ID: 41075520
Title: Xinqingning tablet attenuates ischemic stroke complicated by gut dysbiosis through regulating the miR-126-driven gut-brain axis.
Abstract: Ischemic stroke (IS), the predominant clinical stroke subtype, is increasingly linked to dysregulation of the gut-brain axis (GBA)-a bidirectional neuroendocrine-immune interface connecting intestinal homeostasis with cerebrovascular pathophysiology. Xinqingning Tablet (XQNT) demonstrates neuroprotective potential in IS complicated by gut dysbiosis (GD), yet its mechanisms of GBA modulation remain unclear. A dual-hit IS-GD mouse model was established via fecal slurry transplantation and permanent middle cerebral artery occlusion (pMCAO) surgery. Gut function was evaluated by constipation indices and histopathological changes, while the neuroprotective efficacy of XQNT (0.36, 0.48, and 0.61 g kg⁻¹) was assessed via TTC staining, neurological deficit scores, cerebral water content, and Evans blue (EB) extravasation assays. Additionally, Western blot was employed to quantify blood-brain barrier (BBB) and inflammation-associated proteins. microRNA sequencing was used to screen the differentially expressed miRNAs. miR-126 expression levels were measured by RT-qPCR, while concentrations of LPS, IL-6 and IL-10 were determined by ELISA. Finally, mechanistic validation employed intravenous miR-126 agonism/antagonism coupled with phenotypic rescue experiments. XQNT conferred robust survival benefits, while concurrently ameliorating intestinal dysfunction and neurovascular injury. Mechanistically, XQNT elevated miR-126 expression, suppressing NF-κB-driven neuroinflammation. Additionally, miR-126 agonism phenocopied XQNT efficacy, whereas miR-126 inhibition abrogated therapeutic benefits. This study provides early evidence that XQNT functions as a dual-target GBA modulator that alleviates IS with GD via regulation of the miR-126/NF-κB axis. By simultaneously promoting barrier restoration and inflammatory resolution, XQNT offers a promising therapeutic approach that links regulation of the gastrointestinal system with cerebrovascular protection.

ID: 41828410
Title: Integrated Untargeted and Targeted Metabolomics Reveals Distinct Bioactive Metabolite Profiles Between Probiotic Supplements and Yogurt.
Abstract: Probiotics are widely consumed as health-promoting agents, with probiotic supplements (PS) and yogurt (YG) representing formulated products and fermented foods, respectively. Despite their broad consumption, systematic comparisons of their biochemical characteristics remain limited. In this study, integrated untargeted and targeted metabolomics approaches were applied to compare the comprehensive metabolite profiles of PS and YG. PS exhibited relatively higher levels of amino acids, dicarboxylic acids, and lysophospholipids, along with short-chain fatty acids such as acetate and propionate, and amino acid-derived bioactive metabolites, including γ-aminobutyric acid, branched-chain hydroxy acids, indole derivatives, and γ-glutamylpeptides. In contrast, YG showed higher relative abundances of carbohydrates, acylcarnitines, sphingolipids, and bioactive metabolites such as butyrate, creatine, carnitine, and orotic acid. Based on these metabolomic differences, 27 PS-specific and 17 YG-specific marker metabolites were identified. To explore their functional relevance, in vitro antioxidant and antiglycation activities were evaluated. PS exhibited significantly higher antioxidant and antiglycation activities than YG, which were positively correlated with amino acids and indole derivatives. Indole-3-acrylic acid, indole-3-acetic acid, and indole-3-propionic acid showed antiglycation activity and were identified as PS-specific bioactive marker metabolites. These findings reveal the distinct biochemical characteristics of PS and YG and highlight potential bioactive candidate metabolites that may contribute to their functional differences.

ID: 41932000
Title: Rhubarb ameliorates ischemic stroke-induced tryptophan-kynurenine metabolic reprogramming and neuroinflammation via modulation of the IDO-1/TREM-1 pathway.
Abstract: Ischemic stroke (IS) elicits intertwined metabolic derangements and neuroinflammatory responses that propagate pathogenic cascades. Rhubarb (RR) is widely applied to treat IS in the clinic. However, its underlying pharmacological mechanisms remain incompletely elucidated. To dissect the mechanism and pharmacological basis of RR's ability to ameliorate IS from the side of modulating tryptophan-kynurenine (TRP-KYN) metabolism and neuroinflammation. An embolic middle cerebral artery occlusion (MCAO) model was employed in rats to simulate human IS. Neurological deficit scores, hematoxylin-eosin, 2,3,5-triphenyltetrazolium chloride, alcian blue-periodic acid-Schiff staining, Western blotting, targeted metabolomics, immunofluorescence, and enzyme-linked immunosorbent assay were utilized to evaluate the efficacy of RR against cerebral ischemic injury, gut permeability, TRP-KYN metabolism levels, and neuroinflammation. Surface plasmon resonance and cell-based assays were further utilized to screen and validate potential bioactive ingredients of RR for the treatment of IS. In addition to mitigating cerebral ischemic damage, RR treatment substantially restored intestinal barrier function in IS rats by reducing leaky gut biomarkers, ameliorating histopathological alterations, and upregulating colonic tight junction proteins. Moreover, RR modulated TRP-KYN metabolism, concomitant with regulated expression and enzymatic activity of indoleamine 2,3-dioxygenase 1 (IDO-1) and the triggering receptor expressed on myeloid cells-1 (TREM-1) levels in both colon tissue and serum. Within the central nervous system, RR attenuated neuroinflammation triggered by MCAO through orchestrating microglial polarization and cytokine levels, accompanied by suppression of the TREM-1-mediated inflammatory signaling cascade. Chrysophanol 8-O-β-d-glucoside, rutinum, lindleyin, and (-)-catechin gallate from RR were identified as potential IDO-1 inhibitors, while rhein, lindleyin, methyl gallate, and chrysophanol 8-O-β-d-glucoside were identified as potential TREM-1 inhibitors, capable of attenuating the overexpression of IDO-1 and TREM-1 or TREM-1 and NOD-like receptor protein 3 (NLRP3). This study demonstrates that RR exerts therapeutic effects in IS by improving the intestinal barrier function, reprogramming the IDO-1-dependent TRP-KYN pathway, and attenuating neuroinflammation. These effects are attributed to its bioactive components, including rutinum, chrysophanol 8-O-β-d-glucoside, lindleyin, (-)-catechin gallate, rhein, and methyl gallate.

ID: 41936926
Title: β-Hydroxybutyrate modulates intestinal barrier function and visceral sensitivity via a brain AMPK-orexin pathway recruiting histamine H1 receptors, basal forebrain cholinergic neurons, adenosine A2B receptors, and vagal output in rats.
Abstract: Irritable bowel syndrome (IBS) is characterized by chronic abdominal pain and altered bowel habits, with visceral hypersensitivity and impaired intestinal barrier function as key pathophysiological features. Although peripheral determinants of barrier dysfunction have been studied, the contribution of central regulatory mechanisms remains unclear. β-Hydroxybutyrate (BHB), a major ketone body elevated during fasting, exhibits anti-inflammatory and barrier-protective effects peripherally, but its central actions are unknown. Here, we investigated whether BHB acts within the brain to regulate intestinal barrier function and visceral sensitivity using an LPS-induced rat model. Intracisternal BHB dose-dependently attenuated LPS-induced colonic hyperpermeability and visceral hypersensitivity, whereas an equivalent subcutaneous dose was ineffective, indicating a centrally mediated effect. The protection conferred by intracisternal BHB was abolished by vagotomy and by pharmacological inhibition of brain AMPK, orexin 1 receptors, histamine H1 receptors, basal forebrain cholinergic neurons (BFCNs), or adenosine A2B receptors. Peripheral BHB also ameliorated barrier dysfunction and visceral hypersensitivity; however, these effects persisted after vagotomy while remaining sensitive to central pharmacological blockade, suggesting engagement of shared brain signaling modules together with vagus-nonobligatory components. Collectively, these findings demonstrate that BHB regulates intestinal barrier function and visceral sensitivity through both central and peripheral mechanisms. Central BHB signaling engages an AMPK-orexin pathway involving histamine H1 receptors, BFCNs, adenosine A2B receptor-related mechanisms, and vagal pathways. BHB thus emerges as a neuro-metabolic signal modulating core gut-brain interaction processes and represents a promising therapeutic target for leaky gut-associated disorders, particularly IBS.

