ID: 39911696
Title: Reshaping lipid metabolism with long-term alternate day feeding in type 2 diabetes mice.
Abstract: Strategies to improve metabolic health include calorie restriction, time restricted eating and fasting several days per week or month. These approaches have demonstrated benefits for individuals experiencing obesity, metabolic syndrome, and prediabetes. However, their impact on established diabetes remains incompletely studied. The chronicity of type 2 diabetes (T2D) requires that interventions must be undertaken for extended periods of time, typically the entire lifetime of the individual. In this study, we examined the impact of intermittent fasting (IF), with an every-other-day protocol for a duration of 6 months in a murine model of T2D, the db/db (D) mouse on metabolism and liver steatosis. We compared D-IF mice with diabetic ad-libitum (AL; D-AL), control-IF (C-IF) and control-AL (C-AL) cohorts. We demonstrated using lipidomic, microbiome, metabolomic and liver transcriptomic studies that chronic IF improved carbohydrate utilization and glucose homeostasis without weight loss and reduced white adipose tissue inflammation and significantly impacted lipid metabolism in the liver. Microbiome studies and predicted functional analysis of gut microbiota showed that IF increased beneficial bacteria involved in sphingolipid (SL) metabolism. The metabolomic studies showed that oxidation of lipid species and ceramide levels were reduced in D-IF compared to D-AL. The liver lipidomic analysis and liver microarray confirmed a reduction in overall lipid content in D-IF mice compared to D-AL mice, especially in the feeding state as well as an overall reduction in oxidized lipids and ceramides. These studies support that long-term IF can improve glucose homeostasis and dramatically altered lipid metabolism in the absence of weight loss.

ID: 40570250
Title: Plasma Sphingolipids in Relation to Glycemia and Glucose Tolerance in People Without Diabetes.
Abstract: Sphingolipids have been linked to the pathogenesis of type 2 diabetes. To examine the association of plasma sphingolipids with glycemic measures in adults without diabetes. Plasma sphingolipid species (ceramides, monohexosyl ceramides, lactosyl ceramides, sphingomyelins, and sphingosines) were assayed using liquid chromatography tandem mass spectrometry in baseline specimens obtained from participants in the Pathobiology of Prediabetes in a Biracial Cohort study (n = 240) and the Diabetes Prevention Program (n = 280). Based on oral glucose tolerance tests, we identified participants with (1) normal fasting plasma glucose (NFG) (<100 mg/dL) and normal glucose tolerance (NGT) [2-hour plasma glucose (2hPG) < 140 mg/dL]; (2) impaired fasting glucose (IFG; 100-125 mg/dL) with normal 2hPG; (3) impaired glucose tolerance (IGT) (2hPG 140-199 mg/dL with NFG); and (4) IFG and IGT. The participants (63% female; 48% Black, 52% White) had a mean age of 45.5 ± 9.84 years, body mass index (BMI) 32.4 ± 7.24 kg/m2, fasting plasma glucose (FPG) 99.8 ± 10.5 mg/dL, and 2hPG 145 ± 29.4 mg/dL. FPG and 2hPG levels correlated positively with ceramides, sphingomyelins, and sphingosine and inversely with monohexosyl ceramides, lactosyl ceramides, and sphingosine-1 phosphate levels, adjusted for age, sex, race, and BMI. Plasma ceramides, sphingomyelins, and sphingosine increased progressively across participants with NFG-NGT, isolated IGT, and IFG-IGT, whereas the opposite was seen for monohexosyl ceramides, lactosyl ceramides, and sphingosine-1 phosphate levels (ANOVA P < .0001). Circulating levels of major sphingolipid species are significantly associated with glycemia and glucose tolerance, indicating a possible link between sphingolipid metabolism and glucoregulation in people without diabetes.

