PubMed

Front Endocrinol (Lausanne). 2026 Feb 19;16:1685306. doi: 10.3389/fendo.2025.1685306. eCollection 2025.ABSTRACTPremature ovarian insufficiency (POI) refers to the decline in ovarian function in women before the age of 40, which can lead to premature ovarian failure and ultimately lead to infertility. In recent years, the incidence of POI has continued to rise, posing a serious threat to women's reproductive health and mental well-being. Although hormone replacement therapy (HRT) is currently the most widely used Western medical treatment method, its long-term use may carry risks such as thrombosis and breast cancer, and it is not yet an ideal treatment option. Electroacupuncture(EA), as an important intervention method in complementary and alternative medicine (CAM), has been shown to exert multisystem regulatory effects, particularly showing promising prospects in the intervention of POI. This review focuses on the mechanism of action of EA in the treatment of POI. First, the advantages and disadvantages of common animal modeling methods were analyzed. The effects of EA have been studied in terms of improving ovarian function, regulating the hypothalamic-pituitary-ovarian (HPO) axis, balancing the neuroendocrine-immune network, alleviating inflammatory responses, regulating local ovarian blood flow, activating mesenchymal stem cell function, and regulating the intestinal microbiota. Research on the mechanism of EA regulation of POI focused on analyzing the phospholipid 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, Hippo signaling pathway, cell apoptosis, and oxidative stress factors. In addition, this paper summarizes the clinical research progress of different EA treatment regimens in recent years, further verifying their efficacy and safety. Looking ahead, research on EA for POI is expected to achieve breakthroughs with the help of cutting-edge technologies, such as establishing personalized and standardized treatment plans; integrating multidimensional technologies such as genomics, transcriptomics, metabolomics, and tissue clearing; and conducting systematic research on the temporal and spatial dynamic changes in ovarian function. Through the interdisciplinary integration of traditional acupuncture theory and modern life science technology, it is hoped that the underlying mechanisms of EA treatment for POI can be further elucidated, thereby providing a solid theoretical foundation and practical guidance for its clinical application.PMID:41799227 | PMC:PMC12960178 | DOI:10.3389/fendo.2025.1685306

Anal Sci Adv. 2026 Mar 6;7(1):e70061. doi: 10.1002/ansa.70061. eCollection 2026 Jun.ABSTRACTVarious factors can trigger water stress in plants, particularly in those growing in dry tropical regions. To survive under such conditions, plants produce metabolites with adaptive functions. However, metabolomic data on the leaves of Malpighiaceae species cultivated in both dry and humid tropical areas of Brazil remain scarce. This study aimed to evaluate seasonal water stress in 10 species (from 7 genera) of Malpighiaceae inhabiting contrasting Brazilian biomes: Cerrado and Caatinga (dry areas), and Atlantic and Amazon Forests (humid areas). Metabolic profiles obtained by liquid chromatography coupled to mass spectrometry were compared using Variable Importance in Projection Scores from Partial Least Squares Discriminant Analysis. The results revealed a clear distinction between the leaf metabolites from dry versus humid environments. Cyanidin-3-O-sambubioside (positive ionization mode) and 3,4-di-O-galloylquinic acid (negative ionization mode) were identified as key discriminant compounds. Additionally, 15 previously unreported metabolites were annotated in the chromatographic profiles of Malpighiaceae leaves. This is the first study to demonstrate the influence of water availability on metabolomic synthesis across multiple species of Malpighiaceae. By integrating chromatographic and chemometric approaches, this study proposes a novel analytical strategy capable of revealing how environmental conditions shape metabolomic synthesis, thereby reinforcing its methodological relevance within analytical science.PMID:41799037 | PMC:PMC12965184 | DOI:10.1002/ansa.70061

Transplant Direct. 2026 Mar 4;12(4):e1929. doi: 10.1097/TXD.0000000000001929. eCollection 2026 Apr.ABSTRACTBACKGROUND: Kidney preservation techniques, such as hypothermic machine perfusion (HMP), improve graft outcomes in deceased-donor kidney transplantation by pausing graft metabolism and ameliorated ischemia-reperfusion injury (IRI) but do not completely eliminate injury. Alkaline phosphatase (ALP) has been postulated to reduce IRI-induced kidney injury through the conversion of extracellular adenosine triphosphate into adenosine. This study aimed to evaluate whether ALP offers protection during deceased-donor kidney storage.METHODS: Sixteen abattoir porcine kidneys (8 ALP and 8 with placebo) were procured after euthanization and exposed to 30 min of warm ischemia followed by 24 h of HMP or static cold storage (SCS). Reperfusion was partly simulated by 240 min of normothermic machine perfusion (NMP). Throughout NMP, we obtained functional, biochemical, and histological parameters.RESULTS: Significantly lower urine production accompanied by lower perfusate pCO2 and higher pH were observed in the ALP group throughout NMP. At the end of NMP, intracellular ATP reserves and oxygen consumption were significantly higher in the ALP-treated group. Metabolomics analysis with principal component analysis demonstrated significant differences between the ALP and placebo groups in glycolysis and mitochondrial metabolites, along with a significantly attenuated rise in perfusate lactate dehydrogenase levels.CONCLUSIONS: ALP supplementation during HMP was associated with lower urine production and energetic stress, with a shift toward less metabolic dysfunction and graft injury by the end of NMP. Our findings suggest an improvement in the early metabolic incompetency that characterizes delayed graft function in humans. Further research should elucidate whether these findings result in enhancement of graft functionality after transplantation.PMID:41799024 | PMC:PMC12962581 | DOI:10.1097/TXD.0000000000001929

