PubMed

J Neurochem. 2025 Mar;169(3):e70030. doi: 10.1111/jnc.70030.ABSTRACTMicroglia, key immune cells in the brain, play a pivotal role in brain homeostasis and immune responses. Emerging evidence suggests their critical involvement in Alzheimer's disease (AD) pathogenesis and propagation. The propagation of AD pathology is related to the extracellular matrix of microglia, including extracellular vesicles (EV). Recently, microglia-derived EVs are implicated in inflammatory processes and neuronal death. This study aimed to extensively profile and propose the metabolic role of microglial EVs in AD. Accordingly, we determined the significant alterations of the EV metabolome associated with the metabolites in primary microglial cells. Aβ exposure induced significant metabolic alteration of 39, 18, and 28 metabolites in microglial cells, cultured media, and EVs, respectively. Aβ exposure triggered common alteration of key metabolic pathways between microglial cells and EVs, including purine, amino acid, and fatty acid metabolisms. While most of the common metabolites showed the same directional changes among the microglial system, N-acetyl aspartic acid displayed the opposite directional change in EVs. N-acetyl aspartic acid decreased 2.3-fold and twofold in microglial cells and media, respectively, but increased 3.5-fold in EVs under Aβ exposure. Moreover, mediation analysis proposed key EV metabolites that were directly affected by the metabolic dysregulation of Aβ-exposed microglial cells. The up-regulation of cysteic acid in EVs was mediated by up-regulated IMP in microglial cells. The down-regulation of 1-16:0-lysoPE in EVs was mediated by stearoyl-L-carnitine in microglial cells. Our study sheds new light on the role of microglia and EVs in neurodegenerative diseases, offering promising avenues for future therapeutic interventions.PMID:40042046 | DOI:10.1111/jnc.70030

Adv Sci (Weinh). 2025 Mar 5:e2415041. doi: 10.1002/advs.202415041. Online ahead of print.ABSTRACTCertain medications, including cisplatin and neomycin, often cause both hearing loss and renal dysfunction. This study aims to uncover the common mechanisms behind drug-induced ototoxicity and nephrotoxicity to aid early diagnosis and treatment. Metabolomic analyses reveal simultaneous disruptions in endogenous metabolic networks in the kidney, inner ear, and serum after administrating cisplatin or neomycin. Notably, a marked elevation in uric acid (UA), a recognized indicator of renal tubular injury, is identified. Supplementing UA and inhibiting its renal excretion worsen hearing loss and hair cell damage. Single-cell nucleus sequencing and immunohistochemistry reveal major changes in xanthine oxidase and ABCG2, crucial for UA metabolism, primarily in cochlear stria vascularis cells rather than hair cells. Cisplatin triggers a significant release of UA from stria vascularis cells, reaching concentrations sufficient to induce autophagy-dependent ferroptosis in hair cells. In a coculture system, targeted interventions against these two proteins in stria vascularis cells, through either pharmacological inhibition or genetic manipulation, markedly decrease the elevated UA release and the subsequent ferroptosis of hair cells. These findings suggest a metabolic connection between the inner ear and the kidney, highlighting the therapeutic potential of modulating UA to mitigate drug-induced nephrotoxicity and ototoxicity.PMID:40041973 | DOI:10.1002/advs.202415041

J Exp Zool A Ecol Integr Physiol. 2025 Mar 5. doi: 10.1002/jez.2912. Online ahead of print.ABSTRACTIn the integrated rice-crayfish aquaculture systems, crayfish Procambarus clarkii need to spend a long winter in the ring ditch, which is vulnerable to low temperature stress, especially in the northern part of China, where cold waves and other low-temperature climates are frequent. To study the metabolic response of P. clarkii to low temperature stress experimentally, the temperature was lowered from the control (23°C) to the low temperature group (9°C, 5°C, and 1°C) by slow and uniform cooling, and molecular and physiological samples were collected for measurement. The results showed that low temperature stress damaged the gill membrane and the epithelial layer of gill tissues, with an increase in vacuoles area and a reduced and irregular distribution of hemocytes. As the temperature decreased, the oxygen consumption rate, ammonia excretion rate and maximum metabolic rate of P. clarkii decreased gradually, the oxygen-nitrogen ratio decreased but still remained at a high level, and the metabolic energy supply substances were always mainly lipids and carbohydrates. The pyruvate kinase activity tended to increase with decreasing temperature under low temperature stress, while hexokinase, succinate dehydrogenase and lactate dehydrogenase activities decreased gradually. The 183 differential metabolites were screened in the low temperature group compared with the control mostly enriched in amino acid metabolism and citrate cycle metabolic pathways. In conclusion, under low temperature stress, the gill was damaged, respiratory metabolism decreased, and glycolysis was enhanced. Since the citrate cycle metabolism was suppressed, P. clarkii needed to resist low temperature stress by increasing the amino acid metabolism to provide more energy to maintain cellular activity. The results unraveled metabolic response mechanisms of metabolic response mechanism of P. clarkii to low temperature stress, and provided theoretical references for the selection and breeding of low-temperature-tolerant strains of P. clarkii.PMID:40041957 | DOI:10.1002/jez.2912

