PubMed

Cell Death Dis. 2025 Apr 7;16(1):259. doi: 10.1038/s41419-025-07595-z.ABSTRACTDuchenne muscular dystrophy (DMD) is a devastating genetic disorder, whose management is still a major challenge, despite progress in genetic and pharmacological disease-modifying treatments have been made. Mitochondrial dysfunctions contribute to DMD, however, there are no effective mitochondrial therapies for DMD. SIRT1 is a NAD+-dependent deacetylase that controls several key processes and whose impairment is involved in determining mitochondrial dysfunction in DMD. In addition to well-known resveratrol, other potent selective activators of SIRT1 exist, with better pharmacokinetics properties and a safer profile. Among these, SRT2104 is the most promising and advanced in clinical studies. Here we unveil the beneficial effects of SRT2104 in flies, mice, and patient-derived myoblasts as different models of DMD, demonstrating an anti-inflammatory, anti-fibrotic, and pro-regenerative action of the drug. We elucidate, by molecular dynamics simulations, that a conformational selection mechanism is responsible for the activation of SIRT1. Further, the impact of SRT2104 in reshaping muscle proteome and acetylome profiles has been investigated, highlighting effects that mimic those induced by exercise. Overall, our data suggest SRT2104 as a possible therapeutic candidate to successfully counteract DMD progression.PMID:40195304 | DOI:10.1038/s41419-025-07595-z

Neurocrit Care. 2025 Apr 7. doi: 10.1007/s12028-025-02257-6. Online ahead of print.ABSTRACTBACKGROUND: Metabolism is essential for life maintenance, neurological function, and injury repair, yet its role in diffuse axonal injury (DAI) is not fully understood.METHODS: Thirty patients with DAI and 34 patients without DAI were recruited based on the classification criteria using magnetic resonance imaging within 30 days of admission in this exploratory research. Serum samples and clinical parameters were collected on admission, with the Glasgow Outcome Scale Extended at 6 months after injury used as the neurological functional outcome. We did an untargeted metabolomic analysis using liquid chromatography-mass spectrometry.RESULTS: The DAI group and non-DAI group showed significant differences in the expression levels of 27 metabolites in serum, as well as in pupillary light reflex, Glasgow Coma Scale score, and Marshall computed tomography score. Random forest analysis indicated that lysophosphatidylcholine 22:3 sn-2 and carnitine C8:1 greatly contributed to distinguishing patients with DAI from patients without DAI (MeanDecreaseGini: 3.81, 5.16). The combined prediction of DAI using these two metabolites yielded an area under the curve of 0.944, which was higher than the combination of clinical parameters.CONCLUSIONS: The serum metabolomics revealed potential biomarkers for DAI and has significant value for exploring pathogenesis, determining early diagnosis, and improving long-term neurological function.PMID:40195240 | DOI:10.1007/s12028-025-02257-6

Mol Neurobiol. 2025 Apr 7. doi: 10.1007/s12035-025-04906-5. Online ahead of print.ABSTRACTNeuropathic pain (NeP) is a most intractable health problem due to its unsatisfactory treatment effect. Emodin, a natural anthraquinone derivative extracted from Rheum palmatum and Polygonam cuspidatum, exhibits the analgesic effects in various NeP models. However, the underlying mechanisms remain elusive. This study employed whole transcriptome sequencing and metabolomics to elucidate emodin's analgesic mechanism in the spinal cord of chronic constriction injury (CCI) rats. Fifteen-day emodin treatment reversed hyperalgesia and deficit of sciatic nerve function induced by CCI and significantly decreased the concentrations of TNF-α, IL- 1β, IL- 6, IL- 18, and BDNF in the spinal cord of the CCI rats. Transcriptome sequencing revealed altered expression of 85 mRNAs in the spinal cord of emodin-treated and CCI rats, with 53 mRNAs upregulated and 32 mRNAs downregulated. Notably, seven genes (P2RX4, CXCL10, ALOX5, SCN4 A, AURKB, AQP9) overlapped with established NeP targets. Untargeted metabolomic analyses identified 67 significantly altered metabolites (46 upregulated, 32 downregulated) in the spinal cord upon emodin treatment. Integrative analysis highlighted shared pathways between differentially expressed genes and metabolites, including arachidonic acid metabolism, cAMP signaling pathway, and Fc epsilon RI signaling pathway. Western blot and immunofluorescent staining further proved the decreased expression of IBA1, P2X4R, p38 MAPK, p-p38 MAPK, NF-κB, p-NF-κB, and TNF-α, IL- 1β. In conclusion, this study demonstrated that emodin played the analgesic effect in the CCI rats, possibly through suppression of P2X4 purinoceptor signaling in spinal microglia, suggesting a potential therapeutic target for NeP.PMID:40195215 | DOI:10.1007/s12035-025-04906-5