Front Immunol. 2026 Feb 20;17:1761558. doi: 10.3389/fimmu.2026.1761558. eCollection 2026.ABSTRACTBACKGROUND: Gout is a prevalent metabolic disorder characterized by hyperuricemia and inflammation. Verbenalin, an iridoid glycoside from Verbena officinalis, possesses anti-inflammatory properties; however, its therapeutic potential and underlying mechanisms in gout remain underexplored.OBJECTIVE: This study aimed to evaluate the pharmacological effects and elucidate the molecular mechanisms of verbenalin in a rat model of gout.METHODS: Hyperuricemia and acute gouty arthritis were induced in rats using potassium oxonate/hypoxanthine and monosodium urate, respectively. Verbenalin was administered orally for 7 days. Therapeutic efficacy was assessed via physical symptom scores (inflammation, gait, swelling), renal/hepatic function indices, and histopathology. Furthermore, a multi-omics strategy integrating transcriptomics, metagenomics, and metabolomics, combined with Western blotting, was employed to investigate the pharmacological mechanisms.RESULTS: Verbenalin treatment significantly alleviated joint inflammation and swelling while improving gait scores. It effectively lowered serum uric acid (UA), creatinine, and BUN levels, inhibited hepatic xanthine oxidase (XOD) activity, and promoted urinary UA excretion. Histopathological damage in the joints, kidneys, and liver was markedly mitigated. Mechanistically, verbenalin downregulated the expression of urate transporters (URAT1, GLUT9) and inflammatory mediators (NLRP3, IL-1β) by inhibiting the PI3K-AKT and MAPK signaling pathways. Multi-omics analysis further revealed that verbenalin restored gut microbiota diversity and modulated purine metabolism, correlating with reduced UA levels.CONCLUSION: These findings demonstrate that verbenalin may exert anti-gout effects through the potential synergy of modulating purine metabolism, shifting gut microbiota composition, and suppressing PI3K-AKT and MAPK inflammatory signaling pathways. This study provides a preliminary scientific basis for further investigation into verbenalin as a prospective multi-target therapeutic candidate.PMID:41798955 | PMC:PMC12963231 | DOI:10.3389/fimmu.2026.1761558

Front Immunol. 2026 Feb 19;17:1746350. doi: 10.3389/fimmu.2026.1746350. eCollection 2026.ABSTRACTBACKGROUND: Osteoarthritis (OA) is a debilitating joint disorder for which with no effective disease-modifying drugs are currently available. Liubao tea, a traditional Chinese post-fermented tea, exhibits diverse bioactivities, including anti-inflammatory properties and the ability to regulate gut microbiota. However, its potential therapeutic efficacy and underlying mechanism in the context of OA remain insufficiently elucidated.METHODS: A mouse model of osteoarthritis (OA) induced by destabilization of the medial meniscus (DMM) was established, and the mice were treated with low- and high-dose Liubao tea extract. Micro-CT, histological staining (H&E, Safranin O-Fast Green), and enzyme-linked immunosorbent assay (ELISA) were performed to evaluate joint structure, cartilage damage, and inflammatory cytokine levels. 16S rRNA sequencing, fecal microbiota transplantation (FMT), and untargeted serum metabolomics were conducted to explore gut microbiota and metabolic changes. Additionally, Brequinar, a de novo pyrimidine synthesis inhibitor, was used to verify the role of pyrimidine metabolism. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was used to analyze the chemical components of Liubao tea. Network pharmacology was employed to identify the active components and their potential targets in OA treatment. Molecular docking was performed to evaluate the interactions between key components and hub targets.RESULTS: Liubao tea treatment significantly ameliorated DMM-induced OA progression, as evidenced by improved subchondral bone microarchitecture (increased bone volume/total volume [BV/TV], trabecular number [Tb.N], trabecular thickness [Tb.Th]; decreased trabecular separation [Tb.Sp]), the reduced cartilage erosion (lowered the modified Mankin and OARSI scores), and the suppressed systemic inflammation (decreased interleukin [IL]-6, IL-1β, tumor necrosis factor [TNF]-α levels). Liubao tea remodeled gut microbiota homeostasis (increased α-diversity and altered bacterial taxa), and fecal microbiota transplantation (FMT) from Liubao tea-treated mice recapitulated its anti-OA effects. Metabolomic analysis revealed that Liubao tea significantly downregulated the pyrimidine metabolism pathway, and Brequinar treatment mimicked its therapeutic benefits, confirming the role of pyrimidine metabolism suppression in OA alleviation. UPLC-MS/MS and network pharmacology analyses identified 1,989 metabolites in Liubao tea, including 273 bioactive components (e.g., flavonoids, lignans) that targeted 324 OA-related genes. The molecular docking results demonstrated that Eupatilin, 5,6,7,8-Tetramethoxyflavone, and 5-Hydroxy-6,7,3',4',5'-Pentamethoxyflavone exhibited potential interactions with the hub targets TP53, IL6, and TNF.CONCLUSION: Liubao tea attenuates OA progression by modulating the composition of the gut microbiota and inhibiting the pyrimidine metabolism pathway, highlighting its potential as a novel natural therapeutic agent for OA.PMID:41798939 | PMC:PMC12960094 | DOI:10.3389/fimmu.2026.1746350

