocyte apoptosis and the control of inflammation.\nAbstract: We have described a novel pathway available for the clearance of extravasated granulocytes from inflamed tissues whereby aging granulocytes undergo apoptosis, a process which leads to their phagocytosis by inflammatory macrophages. By contrast with necrosis, which may also be seen at inflamed sites, apoptosis represents a granulocyte fate which by a number of mechanisms would tend to limit inflammatory tissue injury and promote resolution rather than progression of inflammation: (i) apoptosis is responsible for macrophage recognition of senescent neutrophils with intact cell membranes which exclude vital dyes and retain their potentially histotoxic granule contents; (ii) the apoptotic neutrophil loses its ability to secrete granule enzymes on deliberate external stimulation; (iii) the macrophage possesses a huge phagocytic capacity for apoptotic neutrophils which it rapidly ingests and degrades without disgorging neutrophil contents; and (iv) the macrophage utilizes a novel phagocytic recognition mechanism which fails to trigger the release of pro-inflammatory macrophage mediators during the phagocytosis of apoptotic neutrophils. Preliminary characterization of the recognition mechanism implicates the integrin alpha v beta 3 (vitronectin receptor) and CD36 (thrombospondin receptor) on the macrophage surface. Macrophage phagocytosis of apoptotic neutrophils is greatly influenced by the microenvironmental pH and by the presence of cationic molecules. Moreover, it can be specifically modulated by external cytokines and intracellular second messenger systems. By controlling the functional longevity of neutrophil and eosinophil granulocytes and their subsequent removal by macrophages, granulocyte apoptosis, with its potential for modulation by external mediators, is likely to play a key dynamic role in the control of the 'tissue load' of granulocytes at inflamed sites.(ABSTRACT TRUNCATED AT 250 WORDS)\n\nID: 8113673\nTitle: bcl-2 inhibits apoptosis of neutrophils but not their engulfment by macrophages.\nAbstract: Neutrophils, the most common inflammatory leukocytes, have the most limited life span of all blood cells. After they undergo apoptosis, they are recognized and engulfed by macrophages. bcl-2, a proto-oncogene rearranged and deregulated in B cell lymphomas bearing the t(14;18) translocation, is known to inhibit programmed death. bcl-2 expression is localized in early myeloid cells of the bone marrow but is absent in mature neutrophils. Transgenic mice that expressed bcl-2 in mature neutrophils showed that bcl-2 blocked neutrophil apoptosis. Despite this, homeostasis of neutrophil population is essentially unaffected. In fact, macrophage uptake of neutrophils expressing bcl-2 still occurred. This transgenic model indicates that the mechanism that triggers phagocytosis of aging neutrophils operates independently of the process of apoptosis regulated by bcl-2.\n\nID: 8222557\nTitle: Immunology of the aging lung.\nAbstract: The aging process is associated with multiple deficits in pulmonary immune function. Defense of the airway is impaired in the elderly by decreased mucociliary clearance, alteration in respiratory mechanics and, in some cases, concomitant illnesses that predispose to aspiration. Alveolar defenses can be divided into resident defense mechanisms, inflammatory responses, and specific immune responses. Resident defenses such as macrophage phagocytosis and chemotaxis, although largely intact, may have subtle defects under specific conditions. Inflammatory responses may also be diminished, as evidenced by decreased neutrophil-mediated killing and chemotaxis. Specific immune responses appear to be the most vulnerable to age-associated impairment. Although antigen presentation is well preserved during aging, accessory cell cytokine production may be decreased. T-lymphocyte proliferative responses are markedly decreased, as is the production of and response to intercellular mediators. Age-associated alterations in T cell subpopulations may result in imperfect T cell-B cell interactions leading to expression of abnormal immunoglobulins. These many interacting and compounding impairments may explain the increased susceptibility of the elderly to pulmonary infection and autoimmune diseases.\n\nID: 1494247\nTitle: [Role of neutrophil and T cell functions in host defense mechanisms of the elderly].\nAbstract: We studied neutrophil functions (phagocytosis, intracellular killing and chemotaxis with or without recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) and T cell functions (lymphocyte proliferation and production of GM-CSF in response to phytohemagglutin (PHA)) to clarify host defense mechanisms in the elderly. There was no significant difference in phagocytic activity of neutrophils between the elderly and control young adults. rhGM-CSF enhanced phagocytosis by neutrophils, and a similar degree of enhancement was obtained in both groups. Killing activity of neutrophils evaluated by the new Nitroblue tetrazolium reduction test in the elderly was significantly lower than that in young adults (p < 0.001), however, pretreatment of neutrophils with rhGM-CSF resulted in an increase of killing activity in the elderly, raising their response to a level comparable to that of young adults pretreated with rhGM-CSF. There was no significant difference between the elderly and young adults in chemotaxis of neutrophils. rhGM-CSF alone did not prime chemotaxis, but primed chemotaxis in response to chemoattractant (N-formyl-methionyl-leucyl-phenylalanin) in both individuals. Lymphocyte proliferation and production of GM-CSF in response to PHA in the elderly were significantly lower than those in the young adults (p < 0.001, p < 0.05, respectively). These results indicated that impaired T cell functions may contribute, at least in part, to susceptibility to bacterial infection in the elderly.\n\nID: 2553775\nTitle: Phagocytosis of aged human neutrophils by macrophages is mediated by a novel \"charge-sensitive\" recognition mechanism.\nAbstract: The removal of neutrophils and their histotoxic contents from the inflamed site is a prerequisite for resolution of tissue injury, and a point at which factors critical to the pathogenesis of chronic inflammation may act. Engulfment of intact, senescent neutrophils by macrophages represents an important neutrophil disposal process. In this study the mechanism by which human monocyte-derived macrophages (M phi) recognized and ingested human neutrophils that had been aged in culture was studied using an in vitro phagocytic assay. Inhibition of M phi receptors for Ig Fc and the opsonic complement fragments C3b and iC3b with MAbs to M phi FcR, CR1, CR3, and CR4 had no effect on recognition, and the pattern of inhibition observed when polyanions were included in the medium at 1 mg/ml was different from that reported for the M phi receptor for protein advanced glycosylation end products (AGE), indicating a recognition mechanism different from those proposed for M phi phagocytosis of senescent erythrocytes. Furthermore, although aging neutrophils undergo programmed cell death (or apoptosis), which is directly related to recognition by M phi, the pattern of inhibition observed with monosaccharides was different from that reported to inhibit the binding of apoptotic mouse thymocytes to isologous M phi. By contrast, evidence was obtained for a novel recognition mechanism inhibitable by cationic sugars and amino acids in a charge-dependent fashion, and directly modulated by pH but not affected by inhibitors of the mannose-6-phosphate, sheep erythrocyte, mannosyl-fucosyl, asialoglycoprotein, and scavenger receptors of the macrophage. These observations suggest that hydrogen ions and charged molecules may modulate M phi uptake of senescent neutrophils at inflamed sites, and that recognition itself may involve charged structures on the cells.\n\nID: 2921324\nTitle: Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages.\nAbstract: Mechanisms governing the normal resolution processes of inflammation are poorly understood, yet their elucidation may lead to a greater understanding of the pathogenesis of chronic inflammation. The removal of neutrophils and their potentially histotoxic contents is one prerequisite of resolution. Engulfment by macrophages is an important disposal route, and changes in the senescent neutrophil that are associated with their recognition by macrophages are the subject of this investigation. Over 24 h in culture an increasing proportion of human neutrophils from peripheral blood or acutely inflamed joints underwent morphological changes characteristic of programmed cell death or apoptosis. Time-related chromatin cleavage in an internucleosomal pattern indicative of the endogenous endonuclease activation associated with programmed cell death was also demonstrated. A close correlation was observed between the increasing properties of apoptosis in neutrophils and the degree of macrophage recognition of the aging neutrophil population, and a direct relationship between these parameters was confirmed within aged neutrophil populations separated by counterflow centrifugation into fractions with varying proportions of apoptosis. Macrophages from acutely inflamed joints preferentially ingested apoptotic neutrophils and histological evidence was presented for occurrence of the process in situ. Programmed cell death is a phenomenon of widespread biological importance and has not previously been described in a cell of the myeloid line. Because it leads to recognition of intact senescent neutrophils that have not necessarily disgorged their granule contents, these processes may represent a mechanism for the removal of neutrophils during inflammation that also serves to limit the degree of tissue injury.\n\nID: 42547443\nTitle: [Research progress on the role of calcitonin gene-related peptide in the repair of diabetic wounds].\nAbstract: Diabetic wounds are a severe complication of diabetes, which can lead to amputation or even mortality in severe cases. While normal wound healing consists of four phases: hemostasis, inflammation, proliferation, and remodeling, diabetic wounds tend to become chronic and refractory primarily due to a prolonged inflammatory phase. In diabetic wounds, insufficient synthesis and release of endogenous calcitonin gene-related peptide (CGRP) is a critical upstream mechanism underlying the disrupted neuro-immune communication, the persistent inflammation, and the arrested wound healing process. In contrast to pure skin defect wounds, where CGRP is rapidly upregulated after injury, CGRP remains persistently low in diabetic wound tissue, consequently failing to drive macrophage polarization towards the M2 phenotype or promote vascular maturation and collagen fiber deposition in the later phase of inflammation. In the early inflammatory phase, CGRP exerts pro-inflammatory effects by enhancing angiogenesis and modulating macrophage polarization. In the late inflammatory phase, CGRP upregulates thrombospondin-1, promotes neutrophil apoptosis and phagocytic clearance, thereby inhibiting excessive inflammatory response and shifting the wound microenvironment from a pro-inflammatory state to a pro-reparative state. Restoring CGRP signaling reconstructs the neuroimmunomodulation axis and improves wound repair while relieving diabetic neuropathic pain. Engineered CGRP combined with intelligent delivery systems offers promising prospects for diabetic wound therapy. However, large-scale clinical trials are still required to validate its clinical efficacy and safety. This paper systematically analyzes the mechanisms and application strategies of CGRP in facilitating diabetic wound repair, which can provide a theoretical basis and innovative strategies for clinical management. \u7cd6\u5c3f\u75c5\u521b\u9762\u662f\u4e00\u79cd\u7cd6\u5c3f\u75c5\u5e76\u53d1\u75c7\uff0c\u4e25\u91cd\u8005\u53ef\u81f4\u60a3\u8005\u622a\u80a2\u751a\u81f3\u6b7b\u4ea1\u3002\u6b63\u5e38\u7684\u521b\u9762\u6108\u5408\u5386\u7ecf\u6b62\u8840\u3001\u708e\u75c7\u3001\u589e\u6b96\u3001\u91cd\u58514\u4e2a\u9636\u6bb5\uff0c\u7cd6\u5c3f\u75c5\u521b\u9762\u4e3b\u8981\u56e0\u708e\u75c7\u671f\u5ef6\u957f\u800c\u6162\u6027\u96be\u6108\u3002\u7cd6\u5c3f\u75c5\u521b\u9762\u7ec4\u7ec7\u4e2d\u964d\u9499\u7d20\u57fa\u56e0\u76f8\u5173\u80bd\uff08CGRP\uff09\u5408\u6210\u4e0e\u91ca\u653e\u4e0d\u8db3\uff0c\u8fd9\u662f\u5bfc\u81f4\u521b\u9762\u795e\u7ecf\u514d\u75ab\u901a\u8baf\u4e2d\u65ad\u3001\u708e\u75c7\u65e0\u6cd5\u6d88\u9000\u3001\u6108\u5408\u8fdb\u7a0b\u505c\u6ede\u7684\u5173\u952e\u4e0a\u6e38\u673a\u5236\u3002\u4e0e\u5355\u7eaf\u76ae\u80a4\u7f3a\u635f\u521b\u9762\u4e2dCGRP\u5728\u4f24\u540e\u8fc5\u901f\u4e0a\u8c03\u4e0d\u540c\uff0c\u7cd6\u5c3f\u75c5\u521b\u9762\u7ec4\u7ec7\u4e2dCGRP\u5448\u6301\u7eed\u6027\u4f4e\u6c34\u5e73\u8868\u8fbe\uff0c\u65e0\u6cd5\u5728\u708e\u75c7\u540e\u671f\u9a71\u52a8\u5de8\u566c\u7ec6\u80de\u5411M2\u578b\u6781\u5316\uff0c\u4fc3\u8fdb\u8840\u7ba1\u6210\u719f\u4e0e\u80f6\u539f\u7ea4\u7ef4\u6c89\u79ef\u3002\u5728\u708e\u75c7\u521d\u671f\uff0cCGRP\u901a\u8fc7\u4fc3\u8fdb\u65b0\u8840\u7ba1\u751f\u6210\u3001\u8c03\u8282\u5de8\u566c\u7ec6\u80de\u6781\u5316\u7b49\u53d1\u6325\u4fc3\u708e\u4f5c\u7528\uff1b\u800c\u5728\u708e\u75c7\u540e\u671f\uff0cCGRP\u901a\u8fc7\u4e0a\u8c03\u8840\u5c0f\u677f\u53cd\u5e94\u86cb\u767d-1\uff0c\u4fc3\u8fdb\u4e2d\u6027\u7c92\u7ec6\u80de\u51cb\u4ea1\u4e0e\u80de\u846c\u6e05\u9664\uff0c\u8fdb\u800c\u6291\u5236\u8fc7\u5ea6\u708e\u75c7\u53cd\u5e94\uff0c\u63a8\u52a8\u521b\u9762\u5fae\u73af\u5883\u7531\u4fc3\u708e\u72b6\u6001\u5411\u4fc3\u4fee\u590d\u72b6\u6001\u8f6c\u53d8\u3002\u6062\u590dCGRP\u4fe1\u53f7\u53ef\u91cd\u5851\u795e\u7ecf\u514d\u75ab\u8c03\u63a7\u8f74\uff0c\u517c\u5177\u4fc3\u8fdb\u521b\u9762\u4fee\u590d\u4e0e\u7f13\u89e3\u7cd6\u5c3f\u75c5\u795e\u7ecf\u75c5\u7406\u6027\u75bc\u75db\u7684\u53cc\u91cd\u4f5c\u7528\u3002\u5de5\u7a0b\u5316CGRP\u4e0e\u667a\u80fd\u9012\u9001\u7cfb\u7edf\u4e3a\u7cd6\u5c3f\u75c5\u521b\u9762\u6cbb\u7597\u5e26\u6765\u65b0\u5e0c\u671b\uff0c\u4f46\u5176\u5728\u4e34\u5e8a\u5e94\u7528\u4e2d\u7684\u6709\u6548\u6027\u4e0e\u5b89\u5168\u6027\u4ecd\u9700\u5927\u89c4\u6a21\u7814\u7a76\u9a8c\u8bc1\u3002\u8be5\u6587\u6df1\u5165\u5256\u6790CGRP\u5728\u7cd6\u5c3f\u75c5\u521b\u9762\u4fee\u590d\u4e2d\u7684\u4f5c\u7528\u673a\u5236\u53ca\u5e94\u7528\u7b56\u7565\uff0c\u4e3a\u4e34\u5e8a\u6cbb\u7597\u63d0\u4f9b\u7406\u8bba\u4f9d\u636e\u4e0e\u65b0\u601d\u8def\u3002.\n\nID: 42214765\nTitle: Repurposing indacaterol as a novel NETs inhibitor for the treatment of colorectal tumor metastasis.\nAbstract: Metastasis remains the leading cause of cancer-related mortality, driven by multifaceted interactions within the tumor microenvironment (TME). Recently, Neutrophil Extracellular Traps (NETs) have emerged as critical facilitators of metastatic progression. This study aimed to systematically screen FDA-approved drugs to identify novel NET inhibitors and evaluate the potential of indacaterol (IND) as an anti-metastatic agent. The screening identified IND as a potent inhibitor of NETosis (IC50\u00a0=\u00a06.567\u00a0\u03bcM), significantly suppressing extracellular DNA release and Citrullinated Histone H3 expression in a dose-dependent manner. In vitro investigations revealed that IND exerts a dual therapeutic effect: directly inhibiting tumor cell proliferation and migration, and indirectly restoring anti-tumor immunity by dismantling the NET barrier, evidenced by revitalized CD8\u00a0+\u00a0T cell activation (CD25\u00a0+\u00a0) and IFN-\u03b3 secretion. Additionally, IND promoted macrophage polarization toward an M2 phenotype, facilitating the phagocytic clearance of NETs. In vivo, IND treatment markedly reduced circulating NET levels and significantly suppressed metastatic colonization in the liver and spleen. This study provides the first systematic evidence positioning Indacaterol as a novel and potent NETs inhibitor. By effectively blocking NET formation and remodeling the immune microenvironment, IND demonstrates significant anti-metastatic potential. Leveraging its established pharmacological and safety profile, Indacaterol represents a promising candidate for rapid clinical repurposing to target NET-mediated metastasis, particularly in malignancies characterized by systemic inflammation.\n\nID: 42183275\nTitle: Neutrophil efferocytosis in chronic inflammatory gastrointestinal diseases: mechanistic insights and therapeutic potential.\nAbstract: Efferocytosis-the phagocytic clearance of apoptotic cells-is central to tissue homeostasis and the active resolution of inflammation. Although its mechanistic basis and disease relevance have been studied in isolation, no review has comprehensively integrated neutrophil efferocytosis mechanisms, their pathophysiological roles across major chronic inflammatory gastrointestinal diseases, and natural product-based therapeutic strategies-a gap this work addresses. We systematically describe the efferocytic recognition cascade, encompassing find-me signals, eat-me signals (including phosphatidylserine and the underappreciated plasminogen/M6P-IGF2R axis), and don't-eat-me checkpoints (CD47-SIRP\u03b1). We clarify that efferocytosis is not restricted to M2-polarized macrophages-M0 and M1 macrophages also participate-but that polarization state critically determines the pro-resolving coupling of downstream signaling. We analyze shared and disease-specific efferocytic defect mechanisms in inflammatory bowel disease, chronic gastritis, NAFLD/NASH, and pancreatitis, identifying IL-10R signaling failure, receptor shedding, CD47 upregulation, and SPM deficiency as convergent pathological nodes. Against this backdrop, we critically evaluate natural product strategies-flavonoids, polyphenols, alkaloids, terpenoids, polysaccharides, and omega-3 fatty acids-targeting these nodes, with explicit grading of evidence levels. Translational challenges and the potential of single-cell sequencing, spatial transcriptomics, and patient-derived organoid co-culture systems are also discussed. Restoring efferocytosis represents a mechanistically grounded therapeutic frontier for chronic gastrointestinal disease.\n\nID: 42041579\nTitle: Small Subset, Big Impact: Regulatory Function of \u03b3\u03b4 T Cells in Arteriogenesis.\nAbstract: Despite the identification of several mediators of arteriogenesis, the growth of natural bypass, the role of lymphocytes, particularly T cells, in this process remains poorly defined. Among these, \u03b3\u03b4 T cells, which express alternative T cell receptors, have emerged as a key immune component. This study examined the roles of \u03b1\u03b2 and \u03b3\u03b4 T cells in arteriogenesis using a murine hindlimb model. While the absence of \u03b1\u03b2 T cells did not affect arteriogenesis, \u03b3\u03b4 T cell depletion markedly reduced vascular cell proliferation and perfusion recovery. Early phase analyses revealed impaired mast cell activation, whereas platelet-neutrophil aggregates and neutrophil extravasation were unaffected. In the later proliferative phase, \u03b3\u03b4 T cell depletion hindered perivascular M2-like (MRC1+) macrophage accumulation. Flow cytometric analysis of whole blood in wildtype mice revealed a temporal shift in \u03b3\u03b4 T cell populations from a CD27+/CD39- phenotype, commonly associated with pro-inflammatory functions and IFN\u03b3 production, to CD39+ phenotypes, which have been linked to anti-inflammatory properties and IL-10 production. In rescue experiments, administration of IFN\u03b3 to \u03b3\u03b4 T cell-depleted mice restored mast cell activation, whereas IL-10 treatment reestablished M2-like (MRC1+) macrophage accumulation. These findings collectively identify \u03b3\u03b4 T cells as critical regulators of both early and late phases of arteriogenesis through coordinated inflammatory and regenerative mechanisms.\n\nID: 42017459\nTitle: Cholesterol-Induced Senescent Macrophages and Evaluation of Cellular Senescence Phenotypes.\nAbstract: Recent discoveries linking cellular senescence to inflammaging and age-associated metabolic diseases have intensified interest in defining the mechanisms that drive cellular senescence. Single-cell transcriptomic studies have identified tissue-resident macrophages, long-lived and self-renewing innate immune cells, as a major reservoir of senescent cells and key contributors to age-associated chronic inflammation. Despite this progress, the upstream drivers that induce and stabilize macrophage senescence during aging and other comorbidities remain incompletely defined. Accumulating evidence now supports cholesterol loading as a\u00a0causal trigger of macrophage senescence, both in vitro and in vivo under hypercholesterolemic and high-fat diet conditions. However, a critical gap in the field has been the lack of well-defined experimental models to determine whether cholesterol-loaded macrophages undergo true, stable cellular senescence, rather than a transient stress response that engages senescence-associated pathways. Addressing this gap is essential for mechanistic studies and therapeutic targeting. Here, we describe the step-by-step methods to generate senescent macrophages using acetylated low-density lipoprotein (Ac-LDL), a model that we established and benchmarked against canonical DNA damage-induced senescence macrophage models. We demonstrate that prolonged cholesterol loading drives a stable and reproducible senescent state in macrophages, characterized by persistent cell-cycle arrest, expression of senescence-associated secretory phenotype genes, and hallmark senescent phenotypes. This article provides a detailed protocol for generating and validating cholesterol-induced senescent macrophages using Ac-LDL, including complementary senescence assays to distinguish bona fide senescence from transient activation states. By standardizing experimental approaches to model macrophage senescence, these protocols will facilitate mechanistic studies and accelerate the development of targeted pharmacological strategies aimed at senescent immune cells in aging and metabolic disease. \u00a9 2026 Wiley Periodicals LLC. Basic Protocol: Ac-LDL-induced macrophage senescence in vitro Support Protocol: Evaluation of cellular senescence in Ac-LDL induced macrophage senescence.\n\nID: 41351868\nTitle: Fucoidan Alleviates Chemotherapy-Induced Peripheral Neuropathy via Activating the Gas6/MerTK Signaling Pathway to Reduce Neuroinflammation.\nAbstract: Chemotherapy-induced peripheral neuropathy (CIPN), a prevalent dose-limiting toxicity in cancer chemotherapy, remains mechanistically elusive and therapeutically challenging. Neutrophil extracellular trap (NETs)-mediated neuroinflammation constitutes a critical mechanism for CIPN. Oxaliplatin was used to establish a murine CIPN model. Fucoidan could dose-dependently ameliorate mechanical allodynia in CIPN mice while reducing NETs accumulation and neuroinflammation. RNA-Seq profiling identified the anti-inflammatory factor SOCS3 as a pivotal target of fucoidan. SOCS3 knockdown abolished fucoidan's anti-inflammatory efficacy. RNA-seq analysis revealed MerTK, upstream of SOCS3, was significantly downregulated in peripheral nerve tissues of CIPN patients. Fucoidan activated the Gas6/MerTK axis in macrophages. The therapeutic effects were abrogated by the MerTK-specific inhibitor MI, MerTK siRNA, and Gas6 knockout. Furthermore, fucoidan enhanced MerTK-mediated macrophage phagocytosis of NETs and alleviated neuroinflammation. Fucoidan alleviates CIPN through activating the Gas6/MerTK signaling to induce SOCS3-mediated neuroinflammation inhibition and to promote macrophage-mediated phagocytic clearance of NETs. These findings propose a promising drug candidate for CIPN.\n\nID: 40806194\nTitle: Lipopolysaccharide-Activated Macrophages Suppress Cellular Senescence and Promote Rejuvenation in Human Dermal Fibroblasts.\nAbstract: Tissue-resident macrophages are essential for skin homeostasis. This study investigated whether lipopolysaccharide (LPS)-activated macrophages affect senescence and rejuvenation in human dermal fibroblasts. Human monocytic THP-1 cells were stimulated with Pantoea agglomerans-derived LPS (1-1000 ng/mL), and culture supernatants were collected. These were applied to two NB1RGB fibroblast populations: young, actively dividing cells (Young cells) and senescent cells with high population doubling levels and reduced proliferation (Old cells). Senescence markers P16, P21, and Ki-67 were analyzed at gene and protein levels. Conditioned medium from Old cells induced senescence in Young cells, increasing P16 and P21 expression levels. This effect was suppressed by cotreatment with LPS-activated THP-1 supernatant. Old cells treated with the LPS-activated supernatant exhibited decreased P16 and P21 levels as well as increased Ki-67 expression, indicating partial rejuvenation. These effects were not observed following treatment with unstimulated THP-1 supernatants or LPS alone. Overall, these findings suggest that secretory factors from LPS-activated macrophages can suppress cellular senescence and promote human dermal fibroblast rejuvenation, highlighting the potential role of macrophage activation in regulating cellular aging and offering a promising strategy for skin aging intervention.\n\nID: 40073809\nTitle: Nicotinamide mononucleotide supplementation ameliorates testicular damage induced by ischemia-reperfusion through reshaping macrophage and neutrophil inflammatory properties.\nAbstract: Ischemia-reperfusion (I/R) injury is the main pathophysiology of testicular torsion-detorsion (T/D). However, there is no safe and effective treatment for testicular I/R injury. The levels of NAD+ related genes were measured in the sham group, I/R\u00a0+\u00a0saline-treated group, and I/R\u00a0+\u00a0NMN-treated group by quantitative reverse transcription PCR (qRT-PCR). Testicular NAD+, Malondialdehyde (MDA), and superoxide dismutase (SOD) were evaluated. The markers of testicular function, including sperm quality, testosterone secretion, and the number of germ cells, were compared between groups. The reactive oxygen species (ROS), apoptosis, and immune cells were analyzed by flow cytometry. The expression of inflammatory genes, germ cell markers, and the phosphorylation of p65 and STAT3 were assessed by qRT-PCR, immunofluorescence, and western blot, respectively. In this study, we analyzed the therapeutic potentials of NMN supplementation in testicular injury induced by torsion-detorsion in mice. NMN supplementation could increase testicular NAD+ content, increase serum testosterone levels, prevent Leydig cell and germ cell injury, and improve sperm quantity. Mechanistically, NMN supplementation relieved the sharply hostile immune microenvironment. Specifically, NMN supplementation could mitigate the oxidative stress and cell apoptosis in the I/R injured testes, downregulate the protein expression of p-p65 and p-STAT3 in inflammatory pathways, limit the excessive activation of inflammatory responses in testicular tissues, and reshape the inflammatory properties of macrophages and neutrophils. The beneficial effects of NMN supplementation indicated that boosting NAD+ may be a promising and safe strategy to improve clinical outcomes in I/R-induced testicular damage.\n\nID: 40010762\nTitle: Neutrophil extracellular traps impede cancer metastatic seeding via protease-activated receptor 2-mediated downregulation of phagocytic checkpoint CD24.\nAbstract: Phagocytic clearance by macrophages represents a critical immune surveillance mechanism in cancer liver metastasis. Neutrophils, the most abundant immune cells encountered by cancer cells in circulation, play key roles in metastasis through neutrophil extracellular traps (NETs). Although NETs promote macrophage phagocytosis during infection, whether they regulate phagocytosis during cancer metastasis is unknown. The present study aimed to explore the roles of NETs in regulating macrophage phagocytosis during the seeding process of liver metastasis and the mechanisms underlying the roles. A lipopolysaccharide-induced NET model was applied to study the role of NETs on colorectal cancer (CRC) liver metastasis. The neutrophils isolated from human peripheral blood were stimulated with PMA to release NETs, which were collected and added to the cultures of different CRC cell lines for in vitro studies. Macrophage phagocytosis was assessed with flow cytometry in vitro and in vivo. RNA-seq and microRNA array analyses were performed to identify key pathways regulated by NETs and downstream key molecules. The macrophage phenotypes were evaluated using immunohistochemistry, flow cytometry, and cytokine and chemokine arrays. NETs promote macrophage phagocytosis both in vitro and in vivo. Neutrophil elastase (NE), which was able to inactivate the canonical signal of protease-activated receptor 2 (PAR2), downregulated the phagocytotic checkpoint CD24. Notably, PAR2 deficiency imitated the effect of NETs on phagocytosis and CD24. Mechanistic studies indicated that inhibiting PAR2 expression upregulated miR-34a and miR-146a and downregulated CD24 in cancer cells. In addition, PAR2 depletion enhanced the recruitment and M1 polarization of macrophages by upregulating CSF-1 and CXCL1. The correlation of NETs/NE and CD24 was corroborated using human CRC specimens. Furthermore, PAR2 blockade combined with an anti-EGFR antibody (cetuximab (CTX)) synergistically enhanced the phagocytic ability of macrophages and suppressed liver metastasis in vivo. NET-derived elastase inactivated PAR2 canonical signaling and promoted phagocytosis by downregulating CD24, which functions as a phagocytotic checkpoint in CRC liver metastasis. Thus, PAR2 inhibitors combined with CTX may serve as a novel therapeutic strategy against advanced CRC.\n\nID: 39836688\nTitle: Gingipains protect Porphyromonas gingivalis from macrophage-mediated phagocytic clearance.\nAbstract: Porphyromonas gingivalis (Pg) is a keystone pathogen in periodontitis, a highly prevalent disease manifested by chronic inflammation of the periodontium, alveolar bone resorption and tooth loss. During periodontitis pathobionts such as Pg can enter the bloodstream and growing evidence correlates periodontitis with increased risk of cardiovascular and neurodegenerative diseases. However, the mechanism by which immune cells respond to Pg challenge in vivo remains elusive. Pg produce aggressive proteolytic virulence factors termed gingipains which not only provide nutrients necessary for bacterial growth, but also subvert the host immune response, facilitating bacterial survival. Using transgenic zebrafish with fluorescently labelled macrophages and neutrophils, the role of gingipains in bacterial survival and interaction with phagocytes during systemic and local infection was examined. In contrast to the wild-type (W83) Pg, isogenic gingipain-null (\u0394K/R-ab) or wild-type Pg treated with gingipain inhibitors caused less zebrafish mortality, bacteria were rapidly phagocytosed, acidified in phagosomes and eradicated when systemically injected, showing that gingipains are instrumental in preventing phagocytosis and intracellular killing of Pg by innate immune cells. Moreover, Pg were predominantly phagocytosed by macrophages, and gingipain depletion/inactivation increased bacterial phagocytosis when bacteria were injected either systemically or locally in the otic vesicle, with less bacteria internalised by neutrophils. This phenomenon was Pg-specific as Fusobacterium nucleatum caused neutrophil recruitment that then effectively phagocytosed these bacteria. These data demonstrate the important role of phagocytes, especially macrophages, in combating Pg infection and highlight the crucial protective role of gingipains in subverting the innate immune response. This study also emphasizes the advantages of using zebrafish to study interactions of Pg with phagocytes in vivo in real-time, providing a valuable experimental system for testing new therapeutic strategies aimed at reducing periodontal-associated systemic or neurodegenerative disease.\n\nID: 38343542\nTitle: Transcriptomic profiling of immune cells in murine polymicrobial sepsis.\nAbstract: Various immune cell types play critical roles in sepsis with numerous distinct subsets exhibiting unique phenotypes even within the same cell population. Single-cell RNA sequencing (scRNA-seq) enables comprehensive transcriptome profiling and unbiased cell classification. In this study, we have unveiled the transcriptomic landscape of immune cells in sepsis through scRNA-seq analysis. We induced sepsis in mice by cecal ligation and puncture. 20 h after the surgery, the spleen and peritoneal lavage were collected. Single-cell suspensions were processed using a 10\u00d7 Genomics pipeline and sequenced on an Illumina platform. Count matrices were generated using the Cell Ranger pipeline, which maps reads to the mouse reference transcriptome, GRCm38/mm10. Subsequent scRNA-seq analysis was performed using the R package Seurat. After quality control, we subjected the entire data set to unsupervised classification. Four major clusters were identified as neutrophils, macrophages, B cells, and T cells according to their putative markers. Based on the differentially expressed genes, we identified activated pathways in sepsis for each cell type. In neutrophils, pathways related to inflammatory signaling, such as NF-\u03baB and responses to pathogen-associated molecular patterns (PAMPs), cytokines, and hypoxia were activated. In macrophages, activated pathways were the ones related to cell aging, inflammatory signaling, and responses to PAMPs. In B cells, pathways related to endoplasmic reticulum stress were activated. In T cells, activated pathways were the ones related to inflammatory signaling, responses to PAMPs, and acute lung injury. Next, we further classified each cell type into subsets. Neutrophils consisted of four clusters. Some subsets were activated in inflammatory signaling or cell metabolism, whereas others possessed immunoregulatory or aging properties. Macrophages consisted of four clusters, namely, the ones with enhanced aging, lymphocyte activation, extracellular matrix organization, or cytokine activity. B cells consisted of four clusters, including the ones possessing the phenotype of cell maturation or aging. T cells consisted of six clusters, whose phenotypes include molecular translocation or cell activation. Transcriptomic analysis by scRNA-seq has unveiled a comprehensive spectrum of immune cell responses and distinct subsets in the context of sepsis. These findings are poised to enhance our understanding of sepsis pathophysiology, offering avenues for targeting novel molecules, cells, and pathways to combat infectious diseases.\n\nID: 37267954\nTitle: Senescent alveolar macrophages promote early-stage lung tumorigenesis.\nAbstract: Senescent cells play relevant but context-dependent roles during tumorigenesis. Here, in an oncogenic Kras-driven lung cancer mouse model, we found that senescent cells, specifically alveolar macrophages, accumulate early in neoplasia. These macrophages have upregulated expression of p16INK4a and Cxcr1, are distinct from previously defined subsets and are sensitive to senolytic interventions, and suppress cytotoxic T\u00a0cell responses. Their removal attenuates adenoma development and progression in mice, indicating their tumorigenesis-promoting role. Importantly, we found that alveolar macrophages with these properties increase with normal aging in mouse lung and in human lung adenocarcinoma in situ. Collectively, our study indicates that a subset of tissue-resident macrophages can support neoplastic transformation through altering their local microenvironment, suggesting that therapeutic interventions targeting senescent macrophages may attenuate lung cancer progression during early stages of disease.\n\nID: 35929736\nTitle: Cellular communication network factor 1-stimulated liver macrophage efferocytosis drives hepatic stellate cell activation and liver fibrosis.\nAbstract: Following inflammatory injury in the liver, neutrophils quickly infiltrate the injured tissue to defend against microbes and initiate the repair process; these neutrophils are short lived and rapidly undergo apoptosis. Hepatic stellate cells (HSCs) are the principal precursor cells that transdifferentiate into myofibroblast-like cells, which produce a large amount of extracellular matrix that promotes repair but can also lead to fibrosis if the injury becomes chronic. The matricellular protein cellular communication network factor 1 (CCN1) acts as a bridging molecule by binding phosphatidylserine in apoptotic cells and integrin \u03b1v \u03b23 in phagocytes, thereby triggering efferocytosis or phagocytic clearance of the apoptotic cells. Here, we show that CCN1 induces liver macrophage efferocytosis of apoptotic neutrophils in carbon tetrachloride (CCl4 )-induced liver injury, leading to the production of activated transforming growth factor (TGF)-\u03b21, which in turn induces HSC transdifferentiation into myofibroblast-like cells that promote fibrosis development. Consequently, knock-in mice expressing a single amino acid substitution in CCN1 rendering it unable to bind \u03b1v \u03b23 or induce efferocytosis are impaired in neutrophil clearance, production of activated TGF-\u03b21, and HSC transdifferentiation, resulting in greatly diminished liver fibrosis following exposure to CCl4 . Conclusion: These results reveal the crucial role of CCN1 in stimulating liver macrophage clearance of apoptotic neutrophils, a process that drives HSC transdifferentiation into myofibroblastic cells and underlies fibrogenesis in chronic liver injury.\n\nID: 34557866\nTitle: Function of Mitogen-Activated Protein Kinases in Hepatic Inflammation.\nAbstract: The western diet and overuse of anti-inflammatory medication have caused a great deal of stress on the liver. Obesity and the associated inflammatory state in insulin-responsive tissues result in the release of pro-inflammatory cytokine that activates the stress-responsive MAPKs, p38 MAPK, and JNK. These MAPKs have figured prominently as critical effectors in physiological and pathophysiological hepatic inflammation. In contrast, evidence for a role for ERK1/2 in hepatic inflammation has been less well developed. In this review article, we describe recent insights into the physiology and pathophysiology of the role of stress-responsive MAPKs in hepatic inflammation during obesity and liver injury with a focus on macrophages, hepatocytes and hepatic stellate cells. In response to metabolic stress and liver injury, JNK activation in macrophages and hepatocytes promotes the secretion of inflammatory cytokines and macrophage and neutrophil infiltration. p38 MAPK plays an important role in contributing to the progression of hepatic inflammation in response to various hepatic cellular stresses, although the precise substrates mediating these effects in hepatocytes and hepatic stellate cells remain to be identified. Both JNK and p38 MAPK promotes profibrotic behavior in hepatic stellate cells.\n\nID: 34490541\nTitle: Perspectives on the dynamic implications of cellular senescence and immunosenescence on macrophage aging biology.\nAbstract: An intricate relationship between impaired immune functions and the age-related accumulation of tissue senescent cells is rapidly emerging. The immune system is unique as it undergoes mutually inclusive and deleterious processes of immunosenescence and cellular senescence with advancing age. While factors inducing immunosenescence and cellular senescence may be shared, however, both these processes are fundamentally different which holistically influence the aging immune system. Our understanding of the biological impact of immunosenescence is relatively well-understood, but such knowledge regarding cellular senescence in immune cells, especially in the innate immune cells such as macrophages, is only beginning to be elucidated. Tissue-resident macrophages are long-lived, and while functioning in tissue-specific and niche-specific microenvironments, senescence in macrophages can be directly influenced by senescent host cells which may impact organismal aging. In addition, evidence of age-associated immunometabolic changes as drivers of altered macrophage phenotype and functions such as inflamm-aging is also emerging. The present review describes the emerging impact of cellular senescence vis-\u00e0-vis immunosenescence in aging macrophages, its biological relevance with other senescent non-immune cells, and known immunometabolic regulators. Gaps in our present knowledge, as well as strategies aimed at understanding cellular senescence and its therapeutics in the context of macrophages, have been reviewed.\n\nID: 34153003\nTitle: Cell landscape atlas for patients with chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy constructed using single-cell RNA sequencing.\nAbstract: This study aimed to construct an atlas of the cell landscape and comprehensively characterize the cellular repertoire of the pulmonary endarterectomized tissues of patients with chronic thromboembolic pulmonary hypertension (CTEPH). Five pulmonary endarterectomized tissues were collected. 10\u00d7 Genomics single-cell RNA sequencing was performed, followed by the identification of cluster marker genes and cell types. Gene Ontology (GO) enrichment analysis was conducted. Seventeen cell clusters were characterized, corresponding to 10,518 marker genes, and then classified into eight cell types, including fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, cysteine rich secretory protein LCCL domain containing 2 (CRISPLD2)+ cell, cancer stem cell, and undefined. The specific marker genes of fibroblast/smooth muscle cell, endothelial cell, T cell/NK cell, macrophage, mast cell, and cancer stem cell were significantly enriched for multiple functions associated with muscle cell migration, endothelial cell migration, T cell activation, neutrophil activation, erythrocyte homeostasis, and tissue remodeling, respectively. No functions were significantly enriched for the marker gene of CRISPLD2+ cell. Our study, for the first time, provides an atlas of the cell landscape of the pulmonary endarterectomized tissues of CTEPH patients at single-cell resolution, which may serve as a valuable resource for further elucidation of disease pathophysiology.\n\nID: 33380498\nTitle: Inhibition of Efferocytosis by Extracellular CIRP-Induced Neutrophil Extracellular Traps.\nAbstract: Phagocytic clearance of apoptotic cells by the macrophages (efferocytosis) is impaired in sepsis, but its mechanism is poorly understood. Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel damage-associated molecular pattern that fuels inflammation. We identify that eCIRP-induced neutrophil extracellular traps (NETs) impair efferocytosis through a novel mechanism. Coculture of macrophages and apoptotic thymocytes in the presence of recombinant murine CIRP (rmCIRP)-induced NETs significantly inhibited efferocytosis. Efferocytosis was significantly inhibited in the presence of rmCIRP-treated wild-type (WT), but not PAD4-/- neutrophils. Efferocytosis in the peritoneal cavity of rmCIRP-injected PAD4-/- mice was higher than WT mice. Milk fat globule-EGF-factor VIII (MFG-E8), an opsonin, increased macrophage efferocytosis, whereas the inhibition of efferocytosis by NETs was not rescued upon addition of MFG-E8, indicating disruption of MFG-E8's receptor(s) \u03b1v\u03b23 or \u03b1v\u03b25 integrin by the NETs. We identified neutrophil elastase in the NETs significantly inhibited efferocytosis by cleaving macrophage surface integrins \u03b1v\u03b23 and \u03b1v\u03b25 Using a preclinical model of sepsis, we found that CIRP-/- mice exhibited significantly increased rate of efferocytosis in the peritoneal cavity compared with WT mice. We discovered a novel role of eCIRP-induced NETs to inhibit efferocytosis by the neutrophil elastase-dependent decrease of \u03b1v\u03b23/\u03b1v\u03b25 integrins in macrophages. Targeting eCIRP ameliorates sepsis by enhancing efferocytosis.\n\nID: 31728991\nTitle: Assessment of Neutrophil Apoptosis.\nAbstract: The process of neutrophil apoptosis has an important role in the resolution of acute inflammation. Apoptotic cell death is characterized by a coordinated sequence of cellular alterations that serve to uncouple neutrophil effector functions whilst maintaining plasma membrane integrity. In this way the release on neutrophil intracellular contents, including proteases, glycosidases, and reactive oxygen species, is limited during apoptosis. In addition, plasma membrane alterations associated with neutrophil apoptosis provide molecular cues that enable recognition by phagocytic cells, including macrophages. The recognition and uptake of apoptotic neutrophils by macrophages dampens proinflammatory responses to pathogen- or damage-associated molecular patterns and triggers release of proresolution mediators, that further promote resolution of inflammation. The key cellular and molecular events that act to control neutrophil apoptosis and subsequent macrophage phagocytosis have been characterized by in vitro studies, unveiling potential therapeutic targets for the manipulation of these regulatory pathways. In this chapter, we outline some of the key assays that are used to assess neutrophil apoptosis in vitro, together with methods to assess activation of the apoptotic machinery and phagocytic clearance of apoptotic neutrophils.\n\nID: 27852744\nTitle: Integrin Cross-Talk Regulates the Human Neutrophil Response to Fungal \u03b2-Glucan in the Context of the Extracellular Matrix: A Prominent Role for VLA3 in the Antifungal Response.\nAbstract: Candida albicans infection produces elongated hyphae resistant to phagocytic clearance compelling alternative neutrophil effector mechanisms to destroy these physically large microbial structures. Additionally, all tissue-based neutrophilic responses to fungal infections necessitate contact with the extracellular matrix (ECM). Neutrophils undergo a rapid, ECM-dependent mechanism of homotypic aggregation and NETosis in response to C. albicans mediated by the \u03b22 integrin, complement receptor 3 (CR3, CD11b/CD18, \u03b1M\u03b22). Neither homotypic aggregation nor NETosis occurs when human neutrophils are exposed either to immobilized fungal \u03b2-glucan or to C. albicans hyphae without ECM. The current study provides a mechanistic basis to explain how matrix controls the antifungal effector functions of neutrophils under conditions that preclude phagocytosis. We show that CR3 ligation initiates a complex mechanism of integrin cross-talk resulting in differential regulation of the \u03b21 integrins VLA3 (\u03b13\u03b21) and VLA5 (\u03b15\u03b21). These \u03b21 integrins control distinct antifungal effector functions in response to either fungal \u03b2-glucan or C. albicans hyphae and fibronectin, with VLA3 inducing homotypic aggregation and VLA5 regulating NETosis. These integrin-dependent effector functions are controlled temporally whereby VLA5 and CR3 induce rapid, focal NETosis early after binding fibronectin and \u03b2-glucan. Within minutes, CR3 undergoes inside-out auto-activation that drives the downregulation of VLA5 and the upregulation of VLA3 to support neutrophil swarming and aggregation. Forcing VLA5 to remain in the activated state permits NETosis but prevents homotypic aggregation. Therefore, CR3 serves as a master regulator during the antifungal neutrophil response, controlling the affinity states of two different \u03b21 integrins, which in turn elicit distinct effector functions.\n\nID: 27725186\nTitle: Effect of aging on sputum inflammation and asthma control.\nAbstract: Aged asthmatic patients experience increased morbidity and mortality. Knowledge of the aging effect on airway inflammation and asthma control is limited. We sought to compare airway inflammation and its relationship to asthma control in aged versus younger patients and determine whether differences are asthma specific or caused by \"inflamm-aging.\" We performed a prospective study of aged (>60\u00a0years) and younger (21-40\u00a0years) inner-city patients with asthma. After a run-in period to control for inhaled corticosteroid use, induced sputum was collected. Age-matched nonasthmatic control subjects were included to measure age-related inflammatory changes. Aged (mean age, 67.9\u00a0\u00b1\u00a05.1\u00a0years; n\u00a0=\u00a035) compared with younger (mean age, 30.8\u00a0\u00b1\u00a05.9\u00a0years; n\u00a0=\u00a037) asthmatic patients had significantly worse asthma control and lower FEV1. Aged asthmatic patients had higher sputum neutrophil (30.5\u00a0\u00d7\u00a0104/mL and 23.1%) and eosinophil (7.0\u00a0\u00d7\u00a0104/mL and 3.8%) numbers and percentages compared with younger patients (neutrophils, 13.0\u00a0\u00d7\u00a0104/mL [P\u00a0<\u00a0.01] and 6.9% [P\u00a0<\u00a0.01]; eosinophils, 2.0\u00a0\u00d7\u00a0104/mL [P\u00a0<\u00a0.01] and 1.2% [P\u00a0<\u00a0.01]). Aged asthmatic patients had higher sputum IL-6 (P\u00a0<\u00a0.01) and IL-8 (P\u00a0=\u00a0.01) levels. No significant inflammatory differences between aged and younger control subjects were observed. In aged asthmatic patients increased sputum IL-6 and macrophage inflammatory protein 3\u03b1/CCL20 levels were significantly associated with decreased asthma control and increased sputum neutrophil numbers and IL-1\u03b2, IL-6, and macrophage inflammatory protein 3\u03b1/CCL20 levels were associated with hospitalization. The inflammatory patterns of aged versus younger asthmatic patients are associated with increased sputum neutrophil and eosinophil values and cytokine levels related to neutrophil recruitment. Differences in airway inflammation can contribute to diminished asthma control in the aged. Further understanding of asthma pathophysiology in aged patients is needed to improve management of this vulnerable population.\n\nID: 24504951\nTitle: Assessment of neutrophil apoptosis.\nAbstract: Timely neutrophil apoptosis and cell clearance by surrounding phagocytes are essential components of the resolution phase of acute inflammation. Programmed cell death by apoptosis occurs with maintenance of an intact cell membrane in order to prevent the release of histotoxic intracellular products such as proteases and reactive oxidant species into the extracellular surroundings as occurs during necrosis. Macrophage phagocytosis results in attenuation of toll-like receptor-driven proinflammatory mediator production further promoting inflammation resolution. Failures in this cascade of events can result in tissue damage, chronic inflammation and disease. By studying human neutrophil apoptosis and phagocytic clearance in vitro, it is possible to delineate key control mechanisms in the regulation of these processes and therefore also identify potential therapeutic targets. Apoptotic signalling pathways are well described in the literature using a variety of laboratory techniques. In this paper, we outline the key in vitro assays used to assess neutrophil apoptosis, activation of key components of the apoptotic machinery, and phagocytic clearance of these cells.\n\nID: 22057273\nTitle: Real-time imaging reveals that P2Y2 and P2Y12 receptor agonists are not chemoattractants and macrophage chemotaxis to complement C5a is phosphatidylinositol 3-kinase (PI3K)- and p38 mitogen-activated protein kinase (MAPK)-independent.\nAbstract: Adenosine 5'-triphosphate (ATP) has been implicated in the recruitment of professional phagocytes (neutrophils and macrophages) to sites of infection and tissue injury in two distinct ways. First, ATP itself is thought to be a chemotactic \"find me\" signal released by dying cells, and second, autocrine ATP signaling is implicated as an amplifier mechanism for chemotactic navigation to end-target chemoattractants, such as complement C5a. Here we show using real-time chemotaxis assays that mouse peritoneal macrophages do not directionally migrate to stable analogs of ATP (adenosine-5'-(\u03b3-thio)-triphosphate (ATP\u03b3S)) or its hydrolysis product ADP (adenosine-5'-(\u03b2-thio)-diphosphate (ADP\u03b2S)). HPLC revealed that these synthetic P2Y(2) (ATP\u03b3S) and P2Y(12) (ADP\u03b2S) receptor ligands were in fact slowly degraded. We also found that ATP\u03b3S, but not ADP\u03b2S, promoted chemokinesis (increased random migration). Furthermore, we found that photorelease of ATP or ADP induced lamellipodial membrane extensions. At the cell signaling level, C5a, but not ATP\u03b3S, activated Akt, whereas both ligands induced p38 MAPK activation. p38 MAPK and Akt activation are strongly implicated in neutrophil chemotaxis. However, we found that inhibitors of phosphatidylinositol 3-kinase (PI3K; upstream of Akt) and p38 MAPK (or conditional deletion of p38\u03b1 MAPK) did not impair macrophage chemotactic efficiency or migration velocity. Our results suggest that PI3K and p38 MAPK are redundant for macrophage chemotaxis and that purinergic P2Y(2) and P2Y(12) receptor ligands are not chemotactic. We propose that ATP signaling is strictly autocrine or paracrine and that ATP and ADP may act as short-range \"touch me\" (rather than long-range find me) signals to promote phagocytic clearance via cell spreading.\n\nID: 21802768\nTitle: A glimpse on the phenomenon of macrophage polarization during atherosclerosis.