Acta Pharm Sin B. 2025 Jan;15(1):239-255. doi: 10.1016/j.apsb.2024.10.003. Epub 2024 Oct 15.ABSTRACTIncreasing evidence has underscored the significance of post-stroke alterations along gut-brain axis, while its role in pathogenesis and treatment of ischemic stroke (IS) remains largely unexplored. This study aimed to elucidate the therapeutic effects and action targets of Panax notoginseng saponins (PNS) on IS and explore a novel pathogenesis and treatment strategy of IS via profiling the microbial community and metabolic characteristics along gut-brain axis. Our findings revealed for the first time that the therapeutic effect of PNS on IS was microbiota-dependent. Ischemia/reperfusion (I/R) modeling significantly down-regulated Lactobacilli in rats, and PNS markedly recovered Lactobacilli, particularly Lactobacillus reuteri (L.Reu). Metabolomics showed a significant reduction in serum histidine (HIS) in clinical obsolete IS patients and rehabilitation period I/R rats. Meanwhile, the L.Reu colonization in I/R rats exhibited significant neuroprotective activity and greatly increased HIS in serum, gut microbiota, and brain. Moreover, exogenous HIS demonstrated indirect neuroprotective effects through metabolizing to histamine. Notably, vagus nerve severance in I/R rats was performed to investigate HIS's neuroprotective mechanism. The results innovatively revealed that PNS could promote HIS synthesis in gut by enhancing L.Reu proportion, thereby increasing intracerebral HIS through peripheral pathway. Consequently, our data provided novel insights into HIS metabolism mediated by L.Reu in the pathogenesis and treatment of IS.PMID:40041923 | PMC:PMC11873608 | DOI:10.1016/j.apsb.2024.10.003

Acta Pharm Sin B. 2025 Jan;15(1):205-223. doi: 10.1016/j.apsb.2024.11.009. Epub 2024 Nov 22.ABSTRACTDisruption of the intestinal mucosal barrier caused by gut dysbiosis and metabolic imbalance is the underlying pathology of inflammatory bowel disease (IBD). Traditional Chinese medicine Wuji Wan (WJW) is commonly used to treat digestive system disorders and showed therapeutic potential for IBD. In this interdisciplinary study, we aim to investigate the pharmacological effects of WJW against experimental colitis by combining functional metabolomics and gut-microbiota sequencing techniques. Treatment with WJW altered the profile of the intestinal microbiota and notably increased the abundance of Lactobacillus, thereby facilitating the conversion of tryptophan into indole-3-acetic acid (IAA) and indoleacrylic acid (IA). These indole derivatives activated the aryl hydrocarbon receptor (AhR) pathway, which reduced colonic inflammation and restored the expression of intestinal barrier proteins. Interestingly, the beneficial effects of WJW on gut barrier function improvement and tryptophan metabolism were disappeared in the absence of gut microbiota. Finally, pre-treatment with the AhR antagonist CH-223191 confirmed the essential role of IAA-mediated AhR activation in the therapeutic effects of WJW. Overall, WJW enhanced intestinal barrier function and reduced colonic inflammation in a murine colitis model by modulating Lactobacillus-IAA-AhR signaling pathway. This study provides novel insights into colitis pathogenesis and presents an effective therapeutic and preventive approach against IBD.PMID:40041900 | PMC:PMC11873645 | DOI:10.1016/j.apsb.2024.11.009

Front Microbiol. 2025 Feb 18;16:1529596. doi: 10.3389/fmicb.2025.1529596. eCollection 2025.ABSTRACTThis study aimed to investigate the effects of rumen-protected guanidinoacetic acid (RP-GAA) on growth performance, gut microbiota, and serum metabolism in beef cattle under chronic heat stress. A randomized block design was employed to allocate 14 F1 Simmental crossbred cattle (Simmental ♂ × Bos indicus ♀) with an average body weight of 312.5 ± 55.0 kg into two groups (n = 7): a control group was fed a basal diet without RP-GAA and a treatment group was fed the same basal diet supplemented with 10.0 g/day of RP-GAA. During feeding experiments, at 2 p.m., the average temperature increased to 31.5°C, with a relative humidity of 69.5% and a THI of 83.2. All animals are under chronic heat stress. The results indicated that RP-GAA supplementation significantly increased dry matter intake and feed conversion ratio in beef cattle under chronic heat stress (p < 0.05). RP-GAA supplementation tended to reduce respiratory rate or rectal temperature (p < 0.1). Compared to the control group, the treatment group exhibited significantly higher glucose, blood urea nitrogen, total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels (p < 0.05). 16S rRNA gene sequencing revealed that RP-GAA supplementation significantly altered the ruminal microbiota composition, increasing the abundance of Firmicutes and Bacteroidota (p < 0.05), while reducing Proteobacteria (p < 0.01). Principal coordinate analysis (PCoA) and Adonis test (R 2 = 0.190, p = 0.003) jointly revealed a distinct difference in fecal microbiota structures between the two groups. Metabolomic analysis identified significant changes in pathways related to creatine synthesis, energy metabolism, and nitrogen utilization, supported by the orthogonal partial least squares discriminant analysis model (R 2 Y = 0.983, Q 2 = 0.836, p < 0.05). These findings suggest that RP-GAAenhances energy homeostasis, supports gut health, and mitigates the adverse effects of heat stress, providing a promising strategy to improve production efficiency and animal welfare in heat-stressed cattle.PMID:40041874 | PMC:PMC11877906 | DOI:10.3389/fmicb.2025.1529596