ID: 41968935
Title: The end of 'leaky gut': pathway-specific mechanistic approaches to barrier restoration.
Abstract: For over 50 years, increased intestinal permeability has been associated with diverse inflammatory and systemic diseases. Yet the oversimplified concept of 'leaky gut' as a singular phenomenon has limited both mechanistic understanding and therapeutic development. It is now recognized that intestinal permeability occurs via two molecularly distinct, differentially regulated trans-tight junction pathways, while a tight junction-independent unrestricted pathway allows flux at sites of epithelial damage. The pore pathway is a high-conductance, size-selective and charge-selective flux route that mediates ion and water flux. Its upregulation can be either protective, as in infectious enterocolitis, or pathogenic, as in immune-mediated disease or, as shown recently, in sepsis. Myosin light chain kinase activation enhances flux across the leak pathway, a low-conductance macromolecular flux route, that promotes progression of immune-mediated diseases. Recently developed molecularly targeted, pathway-specific approaches to barrier restoration are effective and can outperform current therapies without the complications of broad immunosuppression. The evolving pathway-resolved framework transforms intestinal barrier biology from a descriptive science into mechanism-specific therapeutic approaches that have promise as independent agents and as complements to available immune-targeted therapies.

ID: 41972275
Title: Enhanced Antiaging Effect of Fermented Ginseng through Biotransformation of Protopanaxadiol (PPD)-Type Ginsenosides to PPD.
Abstract: Aging couples oxidative stress, inflammation, and leaky gut; ginsenosides are promising yet hobbled by poor conversion. We asked whether probiotic fermentation enriching PPD-type ginsenosides converts ginseng into a potent, low-dose antiaging agent. In D-galactose-aged mice, 20 mg/kg of probiotic-fermented ginseng (GFB) outperformed 600 mg/kg native ginseng: Rg3/Rg5/Rd and antioxidant capacity surged, cytokines fell, redox balance, barrier integrity, and youthful microbiota were restored. Plasma 20(S)-protopanaxadiol (PPD) increased 4-6-fold only in fermented-ginseng mice; PPD down-regulated barrier-destabilizing genes and docked stably into CC-chemokine receptor 6 (CCR6), suggesting a potential mechanism for blocking CCL20-driven chemotaxis. Thus, fermentation transforms ginseng into a food-grade, microbe-activated pro-drug that delivers systemic PPD, antagonizes CCR6, and simultaneously quells inflammation, seals the gut, and resets redox homeostasis for precision geroprotection.

ID: 42009106
Title: 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.
Abstract: 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 β-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.

ID: 42033495
Title: Inhibition of SARS-CoV-2 spike S1-ACE2 binding interaction and downregulation of ACE2 gene expression by Malaysian stingless bee honey and its bioactive compound, stilbamidine (SDC).
Abstract: The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus infects host cells by binding to angiotensin-converting enzyme 2 (ACE2). Stilbamidine (SDC), a compound identified in Malaysian Kelulut honey (KH), has been reported to exhibit favourable binding affinity towards ACE2. This study aims to determine the effects of KH and SDC on the binding of spike protein to the ACE2 receptor, as well as to assess their modulatory potential on ACE2 gene and protein expression in lung and kidney cells. KH, SDC, and MLN 4760 (ACE2 inhibitor) were tested using an in vitro spike S1:ACE2 inhibition assay. Their modulatory effects on the ACE2 gene and protein expression were further examined through real-time PCR and western blot analysis. KH inhibited the binding of Spike S1 to ACE2, surpassing MLN4760, with maximum effects (Emax) of 82.66 ± 0.24% and 59.81 ± 8.00%, respectively, while the Emax for SDC was 19.93 ± 0.4%. KH caused a significant, dose-dependent downregulation of ACE2 gene expression in kidney-derived Vero E6 cells after 24 h of treatment, whereas SDC reduced ACE2 gene expression in lung-derived A549-ACE2-TMPRSS2 cells after 72 h. Nevertheless, ACE2 protein expression remained unchanged following both treatments. KH and SDC inhibit the binding of the SARS-CoV-2 spike S1 protein to the ACE2 receptor and reduce ACE2 gene expression. The efficacy of ACE2-targeted interventions may be limited by ACE2 polymorphisms and inter-individual expression differences. Further in vivo studies are needed to confirm their prophylactic and therapeutic potential against SARS-CoV-2 infection.

ID: 42151371
Title: Protein yogurt and whey protein produce comparable muscle gains, but divergent microbiome shifts during strength training in older adults.
Abstract: Sarcopenia, the age-related decline in muscle mass and strength, affects the functional capacity of older adults. Strength training (ST) combined with adequate protein intake is a key element in reversing and improving functional capacity. Protein, especially Whey Protein isolates (WPI), is widely used to improve muscle mass. In contrast, high-protein products, such as protein yogurt (PY), may offer similar benefits for muscle health and drive additional effects on gut health, which is altered in older adults. For this, we aim to compare WP and PY supplementation during ST on body composition, strength, and gut microbiome in untrained older adults. Seventeen untrained adults (60-70 years) were randomized to either consume WP (25 g) or PY (24.5 g) along with an 8-week supervised ST program (3 sessions/week). Initial and final assessments included body composition (BIA), strength (10RM, isokinetic torque, handgrip), gait speed, resting metabolic rate, and gut microbiome (16 S rRNA sequencing). Data were analyzed using repeated-measures ANOVA and diversity metrics. Both groups increased skeletal muscle mass (WP: +0.47 kg; PY: +0.50 kg) and improved strength and gait speed (p < 0.01), with no between-group differences. Fat mass decreased only in WP (p = 0.02), while resting metabolic rate increased in PY (p = 0.03). Microbiome analysis revealed distinct shifts: WP increased the Firmicutes/Bacteroidota ratio and enriched Subdoligranulum, whereas PY enhanced alpha diversity and increased the abundance of Coprococcus. Functional pathway predictions indicated differential enrichment in metabolic and signaling processes. High-protein yogurt and whey protein similarly improve muscle mass, strength, and functional capacity during ST, while exerting distinct effects on gut microbiome composition. Yogurt represents a cost-effective alternative to whey protein and may confer additional gut health benefits.Trial registration: Clinicaltrials.gov identifier NCT06412302. Date of registration 06/05/2024.

ID: 42207404
Title: Targeting Gut Microbiota by DPP-4 Inhibitors in Obesity: Mechanistic Insights and Therapeutic Implications.
Abstract: Obesity is a complex metabolic disorder driven by factors such as chronic inflammation, insulin resistance, and significant alterations in the gut microbiota. Dipeptidyl peptidase-4 (DPP-4), an enzyme primarily known for inactivating incretin hormones like glucagon-like peptide-1 (GLP-1), is now recognized as a critical link between metabolic dysfunction and gut microbiome dysbiosis. This review aims to examine the mechanistic role of DPP-4 and its inhibitors in obesity, specifically focusing on how they modulate the gut microbiome to influence host energy balance and metabolic health. Recent experimental and clinical evidence indicates that DPP-4 activity contributes to obesity by influencing microbial composition, diversity, and function. Studies demonstrate that DPP-4 inhibitors can reshape the gut microbiota by reducing dysbiosis, decreasing the Firmicutes-to-Bacteroidetes ratio, and enhancing the production of short-chain fatty acids (SCFAs). Furthermore, these inhibitors improve gut barrier integrity and regulate bile acid metabolism, which helps attenuate systemic inflammation and restore insulin sensitivity. While DPP-4 inhibitors are often weight-neutral in clinical settings, they appear to assist in maintaining metabolic stability by enhancing central satiety signaling and reducing neuroinflammation. The gut microbiome acts as a key intermediary in the metabolic regulation managed by DPP-4. By restoring microbial balance and promoting beneficial metabolites, DPP-4 inhibitors offer therapeutic advantages that extend beyond traditional glycemic control to include improved energy equilibrium and reduced adiposity. Targeting the interactions between DPP-4 and the microbiota represents a promising future therapeutic strategy for managing obesity and its associated metabolic complications.

ID: 42212401
Title: Texture Engineering of Nondairy Yogurt Alternatives: Ingredient Selection, Processing Strategies, and the Role of In Situ Dextrans.
Abstract: A global shift from diets rich in animal-based products toward plant-based diets has been widely promoted as a key strategy for creating more sustainable food systems. However, the adoption of plant-based alternatives depends on multiple factors, including consumer preferences, sensory quality, product affordability, and availability, in addition to sustainability and ethical considerations. Although nondairy yogurt alternatives may offer environmental advantages over conventional dairy products, their broader adoption is often constrained by textural limitations, which remain a major barrier to consumer acceptance. Addressing texture deficiencies requires strategic ingredient selection and optimized processing techniques. While existing literature focuses primarily on plant-based systems, alternative protein sources such as fungal proteins remain underexplored, with few studies evaluating fungal protein-based yogurt analogues. This review summarizes recent advances in improving the texture of nondairy yogurt alternatives, with particular attention to in situ dextran synthesis during fermentation as a natural biothickening strategy. Compared with many heteropolysaccharides often produced at relatively low yields by yogurt starters, dextran, a homopolysaccharide, can be synthesized at higher levels by certain lactic acid bacteria (LAB) and contributes to enhanced viscosity and gel formation in plant-based matrices. We discuss the mechanisms underlying these effects, including dextran-protein interactions and water-binding capacity, as well as their relevance to clean-label and functional food trends. Key research priorities include identifying food-grade, high-yield dextran-producing LAB strains, assessing their safety and allergenicity, and investigating the digestive fate and health effects of in situ-produced dextrans. Overall, in situ dextran production represents a promising strategy for improving the texture and consumer acceptance of nondairy yogurt alternatives.