J Endocr Soc. 2026 Jan 28;10(4):bvag020. doi: 10.1210/jendso/bvag020. eCollection 2026 Apr.ABSTRACTCONTEXT: Insulin action is critical for energy homeostasis and its dysfunction in muscle cells is associated with type 2 diabetes. Insulin receptor (INSR) internalization and cell-surface dynamics at rest and during insulin exposure are incompletely understood in muscle cells.OBJECTIVE: We aimed to characterized the INSR dynamics and interactions in muscle.METHODS: We applied inter-domain tagged INSR, microscopy, immunoprecipitation, mass spectrometry, and AlphaFold multimer to comprehensively profile INSR internalization and interactions with or without insulin stimulation.RESULTS: Using surface labeling and live-cell imaging, we observed robust basal internalization of INSR in C2C12 myoblasts, without an effect of added insulin. Mass spectrometry using INSR knockout cells as controls identified high-confidence binding partners, including proteins associated with internalization. We confirmed known interactors, including insulin-like growth factor 1 receptor, and also identified underappreciated INSR-binding factors, such as annexin A2. AlphaFold multimer analysis predicted potential INSR-binding sites of these proteins. Protein-protein interaction network mapping suggested links between INSR and caveolin-mediated endocytosis. INSR interacted with both caveolin and clathrin heavy chain (CLTC) in mouse skeletal muscle and C2C12 myoblasts. Whole-cell 2-dimensional super-resolution imaging revealed that high levels of insulin (20 nM) increased INSR colocalization with caveolin-1 (CAV1) but decreased its colocalization with CLTC. Single-particle tracking confirmed the colocalization of cell-surface INSR with both overexpressed CAV1-mRFP (monomeric red fluorescent protein) and CLTC-mRFP. INSR tracks that colocalized with CAV1 exhibited longer radii and lifetimes, regardless of insulin exposure, compared with noncolocalized tracks, whereas insulin further increased the lifetime of INSR/CLTC-colocalized tracks.CONCLUSION: Overall, these data suggest that muscle cells utilize both CAV1- and CLTC-dependent pathways for INSR mobilization and internalization.PMID:41798897 | PMC:PMC12963976 | DOI:10.1210/jendso/bvag020

J Endocr Soc. 2026 Feb 24;10(4):bvag035. doi: 10.1210/jendso/bvag035. eCollection 2026 Apr.ABSTRACTCONTEXT: Prepregnancy body mass index (pBMI) is associated with the maternal metabolome during pregnancy. However, evidence remains inconclusive whether pBMI is also associated with alterations in the fetal cord blood metabolome, and whether pBMI modifies the associations between maternal and fetal metabolomes.OBJECTIVE: This work aimed to examine whether pBMI is associated with the fetal cord blood metabolome and whether maternal and fetal metabolomes are associated and vary according to the degree of maternal pBMI.METHODS: We derived pBMI from medical records and tested it in relation to 95 cord blood metabolic measures of 1702 newborns in the PREDO, RADIEL, and ITU studies. We tested the associations between maternal and fetal metabolomes and moderation by pBMI in 556 mother-child dyads of the PREDO and RADIEL studies contributing maternal blood samples at 3 time points during pregnancy.RESULTS: In the meta-analysis of the 3 studies, higher pBMI was associated with 12 of the 95 cord blood metabolic measures, including lower levels of high-density lipoprotein-associated measures and higher levels of branched-chain and aromatic amino acids, as well as ketone bodies. Associations between maternal and fetal metabolomes were significant for 61 of the 95 measures; 26 of the 95 associations were modified by maternal pBMI, being stronger among mothers with obesity than those without.CONCLUSION: Maternal pBMI is associated with alterations in fetal cord blood metabolome. Maternal and fetal metabolomes are associated, and associations vary according to maternal pBMI.PMID:41798895 | PMC:PMC12964119 | DOI:10.1210/jendso/bvag035