ID: 41344402
Title: Modulation of ceramides through nutrition: A new target in obesity and insulin resistance (Narrative Review).
Abstract: Ceramides (Cer) are signaling sphingolipids that participate in insulin signaling, mitochondrial integrity, and inflammation. In obesity and insulin resistance (IR), Cer biosynthesis is exacerbated, leading to metabolic dysfunction and chronic diseases. This narrative review synthesizes current evidence on how Cer metabolism can be modulated through dietary components and dietary patterns, with emphasis on lipidomic analyses. The synthesis and accumulation of Cer are influenced by dietary abundance and quality, such as carbohydrates, fat and phenolic compounds. High-fructose corn syrup and saturated fatty acids promote Cer accumulation and IR, while monounsaturated and polyunsaturated fatty acids-abundant in the Mediterranean and Nordic diets-attenuate these effects. Polyphenol-rich foods and caloric restriction may also reduce Cer concentrations and improve metabolic markers. The emerging evidence from lipidomic analyses is expanding our knowledge on the role of diet in Cer modulation. Nutritional strategies targeting ceramide metabolism represent a promising approach to improve metabolic health. Beyond their therapeutic potential, ceramides also emerge as dynamic lipidomic biomarkers capable of reflecting early metabolic changes and monitoring the efficacy of nutritional interventions.

ID: 41390113
Title: Arsenic exposure, arsenic metabolism, and plasma lipidome in relation to type 2 diabetes and glycemic traits: a lipidome-wide association study.
Abstract: Both arsenic exposure and lipid metabolism disturbances are implicated in type 2 diabetes (T2D), whereas arsenic-associated lipidomic alterations and their contributions to T2D remain unclear. To map the plasma lipidomic profiles of incident T2D, glycemic traits, and arsenic exposure/metabolism, and to assess the mediating roles of lipids in arsenic-related diabetogenesis. A nested case-control study of 92 incident T2D cases and 184 controls was conducted within an urban adult-based prospective cohort. Plasma lipidome and urinary arsenic species (As3+, As5+, MMA, DMA, and AsB) were measured. Orthogonal partial least squares-discriminant analysis, t-test, and conditional logistic regression were applied to identify T2D-associated lipids, while partial least squares regression, t-test, and linear regression were conducted to identify glycemic traits- and arsenic-associated lipids. Mediation analyses quantified lipid-mediated effects. Several arsenic exposure indicators (tAs, iAs, As3+, As5+, and DMA) were associated with increased T2D incidence (odds ratios [ORs]: 1.37-1.76), whereas metabolism indices (MMA% and primary methylation index [PMI]) showed protective associations with T2D (ORs: 0.59-0.61) and improved glucose homeostasis. We identified 163 T2D-associated lipids, characterized by increased triacylglycerols (TGs) and diacylglycerols (DGs) but reduced lysophosphatidylcholines, sphingomyelins (SMs), and hexosylceramides. Most TGs, DGs, and ceramides (Cers) were positively associated with fasting plasma insulin and HOMA-IR. Arsenic exposure was associated with higher TGs but lower DGs, Cers, and SMs. Efficient arsenic metabolism (higher DMA% and secondary methylation index [SMI]) was positively associated with most lipids, whereas MMA% and iAs% were inversely associated. Mediation analyses revealed 19 (mainly TGs/DGs), 16 (mainly SMs/phosphatidylcholines), and 35 (mainly TGs/Cers) lipids that partially mediated arsenic exposure-T2D, arsenic metabolism-T2D, and arsenic metabolism-insulin resistance associations, respectively, with mediation proportions of 11.4%-54.7%. Arsenic exposure and metabolism are associated with distinct lipidomic profiles that may precede T2D onset. Specific lipids partially mediated arsenic-related diabetogenic effects, providing candidate biomarkers and intervention targets.

ID: 41727679
Title: Biliopancreatic diversion with duodenal switch improve polycystic ovary syndrome with decreased serum ceramides.
Abstract: Polycystic ovary syndrome (PCOS) is characterized primarily by insulin resistance and reproductive disorders. Biliopancreatic diversion with duodenal switch (BPD/DS) could significantly improve insulin sensitivity with significantly elevated level of bile acids. We aimed to explore changes in PCOS manifestations after BPD/DS and the possible mechanisms. Twenty PCOS rat models were assigned into the BPD/DS group and the sham BD (S-BPD) group randomly. The fasting blood glucose, bile acids, and ceramides levels in serum samples were assessed. The reproductive disorders of BPD/DS group were almost completely restored 8 weeks after surgery, and the AUCOGTT value and the AUCITT value were statistically less than those of the S-BPD group (P =0.001). The concentration of serum testosterone, luteinizing hormone, and follicle-stimulating hormone of the BPD/DS group was statistically less than that of the S-BPD group (P <0.05). Moreover, high level of bile acids and low level of ceramides were observed in the BPD/DS group (P <0.001). Bile acid sequestrant was given to the BPD/DS group rats for 1 week, the level of bile acids decreased and ceramides increased, the insulin resistance worsened. The AUCOGTT value increased from 818.3 ± 297.3 mmol/L·min to 1147.9 ± 167.9 mmol/L·min (P =0.007) and the AUCITT value increased from 525.6 ± 52.3 mmol/L·min to 577.7 ± 102.9 mmol/L·min (P =0.023). Our study showed the improvement of insulin resistance in PCOS models after BPD/DS with decreased serum ceramides. The sequestrant of bile acid reversed the improvement of insulin resistance with higher ceramides level.