Front Microbiol. 2025 Feb 18;16:1530319. doi: 10.3389/fmicb.2025.1530319. eCollection 2025.ABSTRACTINTRODUCTION: Pediococcus acidilactici CNCM I-4622 (PA) is a homofermentative Gram-positive coccus that produces lactic acid as a major metabolic by-product. However, the potential of PA to improve intestinal function and, as a result, improve production performance and quality in aged laying hens remains unclear. This study aimed to investigate the effects of PA on egg production, egg quality, intestinal health, and cecal microbiota in aged laying hens.METHODS: A total of 180 Lohmann pink laying hens, aged 80 weeks, were randomly assigned to five groups and fed either a basal diet (PA0) or basal diets supplemented with PA at concentrations of 50, 100, 150, and 200 mg/kg (PA50, PA100, PA150, and PA200).RESULTS: Compared to the PA0 group, PA did not have a significant effect on the production performance of laying hens (p > 0.05). However, the content of diamine oxidase and the expression level of IL-8 mRNA in the PA50, P100, P150, and P200 groups were significantly reduced (p < 0.05). Additionally, the ileal villus height was significantly increased (p < 0.05). The cecal chowder pH and ileal crypt depth were also significantly lower (p < 0.05), while lipase activity in the ileal mucosa of the PA50 group was significantly increased compared to the PA0 group (p < 0.05). Furthermore, the expression of INF-γ and TNF-α mRNA in the jejunal mucosa was significantly down-regulated (p < 0.05), whereas the expression of Claudin mRNA was significantly up-regulated (p < 0.05). Notably, the relative abundance of Bacteroidota, Fusobacteriota, and Fusobacterium in the PA50 group was significantly higher than that in the PA0 group (p < 0.05).DISCUSSION: Additionally, cecal metabolomic analysis indicated that following the addition of PA, the pathways enriched with differential metabolites were primarily related to arginine and proline metabolism. Therefore, PA has the potential to improve intestinal morphology and flora, mitigate intestinal inflammatory factors, and strengthen intestinal barrier function. These benefits are attributed to the modulation of arginine and proline metabolic pathways, with optimal effects observed at an addition of 50 mg/kg.PMID:40041866 | PMC:PMC11877211 | DOI:10.3389/fmicb.2025.1530319

Res Pract Thromb Haemost. 2025 Jan 9;9(1):102677. doi: 10.1016/j.rpth.2025.102677. eCollection 2025 Jan.ABSTRACTBACKGROUND: VITT has emerged as a rare but serious adverse event linked primarily to adenoviral vector COVID-19 vaccinations, such as ChAdOx1-S (Oxford/AstraZeneca) vaccination. The syndrome is characterized by thrombosis with thrombocytopenia, elevated D-dimer, and pathologic platelet factor 4 antibodies within 42 days of vaccination.OBJECTIVES: Despite dysregulated lipid metabolism underpinning many thrombotic conditions, the role of lipid alterations in VITT remains unexplored. Here, we examined the plasma lipidome of patients with VITT and compared it with those following ChAdOx1-S vaccination and with unprovoked venous thromboembolism (VTE) to understand the role of lipids in VITT pathophysiology.METHODS: This was a multicenter, prospective cohort study evaluating plasma lipidomics in newly diagnosed VITT samples, which were compared with both healthy controls following ChAdOx1-S vaccination and with unprovoked VTE.RESULTS: Comparison with ChAdOx1-S controls reveals a distinct lipid signature in VITT, characterized by elevations in phosphatidylserine and ceramide species, alongside reductions in several plasmalogens and acylcarnitine species. Notably, similarities between VITT lipid profiles and insulin resistance phenotypes suggest potential metabolic susceptibility. While few significant associations were found between VITT and VTE, an inverse correlation with several acylcarnitine species was demonstrated. Given the known anticoagulant role of acylcarnitine species, these findings suggest a plausible mechanistic pathway elevating the thrombotic potential of VITT above that of standard VTE.CONCLUSION: These findings underscore the important role of lipid metabolism in VITT pathophysiology and highlight the complex interplay between lipids, coagulation, and pathologic thrombosis.PMID:40041449 | PMC:PMC11879676 | DOI:10.1016/j.rpth.2025.102677