ID: 42280098
Title: Striatal Metabolomic Profiling Links Brazilian Green Propolis to Suberic Acid Modulation and Nigrostriatal Neuroprotection in a Rat Model of Parkinson's Disease.
Abstract: Parkinson's disease (PD) is characterized by progressive nigrostriatal degeneration and striatal dysfunction, yet its metabolic remodeling remains incompletely defined. Here, untargeted GC-MS metabolomics was used to investigate the effects of standardized Brazilian green propolis on the striatal metabolic profile in the 6-hydroxydopamine (6-OHDA) rat model. Discriminant metabolites, including suberic acid, gluconic acid, heptadecane, and tartaric acid, distinguished experimental groups, capturing key features of the metabolic response to dopaminergic injury and treatment. Suberic acid emerged as a prominently modulated metabolite, potentially linked to alterations in lipid catabolism associated with mitochondrial-peroxisomal pathways. Propolis treatment attenuated the elevation of suberic acid, accompanied by a reduction in gluconic acid levels, suggesting a metabolic profile linked to pathways involved in redox balance and glucose handling. Given previous reports identifying heptadecane as a hydrocarbon constituent of volatile propolis fractions, complementary GC-Q-TOF analyses demonstrated that heptadecane was absent from the administered extract, despite its consistent association with propolis-treated groups. Metabolic changes were accompanied by attenuation of nigrostriatal dopaminergic neurodegeneration and improved motor performance. Together, these findings delineate a striatal metabolic signature associated with Brazilian green propolis and identify suberic acid as a key metabolite linked to neuroprotection in experimental Parkinsonism.

ID: 42304659
Title: The leaky gut and microbiome in critical illness: emerging insights into microbial "translocation".
Abstract: Microbial translocation has long been viewed as a nonspecific consequence of gut barrier failure in critical illness, with downstream effects attributed primarily to the host immune response. This review examines emerging evidence that the gut microbiome plays a more active and specific role in this process than previously appreciated. Dysbiosis during critical illness directly contributes to barrier dysfunction through depletion of metabolites that sustain epithelial integrity. Culture-independent approaches have revealed that gut-derived organisms are a major reservoir for secondary infection, with translocation governed by microbial virulence, community dynamics, and immune cell-mediated transport rather than barrier permeability alone. In parallel, organism-specific microbial components - including structurally diverse forms of lipopolysaccharide and bacterial DNA detected across multiple blood fractions - enter the circulation and differentially modulate host immune responses. Recent studies link circulating microbial DNA composition to distinct inflammatory phenotypes in sepsis and acute respiratory distress syndrome, suggesting these signals contribute to clinical heterogeneity. These findings support a revised framework in which translocation reflects the composition of the dysbiotic gut, not barrier integrity alone. Integrating microbial data with host phenotyping may enable more precise risk stratification and microbiome-informed therapeutic strategies in critical illness.

ID: 42438036
Title: Protective Effect of Uric Acid on Rat Model of Irritable Bowel Syndrome Requires Brain-Gut Communication Through Vagal Cholinergic Pathways.
Abstract: Uric acid (UA) is an endogenous antioxidant that protects against neuroinflammatory diseases. Although irritable bowel syndrome (IBS) is considered a disorder of gut-brain interaction, the role of UA in IBS remains unclear. An experimental rat model of IBS was induced using laser-induced shock waves (LISW) applied to the head. Hyperuricemia (HUA) was induced by intraperitoneal administration of inosine monophosphate and potassium oxonate. Visceral hypersensitivity was assessed by colorectal distension. Ileal mucosal permeability was measured using the Evans blue method. CRFR1 mRNA expression in the rectum, IL-10 and TGF-β1 expression in the ileum, and IL-1α, IL-1β, and TNF expression in the medial prefrontal cortex (mPFC) and paraventricular nucleus (PVN) were quantified by qRT-PCR. Vagal involvement was assessed using subdiaphragmatic vagotomy or atropine treatment. LISW increased visceral hypersensitivity, ileal mucosal permeability, and rectal CRFR1 expression and reduced IL-10 expression in the ileum. HUA significantly ameliorated these changes. HUA was also associated with reduced IL-1β expression in the mPFC and reduced IL-1α and IL-1β expression in the PVN in LISW-treated animals. Importantly, the ameliorative effects of HUA on visceral hypersensitivity were abolished by vagotomy or atropine treatment. Hyperuricemia ameliorated LISW-induced visceral hypersensitivity, improved ileal mucosal permeability, restored IL-10 expression in the ileal mucosa, and reduced proinflammatory cytokine expression in the brain. The loss of HUA-induced suppression of visceral hypersensitivity after vagotomy or atropine treatment suggests the possible involvement of vagal and cholinergic brain-gut communication. Irritable bowel syndrome (IBS) is a common disorder in which people experience abdominal pain and bowel problems, often worsened by stress. We examined whether uric acid, a major endogenous antioxidant in the human body, can protect against changes seen in a rat model of IBS. An experimental model of IBS was created by applying laser‐induced shock waves to the head, leading to increased sensitivity to colorectal distension (a measure of visceral hypersensitivity), impaired barrier function of the lower small intestine, and reduced a protective anti‐inflammatory signal (IL‐10) in the gut. Increasing blood uric acid levels reduced visceral hypersensitivity, improved the barrier function of the lower small intestine, and restored IL‐10 levels. Importantly, the uric acid–induced suppression of visceral hypersensitivity was lost when vagus nerve signaling was disrupted, indicating that vagal and cholinergic signaling is involved in this effect.

ID: 42474276
Title: Targeted β-Glucan-Veiled Oral Apremilast Nanotherapy Modulates Key Dysbiosis-Associated Gut Microbiota and Alleviates Ulcerative Colitis-Associated Anxiety, Depression, and Neuropsychiatric Behaviors.
Abstract: Oral nanomedicines that modulate gut microbiota and gut-brain interactions are crucial for effectively treating inflammatory bowel disease (IBD) and associated psychiatric disorders, such as anxiety and depression. However, the underlying causes of psychiatric disorders in patients with IBD remain unclear, and effective treatment strategies have yet to be established. Herein, we developed oral gastroprotective βG@Apr-WPG NMs (β-glucan armored apremilast encapsulating tryptophan-poly(lactic-co-glycolic acid)-glutathione nanomicelles). This system effectively treats IBD and associated anxiety/depression by modulating the microbiota-gut-brain axis. βG@Apr-WPG NMs demonstrated gastroprotection enhances retention, and enables sustained release within the inflamed colon, enhances drug solubility, and inflammation-responsive apremilast release significantly improving oral therapeutic efficacy. Oral βG@Apr-WPG NMs administration outperformed free apremilast by restoring gut barrier integrity, reducing histopathological damage, and modulating microbial dysbiosis. Systemic inflammation and neuroinflammation were markedly suppressed. Notably, the βG@Apr-WPG NMs ameliorated anxiety- and depression-like symptoms, as well as cognitive deficits in colitis-induced mice, highlighting its therapeutic impact beyond the gut. Addressing reduced efficacy of conventional therapies, this multifunctional βG@Apr-WPG NMs platform offers safe, simple, and highly efficient therapeutic strategy integrating targets intestinal inflammation, microbiota-gut-brain axis modulation, in the pathogenesis of IBD with comorbid neuropsychiatric disorders with confirmed safety.

ID: 42505396
Title: Mediterranean Diet and Neurodegenerative Diseases: Recent Advances from the Gut-Immune-Brain Axis to Multi-Omics-Guided Precision Nutrition.
Abstract: Neurodegenerative diseases like Alzheimer's disease (AD) and Parkinson's disease (PD) are regarded as systemic illnesses, mainly characterized by long-term neuroinflammation, metabolic dysregulation and barrier dysfunction. All these factors interact through the gut-immune-brain axis. The Mediterranean diet, rich in plant-based foods, olive oil, and fish, has been consistently associated with slower cognitive decline and reduced risk of neurodegeneration in observational studies and some clinical trials. This review provides a systems-level synthesis that distinguishes itself from previous narratives by integrating disease-specific mechanistic frameworks with multi-omics-guided precision nutrition strategies. We summarize recent evidence showing that this dietary pattern can remodel gut microbiota composition and enhance the production of bioactive metabolites such as short-chain fatty acids (SCFAs). These metabolites are associated with improved intestinal barrier integrity, reduced systemic inflammation, and potential modulation of brain functions. Within the central nervous system, diet-related metabolites have been linked to reduced neuroinflammation via modulation of microglial and astrocytic states. They have been linked to protection of mitochondrial function, maintenance of proteostasis, and preservation of blood-brain barrier (BBB) integrity. In AD and PD patients, adherence to this diet is associated with favorable changes in pathological hallmarks, including amyloid-beta (Aβ), tau, and α-synuclein accumulation. Nowadays, multi-omics tools, including single-cell transcriptomics, spatial transcriptomics and microbiome analysis, are widely used in this field, which helps researchers explore these complicated effects more deeply. Importantly, individual responses to the diet vary considerably due to differences in genetic background, gut microbial composition, and metabolic phenotypes, which underscore the need to move from generalized dietary guidelines toward personalized precision nutrition. The Mediterranean diet is not only a dietary pattern but also an effective way to modulate neuro-immune and metabolic networks. However, current evidence remains largely observational, and we critically discuss the need for more randomized controlled trials (RCTs) and standardized multi-omics data analysis frameworks. To sum up, the Mediterranean diet plays a neuroprotective role via the gut-immune-brain axis, and multi-omics techniques promote the development of precision nutrition. More trials and improved multi-omics systems are required to apply these research results in clinical practice.