ID: 41793053
Title: Molecular Mechanisms of Lipid-Modifying Enzymes in Cellular Adaptation and Systemic Glucose Homeostasis.
Abstract: Lipid-modifying enzymes dynamically regulate membrane architecture, signaling compartmentalization, and inter-organ metabolic communication, thereby influencing systemic glucose homeostasis. Advances in lipidomics and structural enzymology reveal how enzymatic remodeling of phospholipids, sphingolipids, and acyl chains governs insulin receptor organization, PI3K-AKT signaling, and GLUT4 trafficking. Dysregulated lipid flux mediated by factors such as FABP4, ceramides, and diacylglycerols disrupts membrane microdomains, impairs β-cell function, and promotes hepatic gluconeogenesis and skeletal muscle insulin resistance. Conversely, omega-3 polyunsaturated fatty acids enhance membrane fluidity and anti-inflammatory signaling. Integrating lipid enzymology with metabolic physiology establishes a unified mechanistic framework linking membrane remodeling to insulin responsiveness and diabetes pathogenesis.

ID: 42039969
Title: Intermittent fasting ameliorates diabetes-induced meibomian gland dysfunction in mice.
Abstract: To investigate the effect of intermittent fasting (IF) on diabetes-induced meibomian gland dysfunction (MGD) in a mice model. The diabetic mice underwent an 8-week dietary intervention of ad libitum (AL) and IF diet. Meibomian gland (MG) proliferative potential, apoptosis, and ductal hyperkeratinization were assessed using immunofluorescence. Gene expression levels were evaluated by Western blot. Lipid accumulation was observed via LipidTox staining. Transmission electron microscopy (TEM) examined intracellular lipids and mitochondrial ultrastructure in acinar cells. Lipidomic and transcriptomic analyses compared MG gene expression and lipid profiles between groups. IF ameliorated diabetes-induced MGD. IF significantly improved diabetic MG proliferation, apoptosis and lipid metabolism imbalance, as well as improved the expression of the genes involved in lipid metabolism. Simultaneously, the results of lipidomics indicated that IF can effectively modify the types and content of lipids, especially ceramides and cholesterol esters. Transcriptomic results suggested that IF effectively ameliorated cell death and modulated ion channels signaling. IF could ameliorate cell death which might be mediated by the calcium ion signaling pathway to mitigate diabetes-induced MGD. These results provide direct evidence for the feasibility of dietary intervention to improve diabetes-induced MGD. IF can alter MG lipid composition and inhibit apoptosis in diabetic condition. The underlying mechanism may be associated with calcium ion signaling pathway.

ID: 42282667
Title: Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling.
Abstract: Adipocyte lipid metabolism is coordinated by circadian rhythms, diet, and environmental temperature. Yet how these diverse signals are molecularly integrated remains unknown. Here we show that clock, diet, and temperature cues converge on the orphan mitochondrial transporter, SLC25A34, to orchestrate thermogenic cycling of lipid synthesis and oxidation. During sleep, the clock suppresses Slc25a34 transcription through REV-ERBα. Waking, lipid-rich diets, or cold exposure abolish this repression, allowing lipolytic signals to stimulate Slc25a34 expression via PPARα. SLC25A34 then imports oxaloacetate into mitochondria to accelerate the export of substrates used for acetyl-CoA production in the cytosol. This feeds into cytosolic lipid synthesis and transcriptional induction of mitochondrial biogenesis, which collectively promote mitochondrial lipid oxidation. Thus, SLC25A34 confers circadian, dietary, and environmental control of thermogenic metabolism through interorganellar lipid cycling.