Biomed Chromatogr. 2025 May;39(5):e70078. doi: 10.1002/bmc.70078.ABSTRACTShenhua tablets (SHT), a traditional Chinese medicine (TCM), have shown significant clinical efficacy in treating IgA nephropathy (IgAN), but the underlying mechanisms are not fully understood. This study aims to elucidate the renoprotective effects of SHT on IgAN and explore the potential mechanisms of its action using metabolomics approaches. The renoprotective effects of SHT on IgAN were evaluated in a Thy-1 antibody-induced IgAN rat model. Metabolomics techniques were employed to detect and analyze urine biomarkers of IgAN, and to identify SHT targets and metabolic pathways. SHT significantly reduced the levels of 24-h urine protein (Upro), albumin-to-creatinine ratio (ACR), Interleukin 1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin 6 (IL-6), alleviated kidney tissue damage, and inhibited mesangial cell proliferation. Seventeen urine metabolites were identified as biomarkers for IgAN, 14 of which were restored by SHT. SHT primarily modulated metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis/gluconeogenesis, pyruvate metabolism, and β-alanine metabolism, upregulating citric acid and succinic acid while downregulating pyruvic acid, L-lactic acid, uracil, and malonic semialdehyde. SHT exerts renoprotective effects in IgAN by modulating key metabolic pathways and normalizing abnormal metabolites levels.PMID:40195069 | DOI:10.1002/bmc.70078

J Am Heart Assoc. 2025 Apr 7:e036507. doi: 10.1161/JAHA.124.036507. Online ahead of print.ABSTRACTBACKGROUND: Cardiovascular disease (CVD) is a leading cause of death in women with systemic lupus erythematosus (SLE) due to accelerated atherosclerosis that is not predicted by established CVD risk scores. This study aimed to develop, validate, and test a female-focused predictive atherosclerosis risk signature based on serum metabolites in patients with SLE.METHODS AND RESULTS: Female patients with SLE were assessed for the presence (SLE-P; n=18) or absence (SLE-NP; n=26) of subclinical atherosclerosis using vascular ultrasound for carotid/femoral intima-media thickness. CVD risk was assessed using QRISK3 (which includes SLE diagnosis as a risk factor) and Framingham Risk Score. Serum metabolomics (n≥250) was performed and analyzed using machine learning pipelines. Despite having subclinical atherosclerosis, 44.8% to 100% of patients with SLE-P had low CVD risk according to QRISK3/Framlingham Risk Score scores. Using a lipid-focused metabolomic analysis, an improved atherosclerosis risk predictive signature was developed comprising 35 metabolites/5 clinical traits that classified patients with SLE-P and outperformed CVD risk assessment tools, lipid profiles measured in routine care, and clinical features alone. This "atherosclerosis risk signature" was validated in a second adult female SLE cohort (n=98) that predicted plaque status with moderate accuracy (area under the receiver operating characteristic curve, 0.79). The signature was then refined into a 5-feature subclinical plaque-predictive score that not only stratified the combined SLE-P/SLE-NP cohorts (n=142; area under the receiver operating characteristic curve, 0.84) but also predicted 3-year atherosclerosis progression in female postpubertal patients with juvenile-onset SLE (n=36; area under the receiver operating characteristic curve, 0.79). Finally, the 5-feature score identified distinct high and low subclinical atherosclerosis risk subgroups in a "real-world" setting of unscanned adult patients with SLE (n=38).CONCLUSIONS: This atherosclerosis risk score could improve CVD risk assessment/management in female patients with SLE across age. Validation in non-SLE and healthy cohorts could further substantiate these findings.PMID:40194967 | DOI:10.1161/JAHA.124.036507