ID: 42514135
Title: Maternal Microbiome in Gestational Diabetes Mellitus: Mechanisms, Biomarkers, and Therapeutic Perspectives.
Abstract: Gestational diabetes mellitus (GDM) is an increasingly prevalent metabolic disorder of pregnancy, driven by rising maternal age, obesity, and complex metabolic-inflammatory interactions. Emerging evidence implicates the maternal microbiome as a key modulator of metabolic adaptation during gestation; however, its precise role in GDM pathogenesis remains incompletely defined. This narrative review synthesizes current knowledge on microbiome alterations across gut, vaginal, and oral niches, focusing on their contribution to insulin resistance, metabolic endotoxemia, and immune dysregulation. GDM is consistently associated with reduced microbial diversity, depletion of beneficial taxa (e.g., Akkermansia, Bifidobacterium, Faecalibacterium), and expansion of pro-inflammatory pathobionts, which collectively may impair intestinal barrier integrity and promote low-grade systemic inflammation. These mechanisms are linked to altered insulin signaling and adverse maternal-fetal outcomes. In parallel, microbiome-derived metabolites and early taxonomic signatures have been proposed as potential biomarkers for first-trimester risk stratification, offering an opportunity to overcome the limitations of late diagnostic approaches such as the oral glucose tolerance test. Despite these advances, most available evidence remains associative, with substantial heterogeneity across studies and limited mechanistic validation. The clinical utility of microbiome-based interventions-including dietary modulation, prebiotics, and probiotics-remains promising but inconclusive, with outcomes highly dependent on individual, microbial, and methodological factors. Overall, the maternal microbiome represents a compelling but still evolving target in GDM research. Future progress will depend on standardized methodologies, longitudinal multi-omics studies, and the development of precision medicine approaches capable of integrating microbial, metabolic, and host data. Such advances may enable earlier diagnosis, targeted prevention, and ultimately the disruption of intergenerational metabolic risk.

ID: 42522048
Title: Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.
Abstract: Neuroinflammation is increasingly recognized as a key contributor and amplifier associated with the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Neuroinflammation occurs throughout various stages of these diseases with expanding complexity. Currently, no effective therapies exist that specifically target neuroinflammatory processes in these disorders. In this review, we synthesize current understanding of central and peripheral inflammatory mechanisms implicated in both diseases. We illustrate how endogenous pathological triggers, such as amyloid-β (Aβ) peptide, hyperphosphorylated tau, and α-synuclein, activate glial cells, contributing to chronic neuroinflammation that exacerbates neurodegeneration. Additionally, peripheral factors, including systemic inflammation, environmental exposures, and gut-brain axis interactions, are discussed for their roles in modulating neuroinflammatory responses. Notably, the underappreciated roles of oligodendrocyte precursor cells and oligodendrocytes in neuroimmune crosstalk are also highlighted. Advanced methodologies, including glial cell imaging, single-cell transcriptomics, and human induced pluripotent stem cell-derived organoid models, are providing unprecedented insights into the molecular and cellular mechanisms underlying neuroinflammation. Finally, we evaluate emerging therapeutic strategies and ongoing clinical trials targeting neuroinflammatory pathways and analyze the potential of immunomodulatory approaches to slow disease progression. This comprehensive review emphasizes that precise targeting of neuroinflammation represents a tractable strategy for developing effective disease‑modifying treatments for AD and PD.

ID: 42526737
Title: Cannabinoid receptor-mediated modulation of the gut-brain axis under chronic stress: Neuroinflammatory mechanisms, microbial metabolites, and sexual dimorphism.
Abstract: Chronic stress disrupts the gut-brain axis (GBA) through coordinated dysfunction of the intestinal barrier and of the vascular interfaces that protect the brain, fostering a neuroinflammatory state implicated in mood disorders, neuropsychiatric conditions, and chronic pain. This narrative review synthesizes evidence across five domains. First, the inflammatory cascade by which stress-induced disruption of the epithelial and gut vascular barriers activates the NLRP3 inflammasome and sustains central neuroinflammation. Second, microbial metabolites, namely short-chain fatty acids (SCFAs), tryptophan-kynurenine products, and indole derivatives, as modulators of gut-brain homeostasis. Third, the gut microbiome-endocannabinoidome axis, including the capacity of commensal bacteria to generate endocannabinoid-like N-acyl amides that engage host receptors. Fourth, the receptor-specific pharmacology of phytocannabinoids, distinguishing Δ9-tetrahydrocannabinol (THC), which acts principally at CB1 and CB2 with comparable affinity, from cannabidiol (CBD), which has low affinity for these receptors and signals mainly through TRPV1, TRPA1, GPR55, PPARs, and 5-HT1A. Fifth, sexual dimorphism in barrier vulnerability and treatment response. In rodent models, chronic stress reduces intestinal and blood-brain barrier tight junction expression, elevates circulating lipopolysaccharide, and activates the NLRP3 inflammasome, while tryptophan metabolism shifts toward neurotoxic kynurenine products. Cannabinoid modulation of the kynurenine pathway and cannabinoid-mediated restoration of blood-brain barrier integrity remain mechanistic hypotheses extrapolated from indirect evidence rather than demonstrated mechanisms in chronic psychological stress paradigms. Human data are largely limited to small trials of microbiota-targeted interventions and of CBD in anxiety, and to observational endocannabinoidome-microbiome studies. These observations provide a preclinical rationale for GBA-targeted pharmacological strategies, with translational claims explicitly separated from mechanistic plausibility.

ID: 42528156
Title: Decoding Akkermansia muciniphila Effector Biology: From Microbial Molecules to Host Outcomes.
Abstract: Akkermansia muciniphila is increasingly linked to host metabolic, immune, and neurobehavioral phenotypes, yet taxon-level associations are often inconsistent across studies and disease contexts. This review advances an effector-centered framework to explain how A. muciniphila acts through host-facing molecules, including outer membrane and secreted proteins such as Amuc_1100 (pilus-associated signaling, PAS) and P9, extracellular vesicles (EVs) and outer membrane vesicles (OMVs), and shed cell-envelope fragments and lipids. We synthesize evidence spanning barrier biology, immunometabolic regulation, infection and inflammatory injury, cancer immunology, and microbiota-gut-brain axis research. Across models, effectors modulate the mucus and epithelial barrier to limit translocation and dampen Toll-like receptor (TLR) signaling, but mucus-active enzymes or antigenic epitopes may also create liabilities in susceptible hosts. Defined effectors can reproduce key whole-cell effects: in high-fat diet (HFD)/carbon tetrachloride (CCl4) liver injury, vesicle preparations matched or exceeded pasteurized bacteria; Amuc_1100 maps to immune reprogramming and barrier signaling; and P9 links microbial cues to glucagon-like peptide 1 (GLP-1) release. Key gaps include physiological dose realism, equivalence across colony-forming units (CFU) and protein or vesicle doses, strain and culture-condition dependence of effector expression, and limited human data for brain-relevant endpoints. Effector-defined preparations and engineered delivery systems may improve standardization and safety, but translation will require rigorous characterization, dose-response validation, and mechanism-linked biomarkers.

ID: 42528699
Title: Gut-brain axis mechanisms of remote brain dysfunction after traumatic spinal cord injury: immune inflammation, the vagus nerve, and neuroendocrine pathways.
Abstract: Traumatic spinal cord injury (SCI) has traditionally been regarded as a central nervous system injury mainly confined to the injured segment. However, increasing evidence indicates that SCI can also induce neuroinflammation, cognitive decline, and emotional disorders in remote brain regions, suggesting that its pathological impact is systemic rather than purely local. Remote brain dysfunction after SCI is unlikely to be driven by a single pathway, but may arise from the combined effects of systemic inflammation, autonomic imbalance, neuroendocrine dysregulation, and disruption of intestinal homeostasis. Unlike previous reviews that mainly discuss SCI-associated gut dysbiosis, neuroinflammation, or gut-brain communication separately, this review organizes SCI-related intestinal abnormalities around the concept of "gut-derived pathological signals" and further distinguishes direct SCI evidence from cross-disease mechanistic evidence and proposed mechanistic inference. Specifically, we summarize how intestinal dysmotility, microbial metabolic remodeling, abnormalities in short-chain fatty acids (SCFAs), barrier vulnerability, and mucosal immune imbalance after SCI may generate persistent pathological signals. We then analyze how these signals may affect the central nervous system through an immune-inflammatory main axis, a vagal neural relay branch, and a neuroendocrine modulatory branch, ultimately converging on a common downstream brain effector stage characterized by blood-brain barrier impairment, neuroinflammation, synaptic plasticity deficits, and dysfunction of key brain regions such as the hippocampus and medial prefrontal cortex (mPFC). Based on this cascade, we propose a stratified intervention framework involving upstream restoration of intestinal homeostasis, midstream regulation of interorgan transmission pathways, and downstream protection of brain effector mechanisms. Overall, this review provides an evidence-stratified gut-brain axis framework for understanding remote brain dysfunction after SCI and highlights the need for SCI-specific temporal mapping and pathway-selective causal validation.