ID: 42425963
Title: Caloric restriction improves glycemic control via the adiponectin-ceramide axis in non-obese men and women: the CALERIE™ 2 randomized controlled trial.
Abstract: Caloric restriction (CR) improves metabolic health across species, but the molecular mediators of its effects in humans remain incompletely defined. In a 24-month non-blinded randomized controlled trial (Clinicaltrial.gov: NCT00427193) of non-obese (BMI 22-27.9 kg/m2) men and premenopausal women aged 21 to 50 years, we assessed prespecified outcomes. Participants were randomized to an ad libitum or CR diet. We found that CR was associated with increased high-molecular-weight (HMW) adiponectin and reduced circulating ceramide species implicated in insulin resistance, including C16:0, C18:0, and C24:0. Mediation analysis indicated that reductions in ceramides were statistically compatible with partial mediation of the CR-associated improvements in insulin secretion, insulin sensitivity, and IGF-1 signaling markers. These effects were most pronounced at 12 months and attenuated by 24 months, suggesting partial metabolic adaptation over time. Overall, our findings are consistent with a model in which CR remodels bioactive lipid profiles and may enhance glucose metabolism in part through an adiponectin-ceramide-linked mechanism, highlighting a potential therapeutic axis for enhancing metabolic health.

ID: 42439678
Title: Follistatin Mitigates Atherosclerosis Through Activation of Arginine Metabolism and Adipose Browning.
Abstract: Follistatin (FST) binds to and neutralizes members of the transforming growth factor-beta (TGF-β) 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-α) 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.

ID: 42462036
Title: Restored clearance of senescent neutrophils by tissue-resident macrophages limits organ aging.
Abstract: 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.

ID: 42479460
Title: Efferocytosis activates a DNMT3A-mediated oxidized DNA repair pathway to enable tissue resolution.
Abstract: Efferocytosis, the clearance of apoptotic cells by macrophages, promotes tissue resolution. Efficient resolution requires efferocytosis-induced macrophage proliferation (EIMP) to expand pro-resolving macrophages. Here, we show that efferocytosis activates base excision repair (BER) to remove 8-OHdG from DNA, enabling EIMP. Mechanistically, efferocytosis promotes poly(ADP-ribose) polymerase-1 (PARP1) chromatin binding and PARylation to facilitate DNA repair complex assembly, and increases nuclear MTH1/NUDT1, which hydrolyzes 8-OHdG. Both processes require DNA-methyltransferase-3A (DNMT3A), which is activated during efferocytosis. Using a model where dexamethasone-induced thymocyte apoptosis triggers efferocytosis-mediated thymic repair, we showed that DNMT3A is required for increases in nuclear PARP1/MTH1, oxidized DNA suppression, EIMP in thymic macrophages, and thymic repair. We next studied a human-relevant model of atherosclerosis regression, where efferocytosis drives protective lesional fibrous cap thickening. We compared WT mice with a model of DNMT3A-clonal hematopoiesis (CH), in which loss-of-function DNMT3A mutations promote atherosclerotic disease. Atherosclerosis regression in WT mice led to decreased nuclear 8-OHdG and increases in nuclear PARP1/MTH1 and EIMP in lesional macrophages and fibrous cap thickening, all of which were impaired in DNMT3A-CH regression. These findings reveal that efferocytosis initiates a BER pathway to allow macrophage proliferation for tissue resolution, with possible therapeutic relevance to atherosclerosis regression and DNMT3A-CH.

ID: 42511292
Title: Combined Supplementation of Rumen-Protected Algae Powder and Rumen-Protected Choline Increases Docosahexaenoic Acid Content in Goat Milk.
Abstract: Docosahexaenoic acid (DHA) is an essential omega-3 polyunsaturated fatty acid with important health benefits. However, DHA enrichment in ruminant milk is limited by inefficient post-absorptive transport. This study evaluated whether combined supplementation of rumen-protected algae powder (RPA) and rumen-protected choline (RPC) enhances DHA enrichment in goat milk. Nine lactating dairy goats were assigned to three groups (n = 3/group) for 28 days: RPA alone, RPA + low-dose RPC (5 g/d), and RPA + high-dose RPC (10 g/d). Milk DHA content, bioconversion efficiency, serum biochemical parameters, and lipid profiles were analyzed. Compared with RPA alone, low- and high-dose RPC increased milk DHA content to 27.98 and 33.50 mg/100 mL, respectively, representing increases of 23.0% and 47.3%, and enhanced DHA bioconversion efficiency to 20.66% and 24.29% compared with 16.86% in the RPA group. RPC supplementation increased serum VLDL and triglyceride concentrations, and lipidomics revealed increased DHA-containing triglycerides (TG-DHA). These findings suggest that RPC may enhance DHA enrichment in goat milk by promoting VLDL-mediated DHA transport. Further studies with larger animal populations are required to confirm these effects. These findings contribute to a better understanding of nutritional regulation of DHA transfer and provide insights into strategies for developing DHA-enriched dairy products.