Biochem Biophys Rep. 2025 Feb 18;41:101943. doi: 10.1016/j.bbrep.2025.101943. eCollection 2025 Mar.ABSTRACTOBJECTIVE: To investigate the associations between metabolic changes and functions, including energy metabolism, immune response, and redox balance, under short-term hypobaric hypoxia exposure. Non-targeted metabolomics and bioinformatics analysis were applied to explore the adaptive mechanisms of organisms in hypobaric hypoxia.METHODS: Healthy adult male Sprague-Dawley rats were placed in environments simulating altitudes of 6500 m (HC group) and 1588 m (Control group). After 14 days, arterial serum samples were analyzed using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Significant metabolites (P < 0.05, VIP >1) were identified, and KEGG enrichment analysis was conducted. Differential metabolites were globally analyzed with MetaboAnalyst 5.0.RESULTS: A total of 117 significantly altered metabolites were identified. In the HC group, 84 metabolites significantly increased, while 33 metabolites significantly decreased compared to the Control group. KEGG enrichment analysis revealed significant metabolic pathways, including the PPAR signaling pathway, bile secretion, arginine biosynthesis, alcoholism, and cholesterol metabolism (P < 0.05). Global analysis indicated that these differential metabolites were involved in various pathways, such as energy metabolism, amino acid metabolism, nucleotide metabolism, lipid metabolism, vitamin and cofactor metabolism, steroid metabolism, neurotransmitter metabolism, and heme metabolism, all of which play crucial roles in multiple biological processes.CONCLUSION: Short-term hypobaric hypoxia exposure significantly altered the metabolite profiles in the arterial serum samples of rats, revealing adaptive metabolic reprogramming in energy metabolism, redox balance, immune function, endocrine regulation, and neurological systems.PMID:40041253 | PMC:PMC11876769 | DOI:10.1016/j.bbrep.2025.101943

Front Cell Infect Microbiol. 2025 Feb 18;15:1511900. doi: 10.3389/fcimb.2025.1511900. eCollection 2025.ABSTRACTINTRODUCTION: Body mass index (BMI) is considered an important factor in tumor prognosis, but its role in gastric cancer (GC) remains controversial. There is a lack of studies exploring the effect of BMI on gastric cancer from the perspective of intratumoral microbiota. This study aimed to compare and analyze the differences in and functions of intratumoral microbiota among GC patients with varying BMIs, aiming to ascertain whether specific microbial features are associated with prognosis in low-BMI (LBMI) gastric cancer patients.METHODS: A retrospective analysis of the clinicopathological features and prognosis of 5567 patients with different BMIs was performed between January 2010 and December 2019. Tumor tissues from 189 GC patients were collected for 16S rRNA sequencing, 64 samples were selected for transcriptome sequencing, and 57 samples were selected for untargeted metabolomic analysis.RESULTS: Clinical cohort analysis revealed that GC patients with a low BMI presented poorer clinical and pathological characteristics than those with a non-low-BMI (NLBMI). LBMI was identified as a significant independent risk factor for adverse prognosis, potentially exerting immunosuppressive effects on postoperative adjuvant chemotherapy. 16S rRNA sequencing revealed no significant differences in the alpha and beta diversity of the intratumoral microbiota between the two groups of GC patients. However, LEfSe analysis revealed 32 differential intratumoral microbiota between the LBMI and NLBMI groups. Notably, the genus Abiotrophia was significantly enriched in the LBMI group. Further in-depth analysis indicated that the genus Abiotrophia was inversely associated with eosinophils, P2RY12, and SCN4B genes, and positively linked with LGR6 in LBMI gastric cancer patients. Metabolomic assessments revealed that LBMI was positively associated with purine metabolites, specifically guanine and inosine diphosphate (IDP).DISCUSSION: In conclusion, LBMI is an independent risk factor for poor prognosis in gastric cancer patients and may have an inhibitory effect on postoperative adjuvant chemotherapy. Intratumor flora of gastric cancer patients with different BMI levels differed, with different immune cell infiltration and metabolic characteristics. The genus Abiotrophia may promote gastric cancer development and progression by regulating eosinophils and the purine metabolism pathway, which provides a new idea for the precise treatment of gastric cancer.PMID:40041144 | PMC:PMC11876552 | DOI:10.3389/fcimb.2025.1511900