\nAbstract: Atherosclerosis and associated cardiovascular disease are the leading causes of mortality in developed countries and the World Health Organization has estimated that by 2020 these disorders will be the main sanitary and socio-economic problem world-wide due in part to the progressive aging of our societies. Atherosclerosis is a complex chronic inflammatory process triggered and perpetuated by cardiovascular risk factors which cause endothelial dysfunction and leukocyte infiltration within the subendothelial space in the artery wall. In this review, we summarize the mechanisms that govern the recruitment of circulating monocytes into the incipient atherosclerotic lesion and their differentiation into macrophages. Moreover, we discuss current knowledge on macrophage polarization, a phenomenon of increasing interest given recent work suggesting that different stages in the progression of atherosclerosis are associated with the presence of distinct macrophage subtypes. Understanding the molecular mechanisms that orchestrate macrophage polarization and the precise role of distinct macrophage subsets should provide a basis for novel treatment strategies to limit the progression of atherosclerosis.\n\nID: 19097983\nTitle: Matrix metalloproteinase-9 deficiency worsens lung injury in a model of bronchopulmonary dysplasia.\nAbstract: Increased activity of matrix metalloproteinase (MMP)-9 is associated with the development of bronchopulmonary dysplasia (BPD) in newborn infants, but the role of MMP-9 in the pathophysiology of BPD is unclear. We have shown that perinatal expression of interleukin-1 beta (IL-1 beta) in the lung is sufficient to cause a BPD-like illness in infant mice. To study the hypothesis that MMP-9 is an important downstream mediator in IL-1 beta-induced lung injury in the newborn, we compared the effects of IL-1 beta on fetal and postnatal lung inflammation and development in transgenic mice with regulatable pulmonary overexpression of human mature IL-1 beta with wild-type (IL-1 beta/MMP-9(+/+)) or null (IL-1 beta/MMP-9(-/-)) MMP-9 loci. IL-1 beta increased the expression of MMP-9 mRNA and amount of MMP-9 protein in the lungs of MMP-9(+/+) mice. IL-1 beta/MMP-9(-/-) mice had fewer neutrophils but more macrophages in the lungs than did IL-1 beta/MMP-9(+/+) mice. MMP-9 deficiency increased pulmonary cell death and macrophage clearance of dying cells in IL-1 beta-expressing mice. IL-1 beta/MMP-9(-/-) mice had more severe alveolar hypoplasia than IL-1 beta/MMP-9(+/+) mice, implying that IL-1 beta-induced lung disease was worsened in the absence of MMP-9. These results suggest that MMP-9 activity in the inflamed neonatal lung protects the lung against injury.\n\nID: 18467696\nTitle: Mouse-passaged severe acute respiratory syndrome-associated coronavirus leads to lethal pulmonary edema and diffuse alveolar damage in adult but not young mice.\nAbstract: Advanced age is a risk factor of severe acute respiratory syndrome (SARS) in humans. To understand its pathogenesis, we developed an animal model using BALB/c mice and the mouse-passaged Frankfurt 1 isolate of SARS coronavirus (SARS-CoV). We examined the immune responses to SARS-CoV in both young and adult mice. SARS-CoV induced severe respiratory illness in all adult, but not young, mice on day 2 after inoculation with a mortality rate of 30 to 50%. Moribund adult mice showed severe pulmonary edema and diffuse alveolar damage accompanied by virus replication. Adult murine lungs, which had significantly higher interleukin (IL)-4 and lower IL-10 and IL-13 levels before infection than young murine lungs, rapidly produced high levels of proinflammatory chemokines and cytokines known to induce macrophage and neutrophil infiltration and activation (eg, tumor necrosis factor-alpha). On day 2 after inoculation, young murine lungs produced not only proinflammatory cytokines but also IL-2, interferon-gamma, IL-10, and IL-13. Adult mice showed early and acute excessive proinflammatory responses (ie, cytokine storm) in the lungs after SARS-CoV infection, which led to severe pulmonary edema and diffuse alveolar damage. Intravenous injection with anti-tumor necrosis factor-alpha antibody 3 hours after infection had no effect on SARS-CoV infection. However, intraperitoneal interferon-gamma injection protected adult mice from the lethal respiratory illness. The experimental model described here may be useful for elucidating the pathophysiology of SARS and for evaluating therapies to treat SARS-CoV infection.\n\nID: 16148944\nTitle: Wound-healing defect of CD18(-/-) mice due to a decrease in TGF-beta1 and myofibroblast differentiation.\nAbstract: We studied the mechanisms underlying the severely impaired wound healing associated with human leukocyte-adhesion deficiency syndrome-1 (LAD1) using a murine disease model. In CD18(-/-) mice, healing of full-thickness wounds was severely delayed during granulation-tissue contraction, a phase where myofibroblasts play a major role. Interestingly, expression levels of myofibroblast markers alpha-smooth muscle actin and ED-A fibronectin were substantially reduced in wounds of CD18(-/-) mice, suggesting an impaired myofibroblast differentiation. TGF-beta signalling was clearly involved since TGF-beta1 and TGF-beta receptor type-II protein levels were decreased, while TGF-beta(1) injections into wound margins fully re-established wound closure. Since, in CD18(-/-) mice, defective migration leads to a severe reduction of neutrophils in wounds, infiltrating macrophages might not phagocytose apoptotic CD18(-/-) neutrophils. Macrophages would thus be lacking their main stimulus to secrete TGF-beta1. Indeed, in neutrophil-macrophage cocultures, lack of CD18 on either cell type leads to dramatically reduced TGF-beta1 release by macrophages due to defective adhesion to, and subsequent impaired phagocytic clearance of, neutrophils. Our data demonstrates that the paracrine secretion of growth factors is essential for cellular differentiation in wound healing.\n\nID: 15032637\nTitle: Molecular regulation of neutrophil apoptosis and potential targets for therapeutic strategy against the inflammatory process.\nAbstract: The balance between polymorphonuclear leukocytes (PMNL) apoptosis and necrosis in inflamed tissues is an important determinant of the degree of tissue injury. To prevent senescent PMNL from releasing their toxic contents into surrounding tissues, these cells become apoptotic and are then internalized by tissue macrophages. PMNL apoptosis and subsequent ingestion by macrophages are the major mechanisms for clearing PMNL that have been recruited to the inflamed sites and thus for promoting resolution of the inflammation. PMNL have a short half-life that is extended at the inflamed site by pro-inflammatory cytokines including Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF), Interleukin-8 (IL-8), Gro-alpha, and they contact with the bacterial cell walls containing lipopolysaccharides (LPS). Conversely, anti-inflammatory cytokines, such as IL-10, accelerate the apoptosis of LPS-activated PMNL. Spontaneous PMNL apoptosis does not require Fas ligation but involves proteolytic cascades -caspases (particularly caspases 3 and 8), calpains and the proteasome-that activate kinases, e.g. caspase 3-mediated activation of protein kinase C-delta, dissociate actin-binding proteins from filamentous actin, and participate in cell surface as well as nuclear morphological transformations. Members of the Bcl-2 protein family, Mcl-1 and A1, are involved in the regulation of PMNL apoptosis. Cell surface receptors and protein kinases, particularly mitogen-activated protein kinases (MAPK), also play critical roles in transducing the signals that result in PMNL apoptosis or extended survival. A growing understanding of the mechanisms regulating leukocyte apoptosis and of the molecules mediating safe phagocytic clearance of dying cells may yield new insights into the pathogenesis of inflammatory diseases. In this regard, therapeutic strategies to resolve chronic inflammation could usefully target PMNL. This review summarises current knowledge on the molecular mechanisms and components of PMNL apoptosis.\n\nID: 9308644\nTitle: Effects of resuscitation fluids on nonadaptive immune responses.\nAbstract: Colloidal plasma-expander fluids are commonly used as an alternative to blood components in the resuscitation of patients suffering from hemorrhagic shock and trauma. Of these, hydroxyethyl starch is also used as a cryopreservative, and these dual properties have been utilized in the development of a blood storage system that allows the direct transfusion of red cells. The prolonged intravascular persistence of hydroxyethyl starch suggests that phagocytic clearance may be impaired and that the presence of hydroxyethyl starch could exacerbate transfusion-induced immunomodulation. The effects of colloidal resuscitation fluids on the activation response and phagocytic function of polymorphonuclear cells (PMNs) and monocytes in normal peripheral blood were examined. To mimic the hemolysis associated with cryopreservation, the effects of 1- and 5- percent red cell lysate were studied. Flow cytometric assays were used in all cases. The percentage of phagocytic monocytes and PMNs was not altered; nor were the rates of phagocytosis impaired after incubation with resuscitation fluids. Upregulation of cell surface integrin during activation was similarly unmodified by the fluids. Hydroxyethyl starch and other resuscitation fluids do not affect some important antimicrobial functions of the nonadaptive arm of the immune response. This suggests that posttrauma or transfusion-induced immunomodulation is not exacerbated by inhibition at this level.\n\nID: 42546424\nTitle: The equine mesenchymal stromal cell (MSC) secretome modulates neutrophils and monocyte-derived macrophages and extracellular vesicles (EVs) impact macrophage viability.\nAbstract: Neutrophil chemotaxis and phagocytosis are critical for protection against bacteria, but can be compromised by methicillin-resistant Staphylococcus aureus (MRSA). MRSA can also circumvent macrophage surveillance by affecting polarization and reactive oxygen species (ROS) production. We previously demonstrated that the secretome of equine mesenchymal stromal cells (MSCs), comprised of all secreted bioactive factors and collected as conditioned medium (CM), reduces the growth of MRSA both in vitro and in vivo. This study aimed to determine if the equine MSC secretome has additional anti-MRSA properties by studying its effects on equine neutrophil and macrophage functions in vitro. Transwell assays demonstrated that CM from adipose tissue- and bone marrow-, but not peripheral blood-, derived MSCs significantly enhanced neutrophil migration. In addition, CM from all three MSC sources significantly reduced the phagocytic capacity of neutrophils but did not alter ROS production. MSC CM from all three tissue sources promoted macrophage polarization toward both CD86-positive (M1-like) and CD206-positive (M2-like) phenotypes, but did not change phagocytic capacity or ROS production. Further experiments showed that the complete CM, rather than the soluble and extracellular vesicle (EV) subfractions, was responsible for the increased neutrophil chemotaxis. Additionally, the primary effect of EVs on macrophages was cell death, possibly through autophagy, which can be beneficial if tissue damaging inflammation is diminished with decreased numbers of viable macrophages. Collectively, our findings show that the equine MSC secretome modulates various innate immune responses in vitro and may have therapeutic potential for managing dysregulated inflammation associated with bacterial diseases in vivo.\n\nID: 42533582\nTitle: A non-bactericidal antimicrobial peptide provides protective effect against bacterial sepsis via regulation of antimicrobial immunity and vascular endothelial functions.\nAbstract: The anti-infective properties of bactericidal antimicrobial peptides (AMPs) have been extensively studied, yet the functions and mechanisms of non-bactericidal AMPs in sepsis remain poorly understood. In this study, a novel \u03b2-sheet cathelicidin peptide, named Og-CATH, was identified from the skin of Odorrana grahami. Although Og-CATH showed no detectable direct antimicrobial activity in vitro, it provided both prophylactic and therapeutic protection in mouse models of sepsis induced by Staphylococcus aureus, Escherichia coli, or cecal ligation and puncture. This protection depended on neutrophils and monocytes/macrophages, but not T or B lymphocytes. Og-CATH did not directly chemoattract phagocytes. Instead, it stimulated P2X7 receptor-dependent chemokine release from macrophages, thereby promoting macrophage and neutrophil trafficking to sites of infection. Og-CATH also enhanced oxygen-independent bacterial clearance by increasing phagocytosis and neutrophil degranulation. In parallel, Og-CATH suppressed tissue factor production, a major trigger of the extrinsic coagulation cascade, and increased activated protein C expression in endothelial cells and mice, thereby reducing pulmonary fibrin deposition and thrombosis. Mechanistically, Og-CATH targeted myeloid differentiation protein 2 (MD2) and inhibited lipopolysaccharide (LPS)-induced recruitment of MyD88 to TLR4 in endothelial cells, thus preserving endothelial barrier integrity during sepsis. These findings identify Og-CATH as a non-bactericidal AMP that protects against sepsis by coordinating phagocyte recruitment, antibacterial effector activity, coagulation control, and endothelial stabilization. Og-CATH therefore represents a promising immunomodulatory candidate for further therapeutic development against sepsis. \u6297\u83cc\u80bd\u7684\u6297\u611f\u67d3\u7279\u6027\u5df2\u88ab\u5e7f\u6cdb\u7814\u7a76\uff0c\u4f46\u975e\u6740\u83cc\u6027\u6297\u83cc\u80bd\u5728\u8113\u6bd2\u75c7\u4e2d\u7684\u4f5c\u7528\u53ca\u673a\u5236\u5c1a\u672a\u5b8c\u5168\u660e\u786e\u3002\u672c\u7814\u7a76\u4ece\u65e0\u6307\u76d8\u81ed\u86d9\u4e2d\u9274\u5b9a\u51fa\u4e00\u79cd\u65b0\u578bcathelicidin\u6297\u83cc\u80bd\uff0c\u5176\u4e8c\u7ea7\u7ed3\u6784\u4e3a\u03b2-\u6298\u53e0\uff0c\u547d\u540d\u4e3aOg-CATH\u3002\u4f53\u5916\u5b9e\u9a8c\u8868\u660eOg-CATH\u65e0\u76f4\u63a5\u6297\u83cc\u6d3b\u6027\uff0c\u4f46\u6709\u8da3\u7684\u662f\uff0c\u5728\u91d1\u9ec4\u8272\u8461\u8404\u7403\u83cc\u3001\u5927\u80a0\u6746\u83cc\u611f\u67d3\u53ca\u76f2\u80a0\u7ed3\u624e\u7a7f\u5b54\uff08CLP\uff09\u8bf1\u5bfc\u7684\u8113\u6bd2\u75c7\u5c0f\u9f20\u6a21\u578b\u4e2d\uff0c\u8be5\u80bd\u5747\u5c55\u73b0\u51fa\u663e\u8457\u7684\u9884\u9632\u4e0e\u6cbb\u7597\u6548\u679c\u3002\u8fdb\u4e00\u6b65\u7684\u7814\u7a76\u53d1\u73b0\uff0cOg-CATH\u7684\u4fdd\u62a4\u4f5c\u7528\u4f9d\u8d56\u4e8e\u4e2d\u6027\u7c92\u7ec6\u80de\u548c\u5355\u6838/\u5de8\u566c\u7ec6\u80de\uff0c\u800c\u975eT/B\u6dcb\u5df4\u7ec6\u80de\u3002\u5c3d\u7ba1Og-CATH\u65e0\u6cd5\u76f4\u63a5\u8d8b\u5316\u541e\u566c\u7ec6\u80de\uff0c\u4f46\u53ef\u901a\u8fc7P2X7\u53d7\u4f53\u4fc3\u8fdb\u5de8\u566c\u7ec6\u80de\u5206\u6ccc\u8d8b\u5316\u56e0\u5b50\uff0c\u8fdb\u800c\u95f4\u63a5\u4ecb\u5bfc\u5de8\u566c\u7ec6\u80de\u4e0e\u4e2d\u6027\u7c92\u7ec6\u80de\u5411\u611f\u67d3\u90e8\u4f4d\u8fc1\u79fb\u3002\u6b64\u5916\uff0cOg-CATH\u8fd8\u80fd\u901a\u8fc7\u589e\u5f3a\u4e2d\u6027\u7c92\u7ec6\u80de\u7684\u541e\u566c\u4f5c\u7528\u4e0e\u8131\u9897\u7c92\u529f\u80fd\uff0c\u63d0\u5347\u5176\u975e\u6c27\u4f9d\u8d56\u578b\u6740\u83cc\u6d3b\u6027\u3002\u66f4\u91cd\u8981\u7684\u662f\uff0c\u672c\u7814\u7a76\u8bc1\u5b9eOg-CATH\u53ef\u6291\u5236\u5185\u76ae\u7ec6\u80de\u53ca\u5c0f\u9f20\u4f53\u5185\u7ec4\u7ec7\u56e0\u5b50\uff08\u5916\u6e90\u6027\u51dd\u8840\u7ea7\u8054\u53cd\u5e94\u7684\u5173\u952e\u542f\u52a8\u5b50\uff09\u7684\u4ea7\u751f\uff0c\u540c\u65f6\u4e0a\u8c03\u751f\u7406\u6027\u6297\u51dd\u7269\u8d28\u6d3b\u5316\u86cb\u767dC\uff08APC\uff09\u7684\u8868\u8fbe\uff0c\u51cf\u5c11\u5c0f\u9f20\u80ba\u90e8\u7ea4\u7ef4\u86cb\u767d\u6c89\u79ef\u53ca\u4f53\u5185\u8840\u6813\u5f62\u6210\u3002\u673a\u5236\u4e0a\uff0cOg-CATH\u9776\u5411\u9ad3\u6837\u5206\u5316\u86cb\u767d2\uff08MD2\uff09\uff0c\u6291\u5236\u8102\u591a\u7cd6\u8bf1\u5bfc\u7684\u5185\u76ae\u7ec6\u80de\u4e2dMyD88\u5411TLR4\u53d7\u4f53\u7684\u52df\u96c6\uff0c\u8fdb\u800c\u7f13\u89e3\u5185\u76ae\u5c4f\u969c\u529f\u80fd\u969c\u788d\u3002\u7efc\u4e0a\uff0c\u672c\u7814\u7a76\u8868\u660eOg-CATH\u4e3b\u8981\u901a\u8fc7\u8c03\u63a7\u541e\u566c\u7ec6\u80de\u4e0e\u5185\u76ae\u7ec6\u80de\u529f\u80fd\u53d1\u6325\u8113\u6bd2\u75c7\u4fdd\u62a4\u4f5c\u7528\u3002\u8fd9\u4e9b\u53d1\u73b0\u4e0d\u4ec5\u4e30\u5bcc\u4e86\u6211\u4eec\u5bf9\u975e\u6740\u83cc\u6027\u6297\u83cc\u80bd\u6297\u611f\u67d3\u673a\u5236\u7684\u8ba4\u8bc6\uff0c\u4e5f\u8bc1\u660e\u4e86Og-CATH\u662f\u8113\u6bd2\u75c7\u6cbb\u7597\u836f\u7269\u5f00\u53d1\u7684\u4f18\u826f\u5019\u9009\u5206\u5b50\u3002.\n\nID: 42482994\nTitle: Neutrophil-macrophage crosstalk network in acute lung injury: feedback circuits linking cytokine storm and cell death.\nAbstract: Neutrophils (NE) and macrophages (M\u00f8) are canonical cellular components of the innate immune defense and are involved throughout the course of acute lung injury (ALI). The crosstalk between these two cell types is pivotal for elucidating the complex mechanisms underlying inflammation. This review focuses on the bidirectional interactions between NE and M\u00f8 mediated by cytokines and phagocytosis. In addition, emerging concepts, including exosomes and migrasomes, are discussed to further delineate the role of NE in this crosstalk network. Certain pro-inflammatory cytokines amplify inflammation through cascade effects, ultimately leading to a cytokine storm. Pro-inflammatory and anti-inflammatory processes are dynamically coordinated and diverge at key regulatory nodes, forming multiple positive and negative feedback loops that collectively establish the inflammatory network model of ALI. The terminal outcome of this network is cell death, encompassing apoptosis, necroptosis, pyroptosis, and PANoptosis. By integrating the crosstalk network with cell death pathways, a more comprehensive regulatory framework is constructed, enabling an in-depth exploration of the molecular mechanisms underlying ALI.\n\nID: 42480930\nTitle: Effects of a blend of Saccharomyces cerevisiae fermentation-derived postbiotic and essential oil supplementation on the performance of transition dairy cows.\nAbstract: We aimed to evaluate the effects of a blend (PE) of Saccharomyces cerevisiae fermentation-derived postbiotics (SCFP) and essential oil compounds (EO) on performance, rumen fermentation profile, nutrient digestibility, nitrogen metabolism, blood metabolic profile and immune parameters in transition dairy cows from -35 d to 63 d postpartum. Sixty-two multiparous Holsteins, at 245 \u00b1 3 d of pregnancy, were assigned to control (CON; n = 31) or a blend of SCFP and essential oil compounds (PE; n = 31) in a randomized block design. Diets were formulated based on CNCPS guidelines. The treatment group was top-dressed with PE (25 g/d) on the ad libitum-fed TMR to individual cows. During the prepartum period, BCS and BW were measured weekly. For lactating cows, DMI, milk yield, and BW were recorded daily; milk samples were collected twice weekly for component analysis; and BCS was recorded weekly. Colostrum quality was measured using a Brix refractometer. Rumen fluid was collected at weeks -5, -2, and +2 for fermentation profile analysis. Fecal and urine samples were collected at weeks -4, -1, +2, +4, and +6 for digestibility and nitrogen metabolism analysis. Blood samples were collected on d -35, -28, -14, -7, +3, +7, +14, and +21 relative to calving. Data were analyzed using the GLIMMIX procedure in SAS using treatment, week, interactions, and block as fixed factors, while cows nested in treatment were used as a random factor. Significance was declared at P \u2264 0.05 with tendencies noted at 0.05 0.26). Fluticasone (10-8 and 10-6 M) significantly improved 24 h neutrophil survival and reduced early apoptosis (p < 0.05) but did not translate this survival benefit into enhanced efferocytosis. Salmeterol was cytotoxic at 10-4 M and inactive at 10-8-10-6 M. These findings indicate that the established anti-inflammatory benefits of ICS/LABA in COPD do not extend to augmentation of efferocytosis in this acute, serum-free in vitro setting and that pharmacological restoration of efferocytosis in COPD-a defect implicated in the pathogenesis and progression of comorbid lung cancer-will likely require strategies targeting the efferocytic machinery itself (e.g., MerTK, Rac-1, MFG-E8) rather than relying on current inhaled therapy.\n\nID: 42183253\nTitle: From anti-inflammation to pro-resolution: a new paradigm for specialized pro-resolving mediators in regulating neuroinflammation and repair after cerebral ischemia-reperfusion.\nAbstract: Uncontrolled neuroinflammation following cerebral ischemia-reperfusion is a core pathophysiological process driving secondary brain injury and leading to long-term neurological dysfunction. For decades, traditional \"anti-inflammatory\" strategies targeting the inhibition of key pro-inflammatory pathways have repeatedly failed in clinical translation, compelling a fundamental re-evaluation of the biological nature of inflammation. Inflammation is not a process that passively subsides upon stimulus removal but a dynamic one that requires active \"resolution\" through endogenous programs to restore tissue homeostasis. Within this precisely regulated program, a family of endogenous lipid mediators derived from polyunsaturated fatty acids-Specialized Pro-resolving Mediators (SPMs)-act as central executors. This review systematically proposes a translational framework for post-stroke inflammation management, shifting from traditional \"passive anti-inflammation\" to \"active pro-resolution.\" We first delve into the translational challenges and theoretical limitations of conventional anti-inflammatory therapies. Subsequently, we elaborate on the biosynthetic network of SPMs, their major families (lipoxins, resolvins, protectins, and maresins), and their pleiotropic biological functions, including halting neutrophil infiltration, reprogramming macrophage/microglial functions, enhancing the efficiency of apoptotic cell clearance (efferocytosis), and maintaining blood-brain barrier integrity. The central thesis of this review is that a key mechanism underlying the persistent neuropathological deterioration after cerebral ischemia-reperfusion is the failure of the endogenous inflammation resolution program, termed \"resolution dysfunction.\" By integrating mounting clinical evidence with extensive preclinical studies, this review provides a systematic argument for this hypothesis. Exogenous administration of SPMs or their stable analogs has demonstrated significant neuroprotective effects in various animal models, effectively reducing infarct volume and improving functional outcomes. Finally, this review explores the critical challenges in developing SPMs into novel stroke therapies, such as pharmacokinetics, therapeutic windows, and targeted delivery, and poses forward-looking questions for future research in the field. In summary, targeting and restoring the brain's endogenous inflammation resolution programs not only offers a promising new strategy for stroke treatment but also represents a profound practice of a disruptive therapeutic philosophy aimed at promoting the restoration of tissue homeostasis.\n\nID: 42167937\nTitle: Temporal In Vitro Models of Skin Wound Healing Components: A Cell-Specific Framework for Acute and Chronic Repair Mechanisms.\nAbstract: Wound healing is as much about opportunity (Gk. Karios) and sequence (Gk. Chronos). The sequential healing responses involve concerted responses of cells of various lineages along with both soluble (cytokines and growth factors) and insoluble (matrix composition and topology) that are precisely coordinated for ultimate healing. This motivated the current scoping review to examine the biological relevance and utility of current in vitro models of wound healing, focusing on specific cellular responses. We examined PubMed, Web of Science, and EBSCO of Science for the years 2020-2025, using keywords in vitro wound healing and individual cell type, namely epithelial cells, keratinocytes, fibroblasts, macrophages, platelets, and endothelial cells. This identified 126 relevant studies were selected and categorized by healing stage, cell types, and prototypical biological responses such as proliferation, migration, and lineage-specific functions. This analysis outlined the utility of a temporal framework to organize current in vitro models as acute-initial, early and late, and chronic-delayed. Existing two-dimensional and three-dimensional models focus on platelet function (hemostasis), neutrophil or macrophage chemotaxis and phagocytosis (inflammation), epithelium (closure), fibroblast (matrix synthesis, contraction), and endothelial (angiogenesis). While these models provide key insights into specific phases, cell functions, and molecular mechanisms, they do not fully replicate the integrated, multiorgan processes of wound healing observed in\u00a0vivo. Sequential combinations of these models lend themselves to the advances in artificial intelligence, machine learning, and robotic automation that are integral to developing prognostic and therapeutic wound care agents.\n\nID: 42148927\nTitle: Beyond first responders: neutrophils shape biomaterial-guided regeneration.\nAbstract: Neutrophils have long been regarded as short-lived effector cells responsible for clearing pathogens and inducing acute inflammation. However, emerging evidence has reshaped this paradigm, revealing remarkable neutrophil plasticity and their capacity to actively orchestrate tissue repair and regeneration. Neutrophils modulate angiogenesis, extracellular matrix (ECM) remodeling, macrophage polarization, and resolution of inflammation. Distinct neutrophil subsets-including pro-inflammatory and pro-resolving phenotypes-have been identified, highlighting their dynamic adaptation to microenvironmental cues. Notably, neutrophils contribute to vascular network formation through the release of matrix metalloproteinases, growth factors, reactive oxygen species (ROS), neutrophil extracellular traps (NETs), and specialized pro-resolving mediators (SPMs). In the context of biomaterial implantation, neutrophils are the first immune cells to interact with implanted devices, critically shaping the foreign body response (FBR) and influencing downstream regenerative outcomes. While early tissue engineering strategies aimed to suppress neutrophil recruitment, recent advances in immunomodulatory biomaterials seek instead to harness their plasticity. Approaches include promoting timely apoptosis and efferocytosis, regulating reactive oxygen species and NET formation, and directing neutrophil polarization toward pro-regenerative phenotypes. This review discusses current insights into neutrophil heterogeneity, their role in vascularization and tissue regeneration, and emerging biomaterial-based strategies designed to modulate neutrophil responses. Understanding and strategically directing neutrophil behavior may represent a pivotal step toward the development of next-generation regenerative therapies.\n\nID: 42143054\nTitle: Pharmabiotics, Phocaeicola dorei, ameliorates cholestatic liver fibrosis by alleviating macrophage efferocytosis of neutrophils.\nAbstract: Phocaeicola dorei has been reported to ameliorate metabolic diseases. Its role in liver fibrosis remains unclear. We evaluated the hepatoprotective effect of P. dorei in liver fibrosis. Fecal samples were collected from healthy controls and patients (n\u2009=\u2009285) to assess the clinical relevance of P. dorei. In male mice models (3,5-diethoxycarbonyl-1.4-dihydrocollidine [DDC] diet), P. dorei (109 CFU/g twice/week) was orally administered. Primary HSCs, LX-2, THP-1, and HL-60 cell lines were used for mechanical validation. The relative abundance of P. dorei increased with worsing liver disease in human. P. dorei administration significantly reduced neutrophil degranulation and efferocytosis pathways (Ly6g and F4/80). The dysregulated expression of neutrophil-associated chemokines (Cx3cl1 and Cx3cr1) was restored by P. dorei. P. dorei culture supernatant inhibited macrophage-mediated efferocytosis. P. dorei attenuates liver fibrosis by suppressing neutrophil and macrophage infiltration and disrupting efferocytosis. Our results identify P. dorei as a potential microbiome-based therapeutic candidate for cholestatic liver fibrosis.\n\nID: 42141116\nTitle: Toll-like receptor 7 constrains efferocytosis in myocardial injury.\nAbstract: Toll-like receptor 7 (TLR7) is an endosomal sensor of single-stranded RNA that is highly expressed in macrophages and contributes to post-infarct inflammation. Whether TLR7 also restrains macrophage reparative function, particularly efferocytosis and clearance of inflammatory debris, remain unclear. Using a murine model of myocardial ischemia-reperfusion (I/R) injury, we showed that TLR7 deficiency mitigated inflammation, reduced infarct size and alleviated adverse ventricular remodeling. Beyond its anti-inflammatory effects, TLR7 deficiency reprogrammed macrophages toward a reparative phenotype, characterized by decreased pro-inflammatory cytokine production and increased expression of anti-inflammatory mediators, including IL-10 and TGF-\u03b2, consistent with M2-like polarization. Single-cell RNA sequencing revealed a subset-specific mechanism in which TLR7 deficiency suppressed inflammatory signaling in M1 macrophages while enhancing efferocytosis-related pathways in M2 macrophages. This was accompanied by upregulation of key phagocytic receptors and machinery, including CD36, LRP1, MerTK, AXL and Rac1, and functionally translated into enhanced efferocytic capacity and reduced apoptotic burden. Notably, TLR7 deficiency also promoted macrophage-mediated clearance of neutrophil extracellular traps (NETs) without affecting NETosis, identifying a previously unrecognized role for TLR7 in regulating NET resolution. Consistent with these findings, NET formation was observed following myocardial injury in both murine I/R models and patients undergoing percutaneous coronary intervention.In conclusion, our data identify TLR7 as a macrophage-intrinsic checkpoint that limits efferocytosis and NET disposal, thereby impairing inflammation resolution after myocardial injury. Targeting TLR7 may therefore represent a therapeutic strategy to suppress excessive inflammation while restoring pro-resolving macrophage functions and improving cardiac repair.\n\nID: 42135533\nTitle: Resolution of Skeletal Muscle Inflammation: Role of Specialized Pro-resolving Lipid Mediators in the Recovery from Exercise, Injury, and Disease.\nAbstract: This chapter examines the resolution biology and pharmacology of skeletal muscle inflammation across the physiological contexts of exercise, acute injury, and chronic musculoskeletal disease. Central to these processes are specialized pro-resolving lipid mediators (SPMs), bioactive metabolites of omega-6 (n-6) arachidonic acid (ARA), omega-3 (n-3) eicosapentaenoic acid (EPA), and n-3 docosahexaenoic acid (DHA), formed by the coordinated action of mammalian lipoxygenase (LOX) enzymes. Unlike traditional anti-inflammatory mechanisms that passively dissipate, SPMs actively coordinate resolution by limiting polymorphonuclear neutrophil (PMN) infiltration, stimulating efferocytosis, and orchestrating the macrophage (M\u03a6) transition from a pro-inflammatory to a reparative phenotype. We explore how physical activity serves as a natural stimulus for these pathways, as acute resistance or endurance exercise triggers transient SPM biosynthetic circuits, while chronic training primes the immune system for enhanced resolution. A critical focus is placed on \"resolution-interference\" caused by nonsteroidal anti-inflammatory drugs (NSAIDs), which may delay repair by suppressing endogenous mediators and impairing muscle stem cell (satellite cell) activity. Furthermore, we review a significant paradigm shift involving the discovery that lipid mediator class switching is an intrinsic requirement for the myogenic differentiation program. By evaluating preclinical models of \"resolution deficit,\" including sarcopenia, muscular dystrophy, and volumetric muscle loss, we highlight the therapeutic potential of pharmacological \"immunoresolvents.\" Ultimately, leveraging these pathways represents a sophisticated therapeutic frontier that moves beyond simple inflammation suppression to directly drive stem cell-mediated muscle regeneration and functional recovery.\n\nID: 42123491\nTitle: Immunometabolism in Cardiac Remodeling: Mechanisms and Therapeutic Perspectives.\nAbstract: Cardiovascular diseases remain the leading cause of mortality worldwide, and one of the key mechanisms driving the development of heart failure is pathological remodeling of the myocardium. This process involves complex structural, cellular, and metabolic alterations in which the immune system and its interactions with cardiomyocytes and fibroblasts play a central role. The aim of this work was to present the current state of knowledge on immunometabolism in cardiac remodeling and to discuss its pathophysiological relevance and therapeutic potential. This review focuses on the metabolism of cardiac macrophages, highlighting the differences between the pro-inflammatory (M1) and reparative (M2) phenotypes and their impact on inflammation, fibrosis, and myocardial regeneration. The roles of major metabolic pathways, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, are discussed, as well as the importance of the NLRP3 inflammasome and efferocytosis in regulating the inflammatory response. Furthermore, the review briefly incorporates recent insights into neutrophil, T cell, and regulatory T cell (Treg) metabolism and their contributions to inflammation, repair, and fibrotic remodeling. Particular attention is also given to cardiac fibroblasts and their metabolic reprogramming during fibrosis, with emphasis on the pivotal role of transforming growth factor-\u03b2 (TGF-\u03b2) signaling. The review further discusses the role of microRNAs as mediators of intercellular communication integrating immunological and metabolic signals. The work is complemented by a discussion of therapeutic perspectives, including modulation of macrophage metabolism, fibrogenic signaling pathways, mitochondrial function, and miRNA-based therapies. Immunometabolism emerges as a promising research field whose further exploration may contribute to the development of novel, more precise strategies for the treatment of cardiovascular diseases.\n\nID: 42099533\nTitle: Biomaterials Promote the Regression of Atherosclerotic Plaque by Regulating Cell Behavior.\nAbstract: Atherosclerosis is characterized by the deposition of lipid within arterial walls, precipitating the initiation and progression of atherosclerotic lesions. Over time, these plaques enlarge and rupture, initiating thrombosis cascades that pose significant risks to patient safety. Conventional therapies, including 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (eg, statins) and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, predominantly target lipid reduction while overlooking the intricate microenvironment within atherosclerotic plaque. Statins possess limited lipid-lowering efficacy and may even exhibit insensitivity or intolerance in patients. While PCSK9 inhibitors, as adjuvant therapy, demonstrate potent lipid-lowering effects, they fail to further stabilize vulnerable plaques. In contrast, biomaterials have emerged as pivotal tools for addressing unstable plaques. By restoring endothelial cell (EC) function, inhibiting neutrophil activation, modulating macrophage behavior, and preventing the phenotypic transformation of smooth muscle cells, biomaterials effectively promote plaque regression. This review explores the pathogenesis of atherosclerosis and highlights recent advancements in biomaterial-based therapies for vulnerable plaques, aiming to offer novel insights and solutions to this pressing global health challenge.\n\nID: 42067150\nTitle: Uncovering immune dysfunction in ACLF: Cellular mechanisms, molecular pathways, and therapeutic frontiers.\nAbstract: Acute-on-chronic liver failure (ACLF) is a life-threatening condition characterised by acute hepatic decompensation, multi-organ failure, and high short-term mortality in patients with cirrhosis. A hallmark of ACLF is profound immune dysfunction, which contributes to excessive organ-specific inflammation and impaired host defence, predisposing patients to infection, multi-organ failure and death. This review aims to elucidate the cellular and molecular mechanisms implying systemic immune dysfunction in ACLF, highlighting key pathophysiological pathways and their clinical significance. We provide an overview of ACLF, including its global clinical impact, in the context of immune dysfunction as a central driver of disease pathogenesis. The discussion focuses on alterations in innate immunity, including impaired neutrophil and monocyte phagocytosis, excessive neutrophil extracellular trap (NET) formation, and monocyte/macrophage dysfunction, which contribute to immuneparesis and exaggerated inflammation in an organ-specific manner. Also, dysregulation of natural killer (NK) cell cytotoxicity and adaptive immune dysfunction, including changes in T-cell subpopulations and B-cell antibody production in ACLF, are adressed. We further dissect the emerging evidence of molecular pathways driving dysfunction of immune cells and their impaired ability to control infections in ACLF, emphasising the roles of pathogen- and damage-associated molecular patterns (PAMPs/DAMPs), toll-like receptor (TLR) signalling, oxidative stress, mitochondrial dysfunction, epigenetic/metabolic reprogramming and immune checkpoint molecules. In addition, the review explores immune cell communication within the innate and adaptive immune systems, as well as interactions with parenchymal and non-parenchymal cells across organs affected by ACLF. Particular attention is given to inter-organ crosstalk involving the liver, circulation, brain, gut, and kidney. Finally, we summarise recent preclinical and clinical advances in biomarkers of immune dysfunction and immunomodulatory therapeutic strategies aimed at restoring immune homeostasis in patients with ACLF.\n\nID: 42054454\nTitle: A robust adhesive microneedle for oral infections therapy via synergistic antibacterial and neutrophil-macrophage axis immunomodulation.\nAbstract: Oral infectious diseases are challenging to treat, as conventional therapies struggle to maintain effective drug levels and simultaneously address both infection and immune dysregulation. To address this, we developed a mussel-inspired microneedle patch (PCA@FeCO MN) by incorporating Fe3(CO)12 into a caffeic acid-grafted polyvinyl alcohol network. This design overcomes existing barriers through a dual-adhesion mechanism: a catechol-metal coordination network for strong chemical bonding and an optimized taper geometry for mechanical interlocking in wet oral tissues. Upon near-infrared irradiation, PCA@FeCO MN activates a photothermal-ferroptosis-gas therapy cascade, synergistically eradicating pathogens. Crucially, this strategy also disrupts the inflammation cycle by steering neutrophils toward function activation, timely apoptosis and boosting macrophage efferocytosis. In both rat and beagle dog models of oral infections, PCA@FeCO MN achieved robust tissue adhesion, highly efficient synergistic antibacterial activity, and precise immunomodulation, demonstrating its promising therapeutic potential for future clinical translation.\n\nID: 42047332\nTitle: Exploiting autophagy-targeting natural compounds for potential antimicrobial actions.\nAbstract: Natural products are biologically active compounds used for therapeutic interventions for various diseases, particularly infections. Autophagy is an intracellular catabolic pathway involving lysosomal degradation and is closely associated with immunological pathways, effectively combating bacterial, viral, fungal, and parasitic infections. Accumulating evidence suggests that autophagy activation or inhibition by natural products promotes antimicrobial responses against various pathogens. Numerous natural products can modulate autophagy through diverse signaling pathways, suggesting their potential as a host-directed therapeutic strategy that may complement conventional drug regimens or help mitigate drug resistance in various infectious diseases. However, it remains largely unclear whether these effects are mediated by direct modulation of autophagy or indirectly through associated mechanisms, including enhanced immune defense, attenuation of pathological inflammation, or crosstalk with other organelle functions. Additionally, multiple pathogens can evade host responses; thus, autophagy activation may inadvertently create favorable conditions for certain pathogens. This review discusses the current knowledge of natural products in terms of their antimicrobial actions through autophagy regulation, particularly the roles of distinct natural product classes, such as polyphenols, alkaloids, terpenoids, quinones, peptides, and macrolides in modulating autophagy for potentially contributing to control various infectious diseases. Exploring the intricate molecular interplay between natural products and autophagy in limiting infections may provide valuable insights that could inform the development of innovative host-directed antimicrobial treatments based on autophagy regulation.Abbreviations: 3-MA: 3-methyladenine; AM: alveolar macrophages; AMP: antimicrobial peptides; AMPK: 5' adenosine monophosphate-activated protein kinase; ARDS: acute respiratory distress syndrome; ART: artemisinin; ASFV: African swine fever virus; ATG: autophagy related; AZM: azithromycin; BafA1: bafilomycin A1; BECN1: beclin 1; BMDM: bone marrow-derived macrophage; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2; CBD: cannabidiol; CF: cystic fibrosis; CGA: chlorogenic acid; CGAS: cyclic GMP-AMP synthase; CHUK/IKK\u03b1: component of inhibitor of nuclear factor kappa B kinase complex; CLP: cecal ligation and puncture; CLR: clarithromycin; CMA: chaperone-mediated autophagy; CoV: coronavirus; DHT: dihydrotanshinone I; EGCG: epigallocatechin-3-gallate; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK2: eukaryotic translation initiation factor 2 alpha kinase 2; ESKAPE: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.; ESRRA: estrogen related receptor alpha; FOXO1: forkhead box O1; FUNDC1: FUN14 domain containing 1; HBV: hepatitis B virus; HCV: hepatitis C virus; HDT: host-directed therapy; HIV: human immunodeficiency virus; HMGB1: high mobility group box 1; HSV: herpes simplex virus; IAV: influenza A virus; ICT: isocryptotanshinone; IFN: interferon; IKBKB/IKK\u03b2: inhibitor of nuclear factor kappa B kinase subunit beta; IL: interleukin; INH: isoniazid; IRF3: IFN regulatory factor 3; KEAP1: kelch like ECH associated protein 1; LAMP: lysosomal associated membrane protein; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDM: monocyte-derived macrophage; MDR: multidrug-resistant; MON: monotropein; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin kinase; mtROS: mitochondrial ROS; NET: neutrophil extracellular trap; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; NFKB/NF-\u03baB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; NLRX1: NLR family member X1; NOTCH1: notch receptor 1; NTM: nontuberculous mycobacteria; OMS: ohmyungsamycin; PAK1: p21 (RAC1) activated kinase 1; PINK1: PTEN induced kinase 1; PKM/PKM2: pyruvate kinase M1/2; PLD: phospholipase D; PM: peritoneal macrophage; PPM1A: protein phosphatase, Mg2+/Mn2+ dependent 1A; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RELA/p65: RELA proto-oncogene, NF-kB subunit; RIF: rifampicin; ROS: reactive oxygen species; RSV: resveratrol; RUBCN/rubicon: rubicon autophagy regulator; SAR: selective autophagy receptor; SIRT: sirtuin; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; Tat: trans-activator of transcription; TB: tuberculosis; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TLR: toll like receptor; TNA: tanshinone IIA; TNF: tumor necrosis factor; UA: ursolic acid; ULK1/Atg1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; UVRAG: UV radiation resistance associated; VAMP8: vesicle associated membrane protein 8; VDR: vitamin D receptor; WIPI2: WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1; ZIKV: Zika virus.\n\nID: 42041175\nTitle: Corneal Nerves Promote Alkali Burn Repair by Modulating Macrophages and Neutrophils via Calcitonin Gene-Related Peptide.\nAbstract: This study aims to investigate the role of calcitonin gene-related peptide (CGRP) in corneal tissue repair in alkali burn and its underlying neuro-immune mechanisms. Mouse corneal nerves were ablated via surgery or resiniferatoxin (RTX) to study their role in tissue healing after an alkali burn. CGRP and its receptor levels were quantified by Western blot and quantitative PCR (qPCR). Alkali-burned corneas were treated topically with CGRP or BIBN-4096. Tissue repair, inflammatory cytokine expression, and immune cell infiltration were subsequently assessed. Macrophages were depleted using PLX5622 to evaluate their effect on healing. Furthermore, mouse macrophages and neutrophils were cultured in vitro, and transcriptomic analysis was performed to elucidate functional and molecular alterations, which were validated experimentally. Corneal nerve ablation significantly delayed corneal alkali burns healing. In alkali burns, corneal nerves released CGRP, leading to elevated CGRP levels in the cornea. Topical CGRP application promoted tissue repair and reduced inflammation, whereas its antagonist BIBN-4096 impeded healing. Macrophage depletion not only delayed repair but also abolished the therapeutic effect of CGRP, indicating that macrophages are crucial for CGRP-mediated repair. Mechanistically, CGRP promoted neutrophil apoptosis and enhanced macrophage apoptosis, efferocytosis, and anti-inflammatory functions via the cAMP-TSP-1 pathway, thereby facilitating tissue repair. This study reveals that in corneal alkali burns, corneal nerves promote tissue repair by secreting CGRP to regulate neuro-immune interactions, providing new insights for the treatment of corneal alkali burns.\n\nID: 42040217\nTitle: Hybrid nanovesicles promote diabetic wound healing via dual-targeted multimodal therapy.\nAbstract: Diabetic wounds remain difficult to treat due to persistent oxidative stress, chronic inflammation, and vascular dysfunction. These factors reinforce each other, forming a vicious cycle that leads to delayed healing, poor angiogenesis, and high amputation risk. Existing therapies often fail because they are unable to address these challenges simultaneously. Therefore, this study aimed to develop a hybrid extracellular vesicle system that targets these multiple barriers concurrently to promote diabetic wound healing. A biohybrid nanovesicle system (DFO@HEVs) was built by fusing endothelial cell-derived extracellular vesicles with neutrophil-derived nanovesicles (forming hybrid extracellular vesicles, HEVs), which were loaded with deferoxamine (DFO). The vesicles were tested for their physicochemical properties, drug loading, and safety. Therapeutic effects were studied in vitro using HG/PA-stimulated endothelial cells and macrophages and in vivo in diabetic mouse wounds. The analyses included microscopy, flow cytometry, histology, transcriptomics, and database-based single-cell RNA sequencing. DFO@HEVs showed dual targeting: homing to endothelial cells via CXCR4 and to inflamed sites via \u03b22 integrin. They enhanced endothelial uptake, promoted angiogenesis through PI3K/AKT/HIF-1\u03b1 and VEGF signaling pathways, and reduced oxidative stress and ferroptosis by activating Nrf2 and upregulating antioxidant genes. They also shifted macrophages toward an anti-inflammatory M2 phenotype, boosted efferocytosis, and suppressed NF-\u03baB/NLRP3-driven inflammation. In diabetic mice, treatment with DFO@HEVs accelerated wound closure, re-epithelialization, collagen deposition, and new vessel formation, while lowering neutrophil infiltration, reactive oxygen species levels, ferroptosis, and pro-inflammatory cytokines, creating a healing-supportive environment. DFO@HEVs provided a hybrid nanovesicle system for combined membrane and drug delivery. By promoting angiogenesis, limiting ferroptosis, and resolving inflammation, they disrupted the cycle that prevented diabetic wound repair. This approach shows a strong potential as a new treatment for chronic wounds.\n\nID: 42011203\nTitle: Polysaccharide-engineered mitochondria reprogram macrophages to resolve diabetic wound inflammation and promote repair.\nAbstract: Chronic diabetic wounds are characterized by persistent inflammation, defective resolution and impaired tissue regeneration, in which macrophage dysfunction and mitochondrial damage play central roles. Here, we developed a macrophage-targeted engineered mitochondrial transplantation system by coating adipose-derived stem cell (ADSC) mitochondria with triphenylphosphonium-modified konjac glucomannan (Mito-TPP-KGM). This design preserves mitochondrial membrane potential and ATP production while reducing ROS generation, and provides a mannose-rich corona for lectin receptor-related uptake. In RAW264.7 macrophages exposed to high glucose plus H2O2 or LPS, Mito-TPP-KGM is efficiently internalized, restores mitochondrial homeostasis, rebalances glycolysis and oxidative phosphorylation, and shifts inflammatory profiles toward a less inflammatory and more reparative phenotype. Engineered mitochondria also restore efferocytosis of apoptotic neutrophil-like cells and enhance the pro-angiogenic capacity of macrophage-conditioned media, thereby improving endothelial tube formation, migration and proliferation. Blocking experiments with mannan and anti-CD206/anti-DC-SIGN antibodies, together with species-specific mtDNA quantification, indicate that mannose-type lectin receptors contribute to the uptake and immunomodulatory effects of Mito-TPP-KGM. In a db/db mouse full-thickness wound model, local delivery of Mito-TPP-KGM promotes wound repair, improves histological healing, reduces oxidative damage, enhances angiogenesis, and modulates wound macrophage phenotype, leading to accelerated wound closure; these therapeutic benefits are partially attenuated by local CD206 blockade. Collectively, these findings demonstrate that polysaccharide-engineered mitochondria can reprogram diabetic wound macrophages via targeted mitochondrial transplantation, offering a promising immunometabolic strategy for chronic wound therapy.\n\nID: 41997054\nTitle: Deciphering transcriptome alterations in bone marrow immune cells at single-cell resolution under denosumab treatment.\nAbstract: Denosumab, an anti-RANKL antibody, effectively inhibits bone resorption, increases bone mass, and reduces fracture risk; however, its immunomodulatory effects raise concerns about possible immune imbalances during the treatment. Given the key role of bone marrows in immune cell development, this study aimed to evaluate alternations in the bone marrow osteoimmune microenvironment under denosumab treatment. Adult female mice were administered 10\u00a0mg/kg anti-RANKL antibody via intraperitoneal injections twice weekly for 4\u00a0weeks. Bone marrow cells from both treated and control mice were analyzed via single-cell RNA sequencing (scRNA-seq) to characterize cell-type-specific changes. Shifts in cell populations were validated using single-cell flow cytometry and immunofluorescence. Transcriptomic profiling identified 10 distinct bone marrow cell clusters under the anti-RANKL antibody treatment. The anti-RANKL antibody treatment resulted in an increase proportion of neutrophils and B lymphocytes, with a concomitant decrease in T lymphocytes. These changes were validated by single-cell flow cytometry and immunofluorescence. Among neutrophils, the Mmp8hi mNeu subset showed the greatest expansion and activated neutrophil extracellular trap (NET) formation in the anti-RANKL antibody-treated group. Furthermore, elevated Mmp8hi mNeu interacted with macrophages via the THBS1-CD36 signaling pathway, suggesting a role in modulating macrophage polarization under anti-RANKL antibody treatment. Anti-RANKL antibody induces notable alterations in the bone marrow osteoimmune microenvironment, including expansion of Mmp8hi mNeu and altered lymphocyte composition. These findings underscore the need for further investigation into the impact of Mmp8hi mNeu and neutrophil-macrophage interactions on immune balance during denosumab treatment. This study presents a potential therapeutic target for mitigating the immune-related adverse effects in osteoporosis management.\n\nID: 41987271\nTitle: Repetitive trans-spinal magnetic stimulation promotes repair in inflammatory spinal cord injury through sex-dependent immune modulation.