ID: 42514304
Title: Olive Oil as a Modulator of Gut Microbiota and Intestinal Health: A Narrative Review from Microbial Metabolism to Host Responses.
Abstract: Olive oil, particularly virgin (VOO) and extra-virgin olive oil (EVOO), is a central component of the Mediterranean diet and has been associated with cardiometabolic, anti-inflammatory, and intestinal health benefits. Increasing evidence suggests that these effects may involve interactions with the gut microbiota, intestinal barrier, and host inflammatory pathways. This narrative review summarizes current evidence on the impact of olive oil, olive-derived phenolics, and olive oil-rich dietary patterns on gut microbiota modulation, barrier function, inflammatory bowel diseases, and related systemic outcomes. The available literature indicates that olive oil may interact with the gut ecosystem through both its oleic acid-rich lipid matrix and its minor phenolic fraction. VOO and EVOO appear more consistently associated than refined oils with microbial or microbial metabolite profiles related to saccharolytic metabolism, short-chain fatty acid production, mucus-layer dynamics, and anti-inflammatory intestinal environments. Olive-derived phenolics, including hydroxytyrosol, tyrosol, oleuropein derivatives, and oleocanthal, can undergo microbial biotransformation and may influence bile acid metabolism, epithelial barrier integrity, and inflammatory signaling. Whole EVOO evidence is strongest in experimental colitis models, whereas human evidence mainly supports effects on postprandial endotoxemia, lipid oxidation, and selected inflammatory markers. However, findings remain heterogeneous and depend on oil quality, phenolic composition, comparator fat, dietary context, and host condition. Well-controlled human studies directly comparing EVOO, VOO, refined olive oil, and oleic acid-rich controls are needed to clarify reproducible microbiota-mediated effects and their relevance to intestinal and systemic health.

ID: 42528838
Title: The diet-microbiota-inflammation axis and colorectal cancer.
Abstract: Colorectal cancer (CRC) is still one of the leading causes of cancer morbidity and mortality worldwide. There is increasing evidence that diet, gut microbiota, microbial metabolites and chronic inflammation are important factors in colorectal carcinogenesis and may provide novel opportunities for prevention, diagnosis and treatment. To provide a comprehensive review of the current evidence on the role of diet, nutrition, microbial metabolism and chronic inflammation in CRC, with emphasis on emerging translational applications including microbiome-based biomarkers and microbiota-targeted therapeutic strategies. A literature search was performed with PubMed, Scopus and the Cochrane Library. Relevant studies on diet-microbiota interactions, microbial metabolites, inflammatory mechanisms, colorectal carcinogenesis, microbiome-derived biomarkers, and microbiota-targeted interventions were identified and reviewed. Preclinical and clinical studies and high quality reviews and meta-analyses were considered. Dietary patterns have been shown to have a major impact on the composition and function of the gut microbiota. Rich-fiber diets and short-chain fatty acids (SCFAs) production seem protective against CRC, while western dietary patterns, ultra-processed foods and dysbiosis-associated metabolites promote a pro-inflammatory environment associated with carcinogenesis. Some microorganisms such as Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis and pks-positive Escherichia coli have been associated with CRC by inflammatory, genotoxic and immune-modulatory mechanisms. Recent advances in sequencing technologies and multi-omics approaches have enabled the identification of microbial signatures with potential diagnostic and prognostic value. Moreover, microbiota-targeted interventions such as probiotics, prebiotics, postbiotics, faecal microbiota transplantation, and next-generation microbial therapies have yielded promising preclinical and early clinical results. The diet-microbiota-inflammation axis is a key player in colorectal carcinogenesis and a promising target for translational research. Microbiome-based biomarkers and microbiota-targeted therapies may have a role in future precision prevention and personalised management strategies of colorectal cancer despite significant challenges in terms of causation, standardisation and translation into clinical practice.