Front Plant Sci. 2025 Feb 18;16:1526733. doi: 10.3389/fpls.2025.1526733. eCollection 2025.ABSTRACTINTRODUCTION: Fruit color is a crucial quality factor strongly influencing consumer preference for citrus. The coloration of citrus fruit is primarily determined by carotenoids, which produce a range of hues. Gibberellic acid (GA) and ethylene are critical in fruit coloration during the ripening process. Nevertheless, the underlying mechanisms remain poorly understood.METHODS: The present study utilized transcriptomic and metabolomic analyses to investigate the molecular regulatory mechanisms affecting peel pigment metabolism in tangors (Citrus reticulata Blanco×Citrus sinensis L. Osbeck) following GA and ethephon (ETH) treatments.RESULTS AND DISCUSSION: Collectively, our findings indicated that GA inhibits chlorophyll degradation and the accumulation of numerous carotenoids, including five violaxanthin esters (violaxanthin palmitate, violaxanthin myristate-caprate, violaxanthin myristate-laurate, violaxanthin dilaurate, violaxanthin myristate) and two β-cryptoxanthin derivatives (β-cryptoxanthin laurate, β-cryptoxanthin myristate), while ETH promotes these processes. Furthermore, GA inhibited the downregulation of lutein, the predominant carotenoid in immature fruits. Notably, integrated transcriptomic and metabolomic analyses identified 33 transcription factors associated with pigment metabolism. Of these, two novel transcription factors, the ethylene-responsive transcription factor ABR1 and the HD-Zip transcription factor ATHB7, were uncovered through both transcriptomic analysis and weighted gene co-expression network analysis. These two transcription factors positively regulated the colouration process, as validated by transient overexpression assays in tobacco. Taken together, our findings elucidated the global carotenoid changes and transcriptional alterations in regulating citrus peel color under hormone induction, with significant implications for improving citrus production.PMID:40041021 | PMC:PMC11876184 | DOI:10.3389/fpls.2025.1526733

iScience. 2025 Jan 30;28(3):111915. doi: 10.1016/j.isci.2025.111915. eCollection 2025 Mar 21.ABSTRACTContamination of heavy metals (HMs) in agroecosystem presented an additional dimension of complexity along with the adverse consequences of climate change for the scientific fraternity. The increasing population and urbanization on the other hand are regarded as the main sources of urban waste (UW). Holistic utilization of UW-derived biochar (BC) has shown potential to be utilized as a source of soil supplement in the agriculture sector, fulfilling several sustainable development goals (SDGs). An attempt has been made to evaluate the techno-economical prospect, efficacy of UW-BC in remediation HMs from SDGs and circular bio-economy prospective. Current review has highlighted that biochar, when amended alone/in combination, enhances HMs remediation potential. Economic analysis of UW-BC reinforces its viability as a sustainable solution for waste management. Consequently, the application of UW-BC has the potential to contribute significantly to the achievement of multiple SDGs, warranting further research and increased investment in this field.PMID:40040805 | PMC:PMC11879596 | DOI:10.1016/j.isci.2025.111915

Plant J. 2025 Mar;121(5):e70039. doi: 10.1111/tpj.70039.ABSTRACTThe aromatic composition of lignin greatly influences the potential utility of lignocellulosic biomass. Previously, we generated transgenic rice plants with altered lignin aromatic composition and enhanced biomass utilization properties by suppressing the expression of p-COUMAROYL ESTER 3-HYDROXYLASE (C3'H). While RNAi-derived C3'H-knockdown lines displayed relatively normal growth with substantially augmented levels of p-hydroxyphenyl-type lignin units, genome-edited C3'H-knockout lines exhibited severely impaired growth phenotype, leading to arrested seedling development. In this study, we further characterized the genome-edited C3'H-knockout rice by analyzing gene expression and phenolic metabolite profiles alongside phenotypic traits and cell wall lignin structure. The seedlings of the C3'H-knockout rice displayed irregular vasculature and ectopic lignification. RNA-sequencing analysis detected widespread changes in the expression of genes associated with plant growth, hormone biosynthesis and signaling, and stress responses in the C3'H-knockout rice. Overall, our data suggested that C3'H disruption activates metabolic sensor-mediated signaling pathways, which in turn regulate phenylpropanoid metabolism. In line with this, phenolic metabolite profiling of the C3'H-knockout rice revealed not only shifts in monolignol-associated phenylpropanoids but also reductions in flavonoids and salicylic acid derivatives. Moreover, changes in the aromatic composition of the mutant lignin and phenolic metabolites indicated the presence of parallel monolignol pathways enabling rice to produce guaiacyl- and syringyl-type monolignol derivatives in the absence of C3'H activity. Our findings contribute to a deeper understanding of the mechanisms underlying the growth defects of lignin-modified mutants, with implications for optimizing the utility of grass lignocellulose.PMID:40040338 | DOI:10.1111/tpj.70039

