PubMed

BMC Oral Health. 2025 Feb 19;25(1):264. doi: 10.1186/s12903-025-05525-1.ABSTRACTBACKGROUND: Type 2 diabetes mellitus (T2DM) exhibits a bidirectional relationship with periodontitis, wherein each condition influences the progression of the other. Arachidonic acid (AA) exerts an anti-diabetic effect, while showing a protective effect by regulating the inflammatory response independently of its metabolites. However, its impact on periodontitis with T2DM remains poorly understood.METHODS: The T2DM mouse model was established by combining a high-sugar and high-fat diet with streptozotocin injection, followed by silk ligation to induce periodontitis. Alterations in diabetes-associated symptoms were evaluated. Micro-computed tomography was used to measure bone-related parameters, including the distance from the cementoenamel junction to the alveolar bone crest, bone volume/total volume and bone mineral density. Targeted metabolomics analysis was conducted to evaluate the impact of exogenous AA on serum metabolite levels of AA in mice with type 2 diabetic periodontitis. 16S rRNA gene sequencing was utilized to analyze the microbial diversity. The activity of osteoclasts, levels of inflammatory factors and gene expression related to osteoclasts were investigated using TRAP staining and real-time quantitative PCR.RESULTS: The periodontitis mouse model with T2DM was successfully established. Following two weeks of exogenous AA treatment, a reduction in fasting blood glucose levels was observed in the diabetic periodontitis mice. Exogenous AA alleviated alveolar bone loss in type 2 diabetic periodontitis mice. However, it had no substantial effect on the contents of serum AA-targeted metabolites. Exogenous AA reduced Staphylococcus in subgingival flora of type 2 diabetic periodontitis mice, but had no significant impact on microbial community structure or diversity. Furthermore, it decreased the number of osteoclasts in the alveolar bone of periodontitis with T2DM mice and increased IL-10 mRNA expression in its gingival tissue.CONCLUSION: Exogenous AA may alleviate alveolar bone loss in T2DM mice with periodontitis by reducing the number of osteoclasts and increasing the expression of IL-10 mRNA in periodontal tissues, rather than the change of AA-targeted metabolites in serum or the composition and diversity of microorganisms in subgingival plaque. These findings may provide a potential therapeutic approach for the prevention and treatment of periodontitis with T2DM.PMID:39972454 | DOI:10.1186/s12903-025-05525-1

Mol Med. 2025 Feb 19;31(1):66. doi: 10.1186/s10020-025-01122-8.ABSTRACTBACKGROUND: FOLFOX is the recommended chemotherapy regimen for colorectal cancer (CRC), but its response rate remains low. Our previous studies have established a close relationship between gut microbiota and the anti-CRC effect of FOLFOX, though the underlying mechanisms remain unclear. Diet has been confirmed as a key factor influencing gut microbiota, and high-salt diets, representative of western dietary habits, has been shown to affect gut microbiota, immune function, and the risk of developing CRC. However, the impact of high-salt diets on the anti-CRC efficacy of FOLFOX remains unstudied. Therefore, we aimed to investigate the effect and mechanism of high-salt diets on the anti-CRC effect of FOLFOX.METHODS: We performed 16 S rRNA sequencing and T500 targeted metabolomics analysis on fecal samples from CRC patients and healthy adults. A CRC orthotopic xenograft mouse model was used to study the effect of a high-salt diet on FOLFOX's anti-CRC efficacy. 16 S rRNA sequencing and non-targeted metabolomics were conducted on mouse fecal samples. Flow cytometry was used to assess immune cell infiltration in tumor and paracancerous tissues. A mouse macrophage conditioned medium system, with tryptophan metabolites, was employed to annotate the functional metabolites, followed by in vivo verification using the orthotopic xenograft mouse model.RESULTS: The structure and metabolic profiles of gut microbiota are significantly different between 9 healthy adults and 6 CRC patients. A high-salt diet significantly reduced the efficacy of FOLFOX in mice, with notable changes in gut microbiota and related metabolites. Correlation analysis revealed a significant relationship between gut microbiota, tryptophan metabolites and FOLFOX efficacy. Flow cytometry indicated that a high-salt diet altered macrophage infiltration (CD45+F4/80+) in both the tumor and paracancerous tissues. In vitro experiments confirmed that the tryptophan metabolite SK reduced FOLFOX efficacy, while IPA enhanced it through macrophage-conditioned medium. In vivo, we verified that under a high-salt diet, SK inhibited the efficacy of FOLFOX, while IPA promoted it.CONCLUSION: A high-salt diet reduces the anti-CRC efficacy of FOLFOX through gut bacterial tryptophan metabolism mediated macrophage immunomodulation.PMID:39972411 | DOI:10.1186/s10020-025-01122-8