ID: 42544286
Title: Can increasing footwear bending stiffness ameliorate age-related mechanical and metabolic deficits in walking?
Abstract: Older adults consume metabolic energy faster than their younger adult counterparts while walking, particularly on sloped terrain. This increased rate is likely in part due to an age-related shift in moment and power production from the ankle joint to the hip. Shifting these mechanics proximally may occur due to older adults losing more mechanical energy at the foot and producing lower ankle joint moments, deficits that are exaggerated when walking uphill or against impeding forces. A promising method to target some of these foot and ankle mechanics differences is increasing footwear longitudinal bending stiffness via carbon fiber insoles. We examined how increasing footwear stiffness alters older adult (9F/10M, 70 ± 5.9 yrs) walking energetics across slopes. Increasing footwear stiffness reduced the magnitude of negative power from the foot+shoe structures distal to the forefoot, but increased negative power of the foot+shoe structures distal to the hindfoot (foot+shoe complex as a whole). At the ankle, peak joint moment increased by ∼10% in the stiffest footwear compared with the baseline standardized shoe. Neither knee and hip mechanics nor net metabolic power were consistently affected by footwear stiffness. These results indicate that increasing older adult footwear stiffness via flat carbon fiber insoles attenuates some age-related deficits in foot and ankle mechanics, but does not result in a clear attenuation of the age-related distal to proximal shift in joint mechanics or clear metabolic benefits. The increase in ankle joint moment with stiffer footwear could be useful longer-term as a means to strengthen the calf musculature of older adults. Future work should examine the effects of footwear stiffening on ankle muscle-level outcomes such as force production, excitation, and fascicle mechanics.

ID: 42547443
Title: [Research progress on the role of calcitonin gene-related peptide in the repair of diabetic wounds].
Abstract: 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. 糖尿病创面是一种糖尿病并发症，严重者可致患者截肢甚至死亡。正常的创面愈合历经止血、炎症、增殖、重塑4个阶段，糖尿病创面主要因炎症期延长而慢性难愈。糖尿病创面组织中降钙素基因相关肽（CGRP）合成与释放不足，这是导致创面神经免疫通讯中断、炎症无法消退、愈合进程停滞的关键上游机制。与单纯皮肤缺损创面中CGRP在伤后迅速上调不同，糖尿病创面组织中CGRP呈持续性低水平表达，无法在炎症后期驱动巨噬细胞向M2型极化，促进血管成熟与胶原纤维沉积。在炎症初期，CGRP通过促进新血管生成、调节巨噬细胞极化等发挥促炎作用；而在炎症后期，CGRP通过上调血小板反应蛋白-1，促进中性粒细胞凋亡与胞葬清除，进而抑制过度炎症反应，推动创面微环境由促炎状态向促修复状态转变。恢复CGRP信号可重塑神经免疫调控轴，兼具促进创面修复与缓解糖尿病神经病理性疼痛的双重作用。工程化CGRP与智能递送系统为糖尿病创面治疗带来新希望，但其在临床应用中的有效性与安全性仍需大规模研究验证。该文深入剖析CGRP在糖尿病创面修复中的作用机制及应用策略，为临床治疗提供理论依据与新思路。.

ID: 42548269
Title: Time of day effects of high-intensity interval resistance training on metabolism, adiposity, and adipogenic markers in male mice.
Abstract: The circadian system regulates physiological and metabolic processes, and exercise timing may influence metabolism and adiposity. To investigate the time-of-day effects of high-intensity interval resistance training (HIRT) on metabolism, adiposity, and adipogenic markers, male Swiss mice (n = 111) were allocated to control or HIRT groups during the light (C6 and T6) or dark phase (C18 and T18). HIRT was performed for 8 weeks (3 sessions/week) on a ladder at 90% of maximal load until exhaustion. Metabolic biomarkers, adiposity, adipocyte morphology, and protein expression of PPARγ and adiponectin were assessed. Maximal strength increased in trained groups. Training-time interactions were observed for triglycerides and total cholesterol, with higher values in T6 than in C6 and T18. Glucose and PPARγ were higher during the dark phase. PPARγ was also higher in trained than control groups, irrespective of the time of day. HIRT reduced adiposity across multiple depots regardless of training time. No significant differences were observed for adipocyte area, adiponectin, insulin, or HOMA-IR. HIRT reduced adiposity independently of training time, suggesting that chronic adaptations in adipose tissue were primarily driven by the training. However, time of day modulated metabolic responses, particularly lipid metabolism.