Stem Cell Res Ther. 2025 Mar 5;16(1):115. doi: 10.1186/s13287-025-04213-9.ABSTRACTBACKGROUND: Spaceflight and microgravity environments have been shown to cause significant health impairments, including bone loss, immune dysfunction, and hematopoietic disorders. Hematopoietic stem cells (HSCs), as progenitors of the hematopoietic system, are critical for the continuous renewal and regulation of immune cells. Therefore, elucidating the regulatory mechanisms governing HSC fate and differentiation in microgravity environments is of paramount importance.METHODS: In this study, hindlimb unloading (HU) was employed in mice to simulate microgravity conditions. After 28 days of HU, cells were isolated for analysis. Flow cytometry and colony-forming assays were utilized to assess changes in HSC proliferation and differentiation. Additionally, transcriptomic and untargeted metabolomic sequencing were performed to elucidate alterations in the metabolic pathways of the bone marrow microenvironment and their molecular regulatory effects on HSCs fate.RESULTS: Our findings revealed that 28 days of HU impaired hematopoietic function, leading to multi-organ damage and hematological disorders. The simulated microgravity environment significantly increased the HSCs population in the bone marrow, particularly within the long-term and short-term subtypes, while severely compromising the differentiation capacity of hematopoietic stem/progenitor cells. Transcriptomic analysis of HSCs, combined with metabolomic profiling of bone marrow supernatants, identified 1,631 differentially expressed genes and 58 metabolites with altered abundance. Gene set enrichment analysis indicated that HU suppressed key pathways, including hematopoietic cell lineage and MAPK signaling. Furthermore, integrated analyses revealed that metabolites affected by HU, particularly hypoxanthine enriched in the purine metabolism pathway, were closely associated with hematopoietic cell lineage and MAPK signaling pathways. Molecular docking simulations and in vitro experiments confirmed that hypoxanthine interacts directly with core molecules within these pathways, influencing their expression.CONCLUSIONS: These findings demonstrate that hypoxanthine in the bone marrow supernatant acts as a signaling mediator under microgravity, influencing HSCs fate by modulating hematopoietic cell lineage and MAPK signaling pathways. This study offers novel insights into the impact of microgravity on HSC fate and gene expression, underscoring the pivotal role of bone marrow microenvironmental metabolic changes in regulating key signaling pathways that determine hematopoietic destiny.PMID:40038750 | DOI:10.1186/s13287-025-04213-9

J Transl Med. 2025 Mar 4;23(1):260. doi: 10.1186/s12967-025-06296-7.ABSTRACTBACKGROUND: Microglia-evoked neuroinflammation contributes to neurodegenerative diseases such as multiple sclerosis (MS). Metabolic reprogramming, including changes in polyunsaturated fatty acids (PUFAs), plays a critical role in MS pathophysiology. Previous studies identified reduced plasma α-dimorphecolic acid (α-DIPA), a linoleic acid derivative, in MS patients. This study investigated the anti-inflammatory effects of α-DIPA on microglia and the underlying pathways.METHODS: Lipopolysaccharide (LPS)-induced BV-2 microglial inflammation was used as an in vitro model. α-DIPA effects were assessed via ELISA for nitric oxide (NO) release, flow cytometry was used to examine cell proliferation, activation and polarization, and transcriptomic analysis was applied to identify key signaling pathways regulated by α-DIPA.RESULTS: ELISA results showed that exogenous α-DIPA treatment significantly inhibited LPS-induced NO release from BV-2 cells in a concentration-dependent manner. Moreover, flow cytometry analysis suggested that 40 µM α-DIPA treatment significantly repressed LPS-induced BV-2 cell proliferation, activation, as well as M1 and M2 type polarization. Furthermore, transcriptome analysis revealed that exogenous α-DIPA extensively and drastically decreased the transcriptional level of numerous genes that are involved in the regulation of inflammatory responses, for instance, proinflammatory genes such as Tnf and Ccl3 related to IL-17 and TNF-α signaling. In addition, we also observed that the expression of multiple genes in NF-κB signaling were also inhibited greatly by α-DIPA, such as Nfkb2 and Nfkbia. Notably, α-DIPA robustly suppressed LPS-induced mRNA expression of abundant genes participating in the ferroptosis pathway, including Acsl4, Slc7a11, Me1, and Hmox1. Interestingly, the expressions of multiple ferroptosis-related genes were regulated specifically by α-DIPA but not LPS, such as Acsl5, Acsl6, Alox5, Cars, Dpp3, Dpp10, Slc2a5, and Slc7a1.CONCLUSION: α-DIPA inhibits microglial inflammation likely through regulating the pathways of the ferroptosis and NF-κB signaling. These results provided preliminary evidence for α-DIPA as a potential therapeutic candidate for neurodegenerative diseases like MS.PMID:40038710 | DOI:10.1186/s12967-025-06296-7