Semin Cancer Biol. 2025 Apr 5:S1044-579X(25)00055-0. doi: 10.1016/j.semcancer.2025.03.008. Online ahead of print.ABSTRACTGliomas carry a dismal prognosis and have proven difficult to treat. Current treatments and efforts to target individual signaling pathways have failed. This is thought to be due to genetic and epigenetic heterogeneity and resistance. Therefore, interest has grown in developing a deeper understanding of the metabolic alterations that represent drivers and dependencies in gliomas. Therapies that target glioma-specific metabolic dependencies overcome the challenges of disease heterogeneity. Here, we present the diverse metabolic features of each current clinical subtype of glioma. We believe that this approach will enable the development of novel strategies to specifically target the various clinical and molecular subtypes of glioma using these metabolic features.PMID:40194749 | DOI:10.1016/j.semcancer.2025.03.008

Environ Toxicol Pharmacol. 2025 Apr 5:104684. doi: 10.1016/j.etap.2025.104684. Online ahead of print.ABSTRACTLithium has long been the primary treatment for bipolar disorder and shows promise for managing other neurological and psychiatric conditions. We previously identified the Lithium-inducible SLC6 transporter (List) in Drosophila melanogaster as a gene significantly upregulated in response to lithium chloride supplementation. List encodes a putative amino acid transporter belonging to the Na⁺-dependent solute carrier family 6. Here, we show that List is expressed in the Malpighian tubules, glia, and hindgut. RNA interference-mediated List knockdown in the Malpighian tubules drastically increases lithium-induced mortality. Additionally, List loss-of-function mutants (ListTG4.2) accumulate six times more internal lithium than controls after lithium exposure. Metabolomic analysis revealed disrupted amino acid metabolism and a shift toward a more oxidized cellular redox state in lithium-treated ListTG4.2 mutants. Overall, our findings suggest that List protects flies from lithium toxicity by regulating internal lithium levels and maintaining metabolic and redox balance.PMID:40194719 | DOI:10.1016/j.etap.2025.104684

Reprod Toxicol. 2025 Apr 5:108901. doi: 10.1016/j.reprotox.2025.108901. Online ahead of print.ABSTRACTDisinfection of drinking water is a critical measure for ensuring water safety and controlling waterborne infectious diseases. However, during the disinfection process, a variety of disinfection by-products (DBPs), some of which exhibit reproductive toxicity, are generated. This study aimed to assess whether DBP exposure contributes to the risk of diminished ovarian reserve (DOR) and explored the underlying metabolic mechanisms. A total of 182 participants, including 91 healthy women and 91 women with DOR, were recruited for a case-control study conducted between October 2023 and February 2024. Serum concentrations of DBPs, including dibromoacetic acid (DBAA), monochloroacetic acid (MCAA), dichloroacetic acid (DCAA), trichloroacetic acid (TCAA), chlorate, and perchlorate, were measured to evaluate DBP exposure. Key indicators for evaluating DOR included antral follicle count (AFC), anti-Mullerian hormone (AMH), and follicle-stimulating hormone (FSH). All six DBPs were higher in DOR patients (all p < 0.05). After controlling for covariates, all DBPs showed negative correlations with AMH and AFC, positive correlations with basal FSH, and a significant association with the risk of DOR (all p < 0.05). To further investigate the underlying mechanisms, we conducted an in vitro study using human ovarian granulosa cell line (KGN). KGN cells were exposed to DBAA and perchlorate for 48hours, and metabolomic analysis was performed to identify altered metabolic pathways. Metabolomics data suggested that DBAA and perchlorate might have contributed to DOR by disrupting arginine biosynthesis and purine metabolism, respectively. In conclusion, DBPs exposure might have contributed to DOR risk by disrupting granulosa cell (GC) metabolism.PMID:40194714 | DOI:10.1016/j.reprotox.2025.108901