ID: 42529162
Title: Reframing brain aging: neuroinflammation as an interconnected network process.
Abstract: Neuroinflammation has emerged as a central component of brain aging, shaping the balance between neural resilience and vulnerability to cognitive decline. Rather than representing a simple consequence of neuronal damage, neuroinflammatory processes are increasingly recognized as active regulators of synaptic integrity, neuronal survival, and circuit function. Under physiological conditions, neuroimmune signaling may contribute to tissue homeostasis, synaptic maintenance, and adaptive responses to cellular stress; however, persistent or dysregulated inflammatory activity may disrupt these functions, promoting network instability and increasing vulnerability to age-related pathology. These processes arise from complex interactions among neurons, glial cells, vascular elements, and peripheral immune signals that together form dynamic neuroimmune networks. Within the aging brain, microglia and astrocytes play key roles in coordinating immune surveillance, synaptic remodeling, and inflammatory signaling. Age-related alterations in glial function can disrupt homeostatic communication within neuron-glia networks, promoting persistent low-grade inflammation and altered synaptic regulation. Importantly, neuroinflammatory activity in the brain is strongly influenced by systemic factors, including peripheral immune aging, changes in blood-brain barrier integrity, and signals originating from the gut-brain axis. In this mini-review, we discuss brain aging from a network perspective, emphasizing how multiscale interactions between cellular and systemic processes shape neuroinflammatory trajectories across the lifespan. We further highlight emerging approaches-including multi-omics technologies, advanced neuroimaging, and systems-level analyses-that are enabling a more integrated understanding of neuroinflammatory dynamics. Viewing neuroinflammation as a network phenomenon may provide new insights into mechanisms of cognitive aging and identify potential targets for strategies aimed at preserving brain health.

ID: 42531785
Title: Curdlan alleviates non-alcoholic fatty liver disease by enriching butyrate-producing gut microbiota-liver axis.
Abstract: The gut microbiota-liver axis is a critical target for non-alcoholic fatty liver disease (NAFLD) intervention, yet effective strategies to restore gut microbiota balance and mitigate hepatic metabolic inflammation remain limited. Curdlan, a Food and Drug Administration-approved microbial exopolysaccharide, is widely used as a food additive, but its role in modulating the gut-liver axis to combat NAFLD has never been explored. Here, we demonstrate that curdlan alleviates high-fat and fiber-deficient (HFFD) diet-induced NAFLD by orchestrating gut microbiota remodeling and enhancing gut-liver crosstalk associated with the enrichment of butyrate-producing bacteria. In the mouse model of NAFLD, curdlan significantly attenuated hepatic steatosis, inflammation, and M1 macrophage infiltration. Hepatic transcriptome analysis revealed that curdlan modulated immune response and metabolism pathways, as further evidenced by the improvement of the NFκB-PTP1B-Akt signaling axis. Crucially, curdlan reversed gut barrier disruption by enhancing tight junction proteins and enriching butyrate-producing genera (Clostridium_sensu_stricto_1, Anaerovorax, Roseburia, Turicibacter, and others), thereby increasing serum butyrate levels. Integrative correlation analysis revealed a significant correlation between butyrate-producing bacteria, increased serum butyrate levels, reduced serum lipopolysaccharide, and downregulated hepatic proinflammatory cytokines. Strikingly, Clostridium butyricum supplementation recapitulated the protective effects of curdlan, suggesting a role for butyrate in mediating gut-liver interactions. These findings establish curdlan as a novel prebiotic and metabolic modulator with therapeutic potential for NAFLD and support the translational application of functional food additives in metabolic disease management.

ID: 42531833
Title: Poricoic acid a ameliorates ulcerative colitis via AMPK/PPARγ pathway-dependent cellular senescence inhibition and concomitant gut microbiota-metabolome modulation.
Abstract: Ulcerative colitis (UC) is an intractable inflammatory bowel disorder characterized by persistent intestinal inflammation and impaired gut barrier integrity. Its pathogenesis is multifactorial, involving gut microbiota dysbiosis, metabolic dysfunction, and cellular senescence. Current therapeutic regimens remain limited, underscoring an urgent need for innovative agents that target these interrelated pathological cascades. This study aimed to evaluate the pharmacological effects of poricoic acid A (PAA) on DSS-induced senescence in intestinal epithelial cells and in a murine model of ulcerative colitis (UC), as well as the underlying molecular mechanisms. We established a DSS-stimulated senescent intestinal epithelial cell model and a DSS-induced UC mouse model. Multi-omics and bioinformatics strategies, including network pharmacology, transcriptome profiling, gut metagenomics, and intestinal targeted metabolomics, were combined with molecular docking to predict candidate signaling axes. Subsequent pharmacological inhibition and siRNA-mediated silencing assays were performed to validate core pathways functionally. PAA robustly suppressed DSS-induced senescence and inflammatory responses in intestinal epithelial cells. In vivo assays verified that PAA alleviated UC-related manifestations, including body weight loss, rectal hemorrhage, and colonic histological injury. Joint network pharmacology and transcriptomic screening identified the AMPK/PPARγ as the core pathway mediating PAA's bioactivity. Mechanistic experiments confirmed that PAA directly bound and activated PPAR, further functionally triggering downstream AMPK/SirT1/PGC1α signaling. Blockade of AMPK via pharmaceutical antagonists or siRNA largely abolished PAA's anti-senescence and anti-inflammatory capacities; PPARγ suppression, in turn, secondary deactivated the AMPK and its downstream functional effectors. In mouse models, AMPK inhibition drastically compromised PAA's protective effects against UC. Moreover, PAA treatment of UC is closely associated with remodeling of the gut microbiome-metabolome axis and restoration of intestinal homeostasis. PAA exerts potent anti-senescence, anti-inflammatory, and colon-protective effects in UC via activating the AMPK/PPARγ signaling pathway. Such beneficial activity may be associated with the normalization of gut microbiota-metabolome homeostasis. This work identifies novel molecular targets and a promising lead compound for the intervention of ulcerative colitis.

ID: 42532957
Title: Two Mechanisms One Molecule: Developing a 'Truly' Bifunctional Degrader Targeting Rpn13 and CRBN.
Abstract: Targeted protein degradation (TPD) has emerged as a powerful strategy to eliminate disease-relevant proteins, yet current approaches remain largely constrained to hijacking ubiquitin ligases. We previously introduced ByeTACs, bifunctional molecules that directly recruit proteins to the proteasome for E-ligase independent degradation. Here, we report "Truly" degraders, a new class of dual-mechanism molecules that combine a ligand for the proteasomal receptor Rpn13 with a ligand for cereblon (CRBN) to simultaneously engage both ubiquitin-independent and ubiquitin-dependent degradation pathways. Structure-guided design identified an optimal linker length that supports efficient substrate processing, with the PEG4 derivative (Truly-4) inducing robust depletion of both Rpn13 and CRBN in several cancer cell types. Remarkably, Truly-4 is the first noncovalent small molecule shown to degrade full-length Rpn13, a target previously approached using covalent or domain-restricted strategies. Mechanistic studies confirmed that degradation of Rpn13 proceeds via CRBN-dependent E3 ligase activity, whereas CRBN degradation occurs through an E-ligase independent process, consistent with a ByeTAC mechanism. Importantly, Truly-4 induces selective cytotoxicity in hematologic and solid cancer cell lines but not in healthy cells, despite comparable Rpn13 depletion, indicating that dual degradation can uncouple target engagement from toxicity. These findings establish a generalizable framework for engineering bifunctional degraders that program the proteasome to execute parallel degradation mechanisms and highlight proteasome receptors as druggable nodes for selective destruction of disease-relevant proteins.