\nAbstract: Spinal cord injuries (SCI), whether traumatic or inflammatory such as transverse myelitis (TM), are characterized by severe neuroinflammation, demyelination, and long-term disabilities. Current treatments remain limited, highlighting the need for novel non-invasive therapeutic approaches. Repetitive magnetic stimulation (RMS) has emerged as a promising strategy, but its mechanisms and efficacy in inflammatory contexts remain poorly described. Here, we investigated the effects of RMS applied as trans-spinal RMS (rTSMS) in a mouse model of focal spinal cord demyelination induced by lysophosphatidylcholine (LPC). When applied one day after LPC injection, rTSMS reduced inflammation, demyelination, and fibroglial scar formation, while promoting early locomotor recovery in both sexes. In contrast, when treatment was initiated three days after LPC injection, corresponding to the peak of motor deficits, rTSMS conferred tissue protection and functional benefits only in female mice. RNA sequencing analyses revealed sex-dependent immune modulation: in females, rTSMS primarily regulated adaptive T cell-related pathways, whereas in males, it mainly targeted innate immune responses such as neutrophil activity and phagocytosis. Complementary in vitro experiments using microglial and macrophage cultures further demonstrated that RMS modulates transcriptomic responses differently depending on cell type and inflammatory state. Specifically, RMS attenuated IL-1-induced pro-inflammatory signaling in macrophages and completely abolished these effects in microglia. Altogether, our findings establish rTSMS as a non-invasive therapy capable of reducing neuroinflammation and demyelination in inflammatory SCI, with pronounced sex-dependent effects. By uncovering distinct immune pathways engaged in male and female mice, this study provides mechanistic insights into rTSMS action and opens perspectives for its translational use in neuroinflammatory diseases.\n\nID: 41922994\nTitle: Time-associated phenotypic changes related to virulence and immune interaction of Staphylococcus aureus during relapsing infection within individual hosts.\nAbstract: Staphylococcus aureus is a major cause of relapsing infection. However, how its phenotypic traits change over time within individual hosts during relapsing infection remains incompletely characterized. In this study, we analyzed five longitudinal S. aureus isolates obtained from two patients with relapsing infection to investigate within-host phenotypic and genomic changes. Whole-genome sequencing was combined with a series of phenotypic assays, including antimicrobial susceptibility testing, erythrocyte lysis assays, whole-blood survival assays, neutrophil extracellular trap (NET) degradation analysis, growth curve determination, antibiotic time-kill assays with levofloxacin, and macrophage phagocytosis and intracellular survival in iBMDMs and murine bloodstream infection models. Isolates recovered from each patient were clonally related (ST630/t377 and ST239/t030). Across both clinical trajectories, later isolates showed reduced in vitro growth. Virulence-associated readouts changed over time, including reduced erythrocyte lysis and lower mouse mortality for later isolates in one patient, whereas changes were not uniform between patients. Later isolates displayed improved survival in whole blood, and sequential isolates from one patient showed qualitatively increased NET-degrading activity. Antimicrobial susceptibility profiles remained largely stable, but time-kill assays indicated incomplete eradication under levofloxacin exposure, and later isolates exhibited reduced macrophage phagocytosis and increased intracellular survival. Our findings suggest that S. aureus isolates recovered sequentially from individual patients may undergo coordinated, time-associated phenotypic changes during relapsing infection. These observations provide insight into time-associated phenotypic variation of S. aureus during relapsing infection within individual hosts.\n\nID: 41919324\nTitle: Itaconate as a Potent Regulator of Neutrophil Responses in Host Defence and Inflammation.\nAbstract: Itaconate, derived from cis-aconitate decarboxylation by immune-responsive gene 1 (IRG1; also called cis-aconitate decarboxylase 1, ACOD1), is an intermediate metabolite of the tricarboxylic acid (TCA) cycle in the mitochondria. The production of itaconate in myeloid cells is rapidly increased to high levels in pathological conditions, such as infection and cancer. It is well known that itaconate plays an essential role in regulating macrophage-mediated inflammation and immune response through multiple mechanisms, such as regulating signal transduction and protein modification. As the first responders upon infections and injuries, neutrophils contribute to pathogen clearance and inflammation by several mechanisms, such as phagocytosis, producing reactive oxygen species (ROS), and forming neutrophil extracellular traps (NETs). Increasing evidence shows that neutrophils can also produce itaconate, which in turn modulates neutrophil activation, thereby affecting the elimination of pathogens, the resolution of inflammation, and tumour progression. In this review, we summarize the recent advancements in understanding the effects of endogenous itaconate and its derivatives on neutrophil responses, with a focus on the underlying mechanisms and potential therapeutic applications in infectious and inflammatory diseases.\n\nID: 41887381\nTitle: Shengxian decoction mitigate bleomycin-induced pulmonary fibrosis in mice via MerTK mediated macrophage efferocytosis.\nAbstract: Shengxian Decoction (SXD) is a classical multi-herb prescription widely used in traditional Chinese medicine for chronic respiratory ailments. However, its pharmacological rationale and pro-resolving actions in idiopathic pulmonary fibrosis (IPF) have not been fully clarified. This study investigated the anti-fibrotic efficacy of SXD in a bleomycin (BLM)-induced mouse model and explored whether MerTK-dependent macrophage efferocytosis contributes to SXD-driven resolution. Pulmonary fibrosis was induced by BLM in male C57BL/6 mice. Animals received SXD at two doses, with nintedanib (Nin) as a comparator; MerTK signaling was pharmacologically inhibited with UNC 2025. Disease severity was evaluated by survival and body-weight changes, histology (H&E, Masson's trichrome, Sirius Red), immunostaining (\u03b1-SMA, Ly6G, F4/80, CD68, MerTK), and molecular assays (RT-qPCR, ELISA, Western blot). SXD constituents were profiled by LC-MS. Candidate targets/pathways were explored via network pharmacology and lung transcriptomics (RNA-seq). Macrophage efferocytosis was quantified in lung sections (TUNEL/CD68) and in vitro using BALF-derived macrophages co-cultured with fluorescently labeled apoptotic neutrophils. SXD mitigated BLM-induced fibrosis, improving survival and limiting weight loss, while reducing Ashcroft scores, collagen accumulation, \u03b1-SMA production, and profibrotic factors (including Tgf-\u03b2, Pdgf-\u03b1, and Mmp12); the high-dose regimen produced the most pronounced benefit. SXD also blunted early inflammation by decreasing Ly6G+ neutrophil and F4/80+ macrophage recruitment and lowering TNF-\u03b1, IL-6, and IL-1\u03b2. LC-MS revealed a chemically complex formulation enriched in terpenoid components, and integrative network/RNA-seq analyses implicated multiple inflammation-fibrosis signaling programs. Mechanistically, SXD enhanced macrophage efferocytosis and increased MerTK and IL-10 expression; these pro-resolving and anti-fibrotic effects were predominantly abolished when MerTK was inhibited using UNC 2025. SXD conferred multi-target protection in BLM-induced pulmonary fibrosis and promoted resolution by enhancing macrophage apoptotic-cell clearance through a MerTK-dependent mechanism, which supported its translational potential for the intervention of IPF.\n\nID: 41873998\nTitle: Clues to Long COVID Linked to Virulence and Infectivity Found in Shell Proteins.\nAbstract: Clinical, experimental, and computational evidence of COVID-19 virulence and infectivity has been linked to SARS-CoV-2 shell disorder. A strong link was first discovered using an AI disorder-predicting tool, which detected an unusually hard (low disorder) outer shell among all SARS-CoV-2-related viruses but not in the 2003 SARS-CoV-1. This could account for the high infectivity found in SARS-CoV-2-but not in SARS-CoV-1-as it is believed that hard shells protect viral particles from the onslaught of the antimicrobial enzymes present in the respiratory system and saliva. As a result, much larger quantities of particles are shed by COVID-19 patients. Abnormally hard outer shells (M) are associated with burrowing animals, e.g., pangolins, and SARS-CoV-2 likely acquired these shells due to its long-term evolutionary interactions with pangolins. As for virulence, the inner shell of SARS-CoV-2 (N) has been found to exhibit lower disorder than that of SARS-CoV-1. This lower disorder is consistent with the fact that SARS-CoV-2 is less virulent than SARS-CoV-1, as higher disorder in the inner shell is associated with more efficient protein-protein binding during replication. The link between N/M disorder and virulence or infectivity falls under the umbrella of shell disorder models (SDMs), which can connect virulence, infectivity, and long COVID under one coherent concept. Evidence of the reliability and reproducibility of SDMs as applied to COVID-19 is examined. The hard M that is resisting the antimicrobial enzymes in the respiratory system can be extended to immunological enzymes, especially those found in phagocytes such as macrophages, which can therefore become a reservoir for the virus.\n\nID: 41857730\nTitle: The ErbB-tyrosine kinase inhibitor, neratinib, has anti-inflammatory effects in multimorbidity by increasing macrophage efferocytosis via the upregulation of MerTK.\nAbstract: BACKGROUND: Chronic inflammatory disease is responsible for huge and increasing global mortality and morbidity. Unregulated inflammatory cells, including neutrophils and macrophages, are major drivers of chronic inflammatory disease. Efferocytosis plays a critical role in inflammation resolution by removing effete inflammatory cells from tissues. Despite defective efferocytosis being critical in inflammatory disease progression there are no therapies to correct these defects in clinical use. Here, using experimental models of atherosclerosis and lung injury, we identify the ErbB family tyrosine kinase inhibitor (TKI), neratinib, as a putative efferocytosis-targeting therapy. RESULTS: In an experimental model of atherosclerosis and lung injury, two doses of neratinib significantly increased efferocytosis in the lungs of mice concomitant with a reduction in the proportion of lung neutrophils. Neratinib significantly increased human neutrophil apoptosis and efferocytosis of apoptotic neutrophils by monocyte-derived macrophages (MDMs). In addition to increased efferocytosis, neratinib treated macrophages demonstrated both increased phagocytosis and macropinocytosis. Neratinib increased MDM surface expression of the efferocytosis receptor MerTK independent of protein synthesis and transcription which correlated with elevated efferocytosis in MDMs and inhibitors of MerTK blocked neratinib-induced efferocytosis. CONCLUSIONS: Thus, we describe a novel role for neratinib in driving efferocytosis in multimorbidity and suggest that ErbB TKIs may have therapeutic potential in inflammatory disease by restoring macrophage function and promoting inflammation resolution.\n\nID: 41855258\nTitle: Elucidation of a potent pro-resolving mediator of inflammation resolution via human neutrophil-vascular endothelial cell interactions.\nAbstract: The acute inflammatory response is a highly coordinated programmed sequence that enables neutrophils to transmigrate from venules into tissues. Ideally self-limited, the active resolution phase produces specialized molecules that stimulate resolution and prevent collateral tissue damage from excessive neutrophil infiltration. The superfamily of pro-resolving molecules is termed specialized pro-resolving mediators including the essential polyunsaturated fatty acid-derived lipoxins, resolvins, protectins, and maresins. Given the intimate interactions between leukocytes and endothelial cells in inflammation resolution, we investigated whether unique bioactive molecules carrying pro-resolution properties are biosynthesized by human neutrophils coincubated with activated vascular endothelial cells. Using metabololipidomics, we found that human coronary aortic valves from transplants contained 13-hydroxy-4Z,7Z,10Z,14E,16Z,19Z-docosahexaenoic acid (13-HDHA) and inflammatory eicosanoids. We report that human endothelial cells convert DHA to 13-HDHA which in turn is transformed by human neutrophils to a previously unknown bioactive product 4,13-dihydroxy-docosahexaenoic acid. This structure was established using physical properties including tandem-mass spectrometry, UV-analysis, and conversion of deuterated substrate. Biosynthesis of this product during neutrophil-endothelial coincubations involved bidirectional crosstalk between neutrophil 5-LOX and endothelial COX-2 as confirmed using isolated recombinant enzymes. The bioactive 4S,13R-dihydroxy-5E,7Z,10Z,14E,16Z,19Z-docosahexaenoic acid, also produced by M2-like macrophages and mononuclear cells, demonstrated potent nanomolar pro-resolving actions including, a) limiting neutrophil infiltration into mouse air pouch, b) reducing human neutrophil adherence to endothelial cells, c) protecting endothelial cell from senescence, and d) stimulating human macrophage efferocytosis of senescent red blood cells. These results provide evidence for a previously unknown pro-resolving pathway and molecule biosynthesized from DHA via cyclooxygenase-2-5-lipoxygenase during leukocyte crosstalk with the vasculature.\n\nID: 41823322\nTitle: Neutrophil extracellular traps aggravate lung injury by inducing pyroptosis of alveolar macrophages.\nAbstract: Neutrophil extracellular traps (NETs) contribute to chronic obstructive pulmonary disease (COPD) pathogenesis by amplifying airway inflammation. Gasdermin D (GSDMD)-mediated pyroptosis is a critical driver of COPD progression. This study provides insights into COPD pathogenesis and provides a theoretical basis for potential therapeutic targets. Mice were exposed to cigarette smoke (CS) for 16\u2009weeks to establish a COPD model. In vitro, alveolar macrophages (AMs) (MH-S) and alveolar epithelial cells (MLE-12) were treated with cigarette smoke extract (CSE). Subsequently, NETs were isolated from phorbol-12-myristate-13-acetate (PMA)-stimulated neutrophils. Lung histopathology, inflammatory markers, and pyroptosis-related proteins were analyzed. Co-immunoprecipitation analysis was used to verify the binding of GSDMD and ubiquitin molecules in cells. Interventions included DNase1 to degrade NET and GSDMD knockdown. In CS-exposed mice, NETs increased the levels of proinflammatory cells and mediators, and lung structure was further disrupted. Pyroptosis of AMs was increased, while phagocytosis of AMs was inhibited. However, treatment with DNAse1 partially reversed the results caused by CS exposure and NET induction. Consistently, NETs aggravated inflammatory response and pyroptosis in the CSE-induced MH-S cell model. Furthermore, NETs significantly caused an increase in ROS, which promoted the activation of GSDMD deubiquitination and subsequent pyroptosis pathway in AMs. DNase1 treatment or GSDMD silencing attenuated pyroptosis, reduced inflammatory mediators, and improved lung function. NETs aggravated CS-induced lung inflammation and injury by activating GSDMD to promote pyroptosis in AMs. Targeting GSDMD or NETs represents a novel therapeutic strategy for COPD. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n\nID: 41789514\nTitle: Piezoelectric Ceramic Nanofiber Aerogels Direct Neutrophil Fate for Diabetic Tissue Regeneration.\nAbstract: The dysregulation of neutrophil death pathways constitutes a critical barrier to diabetic tissue regeneration, in which pyroptosis perpetuates chronic inflammation while apoptosis promotes tissue homeostasis. However, achieving reliable control over neutrophil death patterns to tune inflammation and repair processes remains a major challenge. Here, we develop a multifunctional aerogel scaffold based on piezoelectric ceramic nanofibers to synergistically direct neutrophil fate. Specifically, (K,Na)NbO3 piezoceramics are incorporated into gelatin/polylactic acid nanofiber membranes, homogenized via high-speed fragmentation, and freeze-dried to form a porous aerogel scaffold. Conjugation with the retinoid derivative peretinoin yields the final piezoelectric ceramic nanofiber aerogel (KAP). Peretinoin released from KAP suppresses caspase-3-mediated cleavage of gasdermin E (GSDME), switching neutrophil death from pyroptosis to apoptosis. Meanwhile, upon ultrasound activation, KAP generates surface potentials to enhance macrophage phagocytic capacity via calcium influx and lysosomal acidification. This dual mechano-chemical approach promotes efferocytosis and reprograms macrophages toward a pro-regenerative phenotype, thereby breaking the cycle of chronic inflammation in diabetic microenvironments. In diabetic rodent models, KAP significantly accelerates the healing of both soft and hard tissues. This study presents a piezoelectric ceramic nanofiber aerogel that offers a potential therapeutic approach for diabetic tissue regeneration.\n\nID: 41778891\nTitle: The CNC-bZIP transcription factor Nrf2 controls expression of matrix metalloproteases in murine macrophages.\nAbstract: Liver fibrosis is a chronic condition that often leads to organ failure. Currently, no effective treatment exists for advanced liver fibrosis. De-repression of the transcription factor Nrf2, by inhibition of the ubiquitin ligase substrate adaptor Keap1, is a promising strategy to treat liver fibrosis because Nrf2 augments cytoprotection and blunts the profibrotic TGF-\u03b2 pathway. Herein, Nrf2 is reported to control matrix metalloproteinase (MMP) expression during chronic liver injury, and more specifically in macrophages, which play a key role in the resolution of fibrosis. We found impaired expression of Mmp8, Mmp9, Mmp12, and Mmp14 in the livers of Nrf2-knockout (Nrf2-ko) mice compared to wild-type (WT) mice, both basally and following CCl4 damage. Investigation of bone-marrow-derived macrophages (BMDMs) revealed profoundly impaired expression of Mmp8 and Mmp12 in Nrf2-ko BMDMs and a concomitant hyper-expression in Keap1-knockdown (Keap1-kd) BMDMs, which were corroborated by siRNA knockdown of Nrf2 and macrophage-specific conditional knockout of Nrf2. This trend was observed under basal conditions and post-efferocytosis. Total MMP activity was also found to be highest in the conditioned medium of Keap1-kd post-efferocytosis BMDMs. ChIP-seq revealed Nrf2-binding sites upstream of Mmp12, which also showed the strongest expression response to Nrf2. Lastly, through pharmacological de-repression of Nrf2, using TBE-31 to inhibit Keap1, upregulation of MMP expression was observed in BMDMs and livers of mice following acute liver injury. In conclusion, Nrf2 has been shown to be a regulator of MMP expression and activity in stimulated macrophages, which reveals a new mechanism by which Nrf2 regulates macrophage function.\n\nID: 41738282\nTitle: Irgm1 Improves Postinfarction Cardiac Repair by Promoting Neutrophil Clearance and Efferocytosis.\nAbstract: Delayed neutrophil clearance after myocardial infarction (MI) significantly disrupts the myocardial microenvironment, but the underlying mechanisms remain unclear. Macrophage-mediated efferocytosis of infiltrating neutrophils is crucial for resolving inflammation and restoring homeostasis post-MI. However, the specific regulatory mechanisms governing neutrophil clearance and efferocytosis remain undefined. This study demonstrates a significant correlation between increased IRGM expression in peripheral blood neutrophils of patients with MI and improved prognostic outcomes. Neutrophil-specific deletion of Irgm1 exacerbates cardiac dysfunction, impairs post-MI repair, and hinders neutrophil clearance and efferocytosis. Irgm1 deficiency further delays neutrophil clearance in the heart and extends neutrophil survival. Mechanistically, Irgm1 directly interacts with PDIA3, promoting its autophagic degradation, which in turn activates the endoplasmic reticulum stress/NF-\u03baB/caspase-3 pathway to facilitate neutrophil clearance and efferocytosis. In vivo administration of LOC14 significantly reduces tissue damage and enhances cardiac recovery in neutrophil Irgm1-deficient mice post-MI. These findings highlight the pivotal role of the Irgm1-PDIA3 axis in facilitating cardiac repair post-MI by promoting neutrophil clearance. LOC14 may serve as a potential therapeutic agent to enhance cardiac function post-MI, particularly in Irgm1-deficient cases.\n\nID: 41715099\nTitle: Indole-acetaldehyde from Rothia mucilaginosa activates the PXR/NRF2 axis to enhance alveolar macrophage phagocytosis and protect against ARDS.\nAbstract: BACKGROUND: Despite advances in therapeutic strategies, acute respiratory distress syndrome (ARDS) mortality remains high. Growing evidence links respiratory microbiome composition to ARDS outcomes. This investigation sought to elucidate how colonizing bacteria and their metabolites influence ARDS pathogenesis. METHODS: Bronchoalveolar lavage fluid (BALF) from patients with pulmonary infections was analyzed by metagenomic next-generation sequencing (mNGS) to identify characteristic bacteria. Bacterial culture supernatants were analyzed by untargeted metabolomics (LC-MS) to identify metabolites. A murine ARDS model was established through intratracheal LPS instillation. Single-cell sequencing datasets from the GEO database were analyzed to reveal differential cell populations and functional alterations in murine ARDS. Potential molecular mechanisms were explored through molecular docking, RNA-seq analysis, Western boltting, and targeted gene knockdown in murine and cellular model. RESULTS: R. mucilaginosa demonstrated enrichment in patients without ARDS (nARDS). The bacterial culture supernatant conferred substantial protection in murine models, whereas viable bacteria showed minimal efficacy. LC-MS analysis identified indole-3-acetaldehyde (IAAld) as the predominant metabolite in the supernatant. Single-cell sequencing suggested that resident alveolar macrophages (RAMs) were pivotal cells in murine ARDS model. IAAld enhanced RAMs phagocytosis, facilitating neutrophil and LPS clearance. Mechanistic studies revealed that IAAld likely activated PXR signaling, promoted NRF2 nuclear translocation, and upregulated the phagocytosis-related gene CD36. Targeted PXR knockdown eliminated these protective effects. CONCLUSION: The respiratory commensal R. mucilaginosa synthesizes IAAld, which\u2014independent of bacterial colonization per se\u2014ameliorates ARDS through PXR/NRF2/CD36 axis activation, thereby enhancing macrophage phagocytic function. These findings suggest that therapeutic targeting of microbial metabolites represents a novel ARDS treatment paradigm.\n\nID: 41701526\nTitle: Inflammation- and resolution-programmed myeloid circuits govern therapeutic resistance in epithelial and mesenchymal triple-negative breast cancer.\nAbstract: Single-cell analysis of human triple-negative breast cancer revealed heterogeneous macrophage populations with opposing phenotypes - proinflammatory and proresolution of inflammation. Paradoxically, both subsets accumulated in therapy-refractory residual tumors but showed inverse correlations across patients, suggesting mutually exclusive resistance mechanisms. Inflammatory macrophages localized preferentially to epithelial-like tumors, whereas proresolution macrophages were enriched in mesenchymal-like tumors. Mouse models faithfully recapitulated these patterns. After chemoimmunotherapy, mesenchymal-like tumors expanded proresolution macrophages through phagocytosis/efferocytosis, \u03c9-3 fatty acid uptake, and resolvin production. Macrophage-secreted C1q emerged as a principal antagonist of T cell function by targeting mitochondria and inducing metabolic dysfunction. By contrast, epithelial-like tumors accumulated inflammatory macrophages and neutrophils that produced prostaglandins via \u03c9-6 fatty acid pathways. Knocking down ELOVL5 - an elongase involved in \u03c9-3 and \u03c9-6 metabolism - mitigated both neutrophil- and macrophage-mediated immunosuppression. These distinct axes, driven by dysregulated inflammation and resolution programs, converged to undermine therapy-induced immunosurveillance; however, targeting their shared upstream regulators may overcome these resistance mechanisms.\n\nID: 42554055\nTitle: Mast Cell St8sia1 Is a Glyco-Epigenetic Checkpoint Driving Cardiac Remodeling.\nAbstract: Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential. We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics. The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of St8sia1 preserved ventricular function, attenuated fibrosis, and markedly reduced neutrophil and Ly6C+ monocyte recruitment after transverse aortic constriction and ischemia-reperfusion. Therapeutic neutralization of GD3 with the clinical-grade monoclonal antibody R24 improved cardiac function and diminished scar formation after ischemia-reperfusion. Mechanistically, GD3 bound specific histone variants, such as H2A.Z and H3.3C, thereby reprogramming chromatin accessibility to activate proinflammatory and profibrotic transcriptional programs in MCs. Consequently, GD3 inhibition suppressed MC degranulation, disrupted pathogenic MC-cardiomyocyte/fibroblast crosstalk, and preserved reparative macrophage populations. The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure.\n\nID: 42553337\nTitle: J2R/F4L deleted oncolytic vaccinia virus synergizes with tumor specific killer (ELANE) promotes antitumor immunity with superior safety.\nAbstract: Oncolytic virotherapy (OVT) represents a promising approach for cancer treatment, employing oncolytic viruses (OVs) that selectively infect and lyse tumor cells while promoting an antitumor immune microenvironment. Vaccinia virus (VACV) serves as an attractive oncolytic vector due to its favorable safety profile, ease of genetic modification, and inherent tumor selectivity. To enhance both safety and tumor-targeting capability, we constructed a recombinant vaccinia virus, VV-dTF/EE, by deleting the viral J2R and F4L genes and inserting the human neutrophil elastase (ELANE) gene, which exhibits tumor-killing activity. Mechanistic studies evaluated with virus replication selectivity, cell apoptosis, genomic damage, immunogenic cell death, alongside analysis of the immune microenvironment. Efficacy was tested in multiple tumor cell models in vitro and lung cancer models in vivo. In tumor cell lines and mouse tumor models, VV-dTF/EE demonstrated tumor-restricted replication, potent oncolytic effects, and induction of immunogenic cell death. Furthermore, VV-dTF/EE augmented VACV-induced antitumor immunity by increasing CD8+ T cell infiltration and suppressing M2-like macrophage polarization. This VV-dTF/EE revealed tumor-selective replication and killing ability while modifying the tumor immune microenvironment to elicit immunogenic cell death. Our findings highlight a novel strategy for safe and effective tumor immunotherapy through dual-gene deletion and ELANE expression in an oncolytic vaccinia platform.\n\nID: 42548844\nTitle: Fecal microbiota transplantation in ulcerative colitis: mucosal immune mechanisms and precision microbiota therapy.\nAbstract: Fecal microbiota transplantation (FMT) has emerged as an investigational microbiota-targeted strategy for ulcerative colitis (UC), aiming to restore dysbiotic gut ecosystems and microbiota-host homeostasis. Mechanistic studies suggest that FMT may reshape microbial community structure, enrich short-chain fatty acid-producing bacteria, remodel bile acid and tryptophan-aryl hydrocarbon signaling, enhance epithelial barrier integrity, and regulate mucosal immunity, including Th17/Treg balance, IgA-associated responses, macrophage reprogramming, IL-10/IL-22 signaling, and neutrophil extracellular trap formation. Randomized controlled trials indicate that FMT can induce clinical and endoscopic remission in selected patients with UC, particularly when administered through the lower gastrointestinal route and using multi-donor or optimized regimens. Current guidelines do not recommend conventional FMT as routine therapy for UC outside clinical trials, reflecting the heterogeneity and low certainty of available evidence. However, its efficacy appears limited in moderate-to-severe or biologic-refractory disease, underscoring the importance of host inflammatory burden and recipient ecological receptivity. Personalized strategies, including donor-recipient functional matching, dietary modulation, combination therapy, and next-generation microbiota therapeutics, may improve response and safety but require prospective validation. This review integrates microbiota-metabolite-barrier-immune mechanisms with clinical evidence to define where FMT may be useful, where its benefit appears limited, and how future studies can move the field toward precision microbiota therapy in UC.\n\nID: 42545624\nTitle: Deciphering the regulatory role of ADAM8 in the PDAC tumor microenvironment.\nAbstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options, driven in part by its immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) and neutrophils (TANs) contribute to tumor progression and immune evasion. A Disintegrin and Metalloproteinase 8 (ADAM8), a zinc-dependent protease, is strongly upregulated in PDAC and correlates with poor clinical outcomes, suggesting a regulatory role in tumor progression. Wild-type (WT) and Adam8 knockout (A8KO) PDAC cell lines were generated using the CRISPR-Cas9 technique, and PDAC mouse models with or without Adam8 expression were established to investigate the role of ADAM8 in tumor and immune cells. In vitro assays, including Western blotting, qPCR, migration and invasion assays, proliferation assays, ELISA, cytokine and proteome analyses, as well as co-culture experiments with PDAC cells and either macrophages or neutrophils, were employed to assess the effects of ADAM8 on tumor-immune cell crosstalk. In parallel, in vivo WT and A8KO KPC models were generated, genotyped, and monitored to evaluate the impact of ADAM8 on survival, tumor growth, and immune cell recruitment within the PDAC TME. ADAM8 deletion reduced tumor cell proliferation and migration, associated with reduced activation of FAK/Src/STAT3 signaling and altered secretion of cytokines including GM-CSF, M-CSF, ICAM-1, and TNF-\u03b1. Co-culture assays demonstrated that ADAM8 enhanced reciprocal signaling between tumor cells and TAMs/TANs, promoting pro-oncogenic activation. Migration assays and in vivo analyses revealed that ADAM8 facilitated recruitment of macrophages and neutrophils in PDAC TME, while Adam8KO tumors exhibited reduced immune infiltration and altered macrophage polarization. Our findings demonstrate that ADAM8 promotes PDAC aggressiveness by enhancing tumor cell proliferation and migration, activating FAK/Src/STAT3 signaling, and driving macrophage and neutrophil recruitment through cytokine regulation. By orchestrating both tumor-intrinsic pathways and tumor-immune interactions, ADAM8 emerges as a key determinant of PDAC progression and a systemic target for therapeutic intervention.\n\nID: 42543326\nTitle: [Research progress on action mechanisms of Rheum palmatum anthraquinones in improving acute lung injury].\nAbstract: Acute lung injury(ALI) and acute respiratory distress syndrome(ARDS) are severe respiratory diseases characterized by uncontrolled inflammatory responses and disruption of the alveolar-capillary barrier. This type of disease is often triggered by multiple factors such as infection, sepsis, trauma, or inhalation injury, and the pathological process involves multiple sections including inflammatory cascade reactions, oxidative stress imbalance, abnormal activation of immune cells, and increased pulmonary microvascular permeability. Owing to their complex pathogenesis and high mortality, available clinical therapeutic approaches remain limited. Therefore, the development of safe and effective therapeutic agents to attenuate ALI has become a major focus of current research field. As a TCM, Rheum palmatum has a long history of use in clearing heat and toxins, purging the bowels, and regulating systemic inflammatory responses. In recent years, increasing attention has been paid to its therapeutic effect in ALI. RESULTS:: show that R. palmatum and its major bioactive anthraquinones, such as emodin and rhein, exert protective effects through multi-target and multi-pathway mechanisms. These mechanisms mainly include inhibition of inflammatory signaling pathways such as nuclear factor-\u03baB(NF-\u03baB), mitogen-activated protein kinase(MAPK), and NOD-like receptor protein 3(NLRP3) inflammasome, attenuation of oxidative stress response, activation of the nuclear factor erythroid 2-related factor 2(Nrf2)-mediated antioxidant defense system, regulation of programmed death in immune cells including macrophages, improvement of immunometabolic status, modulation of macrophage polarization and the gut microbiota as well as the gut-lung axis, and so on. In addition, R. palmatum has been shown to preserve the integrity of the alveolar-capillary barrier and to suppress excessive neutrophil activation and the overformation of neutrophil extracellular traps(NETs), thereby reducing inflammation amplification effect and the risk of immune microthrombi. This paper summarized the action mechanisms and research progress of R. palmatum in the treatment of ALI, aiming to elucidate the unique advantages of R. palmatum anthraquinones in intervening in the complex pathological processes of ALI through systemic regulatory networks and to provide a solid theoretical basis for the research and development of innovative R. palmatum-based medicines and their clinical combination medication.\n\nID: 42535940\nTitle: Metabolic Reprogramming by Engineered Probiotics Potentiates Tumor Chemodynamic Immunotherapy.\nAbstract: Engineered bacteria hold promise for remodeling immunosuppressive tumor microenvironments through innate immunogenicity and localized therapeutic delivery. While bacterial-derived metabolites are increasingly recognized as key mediators, their specific roles in interkingdom crosstalk remain underexplored. Here, we develop a programmable probiotic platform leveraging Lactobacillus gasseri (LG)-tumor metabolic interplay to potentiate bladder cancer therapy. The selected LG strain demonstrates superior tumor-colonizing ability and intrinsic H2O2/lactate biosynthesis, creating an optimal tumor microenvironment for hemoglobin-modified MnOx nanoparticles to enhance chemodynamic therapy efficacy. Mechanistically, microbial metabolites, including L-leucine, orchestrate neutrophil phenotypic reprogramming by suppressing pro-angiogenic dcTRAIL-R1+ neutrophils while activating antigen-presenting CD74+ neutrophil populations. The engineered system elicites coordinated immunomodulation through multiple mechanisms: (1) promoting dendritic cell maturation, (2) increasing CD74+ neutrophil populations, (3) inducing macrophage polarization from M2 to M1 phenotypes, and (4) enhancing tumor infiltration of CD8+ T cells and natural killer cells. This study reveals that bacteria-tumor metabolic crosstalk upregulates beneficial metabolites, notably leucine, which promotes phenotypic reprogramming of neutrophils toward the antigen\u2011presenting CD74+ subset, thereby bridging innate metabolic regulation with adaptive antitumor immunity. This finding goes beyond the material-centric logic of previous probiotic-nanomaterial systems and establishes a metabolism-centric framework for bacteria\u2011mediated cancer immunotherapy.\n\nID: 42524663\nTitle: Endothelial Senescence-Associated Secretory Signaling Promotes Macrophage Extracellular Traps Formation and Contributes to the Exacerbation of Combined Lung Injury.\nAbstract: Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy and can be critically exacerbated by pre-existing pulmonary inflammation, yet the synergistic mechanisms driving this pathology remain elusive. Using a murine model of combined lung injury induced by lipopolysaccharide (LPS) and thoracic irradiation (IR), we identified macrophage extracellular traps (METs), a type of web-like chromatin structure released by macrophages, rather than neutrophil extracellular traps (NETs), as a prominent pathogenic process. Mechanistically, the combination of LPS and irradiation induced an early endothelial senescence-associated phenotype and a CXC chemokine-enriched secretory profile. These signals engaged macrophage CXCR2, leading to p38/ERK pathway activation and reactive oxygen species (ROS) production that contributed to METs formation (METosis). Functionally, METs serve as potential dual-phase mediators, contributing to epithelial barrier disruption during acute injury and promoting epithelial-mesenchymal transition (EMT)-like epithelial remodeling, thereby potentially linking early inflammatory damage to subsequent fibrotic progression. Furthermore, we demonstrate that the bioactive compound Cordycepin exerts protective effects by suppressing p38/ERK pathway activation and attenuating METosis. Collectively, these findings support a potential endothelial senescence-associated secretory signaling-METosis axis, providing a novel mechanistic framework and candidate therapeutic strategies for managing high-risk radiation-induced lung injury.\n\nID: 42524404\nTitle: Biocompatibility Assessment of a Hybrid Material Based on Epoxy-Treated Pericardium and Polyvinyl Alcohol Cryogel in a Rat Vascular and Subcutaneous Implantation Model.\nAbstract: The aim of the study was to evaluate the biocompatibility of a hybrid material based on epoxy-treated bovine pericardium and cryostructured polyvinyl alcohol (PVA) after implantation into the rat aortic wall and subcutaneous tissue. The study evaluated hybrid material patches based on epoxy-treated bovine pericardium and cryostructured PVA; unmodified \"KemPeriplasNeo\" pericardial patches served as controls. The samples were implanted into the abdominal aortic wall and subcutaneously in male Wistar rats. The vascular implantation periods were 5 and 20 days, and the subcutaneous implantation periods were 60 and 120 days. The specimens were excised from the aorta and studied histologically using Russell-Movat staining and immunostaining for neutrophil myeloperoxidase (MPO) and the macrophage marker CD68. The calcium content in subcutaneously implanted samples was assessed by spectrophotometry and alizarin red S staining. The quantitative data were presented as the median, percentiles, minimal and maximal values (Me [25%-75%; min-max]). After implantation into the abdominal aortic wall, the hybrid material samples showed a lower tendency toward thrombotic deposit formation on the surface compared to the pericardium. On day 5 of implantation, the thrombus thickness was 49.1 [34.7-64.6; 27.4-71.6] \u03bcm in the experimental group vs 170.3 [158.1-210.3; 124.4-217.0] \u03bcm in the controls (p<0.001). By day 20 of implantation, the macrophage density was lower in the peri-implant area of the modified samples compared to the controls: 219 [187-275; 112-362] vs 301 [244-338; 194-433] CD68+ cells per field of view (p<0.001), respectively. The neutrophil density at all experimental time points, as well as the macrophage density on day 5 of implantation did not differ significantly between the tested materials (p>0.17). No signs of calcification were detected in either group following the subcutaneous implantation over a period of 60 or 120 days. The control pericardium in the subcutaneous model showed the signs of cell-mediated degradation, whereas the hybrid samples were resistant to immune-cell infiltration and preserved their internal architecture. The modification of epoxy-treated bovine pericardium with cryostructured PVA cryogel improved its biocompatibility and enhanced resistance to biodegradation in a rat model after aortic-wall and subcutaneous implantation. The developed material may be used to create next-generation heart valve bioprostheses with potentially improved resistance to structural valve degeneration.\n\nID: 42523712\nTitle: Impaired NLRP3 inflammasome activation by chitin underlies refractory chromoblastomycosis caused by Fonsecaea pedrosoi muriform cells.\nAbstract: Macrophage NLRP3 activation is crucial for antifungal immunity, yet its role in chromoblastomycosis-a chronic subcutaneous mycosis typically caused by Fonsecaea pedrosoi-remains unclear. Unlike prior self-resolving models using conidia and hyphae, clinical disease features muriform cells, a parasitic form resistant to macrophages and linked to chronicity. Notably, chitin, a weak NLRP3 agonist, accumulates on the surface of muriform cells. This study investigates whether chitin accumulation modulates NLRP3 activation and promotes fungal persistence. Human chromoblastomycosis lesions were analyzed by IHC (MPO, CD86, NLRP3) and RT-PCR for cytokine transcripts. WT and NLRP3-/- mice were footpad-inoculated with F. pedrosoi muriform cells for in vivo assessment. Flow cytometric bead array quantified IL-1\u03b2, IL-6, IL-10, TNF-\u03b1, and IL-17A in footpad homogenates, and the same panel (excluding IL-17A) in stimulated BMDM supernatants. NLRP3 pathway activation in BMDMs was confirmed by western blotting and immunofluorescence. In human lesions, marked MPO+ neutrophil recruitment encapsulated muriform cells, yet multinucleated giant cells sequestered some fungal elements from neutrophils. Despite robust NLRP3 expression and elevated IL-1\u03b2, IL-6, TNF-\u03b1, and IL-10 versus normal skin (all p < 0.01), muriform cells persisted in tissue. In WT mice, lesions transitioned from purulent (day 7) to granulomatous (day 90), concurrent with declining IL-1\u03b2, IL-17A, IL-6, and TNF-\u03b1. MPO+ neutrophils abundantly surrounded muriform cells at day 7; at day 90, F4/80+ macrophages enveloped most fungi without elimination, forming multinucleated giant cells-recapitulating human pathology. In NLRP3-/- mice, IL-1\u03b2 and IL-17A were produced in an NLRP3-independent manner and showed no decline over time. Muriform cells progressively budded and transitioned to hyphae both inside and outside giant cells; MPO+ neutrophils preferentially localized to hyphal areas, while macrophages remained around muriform cells, suggesting compartmentalized inflammation. In vitro, chitinase-treated muriform cells induced higher NLRP3-dependent IL-1\u03b2, IL-6, TNF-\u03b1, and IL-10 in WT BMDMs versus intact cells (all p < 0.01). Mechanistically, chitin accumulation partially suppressed NF-\u03baB phosphorylation, reducing NLRP3 expression, caspase-1 cleavage, and ASC speck formation. NLRP3 mediates host defense against muriform cells yet fails to resolve chronic infection. Chitin accumulation on muriform cells attenuates NLRP3 activation, thereby promoting chromoblastomycosis chronicity.\n\nID: 42521072\nTitle: Physcion alleviates Aspergillus fumigatus keratitis by inhibiting fungal growth and NF-\u03baB-mediated inflammation.\nAbstract: Physcion, a natural anthraquinone, possesses antifungal and anti-inflammatory activities. This study aimed to investigate its antifungal and anti-inflammatory effects in a murine model of Aspergillus fumigatus (AF) keratitis (AFK). The safety of physcion was evaluated using Cell Counting Kit-8 assays, live/dead cell staining and the Draize test. Antifungal activity was assessed by propidium iodide staining, calcofluor white staining, crystal violet biofilm assays and determination of the MIC. Network pharmacology analysis was performed to predict potential therapeutic targets of physcion. Both in vitro and in vivo experiments were conducted using AF spore-infected mouse corneas and RAW264.7 macrophages treated with physcion or phosphate-buffered saline. Inflammatory responses were evaluated by slit-lamp examination, immunofluorescence, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB), focusing on neutrophil and macrophage recruitment together with the expression of pro-inflammatory proteins and components of the NF-\u03baB signalling pathway. Physcion effectively inhibited the growth of AF. In vivo, physcion-treated mice exhibited significantly lower clinical scores compared with untreated infected controls. Immunofluorescence analysis revealed markedly decreased infiltration of neutrophils/macrophages in the corneas of physcion-treated mice. RT-qPCR together with WB analyses demonstrated that physcion treatment obviously reduced the phosphorylated NF-\u03baB p65 and phosphorylated I\u03baB, increased I\u03baB expression and suppressed the expression of IL-1\u03b2, TNF-\u03b1 and IL-18 in infected mouse corneas and RAW264.7\u202fcells. Consistently, IF imaging of RAW264.7\u202fcells showed reduced nuclear localization of NF-\u03baB p65 following physcion treatment. Physcion alleviated AFK by inhibiting fungal growth, limiting neutrophil and macrophage recruitment, and suppressing activation of the NF-\u03baB signalling pathway.\n\nID: 42520679\nTitle: Integrated single-cell and spatial transcriptomic atlas of multi-etiology acute lung injury reveals etiology-dependent neutrophil fate decisions and a prognostic neutrophil-monocyte/macrophage interaction signature.\nAbstract: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening syndrome with heterogeneous etiologies and no effective pharmacological therapy. Although neutrophils are central mediators of lung injury, their functional diversity and interplay with monocyte/macrophage (Mo/M\u03a6) populations across etiologies remain poorly defined. Here, we integrated single-cell RNA-sequencing profiles from 180,031 murine lung cells across seven ALI models spanning infectious, sterile, and extrapulmonary insults to construct a multi-etiology neutrophil atlas. Augur identified neutrophils as the most transcriptionally perturbed immune population. Gene-set variation analysis revealed etiology-specific programs, including NF-\u03baB/IL-6-driven inflammation in infection/sepsis, dual interferon responses in influenza, tissue-remodeling and stress-adaptive programs in bleomycin injury, and ROS-dominated injury with metabolic reprogramming after radiation. Spatial transcriptomics further mapped the spatiotemporal dynamics of neutrophil reprogramming during influenza-induced lung injury. High-resolution re-clustering resolved 13 neutrophil subtypes organized into four macro-states, and pseudotime analysis uncovered an etiology-dependent bifurcation from a bone marrow-like immature origin toward either an IFN/inflammasome-associated effector branch or an NF-\u03baB-driven inflammatory branch, with sepsis and bacterial infection retaining neutrophils near the immature origin. In parallel, we defined 12 Mo/M\u03a6 subtypes and derived a 26-gene Neutrophil-Monocyte/Macrophage Interaction Index with prognostic value for sepsis mortality. Importantly, immunobiological validation showed that conditioned media from LPS-, P. aeruginosa- and CLP-derived neutrophils contained elevated THBS1 and activated NF-\u03baB-MAPK-NLRP3 signaling in macrophages, whereas blockade of THBS1-CD36 with CD36 peptide P(93-110) attenuated inflammatory activation, promoted reparative polarization, and reduced circulating neutrophils in vivo. Together, these findings define an etiology-resolved atlas of ALI and identify THBS1-CD36 as a mechanistically relevant therapeutic target in infection- and endotoxin-driven ALI.\n\nID: 42520196\nTitle: Erythroblast-derived lipid mediators program neutrophil development and function.\nAbstract: Granulopoiesis is a tightly regulated process encompassing the production, maturation, and release of neutrophils in the bone marrow, ensuring their optimal physiological contribution to host defence. The mechanisms that maintain a balanced regulation of neutrophil effector functions during this process remain incompletely understood. Here, we identify bone marrow-resident erythroblasts as a key source of specialized pro-resolving mediators (SPMs) and show that they imprint neutrophil development and function. Terminally differentiating erythroblasts highly express the key SPM biosynthetic enzyme 12/15-lipoxygenase (Alox15) and accordingly generate several SPMs, including n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5n-3 DPA). Conditional erythroblast-specific depletion of Alox15 decreased bone marrow SPM levels and caused altered neutrophil phenotypes, including augmented release of reactive oxygen species and neutrophil extracellular traps, as well as increased migration to chemotactic stimuli. This was accompanied by increased neutrophil sequestration in peripheral organs and concomitant neutropenia. Mice with erythroblast-specific Alox15 depletion displayed impaired bacterial clearance in experimental peritonitis and increased severity in DSS-colitis. Aberrant neutrophil phenotypes were rectified by the reconstitution of RvD5n-3 DPA and were largely recapitulated by the specific depletion of the SPM receptor Gpr101 in bone marrow macrophages, but not in neutrophil precursors, suggesting involvement of the macrophage niche in mediating the SPM effects on granulopoiesis. Our findings establish a central role for erythroblasts and their SPM production in instructing granulopoiesis for balanced functional neutrophil responses.\n\nID: 42519831\nTitle: Neutrophil-promoted macrophage state transition coordinates endothelial migration and barrier resealing in zebrafish microvascular repair.\nAbstract: Microvessels are frequently damaged, yet the in vivo temporal logic that couples endothelial gap closure to barrier resealing, and the immune-cell interactions that coordinate these steps, remains poorly defined. Using live imaging of laser-injured zebrafish intersegmental vessels, we define a staged repair program: endothelial cells migrate to bridge the gap, trapped erythrocytes are cleared, and vascular permeability rises transiently before resealing. Neutrophils arrive first, whereas macrophages persist and undergo a neutrophil-dependent functional transition. Early tnfa-associated macrophages promote endothelial migration and erythrocyte debris removal, while later ccl34a.4+ pro-remodeling macrophages support barrier restoration. Neutrophil ablation delays this transition and selectively prolongs permeability defects. Neutrophils release CD63+ extracellular vesicles that are taken up by macrophages, and inhibiting EV/exosome secretion phenocopies key features of neutrophil loss. These findings provide a temporal framework to dissect immune-endothelial coordination during microvascular repair.\n\nID: 42518682\nTitle: Combination Therapeutic Effect of Asiatic Acid & Curcumin-Loaded Liposomes Modified by Neutrophil Extracellular Traps for the Treatment of Oral Squamous Cell Carcinoma.\nAbstract: Tumor metastasis has been proven to represent the predominant cause of cancer-related mortality; therefore, the strategies simultaneously eradicating primary lesions and blocking dissemination cascades hold revolutionary potential in curative oral squamous cell carcinoma (OSCC) therapy. In this study, we designed novel neutrophil extracellular traps (NETs)-coating liposomes (CUR@AA-NLIP) for co-delivery of curcumin (CUR) and asiatic acid (AA), in which the introduction of NETs was expected to improve tumor-targeting ability, and the combination of CUR and AA was used to synergistically inhibit tumor development. The characteristics analysis showed that CUR@AA-NLIP exhibited uniform size, phospholipid bilayer structure, and sustained drug release. In vitro studies demonstrated that CUR@AA-NLIP enhanced tumor cell uptake and macrophage escape, inhibited fibroblast activation and vessel tube formation, showing enhanced anti-proliferation and anti-migration capacities. In vivo results confirmed that CUR@AA-NLIP increased drug accumulation in the tumor region, showed enhanced anti-tumor efficacy (> 80% tumor suppression), and reduced lung metastasis. CUR@AA-NLIP holds great potentials in OSCC-targeting delivery of synergistic natural compounds and can achieve anti-proliferative and anti-metastatic effects by simultaneously enhancing tumor accumulation, reducing immune system clearance, and inhibiting of cancer-associated fibroblast (CAF) activation and angiogenesis, therefore exhibiting enhanced anti-OSCC efficacy.\n\nID: 42516037\nTitle: Myeloid cell reprogramming combined with zoledronic acid effectively suppresses bone metastasis.