Anim Microbiome. 2025 Feb 19;7(1):17. doi: 10.1186/s42523-024-00358-9.ABSTRACTBACKGROUND: Intrauterine growth restriction (IUGR) affects up to 30% of piglets in a litter. Piglets exposed to IUGR prioritize brain development during gestation, resulting in a higher brain-to-liver weight ratio (BrW/LW) at birth. IUGR is associated with increased mortality, compromised metabolism, and gut health. However, the dynamic metabolic and microbial shifts in IUGR-affected pigs remain poorly understood. This study aimed to investigate the longitudinal effects of IUGR, defined by a high BrW/LW, on the composition of faecal microbiota and plasma metabolome in pigs from birth to slaughter. One day (± 1) after birth, computed tomography was performed on each piglet to assess their brain and liver weights. The pigs with the highest (IUGR = 12) and the lowest (NORM = 12) BrW/LW were selected to collect faeces and blood during lactation (day 16 ± 0.6, T1) and at the end of the starter period (day 63 ± 8.6, T2) and faeces at the beginning (day 119 ± 11.4, T3) and end of the finisher period (day 162 ± 14.3, T4).RESULTS: Faecal microbial Alpha diversity remained unaffected by IUGR across all time points. However, the Beta diversity was influenced by IUGR at T1 (P = 0.002), T2 (P = 0.08), and T3 (P = 0.03). Specifically, IUGR pigs displayed higher abundances of Clostridium sensu stricto 1 (Padj = 0.03) and Romboutsia (Padj = 0.05) at T1, Prevotellaceae NK3B31 group (Padj = 0.02), Rikenellaceae RC9 gut group (Padj = 0.03), and Alloprevotella (Padj = 0.03) at T2, and p-2534-18B5 gut group (Padj = 0.03) at T3. Conversely, the NORM group exhibited higher abundances of Ruminococcus (Padj = 0.01) at T1, HT002 (Padj = 0.05) at T2, and Prevotella_9 (Padj < 0.001) at T3. None of the plasma metabolites showed significant differences at T1 between the IUGR and NORM pigs. However, at T2, asparagine was lower in the IUGR compared to the NORM group (P < 0.05).CONCLUSIONS: These findings show that growth restriction in the uterus has a significant impact on the faecal microbiota composition in pigs, from birth to the beginning of the finisher period, but minimally affects the plasma metabolome profile.PMID:39972381 | DOI:10.1186/s42523-024-00358-9

Nat Metab. 2025 Feb 19. doi: 10.1038/s42255-025-01224-x. Online ahead of print.ABSTRACTMacrophages stimulated by lipopolysaccharide (LPS) generate mitochondria-derived reactive oxygen species (mtROS) that act as antimicrobial agents and redox signals; however, the mechanism of LPS-induced mitochondrial superoxide generation is unknown. Here we show that LPS-stimulated bone-marrow-derived macrophages produce superoxide by reverse electron transport (RET) at complex I of the electron transport chain. Using chemical biology and genetic approaches, we demonstrate that superoxide production is driven by LPS-induced metabolic reprogramming, which increases the proton motive force (∆p), primarily as elevated mitochondrial membrane potential (Δψm) and maintains a reduced CoQ pool. The key metabolic changes are repurposing of ATP production from oxidative phosphorylation to glycolysis, which reduces reliance on F1FO-ATP synthase activity resulting in a higher ∆p, while oxidation of succinate sustains a reduced CoQ pool. Furthermore, the production of mtROS by RET regulates IL-1β release during NLRP3 inflammasome activation. Thus, we demonstrate that ROS generated by RET is an important mitochondria-derived signal that regulates macrophage cytokine production.PMID:39972217 | DOI:10.1038/s42255-025-01224-x