Front Nutr. 2026 Feb 19;13:1772671. doi: 10.3389/fnut.2026.1772671. eCollection 2026.ABSTRACTINTRODUCTION: Patients undergoing dialysis are particularly susceptible to severe COVID-19 outcomes owing to pre-existing metabolic and immunological dysregulation, which may exacerbate clinical severity and elevate the risk of long COVID (LC). Nevertheless, the precise metabolic pathways implicated remain poorly characterized. This study aimed to characterize fecal short-chain fatty acids (SCFAs) and serum metabolomic signatures in dialysis patients with acute COVID-19 and to explore their association with LC.METHODS: Targeted liquid chromatography-tandem mass spectrometry (LC-MS/MS) quantified fecal SCFAs in 27 infected patients and 28 non-infected controls, and untargeted gas chromatography-mass spectrometry (GC-MS)-based metabolomics profiled serum samples from 23 infected patients and all 40 controls in partially overlapping patient subsets, with repeat serum sampling at 3 months and stratification into LC and non-LC groups. Multivariate analyses, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, and Pearson correlation analyses between differential metabolites and routine clinical indicators were performed.RESULTS: Infected patients exhibited significantly lower fecal levels of six SCFAs, including propionate and butyrate, compared with controls. Serum metabolomics identified 54 infection-related differential metabolites enriched in amino acid, energy, carbohydrate, and nucleotide metabolism, and 77 LC-associated metabolites predominantly mapping to amino acid and energy pathways. Pearson correlation analysis showed that amino acids and energy-supporting metabolites (e.g., glutamine, aspartate, methionine, cystine, taurine) were inversely correlated with C-reactive protein, leukocyte and neutrophil counts, and aspartate aminotransferase, but positively correlated with albumin, serum potassium, and lymphocyte or eosinophil counts, whereas purine degradation products and organic acids (e.g., uric acid, hypoxanthine, pyruvate, glycolate) exhibited the opposite pattern.DISCUSSION: COVID-19 infection in dialysis patients is associated with marked depletion of fecal SCFAs and broad perturbations of systemic metabolism, with persistent amino-acid-centered alterations among patients who develop LC. These findings offer a novel metabolic framework supporting the implementation of prolonged follow-up strategies to monitor and ameliorate persistent sequelae in this high-risk population.PMID:41798842 | PMC:PMC12960162 | DOI:10.3389/fnut.2026.1772671

Aquac Nutr. 2026 Mar 5;2026:8260382. doi: 10.1155/anu/8260382. eCollection 2026.ABSTRACTThis research aimed to explore the impact of bile acid (BA) supplementation in low fishmeal diets on growth performance, serum biochemical indices, tissue morphology, lipid metabolism, gene expression, and gut microbiota in triploid rainbow trout (Oncorhynchus mykiss, initial weight 15.97 ± 1.4 g). The experimental design involved a low fishmeal diet (10%), and four treatment groups with BA additions (0.05%, 0.10%, 0.15%, and 0.20%) to the basal diet. The findings indicated that the group receiving 0.10% BA (G3) exhibited an enhancement in final body weight (FBW), specific growth rate (SGR), weight gain rate (WGR), and condition factor (CF), significantly outperforming the control group (G1, p < 0.05). 0.10% BA addition significantly increased whole-body crude protein and lipid content. (p < 0.05). Serum analysis showed a significant reduction in total bilirubin (TBIL) and triglycerides (TG), and an increase in BA and lipoprotein cholesterol (LDL-C) in the G3 group compared to G1 (p < 0.05). The 0.10% BA supplementation downregulated pro-inflammatory gene expression, like il-1β, and upregulated lipid metabolism-related genes, like scdb, in the intestinal tract of O. mykiss (p < 0.05). 16S high-throughput sequencing identified key microbial groups in the intestine of O. mykiss, highlighting significant differences in microbial composition with BA supplementation. Metabolomic analysis revealed that BA addition altered the metabolic profile of O. mykiss, affecting pathways such as polycyclic aromatic hydrocarbon (PAH) catabolism, cysteine (Cys) and methionine (Met) metabolism, the sulfur relay system, arachidonic acid (AA) metabolism, and ovarian steroidogenesis. In summary, a 0.10% BA addition to the diet of O. mykiss significantly improved growth performance, mitigated intestinal inflammation in specimens fed low fishmeal diets, and promoted overall gut health and lipid metabolism.PMID:41798293 | PMC:PMC12961228 | DOI:10.1155/anu/8260382