ID: 42533008
Title: Isolation and preliminary characterization of a glucan-type exopolysaccharide produced by Bacillus tequilensis strain HH from Egyptian fermented cucumber.
Abstract: Exopolysaccharide (EPS) production is a common feature of microbial carbohydrate metabolism during fermentation; however, glucan-type EPS produced by Bacillus species in fermented vegetable systems remain insufficiently characterized. This study aimed to isolate an EPS-producing bacterium from naturally fermented cucumber and to perform a preliminary physicochemical and spectroscopic characterization of the produced polymer. An EPS-producing bacterial isolate was recovered and identified as Bacillus tequilensis, a member of the Bacillus subtilis species complex, based on 16 S rRNA gene sequence analysis. The extracellular polysaccharide was partially purified and analyzed using FTIR and ¹H NMR spectroscopy, revealing structural features consistent with a glucan-type EPS. Rheological analysis demonstrated a concentration-dependent increase in viscosity, confirming the macromolecular nature of the polymer in aqueous systems. Sucrose-hydrolyzing activity was detected under optimized conditions, indicating active carbohydrate metabolism associated with EPS production. In vitro cytocompatibility assessment using Vero and WI-38 cell lines showed high cell viability at low to moderate concentrations, with a dose-dependent reduction observed at higher levels. Overall, this study reports the isolation of an EPS-producing Bacillus tequilensis strain from Egyptian fermented cucumber and provides preliminary insights into the properties of its glucan-type exopolysaccharide, highlighting fermented vegetable microbiota as a potential source of functional biopolymers.

ID: 42533574
Title: Metabolomic insights into the response strategies of bats to high-glucose stimulation.
Abstract: Existing therapeutic options for diabetes remain limited, underscoring the urgent need to explore novel mechanisms for blood glucose regulation. Bats despite diverse dietary habits, making them ideal models for studying hypoglycemic mechanisms. In this study, we performed intraperitoneal glucose tolerance tests (IPGTTs) on five bat species three frugivorous or nectarivorous species (hereafter collectively referred to as frugivorous bats, given the high sugar content of both fruits and nectar) and two insectivorous species. A total of 704 known serum metabolites were analyzed quantitatively using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Compared with insectivorous bats, frugivorous bats exhibited significantly higher levels of amino acid-related metabolites under high-glucose stimulation. These included N-acyl amino acids, aromatic amino acid derivatives, and branched-chain amino acid metabolites, which were enriched significantly in pathways, such as alanine, arginine, and D-amino acid metabolism. Additionally, several known gut-brain axis (GBA) metabolites-such as neurotransmitters, bile acids, and short-chain fatty acids-exhibited strong host dietary and species specificity. Frugivorous bats were enriched in neurotransmitters and short-chain fatty acids associated with insulin regulation, whereas insectivorous bats exhibited relatively higher levels of bile acid metabolites. Overall, this study provides theoretical insights into the metabolic adaptations of frugivorous bats and the glucose-response strategies of insectivorous bats, offering new perspectives on metabolite-based therapeutic approaches to diabetes. 现有的糖尿病治疗手段仍然有限，亟需探索血糖调控的新机制。蝙蝠具有高度多样化的食性，且普遍表现出较长的寿命特征，这使其成为研究降血糖调控机制的理想模型。本研究对五种蝙蝠开展了腹腔葡萄糖耐量试验，其中包括三种食果或食蜜蝙蝠（鉴于水果和花蜜均具有较高的糖含量，下文统称为食果性蝙蝠）以及两种食虫蝙蝠。采用液相色谱-电喷雾电离-串联质谱技术（LC-ESI-MS/MS）对高糖刺激之下蝙蝠血清中共704种已知代谢物进行了定量分析。结果显示，在高糖刺激下，与食虫蝙蝠相比，食果蝙蝠体内多种氨基酸相关代谢物水平显著升高，主要类别包括N-酰基氨基酸、芳香族氨基酸衍生物以及支链氨基酸代谢物，这些代谢物显著富集于丙氨酸、精氨酸和D-氨基酸代谢等通路。此外，多种已知的肠-脑轴相关代谢物（如神经递质、胆汁酸和短链脂肪酸）表现出显著的宿主食性和物种水平的特异性——食果蝙蝠富集了更多的与胰岛素调控相关的神经递质和短链脂肪酸，而食虫蝙蝠则表现出水平相对更高的胆汁酸代谢物。总体而言，本研究为揭示食果蝙蝠的代谢适应机制及食虫蝙蝠的葡萄糖应答策略提供了更多理论依据，并为基于代谢物的糖尿病治疗策略提供了新的研究视角。.

ID: 42536279
Title: TRIM9-Mediated Degradation of SMAD4 Promotes Pyroptosis and Disruption of the Endothelial Barrier in Aortic Dissection Disease.
Abstract: Aortic dissection (AD) is a life-threatening cardiovascular disease with exceedingly high mortality, particularly during the acute phase. Ubiquitination modification is implicated in the pathogenesis of cardiovascular diseases through diverse biological processes. However, the role of TRIM9, an E3 ubiquitin ligase, in AD remains unexplored. In this study, the expression profiles of TRIM9 and SMAD4 were analyzed using clinical samples, as well as Angiotensin II (Ang II)-induced mouse and human aortic endothelial cell (HAEC) models. Endothelial barrier function in AD was assessed through CCK-8 assays, vascular permeability measurements, immunofluorescence staining, hematoxylin-eosin and Verhoeff's van Gieson staining, and Western blot analysis. The underlying molecular mechanisms were elucidated using quantitative real-time PCR, immunoprecipitation (IP), co-immunoprecipitation (Co-IP), and enzyme-linked immunosorbent assay (ELISA). TRIM9 was markedly overexpressed, whereas SMAD4 was significantly downregulated in AD. Knockdown of TRIM9 attenuated endothelial permeability, preserved the endothelial barrier integrity, and inhibited pyroptosis both in vivo and in vitro. Mechanistically, TRIM9 promoted the ubiquitination and subsequent proteasomal degradation of SMAD4, thereby exacerbating AD progression. Collectively, these findings demonstrate that elevated TRIM9 expression aggravates AD progression through SMAD4 destabilization, offering novel therapeutic insights for AD management.

ID: 42538615
Title: Pulp Callus Extract From Malus domestica var. Mela Rosa Marchigiana Preserves Intestinal Barrier Integrity and Confers Neuroprotection in a Gut-Brain Axis Co-Culture Model.
Abstract: The gut-brain axis is a key target in neuroinflammatory disorders. We investigated the protective effects of Mela Rosa Marchigiana pulp callus extract (MRME), a phytocomplex with a unique triterpenic profile. Using a validated transwell co-culture model of the intestinal-neural interface, differentiated Caco-2 cells formed a polarized epithelial barrier (apical), while BV2 microglia or SH-SY5Y neurons were seeded in the basolateral compartment. Apical MRME pretreatment preserved Caco-2 barrier integrity against lipopolysaccharide or dextran sodium sulfate-induced damage. MRME maintained occludin integrity and transepithelial electrical resistance (TEER), effectively neutralizing "leaky gut"-like conditions. By stabilizing the barrier, MRME exerted indirect neuroprotection since high-throughput live-cell imaging revealed dose-dependent reductions in reactive oxygen species generation and apoptosis (caspase-3/7 activation) in both BV2 and SH-SY5Y cells. MRME demonstrated a microbiologically neutral profile, exerting no inhibitory effects on either pathogenic or probiotic strains up to 10,000 μg/mL. MRME provides dual protection by strengthening the intestinal barrier and shielding the neural environment from systemic inflammation through host cellular modulation rather than microbial interference. These findings suggest MRME as a promising nutraceutical candidate for gut-brain axis dysregulation.

ID: 42540505
Title: Lactiplantibacillus plantarum Probio87 supplementation improves functional constipation and is associated with peripheral gene-expression responses related to inflammation and the gut-brain axis: a randomized, double-blind, placebo-controlled trial.
Abstract: Functional constipation is a common disorder of gut-brain interaction that substantially affects bowel function, psychological well-being, and quality of life. Probiotic supplementation represents a microbiota-targeted nutritional strategy for functional constipation, but associated host-response signals remain incompletely understood. This single-center, randomized, double-blind, placebo-controlled trial enrolled 104 adults who met the Rome IV criteria for functional constipation. Participants received either Lactiplantibacillus plantarum Probio87 or placebo for 8 weeks, followed by a 4-week post-intervention follow-up. The primary endpoint was weekly complete spontaneous bowel movements. Secondary outcomes included Rome IV symptom scores, PAC-QOL, HAMD-24, safety parameters, and exploratory whole-blood gene-expression profiles related to inflammation, immune regulation, neuroendocrine signaling, and gut motility. The trial was registered in the Chinese Clinical Trial Registry (ChiCTR2300075360). Probio87 supplementation significantly increased weekly complete spontaneous bowel movements compared with placebo at Week 8 and Week 12. Improvements were also observed in Rome IV symptom scores, constipation-related quality of life, and HAMD-24 domains related to anxiety, sleep, and retardation. Exploratory whole-blood gene-expression analysis showed differential host-response signals after intervention, characterized by increased BDNF expression and reduced expression of IL-1β, CD117, CXCR5, IDO1, DBH, and MLNR in the probiotic group relative to placebo. No intervention-related adverse events or clinically relevant abnormalities in hematological, hepatic, or renal safety parameters were observed. L. plantarum Probio87 supplementation was associated with sustained improvement in bowel function, constipation-related quality of life, and psychological well-being in adults with functional constipation. Exploratory peripheral gene-expression findings suggest that inflammatory, immune, neuroendocrine, and motility-related host-response pathways may be involved, although causal mechanisms require further validation. https://www.chictr.org.cn/showproj.html?proj=205514, identifier (ChiCTR2300075360).