Nature. 2025 Feb 19. doi: 10.1038/s41586-025-08590-2. Online ahead of print.ABSTRACTMitochondrial stress pathways protect mitochondrial health from cellular insults1-8. However, their role under physiological conditions is largely unknown. Here, using 18 single, double and triple whole-body and tissue-specific knockout and mutant mice, along with systematic mitochondrial morphology analysis, untargeted metabolomics and RNA sequencing, we discovered that the synergy between two stress-responsive systems-the ubiquitin E3 ligase Parkin and the metalloprotease OMA1-safeguards mitochondrial structure and genome by mitochondrial fusion, mediated by the outer membrane GTPase MFN1 and the inner membrane GTPase OPA1. Whereas the individual loss of Parkin or OMA1 does not affect mitochondrial integrity, their combined loss results in small body size, low locomotor activity, premature death, mitochondrial abnormalities and innate immune responses. Thus, our data show that Parkin and OMA1 maintain a dual regulatory mechanism that controls mitochondrial fusion at the two membranes, even in the absence of extrinsic stress.PMID:39972141 | DOI:10.1038/s41586-025-08590-2

Sci Rep. 2025 Feb 19;15(1):6032. doi: 10.1038/s41598-025-90100-5.ABSTRACTEupolyphaga sinensis Walker (ESW), a medicinal insect used in traditional Chinese medicine, is renowned for its effects on blood circulation, stasis resolution, and bone and tendon healing. The underlying reasons for the clinical preference for female ESW remain unclear. Previous investigations were limited in scope, focusing narrowly on female specimens, large-molecule compounds, and single pharmacological effect. This study systematically compared female and male ESW in terms of composition and therapeutic efficacy. Metabolomics identified 31 compound types in both female and male ESW, including lipids, amino acids, and fatty acids. Female ESW exhibited significantly higher levels of 8 bioactive compounds, 15 small peptides, and 13 prostaglandins compared to male ESW, which contribute to immunity enhancement, antithrombotic effects, and improved bone metabolism. These differences may underlie the superior medicinal efficacy of female ESW. In the thrombosis model, ESW can cause vasodilation, reduce blood cell aggregation and thrombosis rate of mice tails. It also improved t-PA levels, prolonged APTT, and enhanced hepatic SOD activity, with female ESW showing stronger effects on MDA and D2D levels, indicating its stronger ability to protect cells from damage and fibrinolytic effect. In the osteoporosis model, ESW increased femur length, liver, and thymus indices while regulating serum BALP and Mg levels. Female ESW notably reduced TRACP-5b, OT/BGP, P, and Cu to normal levels, indicating its stronger ability to improved bone metabolism, corrected disturbances in calcium-phosphorus metabolism, and regulated serum inorganic elements. Overall, female ESW exhibited a greater abundance of bioactive components and demonstrated superior anti-thrombotic and anti-osteoporotic effects. These findings highlight the superior therapeutic effects of female ESW due to its enriched bioactive components, supporting its clinical preference while underscoring the potential of male ESW for uilization of resource.PMID:39972042 | DOI:10.1038/s41598-025-90100-5

Nat Commun. 2025 Feb 19;16(1):1780. doi: 10.1038/s41467-025-56939-y.ABSTRACTThe earliest land plants faced a significant challenge in adapting to environmental stressors. Stress on land is unique in its dynamics, entailing swift and drastic changes in light and temperature. While we know that land plants share with their closest streptophyte algal relatives key components of the genetic makeup for dynamic stress responses, their concerted action is little understood. Here, we combine time-course stress profiling using photophysiology, transcriptomics on 2.7 Tbp of data, and metabolite profiling analyses on 270 distinct samples, to study stress kinetics across three 600-million-year-divergent streptophytes. Through co-expression analysis and Granger causal inference we predict a gene regulatory network that retraces a web of ancient signal convergences at ethylene signaling components, osmosensors, and chains of major kinases. These kinase hubs already integrated diverse environmental inputs since before the dawn of plants on land.PMID:39971942 | DOI:10.1038/s41467-025-56939-y