BMC Med. 2025 Mar 5;23(1):134. doi: 10.1186/s12916-025-03971-w.ABSTRACTBACKGROUND: Approximately 10-30% of individuals continue to experience symptoms classified as post-acute sequelae of coronavirus disease 2019 (COVID-19 (PASC)). PASC is a multisystem condition primarily characterized by respiratory symptoms, such as reduced diffusing capacity for carbon monoxide (DLco). Although many studies have investigated the pathogenesis of acute COVID-19, the long-term molecular changes in COVID-19 convalescents with PASC remain poorly understood.METHODS: We prospectively recruited 70 individuals who had been diagnosed with COVID-19 from 7 January 2020 to 29 May 2020 (i.e., COVID-19 convalescents); we performed follow-up visits at 6 months, 1 year, 2 years, and 3 years after hospital discharge. Thirty-five healthy controls (CONs), recruited from a physical examination center before the COVID-19 pandemic, served as a comparison group. We explored the proteomic and metabolomic profiles of 174 plasma samples from the 70 COVID-19 convalescents and 35 CONs.RESULTS: We performed a comprehensive molecular analysis of COVID-19 convalescents to investigate host changes up to 3 years after hospital discharge. Our multi-omics analysis revealed activation of cytoskeletal organization and glycolysis/gluconeogenesis, as well as suppression of gas transport and adaptive immune responses, in COVID-19 convalescents. Additionally, metabolites involved in glutathione metabolism; alanine, aspartate, and glutamate metabolism; and ascorbate and aldarate metabolism were significantly upregulated in COVID-19 convalescents. Pulmonary and molecular abnormalities persisted for 3 years in COVID-19 convalescents; impaired diffusing capacity for carbon monoxide (DLco) was the most prominent feature. We used this multi-omics profile to develop a model involving one protein (heterogeneous nuclear ribonucleoprotein K (HNRNPK)) and two metabolites (arachidonoyl-EA and 1-O-(2r-hydroxy-pentadecyl)-sn-glycerol)) for identification of COVID-19 convalescents with abnormal DLco.CONCLUSIONS: These data provide insights concerning molecular sequelae among COVID-19 convalescents up to 3 years after hospital discharge, clarify mechanisms driving respiratory sequelae, and support the development of a novel model to predict reduced DLco. This longitudinal multi-omics analysis may illuminate the trajectory of altered lung function in COVID-19 convalescents.PMID:40038650 | DOI:10.1186/s12916-025-03971-w

BMC Cancer. 2025 Mar 4;25(1):389. doi: 10.1186/s12885-025-13690-3.ABSTRACTBACKGROUND: Reportedly, there is an association between body metabolites and the risk of Hepatocellular Carcinoma (HCC) & Cholangiocarcinoma (CCA), possibly due to disrupted metabolic pathways leading to oxidative stress and an imbalance in cell proliferation and apoptosis, thereby increasing the risk of cancer. However, whether metabolites play a role in the onset of HCC or CCA remains inconclusive.OBJECTIVE: The aim of our study is to explore the potential causal relationship between metabolites and the risk of HCC&CCA.METHODS: Our study investigated the causal relationship between 1400 metabolites and HCC&CCA using publicly available genome-wide association study data. Single nucleotide polymorphisms (SNPs) associated with both metabolites and HCC&CCA were chosen as instrumental variables (IVs). The main approaches employed include inverse variance weighted (IVW), MR-Egger regression, and weighted median estimator (WME), with odds ratios (OR) used as the assessment criterion. Heterogeneity testing and sensitivity analyses were conducted to validate the results. We also conducted a reverse MR analysis to further validate the relationship between exposure and disease outcomes.RESULTS: This Mendelian Randomization (MR) study indicates a significant causal relationship between 19 metabolites and the risk of HCC&CCA. Among them, the risk factors include "Bilirubin (E, Z or Z, E) levels," "Bilirubin (Z, Z) to taurocholate ratio," "Dimethylarginine (sdma + adma) levels," "N-methyltaurine levels," "4-vinylguaiacol sulfate levels," "Cholate to adenosine 3',5'-cyclic monophosphate (cAMP) ratio," "Glycohyocholate levels," "Cholesterol levels," and "4-methylguaiacol sulfate levels." The incidence risk of HCC and CCA increases with the elevation of these metabolites. Protective factors include "Ursodeoxycholate levels," "3-hydroxybutyroylglycine levels," "Linoleoylcholine levels," "Nonanoylcarnitine (C9) levels," "Pristanate levels," "Heptenedioate (C7:1-DC) levels," "Mannonate levels," "N-acetyl-L-glutamine levels," "Sphinganine levels," and "N-lactoyl isoleucine levels." The incidence risk of HCC and CCA potentially decreases as the levels of these metabolites increase. Heterogeneity tests show that most instrumental variables do not exhibit inter-gene heterogeneity, and the possibility of pleiotropy in the analysis is very low according to the sensitivity analysis. The reverse MR analysis did not yield positive results.CONCLUSION: Our study has unveiled the intricate causal relationships between metabolites and the risk of HCC&CCA. Through our analysis, we identified nine metabolites, including "Bilirubin (E, Z or Z, E) levels," "Dimethylarginine (sdma + adma) levels," "Cholesterol levels,"ect, as risk factors for HCC&CCA. The incidence risk of HCC and CCA increases with their elevation. On the other hand, ten metabolites, such as "Ursodeoxycholate levels," "Linoleoylcholine levels," "Pristanate levels," ect, were identified as protective factors for HCC&CCA. The risk of developing HCC and CCA decreases with an increase in these metabolites. In conclusion, these findings further explore the physiological metabolic pathways underlying the pathogenesis of HCC and CCA, emphasizing future research directions. They pave the way for researchers to delve into the biological mechanisms of these diseases, facilitating early intervention and treatment strategies for these conditions.PMID:40038628 | DOI:10.1186/s12885-025-13690-3