ID: 42542543
Title: STIM1-mediated Treg instability in HFpEF: a new immunological target emerges?
Abstract: Heart failure with preserved ejection fraction (HFpEF) accounts for nearly half of all heart failure cases and remains a major unmet clinical challenge. Increasing evidence supports the view of HFpEF as a systemic inflammatory syndrome driven by aging and cardiometabolic comorbidities, including obesity, hypertension, and chronic kidney disease. Within this framework, regulatory T cells (Tregs), which are essential for maintaining immune tolerance and limiting excessive inflammation, have emerged as important modulators of disease progression. However, the mechanisms underlying Treg dysfunction in HFpEF have remained poorly understood. In this issue, Srinivas et al. identify stromal interaction molecule 1 (STIM1)-dependent calcium signaling as a critical regulator of Treg instability in HFpEF. The authors show that patients with HFpEF exhibit reduced circulating Treg numbers, increased STIM1 expression, and activation of endoplasmic reticulum stress, apoptotic, and inflammatory pathways. Using a cardiometabolic murine model and Treg-specific STIM1 knockout mice, they establish a causal role for Treg-intrinsic STIM1 signaling in disease development. These findings position STIM1 as a molecular link between cardiometabolic stress, immune dysregulation, and cardiac remodeling. They further support the concept that immune-cell plasticity is a major determinant of HFpEF pathogenesis and suggest that preserving Treg stability may represent a novel therapeutic strategy. Although important questions remain regarding disease timing, clinical translation, and sex-specific effects, this work advances our understanding of HFpEF as an immune-mediated disorder and identifies STIM1-dependent calcium signaling as a promising therapeutic target.

ID: 42543264
Title: [Saposhnikoviae Radix enhances resistance to respiratory tract infection by potentiating interferon signaling].
Abstract: This study aimed to investigate the immunopharmacological mechanism of Saposhnikoviae Radix(SR) against respiratory viruses and bacteria infections based on immune signal activation. Mouse models of pneumonia induced by intranasal influenza A virus(H1N1) infection and intratracheal lipopolysaccharide(LPS) instillation were established. The effects of the water extract of SR on pulmonary CT imaging, histological damage, and inflammatory cytokine expression in lung tissues were evaluated. Using bone marrow-derived macrophages, this study analyzed the regulatory effects of the extract on macrophage proliferation and phagocytic function. RNA-seq and bioinformatics analysis, combined with molecular biology experiments, were employed to explore the regulatory role of the water extract of SR on the type Ⅰ interferon(IFN-Ⅰ) signaling pathway. The findings revealed that the water extract of SR significantly alleviated H1N1 infection-induced lung imaging and pathological damage in mice, reduced lung viral gene copies, and downregulated the expression of inflammatory cytokines such as interleukin-6(IL-6), tumor necrosis factor-α(TNF-α), and CXC motif chemokine ligand 10(CXCL10). Concurrently, drug treatment demonstrated similar lung tissue protective functions in the LPS-induced mouse pneumonia model. Cell experiments showed that the extract promoted proliferation of macrophages and enhanced their phagocytic capacity toward neutral red. Transcriptomic analysis revealed that genes upregulated by the extract of SR were significantly enriched in pathways including H1N1 infection, Toll-like receptor signaling, NOD-like receptor signaling, and IFN signaling. Finally, qRT-PCR and Western blot confirmed that the extract activated the interferon signaling pathway. In conclusion, the extract of SR activates innate immunity centered on IFN-Ⅰ signaling and enhances macrophage function, thereby improving the host's defense against viral and bacterial infections. It possesses potential preventive and therapeutic value for respiratory tract infection-associated pneumonia and lung injury.

ID: 42543301
Title: [Comparative research on efficacy of high-pressure Schisandrae Chinensis Fructus decoction pieces and traditional decoction pieces on nonalcoholic fatty liver disease mice based on gut microbiota and metabolomics].
Abstract: This paper aims to evaluate the feasibility of clinical application of high-pressure Schisandrae Chinensis Fructus decoction pieces(HPSCH) compared with that of traditional Schisandrae Chinensis Fructus decoction pieces(SCH), based on the efficacy of mice with nonalcoholic fatty liver disease(NAFLD) induced by a high-fat diet. The optimal preparation process of HPSCH was investigated by using schisandrin content and total extractive yield as indices. After one week of adaptive feeding, C57BL/6 mice were assigned to a normal control group, while the remaining mice were fed an HFD for eight weeks to establish the NAFLD mouse model. After being successfully modeled, the mice were divided into a blank control group, blank administration group, simple model group, fenofibrate group, SCH group, and HPSCH group. All groups were administered by intragastric administration for four weeks. Body weight changes of mice were recorded, and liver indices were calculated. The levels of blood lipid and liver function index in the serum of mice were measured. Hepatic histopathological changes were observed by using hematoxylin-eosin(HE) staining and oil red O staining. Mice's feces were collected, and the 16S rDNA high-throughput sequencing method was employed to analyze changes in the gut microbiota of mice. Untargeted lipidomic analysis of the liver was conducted by using liquid chromatography-mass spectrometry(LC-MS), and principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA) were adopted to screen and identify differential metabolites. Kyoto Encyclopedia of Genes and Genomes(KEGG) database was used to perform relevant pathway analysis. Integrated analyses of gut microbiota and differential metabolites were performed to compare the similarities and differences in efficacy of HPSCH and SCH. The results show that both the HPSCH group and SCH group exert similar effects on biochemical indices in serum and hepatic pathological changes, lipid metabolism can be regulated, and liver injury in NAFLD mice can be improved. The two groups show similar changes in microbial abundance, trending toward the blank control group and maintaining intestinal homeostasis. Compared with those of the simple model group, the differential metabolites and metabolic pathways of both the HPSCH group and SCH group show similarity, and the differential metabolites are mainly triglycerides, diglycerides, phosphatidylcholines, phosphatidylglycerols, and so on. Metabolic pathways include glycerophospholipid metabolism, choline metabolism, retrograde endocannabinoid signaling, thermogenic lipolysis, and so on. This indicates that HPSCH and SCH share common advantages in improving hepatic function in mice and achieve comparable effects. HPSCH can improve blood lipid and liver function indices in NAFLD mice, attaining the therapeutic effect through the regulation of gut microbiota and lipid metabolism. Notably, HPSCH achieved the same efficacy as SCH at half the conventional dose, demonstrating its feasibility for clinical application. Moreover, the application of HPSCH may contribute to the conservation of medicinal resources.

ID: 42543314
Title: [Mechanistic study of Scutellariae Radix against atherosclerosis through inhibition of pyroptosis based on network pharmacology and experimental verification].
Abstract: This study systematically investigated the mechanism of Scutellariae Radix against atherosclerosis(AS) through the integrated application of network pharmacology, molecular docking, and animal experiments. A total of 34 active ingredients of Scutellariae Radix were screened from the TCMSP database, and 65 potential therapeutic targets were identified by combining SwissTargetPrediction and GEO data analysis. Protein-protein interaction(PPI) network construction, molecular docking, and Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analyses indicated that Scutellariae Radix might exert the anti-AS effect by modulating inflammatory responses, negatively regulating pyroptosis, and influencing the NOD-like receptor(NLRP) signaling pathway. In vivo, AS was induced in ApoE~(-/-) mice by 16-week high-fat diet feeding, followed by intervention with Scutellariae Radix extract. The results showed that Scutellariae Radix significantly attenuated lipid deposition and plaque area in the aortic wall, decreased serum levels of total cholesterol(TC), low-density lipoprotein cholesterol(LDL-C), and triglycerides(TG), and increased the high-density lipoprotein cholesterol(HDL-C) level, thereby improving lipid metabolism disorders. Meanwhile, it markedly inhibited the expression of proinflammatory cytokines tumor necrosis factor-α(TNF-α), interleukin(IL)-1β, and IL-6. In addition, Scutellariae Radix significantly suppressed nuclear factor-κB(NF-κB) phosphorylation and downregulated the protein expression of NOD-like receptor pyrin domain-containing protein 3(NLRP3), cleaved caspase-1, and the N-terminal fragment of gasdermin D(N-GSDMD), which suggested that Scutellariae Radix effectively inhibited pyroptosis in arterial tissues. Collectively, these findings suggested that Scutellariae Radix ameliorated AS by suppressing pyroptosis in arterial tissues, attenuating inflammation, and improving lipid metabolism via regulating the NLRP3/caspase-1/GSDMD signaling pathway.