Gut Microbes. 2025 Dec;17(1):2467833. doi: 10.1080/19490976.2025.2467833. Epub 2025 Feb 19.ABSTRACTBariatric surgery is highly effective in achieving weight loss in children and adolescents with severe obesity, however the underlying mechanisms are incompletely understood, and gut microbiome changes are unknown. Here, we show that adolescents exhibit significant gut microbiome and metabolome shifts several months after laparoscopic vertical sleeve gastrectomy (VSG), with increased alpha diversity and notably with enrichment of oral-associated taxa. To assess causality of the microbiome/metabolome changes in phenotype, pre-VSG and post-VSG stool was transplanted into germ-free mice. Post-VSG stool was not associated with any beneficial outcomes such as adiposity reduction compared pre-VSG stool. However, post-VSG stool exhibited a potentially inflammatory phenotype with increased intestinal Th17 and decreased regulatory T cells. Concomitantly, we found elevated fecal calprotectin and an enrichment of proinflammatory pathways in a subset of adolescents post-VSG. We show that in some adolescents, microbiome changes post-VSG may have inflammatory potential, which may be of importance considering the increased incidence of inflammatory bowel disease post-VSG.PMID:39971742 | DOI:10.1080/19490976.2025.2467833

Res Sports Med. 2025 Feb 19:1-15. doi: 10.1080/15438627.2025.2467871. Online ahead of print.ABSTRACTEarly post-traumatic osteoarthritis due to sports injuries is not rare and cell-based therapies are currently used in the treatment. Infrapatellar fat pad (IPFP), synovium (Sy) and subcutaneous adipose (S) tissues were obtained for analysis and MSC isolation. Osteoarthritic (OACs) and normal chondrocytes were co-cultured with MSCs for days seven and 14. Tumour necrosis factor alpha (TNFα), cartilage oligomeric matrix protein (COMP) and matrix metalloproteinase-3 (MMP-3) levels were analysed in the supernatants. Untargeted metabolomic analyses were performed in the collected tissues and co-culture media of the experiment groups. TNFα concentrations were lower in IPFP-MSC and Sy-MSC had lower than OACs on day 14. Likewise, MMP-3 decreased in the same groups on day seven and day 14 (p = 0.036). Metabolomic analysis showed distinct profiles in the tissues and metabolic changes in the co-culture media. The extracellular environment of MSCs derived from the IPFP, Sy and S have distinct features and effects on OACs.PMID:39971374 | DOI:10.1080/15438627.2025.2467871

Eur J Pharmacol. 2025 Feb 17:177388. doi: 10.1016/j.ejphar.2025.177388. Online ahead of print.ABSTRACTAging can cause age-related diseases such as cancer, cardiovascular and neurodegenerative diseases. Cordycepin exerts anti-oxidation, anti-inflammatory and neuroprotective effects. However, the anti-aging effect of cordycepin is still unclear. This study aimed to investigate the anti-aging effect of cordycepin and unravel the underlying mechanism. Cordycepin prolonged the lifespan of C. elegans under normal and heat stress conditions, without effects on the normal growth and reproduction of C. elegans. Cordycepin also improved the locomotion ability, inhibited the deposition of aging pigment lipofuscin and alleviated the oxidative stress damage by decreasing the excessive accumulation of ROS and raising the antioxidant enzyme activities in C. elegans. The metabolomics study showed that cordycepin changed 19 metabolites including citric acid, linoleic acid, oleic acid, glutamic acid, pyruvic acid and so on. Transcriptomics study revealed that cordycepin up-regulated the gene expression of acox-1.2, acox-1.3, acox-1.4, acs-1, acs-15, acdh-1, acdh-4 and acdh-8 in C. elegans, suggesting that cordycepin prolonged its lifespan via regulating fatty acid degradation, fatty acid metabolism and so on. In summary, the current study demonstrated that cordycepin exerted the anti-aging effect on C. elegans by improving the antioxidant system and regulating the genes involved in fatty acid metabolism to inhibit the accumulation of linoleic acid and oleic acid. Therefore, cordycepin might be a promising agent for aging and age-related diseases.PMID:39971228 | DOI:10.1016/j.ejphar.2025.177388