\nAbstract: Bone metastases are refractory to current therapies, primarily owing to the immunosuppressive metastasis tumor microenvironment (TME), which is dominated by myeloid cells. However, the function and regulatory mechanisms of myeloid compartments within the bone TME are incompletely understood. Herein we sought to delineate the role of the DKK1-CKAP4 axis in shaping myeloid cell-mediated immunosuppression in bone metastases and to identify potential therapeutic strategies targeting this pathway. The composition and phenotypic characteristics of myeloid cells in the bone TME were analyzed. Mechanistic studies were conducted using ex vivo co-culture systems and an in vivo Ckap4fl/flS100a8Cre (neutrophil-specific Ckap4 knockout) mouse model to delineate the role of the DKK1-CKAP4 axis in regulating neutrophil maturation, osteoclast-like cell differentiation, and macrophage polarization. The therapeutic efficacy of DKK1 blockade in combination with zoledronic acid, as well as the impact on remodeling the TME, was further validated in bone metastasis mouse models. Significant expansion and predominance of myeloid cells within the bone TME was noted. Mechanistically, the DKK1-CKAP4 axis regulated the development and function of multiple myeloid populations. The DKK1-CKAP4 axis drove neutrophils toward an immature-like, immunosuppressive phenotype, promoted osteoclast-like cell differentiation, and induced macrophage polarization into an M2-like phenotype. Importantly, combined therapy with DKK1 blockade and zoledronic acid reprogrammed immunosuppressive myeloid cells, restored antitumor immunity, and significantly reduced tumor burden in bone metastasis models. The findings herein showed the DKK1-CKAP4 axis to be a key regulator of myeloid-driven immunosuppression in the bone TME. The combination of DKK1 blockade with zoledronic acid represents a potential therapeutic strategy for bone metastases.\n\nID: 42515755\nTitle: Targeting the Immune Network in Endometriosis: A Comprehensive Review of Pathogenesis, Immunomodulation, and Emerging Therapies.\nAbstract: Endometriosis is a chronic inflammatory disease characterized by the ectopic growth of endometrial-like tissue and is closely associated with pain and infertility. This review summarizes current evidence on immune dysregulation and emerging immunomodulatory therapies in endometriosis. Relevant clinical and mechanistic studies were identified through a structured literature review and qualitatively synthesized. Increasing evidence suggests that immune dysregulation plays a critical role in disease pathogenesis. Within the immune microenvironment, innate and adaptive immune cells-including macrophages, dendritic cells, neutrophils, mast cells, T cells, and B cells-collectively promote inflammation, angiogenesis, fibrosis, and immune evasion. Emerging immunotherapeutic strategies, including macrophage repolarization, NK cell restoration, dendritic cell modulation, neutrophil extracellular traps inhibition, immune checkpoint blockade, and cytokine/chemokine targeting, have shown promising preclinical and early clinical potential. However, disease heterogeneity, reproductive safety concerns, and the lack of validated biomarkers remain major barriers to clinical translation, highlighting the potential of immunomodulatory therapies as future non-hormonal treatment strategies.\n\nID: 42511279\nTitle: The Effects of Multiple Maillard Reaction Products in Infant Formula on Host Immunity and Neurotoxicity.\nAbstract: Various Maillard reaction products (MRPs) are formed in infant formula during thermal processing and storage. However, safety assessments are often based on individual compounds, which may not adequately reflect the potential risks associated with exposure to multiple coexisting components in real food products. Therefore, this study used GC-MS to screen for typical MRPs in infant formula. Based on the detection results, glyoxal, 2-acetylfuran, 2-furfural, and 5-hydroxymethylfurfural (5-HMF) were selected to establish a mixed-exposure system. Subsequently, using zebrafish as a model, we systematically evaluated the toxic effects of two mixture concentrations, 1/9 maximum non-lethal concentration (MNLC) and 1/3 MNLC, on the immune system, nervous system, gastrointestinal tract, and liver. The results showed that these four MRPs coexisted in infant formula and that combined exposure induced significant biological damage even at low doses. Both mixture concentrations significantly reduced neutrophil and macrophage levels and promoted apoptosis in central nervous system cells. The higher-concentration mixture further reduced T-cell counts, suppressed motor neuron development, and decreased locomotor activity during the light phase. In addition, the higher-concentration mixture decreased the gastrointestinal area, increased the liver area, delayed yolk sac absorption, and caused marked histopathological damage. Compared with single-compound exposure, combined exposure exerted more pronounced effects on immune- and neuro-related endpoints, suggesting synergistic interactions among different MRPs and identifying the immune and nervous systems as the more sensitive targets of toxicity. In summary, mixed exposure to typical MRPs in infant formula may pose a greater biological risk than that predicted by evaluations based on individual components alone. This study provides experimental evidence for identifying combined toxicity and improving the safety risk assessment of MRPs in thermally processed infant foods.\n\nID: 42510635\nTitle: Mechanistic Insights into Redox-Dependent Macropinocytosis in Primary Human Neutrophils.\nAbstract: Macropinocytosis is an actin-driven endocytic process mediating nonspecific uptake of extracellular fluid through membrane ruffling. Neutrophil macropinocytosis has been reported only in limited descriptive studies, and its signaling mechanisms have not been defined. Here, we provide a characterization of macropinocytosis in primary human neutrophils and investigate signaling pathways that contribute to the regulation of this process. Quantitative flow cytometry using a high-molecular-weight fluid-phase tracer showed that the diacylglycerol (DAG) mimetic 4\u03b2-phorbol 12-myristate 13-acetate (4\u03b2-PMA) induces macropinocytic activity in primary human neutrophils. Granulocyte macrophage-colony stimulating factor (GM-CSF) and hepatocyte growth factor (HGF) also promoted fluid-phase uptake. Inhibition of actin polymerization or macropinocytosis reduced tracer uptake, confirming dependence on actin-driven machinery. Scanning electron microscopy revealed dorsal membrane ruffling and cup-like structures after stimulation. Mechanistically, DAG-dependent activation of protein kinase C beta (PKC\u03b2) acted upstream of NADPH oxidase 2 (NOX2)-derived superoxide anion production, driving membrane remodeling. Collectively, these findings define a DAG-PKC\u03b2-NOX2-superoxide signaling axis, as a key regulator of macropinocytosis in primary human neutrophils and provide the first mechanistic framework for its redox-dependent regulation.\n\nID: 42509849\nTitle: DADA2 as a Model of Monogenic Immune Vasculopathy: From Immunopathogenesis to Precision Therapeutics.\nAbstract: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic autoinflammatory disorder caused by biallelic loss-of-function mutations in the ADA2 gene (formerly CECR1). First described in 2014, DADA2 has emerged as a paradigm for monogenic vasculitis, bridging the gap between primary immunodeficiencies and systemic vasculitides. The disease is characterized by a remarkably broad clinical spectrum encompassing early-onset lacunar stroke, systemic vasculitis resembling polyarteritis nodosa (PAN), hematologic abnormalities ranging from pure red cell aplasia to pancytopenia, humoral immunodeficiency, and variable lymphoproliferation. ADA2, predominantly secreted by myeloid cells, serves dual functions as a growth factor for endothelial cells and a modulator of extracellular adenosine metabolism. Its deficiency leads to a proinflammatory state driven by macrophage dysregulation, excessive tumor necrosis factor (TNF) production, neutrophil extracellular trap (NET) formation, and endothelial dysfunction. The genotype-phenotype correlation is complex, with certain mutations predisposing to vasculitic versus hematologic-predominant phenotypes. Emerging evidence further links ADA2 deficiency to cellular senescence and inflammaging pathways, suggesting a connection between monogenic vasculitis and aging-related biological mechanisms. Anti-TNF therapy has revolutionized disease management, achieving sustained remission in the majority of vasculitic manifestations. Hematopoietic stem cell transplantation (HSCT) offers a definitive cure for severe hematologic disease, while gene therapy approaches are under active investigation. This review synthesizes current knowledge on the immunopathogenesis, clinical heterogeneity, genotype-phenotype correlations, multi-omics insights, and evolving precision therapeutic strategies for DADA2, positioning it as an instructive model for understanding monogenic immune vasculopathy. Despite this progress, fundamental questions remain-including the relative contribution of ADA2 enzymatic versus growth factor functions to disease pathogenesis, the mechanisms underlying tissue-specific vulnerability, the basis of differential treatment responsiveness, and the identity of genetic and environmental modifiers that determine phenotypic heterogeneity-that define the frontier of current DADA2 research. This review critically evaluates both established knowledge and persistent uncertainties, positioning DADA2 as an instructive model for the study of monogenic immune vasculopathy.\n\nID: 42509795\nTitle: Evaluation of Topical Reconstituted HDL as a Treatment for Diabetic Wounds in Murine and Porcine Models.\nAbstract: Chronic, non-healing foot ulcers are the most common complication of diabetes and are associated with high morbidity, mortality, and substantial health-care costs. Impaired wound healing in diabetes results from a complex pathophysiology involving persistent inflammation, interrupted re-epithelialization, impaired neovascularization, and defective granulation tissue formation. Reconstituted high-density lipoprotein (rHDL), with its antioxidant and anti-inflammatory properties, may counteract these processes and thereby promote wound repair. We investigated the effect of topical administration of rHDL in full thickness excisional wounds in murine and porcine diabetic models. rHDL significantly enhanced wound closure in diabetic mice in a dose-dependent manner as compared to phosphate-buffered saline (PBS) control. Histological and immunohisto-chemical analysis showed that rHDL-treated wounds had increased collagen deposition, a higher number of alpha-smooth muscle actin-positive cells, greater macrophage infiltration, and decreased neutrophil infiltration compared to PBS controls. In contrast, in the porcine model no wound healing improvement was observed after daily topical application of rHDL. Administration of rHDL enhances wound closure in a murine model of diabetic wound healing by promoting collagen production and modulating inflammation. However, lack of efficacy in a more physiologically relevant pre-clinical porcine model under the experimental conditions tested does not support further development of a topical rHDL formulation for diabetic wound healing indications.\n\nID: 42508767\nTitle: Biomineralized nanozymes remodel the infectious microenvironment for precision MRSA pneumonia therapy.\nAbstract: Methicillin-resistant Staphylococcus aureus (MRSA)-induced pneumonia remains clinically challenging because antibiotic monotherapy is often insufficient to eradicate bacteria at pulmonary lesions and fails to resolve infection-amplified oxidative and inflammatory injury. Herein, we report a neutrophil membrane-cloaked, melanin-biomineralized MnO2 nanozyme platform co-loaded with curcumin and vancomycin (VC@NMM) for targeted antibacterial and immunoregulatory therapy of MRSA pneumonia. Through melanin-mediated biomineralization with KMnO4, a biocompatible MnO2 nanozyme framework is constructed with abundant interfacial sites for dual-drug loading and catalytic microenvironment regulation. In this integrated system, vancomycin directly inhibits MRSA growth, curcumin potentiates antibacterial activity and attenuates oxidative inflammation, and the MnO2 nanozyme mediates ROS scavenging, H2O2 decomposition, oxygenation improvement, and bacterial disruption. Neutrophil membrane cloaking further confers prolonged circulation and inflammation-tropic accumulation at MRSA-colonized lung tissues. Consequently, VC@NMM effectively reduces the required vancomycin dosage, disrupts bacterial integrity, induces protein leakage, impairs ATP metabolism, and suppresses MRSA survival in vitro. In MRSA pneumonia mouse model, VC@NMM significantly reduces pulmonary bacterial burden, alleviates edema and histopathological injury, inhibits ROS/NF-\u03baB inflammatory signaling, remodels macrophage polarization, and prolongs survival. Collectively, this work establishes a biomineralized biomimetic nanozyme strategy that couples targeted antibiotic delivery with catalytic microenvironment remodeling and inflammation resolution for effective bacterial pneumonia therapy.\n\nID: 42506892\nTitle: High-Fat Diet Reprograms the Periapical Immune Landscape in a Mouse Model of Apical Periodontitis: A Spatial Transcriptomics Study.\nAbstract: Apical periodontitis (AP) is an inflammatory disease of the periapical tissues driven by host responses to endodontic infection, and systemic metabolic disturbances, such as high-fat diet (HFD)-induced dysmetabolism, may exacerbate tissue destruction. This study aimed to determine how chronic HFD exposure alters periapical myeloid cell states and lesion characteristics in a mouse model of AP using spatially resolved transcriptomics. Male C57BL/6 mice (n\u2009=\u200920; 6-8\u2009weeks, specific pathogen-free) were randomly assigned to normal chow (NC) or 60% HFD for 18\u2009weeks, with AP induced by pulp exposure in first molars after 14\u2009weeks. Body weight and fasting blood glucose were monitored longitudinally; apical lesion volume was quantified by high-resolution micro-CT and histology at 28\u2009days post-induction; and periapical tissues from AP and contralateral control sites underwent 10\u00d7 Genomics Xenium in\u00a0situ spatial transcriptomics focused on neutrophils and macrophages. Compared with NC, HFD mice developed greater body weight gain, higher fasting glucose (approximately 9-11\u2009mM vs. 6-8\u2009mM) and significantly larger apical lesion volumes by micro-CT (p\u2009\u2264\u20090.05), confirming an obese, dysmetabolic background with exacerbated AP-associated bone loss. Spatial transcriptomics revealed that in non-lesion tissues, HFD-conditioned neutrophils and macrophages were biased toward lipid-handling, stress-adaptive and inflammasome-associated programs, whereas NC maintained antimicrobial and oxidative effector signatures. Within AP lesions, HFD was associated with foam cell-like macrophage phenotypes and neutrophils with reduced degranulation and bactericidal gene expression, while NC lesions preserved antigen presentation, neutrophil effector pathways and structured tissue-remodelling responses. Chronic high-fat feeding reprograms periapical innate immunity from antimicrobial defence toward lipid-driven fibro-inflammatory states, thereby amplifying apical bone loss in AP. These findings highlight spatial transcriptomics as a powerful approach to map immunometabolic circuits in endodontic disease and suggest potential targets for managing AP in metabolically compromised patients.\n\nID: 42505352\nTitle: Macrophage Extracellular Traps in Health and Disease: Current Concepts, Pathogenic Mechanisms and Clinical Implications.\nAbstract: Macrophage extracellular traps (METs) are chromatin-based structures released by activated macrophages and are increasingly recognized as distinct, context-dependent effectors of innate immunity. Although initially described in antimicrobial defense, METs are now implicated in sterile inflammation, autoimmunity, fibrosis, metabolic and vascular injury, organ-specific damage, and cancer. This review integrates dispersed evidence on MET biology across physiological and pathological settings, moving beyond neutrophil-centered interpretations of extracellular trap biology. We summarize the molecular composition, structural heterogeneity, major forms of METosis, and key regulatory pathways, including PAD-dependent chromatin remodeling, reactive oxygen species and calcium signaling, mitochondrial DNA release, extracellular DNA sensing, protease-mediated injury, and macrophage-stromal crosstalk. We also discuss the dual nature of METs as protective structures that can contain pathogens and amplify early innate responses, but also as pathogenic platforms when excessive, persistent, or insufficiently cleared. Overall, current evidence supports METs as functionally versatile macrophage-derived immune structures whose biological effects depend on the stimulus, tissue microenvironment, and disease context. By providing a unified framework, this review highlights the relevance of METs as potential biomarkers and therapeutic targets in inflammatory, fibrotic, vascular, autoimmune, and malignant diseases.\n\nID: 42505091\nTitle: Itaconate negatively regulates innate immunity during fungal pneumonia.\nAbstract: The innate immune response to pathogens often involves metabolic reprogramming, such as disruption of the Krebs cycle, leading to the accumulation of various metabolites that can further influence innate cell responses during infection. Of these, the immunomodulatory metabolite itaconate has been shown to positively or negatively influence lung immune responses, depending on the pathogen. In the current study, we found that mice deficient in aconitate decarboxylase (Acod1-/- mice), the enzyme that produces itaconate from cis-aconitate, cleared the opportunistic mold Aspergillus fumigatus from the lung more effectively than wild-type (WT) control mice. Augmented fungal clearance in Acod1-/- mice correlated with increased type 17 responses, which themselves correlated with higher IL-1\u03b2, PGE2, and \u03b3\u03b4 T cell levels. Intriguingly, we show that alveolar macrophages and neutrophils from na\u00efve Acod1-/- mice kill A. fumigatus more efficiently. Conversely, the addition of exogenous itaconate to alveolar macrophages and neutrophils from na\u00efve WT mice reduced their antifungal capacity. Mechanistically, alveolar macrophages, but not neutrophils, from na\u00efve Acod1-/- mice demonstrated enhanced ROS production when stimulated with A. fumigatus. We further show that mice with macrophage-specific, but not neutrophil-specific, Acod1 deficiency cleared A. fumigatus more effectively. Itaconate deficiency also protected against fungus-induced mortality during corticosteroid-mediated immunosuppression. Finally, itaconate reduced the antifungal activity of human monocyte-derived macrophages. Collectively, these data identify an immune regulatory role for itaconate during A. fumigatus fungal pneumonia and potentially identify a new therapeutic target for enhancing protection against A. fumigatus.IMPORTANCEFungal infections by invasive molds such as Aspergillus fumigatus are leading causes of morbidity and mortality in immunocompromised individuals, such as patients with hematologic malignancies, and recipients of hematopoietic stem cell transplant (HCT), solid organ transplant (SOT), and cellular therapies. A major shift in the increased incidence of these infections is a result of a rapidly expanding global immunocompromised population due to targeted immunotherapies and biologics for the treatment of cancer, combination therapies, cellular therapies, and bispecific and trispecific antibody therapies. The advancement in these immunomodulatory/immunosuppressive therapies is outpacing our understanding of mechanisms that lead to the development of infections such as invasive aspergillosis. Therefore, the continuing evolution of our understanding of protective and immunoregulatory responses would be expected to reveal new mechanisms that govern susceptibility to fungal pneumonia. To this end, in the current report, we show that the TCA cycle intermediate itaconate hinders lung clearance of A. fumigatus via regulating multiple immune mechanisms. Overall, our study uncovers a new mechanism of immune regulation during fungal pneumonia.\n\nID: 42502322\nTitle: Mechano-immunomodulatory biomaterials: From immune mechanosensing to translational design.\nAbstract: Mechanical cues are increasingly recognized as active regulators of immune-cell behavior rather than passive properties of tissues or biomaterials. In mechano-immunology, matrix stiffness, viscoelasticity, topography, shear stress, tensile strain, compression, and interstitial fluid pressure are understood to shape macrophage polarization, dendritic-cell maturation, neutrophil trafficking, T-cell activation, and tissue repair through coordinated mechanosensing and mechanotransduction. Yet immune responses to mechanical cues remain highly context-dependent, making simplified rules such as \"stiff matrices promote inflammation\" or \"soft matrices promote repair\" difficult to generalize across material systems, dimensionalities, ligand-presentation profiles, immune-cell sources, and activation states. Key bottlenecks include reconstructing multidimensional in vivo mechanical microenvironments, standardizing mechanical characterization and reporting, resolving immune-cell heterogeneity, and bridging reductionist platforms with clinically deployable biomaterials. Here, we summarize how immune cells decode mechanical signals through membrane-proximal mechanosensors, cytoskeletal remodeling, nuclear mechanotransduction, epigenetic regulation, and mechano-metabolic coupling. We then discuss how biomaterial parameters, including stiffness, viscoelasticity, mechanical stimulation, surface topography, degradation, and mechano-responsive delivery, can be engineered to modulate immunity in tissue regeneration, drug delivery, and theranostics. Finally, we highlight how artificial intelligence (AI)-enabled biophysical modeling and multimodal data integration may define context-specific mechanical design windows and accelerate next-generation mechano-immunomodulatory biomaterials.\n\nID: 42501967\nTitle: Anti-IL-33 monoclonal antibody attenuates MAILD by suppressing the PI3K/AKT/mTOR signal pathway.\nAbstract: Interstitial lung disease (ILD) is a serious complication of idiopathic inflammatory myopathies (IIM) for which targeted therapies are lacking. Our previous work identified interleukin\u201133 (IL\u201133) as playing a key role in the pathogenesis of IIM-ILD. Using a mouse model of myositis-associated ILD (MAILD), including IL\u201133 knockout (IL\u201133 KO) mice, together with clinical samples, proteomics and multiple cellular reporter systems (dual luciferase, mTOR nuclear translocation reporter), we assessed the effects of IL\u201133 NAb on lung injury repair, macrophage polarisation and endothelial/epithelial protection. IL\u201133 NAb significantly reduced pulmonary inflammation and collagen deposition, improved body weight, and ameliorated liver and muscle biochemical parameters in MAILD mice. Notably, IL\u201133 KO MAILD mice exhibited almost identical phenotypic improvements to the IL\u201133 NAb\u2011treated group, confirming IL\u201133 as a core driver of the disease. Mechanistically, IL\u201133 NAb blocked aberrant NETs deposition, reduced PI3K/AKT/mTOR phosphorylation, and suppressed NF\u2011\u03baB and STAT3 activation. Consequently, it inhibited both pro\u2011inflammatory M1 and pro\u2011fibrotic M2 macrophage polarisation, alleviated alveolar epithelial\u2011mesenchymal transition (EMT), preserved endothelial CD31 expression, and enhanced tissue repair via cytoskeletal remodelling. IL\u201133 NAb exerts significant anti\u2011inflammatory and anti\u2011fibrotic effects through multi\u2011target interventions. Both genetic (IL\u201133 KO) and pharmacological (IL\u201133 NAb) evidence demonstrate that IL\u201133 is a key driver of IIM-ILD, acting via PI3K/AKT/mTOR\u2011mediated NF\u2011\u03baB/STAT3 activation. This provides a novel therapeutic strategy for IIM-ILD.\n\nID: 42500649\nTitle: Natural products and immune-cell responses in osteoarthritis: mechanisms, evidence maturity, and translational gaps.\nAbstract: Osteoarthritis (OA) is increasingly recognized as an immune-associated whole-joint disorder characterized by chronic low-grade inflammation, which contributes to joint degeneration, structural deterioration, and persistent pain. Innate and adaptive immune cells, including macrophages, T cells, neutrophils, and mast cells, participate in OA pathogenesis by releasing pro-inflammatory cytokines, reactive oxygen species, and matrix-degrading enzymes, as well as by interacting with chondrocytes, synovial fibroblasts, and subchondral bone cells. Natural products, because of their multi-target pharmacological properties, have emerged as potential modulators of this complex immune microenvironment. This review critically appraises current evidence on natural-product interventions modulating OA-associated immune-cell responses, with particular emphasis on mechanistic evidence, evidence maturity, and translational potential. It further compares evidence across immune-cell populations to identify shared mechanisms, population-specific differences, and key translational gaps. Macrophage- and T-cell-associated responses have the most developed evidence base, with relatively consistent evidence supporting modulation of M1-like/M2-like macrophage phenotypes and the T helper 17 (Th17)/regulatory T (Treg) cell balance. Neutrophil- and mast-cell-associated responses represent emerging or auxiliary areas of evidence, as these immune-cell populations may amplify inflammation and pain through reactive oxygen species production, neutrophil extracellular trap formation, degranulation, and inflammatory mediator release. Evidence for B cells, dendritic cells (DCs), and natural killer (NK) cells remains limited; therefore, these immune-cell populations should currently be regarded as potential research directions rather than established therapeutic targets. Most available data derive from in vitro and animal studies, whereas clinical evidence is largely restricted to peripheral immune-marker changes and short-term symptom improvement. Future studies should integrate local joint immune profiling, functional validation, and stratified clinical designs to clarify the translational potential of natural products in OA immunomodulation.\n\nID: 42496581\nTitle: Macrophage membrane-coated nanoparticles control pathological inflammation and enhance survival in models of severe bacterial pneumonia.\nAbstract: Severe bacterial pneumonia is a leading cause of death worldwide, and mortality rates remain unacceptably high despite appropriate antibiotic treatment. Macrophage membrane-coated nanoparticles (M\u03a6-NPs) are biomimetic constructs engineered to neutralize bacterial toxins, pathogen-associated molecular patterns, and proinflammatory cytokines. To evaluate the therapeutic potential of M\u03a6-NPs for the treatment of severe bacterial pneumonia. We evaluated the therapeutic potential of M\u03a6-NPs using in vitro models of infection involving human lung endothelial and epithelial cells, as well as primary human neutrophils, and in vivo murine models of Pseudomonas aeruginosa (PA) and methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. M\u03a6-NPs demonstrated potent cytoprotective and anti-inflammatory activity in vitro, without impairing neutrophil antimicrobial function. In both PA and MRSA pneumonia models, M\u03a6-NP treatment significantly improved survival, reduced bacterial burden, lowered proinflammatory cytokines, and preserved lung architecture. Quantitative proteomics further revealed suppression of inflammatory, coagulation, and fibrotic pathways associated with poor outcomes in human pneumonia and ARDS. These findings establish M\u03a6-NPs as a promising host-directed therapeutic strategy for mitigating the deleterious inflammatory sequelae of severe bacterial pneumonia.\n\nID: 42492266\nTitle: Astragalus polysaccharides alleviate cantharidin-induced liver injury by inhibiting the S100A8/A9-mediated TLR4/NF-\u03baB inflammatory pathway.\nAbstract: Cantharidin (CTD), a potent anti-tumor compound from traditional medicine, has its clinical application restricted by severe hepatotoxicity. Astragalus polysaccharides (APS), the primary active components of the food-medicine homologous herb Astragalus membranaceus, are recognized for their hepatoprotective properties. This study aimed to elucidate the molecular mechanism by which APS protects against CTD-induced liver injury. In vivo and in vitro models of CTD-induced liver injury were established. The protective effects of APS were evaluated by serum biochemistry, histopathology, and ultrastructural observation. RNA-sequencing was employed to screen for key targets, which were subsequently validated using qRT-PCR, Western blot, and immunohistochemistry. The cellular origin of S100A8/A9 was identified by immunofluorescence co-localization. The functional role of S100A8/A9 was confirmed via siRNA-mediated gene knockdown. The effect of APS on the anti-tumor activity of CTD was evaluated in human hepatocellular carcinoma cell lines HepG2 and Huh7. APS (characterized by a weight-average molecular weight of 35.002 kDa) ameliorated CTD-induced liver injury, reducing biochemical markers and histopathological damage. RNA-seq identified S100A8/A9 as key targets whose CTD-induced upregulation was reversed by APS. Mechanistically, APS significantly inhibited CTD-induced neutrophil and macrophage infiltration in the liver, and immunofluorescence co-localization confirmed that the elevated S100A8/A9 was mainly derived from infiltrating neutrophils. APS downregulated S100A8/A9 expression, thereby inhibiting the TLR4/NF-\u03baB pathway and the release of pro-inflammatory cytokines (TNF-\u03b1, IL-1\u03b2, IL-6). Critically, S100A8/A9 knockdown confirmed their pivotal role in the inflammatory response and demonstrated a synergistic protective effect when combined with APS. Importantly, APS did not impair the anti-proliferative and pro-apoptotic effects of CTD on human hepatocellular carcinoma cells; instead, it exhibited synergistic anti-tumor activity with CTD in HepG2 cells. APS alleviates CTD-induced hepatotoxicity by downregulating the S100A8/A9-mediated TLR4/NF-\u03baB inflammatory cascade, primarily through inhibiting neutrophil recruitment. Furthermore, APS enhances rather than compromises the anti-tumor efficacy of CTD in vitro. These findings support the development of APS as a therapeutic adjuvant to enhance the safety of CTD-based chemotherapy.\n\nID: 42490267\nTitle: Mass-Spectrometry-Identified Quality Markers of Jingtong Granules Are Predicted to Engage Upregulated Neutrophil Granule Enzymes in Cervical Spondylotic Radiculopathy: An Integrative Machine-Learning and Molecular-Dynamics Study.\nAbstract: Jingtong Granules is a clinically approved seven-herb formula for CSR, a condition in which radicular pain is sustained partly by inflammatory and immune processes, yet the immune-cellular state of CSR and the immune-level mechanism of the formula remain poorly defined. Using peripheral-blood transcriptomes from GSE223227 (7 controls, 9 CSR, and 30 degenerative cervical myelopathy), we profiled nine immune lineages by signature scoring, prioritized CSR-associated features with six machine-learning methods under permutation-based specificity testing, localized signature genes on the Human Protein Atlas sorted immune-cell reference, and linked the immune program to mass-spectrometry-confirmed constituents of Jingtong Granules by network pharmacology, molecular docking, molecular dynamics, and MM-GBSA. Two-level Mendelian randomization against cervical-specific FinnGen endpoints tested genetic causal directionality. CSR blood showed a bidirectional immune-rebalancing pattern: reduced NK-cell activity (p\u2009=\u20090.0164), increased M1-macrophage activity (p\u2009=\u20090.0311), and directionally higher neutrophil and lower CD8-cytotoxic scores. The neutrophil/myeloid effector program discriminated CSR from controls (AUROC 0.79), exceeding a size-matched random-panel null, whereas a generic NF-\u03baB/TNF panel performed near chance; a composite rebalancing score reached a preliminary AUROC of 0.90 (95% CI 0.71-1.00). Network pharmacology nominated MPO as a formula-associated immune target, whereas patient-upregulated, neutrophil-localized ELANE and CTSG were prioritized as structurally tractable granule enzymes. The validated quality markers nodakenin and paeoniflorin docked favorably to ELANE and CTSG and remained in their catalytic pockets during molecular dynamics, with MM-GBSA binding free energies of -16.0 to -33.5\u2009kcal/mol. Both markers also showed favorable drug-like physicochemical profiles. Mendelian randomization gave no support for an upstream genetic-causal role of the myeloid-skewed immune state in cervical disk disorders or radiculopathy. These exploratory, single-cohort findings characterize CSR peripheral blood as myeloid-skewed and cytotoxic-attenuated and nominate a traceable constituent-to-enzyme hypothesis in which mass-spectrometry-confirmed Jingtong Granules markers may engage patient-upregulated neutrophil granule enzymes, warranting replication and experimental validation.\n\nID: 42489855\nTitle: Immune Microenvironment Engineering for Functional Periodontal Regeneration: Mechanisms, Biomaterial Strategies, and Translational Perspectives.\nAbstract: Periodontitis is a chronic inflammatory disease characterized by irreversible destruction of alveolar bone, periodontal ligament attachment, and supporting tooth structures. Emerging evidence suggests that periodontal tissue breakdown and regenerative failure are primarily driven by dysregulation of the local immune microenvironment rather than by direct bacterial insult. Therefore, conventional therapies focused primarily on microbial control are insufficient to restore immune homeostasis and functional regeneration of the cementum-periodontal ligament-alveolar bone complex. Effective periodontal regeneration requires coordinated infection management, immune modulation, oxidative stress clearance, and inflammatory microenvironment reprogramming to relieve the suppression of regenerative cells, particularly periodontal ligament stem cells. This review summarizes key regulatory networks of the periodontal immune microenvironment, with emphasis on macrophage polarization, neutrophil heterogeneity, and the imbalance between Th17 cells and regulatory T cells. We further discuss recent immune-engineering strategies for restoring periodontal homeostasis, including surface-modified biomaterials, ion-delivery systems, stem cell-derived extracellular vesicles, gene-editing technologies, and smart responsive therapeutic scaffolds. Advances in single-cell and spatial transcriptomics have revealed previously unrecognized functional subpopulations, such as NLRP3+ macrophages and SAA1+ fibroblasts, offering new opportunities for precision immunomodulation. Collectively, this review provides an integrated and translational framework for leveraging immune microenvironment-based interventions to achieve functional and predictable periodontal regeneration.\n\nID: 42488422\nTitle: Role of the gut-lung axis in sepsis and the effect of probiotics on pulmonary complications.\nAbstract: Sepsis is a major cause of mortality and organ failure, particularly associated with pulmonary complications. This study investigates the role of the gut-lung axis in sepsis-induced lung injury and explores the therapeutic potential of the probiotic Lactobacillus rhamnosus GG in improving these effects. Using a cecal ligation and puncture (CLP) model in male Wistar rats, we assessed pulmonary function, histopathology, and inflammation. Twenty-four animals were randomly assigned into four groups (n = 8/group): Control, Sepsis, Probiotic, and Sepsis + Probiotic. Lactobacillus rhamnosus GG (2 \u00d7 10\u2078 CFU/day) was administered orally for seven days. Pulmonary function was assessed using whole-body plethysmography and flexiVent, while lung histopathology and fibrosis were evaluated using hematoxylin and eosin and Masson's trichrome staining. Inflammatory cytokines (TNF-\u03b1, IL-1\u03b2, IL-6, IL-10) were quantified by ELISA, gut microbiota composition was analyzed by 16S rRNA sequencing, and arterial blood gas and hemodynamic parameters were recorded. Sepsis significantly impaired pulmonary function, characterized by reduced tidal volume and lung compliance, increased respiratory rate, hypoxemia, hypercapnia, metabolic acidosis, hypotension, and tachycardia (p < 0.01). Peripheral neutrophil and macrophage counts were elevated, and severe gut dysbiosis was observed, marked by reduced microbial diversity and increased Proteobacteria abundance. Probiotic treatment significantly improved pulmonary mechanics and lung histology compared to untreated septic animals. Probiotic supplementation also restored gut microbiota diversity, reduced pro-inflammatory cytokines, and enhanced anti-inflammatory responses. These results suggest that Lactobacillus rhamnosus GG acts via the gut-lung axis to alleviate sepsis-induced pulmonary dysfunction, supporting its potential as an adjunctive therapy for sepsis.\n\nID: 42485758\nTitle: IL-1Ra overexpression enhances the therapeutic efficacy of mesenchymal stem cells in acute lung injury.\nAbstract: Acute lung injury (ALI) is a severe lung condition that can lead to acute respiratory failure. Given their anti-inflammatory and reparative properties, mesenchymal stem cells (MSCs) represent a promising therapeutic approach. This study aims to investigate the therapeutic potential and underlying mechanisms of interleukin-1 receptor antagonist (IL-1Ra) overexpressing MSCs (oeIL-1Ra-MSCs) in a murine ALI model. Following ALI induction, mice were treated with either oeIL-1Ra-MSCs or control MSCs (Mock-MSCs). The therapeutic effects on the lungs were evaluated using micro-CT, histopathology, and analysis of pro-inflammatory cytokines. Additionally, immunohistochemical and immunofluorescent analyses were performed on lung tissue, and mRNA sequencing was conducted to compare gene expression profiles between oeIL-1Ra-MSCs and Mock-MSCs. oeIL-1Ra-MSCs more effectively improved lung function in ALI mice, as evidenced by reduced patchy opacities, increased lung volume, decreased injury scores, and attenuated pulmonary edema. The treatment also significantly suppressed inflammation by decreasing pro-inflammatory cytokines and reducing macrophage and neutrophil infiltration. Furthermore, oeIL-1Ra-MSCs promoted tissue repair by enhancing the proliferation of alveolar type II epithelial (ATII) cells. mRNA sequencing identified elevated expression of insulin-like growth factor 2 (IGF2) in oeIL-1Ra-MSCs compared with Mock-MSCs. In vitro studies confirmed that IGF2 mediated the therapeutic effects partly by regulating the AKT/Bcl-2 and AKT/GSK-3\u03b2/Cyclin D1 signaling pathways, thereby inhibiting apoptosis and promoting the proliferation of ATII cells. In conclusion, IL-1Ra overexpression markedly enhances the therapeutic efficacy of MSCs in ALI by dual mechanisms: IL-1Ra secretion to counteract inflammation, and subsequent secretion of IGF2 to drive tissue regeneration, highlighting their strong potential for ALI.\n\nID: 42484928\nTitle: Beyond fibrosis: Emerging role of IL-11 in regulating innate and adaptive immune cell plasticity.\nAbstract: Interleukin-11 (IL-11), a member of the IL-6 cytokine family, is well-recognized for its role in driving fibrosis and stromal remodeling. Extensive research on this fibroblast-associated cytokine have focused on its roles in tissue scarring and extracellular matrix deposition. However, emerging evidence has unveiled its sophisticated role in immunomodulation, extending far beyond its conventional pro-fibrotic functions. This review demonstrates how IL-11 influences phenotypic shifts of immune cell plasticity within both innate and adaptive compartments. In the myeloid lineage, IL-11 orchestrates macrophage polarization and macrophage-to-mesenchymal transition (MMT), regulates neutrophil extracellular traps (NETs) formation, and modulates the plasticity of NK cells, while in the lymphoid compartment, it influences T helper cell differentiation, regulatory T cell stability, and B cell responses. Of note, the effect of IL-11 on immune cells may be exerted either directly through engagement with the target cells or indirectly via intercellular crosstalk. Furthermore, we also highlight the therapeutic potential of modulating the IL-11 signaling axis through monoclonal antibodies, siRNAs, peptides, recombinant proteins, and small molecules to restore immune homeostasis across multiple disease states.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 20 quotes\" then there must be at least 20 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH ... tags at the very beginning of your response.\n\n=======================================================\nCONTEXT LITERATURE (STATIC CACHE):\nID: 42462036\nTitle: Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.\nAbstract: Aging disrupts tissue homeostasis across organ systems. Here, we identify tissue-resident macrophages (TRMs) as central coordinators of age-related organ decline through impaired clearance of senescent neutrophils, a process regulated by the immunomodulatory prostaglandin E2 (PGE2) receptor EP2. Reducing TRM EP2 signaling in aged mice preserved youthful mitochondrial fitness and prevented cognitive decline, frailty, sarcopenia, adiposity, cardiac impairment, and systemic inflammation. Plasma proteomics implicated the liver as a major source of age-associated immune change, in which reduced TRM EP2 signaling rescued neutrophil efferocytosis and prevented paracrine stress in neighboring cells. Elevated TRM EP2 expression and senescent neutrophils were also observed in aged and diseased human tissues. Pharmacologic EP2 inhibition restored youthful neutrophil clearance, establishing impaired TRM efferocytosis as a reversible driver of organ decline in aging.\n\nID: 41715099\nTitle: Indole-acetaldehyde from Rothia mucilaginosa activates the PXR/NRF2 axis to enhance alveolar macrophage phagocytosis and protect against ARDS.\nAbstract: BACKGROUND: Despite advances in therapeutic strategies, acute respiratory distress syndrome (ARDS) mortality remains high. Growing evidence links respiratory microbiome composition to ARDS outcomes. This investigation sought to elucidate how colonizing bacteria and their metabolites influence ARDS pathogenesis. METHODS: Bronchoalveolar lavage fluid (BALF) from patients with pulmonary infections was analyzed by metagenomic next-generation sequencing (mNGS) to identify characteristic bacteria. Bacterial culture supernatants were analyzed by untargeted metabolomics (LC-MS) to identify metabolites. A murine ARDS model was established through intratracheal LPS instillation. Single-cell sequencing datasets from the GEO database were analyzed to reveal differential cell populations and functional alterations in murine ARDS. Potential molecular mechanisms were explored through molecular docking, RNA-seq analysis, Western boltting, and targeted gene knockdown in murine and cellular model. RESULTS: R. mucilaginosa demonstrated enrichment in patients without ARDS (nARDS). The bacterial culture supernatant conferred substantial protection in murine models, whereas viable bacteria showed minimal efficacy. LC-MS analysis identified indole-3-acetaldehyde (IAAld) as the predominant metabolite in the supernatant. Single-cell sequencing suggested that resident alveolar macrophages (RAMs) were pivotal cells in murine ARDS model. IAAld enhanced RAMs phagocytosis, facilitating neutrophil and LPS clearance. Mechanistic studies revealed that IAAld likely activated PXR signaling, promoted NRF2 nuclear translocation, and upregulated the phagocytosis-related gene CD36. Targeted PXR knockdown eliminated these protective effects. CONCLUSION: The respiratory commensal R. mucilaginosa synthesizes IAAld, which\u2014independent of bacterial colonization per se\u2014ameliorates ARDS through PXR/NRF2/CD36 axis activation, thereby enhancing macrophage phagocytic function. These findings suggest that therapeutic targeting of microbial metabolites represents a novel ARDS treatment paradigm.\n\nID: 41565804\nTitle: The transition from monocyte to tissue-resident macrophage requires DHPS.\nAbstract: Tissue-resident macrophages (RTMs) form during embryogenesis, self-renew locally, and regulate tissue homeostasis by clearing dead cells and debris1-6. During tissue damage, however, bone-marrow-derived monocytes enter tissues and differentiate into RTMs, repairing the tissue and replenishing macrophages in the niche1. The universal cell-intrinsic mechanisms that control the monocyte-to-RTM transition and the maintenance of mature RTMs across tissues remain elusive3. Here we show that deoxyhypusine synthase (DHPS), an enzyme that mediates spermidine-dependent hypusine modification of translation factor eIF5A5,7, is required for RTM differentiation and maintenance. Mice with myeloid cell lack of DHPS (Dhps-\u0394M mice) had a global defect in RTMs across tissues, resulting in persistent but ultimately futile monocyte influx. Transcriptional analyses of DHPS-deficient macrophages indicated a block in their ability to differentiate into mature RTMs, whereas proteomics revealed defects in cell adhesion and signalling pathways. Sequencing of ribosome-engaged transcripts identified a subset of mRNAs involved in cell adhesion and signalling that rely on DHPS for efficient translation. Imaging of DHPS-deficient macrophages in tissues showed differences in morphology and tissue interactions, which were correlated with their failed RTM differentiation. DHPS-deficient macrophages were also defective in critical homeostatic RTM functions including efferocytosis and tissue maintenance. Together, our results demonstrate a cell-intrinsic, tissue-agnostic pathway that drives differentiation of monocyte-derived macrophages into RTMs.\n\nID: 41554295\nTitle: Maresin 1 ameliorates myocardial ischaemia\u2012reperfusion injury by promoting tissue resident macrophage efferocytosis.\nAbstract: Myocardial ischaemia\u2012reperfusion (I/R) injury triggers a robust inflammatory storm cascade that critically compromises reperfusion efficacy following acute myocardial infarction. Enhanced efferocytosis by cardiac resident macrophages (RMs) has therapeutic potential for inflammation resolution. The unsaturated long-chain fatty acid Maresin1 (MaR1) exhibits potent anti-inflammatory properties that is devoid of immunosuppressive effects. However, its therapeutic potential in myocardial I/R injury and regulatory mechanisms in cardiac RMs remains unexplored. A clinical case\u2012control study was conducted and revealed a negative association between circulating MaR1 levels and inflammatory markers and the severity of I/R injury in patients with ST-elevation myocardial infarction. Mice treated with MaR1 after myocardial I/R injury showed improvements in cardiac function and efferocytosis by cardiac RMs. Genetic ablation of cardiac RMs abolished MaR1-mediated cardioprotection. To explore the mechanism underlying this protection, we performed transcriptomic, metabolomics, and lipidomic analyses and identified fatty acid \u03b2-oxidation potentiation as a key metabolic signature in MaR1-treated RMs. Moreover, MaR1 directly bound peroxisome proliferator-activated receptor \u03b3 (PPAR\u03b3), inducing the transcriptional activation of its downstream efferocytosis-related target CD204. Specific knockout of PPAR\u03b3 in RMs significantly attenuated MaR1-enhanced efferocytosis. Notably, oral supplementation with the MaR1 precursor docosahexaenoic acid (DHA) recapitulated these cardioprotective effects. Our findings prove that MaR1 plays a protective role in myocardial I/R injury by facilitating efferocytosis by RMs and the resolution of inflammation. These results offer novel therapeutic perspectives for the management of myocardial I/R injury.\n\nID: 41151577\nTitle: Human heart-macrophage assembloids mimic immune-cardiac interactions and enable arrhythmia disease modeling.\nAbstract: Yolk-sac-derived embryonic cardiac tissue-resident macrophages (TRMPs) colonize the heart early in development and are essential for proper heart development, supporting tissue remodeling, angiogenesis, electrical conduction, efferocytosis, and immune regulation. We present here a human heart-macrophage assembloid (hHMA) model by integrating autologous human pluripotent stem cell (hPSC)-derived embryonic monocytes into heart organoids to generate physiologically relevant TRMPs that persist long-term and contribute to cardiogenesis. Using single-cell transcriptomics, live imaging, and proteomics, we demonstrate that TRMPs modulate cardiac paracrine signaling, perform efferocytosis, and regulate extracellular matrix remodeling and electrical conduction. In a proof-of-concept maturated hHMA model of chronic inflammation, TRMPs adopt pro-inflammatory phenotypes that promote arrhythmogenic activity, consistent with atrial fibrillation through activation of the NOD-like receptor pyrin domain-containing 3 (NLRP3) inflammasome. This system enables detailed mechanistic studies of immune-cardiac interactions and provides a powerful in vitro platform for modeling human heart development and inflammation-driven arrhythmias.\n\nID: 40577069\nTitle: M2-Like Macrophages Exhibit Sialic Acid-Enhanced Efferocytosis via the Siglec CD22.\nAbstract: The sialic acid/Siglec axis is an important immunologic regulatory pathway in which host-specific \u03b12,6-sialylated glycans are recognized as markers of self. CD22, known primarily as a surface receptor on B cells, directly prevents autoantigen responses through concurrent recognition of \u03b12,6-linked sialic acids. Here, we report that CD22 is expressed in macrophages polarized to an M2-like, immunomodulatory phenotype. Tissue-resident macrophage populations classically showing an M2-like skew, such as in the lung, were found to be significantly enriched for CD22 expression. We also discovered that CD22 promotes efferocytosis of sialylated glycoproteins and apoptotic debris and is associated with increased protein processing but reduced T cell activation. These findings support a model whereby CD22+ M2-like macrophages participate in the resolution of inflammation and a return to tissue homeostasis via the clearance of host-derived \u03b12,6-sialylated debris, degrading this material without further exacerbation of T cell-mediated inflammation.\n\nID: 39938482\nTitle: Early-age efferocytosis directs macrophage arachidonic acid metabolism for tissue regeneration.\nAbstract: In response to organ injury in adults, macrophages often promote scarring, yet during early life, they are required for tissue regeneration. To elucidate the mechanisms underlying age-associated regeneration, we compared the macrophage injury response in newborn versus adult hearts. Single-cell analysis revealed an accumulation of tissue-resident macrophages in neonates that were selectively polarized for apoptotic cell recognition and uptake (efferocytosis). Ablation of the apoptotic cell recognition receptor Mertk in newborns prevented cardiac regeneration. These findings could be attributed to reprogramming of macrophage gene expression that was required for biosynthesis of the eicosanoid thromboxane A2, which unexpectedly activated parenchymal cell proliferation. Markers of thromboxane A2 production were suppressed in adult macrophages after efferocytosis. Moreover, macrophage-neighboring neonatal cardiomyocytes expressed the thromboxane A2 receptor, whose activation induced a metabolic shift that supported cellular proliferation. Our data reveal a fundamental age-defined macrophage response in which lipid mitogens produced during efferocytosis support receptor-mediated tissue regeneration.\n\nID: 35830797\nTitle: Multiomics reveal the central role of pentose phosphate pathway in resident thymic macrophages to cope with efferocytosis-associated stress.\nAbstract: Tissue-resident macrophages (TRMs) are heterogeneous cell populations found throughout the body. Depending on their location, they perform diverse functions maintaining tissue homeostasis and providing immune surveillance. To survive and function within, TRMs adapt metabolically to the distinct microenvironments. However, little is known about the metabolic signatures of TRMs. The thymus provides a nurturing milieu for developing thymocytes yet efficiently removes those that fail the selection, relying on the resident thymic macrophages (TM\u03c6s). This study harnesses multiomics analyses to characterize TM\u03c6s and unveils their metabolic features. We find that the pentose phosphate pathway (PPP) is preferentially activated in TM\u03c6s, responding to the reduction-oxidation demands associated with the efferocytosis of dying thymocytes. The blockade of PPP in M\u03c6s leads to decreased efferocytosis, which can be rescued by reactive oxygen species (ROS) scavengers. Our study reveals the key role of the PPP in TM\u03c6s and underscores the importance of metabolic adaptation in supporting M\u03c6 efferocytosis.\n\nID: 35085834\nTitle: Role of indoleamine 2,3-dioxygenase 1 (IDO1) and kynurenine pathway in the regulation of the aging process.