Therap Adv Gastroenterol. 2026 Mar 5;19:17562848261426284. doi: 10.1177/17562848261426284. eCollection 2026.ABSTRACTUlcerative colitis (UC) is a chronic inflammatory bowel disease strongly associated with intestinal dysbiosis, reduced microbial diversity, and disrupted microbial metabolite profiles. Fecal microbiota transplantation (FMT) aims to restore microbial homeostasis and has shown a signal of benefit for induction of remission in some trials, but results are heterogeneous and long-term maintenance efficacy remains uncertain. In this narrative review, we synthesize randomized controlled trials (RCTs), systematic reviews/meta-analyses, and recent guideline and regulatory updates on FMT in UC, and integrate mechanistic insights from microbiome and metabolomics research. Across RCTs, intensive lower-gastrointestinal regimens using pooled, multidonor material, and/or anaerobic processing have most consistently achieved modestly higher steroid-free clinical and endoscopic remission than placebo in mild-to-moderate UC (approximately 25%-32% vs 5%-10% in representative studies), whereas upper-gastrointestinal delivery or oral lyophilized formulations and highly restrictive donor selection have yielded mixed or negative results. Mechanistically, responders commonly demonstrate engraftment of short-chain fatty acid producing taxa and restoration of secondary bile acid pathways. Safety profiles in trials are generally comparable to placebo for common mild adverse events, but rare severe transmissions (e.g., multidrug-resistant Escherichia coli and SARS-CoV-2) have driven stricter donor screening and have limited routine use outside regulated programs. Current guidelines recommend against FMT for UC outside clinical trials. Future work should prioritize standardized protocols, biomarker-guided personalization, combination strategies (diet/priming), and development of defined microbial therapeutics to improve efficacy and safety.PMID:41798257 | PMC:PMC12966540 | DOI:10.1177/17562848261426284

3 Biotech. 2026 Apr;16(4):115. doi: 10.1007/s13205-026-04715-0. Epub 2026 Mar 6.ABSTRACTMultiple sclerosis is a debilitating demyelinating progressive neurodegenerative disease, that eventually leads to the death of patients. Transcriptomic patient dataset analysis revealed marked alterations in P2Y12 expression in microglia from individuals with Multiple Sclerosis. Absorption, Distribution, Metabolism, and Excretion (ADME) profiling highlighted clopidogrel, a P2Y12 inhibitor, as a potentially promising treatment option for advanced stages of the disease. Our previous invitro studies using N9 microglial cells showed that, clopidogrel effectively mitigated TNF-α mediated inflammatory response and chemotaxis. We employed targeted metabolomic analysis of healthy, cuprizone-fed, clopidogrel-treated, and clopidogrel-treated cuprizone-fed mice to understand the metabolic modulation associated with clopidogrel treatment. Our analysis reveals that cuprizone-fed mice show deregulation of metabolic pathways important for lipid, oxidative stress, and biotin metabolism. Notably, clopidogrel modulates metabolic pathways in cuprizone-fed mice particularly involved in lipid, biotin and myelin biosynthesis. Taken together, our earlier findings with N9 microglial cells and current results from the cuprizone-fed mice model suggest clopidogrel as a potential therapeutic agent in Multiple Sclerosis.SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s13205-026-04715-0.PMID:41798220 | PMC:PMC12963599 | DOI:10.1007/s13205-026-04715-0

J Pharm Anal. 2026 Feb;16(2):101409. doi: 10.1016/j.jpha.2025.101409. Epub 2025 Jul 24.ABSTRACTUlcerative colitis (UC) is an idiopathic, chronic inflammatory disorder with an increasing incidence worldwide. Due to the complex and unclear therapeutic targets, unmet UC therapeutic drugs still exist. Recently, acylcarnitine metabolism disorder has been linked to intestinal inflammation, but its role in UC remains elusive. According to our preliminary non-targeted metabolomics data, acylcarnitines (ACs) was screened as the disturbed metabolites in the different intestinal inflammation-related diseases. Here we quantified 26 ACs within liquid chromatography-tandem mass spectrometry (LC-MS/MS) in the dextran sulfate sodium (DSS)-induced UC rat model, and found that long-chain acylcarnitines (LCACs) were increased to varying degrees. As the key metabolites of fatty acid β-oxidation (FAO), the upstream metabolites long-chain fatty acids (LCFAs) and the related metabolic enzymes were further characterized, the results showed that the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A)-mediated LCFAs-LCACs metabolic axis was activated sharply. Next in vitro experiments exhibited that CPT1A was significantly upregulated in both inflammatory macrophages and colonic epithelial cells, and inhibition or knockdown of CPT1A could reduce the inflammation level remarkably. Thus, we screened the pharmacologic inhibitors of CPT1A from US Food and Drug Administration (FDA) approved drugs, within molecular docking, Western blot and cell membrane chromatography (CMC) technology, gliquidone was found to inhibit CPT1A in a dose-dependent manner and exert anti-inflammatory effects in vitro. Animal experiments also showed that gliquidone alleviated DSS-induced UC significantly. In summary, our study presents that within metabolomics analysis, inhibiting CPT1A is focused to be a potential therapeutic strategy against UC, and gliquidone represents an alternative treatment.PMID:41798070 | PMC:PMC12966598 | DOI:10.1016/j.jpha.2025.101409