J Ethnopharmacol. 2025 Apr 5:119754. doi: 10.1016/j.jep.2025.119754. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Wuwei Leze Powder (WLP, སླྱེ་ཏྱེསལྔ་ཐང།) is a classic Traditional Tibetan medicine formula, which has certain clinical efficacy for rheumatoid arthritis (RA). Nevertheless, the pharmacological effects and potential therapeutic mechanisms of WLP on RA remain unclear.AIM OF THE STUDY: The present study aimed to investigate the potential pharmacological mechanisms of anti- RA effect of WLP.MATERIALS AND METHODS: The chemical constituents of WLP were analyzed by UPLC-Q-TOF-MS. A collagen-induced arthritis (CIA) rat model was established to evaluate the swelling, arthritis index. Pathohistological staining and micro-CT were employed to evaluate the therapeutic effects of WLP. Subsequently, serum metabolomic analysis was conducted to elucidate the potential biomarkers and pathways. Finally, an enzyme-linked immunosorbent assay, along with immunofluorescence, RT-qPCR and western blotting, were utilized to verify the anti-RA mechanism of WLP.RESULTS: A total of 109 chemical constituents from WLP were identified by UPLC-Q-TOF-MS. WLP reduced paw swelling, arthritis scores and organ index in the CIA rat model. Histopathological staining and micro-CT observed WLP possesses both anti-inflammatory and bone-protective properties. Subsequently, serum metabolomics identified 12 potential biomarkers, mainly related to amino acid metabolism and the mTOR signaling pathway. ELISA showed that WLP can regulate abnormal levels of inflammatory cytokines (IL-4, IL-10, TNF-α, IL-6, INF-γ and IL-17). Immunofluorescence demonstrated that WLP could regulate the expression of MMP-1, MMP-9, MMP-13 and RANKL. The effect of WLP on the expression of Wnt3a, Wnt10b, β-catenin, RANKL, OPG, p65 and MMP-9 were verified using RT-qPCR and WB, thereby elucidating the anti-arthritis mechanism of WLP.CONCLUSION: The possible mechanism underlying the anti-RA of WLP involves the downregulation of the Wnt/RANKL/NF-κB axis, the restoration of abnormal host metabolite levels, the suppression of synovitis responses, and the attenuation of bone erosion. Considering the high variability of plant materials, the present study takes a batch of WLP as an example, which inevitably has limitations.PMID:40194641 | DOI:10.1016/j.jep.2025.119754

J Pharm Biomed Anal. 2025 Apr 3;262:116868. doi: 10.1016/j.jpba.2025.116868. Online ahead of print.ABSTRACTIdiopathic pulmonary fibrosis is a high-mortality chronic lung disease, and currently existing medications have limited therapeutic efficacy with noticeable adverse effects, urgently necessitating the exploration of more effective and safer treatment options. Our preliminary studies have demonstrated that the leech extract group with molecular weight greater than 10 kDa (>10 kDa group) exhibited superior anti-idiopathic pulmonary fibrosis efficacy. To trace the active components of > 10 kDa group, it was separated by gel electrophoresis and analyzed by Nano LC-MS/MS. To further analyze the effects of these active components on the regulation of metabolic pathways in fibrotic lung tissue, the metabolites of lung tissue were analyzed by UPLC/MS after administration of > 10 kDa group in bleomycin-induced pulmonary fibrosis (BML-induced PF) mice for 28 days at a 0.179 mg/g per day. A total of 17 proteins were identified in > 10 kDa group and 46 endogenous metabolites were identified in lung tissue, among which 18 significantly differential metabolites were screened as potential metabolomics biomarkers. Metabolic pathway analysis demonstrated that these identified differential metabolites mainly involved biosynthesis of unsaturated fatty acids, phenylalanine-tyrosine and tryptophan biosynthesis and tryptophan metabolism signaling pathway, indicating that the active components of > 10 kDa group mainly regulated the metabolic disorders of lung tissue in BLM-induced mice by up-regulating the biosynthesis of unsaturated fatty acids, down-regulating phenylalanine-tyrosine and tryptophan biosynthesis, and adjusting tryptophan metabolism signaling pathway.PMID:40194473 | DOI:10.1016/j.jpba.2025.116868