Int J Biol Macromol. 2025 Feb 17:141123. doi: 10.1016/j.ijbiomac.2025.141123. Online ahead of print.ABSTRACTSoybean hull polysaccharide (ASP), a pectic polysaccharide with potential effects on regulating lipid metabolism through gut microbiota and their metabolites, was studied to explore its regulatory mechanisms. The study examined the alleviating effect of ASP on high-fat diet (HFD) zebrafish through histopathological examination and biochemical analysis. Additionally, the lipid-lowering mechanism was analyzed combined with metabolomics and the proliferation of gut microbiota. Results showed that ASP significantly ameliorated body weight and blood lipids and also reduced hepatic lipid accumulation and hepatic lipid peroxidation damage. Bioinformatics analyses showed that ASP administration (240 μg/day) generated significant gut microbiota structural changes in high-fat diet-fed zebrafish, in particular, reducing Proteobacteria and increasing Cetobacterium relative abundance levels. ASP upregulates propionic acid, linoleic acid, 6-hydroxyhexanoic acid, and l-threonine biosynthesis by mediating gut microbiota regulation of amino acid and lipid metabolic pathways. Utilizing a correlation network derived from Spearman's correlation coefficients, significant microbial phylotypes that react to ASP demonstrated a strong association with parameters linked to lipid metabolic disorders. Fecal metabolites (e.g. propionic acid) were positively correlated with gut microbiota (e.g. Cetobacterium) in the high-dose ASP group. Our results provide a theoretical basis for new ASP prebiotic formulations to target the gut microbiota and prevent lipid metabolic disorders.PMID:39971075 | DOI:10.1016/j.ijbiomac.2025.141123

Nucl Med Biol. 2025 Feb 16;144-145:109000. doi: 10.1016/j.nucmedbio.2025.109000. Online ahead of print.ABSTRACTBACKGROUND: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, globally. There is a need for novel biomarkers for early detection and novel, effective targeted therapies. Molecular imaging can faithfully visualize, characterize and quantify specific relevant biological processes.BASIC PROCEDURE: We performed longitudinal dedicated small-animal positron emission tomography-computed tomography (PET/CT) imaging to analyze changes in glucose metabolism using [18F]fluorodeoxyglucose ([18F]FDG), amino acid turnover with [18F]fluoroethyltyrosine ([18F]FET), and chemokine receptor expression using [68Ga]pentixafor targeting CXCR4, during stages of early tumor development, overt HCC and regression. We used two conditional transgenic mouse models of HCC, driven by clinically relevant oncogenes c-MYC (LT2/MYC) or HRASV12 (LT2/RAS). Conditional doxycycline-regulated mouse models, enable liver-specific oncogene activation or inhibition, leading to liver tumor development and regression, respectively. Correlation of our PET/CT findings with our gene expression and metabolomics data and with histological analyses followed.MAIN FINDINGS: We show PET/CT identifies HCC stage-specific and oncogene-specific molecular changes that may serve as potential novel biomarkers and therapeutic targets. Glucose metabolism and CXCR4 chemokine expression are differentially deregulated during HCC development in an oncogene-specific manner. Our [18F]FDG results correlated with glucose transporter GLUT1 gene expression and with our metabolomics data. Increased expression of CXCR4 and CD68 inflammatory markers mirrored [68Ga]pentixafor results in LT2/MYC mice. FET-based measurement of amino acid turnover are insensitive to stages of HCC-development, in our studies. Concurrently, no significant changes in expression of tyrosine metabolism genes were observed.PRINCIPAL CONCLUSIONS: Our study highlights that identified changes in targeted molecular imaging can facilitate a better understanding of underlying biological processes and may help guide novel oncogene-specific targeted anti-tumor therapies in HCC, with promising translational potential.PMID:39970776 | DOI:10.1016/j.nucmedbio.2025.109000