ID: 42543363
Title: [Huangqin Qingre Chubi Capsules alleviate rheumatoid arthritis by inhibiting entry of intestine-derived LPS into bloodstream and blocking M1 macrophage-FLS cell communication].
Abstract: This study aimed to investigate the therapeutic effect of Huangqin Qingre Chubi Capsules(HQC) on rheumatoid arthritis(RA) and the mechanism of inhibiting RA macrophage polarization by reducing the entry of intestine-derived lipopolysaccharide(LPS) into the bloodstream. ELISA and 16S rRNA analysis were used to assess the inhibitory effect of HQC on LPS in the intestinal contents of mice in vivo. The effect of HQC on macrophage proliferation was detected by CCK-8 assay to determine the appropriate dose of drug-containing serum. RT-qPCR and immunofluorescence assay were used to detect the expression of genes related to macrophage polarization. Transcriptomics was used to predict the biomolecular function of macrophages upon LPS stimulation, and molecular docking was utilized to verify the binding of key HQC components to Wnt family member 7b(Wnt7b). Following co-culture of macrophages with fibroblast-like synoviocytes(FLS), RT-qPCR, Western blot, scratch assay, flow cytometry, and immunofluorescence assay were employed to investigate the regulatory mechanism of HQC on M1 macrophage-FLS communication via the Wnt/β-catenin signaling pathway. The results showed that LPS was highly expressed in the intestinal contents of collagen-induced arthritis(CIA) model mice, and HQC administration exhibited a negative correlation with this expression. M1 macrophages promoted the expression of inflammatory factors such as inducible nitric oxide synthase(iNOS), tumor necrosis factor-α(TNF-α), and interleukin-6(IL-6), and also increased oxidative activity; these effects could be reversed by HQC. Transcriptomic analysis predicted that the Wnt/β-catenin signaling pathway was highly correlated with the effect of HQC on macrophage polarization in RA treatment. HQC-containing serum inhibited FLS migration, promoted apoptosis, and suppressed the expression of key genes in the Wnt signaling pathway, including c-Myc, CCND1, and β-catenin. Molecular docking indicated strong binding affinity between key components of HQC and Wnt7b. Overexpression of Wnt7b in macrophages, followed by co-culture with FLS, significantly interfered with the therapeutic effects of HQC. These findings demonstrated that HQC alleviates RA by inhibiting the entry of intestine-derived LPS into the bloodstream, thereby blocking M1 macrophages-FLS communication.

ID: 42543530
Title: Impact of 3-day turmeric supplementation on fasting and postprandial LPS and chylomicron-related markers in patients with IBS: A randomized crossover trial.
Abstract: Lipopolysaccharide (LPS) has been implicated in increased gut permeability and low-grade mucosal inflammation, conditions that are linked to the pathophysiology of irritable bowel syndrome (IBS). Because increased dietary fat intake can both trigger IBS symptoms and promote LPS translocation in the gut, this study aimed to better understand how a turmeric formula (TF) affects fasting and postprandial LPS response, after a high-fat challenge in patients with IBS (primary outcome). Secondary outcomes included postprandial ApolipoproteinB48 (Apo-B48) and triglycerides (TG) as markers of chylomicron-mediated LPS translocation, as well as gastrointestinal (GI) symptoms and stool pattern. In this randomized, double-blind, placebo-controlled cross-over trial, eighteen patients with IBS completed two high-fat challenge tests after 3-day supplementation with either 300 mg TF or placebo. Blood was collected in the fasting state and up to 5 hours postprandially. Data were analyzed using repeated measures mixed models. TF did not significantly alter postprandial LPS levels compared with placebo but significantly reduced postprandial Apo-B48 and TG (mean ratios 0.82 and 0.87, p=0.04 and p=0.01, respectively). Fasting LPS and TG showed a non-significant reduction after TF (mean ratios 0.79 and 0.87; both p=0.06, respectively). No differences were observed in gastrointestinal symptoms or stool characteristics. To conclude, TF did not influence dietary fat-mediated LPS translocation, but it reduced postprandial chylomicron markers, indicating a potential attenuation of chylomicron-mediated postprandial inflammation. Together with the observed trend towards reduced fasting LPS levels, these findings suggest that TF might have beneficial effects on low-grade subclinical inflammation, which could be relevant for IBS patients.

ID: 42544276
Title: Magnolia biondii-Derived Exosome-Like Nanoparticles Ameliorate Ulcerative Colitis by Suppressing Inflammation, Reducing Oxidative Stress, and Modulating Gut Microbiota.
Abstract: Ulcerative colitis (UC) is a chronic, relapsing inflammatory bowel disease with limited treatment options and suboptimal remission rates. Plant-derived exosome-like nanoparticles have emerged as promising therapeutic agents due to their natural origin, biocompatibility, and capacity to deliver bioactive cargo. This study aimed to isolate exosome-like nanoparticles from the decoction of Magnolia biondii flower buds (Xinyi) (MFELNs) and evaluate their therapeutic potential in a murine model of UC. MFELNs were isolated from Xinyi decoction using differential centrifugation and ultracentrifugation. MFELNs were characterized by transmission electron microscopy, nanoparticle size and potential analysis, and metabolomic profiling. The in vitro antioxidant activity was assessed by DPPH scavenging and intracellular ROS suppression assays. Anti-inflammatory effects were evaluated in LPS-stimulated RAW 264.7 macrophages by measuring cytokine expression and macrophage polarization via flow cytometry. The promotion of cell migration was assessed in NIH3T3 cells by scratch assay. UC was induced in C57BL/6 mice using dextran sodium sulfate (DSS), and MFELNs were orally administered daily for 14 days. Disease activity index, colon length, histopathology, colonic cytokine expression, and gut microbiota composition were evaluated. Bioinformatics analysis, molecular docking, and Western blot were performed to elucidate the underlying molecular mechanisms. MFELNs exhibited typical exosome-like morphology with a size of 66.7 ± 1.3 nm and a negative surface charge. Metabolomic profiling revealed enrichment in flavonoids, alkaloids, lignans, and phenolic acids. MFELNs demonstrated satisfactory biocompatibility and gastrointestinal stability. In vitro, MFELNs scavenged DPPH radicals, suppressed H2O2-induced ROS generation, downregulated LPS-induced pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), restored IL-10 expression, and promoted macrophage polarization from M1 to M2 phenotype. In vivo, MFELNs attenuated DSS-induced body‑weight loss, reduced DAI scores, prevented colon shortening, and alleviated histopathological damage. MFELNs downregulated colonic pro-inflammatory cytokines and restored IL-10 expression. Gut microbiota analysis revealed that MFELNs restored the DSS-elevated Firmicutes/Bacteroidota ratio without significantly affecting α-diversity. Bioinformatics screening identified four potential bioactive components (sesamin, litsoeine/laurotetanine, demethylwedelolactone, and armepavine) that target SRC. Molecular docking demonstrated favorable binding between these components and SRC, while Western blot confirmed that MFELNs suppressed the SRC/NF-κB signaling pathway. MFELNs represent a novel class of decoction-derived exosome-like nanoparticles that ameliorate UC through integrated anti-inflammatory, antioxidant, and microbiota-modulating mechanisms. Their therapeutic effects are mediated, at least in part, through suppression of the SRC/NF-κB signaling pathway. These findings position MFELNs as a promising natural nanotherapeutic strategy for UC and support the concept that self-assembled nanoparticles formed during herbal decoction constitute an important material basis for the efficacy of traditional Chinese herbals.

ID: 42544450
Title: Gene dosage imbalance disrupts systemic metabolism in the Dp16 Down syndrome mouse model.
Abstract: Gene dosage imbalance resulting from an extra copy of human chromosome 21 (Hsa21) contributes to numerous clinical features in Down syndrome (DS). While dysregulated metabolism has long been noted in DS, the underlying cause is poorly understood and vastly understudied. To fill this critical knowledge gap, we conducted a comprehensive metabolic analysis of Dp(16)1Yey/+mice (abbreviated Dp16), a segmental duplication model carrying ~58% of the triplicated Hsa21 gene orthologs. Our multi-tissue transcriptomic analyses reveal shared and sex-specific increases in expression dosage of the triplicated genes in white and brown adipose tissues, liver, skeletal muscle, and hypothalamus. Despite sexual dimorphism in body weight, body temperature, food intake, and physical activity, Dp16 males and females share striking core phenotypes of pronounced insulin resistance, glucose intolerance, impaired lipid clearance, and dyslipidemia. Functional assessments, combined with biochemical, transcriptomic, and metabolomic analyses reveal tissue signatures of immune activation and a pro-inflammatory state, ER and oxidative stress, fibrosis, impaired glucose and fatty acid catabolism, altered lipid and bile acid profiles, and reduced mitochondrial respiratory capacity in Dp16 mice. These concerted changes disrupt homeostatic mechanisms that underpin metabolic health, contributing to systemic metabolic dysfunction. An obesogenic diet further exacerbates insulin resistance in Dp16 males and females despite divergent weight gain. The collective phenotypes broadly reflect the metabolic profile of DS. Our extensive molecular, biochemical, and physiological data provide an essential foundation for genetic dissection of dosage-sensitive genes affecting glucose and lipid metabolism, and for testing therapeutic strategies to improve metabolic outcomes in DS.