iScience. 2026 Feb 9;29(3):114947. doi: 10.1016/j.isci.2026.114947. eCollection 2026 Mar 20.ABSTRACTGlycolysis plays a crucial role in neuronal homeostasis and is regulated by neuroendocrine signals, particularly dopamine, yet the underlying mechanisms remain unclear. Metabolomics showed that bromocriptine (BRC), a dopamine receptor agonist, increased glycolytic flux in forager bees, as indicated by higher glucose levels, accumulation of glycolytic intermediates, and reduced pentose-phosphate pathway metabolites. Single-cell and single-nucleus RNA-seq further indicated that acetylcholine (ACh) released by Kenyon cells may mediate dopamine-regulated glycolysis in surface glia (SG). We also observed coordinated insulin/insulin-like growth factor signaling (IIS) between cortex glia (CG) and SG. Mechanistically, co-administration of a nicotinic ACh receptor agonist with BRC attenuated the BRC-induced upregulation of SLC2A1, HK, and IGF transcripts, consistent with the proposed pathway. Together, these findings are consistent with a dual regulatory scheme in which a dopamine-ACh axis operates in concert with IIS to shape glial metabolic plasticity with cell-type specificity.PMID:41797926 | PMC:PMC12964235 | DOI:10.1016/j.isci.2026.114947

Circulation. 2026 Mar 9. doi: 10.1161/CIRCULATIONAHA.125.074956. Online ahead of print.ABSTRACTBACKGROUND: Cardiomyocytes, as highly specialized and differentiated somatic cells, possess a limited capacity for renewal. Neonatal rodents possess the ability to regenerate cardiomyocytes after injury; however, this regenerative capacity declines rapidly with cardiomyocyte maturation, suggesting an inhibitory network between cellular maturation and cardiomyocyte proliferation. Maturing cardiomyocytes undergo a metabolic shift from predominantly glycolysis in the neonatal state to increased fatty acid oxidation in the mature state, which poses a barrier to cardiomyocyte proliferation and cardiac regenerative repair. YAP, a transcriptional cofactor regulated by the Hippo signaling pathway, promotes cardiac regenerative repair. We investigated the role of YAP in mediating metabolic remodeling to overcome the cardiomyocyte proliferation barrier and enable cardiac regenerative repair after heart injury.METHODS: We explored how YAP induces metabolic remodeling through single-nucleus RNA sequencing and metabolomic analyses in mice. Using lipidomic analysis, we demonstrated how YAP remodels the balance of fatty acid catabolism and anabolism. We further used a maternal fat overloading model to stimulate fatty acid oxidation, which activates a maturation program in neonatal cardiomyocytes and counteracts YAP-mediated metabolic dematuration. Using chromatin accessibility (assay for transposase-accessible chromatin with high-throughput sequencing), DNA footprinting, and transcriptional profiling (RNA sequencing), we discovered the key transcription factors that YAP interrupts to reprogram the cardiomyocyte metabolic state.RESULTS: Our results demonstrate that YAP directs metabolic remodeling of mature cardiomyocytes toward a neonatal-like metabolic state and illustrate the role of fatty acid metabolism in proliferating cardiomyocytes. We found that YAP reduces cardiomyocyte fatty acid utilization, driving fatty acid anabolism and phospholipid biosynthesis. Genome-wide analyses revealed that YAP inhibits the cardiac maturation transcription factor MEF2A (myocyte-specific enhancer factor 2A), resulting in decreased gene expression of cardiomyocyte maturity pathways. Given the role of MEF2A in regulating contractility, energy production, and mitochondrial homeostasis, we found that perturbing MEF2A transcriptional activity can serve as a strategy to interrupt the cardiomyocyte maturation program and restore the regenerative capacity of the heart.CONCLUSIONS: Our research endeavors to provide a comprehensive understanding of the balance of cardiomyocyte metabolic maturation and proliferation to overcome barriers to heart regeneration, offering novel insights into the potential for therapeutic intervention in heart failure.PMID:41797725 | DOI:10.1161/CIRCULATIONAHA.125.074956

FASEB J. 2026 Mar 31;40(6):e71658. doi: 10.1096/fj.202503624RR.ABSTRACTExercise is well known to promote tendon healing, an effect traditionally attributed to mechanical loading-induced responses within the tendon itself. However, skeletal muscle also functions as a secretory organ, releasing bioactive factors (secretome) during exercise that influence various tissues. We hypothesized that muscle-derived secretome released during exercise may also contribute to tendon healing. To test this, we applied mechanical loading to cultured muscle cells (myoblasts) using the FlexCell tension system to simulate exercise in vitro. Our previous studies, using 2D-cultured tendon cells (tenocytes), have demonstrated that secretome from statically loaded myoblasts, particularly under 2% loading, enhanced tendon healing-related responses. Building upon these findings, we employed a 3D tendon construct model to more closely mimic in vivo healing conditions. We found that secretome derived from statically loaded myoblasts, especially at 2% loading, promoted tendon healing-related processes as compared with the control group, which received no secretome treatment (no conditioned media). These included increased cell-covered area, expression of the tenocyte marker scleraxis (SCX), and elevated production of Type I and III collagens at an early stage (Day 7). Additionally, a reduction in type III collagen production was found at a later stage (Day 14), suggesting a potentially accelerated healing process. These findings highlight the therapeutic potential of the muscle-derived secretome in promoting tendon healing and may inform future strategies for rehabilitation and regenerative medicine.PMID:41797676 | DOI:10.1096/fj.202503624RR