Plant Physiol Biochem. 2025 Feb 16;221:109658. doi: 10.1016/j.plaphy.2025.109658. Online ahead of print.ABSTRACTPotash fertilizer is important for improving fruit quality, but its specific moderating roles must be further explored. To accomplish this objective, we utilized metabolomics and transcriptomics analyses to reveal the changes in metabolites and differential genes after potassium sulfate treatment, and we determined that the treatment substantially enhanced the intrinsic and external quality of 'Yanli' (Fragaria ×ananassa Duch.). The results showed that 345 metabolites were found in wide metabolomics, with 115 up-regulated and 230 down-regulated, in which the primary metabolites were more sugars, and the secondary metabolites were more flavonoids, accounting for 20.26% of the metabolites. Sugar metabolomics revealed a substantial increase in fructose content of 34.2 mg g-1 after potassium sulfate treatment. 2335 differentially expressed genes were found in the transcriptome. The KEGG enrichment scatter plot revealed that the more enriched pathways were metabolic pathways, starch and sucrose metabolism pathways, and flavonoid biosynthesis pathways. Combined transcriptome and metabolomics analyses showed that three genes, FaGal, FaINV and FaFK were highly influential in the sugar metabolic pathway, five candidate genes were identified in the anthocyanin metabolic pathway. This study revealed the regulatory mechanism of potassium sulfate treatment for improving strawberry fruit quality. Our findings provide an important basis for in-depth research on the mechanism of differentially expressed genes as well as substantial theoretical and practical guidance for the scientific and rational application of potash fertilizers in strawberry production.PMID:39970566 | DOI:10.1016/j.plaphy.2025.109658

Sci Total Environ. 2025 Feb 18;968:178872. doi: 10.1016/j.scitotenv.2025.178872. Online ahead of print.ABSTRACTAdoption of sustainable maize cropping practices is urgently needed. Synthetic microbial communities (SynComs) made of plant growth-promoting microorganisms (PGPMs), coupled with biochar from residual biomass, offer an environmentally compatible alternative to inorganic fertilizers and may improve soil fertility. This article extends in a two-year field trial with preliminary results obtained in previous pot experiments, monitoring plant physiology, soil biology and chemistry, and kernel metabolomics. Here, we report the synergistic effect of the co-application of biochar, SynComs, and arbuscular mycorrhizal fungi on the soil microbiome, maize growth, and kernel metabolomic profile. SynComs application did not affect the diversity and richness of soil microbial communities; therefore, it posed a low risk of long-term effects on soil microbial ecology. With SynComs and biochar co-application to the soil, the physiology of maize plants was characterized by higher chlorophyll content, ear weight, and kernel weight. The combination of SynComs and biochar also affected the kernel metabolome, resulting in enriched health-beneficial and anti-stress metabolites. Since the preliminary evidence on the environmental and economic impact of these new associations was more favorable than that of conventional fertilizers, it seems reasonable that their large-scale implementation can eventually favor the transition to more sustainable agriculture.PMID:39970561 | DOI:10.1016/j.scitotenv.2025.178872

Sci Transl Med. 2025 Feb 19;17(786):eadp4447. doi: 10.1126/scitranslmed.adp4447. Epub 2025 Feb 19.ABSTRACTSystemic lupus erythematosus (SLE) is characterized by dysfunctional regulatory T cells (Tregs). We previously showed that protein phosphatase 2A (PP2A) plays a critical role in maintaining the suppressive function of Tregs. Here, we analyzed phosphoproteomics and metabolomics data from PP2A-wild type and PP2A-deficient Tregs and demonstrated that PP2A regulates Treg function through the pentose phosphate pathway (PPP). Furthermore, we proved that the PPP metabolite gluconolactone (GDL) enhances in vitro induced (i)Treg differentiation and function by promoting forkhead box protein 3 and phosphorylated signal transducer and activator of transcription 5 expression and inhibits T helper 17 (TH17) differentiation in murine cells. In short-term imiquimod-induced autoimmunity in mice, treatment with GDL alleviates inflammation by inhibiting TH17 cells. GDL promotes Tregs function and alleviates skin lesions in MRL.lpr lupus-prone mice in vivo. It also promotes Tregs differentiation and function in ex vivo experiments using cells from patients with SLE. Last, in patients suffering from cutaneous lupus erythematosus, topical application of a GDL-containing cream controlled skin inflammation and improved the clinical and histologic appearance of the skin lesions within 2 weeks. Together, we have identified GDL as a PPP metabolite and showed mechanistically that it restores immune regulation in vitro and in vivo by inducing Treg suppressive function and inhibiting TH17 cells. GDL should be considered as a treatment approach for inflammatory and autoimmune diseases.PMID:39970231 | DOI:10.1126/scitranslmed.adp4447