Neurology. 2025 Apr 8;104(7_Supplement_1):1759. doi: 10.1212/WNL.0000000000208729. Epub 2025 Apr 7.ABSTRACTOBJECTIVE: To develop a novel glioblastoma liquid biopsy through plasma lipidomics.BACKGROUND: Despite aggressive treatment, glioblastoma always recurs because surviving tumor cells acquire new mutations, which can alter cellular metabolism, including that of lipids. Analysis of the lipidomic profile of the plasma of patients with glioblastoma can uncover a deeper understanding of tumor metabolism, while also facilitating the development of a novel liquid biopsy for the diagnosis and monitoring of the disease.DESIGN/METHODS: Thirty six patients with isocitrate dehydrogenase (IDH) wild type glioblastoma were prospectively enrolled and untargeted lipidomics was performed of patient plasma before and after surgery, as well as before and after concurrent chemoradiation. We examined changes in the levels of 472 metabolites at each stage of treatment. Principal component analysis was performed to examine relationships between the lipidomic profiles at different treatment stages, while multiple comparison testing was used to identify metabolites with diagnostic potential.RESULTS: Thirty lipids were identified as significantly increased following surgery, with linoleic acid, TG 54:6, and oleic acid were those with the highest variable of importance (VIP) scores, while CE 22:6 and TG 42:2 were the only two lipids that were significantly decreased following surgery. Three lipids were significantly increased after chemoradiation, including TG 42:1, TG 40:0, and TG 40:1, while TG 49:1 was the only lipid that was decreased. Principal component analysis demonstrates that the lipidomic profile prior to surgery is distinct from those after surgery, prior to chemoradiation, and after chemoradiation.CONCLUSIONS: Plasma lipidomics of patients with glioblastoma reveals multiple lipids as diagnostic biomarkers of tumor presence and treatment stages. The lipidome prior to tumor resection appears to be distinct from that during other treatment stages. These results may lead to the development of a novel liquid biopsy for glioblastoma. Disclaimer: Abstracts were not reviewed by Neurology® and do not reflect the views of Neurology® editors or staff. Disclosure: Dr. Aboubechara has nothing to disclose. Dr. Liu has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Myrobalan. Dr. Liu has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Argenx. Oliver Fiehn has nothing to disclose. Ruben Fragoso has nothing to disclose. An immediate family member of Han Lee has stock in Gilead. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Jonathan Riess has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Regeneron. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Daiichi Sankyo. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Amgen. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche/Genentech. Jonathan Riess has received personal compensation in the range of $500-$4,999 for serving as a Consultant for SeaGen. Jonathan Riess has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Jonathan Riess has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. Rawad Hodeify has nothing to disclose. Orin Bloch has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Monteris Medical. Orin Bloch has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for BrainLab. The institution of Orin Bloch has received research support from NIH. Dr. Aboud has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Servier.PMID:40194073 | DOI:10.1212/WNL.0000000000208729

Elife. 2025 Apr 7;13:RP105039. doi: 10.7554/eLife.105039.ABSTRACTDuring parasitoid wasp infection, activated immune cells of Drosophila melanogaster larvae release adenosine to conserve nutrients for immune response. S-adenosylmethionine (SAM) is a methyl group donor for most methylations in the cell and is synthesized from methionine and ATP. After methylation, SAM is converted to S-adenosylhomocysteine, which is further metabolized to adenosine and homocysteine. Here, we show that the SAM transmethylation pathway is up-regulated during immune cell activation and that the adenosine produced by this pathway in immune cells acts as a systemic signal to delay Drosophila larval development and ensure sufficient nutrient supply to the immune system. We further show that the up-regulation of the SAM transmethylation pathway and the efficiency of the immune response also depend on the recycling of adenosine back to ATP by adenosine kinase and adenylate kinase. We therefore hypothesize that adenosine may act as a sensitive sensor of the balance between cell activity, represented by the sum of methylation events in the cell, and nutrient supply. If the supply of nutrients is insufficient for a given activity, adenosine may not be effectively recycled back into ATP and may be pushed out of the cell to serve as a signal to demand more nutrients.PMID:40193491 | DOI:10.7554/eLife.105039

Rejuvenation Res. 2025 Apr 7. doi: 10.1089/rej.2024.0079. Online ahead of print.ABSTRACTBackground: Although previous observational studies suggest a potential association between gut microbiota (GM) and knee osteoarthritis (KOA), the causal relationships remain unclear, particularly concerning the role of blood metabolites (BMs) as potential mediators. Elucidating these interactions is crucial for understanding the mechanisms underlying KOA progression and may inform the development of novel therapeutic strategies. Objective: This study aimed to determine the causal relationship between GM and KOA and to quantify the potential mediating role of BMs. Methods: Instrumental variables (IVs) for GM and BMs were retrieved from the MiBioGen consortium and metabolomics genome-wide association studies (GWAS) databases. KOA-associated single-nucleotide polymorphisms were sourced from the FinnGen consortium. Inverse-variance weighted approach was utilized as the main analytical method for Mendelian randomization (MR) analysis, complemented by MR-Egger, simple mode, weighted mode, and weighted median methods. The causal relationships between GM, BMs, and KOA were sequentially analyzed by multivariate MR. False discovery rate correction was applied to account for multiple comparisons in the MR results. Sensitivity analyses and reverse MR analysis were also conducted to verify the reliability of the findings. Finally, a two-step approach was employed to determine the proportion of BMs mediating the effects of GM on KOA. Results: MR analysis identified seven gut microbial species that are causally associated with KOA. Additionally, MR analysis of 1091 BMs and 309 metabolite ratios revealed 13 metabolites that influence the risk of KOA. Through two-step analysis, three BMs were identified as mediators of the effects of two GMs on KOA. Among them, 6-hydroxyindole sulfate exhibited the highest mediation percentage (10.26%), followed by N-formylanthranilic acid (6.55%). Sensitivity and reverse causality analyses further supported the robustness of these findings. Conclusion: This research identified specific GMs and BMs that have a causal association with KOA. These findings provide critical insights into how GM may influence KOA risk by modulating specific metabolites, which could be valuable for the targeted treatment and prevention of KOA.PMID:40193247 | DOI:10.1089/rej.2024.0079