\nAbstract: Indoleamine 2,3-dioxygenase 1 (IDO1) is activated in chronic inflammatory states, e.g., in the aging process and age-related diseases. IDO1 enzyme catabolizes L-tryptophan (L-Trp) into kynurenine (KYN) thus stimulating the KYN pathway. The depletion of L-Trp inhibits the proliferation of immune cells in inflamed tissues and it also reduces serotonin synthesis predisposing to psychiatric disorders. Interestingly, IDO1 protein contains two immunoreceptor tyrosine-based inhibitory motifs (ITIM) which trigger suppressive signaling through the binding of PI3K p110 and SHP-1 proteins. This immunosuppressive activity is not dependent on the catalytic activity of IDO1. KYN and its metabolite, kynurenic acid (KYNA), are potent activators of the aryl hydrocarbon receptor (AhR) which can enhance immunosuppression. IDO1-KYN-AhR signaling counteracts excessive pro-inflammatory responses in acute inflammation but in chronic inflammatory states it has many harmful effects. A chronic low-grade inflammation is associated with the aging process, a state called inflammaging. There is substantial evidence that the activation of the IDO1-KYN-AhR pathway robustly increases with the aging process. The activation of IDO1-KYN-AhR signaling does not only suppress the functions of effector immune cells, probably promoting immunosenescence, but it also impairs autophagy, induces cellular senescence, and remodels the extracellular matrix as well as enhancing the development of osteoporosis and vascular diseases. I will review the function of IDO1-KYN-AhR signaling and discuss its activation with aging as an enhancer of the aging process.\n\nID: 34851304\nTitle: Immunometabolism as predictor of frailty.\nAbstract: \n\nID: 28524767\nTitle: Immune biomarkers in older adults: Role of physical activity.\nAbstract: Aging is associated with a decline in the normal functioning of the immune system. Several studies described the relationship between immunological alterations, including immunosenescence and inflammation, and aging or age-related outcomes, such as sarcopenia, depression, and neurodegenerative disorders. Physical activity is known to improve muscle function and to exert a number of benefits on older adult health, including reduced risk for heart and metabolic system chronic diseases. However, the positive influence of physical activity on the immune system has not been elucidated. In order to shed light on the role of physical activity in immune responses of older individuals, a number of immunological parameters comprising % lymphocyte subsets (CD3+, CD4+, CD8+, CD19+, and CD16+56+) and serum levels of neopterin and tryptophan metabolism products were evaluated in peripheral blood samples of older adults performing normal (N = 170) or reduced (N = 89) physical activity. In addition, the potential influence of other clinical and epidemiological factors was also considered. Results showed that subjects with reduced physical activity displayed significantly higher levels of CD4+/CD8+ ratio, kynurenine/tryptophan ratio, and serum neopterin, along with lower %CD19+ cells and tryptophan concentrations. Further, some immunological biomarkers were associated with cognitive impairment and functional status. These data contribute to reinforce the postulation that physical activity supports healthy aging, particularly by helping to protect the immunological system from aging-related changes.\n\nID: 24901869\nTitle: Oxidative stress decreases functional airway mannose binding lectin in COPD.\nAbstract: We have previously established that a defect in the ability of alveolar macrophages (AM) to phagocytose apoptotic cells (efferocytosis) and pathogens is a potential therapeutic target in COPD. We further showed that levels of mannose binding lectin (MBL; required for effective macrophage phagocytic function) were reduced in the airways but not circulation of COPD patients. We hypothesized that increased oxidative stress in the airway could be a cause for such disturbances. We therefore studied the effects of oxidation on the structure of the MBL molecule and its functional interactions with macrophages. Oligomeric structure of plasma derived MBL (pdMBL) before and after oxidation (oxMBL) with 2,2'-azobis(2-methylpropionamidine)dihydrochroride (AAPH) was investigated by blue native PAGE. Macrophage function in the presence of pd/oxMBL was assessed by measuring efferocytosis, phagocytosis of non-typeable Haemophilus influenzae (NTHi) and expression of macrophage scavenger receptors. Oxidation disrupted higher order MBL oligomers. This was associated with changed macrophage function evident by a significantly reduced capacity to phagocytose apoptotic cells and NTHi in the presence of oxMBL vs pdMBL (eg, NTHi by 55.9 and 27.0% respectively). Interestingly, oxidation of MBL significantly reduced macrophage phagocytic ability to below control levels. Flow cytometry and immunofluorescence revealed a significant increase in expression of macrophage scavenger receptor (SRA1) in the presence of pdMBL that was abrogated in the presence of oxMBL. We show the pulmonary macrophage dysfunction in COPD may at least partially result from an oxidative stress-induced effect on MBL, and identify a further potential therapeutic strategy for this debilitating disease.\n\nID: 19124657\nTitle: Efferocytosis impairs pulmonary macrophage and lung antibacterial function via PGE2/EP2 signaling.\nAbstract: The ingestion of apoptotic cells (ACs; termed \"efferocytosis\") by phagocytes has been shown to trigger the release of molecules such as transforming growth factor beta, interleukin-10 (IL-10), nitric oxide, and prostaglandin E(2) (PGE(2)). Although the antiinflammatory actions of these mediators may contribute to the restoration of homeostasis after tissue injury, their potential impact on antibacterial defense is unknown. The lung is highly susceptible to diverse forms of injury, and secondary bacterial infections after injury are of enormous clinical importance. We show that ACs suppress in vitro phagocytosis and bacterial killing by alveolar macrophages and that this is mediated by a cyclooxygenase-PGE(2)-E prostanoid receptor 2 (EP2)-adenylyl cyclase-cyclic AMP pathway. Moreover, intrapulmonary administration of ACs demonstrated that PGE(2) generated during efferocytosis and acting via EP2 accounts for subsequent impairment of lung recruitment of polymorphonuclear leukocytes and clearance of Streptococcus pneumoniae, as well as enhanced generation of IL-10 in vivo. These results suggest that in addition to their beneficial homeostatic influence, antiinflammatory programs activated by efferocytosis in the lung have the undesirable potential to dampen innate antimicrobial responses. They also identify an opportunity to reduce the incidence and severity of pneumonia in the setting of lung injury by pharmacologically targeting synthesis of PGE(2) or ligation of EP2.\n\nID: 42490836\nTitle: Untargeted metabolomic profiling of hydrosalpinx fluid: a descriptive analysis with pelvic fluid as external reference.\nAbstract: Hydrosalpinx is one of the common organic causes of infertility, and the accumulation of fluid in this condition can severely affect embryo implantation and development. We collected fallopian tube fluid from 10 patients with hydrosalpinx and normal pelvic fluid from 10 infertile women undergoing tubal patency testing as an external reference for untargeted metabolomics analysis. Metabolites were annotated using the KEGG and HMDB databases, and key metabolic disorder pathways were identified. Weighted gene co-expression network analysis (WGCNA) was then employed to screen for hub metabolites closely associated with disease status. The results showed that a total of 660 significantly different metabolites were identified, of which 209 were upregulated and 451 were downregulated. Enrichment analysis indicated that these metabolites were mainly involved in the Biosynthesis of unsaturated fatty acids, Efferocytosis, Arachidonic acid metabolism, Tryptophan metabolism, etc. WGCNA further identified several core metabolites, including 5-[1-Carboxy-2-(Trimethylazaniumyl) Ethoxy]-5-Oxopentanoate, D-Dopachrome, etc. Compared with pelvic fluid, the metabolic profile of hydrosalpinx shows differences in lipid and amino acid metabolism, including differences in unsaturated fatty acid Biosynthesis, apoptotic cell clearance, arachidonic acid metabolic pathways, and tryptophan metabolism.\n\nID: 42439678\nTitle: Follistatin Mitigates Atherosclerosis Through Activation of Arginine Metabolism and Adipose Browning.\nAbstract: Follistatin (FST) binds to and neutralizes members of the transforming growth factor-beta (TGF-\u03b2) superfamily, thereby regulating diverse physiological processes, including regulation of skeletal muscle, adipose, and bone homeostasis. FST also promotes adipose browning and enhances energy metabolism, leading to improved plasma lipid profiles and metabolic health in mice. Given the emerging association between brown adipose tissue (BAT) activation and reduced atherosclerosis, we investigated the anti-atherogenic potential of FST. Transcriptomic and metabolomic analyses of the Hybrid Mouse Diversity Panel (HMDP) revealed that Fst expression was negatively correlated with aortic lesion area and positively correlated with the expression of multiple adipose browning-associated genes. Adeno-associated viral delivery of Fst (AAV1-FST344) in Ldlr-/- mice significantly reduced aortic lesion area, improved plasma lipid profiles, and decreased expression of adhesion (VCAM1) and inflammatory (iNOS, TNF-\u03b1) markers in white adipose tissue (WAT), liver, and heart. Fst gene delivery also markedly increased uncoupling protein 1 (UCP1) expression in WAT, consistent with WAT browning. Integrated correlation analyses of Fst expression with tissue metabolites, together with plasma metabolite-lesion associations identified in the HMDP, implicated the arginase 1 (Arg1)-mediated metabolic pathway as a key regulator of atherogenesis. Consistent with these findings, Arg1 expression was significantly elevated in WAT, liver, and heart of AAV1-FST344-treated mice and in wild-type versus Fst-knockout mouse embryonic fibroblasts (MEFs). Immunostaining localized Arg1 predominantly to CD68+ macrophages in heart and liver. Given recent evidence identifying Arg1 as a novel mediator of efferocytosis, these findings suggest that Arg1 may promote macrophage metabolic reprogramming and resolution of inflammation by enhancing the clearance of apoptotic cells. Furthermore, Fst gene delivery increased the expression of fibroblast growth factor 21 (Fgf21) and adiponectin (AdipoQ) in WAT. Collectively, these findings identify Fst as a novel anti-atherogenic regulator that protects against vascular disease by promoting adipose browning, improving lipid metabolism, and activating Arg1-mediated metabolic pathways.\n\nID: 42347596\nTitle: A Virus-Agnostic Cellular Immunomodulatory Platform for Chronic Respiratory Disease: Restoring Immune Competence and Mitigating Exacerbations in the Elderly.\nAbstract: Chronic respiratory diseases (CRDs) represent a significant global mortality burden, largely driven by viral-triggered exacerbations. In the elderly, susceptibility to viral pathogens is critically linked to the \"interferon gap\"-a kinetic delay in innate antiviral signaling resulting from immunosenescence and Th2-skewed inflammaging. While traditional vaccines provide pathogen-specific protection, their efficacy is often compromised by age-related immune hyporesponsiveness and antigenic drift. This perspective paper proposes a dual-phase, virus-agnostic immunomodulatory platform designed to restore mucosal immune competence and provide a rapid-response intervention for incipient exacerbations. Rather than acting as a pathogen-specific vaccine, the platform serves as a comprehensive host immune-rejuvenation engine and cellular adjuvant platform. The platform consists of two integrated stages: Allopriming and Alloantigen Inhalation Recall (AIR). Allopriming utilizes AlloStim\u00ae (activated, allogeneic Th1 cells) to leverage the evolutionarily conserved allo-rejection response, establishing a lung mucosal reservoir of allo-specific Th1 tissue-resident memory cells (Trm). Building on previously published Phase I/II data showing that Allopriming reverses biomarkers of immunosenescence and sustains durable heterologous antiviral responsiveness, the AIR strategy is introduced as a patient-administered rescue mechanism for frail CRD patients. AIR is designed to activate pre-positioned Trm cells at the earliest onset of symptoms, inducing a high-magnitude IFN-\u03b3 surge in the lung mucosa. By bridging the senescent \"interferon gap\" with the rapid effector kinetics of Trm activation, this approach represents a novel paradigm toward reconstituting youthful-like antiviral mucosal immunity to both enhance vaccine efficacy in the elderly and protect against both seasonal pathogens and emerging viral triggers (\"Disease X\") of CRD. Future randomized studies in long-term care settings are planned to evaluate clinical outcomes in high-risk populations.\n\nID: 42307976\nTitle: Personalized Pathogenic Nanoplastic Coronas Orchestrate Efferocytosis-Driven Immune Evasion in Lung Adenocarcinoma.\nAbstract: Airborne nanoplastic (NP) pollution is an emerging threat to respiratory health. Although inhaled NPs rapidly acquire a protein corona that shapes their bioactivity, the consequences of this process in cancer-susceptible lungs remain unclear. Here, we investigated whether NPs form a disease-specific pathogenic protein corona in lung adenocarcinoma that rewires immune signaling and accelerates tumor progression. Polyethylene terephthalate (PET) NPs were generated by mechanical fragmentation and extensively characterized. In tumor-bearing mice, inhaled PET NPs accelerated tumor growth relative to controls. Proteomic analysis of PET NPs incubated with bronchoalveolar lavage fluid from patients with lung adenocarcinoma identified lysozyme (LYZ) as a selectively enriched corona component associated with tumor stage and metastasis. Corona formation induced conformational remodeling of LYZ, enhanced its enzymatic activity, and prolonged its membrane retention. Mechanistically, corona-bound LYZ engaged Toll-like receptor 4 and activated a PGRN-LXR\u03b1 signaling axis, thereby increasing lysosomal acidification-dependent efferocytosis, promoting M2 macrophage polarization, and reducing CD8+ T-cell infiltration. In vivo, AAV9-mediated knockdown of LYZ or PGRN attenuated PET NP-induced efferocytosis, reversed immunosuppressive reprogramming, restored CD8+ T-cell infiltration, and suppressed tumor growth, demonstrating the functional requirement for this corona pathway. These findings establish disease-derived PET NP coronas as active nano-bio interfaces that connect environmental PET NP exposure with efferocytosis-driven immune evasion in lung adenocarcinoma. This work provides a mechanistic link between airborne NPs and tumor progression in susceptible hosts and highlights corona-mediated signaling as a potential therapeutic target and environmental health concern.\n\nID: 42296782\nTitle: Macrophage plasticity as a therapeutic target in inflammatory bowel disease: Immunomodulatory and regenerative strategies.\nAbstract: Inflammatory bowel disease (IBD), which mainly includes Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract characterized by recurrent episodes of intestinal inflammation. The development of IBD is influenced by multiple factors, including genetic predisposition, intestinal dysbiosis, epithelial barrier impairment, and abnormal immune activation. Among innate immune cells, macrophages are key regulators of intestinal immune homeostasis and are involved in inflammatory responses, tissue remodeling, and mucosal repair. Their ability to adopt different functional states in response to local environmental signals has made them an important focus of current therapeutic research in IBD. Traditionally, macrophages have been classified into pro-inflammatory M1 and anti-inflammatory M2 phenotypes. However, recent findings from single-cell transcriptomic and spatial analyses suggest that intestinal macrophages represent a far more diverse and dynamic population than this simplified classification implies. Multiple macrophage subsets with inflammatory, regulatory, reparative, and fibrosis-associated functions coexist within the intestinal microenvironment and contribute differently to disease progression and tissue healing. These observations highlight the importance of developing more selective and targeted macrophage-based therapeutic approaches. In this review, we discuss the current understanding of macrophage plasticity and its role in the pathogenesis of IBD. Particular attention is given to newer macrophage-targeted therapeutic strategies, including adoptive macrophage transfer, engineered macrophages, receptor-targeted therapies, nanoparticle-based delivery systems, microbiome modulation, microbial metabolite regulation, gene-editing approaches, organoid technologies, and biomaterial-assisted platforms. We also examine the contribution of macrophages to epithelial regeneration, mucosal healing, fibrosis, and intestinal tissue remodeling. In addition, we address several major challenges that currently limit the clinical translation of macrophage-targeted therapies. A better understanding of macrophage biology, together with continued advances in immunology, regenerative medicine, microbiome research, and biomaterials science, may support the development of more precise and personalized therapeutic strategies for patients with IBD.\n\nID: 42259776\nTitle: PRAS40-driven pro-inflammatory macrophage polarization is required for inflammatory bowel disease.\nAbstract: Inflammatory bowel diseases (IBDs) are chronic inflammatory disorders with unclear pathogenesis and limited therapeutic options. Macrophage dysfunction is central to IBD progression, yet how metabolic reprogramming governs macrophage function is poorly defined. Although the proline-rich Akt substrate of 40\u2009kDa (PRAS40) is known to be important in colon cancer, its role in IBD is elusive. We found that PRAS40 mRNA expression was elevated in IBD patients, and its protein expression was similarly increased in IBD mouse models. Global PRAS40 deficiency alleviated IBD symptoms in mice, which was reversed by macrophage elimination. Consistently, myeloid-specific PRAS40 knockout mice recapitulated the protective phenotype in IBD mice. Metabolomic analysis revealed decreased amino acid levels in PRAS40-deficient BMDMs, with leucine and tryptophan identified as key drivers of macrophage polarization. Mechanistically, PRAS40 enhanced the phosphorylation of the transcription factor specificity protein 1 (SP1) to stabilize it through activating ERK and JNK signaling pathways. Upregulated SP1 augmented the transcription of solute carrier family 7 member 5 (SLC7A5), thereby boosting leucine and tryptophan uptake. This subsequently activated mTOR signaling, driving the pro-inflammatory polarization of macrophages. Collectively, PRAS40/SP1/SLC7A5 axis drives macrophage pro-inflammatory polarization by enhancing leucine and tryptophan uptake, thereby exacerbating IBD. These findings highlight the importance of amino acid reprogramming in macrophage polarization during IBD progression and propose targeting this axis as a potential therapeutic strategy for IBD.\n\nID: 42145976\nTitle: Single-Cell and Mendelian Randomization Analyses Identify Macrophage Polarization and Efferocytosis Biomarkers in Osteoarthritis and Reveal Their Regulatory Mechanisms.\nAbstract: Osteoarthritis (OA) is a progressive joint disease influenced by macrophage-associated efferocytosis. This study aimed to identify key OA biomarkers by integrating transcriptomic and single-cell RNA sequencing (scRNA-seq) data with Mendelian randomization (MR). We integrated three OA-related transcriptomic datasets (GSE89408, GSE55457, and GSE152805) from synovial tissue with efferocytosis- and macrophage polarization-related genes (ERGs and MPRGs). Differentially expressed genes (DEGs) were identified and analyzed using gene set enrichment (ssGSEA), weighted gene co-expression network analysis (WGCNA), and functional enrichment (GO/KEGG). MR was performed with GWAS data to evaluate causal links between candidate genes and OA. Machine learning methods (LASSO and SVM-RFE), supported by ROC analysis and artificial neural network (ANN) modeling, and were used to screen potential biomarkers. Single-cell RNA-seq analysis was conducted with Seurat, incorporating clustering, functional enrichment, cell-cell communication (CellChat), and pseudotime trajectory analysis (Monocle) to characterize cellular heterogeneity and differentiation pathways in OA. MR and machine learning highlighted FMO4 and GPR65 as risk biomarkers, validated in independent datasets (AUC > 0.7). GPR65 showed strong associations with neutrophils, regulatory T cells, and antigen-presenting cell (APC) co-inhibition, while both genes were enriched in immune and metabolic pathways. Single-cell analysis identified synovial subintimal fibroblasts and HLA-DRA+ cells as key contributors with distinct differentiation patterns. An ANN model further improved OA classification. These findings provide new insights into OA pathogenesis and support FMO4 and GPR65 as promising diagnostic and therapeutic targets.\n\nID: 42143054\nTitle: Pharmabiotics, Phocaeicola dorei, ameliorates cholestatic liver fibrosis by alleviating macrophage efferocytosis of neutrophils.\nAbstract: Phocaeicola dorei has been reported to ameliorate metabolic diseases. Its role in liver fibrosis remains unclear. We evaluated the hepatoprotective effect of P. dorei in liver fibrosis. Fecal samples were collected from healthy controls and patients (n\u2009=\u2009285) to assess the clinical relevance of P. dorei. In male mice models (3,5-diethoxycarbonyl-1.4-dihydrocollidine [DDC] diet), P. dorei (109 CFU/g twice/week) was orally administered. Primary HSCs, LX-2, THP-1, and HL-60 cell lines were used for mechanical validation. The relative abundance of P. dorei increased with worsing liver disease in human. P. dorei administration significantly reduced neutrophil degranulation and efferocytosis pathways (Ly6g and F4/80). The dysregulated expression of neutrophil-associated chemokines (Cx3cl1 and Cx3cr1) was restored by P. dorei. P. dorei culture supernatant inhibited macrophage-mediated efferocytosis. P. dorei attenuates liver fibrosis by suppressing neutrophil and macrophage infiltration and disrupting efferocytosis. Our results identify P. dorei as a potential microbiome-based therapeutic candidate for cholestatic liver fibrosis.\n\nID: 42142240\nTitle: Food-Derived Limosilactobacillus fermentum GR-3 Enhances Anti-PD-1 Immunotherapy Efficacy.\nAbstract: Immune checkpoint blockade (ICB) has improved the cancer treatment, its application remains constrained by heterogeneous response rates and immune-related adverse events. While gut microbiome modulation represents a promising avenue to optimize ICB, rationally selected probiotics with defined mechanistic actions are critically lacking. Here, we selected Lactobacillus fermentum GR-3 (L. fermentum GR-3), a food-derived strain pre-screened for exceptional gastrointestinal resilience (maintaining\u2009>\u2009107\u00a0CFU/mL), antioxidant activity (87.4% DPPH-Scavenging efficiency), and immunomodulatory potential, as an oral combination strategy to enhance anti-PD-1 therapy. In the MC38 murine colorectal cancer model, oral L. fermentum GR-3 synergistically enhanced ICB efficacy, yielding significantly greater tumor suppression than anti-PD-1 monotherapy (51.7% volume reduction vs. untreated controls), while attenuating therapy-associated weight loss. Locally within the tumor microenvironment (TME), the combination therapy promoted dendritic cell maturation (MHC-II\u207a DCs reaching 56.0%), favored pro-inflammatory macrophage polarization (M1 increased to 20.8%, while M2 reduced to 2.57%), and suppressed regulatory T cell infiltration (Tregs decreased to 2.32%). These shifts strongly correlated with enhanced cytotoxic responses, with\u00a0Granzyme B\u207a CD8\u207a T cells reaching 40.4% (doubling the effect of PD-1 monotherapy). Mechanistically, L. fermentum GR-3 colonization partially reversed tumor-associated gut dysbiosis, enriching short-chain fatty acid (SCFA)-producing consortia (e.g., Lachnospiraceae and Bacteroides) and increasing intestinal SCFA concentrations (e.g., propionic and butyric acids recovering to 70.13 and 26.07\u00a0\u03bcM/g, respectively)). This microbial-metabolic shift was accompanied by upregulated expression of mucosal tight junction genes (ZO-1, Occludin). Furthermore, L. fermentum GR-3 facilitated a balanced immune response. Systemically, it alleviated oxidative stress and buffered peripheral inflammatory signals, contributing to immune homeostasis in non-tumor tissues (spleen and colon). Collectively, these findings position L. fermentum GR-3 as a grounded, translatable strategy to simultaneously enhance ICB efficacy and improve therapeutic tolerability.\n\nID: 42123491\nTitle: Immunometabolism in Cardiac Remodeling: Mechanisms and Therapeutic Perspectives.\nAbstract: Cardiovascular diseases remain the leading cause of mortality worldwide, and one of the key mechanisms driving the development of heart failure is pathological remodeling of the myocardium. This process involves complex structural, cellular, and metabolic alterations in which the immune system and its interactions with cardiomyocytes and fibroblasts play a central role. The aim of this work was to present the current state of knowledge on immunometabolism in cardiac remodeling and to discuss its pathophysiological relevance and therapeutic potential. This review focuses on the metabolism of cardiac macrophages, highlighting the differences between the pro-inflammatory (M1) and reparative (M2) phenotypes and their impact on inflammation, fibrosis, and myocardial regeneration. The roles of major metabolic pathways, including glycolysis, oxidative phosphorylation, fatty acid oxidation, and glutaminolysis, are discussed, as well as the importance of the NLRP3 inflammasome and efferocytosis in regulating the inflammatory response. Furthermore, the review briefly incorporates recent insights into neutrophil, T cell, and regulatory T cell (Treg) metabolism and their contributions to inflammation, repair, and fibrotic remodeling. Particular attention is also given to cardiac fibroblasts and their metabolic reprogramming during fibrosis, with emphasis on the pivotal role of transforming growth factor-\u03b2 (TGF-\u03b2) signaling. The review further discusses the role of microRNAs as mediators of intercellular communication integrating immunological and metabolic signals. The work is complemented by a discussion of therapeutic perspectives, including modulation of macrophage metabolism, fibrogenic signaling pathways, mitochondrial function, and miRNA-based therapies. Immunometabolism emerges as a promising research field whose further exploration may contribute to the development of novel, more precise strategies for the treatment of cardiovascular diseases.\n\nID: 42052880\nTitle: Dynamic metabolic programming of monocyte-derived cells defines immunity in CNS disease.\nAbstract: Monocyte-derived cells (MCs) are highly adaptable innate immune cells that play essential roles in central nervous system (CNS) inflammation. Their functional specialization is closely linked to their metabolic state, which is shaped by local cues such as nutrient availability, oxygen levels, and pro- and anti-inflammatory signals. In this review, we examine the major metabolic pathways that regulate MC behaviour, including glycolysis, oxidative phosphorylation, lipid metabolism, and amino acid metabolism. We assess how these pathways support specific effector functions such as cytokine production, phagocytosis, antigen presentation, and efferocytosis. Moving beyond the traditional M1/M2 framework, we discuss the context-dependent nature of MC metabolism and its role in driving diverse functional states. We then explore how these metabolic programs are engaged across key CNS disease settings, including sterile injury, demyelinating disease, and viral encephalitis. By integrating insights from immunometabolism and neuroinflammation, this review provides a framework for understanding the metabolic regulation of MCs in CNS pathology and highlights potential avenues for therapeutic intervention.\n\nID: 42030803\nTitle: Dangshen formula Shengmai-Yin suppresses atherosclerosis through restoring the gut microbiota and homeostatic efferocytosis.\nAbstract: Atherosclerosis (AS) is a chronic progressive vascular disease characterized by lipid deposition and aortic inflammation. On the basis of traditional Chinese medicine (TCM) theory, the Dangshen Formula Shengmai-Yin (DS-SMY) has demonstrated unique advantages in treating AS. However, the mechanism by which DS-SMY affects AS has not been revealed. In this study, high-fat diet-induced apolipoprotein E knockout (ApoE-/-) mice were used to construct AS models. The effects of DS-SMY on aortic collagen deposition and inflammatory infiltration were investigated, and atorvastatin (Ato) was used as a positive control. The composition of the gut microbiota was assessed using high-throughput sequencing of the 16S rRNA gene. Colon morphology was observed via TEM, and apoptosis was assessed with TUNEL staining. The main component of DS-SMY in drug-containing serum was determined by HPLC. The effects of DS-SMY components (lobetyolin and schisandrin) were evaluated in PA-induced RAW 264.7 cells using WB, ELISA, and RT-qPCR. Compared with Ato, DS-SMY also had a therapeutic effect on ApoE-/- mice. In addition, DS-SMY inhibited M1 polarization of macrophages in ApoE-/- mice. Additionally, the results demonstrated that DS-SMY alleviated intestinal inflammation and promoted the formation of colon tight junctions. Furthermore, changes in the gut microbiota composition in ApoE-/- mice after DS-SMY treatment were sufficient to induce changes in colon inflammation. Mechanistically, the results revealed that DS-SMY components suppressed proinflammatory cytokine expression and enhanced macrophage efferocytosis. Furthermore, supplementation with butyric acid (a gut microbiota-derived metabolite) enhanced the effect of DS-SMY, which demonstrated that the effect of DS-SMY involved microbiota-dependent mechanisms. In summary, DS-SMY can alleviate atherogenic dyslipidemia and pathological inflammation in AS by targeting the gut microbiota and homeostatic efferocytosis and is accordingly a potential therapeutic agent for AS.\n\nID: 42009106\nTitle: Chronic inflammation in virus-suppressed people living with human immunodeficiency virus infection: A microbiology-oriented perspective on gut barrier failure, microbial translocation, and immune activation.\nAbstract: Potent antiretroviral therapy (ART) has transformed human immunodeficiency virus (HIV) infection into a chronic manageable condition; however, many people living with HIV (PLWH) exhibit persistent immune activation and inflammation despite long-term virological suppression. Residual inflammation is strongly associated with an increased risk of cardiovascular disease, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, cancer, and neurocognitive impairment. This review summarizes the current evidence on the microbiology-oriented mechanisms that sustain this state. We first outline a multifactorial network in which incomplete repair of intestinal mucosal damage, dysbiosis, reduced short-chain fatty acid production, and disturbed bile acid metabolism generate a patchy \"leaky gut.\" Continuous translocation of bacterial lipopolysaccharide, fungal \u03b2-D-glucan, and other microbial products activates monocyte-macrophage and portal-liver inflammatory circuits. These inputs interact with intermittent HIV antigen expression from latent reservoirs, inflammatory cell death, chronic coinfections, lymphoid tissue fibrosis, mitochondrial dysfunction, and traditional lifestyle-related risk factors. Together, they establish a self-reinforcing gut-liver-immune axis that maintains low-grade inflammation and a procoagulant milieu under viral suppression. We then link these mechanisms to organ-specific complications and review the intervention data, focusing on early ART initiation, statin therapy, and cotrimoxazole prophylaxis as a proof-of-concept that modifying inflammatory and mucosal pressures can improve outcomes. Finally, we highlight research priorities and argue that the effective prevention of long-term complications in virally suppressed PLWH requires combination strategies targeting multiple nodes of this network, with particular attention to gut barrier repair and microbiome modulation.\n\nID: 42000693\nTitle: The role of macrophage metabolic reprogramming in efferocytosis: A dual-edged sword in atherosclerosis and tumor progression.\nAbstract: Macrophage efferocytosis-the process by which macrophages recognize, engulf, and degrade apoptotic cells (ACs)-is essential for maintaining tissue homeostasis and resolving inflammation. Dysregulation of efferocytosis has been implicated in the progression of various diseases, including atherosclerosis (AS) and cancer. In AS, effective efferocytosis reduces inflammation, stabilizes plaques, and slows disease progression. Conversely, in the tumor microenvironment (TME), efferocytosis contributes to immune suppression, supporting cancer cell survival, proliferation, and metastasis. Impaired efferocytosis leads to the accumulation of secondary necrotic ACs, which exacerbate inflammation. Interestingly, in tumors, this process can paradoxically induce pro-inflammatory, anti-tumor immune responses. Therefore, understanding the regulatory mechanisms controlling efferocytosis is critical for the development of targeted therapies for inflammatory diseases and cancer. Recent findings highlight macrophage metabolic reprogramming as a key modulator of efferocytosis. Metabolic pathways, including glycolysis, amino acid metabolism, and fatty acid oxidation (FAO), provide the energy and biosynthetic intermediates necessary for macrophages to execute efferocytosis efficiently. These pathways influence all stages of efferocytosis-recognition, engulfment, and degradation of ACs-while shaping macrophage function and inflammatory responses. Moreover, metabolic adaptations in macrophages exhibit context-specific roles in atherosclerotic plaques and the TME, underscoring the complex and disease-specific effects of efferocytosis in pathological conditions. This review synthesizes current knowledge on the molecular mechanisms underlying efferocytosis and its regulation through macrophage metabolic reprogramming. It discusses how metabolic shifts impact efferocytosis and explores their broader implications in AS and cancer. Understanding the intricate interplay between macrophage metabolism and efferocytosis presents new opportunities for therapeutic intervention, with the potential to transform the clinical management of inflammatory and neoplastic diseases.\n\nID: 41906552\nTitle: Obesity Disrupts H3K4me3-Mediated Lactate Accumulation and Efferocytosis in Hypoxic Macrophages.\nAbstract: Dysregulated macrophage function drives the development of obesity-associated pathologies. While macrophages adapt to their surrounding environment to maintain tissue homeostasis, the impact of obesity on macrophage adaptation to low oxygen levels remains elusive. Here, we show that hypoxia rapidly increases histone 3 lysine-4 trimethylation (H3K4me3) in bone marrow-derived macrophages (BMDMs) and that this response is impaired in BMDMs from high-fat diet (HFD)-induced obese mice, which significantly affected the expression of genes involved in metabolic pathways, resulting in decreased lactate accumulation, histone lactylation, and expression of genes involved in the maintenance of metabolic homeostasis. Moreover, altered adaptation to hypoxia in BMDMs from HFD mice led to a decreased efferocytosis capacity under hypoxia, which was reversed by supplementation with glucose or lactate. Serial bone marrow transplantation indicated that the maladapted hypoxia response for efferocytosis was imprinted in macrophage precursors in the bone marrow of HFD mice. In BMDMs, genetic disruption of the H3K4me3 demethylase KDM5A further enhances hypoxia-induced H3K4me3 and gene expression, along with lactate accumulation. In a dorsal skin biopsy model, while extracellular lactate levels decreased immediately after wounding but sharply increased in the early phase in normal mice, whereas lactate levels remained low in HFD mice, resulting in delayed wound healing. Our findings suggest that metabolic adaptation to hypoxia involves H3K4me3 and lactate accumulation in macrophages to perform efferocytosis under hypoxic conditions. Diet-induced obesity disrupts this pathway, resulting in impaired efferocytosis and delayed healing, with implications for altered macrophage functions in pathologies associated with obesity.\n\nID: 41864480\nTitle: Post-acute sequelae of COVID-19: A disorder of impaired innate immune resolution - A narrative review.\nAbstract: Post-acute sequelae of COVID-19 (PASC) affect millions of people worldwide and are increasingly recognized as a disorder of failed innate immune resolution rather than a persistent viral infection. Emerging evidence shows that residual SARS-CoV-2 antigens, host-derived alarmins, reactivated latent viruses, and mucosal microbiome-derived products from oral-nasopharyngeal and gut reservoirs sustain the chronic activation of pattern-recognition receptors, inflammasomes, and complement pathways. In parallel, deficits in specialized pro-resolving mediators, impaired efferocytosis, and persistent tissue injury prevent physiological termination of inflammation. These unresolved cues drive long-lasting epigenetic and metabolic reprogramming of hematopoietic stem cells and myeloid lineages, creating maladaptive trained immunity states characterized by hyper-responsiveness or exhaustion of these cells. Thromboinflammatory processes, including aberrant NETosis and sustained interface signalingling, further reinforce self-perpetuating inflammatory circuits. Together, these pathways give rise to reproducible molecular endotypes, including thromboinflammatory, interferon-driven, and neuroinflammatory phenotypes, which explain clinical heterogeneity. Framing PASC as a disorder of impaired immune resolution within a mucosal microbial viral context provides a unifying mechanistic scaffold for biomarker identification and host-directed therapies. This review proposes that restoring active resolution programs, rebalancing metabolic-epigenetic networks, and dismantling pathogenic innate feedback loops are promising strategies for reversing the chronic immune imprint of PASC.\n\nID: 41746243\nTitle: Interleukin-18 Inhibition Aggravates Atherosclerosis in Jak2V617F Clonal Hematopoiesis.\nAbstract: Clonal hematopoiesis (CH) driven by JAK2V617F is known to accelerate atherosclerosis through inflammasome activation and release of interleukin (IL)-1\u03b2 and -18; yet, the specific contribution of IL-18 has remained unclear. In this study, we demonstrate that antibody inhibition of IL-18 in JAK2V617F CH mice increases plaque collagen but paradoxically promotes both early lesion growth and advanced necrotic core formation. Mechanistically, IL-18 blockade reverses absent in melanoma 2 inflammasome activation but shifts cell death toward apoptosis, and together with impaired efferocytosis, results in greater necrosis. These events are coordinated by reduced interferon gamma signaling, which enhances collagen deposition while decreasing expression of efferocytotic genes. Our findings challenge the prevailing notion that IL-18 inhibition stabilizes atherosclerotic plaques and provide new mechanistic insight into the interplay among inflammasome biology, adaptive immunity, and plaque stability.\n\nID: 41741422\nTitle: Modulation of immune cells and metabolic reprogramming in efferocytosis.\nAbstract: Under physiological conditions, cell apoptosis is a silent death process during tissue renewal and remodeling. The phagocytosis of apoptotic cells, known as efferocytosis, is a key process performed primarily by macrophages and dendritic cells, as well as by non-professional phagocytes, such as epithelial cells and fibroblasts. This process, which involves the removal of apoptotic cells, is not just a routine task. It plays a significant role in producing anti-inflammatory mediators that are instrumental in maintaining tissue homeostasis. However, during infection, pathogens can induce different patterns of cell death, including apoptosis. Efferocytosis of infected apoptotic cells is a crucial part of the host defense mechanism. It aids in bacterial clearance, activates the effector functions of phagocytes, and directs the activation of CD4+T lymphocytes. The different stages of the efferocytosis process are not just a sequence of events, but a complex interplay that can interfere with the microenvironment by releasing soluble mediators (\"find-me signals\") as a rich source of nutrients for phagocytes during the digestion process (\"digest-me\"), such as amino acids, nucleotides, lipids, and carbohydrates. In recent years, several studies have contributed to unraveling the impact of the different stages of the efferocytosis process on regulating metabolic pathways that support the continuous phagocytosis of apoptotic cells, the activation profile, and the effector functions of phagocytes. In this review, we discuss the impact of efferocytosis on immune cells during homeostasis and infectious diseases, and in the metabolic reprogramming on phagocyte activation. We also explore the role of efferocytosis during the clearance of apoptotic cells in different pathologies.\n\nID: 41717712\nTitle: Polydopamine-Encapsulated Probiotics Restore Gut Homeostasis and Reinstate Macrophage Efferocytosis in Systemic Lupus Erythematosus.\nAbstract: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by immune dysregulation and chronic inflammation, with increasing evidence implicating the gut microbiota in its pathogenesis. Probiotics, such as Lactobacillus rhamnosus GG (LGG), exert anti-inflammatory effects by enhancing gut barrier function and restoring microbial homeostasis, representing a promising therapeutic strategy for SLE. However, conventional probiotic therapies are hindered by poor survival and colonization in the hostile intestinal environment. Here, a polydopamine-coated LGG (LGG@PDA) with improved viability, adhesion, and resistance to oxidative stress is developed. In murine models of lupus, LGG@PDA treatment restored gut and immune homeostasis, enhanced macrophage efferocytosis, reduced autoantibody levels, and ameliorated renal pathology. Metabolomic analysis further identified L-methionine, a metabolite diminished in both lupus mice and SLE patients, as being enriched by LGG@PDA treatment. Functionally, L-methionine enhanced macrophage efferocytosis in a CX3CR1-dependent manner, thereby contributing to the restoration of immune tolerance. Collectively, these findings establish LGG@PDA as a bioengineered probiotic platform that integrates microbiota modulation with immune regulation, highlighting L-methionine as a key metabolic mediator and a promising microbiota-based therapeutic strategy for SLE.\n\nID: 41673107\nTitle: SCARF1 deficiency exacerbates gut inflammation and autoimmune pathology.\nAbstract: Systemic lupus erythematosus (SLE) is a complex autoimmune disease known for its heterogeneity in both manifestation and presentation. Recent evidence has increasingly implicated the gut microbiome within immunomodulation and autoimmunity. This study aims to characterize the intestinal inflammation and microbial profile associated with autoimmune diseases, particularly SLE, and to identify unique biomarkers and shared microbial signatures for potential therapeutic measures. Our lab identified scavenger receptor class F, member 1 (SCARF1, SREC-1) as an efferocytosis receptor essential for the clearance of apoptotic debris, and its deficiency results in the development of lupus-like disease. SCARF1 is crucial in immune homeostasis, and defects in efferocytosis lead to inflammation. However, the role of SCARF1 in gut homeostasis remains to be elucidated. To answer our question, we analyzed and compared the metagenomic datasets generated through whole genome shotgun sequencing between our Scarf1-/- lupus-prone mouse model and healthy counterparts. We found that Scarf1-/- mice had significantly lengthened intestines, elevated immune cell infiltration, and structural changes in the colon. Microbiome analysis revealed gut dysbiosis, including reduced alpha diversity and increased Firmicute/Bacteroidetes ratio. Notably, beneficial taxa such as Akkermansia muciniphila was absent in Scarf1-/- mice. Linear regression analysis identified positive associations between lupus disease severity and increased abundances of Alistipes, Lachnospiraceae, and Clostridium. Function analysis of the gut microbiome in Scarf1-/- mice indicated downregulation of multiple pathways related to cell proliferation. These findings highlight the role of SCARF1 involvement in the gut microbiome and immune regulation in the context of inflammation and SLE.\n\nID: 41643678\nTitle: Ketogenic diet alleviates septic lung injury via microbial gut-lung axis.\nAbstract: Sepsis is characterized by impaired immunity to infection, leading to multi-organ dysfunction, with the lung being the most vulnerable organ. Here, we show that ketogenic diet (KD) alleviates sepsis-induced lung injury through a microbial-gut-lung axis. KD alters the gut microbiota in mice and humans, enriching Limosilactobacillus reuteri and Lactiplantibacillus plantarum. Specific strains of these species produce a flavin-dependent monooxygenase (FMO) that converts oleic acid in KD into azelaic acid (AZA). During sepsis, AZA translocates to the lung, where it promotes neutrophil apoptosis and expands MerTK+ alveolar macrophages (AMs) via PPAR-\u03b3 activation, enhancing efferocytosis and resolution of lung injury. In patients with sepsis, elevated AZA correlates with improved clinical outcomes, including survival rates, ventilation-free days (VFDs), and pulmonary function, along with increased MerTK+ AMs and apoptotic neutrophils in patient lungs. These findings uncover a pathway of gut-lung crosstalk mediated by diet-microbiome interactions, highlighting the therapeutic potential of KD and microbiome modulation in sepsis.\n\nID: 41244711\nTitle: Immunological landscape of colorectal cancer: tumor microenvironment, cellular players and immunotherapeutic opportunities.\nAbstract: Colorectal cancer (CRC) remains one of the most lethal malignancies worldwide, with outcomes shaped not only by genetic alterations but also by the complexity of the tumor microenvironment (TME). The TME encompasses stromal and endothelial cells, extracellular matrix components, gut microbiota, and a diverse array of immune cells that dynamically interact to influence tumor initiation, progression, and therapeutic response. This review delineates the immunological landscape of CRC, highlighting the dual functions of innate immune cells-including tumor-associated macrophages, natural killer cells, dendritic cells, neutrophils, and mast cells-and adaptive immune players such as cytotoxic T lymphocytes, helper T-cell subsets, and B/plasma cells. These cellular interactions contribute to the heterogeneity between immunologically \"hot\" microsatellite instability-high (MSI-H) tumors, which are highly responsive to immunotherapy, and \"cold\" microsatellite-stable (MSS) tumors, which remain resistant. Key mechanisms of immune evasion, such as cancer immunoediting, checkpoint signaling, and exosome-mediated communication, are examined alongside prognostic tools like the Immunoscore that serve as biomarkers of immune infiltration. Emerging immunotherapeutic strategies, including checkpoint blockade, macrophage reprogramming, natural killer cell agonists, and microbiome modulation, are discussed with emphasis on both their promise and limitations in CRC management. By integrating current insights into immune-tumor interactions, the review underscores opportunities for developing personalized, TME-targeted interventions to improve CRC outcomes.\n\nID: 41228418\nTitle: Nutritional Approaches in Neurodegenerative Disorders: A Mini Scoping Review with Emphasis on SPG11-Related Conditions.\nAbstract: Background: Neurodegenerative diseases, including spastic paraplegia type 11 (SPG11), are complex disorders characterized by progressive neurological decline and significant metabolic disturbances. Spatacsin, the protein encoded by the SPG11 gene, plays a critical role in autophagy and lysosomal homeostasis, which are essential for neuronal health. Its impairment leads to defective cellular clearance and neurodegeneration. Recently, personalized and precision nutrition have emerged as promising approaches to enhance clinical outcomes by tailoring dietary interventions to individual genetic, metabolic, and phenotypic profiles. Objectives: This mini scoping review aimed to synthesize current evidence on the application of personalized and precision nutrition in SPG11 and to explore how insights from related neurodegenerative diseases could inform the development of future dietary and metabolic interventions for this rare disorder. Methods: Following PRISMA-ScR guidelines, a scoping review was conducted using PubMed, Scopus, and Web of Science databases (2020-2024). Eligible studies included investigations addressing nutritional, genomic, or metabolic interventions in neurodegenerative diseases. Of 30 screened papers, nine met the inclusion criteria, primarily focusing on nutritional and metabolic interventions related to neurodegenerative and neuromuscular conditions. Results: To date, no dietary intervention trials have been conducted specifically for SPG11. However, evidence from studies on related neurodegenerative diseases suggests that antioxidant, mitochondrial-supportive, and microbiota-targeted dietary approaches may beneficially influence key pathological processes such as oxidative stress, lipid dysregulation, and autophagy-core mechanisms that are also central to SPG11 pathophysiology. Conclusions: Although current evidence remains preliminary, personalized nutrition is a promising supplementary strategy for managing neurodegenerative diseases, including SPG11. Future research should incorporate systems-based approaches that combine dietary, metabolic, and neuroimaging assessments, with sex and comorbidity-stratified analyses, multi-omics profiling, and predictive modeling. These frameworks could help design safe, effective, and personalized nutritional interventions aimed at enhancing metabolic resilience and slowing disease progression in SPG11.\n\nID: 41226638\nTitle: The Role of Carbon Dots in Regulating the Periodontal Immune Microenvironment: Progress and Perspectives.\nAbstract: As a prevalent oral chronic infectious disease, periodontitis is characterized by a complex pathogenesis, including microbial infection, host immune dysregulation, oxidative stress, and abnormal bone metabolism. Given their excellent biocompatibility, multifunctionality, and structural tunability, carbon dots (CDs) have emerged as a novel nanomaterial offering fresh approaches for the pharmacological management of periodontitis. This review systematically summarizes the application characteristics of CDs in biology and the various mechanisms in modulating the periodontal immune microenvironment. These include the roles in antimicrobial and microbiome modulation, regulation of oxidative stress balance, modulation of macrophage polarization, regulation of stem cell functions, and maintenance of bone homeostasis. The unique advantages of CDs in improving the periodontal immune microenvironment through multi-target, multi-pathway mechanisms are emphasized, thereby providing a theoretical foundation for future clinical applications.\n\nID: 41128412\nTitle: Oral Multi-Enzymatic Manganese-Carbon Dots Alleviate Sepsis-Associated Lung Injury via the Gut-Lung Axis.\nAbstract: Sepsis-induced pulmonary injury represents a life-threatening global health challenge due to poorly defined pathological mechanisms. The gut-lung axis has been proven to be widely involved in sepsis-induced lung injury, yet effective interventions targeting gut microbiota homeostasis remain unknown. Single-cell sequencing revealed increased alveolar apoptosis and impaired macrophage efferocytosis during sepsis pathogenesis. Thus, we designed oral manganese-doped carbon dots (Mn-CDs) to alleviate septic lung injury by remodeling gut microbiota homeostasis and targeting the gut-lung axis. Biochemical characterization demonstrated Mn-CDs possess multienzyme mimetic activities (SOD-, CAT-, POD-, GPx-like) and potent ROS scavenging capacity. In murine sepsis models, Mn-CDs significantly improved systemic indices and were associated with macrophage anti-inflammatory states with enhanced efferocytosis, as evidenced by transcriptomic profiling. Integrated metagenomic/metabolomic analyses identified Mn-CDs-mediated enrichment of g_Clostridium and g_Bacteroides, concomitant with elevated indole-3-propionic acid (IPA) production. Subsequent in vitro studies demonstrate that IPA likely binds primarily to the aryl hydrocarbon receptor (AHR), promoting both efferocytosis and anti-inflammatory polarization in macrophages, thereby mitigating septic lung injury. Notably, the fecal microbiota transplantation (FMT) from Mn-CDs-treated mice not only alleviated systemic symptoms but also effectively promoted efferocytic polarization of pulmonary macrophages in septic mice. Depletion of the gut microbiota resulted in a significant loss of the protective efficacy of Mn-CDs in a murine model of septic lung injury. Collectively, the gut-lung axis mediated by microbiota-derived IPA and macrophage efferocytosis contributes to the remediation of septic lung injury, highlighting the potential of Mn-CDs in microbiome-directed critical care.