Oncoimmunology. 2026 Dec 31;15(1):2641424. doi: 10.1080/2162402X.2026.2641424. Epub 2026 Mar 8.ABSTRACTKRAS-mutant pancreatic ductal adenocarcinoma (PDAC) remains largely refractory to immune checkpoint blockade. Wang et al. identified PDIA6 as a KRAS-driven suppressor of PERK-dependent immunogenic cell death, fostering immune exclusion. PDIA6 inhibition restores CD8+ T-cell immunity and sensitizes PDAC to immunotherapy, highlighting a targetable resistance mechanism in KRAS-mutant PDAC.PMID:41797299 | DOI:10.1080/2162402X.2026.2641424

Reprod Biol. 2026 Mar 7;26(2):101207. doi: 10.1016/j.repbio.2026.101207. Online ahead of print.ABSTRACTDespite significant progress in porcine in vitro embryo production (IVP), major challenges persist, particularly regarding the biological quality and developmental competence of gametes and embryos produced in vitro. The lack of standardised and objective evaluation criteria continues to limit the efficiency, reproducibility, and translational value of porcine assisted reproductive technologies (ART). This review provides a comprehensive synthesis of current methodologies used to assess oocyte, sperm, and embryo quality in pigs, integrating insights from other mammalian models to highlight common principles and species-specific challenges. Oocyte competence remains a key determinant of IVP success, yet its assessment is hindered by variable maturation efficiency, polyspermy, and inconsistent handling procedures. Emerging approaches such as advanced imaging, metabolomics, and single-cell transcriptomics show potential for non-invasive and dynamic evaluation of oocyte quality, but their routine implementation in routine practice requires further validation and inter-laboratory standardisation. Similarly, improving sperm assessment requires moving beyond traditional parameters such as motility and morphology toward integrative frameworks that incorporate molecular, biochemical, and imaging-based markers of functionality. The strong link between gamete quality and fertilisation outcomes highlights the need for harmonised protocols and validated species-specific biomarkers to ensure reproducibility across laboratories. At the embryonic level, the development of multiparametric, data-driven frameworks combining morphological, metabolic, and molecular indicators represents a pivotal step toward objective embryo quality assessment. Although artificial intelligence, high-throughput omics, and machine learning hold great promise, their adoption will depend on rigorous validation, cost-effectiveness, and standardisation to minimise operator-dependent variability and guarantee reproducibility. Ultimately, advancing porcine IVP will depend on integrating biological insights with technological innovations through non-invasive tools and robust quality control systems adapted to the species unique physiological characteristics. This convergence offers a pathway toward more efficient, reproducible, and predictive ART in pigs, with broad implications for animal breeding, genetic preservation, and translational biomedical research.PMID:41797246 | DOI:10.1016/j.repbio.2026.101207

Environ Int. 2026 Mar 1;209:110171. doi: 10.1016/j.envint.2026.110171. Online ahead of print.ABSTRACTThe abilities of recent high throughput techniques to measure biological responses is rapidly growing, therefore methods to analyse and organise these vast amounts of data into meaningful results are needed. Adverse outcome pathways (AOPs) and AOP networks (AOPNs) are an increasingly recognised framework for translating mechanistic information into useable knowledge to support policy decisions. However, many traditional statistical approaches may be ineffective at capturing nuances of high throughput data, particularly from multiple disparate layers of biological organisation. We present a comprehensive method that combines univariate differential expression (UD) analysis and multivariate integrative modeling (MIM) approaches, using transcriptomic and metabolomic data from adipocytes exposed to a classic obesogen, to develop a conceptual AOPN (cAOPN) for metabolic syndrome (MetS). Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cells were differentiated in tributyltin (TBT) and analysed using whole genome transcriptome and untargeted metabolomics analysis. UD and MIM results were used to identify perturbed features (PFs) for over-representation analysis for pathways and diseases and followed by integrated network and cluster analyses based on Jaccard similarity to reorganise resultant complex biological phenomena into exploratory depictions of cause-and-effect relationships. The resulting cAOPN for MetS was assembled and corroborated with the literature and mechanistic pathway databases that supported the identified disruptions in lipid regulation, iron transport, growth processes, key signalling processes, adipocyte differentiation, and hormonal homeostasis. Overall, by leveraging the strengths of multiple statistical methods in combination with heterogeneous data from multiple layers of biological organisation, this method facilitated the integration and interpretation of complex data into an exploratory mechanistic schema for AOP and AOPN hypothesis generation and prioritisation.PMID:41797196 | DOI:10.1016/j.envint.2026.110171