J Pineal Res. 2025 Apr;77(3):e70047. doi: 10.1111/jpi.70047.ABSTRACTHepatocyte lipotoxicity is central to the aetiology of nonalcoholic fatty liver disease (NAFLD), a leading cause of liver failure and transplantation worldwide. Long-lasting toxic pollutants have increasingly been considered as environmental risk factors of NAFLD. These include cadmium (Cd), a metal that synergizes with other cellular toxicants and metabolic stimuli to induce fat build-up and lipotoxicity. Recent studies demonstrated that melatonin (MLT) holds great potential as repairing agent in this form of hepatocyte lipotoxicity. In this study, the molecular hints of this MLT effect were investigated by lipidomics analysis in undifferentiated HepaRG cells, a human pre-hepatocyte cell line, exposed to Cd toxicity either alone or combined with prototypical free fatty acids (FFA), namely the saturated species palmitic acid and the monounsaturated oleic acid (OA and PA, respectively), to simulate the cellular lipotoxicity conditions of fatty liver disease. Cd exposure synergized with FFAs to induce cellular steatosis, and PA produced higher levels of lipotoxicity compared to OA by leading to increased levels of H2O2 production and apoptotic death. These effects were associated with changes of the cellular lipidome, which approximate those of NAFLD liver, with differentially expressed lipids in different classes that included triacylglycerols (TG), di- and mono-acylglycerols, phospholipids (PL), sphingolipids, acylcarnitines and FA; characteristic differences were observed in all these classes comparing the combinations of Cd exposure with PA or OA treatments. MLT significantly reduced the effects of either individual or combinatorial treatments of Cd and FFAs on lipotoxicity hallmarks, also repairing most of the alterations of the cellular lipidome, including those of the chain length and number of double bonds of acyl residues esterified to TG and PL classes. These findings and their bioinformatics interpretation suggest a role for the earliest acyl elongase and desaturase steps of FA metabolism in this repairing effect of MLT; biochemistry studies validated such interpretation identifying a specific role for SCD1 activity. This lipidomics study shed light on the cytoprotective mechanism of MLT in Cd and FFA-induced hepatocyte lipotoxicity, highlighting a repairing effect of this molecule on the cellular lipidome, which may hold therapeutic potential in fatty liver diseases.PMID:40193217 | DOI:10.1111/jpi.70047

J Am Soc Nephrol. 2025 Apr 7. doi: 10.1681/ASN.0000000688. Online ahead of print.ABSTRACTBACKGROUND: The APOL1 high-risk haplotype has been associated with chronic kidney disease (CKD) and the deterioration of kidney function, particularly in populations with West African ancestry. However, the mechanisms by which APOL1 risk variants increase the risk for kidney disease and its progression have not been fully elucidated.METHODS: We compared methylation (N = 3,191; 715 [22%] carriers), proteomic (N = 1,240; 169 [14%] carriers), and metabolomic (N = 6,309; 674 [11%] carriers) profiles in African and Hispanic/Latino carriers of two APOL1 high-risk alleles (G1/G1, G2/G2, G1/G2) and non-carriers (G0/G0), excluding heterozygotes (G0/G1, G0/G2), from the PAGE Consortium and UK BioBank. In each study, the associations between the APOL1 high-risk haplotype and up to 722,719 CpG sites, 2,923 proteins, or 836 metabolites were estimated using covariate-adjusted linear regression models, followed by fixed-effects sample size weighted meta-analyses.RESULTS: Significant associations were observed between APOL1 high-risk haplotype and methylation at 52 CpG sites, with 48 located on chromosome 22 and 18 in the vicinity of APOL1 - 4 and MYH9. All significant CpG sites near APOL2 were hypomethylated, whereas those near APOL3 and APOL4 were hypermethylated. APOL1-associated CpG sites were also identified in genes involved in ion transport and mitochondrial stress pathways. Sensitivity analyses indicated consistent yet attenuated effects among heterozygotes, supporting an additive effect of APOL1 risk alleles. Further analyses of the 52 CpG sites identified two near APOL4 exhibiting G1-specific effects, eight associated with CKD but none with eGFR, and three showing heterogeneity by CKD status. Additionally, carrying two APOL1 risk alleles was associated with higher plasma APOL1 protein (β = 1.12, PFDR = 2.26e-70) and lower C18:1 cholesteryl ester metabolite (Z = -4.50, PFDR = 4.83e-3).CONCLUSIONS: Our results demonstrate differential methylation, proteomic, and metabolomic profiles associated with APOL1 high-risk haplotypes.PMID:40193202 | DOI:10.1681/ASN.0000000688