ID: 42549200
Title: Differential shaping of equine gut microbiota structure and function by breed and feeding regimen.
Abstract: The gut microbiota plays an essential role in host energy metabolism and immune function. Horses are non-ruminant herbivores that rely heavily on hindgut microbial fermentation to meet their energy requirements. However, the relative contributions of host genetic background (breed) and environmental factors (feeding regimen and geographical location) to shaping the equine gut microbiota remain poorly understood. In this study, 16S rRNA gene sequencing and functional prediction analysis were performed on 139 equine fecal samples to systematically investigate the differential effects of breed and feeding regimen on the gut microbiota. Samples were collected from 30 Thoroughbreds (TH), 31 stabled hybrid horses (HH1), 30 grazing hybrid horses (HH2) (with HH1 and HH2 sired by Thoroughbreds out of Mongolian mares), 32 Mongolian horses (MH), and 16 Warmblood horses (WBH1 and WBH2). Alpha and beta diversity analyses, taxonomic profiling, and PERMANOVA were used to assess microbial composition and the contributions of different factors. Alpha diversity analysis revealed that the richness and diversity of the TH, HH1, HH2, and MH groups were significantly higher than those of the Warmblood horses (p < 0.001), with Mongolian horses exhibiting the highest diversity and the hybrids showing intermediate levels between their parental breeds. Regarding taxonomic composition, the TH, HH1, HH2, and MH groups shared a microbial structure dominated by Firmicutes and Bacteroidota, yet each possessed distinct characteristics: Thoroughbreds were enriched with Treponema; Mongolian horses harbored the highest abundances of Rikenellaceae_RC9_gut_group and NK4A214_group; and the grazing hybrid horses developed a fiber-degrading bacterial community centered on Ruminococcus and Fibrobacter, demonstrating breed-specific microbial features. In contrast, the Warmblood horses exhibited a gut microbiota with distinct features characterized by significantly reduced microbial diversity and core fiber-degrading genera, concomitant with an enrichment of environmental-associated bacteria from the phylum Proteobacteria (e.g., Acinetobacter, Stenotrophomonas) and other genera (e.g., Comamonas, Brevundimonas). PERMANOVA analysis further quantified the contributions of different factors: breed explained 44.8% of the total variation (R² = 0.448, p < 0.001), followed by feeding regimen (10.3%, p < 0.001) and geographical location (2.7%, *p* < 0.01), confirming breed as the predominant factor. This study provides evidence that breed establishes the foundational framework of the gut microbiota, while feeding regimen performs fine-tuning functions. We also systematically characterized the unique microbial composition of Warmblood horses, offering a scientific basis for breed-specific health management, precision nutritional interventions, and future disease risk monitoring in horses. Although all horses appeared clinically healthy, the distinct microbial composition observed in Warmblood horses warrants further investigation to determine its biological significance.

ID: 42563498
Title: From Gut to Heart: The Emerging Role of Dietary Fermentable Fiber in Heart Failure with Preserved Ejection Fraction.
Abstract: Heart failure with preserved ejection fraction (HFpEF) is a multisystemic syndrome that accounts for more than half of all heart failure cases and causes a substantial burden of morbidity and mortality. In contrast to heart failure with reduced ejection fraction (HFrEF), few disease-modifying therapies exist for HFpEF, reflecting differences in pathophysiology. Low fermentable fiber (FF) intake, gut dysbiosis, and depletion of short-chain fatty acids (SCFAs), microbial metabolites central to immune, metabolic, and vascular homeostasis, are increasingly linked to the pathophysiology of HFpEF. Here, we synthesize preclinical and clinical evidence on FF and SCFAs and evaluate their therapeutic relevance to HFpEF. Preclinical studies demonstrate that FF supplementation or direct SCFA administration improves cardiometabolic function and attenuates cardiac remodeling through SCFA receptor signaling, enhanced nitric oxide bioavailability, reduced inflammation, and metabolic support of the energy-starved failing heart. Supporting the translational relevance of these findings, a systematic review of 27 human randomized controlled trials showed that FF interventions exert microbiome-mediated effects, enriching SCFA-producing taxa and augmenting fecal and circulating SCFA levels, while improving insulin sensitivity and reducing abdominal adiposity and LDL cholesterol. Direct SCFA supplementation increases SCFA availability and provides modest metabolic benefits, including reduced adiposity and liver fat. However, its effects are inconsistent. Collectively, these findings provide a mechanistic and translational rationale for FF-based interventions in HFpEF. To date, no clinical trials have evaluated the effects of FF on HFpEF-specific outcomes. Clinical studies are therefore needed to determine whether increasing FF intake can improve symptoms, cardiac function, and disease progression in HFpEF.