Am J Physiol Cell Physiol. 2025 Feb 19. doi: 10.1152/ajpcell.00873.2024. Online ahead of print.ABSTRACTWe aimed to explore novel pathogenesis in young AR children, and thus finding novel nasal spray reagents for them, especially under 4 years old. In this study, non-targeted metabolomics analyses were employed to explore the differential metabolites in NALF of AR children. CCK-8 and flow cytometry were employed to assess cell proliferation and apoptosis in HNEpCs. HNEpCs were co-cultured with CD4+T cells, and flow cytometry was employed to detect Th17/Treg cells. RNA sequencing was employed to assess the key pathways in xanthine-treated Jurkat T cells. Finally, both the in vitro and in vivo experiments were employed to assess the effect of DPCPX (Adora1 inhibitor) on ATF4 expression and Th17/Treg cells. Xanthine and uric acid levels were increased in NALF of AR children. XDH, PNP, xanthine/hypoxanthine, and uric acid levels were elevated in Derp1-treated HNEpCs, and si-XDH reversed the reduced cell viability and increased cell apoptosis in Derp1-treated HNEpCs. Both xanthine and Derp1-treated HNEpCs increased Th17/Treg ratio. ERS pathway was affected in xanthine-treated Jurkat T cells, and ATF4 was markedly reduced in xanthine-treated Jurkat T cells. Xanthine exhibited no effect on Adora1 expression, while DPCPX elevated ATF4 expression and reduced Th17/Treg ratio in xanthine-treated Jurkat T cells. The in vitro experiments revealed that DPCPX reduced inflammatory infiltration, Th17/Treg ratio, IL-17, TNF-α, and IL-6 in AR mice. These results demonstrated that xanthine inhibited ATF4 expression via Adora1 to elevate Th17/Treg ratio in nasal cavity, thus participating in AR progression. These findings may provide novel therapeutic interventions for young AR children.PMID:39970135 | DOI:10.1152/ajpcell.00873.2024

Mol Biol (Mosk). 2024 Sep-Oct;58(5):684-693.ABSTRACTVarious age-related disorders accumulate during aging, causing a decline in tissue and organ function, raising the risk of disease development, and leading to death. Age-related phenotypes are tightly related to an increase in coordinated, progressive changes in the transcriptome, proteome, metabolome, microbiome, and epigenome. Age-dependent modifications of the transcriptome, caused by changes in epigenetic, transcriptional, and post-transcriptional regulation of gene expression, lead to the accumulation of age-related changes in the proteome and metabolome. In turn, dynamic changes in the microbiota during aging also affect gene expression and thus lead to age-related changes in the proteome and metabolome. Recent studies have shown that multi-omic rejuvenation technologies decrease age-related disorders and extend longevity. For example, the short-term induction of the expression of transcription factors that ensure the reprogramming of somatic cells into pluripotent stem cells is accompanied by the restoration of the DNA methylation pattern and transcriptome expression profile characteristic of younger tissues, resulting in an increased lifespan. In this review, we discuss existing multi-omic rejuvenation technologies and the prospects for extending and improving life.PMID:39970112

Mol Biol Cell. 2025 Feb 19:mbcE25020055. doi: 10.1091/mbc.E25-02-0055. Online ahead of print.ABSTRACTAxonemal dynein assembly occurs in the cytoplasm and numerous cytosolic factors are specifically required for this process. Recently, one factor (DNAAF3/PF22) was identified as a methyltransferase. Examination of Chlamydomonas dyneins found they are methylated at sub-stoichiometric levels on multiple sites, including Lys and Arg residues in several of the nucleotide binding domains and on the microtubule-binding region. Given the highly conserved nature of axonemal dyneins, one key question is whether methylation happens only in dyneins from the chlorophyte algae, or if these modifications occur more broadly throughout the motile ciliated eukaryotes. Here we take a phyloproteomic approach and examine dynein methylation in a wide range of eukaryotic organisms bearing motile cilia. We find unambiguous evidence for methylation of axonemal dyneins in alveolates, chlorophytes, trypanosomes, and a broad range of metazoans. Intriguingly, we were unable to identify a single instance of methylation on Drosophila melanogaster sperm dyneins even though dipterans express a Dnaaf3 ortholog, or in spermatozoids of the fern Ceratopteris, which assembles inner arms but lacks both outer arm dyneins and DNAAF3. Thus, methylation of axonemal dyneins has been broadly conserved in most eukaryotic groups and has the potential to variably modify the function of these motors.PMID:39969973 | DOI:10.1091/mbc.E25-02-0055