J Pineal Res. 2025 Apr;77(3):e70042. doi: 10.1111/jpi.70042.ABSTRACTDisruption of the circadian clock has been closely linked to the initiation, development, and progression of cancer. This study aims to explore the impact of circadian rhythm disruption (CRD) on triple-negative breast cancer (TNBC). We analyzed bulk and single-cell RNA sequencing data to assess circadian rhythm status in TNBC using multiple bioinformatic tools, alongside metabolomic profiles and tumor microenvironment evaluations to understand the influence of CRD on metabolic reprogramming and immune evasion. The results indicate that TNBC experiences profound CRD. Patients with a higher CRDscore exhibit significantly poorer relapse-free survival compared to those with a lower CRDscore. Cyclic ordering by periodic structure (CYCLOPS) identified significant changes in rhythmic gene expression patterns between TNBC and normal tissues, with TNBC showing a "rush hour" effect, where peak expression times are concentrated within specific time windows. Transcripts with disrupted circadian rhythms in TNBC were found to be involved in key pathways related to cell cycle regulation, metabolism, and immune response. Metabolomic analysis further revealed that TNBCs with high CRDscore are enriched in carbohydrate and amino acid metabolism pathways, notably showing upregulation of tryptophan metabolism. High CRDscore was also linked to an immunosuppressive tumor microenvironment, characterized by reduced immune cell infiltration, exhausted CD8+ T cells, and a diminished response to immune checkpoint blockade therapy. These findings suggest that the disrupted molecular clock in TNBC may activate tryptophan metabolism, thereby promoting immune evasion and potentially reducing the effectiveness of immunotherapy.PMID:40193174 | DOI:10.1111/jpi.70042

Metab Brain Dis. 2025 Apr 7;40(4):173. doi: 10.1007/s11011-025-01593-y.ABSTRACTThis study aimed to investigate the differential metabolic profiles across maternal and offspring brains, serum, and placental tissues in preeclampsia (PE), with a particular focus on elucidating the maternal-offspring brain and tissue cross-talk that may contribute to the complex pathophysiology of PE. PE was induced in rats using the nitric oxide synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) to simulate both early-onset PE (EOPE) and late-onset PE (LOPE). We utilized non-targeted proton nuclear magnetic resonance (NMR) metabolomics to characterize the metabolic profiles of serum, placental tissue extracts, and brain tissues from both mothers and offspring. Multivariate analysis, Spearman correlation, Density-Based Spatial Clustering of Applications with Noise algorithm, Data-Driven Statistical Predictive Correlation network analysis and Tissue heterogeneity analysis were employed to explore tissue-specific metabolic signatures and their interactions. Following L-NAME induction, both EOPE and LOPE presented significant metabolic differences and shared traits across tissues, with distinct tissue-specific responses characterizing the metabolic profile of PE. Serum from both PE groups showed a decrease in tryptophan, isobutyrate, and lactate, with an increase in betaine. Lactate was upregulated in placental tissues, highlighting its metabolic role. Extensive intra-tissue metabolic correlations and inter-tissue metabolite exchanges were detected among the maternal brain, serum, placenta, and offspring brain across all three experimental groups. EOPE and LOPE exhibited distinctly different metabolic characteristics and trajectories of differential metabolites, along with diverse interaction patterns between the maternal/offspring brain and the placenta. This study uncovers the multi-tissue metabolic remodeling in response to preeclampsia, implying that addressing pathophysiological stress is crucial and may have potential implications for neurological outcomes. The comprehensive analysis highlights the pivotal role of the brain-placenta axis in preeclampsia, advocating for a classified diagnostic and management approach.PMID:40192930 | DOI:10.1007/s11011-025-01593-y