Phytomedicine. 2026 Feb 26;154:158023. doi: 10.1016/j.phymed.2026.158023. Online ahead of print.ABSTRACTBACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) has emerged as a worldwide health challenge with few therapeutic options. Xiayuxue Decoction (XYXD), a classical herbal formula from the Synopsis of the Golden Chamber (Jin Gui Yao Lue), a classic by Zhang Zhongjing, comprises Prunus persica (Linn.) Batsch, Rheum palmatumLinn., and Eupolyphaga sinensis Walker. While clinically employed for the treatment of chronic liver diseases, including MASH, its precise molecular mechanisms remain undefined.AIM OF THE STUDY: This study aims to clarify the therapeutic mechanisms underlying the effects of XYXD in MASH, with a particular focus on investigating its roles in gut microbiota remodeling, bile acid (BA) metabolism, N6-methyladenosine (m6A) transcriptional modification, and arachidonic acid (AA) metabolism.METHODS: A MASH model was induced by using a methionine-choline-deficient (MCD) diet, and the therapeutic effect of XYXD was evaluated by analyzing lipid profiles, liver function parameters, and histopathological changes. Gut microbiota composition was characterized via 16S rRNA gene sequencing. Meanwhile, the metabolomic profiling of BA metabolites in the liver, serum, and feces, as well as AA derivatives in the liver, was performed by using LC-MS/MS. Additionally, the expression profiles of relevant mRNAs and proteins, including those related to BA metabolism, lipid homeostasis, inflammatory response, and m6A modification, were determined. Deoxycholic acid (DCA) and XYXD-containing serum were used to treat RAW264.7 macrophage cells to verify further their regulatory effects on inflammation, m6A modification, and AA metabolism in vitro.RESULTS: XYXD exhibits therapeutic efficacy against MASH through the dual regulation of inflammatory pathways and lipid metabolic homeostasis. It effectively reverses MCD diet-induced microbiota imbalance and maintains BA homeostasis by activating the farnesoid X receptor (FXR)-small heterodimer partner (SHP) pathway, with a particular role in reducing Clostridium abundance and DCA levels. Further investigations revealed that DCA mediates the upregulation of methyltransferase-like 13/14 mRNA, which in turn enhances m6A modification and influences AA metabolism. This integrated regulation of inflammatory, metabolic, and epigenetic pathways underscores XYXD's systemic therapeutic potential.CONCLUSION: XYXD alleviates MASH via the following multifaceted regulatory mechanism: it modulates gut microbiota dynamics, activates the FXR-SHP axis to maintain BA homeostasis, and ultimately regulates m6A transcriptional modification to influence AA metabolism. This coordinated network establishes functional crosstalk between microbiota and metabolic pathways in disease intervention.PMID:41797191 | DOI:10.1016/j.phymed.2026.158023

Ecotoxicol Environ Saf. 2026 Mar 7;313:119984. doi: 10.1016/j.ecoenv.2026.119984. Online ahead of print.ABSTRACTThe widespread application of silver nanoparticles (AgNPs) raises increasing concerns over their male reproductive toxicity, yet a systematic, single-cell-resolved mechanistic understanding remains lacking. Here, we employed single-cell transcriptomics, metabolomics and functional experiments to explore AgNPs-triggered cellular remodeling of testes. Pubertal rats were orally exposed to AgNPs for 35 consecutive days. The particles traversed the blood-testis barrier (BTB), accumulated within the gonad, and ultimately impaired fertility. Metabolomics revealed that AgNPs altered metabolic milieu and reprogramed lipid metabolism. Then, high-resolution single-cell transcriptomic profiling identified ten distinct testicular cell populations, with spermatogenic cells and Sertoli cells exhibiting heightened susceptibility to AgNPs. Pseudotime trajectory analysis further revealed a selective reduction in undifferentiated spermatogonial stem cells. Functional and molecular pathway explorations were further conducted using C18-4, GC-2, and TM4 cell lines, as well as human primary Sertoli cells. Integrated analysis of in vitro and sequencing data reciprocally demonstrated the cell-type-specific toxicity: suppressed proliferation and elevated apoptosis in spermatogonia; intensified oxidative stress and apoptosis in spermatocytes; impaired spermatid differentiation; and disrupted growth factor synthesis and BTB integrity in Sertoli cells. Mechanically, these toxic effects were driven by AgNPs-induced mitochondrial dysfunction, glutathione metabolism dysregulation, and activation of the PINK1/Parkin-mediated mitophagy pathway, thereby disturbing Sertoli cell homeostasis and ultimately impaired the nutritional support and microenvironmental maintenance essential for spermatogenesis. These findings provide a comprehensive understanding of AgNPs-induced testicular toxicity, delineate cellular vulnerabilities and molecular mechanisms, and promise potential therapeutic countermeasures against nanoparticle-induced male infertility.PMID:41797105 | DOI:10.1016/j.ecoenv.2026.119984