\n\nID: 41000074\nTitle: Metabolic reprogramming in efferocytosis.\nAbstract: Efferocytosis refers to the process by which phagocytes specifically identify and eliminate apoptotic cells. This process is essential for both maintaining tissue homeostasis and suppressing inflammatory responses, as well as facilitating tissue repair. When phagocytes internalize apoptotic cells, which act as \"nutrient packages,\" they undergo significant metabolic reprogramming. This reprogramming not only supplies energy and biosynthetic precursors necessary for engulfment but also critically influences the functional phenotype of phagocytes through complex molecular networks. These networks ultimately determine whether phagocytes adopt an anti-inflammatory resolution or a pathological pro-inflammatory state. This article offers a comprehensive analysis of the molecular regulatory mechanisms that underpin metabolic reprogramming during efferocytosis, aiming to elucidate the intricate regulatory networks formed by the interaction of metabolites as signaling molecules and classical signaling pathways. We examine how the three primary metabolic pathways-glucose, lipid, and amino acid metabolisms-are regulated by signals from efferocytosis and, in turn, modulate phagocyte function. A deeper understanding of the interplay between metabolic reprogramming and efferocytosis will provide a theoretical foundation and novel targets for treating diseases associated with impaired clearance of apoptotic cells.\n\nID: 40957387\nTitle: Chemotaxis-guided nanoplatform for non-alcoholic steatohepatitis therapy via macrophage reprogramming, hepatoprotection and gut microbiome modulation.\nAbstract: Non-alcoholic steatohepatitis (NASH), characterized by hepatic steatosis, inflammation, and varying degrees of fibrosis, has become a growing global health burden. Obeticholic acid (OCA, a farnesoid X receptor agonist) has shown limited efficacy due to poor solubility, single-target mechanisms, and off-target side effects, notwithstanding the great promise of this agent in NASH clinical trials. Here, we designed M2 macrophage-derived membrane (M2M)-camouflaged poly (lactic-co-glycolic acid) (PLGA) nanoparticles (O@PLGA@M) to achieve targeted OCA delivery to the inflamed liver niche for recovering hepatic homeostasis in NASH. The M2M improved the inflamed liver-targeting of the nanoplatforms via chemotaxis and promoted M1-to-M2 macrophage repolarization, as evidenced by a 2.5-fold increase in CD206 expression and 45\u00a0% reduction in CD86 expression in the liver. In a methionine/choline-deficient (MCD) diet-induced murine NASH model, O@PLGA@M exhibited excellent biosafety and multifaceted anti-NASH efficacy, including anti-steatosis, anti-inflammatory, and anti-fibrotic effects. Mechanistically, O@PLGA@M reprogrammed macrophages by modulating macrophage polarization and inhibiting recruitment of immune cells to reduce the inflammatory cascade. They also exerted hepatoprotection effects by reducing steatosis and hepatocyte damage. Moreover, O@PLGA@M modulated the gut microbiome by redirecting it towards a beneficial state, which further relieved NASH through the gut-liver axis. These findings demonstrated that the biomimetic nanoplatforms could be employed as promising strategies that integrated targeted delivery and multimodal synergistic therapy for NASH management.\n\nID: 40935207\nTitle: CD300f enables microglial damage sensing, efferocytosis, and apoptotic cell metabolization after brain injury.\nAbstract: Microglia, the resident phagocytes of the central nervous system (CNS), continuously survey the parenchyma and its borders, acting as first responders to brain injury. Their ability to detect and react to environmental changes is mediated by a repertoire of surface receptors collectively known as themicroglial sensome. Here, we identify the lipid-sensing immunoreceptor CD300f as a key regulator of microglial responses to tissue damage and apoptotic cells. Using intravital two-photon microscopy, we show that CD300f-/- microglia fail to extend processes toward a laser-induced cortical lesion, indicating impaired detection of damage-associated cues. In models of mild traumatic brain injury (mTBI) and intracortical injection of apoptotic cells, CD300f deficiency led to reduced recognition and clearance of dying cells resulting in the accumulation of cellular debris within the parenchyma. At later stages, apoptotic remnants were retained within CD300f-/- microglia in vivo and bone marrow-derived macrophages in vitro, suggesting defective intracellular degradation. Proteomic analysis after a controlled cortical injury (CCI) contusion model revealed widespread dysregulation of autophagy-related and metabolic pathways, consistent with impaired efferocytosis and phagolysosomal processing. In parallel, we observed upregulation of the UDP-degrading ectonucleotidase ENTPD6 protein and downregulation of the microglial purinergic receptor P2ry6 mRNA, indicating a dysfunctional UDP-P2RY6 axis that may underlie impaired damage sensing and phagocytic initiation. Despite greater histological preservation, CD300f-/- mice exhibited worse long-term functional recovery after brain injury. Together, these findings highlight CD300f as a key damage-associated molecular pattern (DAMP) receptor that integrates purinergic signaling, efferocytosis, and metabolic adaptation, highlighting its essential role in coordinating microglial responses to CNS injury.\n\nID: 40868715\nTitle: Hydrogels Modulating the Microbiome: Therapies for Tissue Regeneration with Infection Control.\nAbstract: This review explores the emerging role of functionalized hydrogels in modulating the microbiome for therapeutic applications in tissue regeneration and infection control. The skin and gut microbiomes play crucial roles in maintaining tissue homeostasis, regulating immune responses, and influencing the healing process. Disruptions in microbial balance-such as those observed in chronic wounds, autoimmune conditions, or post-surgical environments-can impair regeneration and increase susceptibility to infection. Hydrogels, due to their tunable physical and chemical properties, serve as versatile platforms for delivering probiotics, prebiotics, antimicrobials, and immune-modulatory agents. The encapsulation of beneficial bacteria, such as Lactobacillus plantarum or Prevotella histicola, within hydrogels could enhance bacterial viability, targeted delivery, and immune tolerance. Additionally, hydrogels functionalized with silver nanoparticles, nitric oxide donors, and bacteriocins have demonstrated effective biofilm disruption and pathogen clearance. These systems also promote favorable immune responses, such as M2 macrophage polarization and the induction of regulatory T cells, which are essential for tissue repair. Innovative approaches, including 3D bioprinting, self-healing materials, and photothermal-responsive hydrogels, expand the clinical versatility of these systems.\n\nID: 40840819\nTitle: Elucidating cellular origins and TME dynamic evolution in NSCLC through multi-omics technologies.\nAbstract: Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality. Despite progress in targeted therapies and immunotherapy, resistance driven by tumor heterogeneity and dynamic tumor microenvironment (TME) remodeling persists. Multi-omics (single-cell/spatial transcriptomics) reveals lung adenocarcinoma (LUAD) origins in alveolar type 2 (AT2) cells and lineage plasticity via SOX2/WNT/YAP pathways driving aggressive subtypes. The TME, a dynamic ecosystem of immune cells and fibroblasts, evolves through immune-editing phases and cancer-associated fibroblasts (CAF)/tumor-associated macrophage (TAM) crosstalk to foster immunosuppression. Multi-omics identifies key immune subsets (CXCL13+CD8+T cells, M1/M2 macrophages) and antigen-presenting cancer-associated fibroblasts (apCAFs) as therapeutic targets. Emerging strategies targeting lineage plasticity, TME reprogramming, and microbiome modulation may overcome immune checkpoint blockade (ICB)/tyrosine kinase inhibitor (TKI) resistance. Challenges in spatiotemporal heterogeneity resolution call for artificial intelligence (AI)-driven TME modeling to guide precision interventions. This review highlights multi-omics in bridging NSCLC evolution with clinical translation for personalized therapies.\n\nID: 40833492\nTitle: Anti-Atherogenic Mechanisms and Therapies.\nAbstract: This review examines anti-atherogenic mechanisms and the crucial role of efferocytosis in promoting inflammation resolution, with a focus on innovative, resolution-based therapeutic strategies that aim to restore vascular homeostasis and mitigate atherosclerosis progression. Atherosclerosis, a chronic inflammatory condition, is exacerbated by impaired efferocytosis, which contributes to plaque instability and the expansion of the necrotic core. Advanced molecular and cellular profiling has revealed diverse macrophage populations and their metabolic adaptations during efferocytosis, which drive the production of resolving mediators essential for tissue repair. Dysregulated signaling and metabolic pathways disrupt the efficient clearance of apoptotic cells, exacerbating inflammation. Molecular regulators, such as microRNAs, further impact efferocytosis, governing cardiovascular outcomes. Resolution-based therapies, including specialized pro-resolving mediators, peptides, and metabolites, enhance the successive clearance of apoptotic cells while maintaining host immune function, offering advantages over traditional immunosuppressive approaches. Additionally, vaccines targeting disease-specific antigens show promise in eliciting protective immune responses that can help ameliorate atherosclerosis. Efferocytosis is a key regulator of inflammation resolution in atherosclerosis, linking macrophage metabolism to plaque stability. Its disruption drives disease progression, but emerging therapies targeting resolution pathways, metabolic reprogramming, and immune modulation hold the potential for effective interventions. Advances in profiling technologies and targeted delivery systems will address translational challenges, paving the way for precision medicine in treating atherosclerotic cardiovascular disease.\n\nID: 40689420\nTitle: Sophoricoside enhances reparative macrophage polarization to promote cardiac repair postmyocardial infarction through PPAR-\u03b3.\nAbstract: Myocardial infarction (MI) represents a significant cardiovascular condition that endangers human health. This research aimed to explore the therapeutic effectiveness of sophoricoside (Sop) using a mouse model of MI. To conduct this investigation, a mice model of MI was utilized, and Sop was delivered through oral administration via gavage. The area of MI in mice was assessed by Masson trichrome staining. Cardiac systolic function and left ventricular dilatation were measured by cardiac ultrasound. Picrosirius red staining and Masson's trichrome staining were performed to detect the collagen deposition and fibrosis. The expressions of reparative macrophage-associated markers were measured by quantitative real-time PCR. Western blotting was utilized to sense expression of lysyl oxidase (LOX), peroxisome proliferator-activated receptor \u03b3 (PPAR-\u03b3), and collagen 1. Flow cytometry was performed to detect the number of macrophages. The Cell Counting Kit-8 assay was performed to detect Sop's cytotoxicity. The M2 polarization and efferocytosis in mice model of MI was verified by immunofluorescence assay. Sop significantly reduced myocardial infarct size. Cardiac ultrasound evaluation further showed that Sop was effective in improving cardiac systolic dysfunction and left ventricular dilatation. In addition, Sop significantly promoted efferocytosis and reparative M2 macrophage polarization and inhibited glycolytic metabolic pathways, thereby promoting cardiac tissue repair. It was further found that Sop could obviously promote expression of PPAR-\u03b3 in the nucleus. GW9662 partially reversed the improvement of Sop on cardiac repair and reparative macrophage polarization in MI mice. In summary, this study elucidates that Sop enhances reparative macrophage polarization to promote cardiac repair post-MI through PPAR-\u03b3.\n\nID: 40585999\nTitle: Gut microbiota depletion accelerates hematoma resolution and neurological recovery after intracerebral hemorrhage via p-coumaric acid-promoted Treg differentiation.\nAbstract: Hematoma volume significantly influences the prognosis of patients with intracerebral hemorrhage (ICH). Effective resolution of hematoma through enhanced clearance mechanisms and reduced hematoma lysis is essential for neurological recovery following ICH. Regulatory T cells (Tregs), known for their anti-inflammatory properties, exert neuroprotective effects in various central nervous system disorders. Additionally, gut microbiota profoundly impacts Treg development through multiple regulatory pathways. Nonetheless, the precise roles of Tregs and gut microbiota in facilitating hematoma resolution after ICH remain unclear. This study, therefore, aimed to investigate the contributions of Tregs and gut microbiota to hematoma resolution post-ICH, as well as the underlying mechanisms. Methods: The impact of gut microbiota depletion on neurological deficits and hematoma resolution, including erythrophagocytosis and erythrocyte lysis, was assessed using antibiotic cocktail (ABX) gavage administered prior to ICH induction in mice. Flow cytometry analysis and targeted cell depletion techniques were employed to identify peripheral immune cell populations mediating the beneficial effects of gut microbiota depletion on neurological recovery and hematoma resolution. The functional roles of Tregs in erythrophagocytosis, erythrocyte lysis, and associated downstream molecular signaling pathways were investigated through adoptive Treg transfer experiments. The mechanisms underlying Treg population expansion post-microbiota depletion in ICH mice were explored using multi-omics analysis of serum and fecal metabolites via mass spectrometry and fecal microbial composition using 16S rRNA sequencing. Additionally, the effects of p-coumaric acid (PCA) gavage and clindamycin-mediated depletion of PCA-metabolizing gut microbiota on Treg abundance, hematoma resolution, and neurological recovery post-ICH were assessed. Results: Gut microbiota depletion by ABX gavage increased brain Treg populations, thereby enhancing erythrophagocytosis, suppressing erythrocyte lysis, and ultimately promoting hematoma resolution and neurological recovery. Adoptive Treg transfer experiments further established that Tregs facilitate scavenger pathway-mediated erythrophagocytosis and suppress complement-mediated erythrocyte lysis. These effects occurred via upregulation of efferocytosis receptors (MERTK and AXL), ligands (Gas6 and C1q), and the hemoglobin scavenger receptor CD163, alongside downregulation of complement C3 expression and reduced formation of membrane attack complexes (MACs). Multi-omics analysis demonstrated that ABX gavage eliminated PCA-metabolizing microbiota, thereby increasing PCA concentrations in serum and feces. Elevated PCA levels promoted peripheral Treg differentiation by inhibiting the PKC\u03b8-AKT-FoxO1/3a signaling pathway, leading to higher brain Treg numbers. PCA gavage and clindamycin treatment similarly enhanced brain Treg populations, accelerated hematoma resolution, and improved neurological recovery following ICH. Conclusion: Gut microbiota depletion facilitates hematoma resolution and neurological recovery through PCA-mediated induction of Treg differentiation.\n\nID: 40567375\nTitle: The effect of Zuogui-Jiangtang-Yishen decoction on the intestinal flora's response to L-\u03b1-phosphatidylcholine and L-tyrosine in patients with diabetic kidney disease: an in vitro study.\nAbstract: Animal and cell studies have demonstrated that Zuogui-Jiangtang-Yishen decoction (ZGJTYS) has a favorable effect on the treatment of diabetic kidney disease (DKD). Our previous clinical research also showed that ZGJTYS prevents DKD in a manner similar to that of benazepril. Nevertheless, the interactions between ZGJTYS and the human gut microbiota require further investigation, particularly its interference in the intestinal flora response to food ingredients that may increase DKD risk, such as L-\u03b1-phosphatidylcholine and L-tyrosine. The aim of this study was to evaluate the regulatory function of ZGJTYS on human gut microbiota and explore the effect of ZGJTYS on the intestinal flora response to L-\u03b1-phosphatidylcholine and L-tyrosine. ZGJTYS was prescribed from the First Affiliated Hospital of Hunan University of Chinese Medicine. High-throughput sequencing of bacterial 16S RNA genes and fungal internal transcribed spacer (ITS) sequences was used for intestinal flora analysis. An in vitro gut microbiota simulation model was used to investigate the effect of ZGJTYS on the intestinal flora's response to L-\u03b1-phosphatidylcholine and L-tyrosine. Ultra-high-performance liquid chromatography and mass spectrometry were used for non-targeted metabolomics analysis. Compared to the control group, the microbial diversity of DKD was significantly reduced by ZGJTYS treatment; three bacterial genera, including Parabacterioids, were significantly higher; eight bacterial genera, including Prevotella_9, and the linoleic acid content were significantly lower. A receiver operating characteristic curve analysis using Parabacterioids and Prevotella_9 showed an area under the curve greater than 0.75, indicating good predictive performance. ZGJTYS intervention restored some of the normal bacterial genera, such as Rickettsia and Metarhizium, which were regulated by L-\u03b1-phosphatidylcholine and L-tyrosine. Furthermore, ZGJTYS effectively restored several significantly different Kyoto Encyclopedia of Genes and Genomes metabolic pathways related to immunity and disease to normal, such as efferocytosis and tryptophan metabolism. ZGJTYS was found to effectively restore the microbiota that were altered by L-\u03b1-phosphatidylcholine and L-tyrosine to normal, along with their metabolites. However, the mechanism by which ZGJTYS exerts its preventive and therapeutic effects on DKD through the gut microbiota still requires further study.\n\nID: 40553443\nTitle: Novel Small-Molecule miR-124 Inducer Acts as \"a Physiological Brake\" of Inflammation in Ulcerative Colitis by Targeting the PIK3R2/PI3K/Akt Axis.\nAbstract: Ulcerative colitis (UC), a chronic inflammatory bowel disease with limited therapeutic options, necessitates novel treatments targeting its complex pathophysiology. This study identified FHND5032, a novel small-molecule miR-124 inducer, as a potent therapeutic candidate for UC. We found that FHND5032 significantly upregulated miR-124 expression in macrophages, surpassing the clinical-stage comparator ABX464 in vitro and in vivo. Mechanistically, miR-124-5p directly targeted PIK3R2, suppressing the PI3K/Akt pathway and decreasing proinflammatory cytokines while promoting M2 macrophage polarization. In dextran sodium sulfate-induced mouse colitis, FHND5032 markedly reduced the disease activity index, restored colon length, preserved mucosal architecture, and repaired intestinal barrier integrity. Additionally, FHND5032 reversed gut dysbiosis by reducing Proteobacteria and enriching beneficial Firmicutes, outperforming ABX464 in microbiome modulation. Safety assessments confirmed no organ toxicity or biochemical abnormalities. Collectively, FHND5032 exerted multifaceted anticolitis effects by targeting the PIK3R2/PI3K/Akt axis, restoring immune homeostasis, and modulating gut microbiota, positioning it as a promising therapeutic agent for UC.\n\nID: 40490493\nTitle: Temporal single-cell sequencing analysis reveals that GPNMB-expressing macrophages potentiate muscle regeneration.\nAbstract: Macrophages play a crucial role in coordinating the skeletal muscle repair response, but their phenotypic diversity and the transition of specialized subsets to resolution-phase macrophages remain poorly understood. Here, to address this issue, we induced injury and performed single-cell RNA sequencing on individual cells in skeletal muscle at different time points. Our analysis revealed a distinct macrophage subset that expressed high levels of Gpnmb and that coexpressed critical factors involved in macrophage-mediated muscle regeneration, including Igf1, Mertk and Nr1h3. Gpnmb gene knockout inhibited macrophage-mediated efferocytosis and impaired skeletal muscle regeneration. Functional studies demonstrated that GPNMB acts directly on muscle cells in vitro and improves muscle regeneration in vivo. These findings provide a comprehensive transcriptomic atlas of macrophages during muscle injury, highlighting the key role of the GPNMB macrophage subset in regenerative processes. Our findings suggest that modulating GPNMB signaling in macrophages may represent a promising avenue for future research into therapeutic strategies for enhancing skeletal muscle regeneration.\n\nID: 40461757\nTitle: Kv1.3 knockdown attenuates alcohol-related liver injury in mice through induction of tryptamine.\nAbstract: Alcohol-related liver disease (ALD) refers to a spectrum of liver diseases caused by chronic or acute excessive alcohol consumption. Excess alcohol consumption and dysregulated immunometabolism are the major contributors to the disease progression. The pathogenesis of ALD remains unclear with macrophage activity playing a key role in disease development. Kv1.3 potassium channel is essential for the regulation of macrophage function. In this study, we investigated whether Kv1.3 channels influenced the progression of ALD by modulating macrophage function. A murine model of ALD was established in male mice. We showed that Kv1.3 knockdown significantly attenuated alcohol-induced liver injury, lipid deposition, and inflammatory responses in ALD mice. Metabolomic analysis revealed that Kv1.3 knockdown significantly increased the levels of tryptamine, a tryptophan metabolite, in the liver of ALD mice. During the last 5 days of the EtOH feeding period, injection of exogenous tryptamine (1, 10, 20\u2009mg\u00b7kg-1\u00b7d-1, i.p.) notably alleviated ethanol-induced liver steatosis and inflammation in ALD mice. In LPS-challenged RAW264.7 cells, tryptamine (62.5, 125, 250\u2009\u03bcM) dose-dependently suppressed the secretion of pro-inflammatory cytokines IL-6, IL-1\u03b2 and TNF-\u03b1. RNA-seq analysis of RAW264.7 cells revealed that tryptamine treatment significantly altered Toll-like receptor and NF-\u03baB signaling pathways. We conclude that in the ALD mice, Kv1.3 negatively regulates tryptamine levels, which inhibits macrophage activation and reduces the inflammatory responses through the TLR4/NF-\u03baB signaling pathway. Our results offer new targets and intervention strategies for the prevention and treatment of ALD.\n\nID: 40437375\nTitle: Comparative efficacy of preventive vs. therapeutic resveratrol in modulating gut microbiota and alleviating inflammation in DSS-induced colitis.\nAbstract: Inflammatory bowel disease (IBD) management remains challenging due to limited preventive strategies and the low bioavailability of therapeutic agents like resveratrol (RSV). While RSV exhibits anti-inflammatory properties, its preventive potential via gut microbiome modulation remains unexplored. A murine colitis model was established using 2.5% DSS, with mice randomized into control (CON), DSS, therapeutic RSV treatment (RSV), and preventive RSV treatment (PRE) groups. Clinical outcomes, intestinal barrier integrity, inflammatory cytokines, macrophage polarization, TLR4/NF-\u03baB signaling, and gut microbiota (16S rRNA sequencing) were systematically evaluated. Preventive RSV (PRE) outperformed therapeutic RSV across all metrics. PRE attenuated colitis severity by 51.4% (weight loss, P\u2009<\u20090.001 vs. RSV) and restored mucosal architecture (P\u2009=\u20090.048 vs. DSS). Mechanistically, PRE normalized barrier function via transcriptional (ZO-1: 56.7% of CON; Occludin: 14-fold induction vs. DSS) and protein-level recovery (ZO-1: 96.5% of CON, P\u2009=\u20090.02), suppressed pro-inflammatory cytokines (TNF-\u03b1: 80.8%; IL-6: 69.9%; IL-18: >96%, P\u2009<\u20090.001 vs. DSS), and promoted M2 macrophage polarization (CD206: 1.7-fold vs. CON, P\u2009=\u20090.02) through TLR4/NF-\u03baB inhibition (53% TLR4 reduction vs. 15% with RSV, P\u2009<\u20090.001). Despite comparable \u03b1-diversity between RSV and PRE, PRE uniquely enriched barrier-protective taxa (Lactococcus, Muribaculum) and restored microbial amino acid biosynthesis. Crucially, PRE's efficacy despite low systemic bioavailability implicated microbiome-mediated \"luminal priming\" as its primary mechanism. This study redefines preventive RSV as a microbial ecosystem engineer that preemptively fortifies the gut against inflammation via microbiome-immune-metabolic crosstalk. By prioritizing ecological prevention over symptom suppression, our findings offer a transformative \"food as medicine\" strategy for IBD, highlighting RSV's potential as a chronotherapeutic agent to reshape clinical paradigms.\n\nID: 40419113\nTitle: Compromised efferocytosis during aging is related to COVID-19 severity in mice.\nAbstract: Aging is one of the greatest risk factors for morbidity caused by the coronavirus disease 2019 (COVID-19). In older individuals, a dysregulated immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection contributes to disease severity; however, the underlying mechanism remains elusive. In this study, we established an aging mouse model of COVID-19, successfully replicating the development of a relatively severe disease in older adults. Further single-cell transcriptome analysis revealed a distinct immune cell landscape in the infected lungs, accompanied by an over-activated inflammatory response, especially in aging mice. Compared to young mice, aging mice showed extensive neutrophil activation, NETosis, and a dramatic decrease in the number of alveolar macrophages (AMs). Moreover, as important executors of efferocytosis, AMs exhibited a low efferocytotic gene signature and downregulation of multiple efferocytosis receptors in aged mice. Further analysis indicated that the efferocytosis of neutrophils, whether undergoing apoptosis or NETosis, was compromised after SARS-CoV-2 infection. Since efferocytosis is a key process in inflammatory resolution, impaired efferocytosis may contribute to hyperinflammation in aging lungs. Our study reveals the characteristics and role of efferocytosis in aging mice after SARS-CoV-2 infection and provides valuable insights for the potential treatment of COVID-19.\n\nID: 40309829\nTitle: HDLR-SR-BI Expression and Cholesterol Uptake are Regulated via Indoleamine-2,3-dioxygenase 1 in Macrophages under Inflammation.\nAbstract: Macrophages play crucial roles in inflammation, and their dysfunction is a contributing factor to various human diseases. Maintaining the balance of cholesterol and lipid metabolism is central to macrophage function, and any disruption in this balance increases the risk of conditions such as cardiovascular disease, atherosclerosis, and others. HDLR-SR-BI (SR-BI) is pivotal for reverse cholesterol transport and cholesterol homeostasis. Our studies demonstrate that the expression of SR-BI is reduced along with a decrease in cholesterol uptake in macrophages, both of which are regulated by the activation of NF-\u03baB. Furthermore, we have discovered that indoleamine-2,3-dioxygenase 1 (IDO1), which is a critical player in tryptophan (Trp) catabolism, is crucial to the regulation of SR-BI expression. Inflammation leads to elevated levels of IDO1 and the associated Trp catabolite kynurenine (KYN) in macrophages. Interestingly, knockdown or inhibition of IDO1 results in the downregulation of LPS-induced inflammation, decreased KYN levels, and the restoration of SR-BI expression as well as cholesterol uptake in macrophages. Beyond LPS, stimulation with pro-inflammatory cytokine IFN\u03b3 exhibits similar trends in inflammatory response, IDO1 regulation, and cholesterol uptake in macrophages. These observations suggest that IDO1 plays a critical role in SR-BI expression and cholesterol uptake in macrophages under inflammation.\n\nID: 40101841\nTitle: Potential targets for synergistic bipolar irreversible electroporation in tumor suppression through transcriptomics and proteomics analysis.\nAbstract: Previous studies have demonstrated that synergistic bipolar irreversible electroporation (SBIRE) is a promising non-thermal tumor ablation technique that effectively targets tumors without causing muscle contractions. Despite its clinical potential, the mechanistic understanding of SBIRE's tumor-suppressive effects remains underexplored. This study aims to identify potential molecular targets for SBIRE-mediated tumor suppression through comprehensive transcriptomics and proteomics analyses. Mice were selected as subjects for the creation of tumor models by the subcutaneous tumor-bearing method. Following the SBIRE intervention, tumor surveillance and pathological investigations were carried out. A comprehensive investigation was conducted using RNA sequencing-based transcriptomics and label-free quantitative proteomics to examine normal and SBIRE treated tumor samples. Differentially expressed genes (DEGs) and crucial signaling pathways were found using bioinformatics analysis. Western blot (WB), immunohistochemistry (IHC), and quantitative real-time PCR (qRT-PCR) were used to validate potentially associated genes. The results demonstrate that a substantial reduction in tumor size was achieved following SBIRE treatment. A total of 86 genes exhibited differential expression in tumors, with 84 genes showing upregulation and 2 genes showing downregulation. According to bioinformatics research, these DEGs were involved in a wide variety of biological activities, such as cell adhesion, positive regulation of tumor necrosis factor production, and immune system process. Beside major enrichment pathways like Efferocytosis, Endocytosis, PPAR signaling pathway and Metabolic pathways. The upregulation of WDFY family member 4 (WDFY4), Thrombospondin 1(THBS1), Pentraxin 3 (PTX3), Superoxide dismutase 3 (SOD3) and Glutathione peroxidase 3 (GPX3) genes were confirmed. These insights into the molecular underpinnings of SBIRE offer a novel therapeutic strategy for enhancing tumor suppression and improving clinical outcomes in cancer treatment.\n\nID: 40047483\nTitle: Refining the impact of early intermittent hyperlipidemia on atherosclerosis: Unveiling the role of neutrophil reprogramming, sex differences, gut microbiota, and maternal hypercholesterolemia.\nAbstract: Atherosclerotic cardiovascular diseases (ASCVDs) remain a leading cause of mortality, with early cholesterol control being pivotal in mitigating long-term risk. Recent findings suggest that intermittent hyperlipidemia, characterized by oscillatory cholesterol exposure, uniquely accelerates atherosclerosis compared to continuous high-fat diets. This review synthesizes emerging evidence on early intermittent hyperlipidemia's impact on atherogenesis, emphasizing macrophage dysfunction, autophagy impairment, and efferocytosis deficits. We also discuss critical gaps, including sex-specific differences, gut-microbiota interactions, and the influence of maternal hypercholesterolemia. Notably, recent insights into IL-1\u03b2-dependent neutrophil reprogramming under oscillatory diets reveal novel inflammatory mechanisms driving plaque destabilization. Addressing these gaps will advance our understanding of early atherogenesis and guide the development of innovative prevention strategies and therapeutic interventions.\n\nID: 39932617\nTitle: Emerging Mechanisms and Biomarkers Associated with T-Cells and B-Cells in Autoimmune Disorders.\nAbstract: Autoimmune diseases are characterized by the dysregulation of B-cells, which are responsible for antibody production against pathogens, and T-cells, which play a crucial role in cell-mediated immunity, including both helper and cytotoxic T-cells. These disorders frequently present with abnormal responses from both B- and T-cells, which can have a significant impact on cardiovascular health, particularly among the female patients. Key mechanisms contributing to these diseases include the activation of the NLRP3 inflammasome impaired efferocytosis is the process by which phagocytes clear apoptotic cells to maintain immune and developmental balance. Defects in this process can lead to inflammatory and autoimmune disorders. The gut microbiota helps defend against pathogens and signals immune cells, playing a vital role in human health and is involved in many aspects of the body. Novel therapeutic strategies such as nanomedicine and targeted treatments are being developed to restore immune balance. The significance of thymic homeostasis the influence of viral infections and the presence of tertiary lymphoid structures highlight the need for multidisciplinary approaches in the management of these conditions. A case study of a 9-year-old girl diagnosed with seronegative autoimmune encephalitis, who displayed severe obsessive-compulsive disorder (OCD) and aggressive behavior, exemplifies the complexities involved in treatment. Promising interventions, including CAR-T-cell therapy and nanomedicine, are under development for various autoimmune diseases, such as vitiligo and refractory autoimmune rheumatic diseases (ARDs). Furthermore, emerging therapies, including CAR-T-cell therapy, mRNA-based strategies, and microbiome modulation, are being explored alongside advancements in personalized medicine and early diagnostic techniques to improve patient outcomes for individuals affected by autoimmune diseases.\n\nID: 39911848\nTitle: Efferocytosis-related gene IL33 predicts prognosis and immune response and mediates proliferation and migration in vitro and in vivo of breast cancer.\nAbstract: Breast cancer (BRCA) has a high incidence among women, with poor prognosis and high mortality, which is increasing year by year. Efferocytosis is a process of phagocytosis of abnormal cells and is of great value in tumor research. Our study seeks to create a predictive model for BRCA using efferocytosis-related genes (ERGs) to explore the significance of efferocytosis in this disease. In this research, Differential analysis, and univariate Cox regression were employed to identify genes linked to prognosis in BRCA patients. Then the BRCA patients were categorized into distinct groups using consensus clustering based on prognosis genes. Survival analysis, PCA, and t-SNE were performed to verify these groups. The enrichment of metabolic pathways within the detected clusters was evaluated using gene set variation analysis (GSVA) and gene set enrichment analysis (GSEA). Additionally, single-sample GSEA (ssGSEA) was used to examine changes in immune infiltration and enrichment. A risk prognostic model was constructed utilizing multivariable Cox regression and Least Absolute Shrinkage and Selection Operator (LASSO) analyses, and subsequently validated its predictive accuracy by stratifying patients according to the median risk score. Ultimately, some crucial independent prognostic genes were pinpointed and their expression, roles, and immune characteristics were explored in both laboratory and live models. Findings revealed 52 differentially expressed genes (DEGs), of which 21 were significantly linked to BRCA outcomes. These 21 genes were utilized for consensus clustering to categorize BRCA patients into two subtypes. Subtype B was linked to a worse prognosis compared to Subtype A, though both subtypes were distinguishable. The enriched pathways were mainly concentrated in Subtype A and were actively expressed in this group. Following this, a prognostic risk model was constructed using five risk genes, which was proven to possess significant predictive value. A significant link was identified between the immune microenvironment and the risk-associated genes and scores. IL33 was identified as an independent prognostic gene with important research value. Its in vivo expression results aligned with the data analysis findings, showing low expression in BRCA. Furthermore, overexpression of IL33 significantly inhibited BRCA growth and motility in vitro and in vivo, while also enhancing their vulnerability to destruction by activated CD8+ T cells. The ERG-based risk model effectively predicts the prognosis of BRCA patients and shows a strong link with the immune microenvironment. IL33 stands out as a significant prognostic marker, crucial in the onset and advancement of BRCA. This highlights the necessity for additional studies and indicates that IL33 might be a potential target for BRCA treatment.\n\nID: 39875956\nTitle: Deciphering the therapeutic effects of Xiyanping injection: insights into pulmonary and gut microbiome modulation, SerpinB2/PAI-2 targeting, and alleviation of influenza a virus-induced lung injury.\nAbstract: Infection with Influenza A virus (IAV) induces severe inflammatory responses and lung injury, contributing significantly to mortality and morbidity rates. Alterations in the microbial composition of the lungs and intestinal tract resulting from infection could influence disease progression and treatment outcomes. Xiyanping (XYP) injection has demonstrated efficacy in clinical treatment across various viral infections. However, its specific effects and mechanisms against IAV remain unclear. In this study, we established an IAV infection mice model, and utilized 16\u00a0S rRNA sequencing, RNA sequencing, protein chips, and molecular docking, to investigate the mechanisms of XYP injection on altering pulmonary and gut microbiota, and identifying its target sites. We revealed that XYP injection significantly reduced mortality, weight loss, lung viral titers, and lung pathology in IAV-infected mice. XYP injection down-regulated the activity of malondialdehyde, and the levels of interleukin (IL)-1\u03b2, IL-5, IL-6, tumor necrosis factor-\u03b1, IL-18, IL-15, granulocyte colony-stimulating factor, IL-9, chemokine (C-C motif) ligand-5, and C-X-C motif chemokine ligand 5, while up-regulated the activities of glutathione peroxidase reactive and superoxide dismutase, and the level of interferon-\u03b3. The diversity of the pulmonary and gut microbiota was altered slightly after XYP injection. The linear discriminant analysis of the gut microbes revealed a higher proportion of potentially beneficial bacteria, including Akkermansia, Parabacteroides goldsteinii, Defluviitaleaceae, Oscillospirales, and Eubacterium_coprostanoligenes_group characterized the XYP group. Peritoneal macrophage RNA sequencing highlighted Serpinb2 as the most significantly regulated gene by XYP injection, along with consistent changes in multiple downstream Th2 structure genes. KEGG pathway analysis indicated significant modifications in genes associated with influenza A, mitogen-activated protein kinase signaling, nuclear factor kappa-B signaling, and apoptosis following XYP injection. Finally, human protein chips and molecular docking were carried out to confirm the binding of the main component of XYP injection, andrographolide, with SERPINB2/PAI-2 protein. Overall, our study provides valuable insights into the therapeutic potential of XYP injection in treating influenza, highlighting its multifaceted effects on host microbiota and immune responses, and pinpointing SerpinB2/PAI-2 as the target for XYP injection in exerting anti-inflammatory and antiviral therapeutic mechanisms.\n\nID: 42434047\nTitle: The Plastic Within: Micro- and Nanoplastics in Human Tissues and the Nutritional Context for Exposure Mitigation.\nAbstract: Microplastics (MPs) and nanoplastics (NPs) are increasingly detected in human tissues, prompting concern about potential biological effects. Yet, for most outcomes, the literature remains dominated by detection studies and preclinical toxicology, with limited human dose-response data. We conducted a narrative review of peer-reviewed literature (2000-2025), prioritizing human biomonitoring and tissue-detection studies, observational health-outcome studies, and mechanistic evidence that plausibly links exposure to cardiometabolic, reproductive, and neuroinflammatory pathways. Certainty of evidence was appraised using GRADE principles where applicable and explicitly separated from mechanistic plausibility. MPs/NPs have been reported in blood, lung, placenta, atherosclerotic plaques, brain, liver, and testicular tissue. The most clinically salient human outcome signal to date is an association between plaque microplastics and subsequent major adverse cardiovascular events in an observational cohort (hazard ratio 4.53, 95% CI 2.00-10.27). However, polymer quantification approaches vary (particle counts vs polymer mass), contamination control is method-dependent, and inter-study comparability remains limited. The current evidence base supports aggressive exposure reduction as the most defensible \"first-line\" strategy. Nutritional approaches (dietary fiber, gut-barrier support, and microbiome modulation) are best framed as adjunctive, mechanistically plausible risk-mitigation strategies rather than proven methods to remove plastics from the body. Well-designed human trials and standardized analytical protocols are needed before clinical \"detoxification\" claims can be justified.\n\nID: 42427432\nTitle: Toward a Dual-Axis Model of Microbiome Modulation in Cancer Immunotherapy: Pathobiont Elimination and Functional Ecosystem Restoration.\nAbstract: The gut microbiome is increasingly recognized as a modulator of cancer immunotherapy efficacy, including responses to immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell (CAR-T) therapy. Recent clinical trials of microbiome-targeted interventions such as fecal microbiome transplantation (FMT) and live biotherapeutic products (LBPs) suggest the potential to enhance antitumor immunity and improve clinical outcomes. Yet responses remain heterogeneous and are not fully explained by engraftment of donor taxa alone. We integrate evidence from interventional trials, observational cohort studies, and principles from gut microbial ecology to develop a model hypothesis on how microbiome-targeted therapies may shape response to immunotherapy, with potential to inform future trial design, analyses, and interpretation. Drawing on the available evidence, we propose that therapeutic perturbation of the gut microbiome may augment immunotherapy efficacy through two parallel axes: (1) elimination of immunosuppressive pathobionts that restrain CD8+ T-cell activation and promote myeloid-mediated immunosuppression, and (2) functional restoration of the gut ecosystem through engraftment of taxa that provide metabolites, structural cues, and immunoregulatory signals required for effective antitumor immunity. The success of both axes appears to depend on ecological processes governed by predator-prey dynamics, including colonization resistance, resilience of the resident microbiota, and the ability of administered organisms to displace entrenched dysbiotic communities. This ecological lens may help to explain discrepancies across trial designs, donor types, and intervention modalities, and suggests that complete donor engraftment is neither necessary nor sufficient for clinical benefit. A dual-mechanism model of pathobiont elimination and functional microbial restoration may help explain microbiome-mediated enhancement of cancer immunotherapy, highlighting a balanced immune permissive gut ecosystem as a key determinant of therapeutic success.\n\nID: 42386309\nTitle: Air pollution-induced airway epithelial barrier dysfunction in COPD: a narrative review of mechanisms and therapeutic implications.\nAbstract: Air pollution is particularly harmful to people with chronic obstructive pulmonary disease (COPD). Exposure to air pollution from sources such as biomass burning leads to a unique COPD phenotype. This phenotype mainly shows airway damage, with less emphysema than typical smoking-related phenotypes. Across various COPD phenotypes, airway epithelial barrier dysfunction is a basic pathological mechanism. This narrative review summarises the current available evidence on how different types of airborne pollutants, including particulate matter (PM), ozone (O3), diesel exhaust and microplastics, damage the airway epithelial barrier. The toxicity of fine PM with a diameter of \u22642.5 \u00b5m, one of its main constituents, largely depends on its chemical composition. Some metals or organic chemicals with redox properties can initiate oxidation reactions and induce pathologic responses. The main injury mechanisms are direct physical damage to apical junctional complexes, serious impairment of mucociliary clearance and induction of oxidative stress. Apart from these immediate harms, pollutants also create epigenetic modifications and disturbed epithelium-immune cell cross-talk, which breaks down the equilibrium of the airway epithelial barrier. These system-wide effects are exacerbated through the gut-lung axis, which aggravates local lung damage via microbiome dysregulation. We evaluate emerging therapeutic strategies that aim to restore barrier integrity, including antioxidants, natural compounds, inhibitors directing specific pathways (e.g. epidermal growth factor receptor (EGFR), NLR family pyrin domain containing 3 (NLRP3)) and microbiome modulation via probiotics. Protection and repair of the airway epithelial barrier offer a promising approach to reducing the onset and progression of pollution-related COPD in populations vulnerable to highly polluted environments.\n\nID: 42305556\nTitle: Sustained complete response to TMEp-CI-M platform in refractory small-cell lung cancer with brainstem metastasis: a case report with over 20 months of disease-free survival.\nAbstract: Brainstem metastasis from small-cell lung cancer (SCLC) is exceedingly rare and is associated with a dismal prognosis. This study presents a case of brainstem metastasis from SCLC treated with the TMEp-CI-M platform, achieving no evidence of disease (NED) for more than 20 months. The TMEp-CI-M platform is designed to overcome resistance in immunologically \"cold\" tumors through sequential tumor microenvironment priming (TMEp), checkpoint inhibition (CI), and microbiome modulation. We have previously reported its efficacy in pancreatic neuroendocrine carcinoma, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, non-small cell lung cancer (NSCLC), and colorectal cancer. A 60-year-old male with programmed death ligand 1 (PD-L1)-negative extensive-stage small-cell lung cancer (ES-SCLC) and brainstem metastasis received the TMEp-CI-M regimen. The TMEp phase integrated stereotactic body radiotherapy (SBRT), low-dose etoposide, and anlotinib, followed by CI with the programmed death 1 (PD-1)/cytotoxic T lymphocyte antigen 4 (CTLA-4) bispecific antibody cadonilimab and concurrent probiotic supplementation. The patient's pro-gastrin-releasing peptide (ProGRP) level normalized after the first cycle (from 1803 pg/mL to 23.71 pg/mL) during a total of 6 treatment cycles. At the time of this report (20 months after treatment initiation), the patient remains NED, with only Grade 1 hypothyroidism as an adverse event. The TMEp-CI-M platform may enhance the efficacy of immunotherapy in ES-SCLC, enabling durable responses even in patients with brainstem metastases. Although this platform has demonstrated promise across multiple tumor types, further prospective and mechanistic studies are warranted to confirm its clinical utility.\n\nID: 42204605\nTitle: The formation and function of tertiary lymphoid structures.\nAbstract: Tertiary lymphoid structures (TLSs) are immune cell aggregates that emerge in nonlymphoid tissues during various disease states, including chronic inflammation, autoimmunity, and cancer. TLSs are structurally and functionally analogous to secondary lymphoid organs, and exhibit a maturation continuum (progressing from initial aggregation to mature structures with germinal centers). TLS formation is synergistically regulated by local chemokine networks (e.g. CXCL13, CCL19, and CCL21), lymphotoxin signaling axes, stromal cells, metabolic reprogramming, and the microbiome. This review comprehensively elucidates the biological foundations of TLSs, including their cellular composition, spatial architecture, and developmental dynamics of maturation. We explore the crucial roles of TLSs as favorable prognostic factors and predictors of the immunotherapy response in various solid tumors, including melanoma, breast cancer, lung cancer, hepatocellular carcinoma, and colorectal cancer. Additionally, we analyze their \"pathogenic\" role in causing tissue damage and disease progression in autoimmune disorders such as rheumatoid arthritis and Sj\u00f6gren's syndrome, as well as chronic inflammatory diseases such as COPD, IgA nephropathy, and atherosclerosis. In addition, we thoroughly examine TLS research methodologies, covering a wide range of approaches from conventional hematoxylin and eosin (H&E) and immunohistochemical staining to advanced multiplex fluorescence staining, imaging mass cytometry, and spatial transcriptomic techniques. We summarize multiple gene expression signatures (e.g. the 12-chemokine signature and TLS score) for TLS identification and quantification. Finally, we highlight multiple strategies for artificially inducing TLS formation, including cytokine delivery, immunotherapy, engineered scaffolds, microbiome modulation, and organoid technologies, designed to enhance antitumor immunity or reverse immunopathology. This review provides a comprehensive framework for understanding the complex functions of TLSs in human disease and explores their clinical translation potential as biomarkers and therapeutic targets.\n\nID: 42199981\nTitle: Phytochemical Monomers Derived from Traditional Chinese Medicine May Prevent and Treat Atherosclerosis by Modulating the Macrophage Mitochondrial-Lysosomal Senescence Axis.\nAbstract: The pathogenesis of atherosclerosis (AS) is evolving from a lipid-centric view to a paradigm of immunosenescence. Stress-induced senescence of plaque macrophages is associated with inflammation and instability via the senescence-associated secretory phenotype (SASP). Dysfunction of the integrated \"mitochondria-lysosome senescence axis\" is thought to play a key role in maintaining this senescent state, which correlates with lipid overload, impaired efferocytosis, and fibrous cap degradation. Multi-targ et monomers from Traditional Chinese Medicine (TCM) such as quercetin, Tanshinone IIA, berberine, and baicalein have been shown to modulate senescent macrophages, potentially via this axis. Proposed mechanisms include inhibiting p38 MAPK/p16 signaling, reducing scavenger receptor-mediated lipid uptake, enhancing cholesterol efflux, suppressing the NF-\u03baB/NLRP3 inflammasome, promoting efferocytosis via TAM receptors, and restoring metabolic support for lysosomal acidification. This review synthesizes the role of the mitochondria-lysosome axis in AS and highlights the potential of TCM monomers to stabilize plaques, providing a novel framework for therapeutic development.\n\nID: 42180801\nTitle: COPD-Lung Cancer Comorbidity: Mechanistic Insights and Precision Oncology Implications.\nAbstract: Chronic obstructive pulmonary disease (COPD) and lung cancer frequently coexist, constituting a clinically consequential comorbidity with major implications for precision medicine. Beyond shared environmental exposures such as tobacco smoke and air pollution, COPD has emerged as an independent driver of pulmonary carcinogenesis, mediated through persistent inflammation, genomic instability, epigenetic remodeling, and microbiome-immune dysregulation. Patients with COPD-associated lung cancer exhibit distinct molecular hallmarks, including reduced EGFR mutation frequency, enrichment of LRP1B truncations, and elevated tumor mutational burden, which collectively reprogram tumor immunogenicity and therapeutic responsiveness, favoring immune checkpoint blockade over targeted EGFR-directed therapy. Recent advances integrating low-dose CT (LDCT) with spirometry, liquid biomarkers (eg, S100A12, TLR4), and AI-enhanced radiomic algorithms have substantially improved early detection capabilities. In parallel, microbiome-derived signatures provide novel tools for risk stratification and treatment personalization. Preventive and therapeutic strategies, including statin therapy, inhaled corticosteroids, preoperative pulmonary optimization, and microbiome modulation, are emerging as promising approaches to intercept the COPD-lung cancer continuum and improve clinical outcomes. This review synthesizes current evidence spanning epidemiology, molecular pathogenesis, diagnostic innovations, and comorbidity-tailored interventions, culminating in a \"comorbidity-centered precision management\" framework. By bridging mechanistic discoveries with clinical implementation, this paradigm may contribute to reducing COPD-lung cancer mortality and could support the advancement of the global precision oncology agenda.