J Agric Food Chem. 2025 Mar 4. doi: 10.1021/acs.jafc.4c12089. Online ahead of print.ABSTRACTCell-cultured fish fat (CCF) has the potential to enhance the flavor and texture of cell-cultured fish meat (CCM). Herein, CCF was developed through the adipogenic transdifferentiation of Larimichthys crocea muscle satellite cells (LCMSCs). A low-serum culture system and a large-scale culture system were established. A rapid transdifferentiation medium was also developed, and the mechanisms in promoting adipogenic transdifferentiation were preliminarily analyzed. The results indicated that the proliferation rate and morphology of cells were not significantly affected by serum reduction following domestication. These cells can be cultured in bioreactors, achieving a 10-fold increase in density. The combination of horse serum and oleic acid enabled adipogenic transdifferentiation within 8 days. Transcriptomic and metabolomic analyses revealed significant changes in gene expression and lipid metabolism, with enrichment of pathways related to fatty acid metabolism. Five inducers were quantified to assess the quality of CFF. This study provides a feasible method for CCF production and lays the theoretical basis for the development of CCM.PMID:40038623 | DOI:10.1021/acs.jafc.4c12089

Nat Genet. 2025 Mar 4. doi: 10.1038/s41588-025-02096-3. Online ahead of print.ABSTRACTThe biological mechanisms through which most nonprotein-coding genetic variants affect disease risk are unknown. To investigate gene-regulatory mechanisms, we mapped blood gene expression and splicing quantitative trait loci (QTLs) through bulk RNA sequencing in 4,732 participants and integrated protein, metabolite and lipid data from the same individuals. We identified cis-QTLs for the expression of 17,233 genes and 29,514 splicing events (in 6,853 genes). Colocalization analyses revealed 3,430 proteomic and metabolomic traits with a shared association signal with either gene expression or splicing. We quantified the relative contribution of the genetic effects at loci with shared etiology, observing 222 molecular phenotypes significantly mediated by gene expression or splicing. We uncovered gene-regulatory mechanisms at disease loci with therapeutic implications, such as WARS1 in hypertension, IL7R in dermatitis and IFNAR2 in COVID-19. Our study provides an open-access resource on the shared genetic etiology across transcriptional phenotypes, molecular traits and health outcomes in humans ( https://IntervalRNA.org.uk ).PMID:40038547 | DOI:10.1038/s41588-025-02096-3

Commun Biol. 2025 Mar 4;8(1):364. doi: 10.1038/s42003-025-07795-5.ABSTRACTInvasive plants threaten global ecosystems, yet traditional analyses of functional traits cannot fully explain their dominance over co-occurring natives. Metabolomics offers insights into plant invasions, but single-technique studies often miss critical biochemical mechanisms. We employ a multimodal metabolomics approach (¹H NMR, LC MS/MS, FT-ICR-MS, and MALDI-MSI) to investigate the biochemical basis of Lehmann lovegrass (Eragrostis lehmanniana) invasion in semi-arid North America, comparing it with a co-occurring native grass, Arizona cottontop (Digitaria californica). Our analysis reveals three metabolomic traits of Lehmann lovegrass compared to Arizona cottontop: Enhanced nitrogen allocation in shoots, reduced defensive metabolites in root layers; and increased root exudate modulation under stress conditions. These traits suggest Lehmann lovegrass succeeds through adaptation to increasing aridity rather than direct competition, demonstrating adaptation to nutrient-poor environments and high phenotypic plasticity in response to increasing aridity. This integrated metabolomic approach provides new mechanistic insights into invasion ecology and plant adaptation under environmental change.PMID:40038433 | DOI:10.1038/s42003-025-07795-5