Metab Brain Dis. 2025 Feb 19;40(3):130. doi: 10.1007/s11011-024-01451-3.ABSTRACTThis study aimed to identify metabolic footprints associated with distinct phenotypes of acute ischemic stroke (AIS) using untargeted metabolomics. We included 20 samples each from AIS phenotype A (n = 251), B (n = 213), and C (n = 43) groups, along with 20 age- and gender-matched healthy controls (HCs). Plasma metabolic profiles were analyzed using liquid chromatography-mass spectrometry (LC-MS). Weighted gene correlation network analysis (WGCNA) evaluated associations between metabolite clusters and clinical traits, including the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). We identified three, five, and six key differential metabolites for diagnosing phenotypes A, B, and C, respectively, demonstrating high diagnostic performance. These metabolites were focused on fatty acids, sex hormones, amino acids, and their derivatives. WGCNA identified 12 core metabolites involved in phenotype progression. Notably, phenylalanylphenylalanine and phenylalanylleucine were inversely correlated with disease severity and disability. Metabolites related to energy supply and inflammation were common across phenotypes, with additional changes in ionic homeostasis in phenotype A and decreased neurotransmitter release in phenotype C. Biosynthesis of unsaturated fatty acids and the pentose phosphate pathway (PPP) were relevant across all phenotypes, while the folate biosynthesis pathway was linked to phenotype C and clinical scales. Key metabolites, including phenylalanylphenylalanine and phenylalanylleucine, and pathways such as folate biosynthesis, significantly contribute to AIS severity and differentiation of phenotypes. These findings offer new insights into the pathogenesis and mechanisms underlying AIS phenotypes.PMID:39969622 | DOI:10.1007/s11011-024-01451-3

Cell Mol Life Sci. 2025 Feb 19;82(1):79. doi: 10.1007/s00018-025-05613-z.ABSTRACTIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial pneumonia, with increasing incidence and prevalence. One of the cellular characteristics is the differentiation of fibroblasts to myofibroblasts. However, the metabolic-related signaling pathway regulated by circular RNAs (circRNAs) during this process remains unclear. Here, we demonstrated that circ0066187 promoted fibroblast-to-myofibroblast differentiation by metabolic-related signaling pathway. Mechanism analysis research identified that circ0066187 directly targeted signal transducer and activator of transcription 3 (STAT3)-mediated metabolism signal pathway to enhance fibroblast-to-myofibroblast differentiation by sponging miR-29b-2-5p, resulting in pulmonary fibrosis. Integrative multi-omics analysis of metabolomics and proteomics revealed three pathways co-enriched in proteomics and metabolomics, namely, Protein digestion and absorption, PI3K-Akt signaling pathway, and FoxO signaling pathway. In these three signaling pathways, seven differentially expressed metabolites such as L-glutamine, L-proline, adenosine monophosphate (AMP), L-arginine, L-phenylalanine, L-lysine and L-tryptophan, and six differentially expressed proteins containing dipeptidyl peptidase-4 (DPP4), cyclin D1 (CCND1), cyclin-dependent kinase 2 (CDK2), fibroblast growth factor 2 (FGF2), collagen type VI alpha 1 (COL6A1) and superoxide dismutase 2 (SOD2) were co-enriched. Gain-and loss-of-function studies and rescue experiments were performed to verify that circ0066187 promoted STAT3 expression by inhibiting miR-29b-2-5p expression to control the above metabolites and proteins. As a result, these metabolites and proteins provided the material basis and energy requirements for the progression of pulmonary fibrosis. In conclusion, circ0066187 can function as a profibrotic metabolism-related factor, and interference with circ0066187 can prevent pulmonary fibrosis. The finding supported that circ0066187 can be a metabolism-related therapeutic target for IPF treatment.PMID:39969586 | DOI:10.1007/s00018-025-05613-z