\n\nID: 42132238\nTitle: Harnessing the immune system in lung cancer: emerging role of the microbiome.\nAbstract: The microbiome has emerged as a critical regulator of tumor biology and immune response in lung cancer. Once considered sterile, the lung is now recognized to harbor a diverse microbiome that interacts with the gut-lung axis to shape inflammation, immune evasion, and therapeutic outcomes. This study reviews current evidence linking microbiome composition and function to lung cancer development and response to immune checkpoint inhibitors (ICIs). We explore mechanisms of microbial influence on host immunity, identify key taxa associated with treatment outcomes, and summarize therapeutic strategies such as fecal microbiota transplantation, probiotics, postbiotics, dietary changes, antibiotics, and engineered live biotherapeutics. The literature search was performed across multiple databases and sources, including PubMed, Scopus, Embase, and clinical trial registries, up to August 2025, focusing on both preclinical and clinical studies related to lung cancer, immunotherapy, and microbiome-targeted interventions. Microbiome research is redefining precision oncology by presenting new biomarkers and therapeutic targets. Although early-phase trials show potential to improve ICI efficacy, implementation is limited by donor variability, methodological differences, and biosafety issues. Standardized protocols, mechanistic studies, and biomarker-driven patient selection will be crucial to incorporating microbiome modulation into routine lung cancer treatment.\n\nID: 41897499\nTitle: Copper Dyshomeostasis, Redox Buffering and Immune Aging Converge on Cuproptosis in Age-Related Diseases.\nAbstract: Cuproptosis is a copper-dependent form of regulated cell death that is triggered when intracellular copper handling is perturbed and mitochondrial metabolism becomes the primary site of damage. Aging provides a biological context for this process because copper trafficking shifts, mitochondrial quality control and proteostasis decline, and immune function is remodeled toward immunosenescence with persistent low-grade inflammation. These age-associated changes can weaken antioxidant buffering, reshape labile copper pools, and lower the threshold at which copper stress is converted into mitochondrial proteotoxic injury. In parallel, inflammaging-related cytokines and NF-\u03baB programs can alter copper import, export, and sequestration, while impaired efferocytosis prolongs danger signaling, creating feedforward loops that sustain tissue injury. In this review, we summarize the molecular features that distinguish cuproptosis from other death programs and discuss how redox buffering capacity, copper transport machinery, and mitochondrial metabolic state jointly determine cuproptosis sensitivity during aging. We then examine disease contexts in which these pathways are plausibly relevant, including hereditary copper-handling disorders and age-related neurodegenerative, cardiovascular, metabolic, and musculoskeletal disorders. Finally, we discuss key knowledge gaps and experimental priorities for interpreting cuproptosis-related signals in aged tissues, with emphasis on how copper handling, mitochondrial state, and immune remodeling jointly shape disease phenotypes.\n\nID: 41852409\nTitle: The microbiome and lung cancer: microbial effects on host immune responses and treatment outcomes.\nAbstract: The human microbiome plays a critical role in shaping physiological processes, immune system function, metabolism, and disease development. Recent research has highlighted the microbiome's profound cancer impact, particularly on lung cancer. This review explores how microbial communities in lung and gut influence tumor progression, immune responses, and treatment outcomes as well as describing the interactions between the microbiome and the host immune system in modulating the efficacy of cancer therapies. Emerging evidence from preclinical and clinical studies investigating the role of the lung and gut microbiome in lung cancer focus on alterations in the microbiota that influence the tumor microenvironment, modulate immune responses, and potentially enhance/hinder treatment effectiveness such as chemotherapy, targeted therapies, and immunotherapy. Microbial diversity plays a significant role in immune regulation, and specific microbial species may activate/suppress immune cells such as T-cells, dendritic cells, and macrophages. Furthermore, this review examines the therapeutic implications of microbiome modulation, including the use of probiotics, antibiotics, and fecal microbiota transplantation in enhancing cancer therapies. Alterations in the lung and gut microbiome and their interaction in the recently described gut-lung axis with its bidirectional communication significantly influence the tumor microenvironment and systemic immune responses. These findings suggest that microbial diversity can regulate immune functions, with specific species capable of activating or suppressing immune cell activity. Furthermore, microbiome-targeted interventions show potential in improving the effectiveness of treatments including chemotherapy, targeted therapies, and immunotherapy, underscoring the importance of the microbiome as a key factor in lung cancer pathogenesis and treatment.\n\nID: 41827848\nTitle: Network Rewiring in the Aging Immune System: From Chronic Inflammation to Age-Related Pathologies.\nAbstract: Aging is accompanied by profound alterations in immune function that collectively drive increased susceptibility to infection, reduced vaccine efficacy, impaired tissue repair, and heightened risk of age-related diseases (ARDs). These alterations are characterized by the coexistence of immunosenescence and inflammaging. Rather than reflecting isolated cellular defects, immune aging emerges as a systems-level reprogramming of immune networks that disrupts the initiation, resolution, and regenerative phases of inflammatory responses. In particular, aging is associated with impaired resolution of inflammation, defective efferocytosis, reduced responsiveness to pro-resolving signals, and diminished regenerative capacity, leading to persistent inflammatory milieus and tissue damage. This review summarizes recent advances in the mechanisms underlying immune dysfunction in aging, with a focus on how chronic inflammation, failed resolution, and defective repair reinforce one another. We discuss how alterations in innate and adaptive immunity, immunometabolism, cellular senescence, and immune-tissue interactions drive inflammaging and contribute to major ARDs, including cancer, neurodegenerative, and cardiometabolic diseases. Finally, we highlight emerging therapeutic strategies aimed at restoring immune balance and resolution. By adopting a systems-level and network-based perspective, this review underscores immune aging as a modifiable driver of ARDs and identifies key knowledge gaps and future directions toward interventions that promote healthy aging and extended healthspan.\n\nID: 41805689\nTitle: Community-Acquired Pneumonia in Patients With Diabetes: Narrative Review.\nAbstract: Patients with diabetes carry a 1.5- to 2-fold higher risk of community-acquired pneumonia (CAP) and experience more severe outcomes, yet the mechanisms that integrate metabolic dysregulation, pathogen shifts, and novel cell death pathways remain fragmented. This study aimed to synthesize current evidence on epidemiology, pathophysiology, causative pathogens, clinical outcomes, and management of CAP in adults with diabetes and to identify research gaps for future trials. A narrative review (1999 to August 2025) of PubMed, EMBASE, the Cochrane Library, and Web of Science was conducted. GRADE (Grading of Recommendations Assessment, Development, and Evaluation) was used to rate evidence from 81 selected English-language studies (randomized controlled trials, cohorts, and meta-analyses). Diabetes increases CAP incidence (relative risk 1.73, 95% CI 1.46-2.04), hospitalization (+30%-50%), and 30-day mortality (odds ratio 1.67, 95 % CI 1.45-1.92). Key drivers include hyperglycemia-induced immune paralysis, pulmonary microangiopathy, ferroptosis, glycation and methylation changes, and gut-lung dysbiosis that collectively favor multidrug-resistant Gram-negative bacilli (Klebsiella and Pseudomonas) and severe viral and fungal coinfections. Host-targeted therapy with moderate glycemic control (5-10 mmol/L), continued metformin, and pathogen-directed antibiotics improves survival, whereas single-dose PCV20 and annual influenza vaccination prevents approximately 45% of CAP admissions. Emerging strategies (nanozymes, ferroptosis inhibitors, probiotics, and proteolysis-targeting chimeras) are still preclinical. CAP in patients with diabetes is a distinct, more severe entity mediated by metabolic-immune crosstalk. Multicenter randomized controlled trials integrating tight glucose monitoring, novel host-directed agents, and microbiome modulation are warranted to translate mechanistic insights into better outcomes.\n\nID: 41787577\nTitle: Effects of Leuconostoc lactis on the antioxidant ability and indole-3-acetaldehyde metabolism via regulating the gut microbiota-liver axis in aged laying hens.\nAbstract: Lactobacillus has antioxidant properties that may benefit poultry production. However, there is no systematic research on antioxidant of Lactobacillus strain and its effects on regulating nutrient metabolism in aged laying hens. This study investigated the influence of Leuconostoc lactis on production and antioxidant capacity in aged laying hens and explored the key biomarkers associated with tryptophan-skatole metabolism and its effects on the intestinal microbiota-liver axis. Hens supplemented with L. lactis showed a higher laying rate, reduced hepatic MDA levels, and increased T-AOC in comparison with the control group (CG). Indole-3-acetaldehyde (IAld) levels were elevated in both feces and yolk, and skatole decreased in feces by the L. lactis group compared to CG. The total polyunsaturated fatty acids (PUFAs), C18:3n3, and C18:2n6c in yolk were raised in the L. lactis group relative to CG. In the liver, mRNA levels of AhR, CYP2D6, and CPT-1 were markedly upregulated in the L. lactis group relative to CG. The L. lactis-treated group also exhibited higher alpha diversity in fecal samples at 30 days and in ileal samples at 60 days. Further, we conducted the hepatocyte validation experiment and found that MDA levels were significantly reduced, and T-AOC was increased in both the L. lactis and IAld-treated groups compared with the CG. IAld treatment significantly affected p38, and NF-\u03baB, and Nrf2 cytokine expression in hepatocytes. The findings provide a reference for the use of L. lactis in improving production and intestinal nutrition in aged laying hens.\n\nID: 41748098\nTitle: NEC-Associated Bronchopulmonary Dysplasia and the Gut-Lung Axis in Preterm Infants.\nAbstract: Prevailing evidence underscores the critical influence of infant gut microbiota on systemic immune responses and intestinal health. The role of functional programming of effector immune cells at extra-intestinal mucosal sites is increasing in interest. Common connections between development of gut and lung microbiomes and reciprocal signaling between the two organ systems has reinforced the concept of a \"gut-lung axis.\" Narrative review of existing literature evaluating mechanistic evidence linking microbial dysbiosis and necrotizing enterocolitis (NEC) to development of preterm acute lung injury and subsequent progression to chronic lung disease or bronchopulmonary dysplasia (BPD). Evidence across animal and human studies indicates that gut-derived microbial ligands and metabolites are foundational in programming respiratory immunity. Conversely, primary pulmonary insults appear to trigger reciprocal shifts in gut microbiome function. This bidirectional signaling likely drives the clinical association between NEC-associated systemic inflammation and the subsequent increased risk of BPD. By focusing on mediators involved in this gut-lung crosstalk, we seek to highlight avenues such as microbiome modulation or targeted anti-inflammatory signaling to prevent or reduce the severity of two of the major morbidities of prematurity. \u00b7 Gut dysbiosis drives systemic inflammation and mediates pro-inflammatory responses in the lungs.. \u00b7 The communication between gut and lungs is mediated by microbiome, metabolites and immune cells.. \u00b7 Modulating the gut microbiome presents a promising strategy for prevention of BPD in preterm infants.\n\nID: 41632104\nTitle: Lactobacillus plantarum TY-S8 ameliorates hyperuricemia through the regulation of gut microbiota and tryptophan metabolism in mice.\nAbstract: Hyperuricemia (HUA) has become a worldwide metabolic disease, which can lead to acute gout attacks, renal dysfunction, uric acid (UA) urolithiasis, and cardiovascular damage. Probiotics, known for their cost-effectiveness, minimal toxic side effects, and high safety profile, have shown potential in alleviating HUA. In the present study, the beneficial function of Lactobacillus plantarum TY-S8 on HUA and related mechanisms were comprehensively investigated by constructing a mice model of hyperuricaemia, combined with the use of microbiomics and metabolomics. Our results demonstrated that L. plantarum TY-S8 markedly lowered serum UA (SUA) concentrations by 22.41%, suppressed xanthine oxidase (XOD) activity and modulated the level of key transporters, including GLUT9, ABCG2, and NTP1. Furthermore, the pathological damage in the liver, kidney and colon of hyperuricemic mice was alleviated by the probiotics. Meanwhile, the strain upregulated the levels of occludin, a key tight junction protein, and promoted the synthesis of short-chain fatty acids (SCFAs), with a notable increase in butyric acid. Microbiome sequencing and analysis revealed that L. plantarum TY-S8 significantly increased the proportions of Lactobacillus johnsonii and Limosilactobacillus reuteri. Additionally, metabolomic analysis of fecal and blood samples indicated that the differential metabolites among the three groups were primarily indole derivatives, such as indole-3-acetic acid (IAA), indole-3-lactic acid (ILA), and indole-3-acetaldehyde (IAAld), which are involved in the tryptophan metabolism pathway. Notably, there is a clear correlation between the key bacterial strains and these differential metabolites. At last, fecal microbiota transplantation (FMT) was performed to confirm that the ameliorative effect of L. plantarum TY-S8 on the hyperuricemic mice is primarily mediated by the regulation of gut microbiota and tryptophan metabolites. In conclusion, L. plantarum TY-S8 exerts probiotic effects on hyperuricemic mice through multiple pathways. In particular, it alleviates intestinal inflammation by regulating tryptophan metabolism, thereby effectively promoting uric acid metabolism, which highlights its potential value in the intervention of HUA.\n\nID: 41548440\nTitle: Limosilactobacillus reuteri alleviates psoriasis via aryl hydrocarbon receptor-mediated regulation of Interkeukin-17A.\nAbstract: Psoriasis is a chronic immune-mediated skin disorder characterized by keratinocyte hyperproliferation and interleukin-17A-driven inflammation. Growing evidence highlights the contribution of microbiome-derived factors to cutaneous immune regulation. The study aimed to evaluate the therapeutic efficacy of heat-killed Limosilactobacillus reuteri NCHBL-005 in an imiquimod-induced psoriasis-like mouse model. Both topical and oral administration of NCHBL-005 significantly alleviated clinical and histological features, including reduced epidermal thickness, improved Psoriasis Area and Severity Index scores, and diminished inflammatory cell infiltration. Mechanistically, NCHBL-005 suppressed interleukin-1 beta and interleukin-17A expression in psoriatic lesions and decreased interleukin-17A-positive RAR-related orphan receptor gamma t-positive T-cells while maintaining regulatory T-cell balance. These effects were retained in Toll-like receptor 2- and nucleotide-binding oligomerization domain-containing protein 2-deficient mice but abolished in aryl hydrocarbon receptor-deficient mice, underscoring the essential role of aryl hydrocarbon receptor signaling. NCHBL-005 directly attenuated inflammatory responses in keratinocytes by suppressing the expressions of interleukin-1 beta, interleukin-17A, and tumor necrosis factor-alpha, and by inhibiting nuclear factor kappa-light-chain-enhancer activation. Liquid chromatography-tandem mass spectrometry profiling identified indole-3-acetaldehyde, indole-3-carbinol, and indole-3-lactic acid as major aryl hydrocarbon receptor ligands derived from NCHBL-005. Among these, indole-3-acetaldehyde most effectively reproduced the therapeutic effects, reducing interleukin-17A-positive cells, epidermal hyperplasia, and nuclear factor kappa-light-chain-enhancer activation. NCHBL-005 and its metabolite indole-3-acetaldehyde alleviate psoriatic inflammation through modulation of the aryl hydrocarbon receptor-interleukin-1 beta-interleukin-17A axis, thereby restoring skin immune homeostasis. This study highlights postbiotic intervention in the aryl hydrocarbon receptor-interleukin-1 beta-interleukin-17A axis as a promising therapeutic strategy for psoriasis.\n\nID: 41500696\nTitle: [Multi-target mechanism and clinical transformation of hyperbaric oxygen therapy in the treatment of hypoxic-ischemic brain injury after cardiopulmonary resuscitation].\nAbstract: Cardiopulmonary resuscitation (CPR) is a critical life-saving intervention for patients who have suffered cardiac arrest (CA), which helps the organism of CA patients to rapidly restore respiratory and circulatory functions. However, the survival rate of patients after CPR is extremely low. Globally, sudden cardiac arrest causes over 3 million deaths annually, and the survival rate after CPR is less than 8%. Hypoxic ischemic brain injury (HIBI) is the primary cause of death in 68% of these cases. Hyperbaric oxygen therapy (HBOT) enhances the dissolution of oxygen in plasma, increases the arterial blood oxygen partial pressure in the body, and improves tissue hypoxia. It is widely used in conditions of cerebral ischemia and hypoxia (such as stroke, CA, etc), but its role in HIBI following CPR has not been fully studied. Therefore, this article systematically reviews the multi-target mechanisms of HBOT in the treatment of HIBI, including the inhibition of cell apoptosis and necrosis, improvement of oxidative stress, reduction of neuroinflammation, and enhancement of blood-brain barrier permeability and collateral circulation. It also discusses emerging treatment strategies such as HBOT combined with gut microbiome modulation and active abdominal compression-decompression CPR (AACD-CPR), exploring their potential as new therapeutic targets for HIBI post-CPR, with the aim of identifying more promising clinical translation paths to improve neurological functional prognosis and quality of life after CPR.\n\nID: 41486167\nTitle: Microbiome modulation of tumorigenesis and immune responses.\nAbstract: The microbiome has emerged as a critical, context-dependent regulator of tumorigenesis and anticancer immunity, capable of either promoting cancer progression or protecting against malignancy. This dual role is mediated by multiple interconnected mechanisms-including chronic inflammation, modulation of immune responses, and alterations in host metabolic signaling. These microbiome-cancer interactions vary across organs, influencing malignancies in the colon, breast, lung, and beyond. Clinically, the microbiome significantly affects patient responses to cancer therapies, particularly immunotherapies such as immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR)-T cell therapy. Although emerging therapeutic strategies aimed at modulating the microbiome have shown promising early results, challenges remain, including individual microbiome variability and the dynamic interplay between the immune system and microbial communities. Nevertheless, harnessing the microbiome holds significant potential to transform precision oncology, offering personalized cancer prevention and treatment strategies tailored to each patient's unique microbial ecosystem.\n\nID: 41351413\nTitle: Microbiome Modulation in Lung Cancer Immunotherapy: Unveiling the Role of Respiratory and Gut Microbiota in the PD-1/PD-L1 Response.\nAbstract: Lung cancer, the leading cause of cancer-related mortality worldwide, poses considerable therapeutic challenges due to the varied responses to programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) inhibitors. Emerging highlight the pivotal role of host-microbiome interactions in modulating antitumor immunity and influencing clinical outcomes. This review examines how the respiratory and gut microbiota contribute to the immunosuppressive tumor microenvironment through dysbiosis-induced T-cell exhaustion and regulatory cell activation, while certain commensals facilitate dendritic cell-mediated recruitment of cytotoxic T lymphocytes. Additionally, this review explores the molecular mechanisms by which microbial metabolites, such as short-chain fatty acids, influence myeloid-derived suppressor cells. Therapeutically, microbiota-modulation strategies-such as tailored probiotic formulations and precision fecal microbiota transplantation-offer potential to enhance immunotherapy efficacy. This review provides a foundation for microbiome-guided immunotherapy, advocating for biomarker-driven patient stratification and the use of engineered microbial consortia to counteract therapeutic resistance. These findings pave the way for the integration of microbiome science into next-generation precision oncology.\n\nID: 41303019\nTitle: Systemic Consequences of Inflammatory Bowel Disease Beyond Immune-Mediated Manifestations.\nAbstract: Inflammatory bowel disease (IBD) management traditionally focuses on intestinal inflammation, yet extraintestinal manifestations can substantially impair patient quality of life. In this perspective, we emphasize the broad systemic impact of IBD-from highly prevalent conditions such as anemia, metabolic dysfunction-associated steatotic liver disease, or fatigue to rare but severe complications like interstitial lung disease and drug-induced glomerulonephritis. We review underlying mechanisms linking gut inflammation to distant organs, including immune dysregulation, microbial translocation, and metabolic derangements. Advances in diagnostics-such as biomarker panels, high-resolution imaging, and genomic/microbiome profiling-enable early detection and risk stratification. Emerging therapies, including targeted biologics (anti-TNF, anti-integrin, anti-IL-23), JAK and S1P modulators, precision nutrition, and microbiome modulation, offer new opportunities to address systemic inflammation. A multidisciplinary framework integrating gastroenterology with hepatology, hematology, neurology, nephrology, endocrinology, dermatology, pulmonology, and cardiology is essential to recognize hidden complications, facilitate timely intervention, and deliver personalized, comprehensive care for IBD.\n\nID: 41301443\nTitle: Emerging Issues Regarding the Effects of the Microbiome on Lung Cancer Immunotherapy.\nAbstract: Lung cancer remains the deadliest malignancy, with limited effective and long-term therapeutic options. Immunotherapy has revolutionized the therapeutic landscape of lung cancer. However, not everyone with lung cancer responds to immunotherapy, while, inpatients who temporarily derive clinical benefit, resistance eventually develops. The host microbiome has emerged as a pivotal player in cancer growth and progression. It has been implicated in the intricate connections between immune cells and tumor cells, ultimately augmenting immunotherapy efficacy in solid tumors, while simultaneously mitigating the immune-related adverse events associated with this type of treatment. Notably, lung cancer patients who obtain benefit from immunotherapy have been found to be colonized with specific bacterial populations, and it is this observation that the scientific community is trying to exploit, aspiring to improve lung cancer immunotherapy response rates. Delving deeper into the molecular mechanisms underpinning the effects of the microbiome on immunotherapy is an area that we should pay attention to if we want to utilize microbiome modulation in everyday clinical practice. Fecal microbiota transplantation, probiotics, targeted antibiotic interventions, and dietary modifications are among the strategies that are under investigation in clinical trials, with the ultimate endpoint of lengthening the life expectancy of lung cancer patients.\n\nID: 41191326\nTitle: Gut microbiome-mediated nutrients alter opportunistic bacterial growth in peritonitis.\nAbstract: Peritonitis is a well-known complication of bowel perforation and abdominal surgery, leading to sepsis and high mortality. Despite its prevalence and severity, the pathogenesis of peritonitis remains incompletely understood, limiting our ability to develop targeted medical therapies. Specifically, little is known about the determinants of the peritoneal nutrient environment for pathogens. The gut microbiome is a well-established source of infectious bacteria in peritonitis, but whether it also modulates levels of nutrients that enable and sustain these infections remains unknown. Using multiple murine models of peritonitis (lipopolysaccharide and cecal slurry), multiple methods of microbiome modulation (germ-free mice and antibiotic-treated mice), novel ex vivo modeling of peritonitis, and nuclear magnetic resonance (NMR) metabolomics of the peritoneal microenvironment, we performed a series of experiments to determine how the gut microbiome influences peritoneal metabolite concentration during peritonitis. We found that both lipopolysaccharide and cecal slurry peritonitis caused consistent changes in high-abundance peritoneal metabolites and that many of these changes were blunted or completely abrogated in antibiotic-treated and germ-free mice. Moreover, we found that peritoneal washings from septic, microbiome-depleted animals supported less bacterial growth of common intra-abdominal pathogens compared with washings from septic conventional animals. We identified the peritoneal nutrients consumed by two common pathogens from the Enterobacteriaceae family and found that supplementation of gut microbiome-mediated nutrients was sufficient to alter bacterial growth in an ex vivo model. Taken together, we identify the gut microbiome as a key driver of the peritoneal nutrient environment, mediating pathogen growth. These findings suggest that microbiome-targeted therapies could mitigate peritonitis risk.NEW & NOTEWORTHY Peritonitis induced via cecal slurry or LPS induced similar changes in prevalent metabolites in the murine peritoneal microenvironment, increasing glutamine and pyruvate and decreasing glucose and butyrate. Gut microbiome depletion using germ-free mice or antibiotic pretreatment blunted many of these peritoneal metabolite changes. Peritoneal fluid from microbiome-depleted LPS-treated mice exhibited reduced bacterial growth of two Enterobacteriaceae commensals in an ex vivo peritonitis model compared with fluid from conventional LPS-treated animals.\n\nID: 41112042\nTitle: The microbiome in cancer.\nAbstract: The human microbiome is now recognized as a central regulator of cancer biology, intricately shaping tumor development, immune dynamics, and therapeutic response. This comprehensive review delineates the multifaceted roles of bacteria, viruses, and fungi in modulating the tumor microenvironment and systemic immunity across diverse cancer types. We synthesize current evidence on how microbial dysbiosis promotes carcinogenesis via chronic inflammation, metabolic reprogramming, genotoxic stress, immune evasion, and epigenetic remodeling. This review emphasizes organ-specific microbiome signatures and highlights their potential as non-invasive biomarkers for early detection, treatment stratification, and prognosis. Furthermore, we explore the impact of intratumoral microbiota on cancer therapies, uncovering how microbial metabolites and host-microbe interactions shape therapeutic efficacy and resistance. Finally, advances in microbiome-targeted strategies, such as probiotics, fecal microbiota transplantation, and engineered microbes offer new avenues for adjunctive cancer therapy. This review provides a roadmap for future investigation and underscores the transformative promise of microbiome modulation in cancer prevention and treatment.\n\nID: 41007859\nTitle: Alveolar Epithelial Cell Dysfunction in Acute Respiratory Distress Syndrome: Mechanistic Insights and Targeted Interventions.\nAbstract: Acute respiratory distress syndrome (ARDS) is a life-threatening condition with high mortality. A central driver in its pathogenesis is alveolar epithelial cell (AEC) dysfunction, which leads to disruption of the epithelial barrier, impaired fluid clearance, and dysregulated inflammatory responses. This review summarizes the key mechanisms underlying AEC injury, including programmed cell death (apoptosis, pyroptosis, necroptosis, ferroptosis), oxidative stress, mitochondrial dysfunction, epigenetic reprogramming (DNA methylation, histone modifications), metabolic rewiring (succinate accumulation), and spatiotemporal heterogeneity revealed by single-cell sequencing and spatial transcriptomics. Multicellular crosstalk involving epithelial-immune-endothelial networks and the gut-lung axis further shapes disease progression. Building on these mechanistic foundations, we evaluate emerging AEC-targeted interventions such as pharmacologic agents (antioxidants, anti-inflammatories), biologics (mesenchymal stem cells and engineered exosomes), and gene-based approaches (adeno-associated virus and CRISPR-Cas9 systems delivered via smart nanocarriers). Complementary strategies include microbiome modulation through probiotics, short-chain fatty acids, or fecal microbiota transplantation, and biomarker-guided precision medicine (e.g., sRAGE, exosomal miRNAs) to enable promise individualized regimens. We also discuss translational hurdles, including nanotoxicity, mesenchymal stem cell (MSC) heterogeneity, and gene-editing safety, and highlight future opportunities involving AI-driven multi-omics, lung-on-chip platforms, and epithelium-centered regenerative therapies. By integrating mechanistic insights with innovative therapeutic strategies, this review aims to outline a roadmap toward epithelium-targeted, precision-guided therapies for ARDS.\n\nID: 40806015\nTitle: Associations Between Serum Gut-Derived Tryptophan Metabolites and Cardiovascular Health Markers in Adolescents with Obesity.\nAbstract: Background/Objectives: Gut-derived tryptophan (Trp) metabolites play important roles in metabolic and cardiovascular regulation. Although animal studies suggest their protective effects against metabolic dysfunction, data in adolescents, particularly those with obesity, remain limited. The objective of this study was to evaluate associations between circulating gut-derived Trp metabolites and markers of cardiometabolic, vascular, and platelet health in adolescents with obesity. Methods: Data were analyzed from 28 adolescents (ages 13-18; mean BMI = 36 \u00b1 6.4 kg/m2). Fasting blood was collected to assess lipid profiles using a clinical analyzer and insulin resistance using the homeostatic model assessment for insulin resistance (HOMA-IR). Gut-derived Trp metabolites were measured by UPLC-mass spectrometry, peak oxygen uptake (VO2 peak) by gas exchange during an incremental cycle ergometer test, and body composition by dual-energy X-ray absorptiometry. Platelet spare respiratory capacity (SRC), endothelial function, and liver fat were measured using high-resolution respirometry, flow-mediated dilation (FMD) of the brachial artery, and magnetic resonance imaging respectively. Results: Indole-3-propionic acid was inversely associated with diastolic blood pressure (rho = -0.39, p = 0.047), total cholesterol (rho = -0.55, p = 0.002), and LDL-C (rho = -0.57, p = 0.0014), independent of sex and obesity severity. Indoxyl sulfate was positively correlated with fasting glucose (rho = 0.47, p = 0.012), and adolescents with impaired fasting glucose had 1.6-fold higher IS levels. Indole-3-acetaldehyde declined with age (rho = -0.50, p = 0.007), and Indole-3-acetic acid and indole were higher in Hispanics vs. non-Hispanics. No significant associations were observed between Trp metabolites and FMD, VO2 peak, or SRC. Conclusions: Gut-derived Trp metabolites, particularly indole-3-propionic and indoxyl sulfate, are associated with markers of cardiometabolic risk in adolescents with obesity. These findings support their potential relevance in early-onset cardiovascular disease risk.\n\nID: 40756341\nTitle: Gut microbiota-derived formate exacerbates pulmonary metastasis in cancer.\nAbstract: Rationale: The gut microbiota and its metabolites significantly influence cancer development and metastasis. Among these, formate, the simplest short-chain fatty acid (SCFA), remains underexplored in the context of metastasis. This study investigates the role of microbiota-derived formate in exacerbating pulmonary metastasis in melanoma and pancreatic ductal adenocarcinoma (PDAC), aiming to elucidate its mechanistic contributions to cancer progression. Methods: Using antibiotics-induced dysbiosis in mice, we quantified plasma formate levels via nuclear magnetic resonance (NMR) metabolomics and identified gut bacterial contributors through 16S rRNA sequencing. Formate's effects on melanoma and PDAC lung metastases were evaluated through in vivo supplementation experiments. Cellular assays, metabolomics, and gene expression analyses further elucidated its mechanistic impact. Results: Dysbiosis significantly increased circulating formate levels, with Enterobacterales identified as key contributors. Formate supplementation enhanced melanoma and PDAC lung metastases by promoting cancer cell proliferation, migration, and nucleotide synthesis. Mechanistic studies revealed that formate upregulated one-carbon metabolism, critical for tumor aggressiveness, and increased the production of metabolites like glutathione, facilitating oxidative stress resistance. Conclusion: Microbiota-derived formate plays a critical role in enhancing pulmonary metastasis by modulating cancer cell metabolism. These findings highlight the therapeutic potential of targeting formate production or its associated metabolic pathways to mitigate cancer spread. Additionally, microbiome modulation emerges as a promising complementary approach to improving cancer treatment outcomes.\n\nID: 40644647\nTitle: Microbiome Modulation for the Treatment of Solid Neoplasms.\nAbstract: The interplay between the human gut microbiome and the immune system has sparked growing interest in microbiome modulation as a therapeutic strategy in oncology. Preclinical studies have identified specific bacterial species linked to improved responses to immune checkpoint inhibitors (ICIs), leading to clinical investigations in melanoma, renal cell carcinoma (RCC), and non-small cell lung cancer (NSCLC). The stool bacterial abundance of Ruminococcaceae, Akkermansia, and Bifidobacterium correlates with favorable clinical outcomes, whereas the disruption of the gut microbiome through antibiotics before or during ICI initiation is associated with higher rates of primary resistance and shorter survival. Biomarkers such as TOPOSCORE have been developed to better predict ICI benefits and estimate dysbiosis and treatment responses. Several microbiome-modulating strategies have shown potential in patients receiving treatment with ICIs-for instance, high dietary fiber intake may be linked to improved outcomes. As a separate strategy, certain probiotics appear to enhance clinical activity in early trials when incorporated into ICI-based regimens. Finally, fecal microbiota transplantation has shown safety and efficacy in ICI-refractory melanoma and yielded encouraging results in treatment-na\u00efve patients with melanoma, NSCLC, and RCC. Although several compelling signals have been observed to date with microbiome manipulation, the field is lacking large, definitive randomized trials-these are indeed a prerequisite for any of the highlighted strategies to become a standard of care.\n=======================================================\n\n### [CUSTOM DATAPOINTS]\nCRITICAL EXTRACTION DIRECTIVE: You MUST extract the following custom datapoints as root-level key/value pairs inside your final JSON block:\n- \"suggested_experiments\": generate 1-3 suggested experiments\n- \"suggested_studies\": generate 1-3 suggested studies\n- \"swansons_literature_based_discovery_candidates\": You are an advanced Literature-Based Discovery (LBD) system executing Swanson\u2019s complementary-but-disjoint (A-B-C) model. Your goal is to find hidden, unpublished connections across the provided dataset. Strict Discovery Protocol: 1. Identify distinct, isolated sub-literatures (Domain A and Domain C) within the dataset that share NO direct citations, co-mentions, or common contextual paragraphs. 2. Find an intermediate biological mechanism, protein, path, or entity (Bridge B) that appears independently in both isolated domains (A-to-B and B-to-C). 3. Synthesize a novel, unstated hypothesis (A-to-C). Negative Constraint (Crucial): DO NOT output any connection if the relationship between Concept A and Concept C is explicitly mentioned, paired, or summarized anywhere in the source text. If a connection (like \"OMN resilience to SMN stabilization\") is already explicitly stated or grouped as a concept in the data, it is considered \"already known\" and must be disqualified. Format your output exactly as follows: - Discovered Hypothesis (A to C): [Clear, novel statement] - Literature A (Origin): [Entity/Concept and source context] - Literature C (Target): [Entity/Concept and source context] - The Intersecting Bridge B: [The shared mechanism/protein linking them] - Biological Rationale: [1-2 sentences explaining why this hidden connection is mechanistically plausible]\n- \"contradictions_between_evidences\": Identify conflicting evidence within the evidence set (if any) and flag the dispute here\n- \"repurposed_solutions\": identify and explain repurposed Solution potentials\n- \"lung_microbiome_axis\": Investigate how commensal metabolites like indole-3-acetaldehyde influence tissue-resident macrophage phagocytic efficiency in aged lung tissue.\n- \"systemic_crosstalk\": Test if restoring alveolar macrophage efferocytic function in the lung creates a systemic dampening of age-related inflammatory markers in distal organs like the liver or heart.\n- \"metabolic_checkpoint\": Examine if NRF2 signaling enhancement (via indole-3-acetaldehyde/PXR pathway) can rescue age-related mitochondrial fitness deficits in tissue-resident macrophages.\n\n\nFormat Requirement:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\nFirst provide disclaimer such as \"Even though this fact check looked at unique up-to-date abstracts, new evidence may refute this answer in the future. Although 'Zero Hallucinated Moneyshot Quotes' is programmatically enforced, AI is not always immune to inadvertently/erroneously misinterpreting data. This is not medical or professional advice, but instead, is an opinion calculated by AI based on the literature evaluated.\"\n---\nWrite in a highly academic, formal thesis tone.\nFormat your readable response using these exact academic headers:\n###[CLAIM EVALUATED AND ANSWER TO USER]\n(Exact wording of the claim evaluated)\n### [ABSTRACT & REWRITTEN CLAIM]\n(Scientific synthesis)\n### [INTRODUCTION & JUSTIFICATION]\n(Mechanistic explanation utilizing the 'moneyshot quotes' you will use in the EVIDENCE, METHODOLOGY & CITATIONS section later as well)\n### [DISCUSSION: NOVEL & OVERLOOKED]\n(5-10 bullet points of surprising facts)\n### [EVIDENCE, METHODOLOGY & CITATIONS]\n(Numbered list matching inline citations) For example \"1. ID: 12345 - Application: The text discusses ... and since no other evidence provided proves nor disproves the claim, the lowest rating allowed across all evidences is required. ID:12345 indicates the claim is overall plausible (Alignment with this ID: 3) - [copied/verbatim Quote text]\"\n\n**CRITICAL: You must include the exact quote you used in the [copied/verbatim Quote text] section.\n\nIf the prompt says \"at least 20 quotes\" then there must be at least 20 matching citations. You must actually use the quotes you select within the conext of the preprint publication you write.\n\nEvaluation Schema:\nRAG AMNESIA IS ACTIVE: You must ONLY use the provided context literature. Do not use outside prior knowledge. If the evidence is missing, insufficient, or requires gap-filling to fully evaluate the claim, you MUST explicitly state the gaps and missing evidence in your justification. Under no circumstances should you invent or hallucinate citations or quotes.\n\n###critical: WRAP YOUR THOUGHTS WITH
80% tumor suppression), and reduced lung metastasis. CUR@AA-NLIP holds great potentials in OSCC-targeting delivery of synergistic natural compounds and can achieve anti-proliferative and anti-metastatic effects by simultaneously enhancing tumor accumulation, reducing immune system clearance, and inhibiting of cancer-associated fibroblast (CAF) activation and angiogenesis, therefore exhibiting enhanced anti-OSCC efficacy.",
"42519831": "ID: 42519831\nTitle: Neutrophil-promoted macrophage state transition coordinates endothelial migration and barrier resealing in zebrafish microvascular repair.\nAbstract: Microvessels are frequently damaged, yet the in vivo temporal logic that couples endothelial gap closure to barrier resealing, and the immune-cell interactions that coordinate these steps, remains poorly defined. Using live imaging of laser-injured zebrafish intersegmental vessels, we define a staged repair program: endothelial cells migrate to bridge the gap, trapped erythrocytes are cleared, and vascular permeability rises transiently before resealing. Neutrophils arrive first, whereas macrophages persist and undergo a neutrophil-dependent functional transition. Early tnfa-associated macrophages promote endothelial migration and erythrocyte debris removal, while later ccl34a.4+ pro-remodeling macrophages support barrier restoration. Neutrophil ablation delays this transition and selectively prolongs permeability defects. Neutrophils release CD63+ extracellular vesicles that are taken up by macrophages, and inhibiting EV/exosome secretion phenocopies key features of neutrophil loss. These findings provide a temporal framework to dissect immune-endothelial coordination during microvascular repair.",
"42520196": "ID: 42520196\nTitle: Erythroblast-derived lipid mediators program neutrophil development and function.\nAbstract: Granulopoiesis is a tightly regulated process encompassing the production, maturation, and release of neutrophils in the bone marrow, ensuring their optimal physiological contribution to host defence. The mechanisms that maintain a balanced regulation of neutrophil effector functions during this process remain incompletely understood. Here, we identify bone marrow-resident erythroblasts as a key source of specialized pro-resolving mediators (SPMs) and show that they imprint neutrophil development and function. Terminally differentiating erythroblasts highly express the key SPM biosynthetic enzyme 12/15-lipoxygenase (Alox15) and accordingly generate several SPMs, including n-3 docosapentaenoic acid-derived Resolvin D5 (RvD5n-3 DPA). Conditional erythroblast-specific depletion of Alox15 decreased bone marrow SPM levels and caused altered neutrophil phenotypes, including augmented release of reactive oxygen species and neutrophil extracellular traps, as well as increased migration to chemotactic stimuli. This was accompanied by increased neutrophil sequestration in peripheral organs and concomitant neutropenia. Mice with erythroblast-specific Alox15 depletion displayed impaired bacterial clearance in experimental peritonitis and increased severity in DSS-colitis. Aberrant neutrophil phenotypes were rectified by the reconstitution of RvD5n-3 DPA and were largely recapitulated by the specific depletion of the SPM receptor Gpr101 in bone marrow macrophages, but not in neutrophil precursors, suggesting involvement of the macrophage niche in mediating the SPM effects on granulopoiesis. Our findings establish a central role for erythroblasts and their SPM production in instructing granulopoiesis for balanced functional neutrophil responses.",
"42520679": "ID: 42520679\nTitle: Integrated single-cell and spatial transcriptomic atlas of multi-etiology acute lung injury reveals etiology-dependent neutrophil fate decisions and a prognostic neutrophil-monocyte/macrophage interaction signature.\nAbstract: Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a life-threatening syndrome with heterogeneous etiologies and no effective pharmacological therapy. Although neutrophils are central mediators of lung injury, their functional diversity and interplay with monocyte/macrophage (Mo/M\u03a6) populations across etiologies remain poorly defined. Here, we integrated single-cell RNA-sequencing profiles from 180,031 murine lung cells across seven ALI models spanning infectious, sterile, and extrapulmonary insults to construct a multi-etiology neutrophil atlas. Augur identified neutrophils as the most transcriptionally perturbed immune population. Gene-set variation analysis revealed etiology-specific programs, including NF-\u03baB/IL-6-driven inflammation in infection/sepsis, dual interferon responses in influenza, tissue-remodeling and stress-adaptive programs in bleomycin injury, and ROS-dominated injury with metabolic reprogramming after radiation. Spatial transcriptomics further mapped the spatiotemporal dynamics of neutrophil reprogramming during influenza-induced lung injury. High-resolution re-clustering resolved 13 neutrophil subtypes organized into four macro-states, and pseudotime analysis uncovered an etiology-dependent bifurcation from a bone marrow-like immature origin toward either an IFN/inflammasome-associated effector branch or an NF-\u03baB-driven inflammatory branch, with sepsis and bacterial infection retaining neutrophils near the immature origin. In parallel, we defined 12 Mo/M\u03a6 subtypes and derived a 26-gene Neutrophil-Monocyte/Macrophage Interaction Index with prognostic value for sepsis mortality. Importantly, immunobiological validation showed that conditioned media from LPS-, P. aeruginosa- and CLP-derived neutrophils contained elevated THBS1 and activated NF-\u03baB-MAPK-NLRP3 signaling in macrophages, whereas blockade of THBS1-CD36 with CD36 peptide P(93-110) attenuated inflammatory activation, promoted reparative polarization, and reduced circulating neutrophils in vivo. Together, these findings define an etiology-resolved atlas of ALI and identify THBS1-CD36 as a mechanistically relevant therapeutic target in infection- and endotoxin-driven ALI.",
"42521072": "ID: 42521072\nTitle: Physcion alleviates Aspergillus fumigatus keratitis by inhibiting fungal growth and NF-\u03baB-mediated inflammation.\nAbstract: Physcion, a natural anthraquinone, possesses antifungal and anti-inflammatory activities. This study aimed to investigate its antifungal and anti-inflammatory effects in a murine model of Aspergillus fumigatus (AF) keratitis (AFK). The safety of physcion was evaluated using Cell Counting Kit-8 assays, live/dead cell staining and the Draize test. Antifungal activity was assessed by propidium iodide staining, calcofluor white staining, crystal violet biofilm assays and determination of the MIC. Network pharmacology analysis was performed to predict potential therapeutic targets of physcion. Both in vitro and in vivo experiments were conducted using AF spore-infected mouse corneas and RAW264.7 macrophages treated with physcion or phosphate-buffered saline. Inflammatory responses were evaluated by slit-lamp examination, immunofluorescence, real-time quantitative polymerase chain reaction (RT-qPCR) and western blotting (WB), focusing on neutrophil and macrophage recruitment together with the expression of pro-inflammatory proteins and components of the NF-\u03baB signalling pathway. Physcion effectively inhibited the growth of AF. In vivo, physcion-treated mice exhibited significantly lower clinical scores compared with untreated infected controls. Immunofluorescence analysis revealed markedly decreased infiltration of neutrophils/macrophages in the corneas of physcion-treated mice. RT-qPCR together with WB analyses demonstrated that physcion treatment obviously reduced the phosphorylated NF-\u03baB p65 and phosphorylated I\u03baB, increased I\u03baB expression and suppressed the expression of IL-1\u03b2, TNF-\u03b1 and IL-18 in infected mouse corneas and RAW264.7\u202fcells. Consistently, IF imaging of RAW264.7\u202fcells showed reduced nuclear localization of NF-\u03baB p65 following physcion treatment. Physcion alleviated AFK by inhibiting fungal growth, limiting neutrophil and macrophage recruitment, and suppressing activation of the NF-\u03baB signalling pathway.",
"42523712": "ID: 42523712\nTitle: Impaired NLRP3 inflammasome activation by chitin underlies refractory chromoblastomycosis caused by Fonsecaea pedrosoi muriform cells.\nAbstract: Macrophage NLRP3 activation is crucial for antifungal immunity, yet its role in chromoblastomycosis-a chronic subcutaneous mycosis typically caused by Fonsecaea pedrosoi-remains unclear. Unlike prior self-resolving models using conidia and hyphae, clinical disease features muriform cells, a parasitic form resistant to macrophages and linked to chronicity. Notably, chitin, a weak NLRP3 agonist, accumulates on the surface of muriform cells. This study investigates whether chitin accumulation modulates NLRP3 activation and promotes fungal persistence. Human chromoblastomycosis lesions were analyzed by IHC (MPO, CD86, NLRP3) and RT-PCR for cytokine transcripts. WT and NLRP3-/- mice were footpad-inoculated with F. pedrosoi muriform cells for in vivo assessment. Flow cytometric bead array quantified IL-1\u03b2, IL-6, IL-10, TNF-\u03b1, and IL-17A in footpad homogenates, and the same panel (excluding IL-17A) in stimulated BMDM supernatants. NLRP3 pathway activation in BMDMs was confirmed by western blotting and immunofluorescence. In human lesions, marked MPO+ neutrophil recruitment encapsulated muriform cells, yet multinucleated giant cells sequestered some fungal elements from neutrophils. Despite robust NLRP3 expression and elevated IL-1\u03b2, IL-6, TNF-\u03b1, and IL-10 versus normal skin (all p < 0.01), muriform cells persisted in tissue. In WT mice, lesions transitioned from purulent (day 7) to granulomatous (day 90), concurrent with declining IL-1\u03b2, IL-17A, IL-6, and TNF-\u03b1. MPO+ neutrophils abundantly surrounded muriform cells at day 7; at day 90, F4/80+ macrophages enveloped most fungi without elimination, forming multinucleated giant cells-recapitulating human pathology. In NLRP3-/- mice, IL-1\u03b2 and IL-17A were produced in an NLRP3-independent manner and showed no decline over time. Muriform cells progressively budded and transitioned to hyphae both inside and outside giant cells; MPO+ neutrophils preferentially localized to hyphal areas, while macrophages remained around muriform cells, suggesting compartmentalized inflammation. In vitro, chitinase-treated muriform cells induced higher NLRP3-dependent IL-1\u03b2, IL-6, TNF-\u03b1, and IL-10 in WT BMDMs versus intact cells (all p < 0.01). Mechanistically, chitin accumulation partially suppressed NF-\u03baB phosphorylation, reducing NLRP3 expression, caspase-1 cleavage, and ASC speck formation. NLRP3 mediates host defense against muriform cells yet fails to resolve chronic infection. Chitin accumulation on muriform cells attenuates NLRP3 activation, thereby promoting chromoblastomycosis chronicity.",
"42524404": "ID: 42524404\nTitle: Biocompatibility Assessment of a Hybrid Material Based on Epoxy-Treated Pericardium and Polyvinyl Alcohol Cryogel in a Rat Vascular and Subcutaneous Implantation Model.\nAbstract: The aim of the study was to evaluate the biocompatibility of a hybrid material based on epoxy-treated bovine pericardium and cryostructured polyvinyl alcohol (PVA) after implantation into the rat aortic wall and subcutaneous tissue. The study evaluated hybrid material patches based on epoxy-treated bovine pericardium and cryostructured PVA; unmodified \"KemPeriplasNeo\" pericardial patches served as controls. The samples were implanted into the abdominal aortic wall and subcutaneously in male Wistar rats. The vascular implantation periods were 5 and 20 days, and the subcutaneous implantation periods were 60 and 120 days. The specimens were excised from the aorta and studied histologically using Russell-Movat staining and immunostaining for neutrophil myeloperoxidase (MPO) and the macrophage marker CD68. The calcium content in subcutaneously implanted samples was assessed by spectrophotometry and alizarin red S staining. The quantitative data were presented as the median, percentiles, minimal and maximal values (Me [25%-75%; min-max]). After implantation into the abdominal aortic wall, the hybrid material samples showed a lower tendency toward thrombotic deposit formation on the surface compared to the pericardium. On day 5 of implantation, the thrombus thickness was 49.1 [34.7-64.6; 27.4-71.6] \u03bcm in the experimental group vs 170.3 [158.1-210.3; 124.4-217.0] \u03bcm in the controls (p<0.001). By day 20 of implantation, the macrophage density was lower in the peri-implant area of the modified samples compared to the controls: 219 [187-275; 112-362] vs 301 [244-338; 194-433] CD68+ cells per field of view (p<0.001), respectively. The neutrophil density at all experimental time points, as well as the macrophage density on day 5 of implantation did not differ significantly between the tested materials (p>0.17). No signs of calcification were detected in either group following the subcutaneous implantation over a period of 60 or 120 days. The control pericardium in the subcutaneous model showed the signs of cell-mediated degradation, whereas the hybrid samples were resistant to immune-cell infiltration and preserved their internal architecture. The modification of epoxy-treated bovine pericardium with cryostructured PVA cryogel improved its biocompatibility and enhanced resistance to biodegradation in a rat model after aortic-wall and subcutaneous implantation. The developed material may be used to create next-generation heart valve bioprostheses with potentially improved resistance to structural valve degeneration.",
"42524663": "ID: 42524663\nTitle: Endothelial Senescence-Associated Secretory Signaling Promotes Macrophage Extracellular Traps Formation and Contributes to the Exacerbation of Combined Lung Injury.\nAbstract: Radiation-induced lung injury (RILI) is a common complication of thoracic radiotherapy and can be critically exacerbated by pre-existing pulmonary inflammation, yet the synergistic mechanisms driving this pathology remain elusive. Using a murine model of combined lung injury induced by lipopolysaccharide (LPS) and thoracic irradiation (IR), we identified macrophage extracellular traps (METs), a type of web-like chromatin structure released by macrophages, rather than neutrophil extracellular traps (NETs), as a prominent pathogenic process. Mechanistically, the combination of LPS and irradiation induced an early endothelial senescence-associated phenotype and a CXC chemokine-enriched secretory profile. These signals engaged macrophage CXCR2, leading to p38/ERK pathway activation and reactive oxygen species (ROS) production that contributed to METs formation (METosis). Functionally, METs serve as potential dual-phase mediators, contributing to epithelial barrier disruption during acute injury and promoting epithelial-mesenchymal transition (EMT)-like epithelial remodeling, thereby potentially linking early inflammatory damage to subsequent fibrotic progression. Furthermore, we demonstrate that the bioactive compound Cordycepin exerts protective effects by suppressing p38/ERK pathway activation and attenuating METosis. Collectively, these findings support a potential endothelial senescence-associated secretory signaling-METosis axis, providing a novel mechanistic framework and candidate therapeutic strategies for managing high-risk radiation-induced lung injury.",
"42533582": "ID: 42533582\nTitle: A non-bactericidal antimicrobial peptide provides protective effect against bacterial sepsis via regulation of antimicrobial immunity and vascular endothelial functions.\nAbstract: The anti-infective properties of bactericidal antimicrobial peptides (AMPs) have been extensively studied, yet the functions and mechanisms of non-bactericidal AMPs in sepsis remain poorly understood. In this study, a novel \u03b2-sheet cathelicidin peptide, named Og-CATH, was identified from the skin of Odorrana grahami. Although Og-CATH showed no detectable direct antimicrobial activity in vitro, it provided both prophylactic and therapeutic protection in mouse models of sepsis induced by Staphylococcus aureus, Escherichia coli, or cecal ligation and puncture. This protection depended on neutrophils and monocytes/macrophages, but not T or B lymphocytes. Og-CATH did not directly chemoattract phagocytes. Instead, it stimulated P2X7 receptor-dependent chemokine release from macrophages, thereby promoting macrophage and neutrophil trafficking to sites of infection. Og-CATH also enhanced oxygen-independent bacterial clearance by increasing phagocytosis and neutrophil degranulation. In parallel, Og-CATH suppressed tissue factor production, a major trigger of the extrinsic coagulation cascade, and increased activated protein C expression in endothelial cells and mice, thereby reducing pulmonary fibrin deposition and thrombosis. Mechanistically, Og-CATH targeted myeloid differentiation protein 2 (MD2) and inhibited lipopolysaccharide (LPS)-induced recruitment of MyD88 to TLR4 in endothelial cells, thus preserving endothelial barrier integrity during sepsis. These findings identify Og-CATH as a non-bactericidal AMP that protects against sepsis by coordinating phagocyte recruitment, antibacterial effector activity, coagulation control, and endothelial stabilization. Og-CATH therefore represents a promising immunomodulatory candidate for further therapeutic development against sepsis. \u6297\u83cc\u80bd\u7684\u6297\u611f\u67d3\u7279\u6027\u5df2\u88ab\u5e7f\u6cdb\u7814\u7a76\uff0c\u4f46\u975e\u6740\u83cc\u6027\u6297\u83cc\u80bd\u5728\u8113\u6bd2\u75c7\u4e2d\u7684\u4f5c\u7528\u53ca\u673a\u5236\u5c1a\u672a\u5b8c\u5168\u660e\u786e\u3002\u672c\u7814\u7a76\u4ece\u65e0\u6307\u76d8\u81ed\u86d9\u4e2d\u9274\u5b9a\u51fa\u4e00\u79cd\u65b0\u578bcathelicidin\u6297\u83cc\u80bd\uff0c\u5176\u4e8c\u7ea7\u7ed3\u6784\u4e3a\u03b2-\u6298\u53e0\uff0c\u547d\u540d\u4e3aOg-CATH\u3002\u4f53\u5916\u5b9e\u9a8c\u8868\u660eOg-CATH\u65e0\u76f4\u63a5\u6297\u83cc\u6d3b\u6027\uff0c\u4f46\u6709\u8da3\u7684\u662f\uff0c\u5728\u91d1\u9ec4\u8272\u8461\u8404\u7403\u83cc\u3001\u5927\u80a0\u6746\u83cc\u611f\u67d3\u53ca\u76f2\u80a0\u7ed3\u624e\u7a7f\u5b54\uff08CLP\uff09\u8bf1\u5bfc\u7684\u8113\u6bd2\u75c7\u5c0f\u9f20\u6a21\u578b\u4e2d\uff0c\u8be5\u80bd\u5747\u5c55\u73b0\u51fa\u663e\u8457\u7684\u9884\u9632\u4e0e\u6cbb\u7597\u6548\u679c\u3002\u8fdb\u4e00\u6b65\u7684\u7814\u7a76\u53d1\u73b0\uff0cOg-CATH\u7684\u4fdd\u62a4\u4f5c\u7528\u4f9d\u8d56\u4e8e\u4e2d\u6027\u7c92\u7ec6\u80de\u548c\u5355\u6838/\u5de8\u566c\u7ec6\u80de\uff0c\u800c\u975eT/B\u6dcb\u5df4\u7ec6\u80de\u3002\u5c3d\u7ba1Og-CATH\u65e0\u6cd5\u76f4\u63a5\u8d8b\u5316\u541e\u566c\u7ec6\u80de\uff0c\u4f46\u53ef\u901a\u8fc7P2X7\u53d7\u4f53\u4fc3\u8fdb\u5de8\u566c\u7ec6\u80de\u5206\u6ccc\u8d8b\u5316\u56e0\u5b50\uff0c\u8fdb\u800c\u95f4\u63a5\u4ecb\u5bfc\u5de8\u566c\u7ec6\u80de\u4e0e\u4e2d\u6027\u7c92\u7ec6\u80de\u5411\u611f\u67d3\u90e8\u4f4d\u8fc1\u79fb\u3002\u6b64\u5916\uff0cOg-CATH\u8fd8\u80fd\u901a\u8fc7\u589e\u5f3a\u4e2d\u6027\u7c92\u7ec6\u80de\u7684\u541e\u566c\u4f5c\u7528\u4e0e\u8131\u9897\u7c92\u529f\u80fd\uff0c\u63d0\u5347\u5176\u975e\u6c27\u4f9d\u8d56\u578b\u6740\u83cc\u6d3b\u6027\u3002\u66f4\u91cd\u8981\u7684\u662f\uff0c\u672c\u7814\u7a76\u8bc1\u5b9eOg-CATH\u53ef\u6291\u5236\u5185\u76ae\u7ec6\u80de\u53ca\u5c0f\u9f20\u4f53\u5185\u7ec4\u7ec7\u56e0\u5b50\uff08\u5916\u6e90\u6027\u51dd\u8840\u7ea7\u8054\u53cd\u5e94\u7684\u5173\u952e\u542f\u52a8\u5b50\uff09\u7684\u4ea7\u751f\uff0c\u540c\u65f6\u4e0a\u8c03\u751f\u7406\u6027\u6297\u51dd\u7269\u8d28\u6d3b\u5316\u86cb\u767dC\uff08APC\uff09\u7684\u8868\u8fbe\uff0c\u51cf\u5c11\u5c0f\u9f20\u80ba\u90e8\u7ea4\u7ef4\u86cb\u767d\u6c89\u79ef\u53ca\u4f53\u5185\u8840\u6813\u5f62\u6210\u3002\u673a\u5236\u4e0a\uff0cOg-CATH\u9776\u5411\u9ad3\u6837\u5206\u5316\u86cb\u767d2\uff08MD2\uff09\uff0c\u6291\u5236\u8102\u591a\u7cd6\u8bf1\u5bfc\u7684\u5185\u76ae\u7ec6\u80de\u4e2dMyD88\u5411TLR4\u53d7\u4f53\u7684\u52df\u96c6\uff0c\u8fdb\u800c\u7f13\u89e3\u5185\u76ae\u5c4f\u969c\u529f\u80fd\u969c\u788d\u3002\u7efc\u4e0a\uff0c\u672c\u7814\u7a76\u8868\u660eOg-CATH\u4e3b\u8981\u901a\u8fc7\u8c03\u63a7\u541e\u566c\u7ec6\u80de\u4e0e\u5185\u76ae\u7ec6\u80de\u529f\u80fd\u53d1\u6325\u8113\u6bd2\u75c7\u4fdd\u62a4\u4f5c\u7528\u3002\u8fd9\u4e9b\u53d1\u73b0\u4e0d\u4ec5\u4e30\u5bcc\u4e86\u6211\u4eec\u5bf9\u975e\u6740\u83cc\u6027\u6297\u83cc\u80bd\u6297\u611f\u67d3\u673a\u5236\u7684\u8ba4\u8bc6\uff0c\u4e5f\u8bc1\u660e\u4e86Og-CATH\u662f\u8113\u6bd2\u75c7\u6cbb\u7597\u836f\u7269\u5f00\u53d1\u7684\u4f18\u826f\u5019\u9009\u5206\u5b50\u3002.",
"42535940": "ID: 42535940\nTitle: Metabolic Reprogramming by Engineered Probiotics Potentiates Tumor Chemodynamic Immunotherapy.\nAbstract: Engineered bacteria hold promise for remodeling immunosuppressive tumor microenvironments through innate immunogenicity and localized therapeutic delivery. While bacterial-derived metabolites are increasingly recognized as key mediators, their specific roles in interkingdom crosstalk remain underexplored. Here, we develop a programmable probiotic platform leveraging Lactobacillus gasseri (LG)-tumor metabolic interplay to potentiate bladder cancer therapy. The selected LG strain demonstrates superior tumor-colonizing ability and intrinsic H2O2/lactate biosynthesis, creating an optimal tumor microenvironment for hemoglobin-modified MnOx nanoparticles to enhance chemodynamic therapy efficacy. Mechanistically, microbial metabolites, including L-leucine, orchestrate neutrophil phenotypic reprogramming by suppressing pro-angiogenic dcTRAIL-R1+ neutrophils while activating antigen-presenting CD74+ neutrophil populations. The engineered system elicites coordinated immunomodulation through multiple mechanisms: (1) promoting dendritic cell maturation, (2) increasing CD74+ neutrophil populations, (3) inducing macrophage polarization from M2 to M1 phenotypes, and (4) enhancing tumor infiltration of CD8+ T cells and natural killer cells. This study reveals that bacteria-tumor metabolic crosstalk upregulates beneficial metabolites, notably leucine, which promotes phenotypic reprogramming of neutrophils toward the antigen\u2011presenting CD74+ subset, thereby bridging innate metabolic regulation with adaptive antitumor immunity. This finding goes beyond the material-centric logic of previous probiotic-nanomaterial systems and establishes a metabolism-centric framework for bacteria\u2011mediated cancer immunotherapy.",
"42543326": "ID: 42543326\nTitle: [Research progress on action mechanisms of Rheum palmatum anthraquinones in improving acute lung injury].\nAbstract: Acute lung injury(ALI) and acute respiratory distress syndrome(ARDS) are severe respiratory diseases characterized by uncontrolled inflammatory responses and disruption of the alveolar-capillary barrier. This type of disease is often triggered by multiple factors such as infection, sepsis, trauma, or inhalation injury, and the pathological process involves multiple sections including inflammatory cascade reactions, oxidative stress imbalance, abnormal activation of immune cells, and increased pulmonary microvascular permeability. Owing to their complex pathogenesis and high mortality, available clinical therapeutic approaches remain limited. Therefore, the development of safe and effective therapeutic agents to attenuate ALI has become a major focus of current research field. As a TCM, Rheum palmatum has a long history of use in clearing heat and toxins, purging the bowels, and regulating systemic inflammatory responses. In recent years, increasing attention has been paid to its therapeutic effect in ALI. RESULTS:: show that R. palmatum and its major bioactive anthraquinones, such as emodin and rhein, exert protective effects through multi-target and multi-pathway mechanisms. These mechanisms mainly include inhibition of inflammatory signaling pathways such as nuclear factor-\u03baB(NF-\u03baB), mitogen-activated protein kinase(MAPK), and NOD-like receptor protein 3(NLRP3) inflammasome, attenuation of oxidative stress response, activation of the nuclear factor erythroid 2-related factor 2(Nrf2)-mediated antioxidant defense system, regulation of programmed death in immune cells including macrophages, improvement of immunometabolic status, modulation of macrophage polarization and the gut microbiota as well as the gut-lung axis, and so on. In addition, R. palmatum has been shown to preserve the integrity of the alveolar-capillary barrier and to suppress excessive neutrophil activation and the overformation of neutrophil extracellular traps(NETs), thereby reducing inflammation amplification effect and the risk of immune microthrombi. This paper summarized the action mechanisms and research progress of R. palmatum in the treatment of ALI, aiming to elucidate the unique advantages of R. palmatum anthraquinones in intervening in the complex pathological processes of ALI through systemic regulatory networks and to provide a solid theoretical basis for the research and development of innovative R. palmatum-based medicines and their clinical combination medication.",
"42545624": "ID: 42545624\nTitle: Deciphering the regulatory role of ADAM8 in the PDAC tumor microenvironment.\nAbstract: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited therapeutic options, driven in part by its immunosuppressive tumor microenvironment (TME). Tumor-associated macrophages (TAMs) and neutrophils (TANs) contribute to tumor progression and immune evasion. A Disintegrin and Metalloproteinase 8 (ADAM8), a zinc-dependent protease, is strongly upregulated in PDAC and correlates with poor clinical outcomes, suggesting a regulatory role in tumor progression. Wild-type (WT) and Adam8 knockout (A8KO) PDAC cell lines were generated using the CRISPR-Cas9 technique, and PDAC mouse models with or without Adam8 expression were established to investigate the role of ADAM8 in tumor and immune cells. In vitro assays, including Western blotting, qPCR, migration and invasion assays, proliferation assays, ELISA, cytokine and proteome analyses, as well as co-culture experiments with PDAC cells and either macrophages or neutrophils, were employed to assess the effects of ADAM8 on tumor-immune cell crosstalk. In parallel, in vivo WT and A8KO KPC models were generated, genotyped, and monitored to evaluate the impact of ADAM8 on survival, tumor growth, and immune cell recruitment within the PDAC TME. ADAM8 deletion reduced tumor cell proliferation and migration, associated with reduced activation of FAK/Src/STAT3 signaling and altered secretion of cytokines including GM-CSF, M-CSF, ICAM-1, and TNF-\u03b1. Co-culture assays demonstrated that ADAM8 enhanced reciprocal signaling between tumor cells and TAMs/TANs, promoting pro-oncogenic activation. Migration assays and in vivo analyses revealed that ADAM8 facilitated recruitment of macrophages and neutrophils in PDAC TME, while Adam8KO tumors exhibited reduced immune infiltration and altered macrophage polarization. Our findings demonstrate that ADAM8 promotes PDAC aggressiveness by enhancing tumor cell proliferation and migration, activating FAK/Src/STAT3 signaling, and driving macrophage and neutrophil recruitment through cytokine regulation. By orchestrating both tumor-intrinsic pathways and tumor-immune interactions, ADAM8 emerges as a key determinant of PDAC progression and a systemic target for therapeutic intervention.",
"42546424": "ID: 42546424\nTitle: The equine mesenchymal stromal cell (MSC) secretome modulates neutrophils and monocyte-derived macrophages and extracellular vesicles (EVs) impact macrophage viability.\nAbstract: Neutrophil chemotaxis and phagocytosis are critical for protection against bacteria, but can be compromised by methicillin-resistant Staphylococcus aureus (MRSA). MRSA can also circumvent macrophage surveillance by affecting polarization and reactive oxygen species (ROS) production. We previously demonstrated that the secretome of equine mesenchymal stromal cells (MSCs), comprised of all secreted bioactive factors and collected as conditioned medium (CM), reduces the growth of MRSA both in vitro and in vivo. This study aimed to determine if the equine MSC secretome has additional anti-MRSA properties by studying its effects on equine neutrophil and macrophage functions in vitro. Transwell assays demonstrated that CM from adipose tissue- and bone marrow-, but not peripheral blood-, derived MSCs significantly enhanced neutrophil migration. In addition, CM from all three MSC sources significantly reduced the phagocytic capacity of neutrophils but did not alter ROS production. MSC CM from all three tissue sources promoted macrophage polarization toward both CD86-positive (M1-like) and CD206-positive (M2-like) phenotypes, but did not change phagocytic capacity or ROS production. Further experiments showed that the complete CM, rather than the soluble and extracellular vesicle (EV) subfractions, was responsible for the increased neutrophil chemotaxis. Additionally, the primary effect of EVs on macrophages was cell death, possibly through autophagy, which can be beneficial if tissue damaging inflammation is diminished with decreased numbers of viable macrophages. Collectively, our findings show that the equine MSC secretome modulates various innate immune responses in vitro and may have therapeutic potential for managing dysregulated inflammation associated with bacterial diseases in vivo.",
"42547443": "ID: 42547443\nTitle: [Research progress on the role of calcitonin gene-related peptide in the repair of diabetic wounds].\nAbstract: Diabetic wounds are a severe complication of diabetes, which can lead to amputation or even mortality in severe cases. While normal wound healing consists of four phases: hemostasis, inflammation, proliferation, and remodeling, diabetic wounds tend to become chronic and refractory primarily due to a prolonged inflammatory phase. In diabetic wounds, insufficient synthesis and release of endogenous calcitonin gene-related peptide (CGRP) is a critical upstream mechanism underlying the disrupted neuro-immune communication, the persistent inflammation, and the arrested wound healing process. In contrast to pure skin defect wounds, where CGRP is rapidly upregulated after injury, CGRP remains persistently low in diabetic wound tissue, consequently failing to drive macrophage polarization towards the M2 phenotype or promote vascular maturation and collagen fiber deposition in the later phase of inflammation. In the early inflammatory phase, CGRP exerts pro-inflammatory effects by enhancing angiogenesis and modulating macrophage polarization. In the late inflammatory phase, CGRP upregulates thrombospondin-1, promotes neutrophil apoptosis and phagocytic clearance, thereby inhibiting excessive inflammatory response and shifting the wound microenvironment from a pro-inflammatory state to a pro-reparative state. Restoring CGRP signaling reconstructs the neuroimmunomodulation axis and improves wound repair while relieving diabetic neuropathic pain. Engineered CGRP combined with intelligent delivery systems offers promising prospects for diabetic wound therapy. However, large-scale clinical trials are still required to validate its clinical efficacy and safety. This paper systematically analyzes the mechanisms and application strategies of CGRP in facilitating diabetic wound repair, which can provide a theoretical basis and innovative strategies for clinical management. \u7cd6\u5c3f\u75c5\u521b\u9762\u662f\u4e00\u79cd\u7cd6\u5c3f\u75c5\u5e76\u53d1\u75c7\uff0c\u4e25\u91cd\u8005\u53ef\u81f4\u60a3\u8005\u622a\u80a2\u751a\u81f3\u6b7b\u4ea1\u3002\u6b63\u5e38\u7684\u521b\u9762\u6108\u5408\u5386\u7ecf\u6b62\u8840\u3001\u708e\u75c7\u3001\u589e\u6b96\u3001\u91cd\u58514\u4e2a\u9636\u6bb5\uff0c\u7cd6\u5c3f\u75c5\u521b\u9762\u4e3b\u8981\u56e0\u708e\u75c7\u671f\u5ef6\u957f\u800c\u6162\u6027\u96be\u6108\u3002\u7cd6\u5c3f\u75c5\u521b\u9762\u7ec4\u7ec7\u4e2d\u964d\u9499\u7d20\u57fa\u56e0\u76f8\u5173\u80bd\uff08CGRP\uff09\u5408\u6210\u4e0e\u91ca\u653e\u4e0d\u8db3\uff0c\u8fd9\u662f\u5bfc\u81f4\u521b\u9762\u795e\u7ecf\u514d\u75ab\u901a\u8baf\u4e2d\u65ad\u3001\u708e\u75c7\u65e0\u6cd5\u6d88\u9000\u3001\u6108\u5408\u8fdb\u7a0b\u505c\u6ede\u7684\u5173\u952e\u4e0a\u6e38\u673a\u5236\u3002\u4e0e\u5355\u7eaf\u76ae\u80a4\u7f3a\u635f\u521b\u9762\u4e2dCGRP\u5728\u4f24\u540e\u8fc5\u901f\u4e0a\u8c03\u4e0d\u540c\uff0c\u7cd6\u5c3f\u75c5\u521b\u9762\u7ec4\u7ec7\u4e2dCGRP\u5448\u6301\u7eed\u6027\u4f4e\u6c34\u5e73\u8868\u8fbe\uff0c\u65e0\u6cd5\u5728\u708e\u75c7\u540e\u671f\u9a71\u52a8\u5de8\u566c\u7ec6\u80de\u5411M2\u578b\u6781\u5316\uff0c\u4fc3\u8fdb\u8840\u7ba1\u6210\u719f\u4e0e\u80f6\u539f\u7ea4\u7ef4\u6c89\u79ef\u3002\u5728\u708e\u75c7\u521d\u671f\uff0cCGRP\u901a\u8fc7\u4fc3\u8fdb\u65b0\u8840\u7ba1\u751f\u6210\u3001\u8c03\u8282\u5de8\u566c\u7ec6\u80de\u6781\u5316\u7b49\u53d1\u6325\u4fc3\u708e\u4f5c\u7528\uff1b\u800c\u5728\u708e\u75c7\u540e\u671f\uff0cCGRP\u901a\u8fc7\u4e0a\u8c03\u8840\u5c0f\u677f\u53cd\u5e94\u86cb\u767d-1\uff0c\u4fc3\u8fdb\u4e2d\u6027\u7c92\u7ec6\u80de\u51cb\u4ea1\u4e0e\u80de\u846c\u6e05\u9664\uff0c\u8fdb\u800c\u6291\u5236\u8fc7\u5ea6\u708e\u75c7\u53cd\u5e94\uff0c\u63a8\u52a8\u521b\u9762\u5fae\u73af\u5883\u7531\u4fc3\u708e\u72b6\u6001\u5411\u4fc3\u4fee\u590d\u72b6\u6001\u8f6c\u53d8\u3002\u6062\u590dCGRP\u4fe1\u53f7\u53ef\u91cd\u5851\u795e\u7ecf\u514d\u75ab\u8c03\u63a7\u8f74\uff0c\u517c\u5177\u4fc3\u8fdb\u521b\u9762\u4fee\u590d\u4e0e\u7f13\u89e3\u7cd6\u5c3f\u75c5\u795e\u7ecf\u75c5\u7406\u6027\u75bc\u75db\u7684\u53cc\u91cd\u4f5c\u7528\u3002\u5de5\u7a0b\u5316CGRP\u4e0e\u667a\u80fd\u9012\u9001\u7cfb\u7edf\u4e3a\u7cd6\u5c3f\u75c5\u521b\u9762\u6cbb\u7597\u5e26\u6765\u65b0\u5e0c\u671b\uff0c\u4f46\u5176\u5728\u4e34\u5e8a\u5e94\u7528\u4e2d\u7684\u6709\u6548\u6027\u4e0e\u5b89\u5168\u6027\u4ecd\u9700\u5927\u89c4\u6a21\u7814\u7a76\u9a8c\u8bc1\u3002\u8be5\u6587\u6df1\u5165\u5256\u6790CGRP\u5728\u7cd6\u5c3f\u75c5\u521b\u9762\u4fee\u590d\u4e2d\u7684\u4f5c\u7528\u673a\u5236\u53ca\u5e94\u7528\u7b56\u7565\uff0c\u4e3a\u4e34\u5e8a\u6cbb\u7597\u63d0\u4f9b\u7406\u8bba\u4f9d\u636e\u4e0e\u65b0\u601d\u8def\u3002.",
"42548844": "ID: 42548844\nTitle: Fecal microbiota transplantation in ulcerative colitis: mucosal immune mechanisms and precision microbiota therapy.\nAbstract: Fecal microbiota transplantation (FMT) has emerged as an investigational microbiota-targeted strategy for ulcerative colitis (UC), aiming to restore dysbiotic gut ecosystems and microbiota-host homeostasis. Mechanistic studies suggest that FMT may reshape microbial community structure, enrich short-chain fatty acid-producing bacteria, remodel bile acid and tryptophan-aryl hydrocarbon signaling, enhance epithelial barrier integrity, and regulate mucosal immunity, including Th17/Treg balance, IgA-associated responses, macrophage reprogramming, IL-10/IL-22 signaling, and neutrophil extracellular trap formation. Randomized controlled trials indicate that FMT can induce clinical and endoscopic remission in selected patients with UC, particularly when administered through the lower gastrointestinal route and using multi-donor or optimized regimens. Current guidelines do not recommend conventional FMT as routine therapy for UC outside clinical trials, reflecting the heterogeneity and low certainty of available evidence. However, its efficacy appears limited in moderate-to-severe or biologic-refractory disease, underscoring the importance of host inflammatory burden and recipient ecological receptivity. Personalized strategies, including donor-recipient functional matching, dietary modulation, combination therapy, and next-generation microbiota therapeutics, may improve response and safety but require prospective validation. This review integrates microbiota-metabolite-barrier-immune mechanisms with clinical evidence to define where FMT may be useful, where its benefit appears limited, and how future studies can move the field toward precision microbiota therapy in UC.",
"42553337": "ID: 42553337\nTitle: J2R/F4L deleted oncolytic vaccinia virus synergizes with tumor specific killer (ELANE) promotes antitumor immunity with superior safety.\nAbstract: Oncolytic virotherapy (OVT) represents a promising approach for cancer treatment, employing oncolytic viruses (OVs) that selectively infect and lyse tumor cells while promoting an antitumor immune microenvironment. Vaccinia virus (VACV) serves as an attractive oncolytic vector due to its favorable safety profile, ease of genetic modification, and inherent tumor selectivity. To enhance both safety and tumor-targeting capability, we constructed a recombinant vaccinia virus, VV-dTF/EE, by deleting the viral J2R and F4L genes and inserting the human neutrophil elastase (ELANE) gene, which exhibits tumor-killing activity. Mechanistic studies evaluated with virus replication selectivity, cell apoptosis, genomic damage, immunogenic cell death, alongside analysis of the immune microenvironment. Efficacy was tested in multiple tumor cell models in vitro and lung cancer models in vivo. In tumor cell lines and mouse tumor models, VV-dTF/EE demonstrated tumor-restricted replication, potent oncolytic effects, and induction of immunogenic cell death. Furthermore, VV-dTF/EE augmented VACV-induced antitumor immunity by increasing CD8+ T cell infiltration and suppressing M2-like macrophage polarization. This VV-dTF/EE revealed tumor-selective replication and killing ability while modifying the tumor immune microenvironment to elicit immunogenic cell death. Our findings highlight a novel strategy for safe and effective tumor immunotherapy through dual-gene deletion and ELANE expression in an oncolytic vaccinia platform.",
"42554055": "ID: 42554055\nTitle: Mast Cell St8sia1 Is a Glyco-Epigenetic Checkpoint Driving Cardiac Remodeling.\nAbstract: Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential. We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics. The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of St8sia1 preserved ventricular function, attenuated fibrosis, and markedly reduced neutrophil and Ly6C+ monocyte recruitment after transverse aortic constriction and ischemia-reperfusion. Therapeutic neutralization of GD3 with the clinical-grade monoclonal antibody R24 improved cardiac function and diminished scar formation after ischemia-reperfusion. Mechanistically, GD3 bound specific histone variants, such as H2A.Z and H3.3C, thereby reprogramming chromatin accessibility to activate proinflammatory and profibrotic transcriptional programs in MCs. Consequently, GD3 inhibition suppressed MC degranulation, disrupted pathogenic MC-cardiomyocyte/fibroblast crosstalk, and preserved reparative macrophage populations. The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure."
},
"globalTags": {
"animals": 120,
"neutrophils": 63,
"aging": 28,
"macrophages": 86,
"efferocytosis": 49,
"mice": 79,
"humans": 105,
"liver": 8,
"cellular senescence": 13,
"signal transduction": 22,
"mice, inbred c57bl": 49,
"mitochondria": 3,
"muscle, smooth, vascular": 1,
"lipoproteins, ldl": 3,
"cells, cultured": 7,
"phagocytosis": 45,
"culture media, conditioned": 3,
"myocytes, smooth muscle": 2,
"senescence-associated secretory phenotype": 2,
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"cell proliferation": 6,
"atherosclerosis": 18,
"middle aged": 6,
"aged": 8,
"phenotype": 4,
"cell differentiation": 6,
"senotherapeutics": 1,
"sepsis": 12,
"amp-activated protein kinases": 1,
"male": 50,
"aged, 80 and over": 4,
"extracellular traps": 14,
"liver diseases": 1,
"female": 28,
"disease models, animal": 30,
"age factors": 5,
"arrhythmias, cardiac": 1,
"myocardium": 5,
"nlr family, pyrin domain-containing 3 protein": 2,
"organoids": 1,
"inflammasomes": 6,
"pluripotent stem cells": 1,
"assembloid": 1,
"atrial fibrillation": 1,
"cardiac development": 1,
"disease modeling": 1,
"embryonic monocyte": 1,
"human heart organoid": 1,
"inflammasome": 1,
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"kruppel-like factor 4": 1,
"c-mer tyrosine kinase": 4,
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"42500649": "Jia J, Zhang Y, Wang W, Qi Y, Gao J (2026). Natural products and immune-cell responses in osteoarthritis: mechanisms, evidence maturity, and translational gaps.. Frontiers in immunology. ID: 42500649.",
"42501967": "Yang J, Huang Z, Men L, Guo Z, Hao M et al. (2026). Anti-IL-33 monoclonal antibody attenuates MAILD by suppressing the PI3K/AKT/mTOR signal pathway.. Translational research : the journal of laboratory and clinical medicine. ID: 42501967.",
"42502322": "Hang R, Yao X, Bai L, Xiao Y, Hang R (2026). Mechano-immunomodulatory biomaterials: From immune mechanosensing to translational design.. Bioactive materials. ID: 42502322.",
"42505091": "Draper T, Dhruva P, Jones M, McCarley R, Bojanowski CM et al. (2026). Itaconate negatively regulates innate immunity during fungal pneumonia.. mBio. ID: 42505091.",
"42505352": "Stojanovic B, Milivojcevic Bevc I, Stojanovic BS, Dimitrijevic Stojanovic M, Zornic N et al. (2026). Macrophage Extracellular Traps in Health and Disease: Current Concepts, Pathogenic Mechanisms and Clinical Implications.. Cells. ID: 42505352.",
"42506892": "Ghaffari M, Ali A, Hartadi C, Shrestha A (2026). High-Fat Diet Reprograms the Periapical Immune Landscape in a Mouse Model of Apical Periodontitis: A Spatial Transcriptomics Study.. International endodontic journal. ID: 42506892.",
"42508767": "Liu H, Yin Y, Yan Z, Fu C, Cao Y et al. (2026). Biomineralized nanozymes remodel the infectious microenvironment for precision MRSA pneumonia therapy.. Journal of controlled release : official journal of the Controlled Release Society. ID: 42508767.",
"42509795": "Camacho Londo\u00f1o JE, Sturgeon S, Dai Y, Navdaev A, Ponnuswamy P et al. (2026). Evaluation of Topical Reconstituted HDL as a Treatment for Diabetic Wounds in Murine and Porcine Models.. Biomolecules. ID: 42509795.",
"42509849": "Peng H, Li C, Mo C, Li B, Ou M (2026). DADA2 as a Model of Monogenic Immune Vasculopathy: From Immunopathogenesis to Precision Therapeutics.. Biomolecules. ID: 42509849.",
"42510635": "Addo SA, Babay I, Sreekumar A, Sloan D, Roy T et al. (2026). Mechanistic Insights into Redox-Dependent Macropinocytosis in Primary Human Neutrophils.. Antioxidants (Basel, Switzerland). ID: 42510635.",
"42511279": "Wei Q, Jia L, Wang X, Luo S, Cui D et al. (2026). The Effects of Multiple Maillard Reaction Products in Infant Formula on Host Immunity and Neurotoxicity.. Foods (Basel, Switzerland). ID: 42511279.",
"42515755": "Mo Y, Li M, Ye W, Jiang Z, Lin X et al. (2026). Targeting the Immune Network in Endometriosis: A Comprehensive Review of Pathogenesis, Immunomodulation, and Emerging Therapies.. Pharmaceuticals (Basel, Switzerland). ID: 42515755.",
"42516037": "Luo Y, Cai Y, Jiang Z, Zheng K, Ren S et al. (2026). Myeloid cell reprogramming combined with zoledronic acid effectively suppresses bone metastasis.. Cancer biology & medicine. ID: 42516037.",
"42518682": "Sun R, Wang Y, Zhang J, Wu J, Yang X et al. (2026). Combination Therapeutic Effect of Asiatic Acid & Curcumin-Loaded Liposomes Modified by Neutrophil Extracellular Traps for the Treatment of Oral Squamous Cell Carcinoma.. International journal of nanomedicine. ID: 42518682.",
"42519831": "Zhang X, Ai R, Zeng Y, Xu Y, Shao W et al. (2026). Neutrophil-promoted macrophage state transition coordinates endothelial migration and barrier resealing in zebrafish microvascular repair.. Cell reports. ID: 42519831.",
"42520196": "Koenis DS, De Matteis R, Gomez Cifuentes EA, Gorur V, Telfer P et al. (2026). Erythroblast-derived lipid mediators program neutrophil development and function.. Blood. ID: 42520196.",
"42520679": "Chen L, Gao X, Jiang L, Lin W, He M et al. (2026). Integrated single-cell and spatial transcriptomic atlas of multi-etiology acute lung injury reveals etiology-dependent neutrophil fate decisions and a prognostic neutrophil-monocyte/macrophage interaction signature.. International immunopharmacology. ID: 42520679.",
"42521072": "Shi W, Xu H, Xu Q, Yang X, Sun X et al. (2026). Physcion alleviates Aspergillus fumigatus keratitis by inhibiting fungal growth and NF-\u03baB-mediated inflammation.. Experimental eye research. ID: 42521072.",
"42523712": "Chen Y, Qu Z, Xie Z, Wang X, Tong Z et al. (2026). Impaired NLRP3 inflammasome activation by chitin underlies refractory chromoblastomycosis caused by Fonsecaea pedrosoi muriform cells.. Frontiers in immunology. ID: 42523712.",
"42524404": "Ovcharenko EA, Glushkova TV, Senokosova EA, Klyshnikov KY, Akentieva TN et al. (2026). Biocompatibility Assessment of a Hybrid Material Based on Epoxy-Treated Pericardium and Polyvinyl Alcohol Cryogel in a Rat Vascular and Subcutaneous Implantation Model.. Sovremennye tekhnologii v meditsine. ID: 42524404.",
"42524663": "Xie W, Liao H, Dai Y, Chen L, Li Y et al. (2026). Endothelial Senescence-Associated Secretory Signaling Promotes Macrophage Extracellular Traps Formation and Contributes to the Exacerbation of Combined Lung Injury.. International journal of biological sciences. ID: 42524663.",
"42533582": "He YM, Lin T, Mu LX, Zhou XY, Shen Y et al. (2026). A non-bactericidal antimicrobial peptide provides protective effect against bacterial sepsis via regulation of antimicrobial immunity and vascular endothelial functions.. Zoological research. ID: 42533582.",
"42535940": "Zhang K, Li H, Ma Z, Yu Y, Bahlol HS et al. (2026). Metabolic Reprogramming by Engineered Probiotics Potentiates Tumor Chemodynamic Immunotherapy.. Advanced materials (Deerfield Beach, Fla.). ID: 42535940.",
"42543326": "Yao GY, Zhu DF, Tan B, Wang H (2026). [Research progress on action mechanisms of Rheum palmatum anthraquinones in improving acute lung injury].. Zhongguo Zhong yao za zhi = Zhongguo zhongyao zazhi = China journal of Chinese materia medica. ID: 42543326.",
"42545624": "Zandieh K, Cook L, Zhao K, Nagl C, Gao Y et al. (2026). Deciphering the regulatory role of ADAM8 in the PDAC tumor microenvironment.. Cellular oncology (Dordrecht, Netherlands). ID: 42545624.",
"42546424": "Rajesh A, Harman RM, Van de Walle GR (2026). The equine mesenchymal stromal cell (MSC) secretome modulates neutrophils and monocyte-derived macrophages and extracellular vesicles (EVs) impact macrophage viability.. Veterinary immunology and immunopathology. ID: 42546424.",
"42547443": "Wang XY, Tan Q (2026). [Research progress on the role of calcitonin gene-related peptide in the repair of diabetic wounds].. Zhonghua shao shang yu chuang mian xiu fu za zhi. ID: 42547443.",
"42548844": "Lu E, Zhang M, Zhao Y, Meng H, Xu Z (2026). Fecal microbiota transplantation in ulcerative colitis: mucosal immune mechanisms and precision microbiota therapy.. Frontiers in immunology. ID: 42548844.",
"42553337": "Huang Y, Wang L, Mei S, Zhao F, Wang L et al. (2026). J2R/F4L deleted oncolytic vaccinia virus synergizes with tumor specific killer (ELANE) promotes antitumor immunity with superior safety.. Frontiers in immunology. ID: 42553337.",
"42554055": "Zhou C, Fu L, Yuan T, Li F, Tang F et al. (2026). Mast Cell St8sia1 Is a Glyco-Epigenetic Checkpoint Driving Cardiac Remodeling.. Circulation research. ID: 42554055."
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"mvcReports": [
{
"id": "mvc_dp_suggested_experiments_1785955500825",
"title": "Suggested Experiments Report",
"plan": {
"title": "SUGGESTED EXPERIMENTS : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Experimental Data Metrics"
},
{
"type": "synthesis",
"title": "Executive Summary",
"content": "The proposed experimental framework centers on restoring efferocytic efficacy in aging organisms through three primary modalities: pharmacological modulation of charge-sensitive recognition mechanisms [ID: Run1_Eval1], systemic metabolic intervention via resolvin D5 [ID: Run1_Eval1], and microbial or inflammatory mitigation techniques [ID: Run2_Eval1]. A significant gap exists in evaluating how these interventions intersect across different tissue-resident niches, particularly in the lungs and systemic vasculature [ID: Run2_Eval1]. Future validation must focus on the interplay between CD36/MerTK signaling axis restoration and insulin sensitivity outcomes in diabetic comorbid models [ID: Run1_Eval1, Run2_Eval1]."
},
{
"type": "logic_network",
"title": "Targeted Experimental Pathways"
},
{
"type": "data_bar_chart",
"title": "Distribution of Experimental Focus",
"xAxisLabel": "Focus Area",
"data": [
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"label": "Pharmacological/Metabolic",
"value": 3
},
{
"label": "Microbiological/Systemic",
"value": 3
}
]
},
{
"type": "comparison_matrix",
"title": "Research Methodology Comparison",
"headers": [
"Methodology",
"Target System",
"Biological Marker"
],
"rows": [
[
"Pharmacological Targeting",
"Neutrophil/Macrophage",
"Charge-sensitive mechanism"
],
[
"FMT/Microbiome",
"Alveolar",
"Efferocytic gene expression"
],
[
"Systemic Signaling",
"Pulmonary/Systemic",
"Insulin sensitivity"
]
]
}
]
}
},
{
"id": "mvc_dp_suggested_studies_1785955514042",
"title": "Suggested Studies Report",
"plan": {
"title": "SUGGESTED STUDIES : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Key Indicators"
},
{
"type": "synthesis",
"title": "Executive Analysis",
"content": "The synthesis of suggested studies reveals two primary research clusters: longitudinal aging dynamics [ID: Run1_Eval1] and metabolic/molecular mechanisms of frailty [ID: Run2_Eval1]. Longitudinal efforts emphasize correlation between efferocytosis and biological aging clocks [ID: Run1_Eval1], while contemporary molecular research prioritizes spatial transcriptomics and gut-lung axis microbial metabolites [ID: Run2_Eval1]. A notable gap exists in the integration of cross-species evolutionary data with real-time microbiome-targeted therapeutic outcomes."
},
{
"type": "logic_network",
"title": "Methodological Logic Pathways"
},
{
"type": "study_matrix",
"title": "Proposed Study Methodologies",
"content": "The proposed research spans longitudinal human cohorts, cross-species evolutionary modeling, and advanced spatial transcriptomic profiling to elucidate pulmonary macrophage functions."
},
{
"type": "bottlenecks",
"title": "Primary Research Limitations"
},
{
"type": "keyword_spectrum",
"title": "Frequency of Research Domains",
"xAxisLabel": "Domain Focus",
"data": [
{
"label": "Efferocytosis",
"value": 6
},
{
"label": "Aging",
"value": 5
},
{
"label": "Microbiome",
"value": 3
},
{
"label": "Pulmonary",
"value": 2
},
{
"label": "Metabolites",
"value": 2
}
]
}
]
}
},
{
"id": "mvc_dp_swansons_literature_based_discovery_candidates_1785955527244",
"title": "Swansons Literature Based Discovery Candidates Report",
"plan": {
"title": "SWANSONS LITERATURE BASED DISCOVERY CANDIDATES : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "LBD Candidate Metadata Scorecard"
},
{
"type": "synthesis",
"title": "Executive Summary: Mechanism of Action Synthesis",
"content": "The analysis of Swanson's Literature-Based Discovery (LBD) candidates highlights two distinct therapeutic pathways for age-associated pathologies. The first identifies the enhancement of erythroblast-derived Resolvin D5 as a method to normalize microglia-driven efferocytosis [ID: 42519831], theoretically paralleling the cognitive-sparing effects seen via TRM EP2 signaling inhibition [ID: 42462036]. The second path proposes Indole-3-acetaldehyde (IAAld) as a therapeutic intervention for cardiac remodeling, leveraging PXR/NRF2-mediated activation [ID: 41715099] to improve myocardial I/R resolution and fibrosis through optimized CRM efferocytosis [ID: 41554295]. Both hypotheses rely on the metabolic reprogramming of tissue-resident macrophages as a bridging mechanism for systemic disease resolution."
},
{
"type": "logic_network",
"title": "Bridge-Linked Biological Pathways"
},
{
"type": "comparison_matrix",
"title": "Discovery Candidate Comparison",
"headers": [
"Candidate Hypothesis",
"Primary Bridge",
"Target Organ"
],
"rows": [
[
"RvD5n-3 DPA Signaling",
"Brain-resident macrophages",
"Brain (Cognitive)"
],
[
"IAAld/PXR/NRF2",
"Cardiac-resident macrophages",
"Heart (Fibrosis)"
]
]
},
{
"type": "node_centrality",
"title": "Top Biological Entities by Impact"
},
{
"type": "bibliography",
"title": "Source Literature Inventory"
}
]
}
},
{
"id": "mvc_dp_contradictions_between_evidences_1785955540557",
"title": "Contradictions Between Evidences Report",
"plan": {
"title": "CONTRADICTIONS BETWEEN EVIDENCES : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Data Integrity Scorecard",
"data": [
{
"label": "Literature Sources",
"value": 2
},
{
"label": "Conflict Nodes",
"value": 1
},
{
"label": "Evidence Variance",
"value": "High"
}
]
},
{
"type": "synthesis",
"title": "Synthesis of Contradictory Evidence",
"content": "Analysis of current literature reveals a significant tension regarding the role of inflammation in aging. While general consensus links macrophage efferocytic dysfunction to pathology, evidence is inconsistent regarding the inflammatory phenotype [ID: 18467696, 18387441]. Data suggests that instead of a uniform 'inflamm-aging' model, resolution dysfunction is context-dependent, manifesting as acute cytokine storms in some models [ID: 18467696] and suppressed inflammatory response/delayed granulation in others [ID: 18387441]."
},
{
"type": "contradiction_topology",
"title": "Directional Conflict Nodes",
"headers": [
"Source A",
"Source B",
"Observed Conflict"
],
"rows": [
[
"ID: 18467696",
"ID: 18387441",
"Acute hyper-inflammation vs. Suppressed inflammation/delayed healing"
]
]
},
{
"type": "pathmap",
"title": "Global Master Systems Map: Aging Resolution Pathways"
},
{
"type": "gap_distribution",
"title": "Gap Identification Analysis",
"data": [
{
"label": "Contextual Alignment",
"value": 60
},
{
"label": "Methodological Variance",
"value": 40
}
]
}
]
}
},
{
"id": "mvc_dp_repurposed_solutions_1785955553461",
"title": "Repurposed Solutions Report",
"plan": {
"title": "REPURPOSED SOLUTIONS : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Evidence Density Metrics"
},
{
"type": "synthesis",
"title": "Executive Analysis of Repurposed Therapeutic Pathways",
"content": "Current literature identifies two primary classes of repurposed agents targeting efferocytic pathways. Neratinib, an ErbB tyrosine kinase inhibitor, demonstrates efficacy as an immunoresolvent capable of restoring MerTK expression in chronic inflammatory states [ID: 41857730]. Additionally, Fucoidan shows therapeutic potential by activating the Gas6/MerTK signaling axis to mitigate neuroinflammation [ID: 41351868]. Emerging evidence suggests that probiotic and postbiotic interventions\u2014specifically L. lactis and Mn-CDs\u2014may be repurposed from gut-lung modulation models for broader cardiac or hepatic tissue repair, contingent upon shared efferocytic mechanism reliance."
},
{
"type": "logic_network",
"title": "Efferocytic Pathway Mechanistic Map"
},
{
"type": "comparison_matrix",
"title": "Repurposed Agent Clinical Utility",
"headers": [
"Agent",
"Primary Mechanism",
"Target Pathology"
],
"rows": [
[
"Neratinib",
"ErbB Inhibition/MerTK Restoration",
"Chronic Inflammation"
],
[
"Fucoidan",
"Gas6/MerTK Activation",
"Neuroinflammation"
],
[
"L. lactis/Mn-CDs",
"Gut-Lung Modulation",
"Cardiac/Hepatic Repair"
]
]
},
{
"type": "bibliography",
"title": "Source Reference List"
}
]
}
},
{
"id": "mvc_dp_lung_microbiome_axis_1785955566363",
"title": "Lung Microbiome Axis Report",
"plan": {
"title": "LUNG MICROBIOME AXIS : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Evidence Integrity Scorecard"
},
{
"type": "synthesis",
"title": "Clinical Synthesis of IALd Mechanism",
"content": "The analysis of the 'Lung Microbiome Axis' indicates that IALd plays a critical role in modulating Resident Alveolar Macrophages (RAMs) and Alveolar Macrophages (AMs) [ID: Run2_Eval1_synthesis]. By enhancing phagocytosis, IALd facilitates the clearance of apoptotic neutrophils and lipopolysaccharides (LPS). This mechanism is particularly significant in the context of aging, where natural efferocytic gene signatures are typically downregulated, suggesting IALd as a potential therapeutic intervention to restore pulmonary homeostasis [ID: Run2_Eval1_synthesis]."
},
{
"type": "node_centrality",
"title": "Key Biological Entity Impact",
"data": [
{
"label": "IALd",
"value": 95
},
{
"label": "RAMs/AMs Phagocytosis",
"value": 90
},
{
"label": "Apoptotic Neutrophils",
"value": 85
},
{
"label": "Efferocytic Genes",
"value": 75
},
{
"label": "Aging Tissues",
"value": 70
},
{
"label": "LPS Clearance",
"value": 65
}
]
},
{
"type": "bottlenecks",
"title": "Literature Gap Analysis",
"content": "Evidence is limited to a singular synthesized observation; lack of longitudinal or multi-factorial data represents a significant gap in validating the universality of the IALd mechanism across diverse microbiome profiles."
}
]
}
},
{
"id": "mvc_dp_systemic_crosstalk_1785955579266",
"title": "Systemic Crosstalk Report",
"plan": {
"title": "SYSTEMIC CROSSTALK : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Systemic Crosstalk Metrics"
},
{
"type": "synthesis",
"title": "Executive Analysis of Crosstalk Pathways",
"content": "Analysis of the provided dataset [ID: Run2_Eval1_synthesis] indicates that the restoration of TRM efferocytosis serves as a critical intervention in aged subjects. By preventing the release of paracrine stress signals from the lung and liver, this process successfully dampens systemic inflammation and reduces distal tissue damage. Gaps remain in identifying the specific molecular mediators of these paracrine signals and determining the threshold of TRM efficiency required to prevent damage entirely."
},
{
"type": "logic_network",
"title": "Systemic Crosstalk Logic Pathway"
},
{
"type": "gap_distribution",
"title": "Literature Gap Strength Analysis"
},
{
"type": "tag_cloud",
"title": "Key Mechanism Terminology"
}
]
}
},
{
"id": "mvc_dp_metabolic_checkpoint_1785955592066",
"title": "Metabolic Checkpoint Report",
"plan": {
"title": "METABOLIC CHECKPOINT : CUSTOM ANALYSIS",
"evidence_tier": "EVALUATED",
"panels": [
{
"type": "metrics",
"title": "Data Integrity Scorecard"
},
{
"type": "synthesis",
"title": "Executive Summary: Metabolic Checkpoint Mechanism",
"content": "The analysis confirms that IAAld-mediated NRF2 nuclear translocation functions as a critical regulatory mechanism. By upregulating CD36 expression, this pathway serves as a metabolic checkpoint capable of restoring both phagocytic potential and mitochondrial fitness that are otherwise compromised during the aging process [ID: Run2_Eval1_synthesis]."
},
{
"type": "logic_network",
"title": "Regulatory Pathway Logic"
},
{
"type": "gap_distribution",
"title": "Evidence Gap Assessment"
},
{
"type": "comparison_matrix",
"title": "Metabolic Function Baseline",
"headers": [
"Indicator",
"Status",
"Impact"
],
"rows": [
[
"NRF2 Translocation",
"Activated",
"High"
],
[
"CD36 Expression",
"Upregulated",
"High"
],
[
"Mitochondrial Fitness",
"Restored",
"Positive"
]
]
}
]
}
}
],
"aggregatedDatapoints": {
"suggested_experiments": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": [
"Assess if pharmacological targeting of the charge-sensitive recognition mechanism (using cationic modulators) enhances neutrophil clearance in an aged mouse model.",
"Determine if systemic administration of resolvin D5 (n-3 DPA) derived from erythroblasts can rejuvenate the peripheral macrophage efferocytic phenotype in aged organisms.",
"Evaluate if inhibiting NETs using DNase I in aged models restores the CD36/MerTK signaling axis in tissue-resident macrophages."
]
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": [
"Assess if aerosolized IAAld treatment in aged mice reduces serum markers of systemic inflammation.",
"Evaluate the impact of FMT from young to aged mice on alveolar macrophage efferocytic gene expression profiles.",
"Measure systemic insulin sensitivity following targeted pulmonary AM efferocytosis restoration in diabetic murine models."
]
}
],
"suggested_studies": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": [
"Longitudinal analysis of human patient cohorts to correlate systemic efferocytosis efficiency with biological markers of aging (e.g., epigenetic clocks).",
"Cross-species study on the evolution of efferocytosis efficiency relative to longevity across long-lived and short-lived mammals.",
"Investigation of the gut-lung axis in regulating efferocytosis via microbial metabolites in age-related respiratory declines."
]
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": [
"Longitudinal cohort analysis of respiratory commensal metabolites in healthy vs. accelerated aging populations.",
"Spatial transcriptomics investigation of pulmonary macrophages in age-related frailty, focused on efferocytic receptor density.",
"Meta-analysis of microbiome-targeted therapies and their impact on systemic inflammatory biomarkers (CRP/IL-6) in patients."
]
}
],
"swansons_literature_based_discovery_candidates": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": {
"Discovered Hypothesis (A to C)": "Enhancement of erythroblast-derived Resolvin D5 (RvD5n-3 DPA) signaling may ameliorate age-associated cognitive decline by normalizing the microglia-driven efferocytic resolution program.",
"Literature A (Origin)": "Erythroblast-derived Resolvin D5 (RvD5n-3 DPA) imprints neutrophil development and function (ID: 42519831).",
"Literature C (Target)": "Reducing TRM EP2 signaling (which coordinates TRM function) limits cognitive decline in aged mice (ID: 42462036).",
"The Intersecting Bridge B": "Microglia/Brain-resident macrophages as the common cell type (specialized tissue-resident macrophages).",
"Biological Rationale": "Since erythroblasts imprint systemic granulopoiesis and tissue-resident macrophage status, and tissue-resident macrophages in the brain coordinate cognitive decline, increasing local pro-resolving lipid mediator signaling (like RvD5) may modulate the resident immune cell niche in the brain, thereby mimicking the cognitive-sparing effects of EP2 signaling inhibition."
}
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": {
"Discovered Hypothesis (A to C)": "Indole-3-acetaldehyde (IAAld) acts as a potential therapeutic agent for age-related cardiac remodeling by modulating the cardiac resident macrophage (CRM) efferocytosis axis.",
"Literature A (Origin)": "IAAld as a metabolite of R. mucilaginosa enhances AM phagocytosis via PXR/NRF2 (ID 41715099).",
"Literature C (Target)": "CRM efferocytosis promotes myocardial I/R resolution and reduces fibrosis (ID 41554295).",
"The Intersecting Bridge B": "PPAR-\u03b3 and NRF2 pathway integration in macrophage metabolism and inflammatory resolution.",
"Biological Rationale": "Both NRF2 and PPAR-\u03b3 converge on metabolic reprogramming of macrophages to improve efferocytic efficiency; IAAld-mediated activation of the PXR/NRF2 axis in AMs may be applicable to CRMs to mitigate age-related myocardial fibrosis."
}
}
],
"contradictions_between_evidences": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": "While most evidence points to increased inflammation and impaired efferocytosis in aging, ID: 18467696 notes that adult mice show an early and acute 'cytokine storm' that is more lethal than in young mice, while ID: 18387441 reports suppressed inflammation and delayed granulation tissue in senescent hearts following injury. This suggests a context-dependent resolution dysfunction rather than simple 'inflamm-aging'."
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "None identified in the current set; all sources consistently link macrophage efferocytic dysfunction to pathology."
}
],
"repurposed_solutions": [
{
"pentamatrix": "Run1_Eval1_synthesis",
"data": "Neratinib (an ErbB tyrosine kinase inhibitor) can be repurposed as an immunoresolvent to restore MerTK expression and efferocytosis in chronic inflammatory diseases (ID: 41857730). Additionally, Fucoidan can be utilized to activate the Gas6/MerTK pathway to reduce neuroinflammation (ID: 41351868)."
},
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Probiotics/postbiotics designed for gut-lung axis modulation (like L. lactis or Mn-CDs) could be repurposed for cardiac or hepatic repair by leveraging common efferocytic pathways."
}
],
"lung_microbiome_axis": [
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "IAAld enhances RAMs/AMs phagocytosis, effectively clearing apoptotic neutrophils and LPS, which is crucial in aged tissues where efferocytic gene signatures are downregulated."
}
],
"systemic_crosstalk": [
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Restoration of TRM efferocytosis prevents the release of paracrine stress signals from the lung/liver, thereby dampening systemic inflammation and distal tissue damage in aged subjects."
}
],
"metabolic_checkpoint": [
{
"pentamatrix": "Run2_Eval1_synthesis",
"data": "Yes, IAAld-mediated NRF2 nuclear translocation upregulates CD36, providing a metabolic checkpoint to restore phagocytic potential and mitochondrial fitness lost during aging."
}
]
},
"stats": {
"promptTokens": 399684,
"completionTokens": 27814,
"totalTokens": 427498
},
"zenodo_doi": "10.5281/zenodo.21812489"
}