J Chem Ecol. 2025 Apr 7;51(2):47. doi: 10.1007/s10886-025-01598-y.ABSTRACTTomato, a globally significant crop, faces continuous threats from pests and pathogens, necessitating alternative approaches to reduce chemical inputs. Beneficial soil microbes, such as arbuscular mycorrhizal fungi (AMF) and plant growth-promoting rhizobacteria (PGPR), offer promising solutions by enhancing plant growth and pest tolerance. However, domestication may have weakened tomatoes' interactions with these microbes, potentially compromising their innate immunity, a hypothesis that remains largely unexplored. To address this gap, we examined the effects of AMF and PGPR inoculation on growth, herbivory resistance, and metabolic responses in the domesticated Solanum lycopersicum 'Moneymaker' and three wild tomato relatives. Our findings reveal that microbial inoculation significantly influences both domesticated and wild tomatoes, with PGPR generally enhancing and AMF reducing plant growth across species. Using targeted and untargeted metabolomics, we found that soil microbes substantially alter plant chemistry above- and belowground in a species-specific manner. Notably, herbivore responses were more affected by AMF presence than by tomato species. These results highlight that while domestication has profoundly shaped tomato traits, microbial interactions can modulate these phenotypes. Thus, selecting microbial strains best suited to modern cultivars is crucial for optimizing plant growth and resilience against pests.PMID:40192909 | DOI:10.1007/s10886-025-01598-y

Reproduction. 2025 Apr 1:REP-24-0378. doi: 10.1530/REP-24-0378. Online ahead of print.ABSTRACTThe placenta plays a crucial role beyond nutrient transfer, acting as a dynamic endocrine organ that significantly influences maternal physiology and fetal development. It responds rapidly to even slight changes in the in utero environment to promote fetal survival. Disruptions in placental function are increasingly recognized as key contributors to the origins of neurodevelopmental disorders. In this study, we employed advanced technology to induce intrauterine inflammation through ultrasound-guided administration of LPS into gestational sacs. We then evaluated its effects on the gene expression of enzymes involved in TRP metabolism and conducted a comprehensive LC/MS analysis of the metabolome in the placenta and fetal brain of Wistar rats. Our results show that intraamniotic injection of LPS induces a robust inflammatory response leading to significant alterations in TRP metabolism, including downregulation of tryptophan hydroxylase (TPH) in the placenta, resulting in a decrease in serotonin (5-HT) levels. Similarly, in the fetal brain, exposure to LPS led to reduced TPH expression and increased monoamine oxidase expression, suggesting a decrease in 5-HT synthesis and an increase in its degradation. Furthermore, an upregulation of the kynurenine pathway was observed in both the placenta and fetal brain. Moreover, we detected a shift towards neurotoxicity, evidenced by an imbalance between neuroprotective and neurotoxic metabolites, including decreased levels of kynurenic acid and upregulation of kynurenine monooxygenase in the fetal brain. In conclusion, our findings reveal significant alterations in TRP metabolism following intrauterine inflammation, potentially contributing to neurodevelopmental disorders.PMID:40192828 | DOI:10.1530/REP-24-0378

Food Funct. 2025 Apr 7. doi: 10.1039/d5fo00469a. Online ahead of print.ABSTRACTAlcoholic liver injury is primarily caused by long-term excessive alcohol consumption and has become a global public health concern. It is well known that selenium (Se) has excellent beneficial effects in regulating oxidative stress and protecting liver function. However, the effects of different species of Se compounds on alcohol-induced liver injury and their underlying mechanisms remain unclear. Hence, this study investigated the intervention of three different species of Se compounds-Se-enriched Cardamine violifolia peptides (CV), Se-enriched soybean peptides (SO), and sodium selenite (SS)-in an alcohol-induced liver injury mice model. The results of serum biochemical indices and hepatic oxidative stress indexes showed that although both Se-enriched peptides and SS exhibited protective effects against alcohol-induced liver injury, Se-enriched peptides exerted a better effect than SS. Liver metabolomics studies revealed that 30, 15, and 30 metabolites with significant differences were identified in the comparisons of CV vs. model group (MC), SO vs. MC, and SS vs. MC groups, respectively. Common differential metabolites in the three comparison groups were dopamine glucuronide, docosahexaenoic acid, glycerophosphocholine, galactinol and sclareol. KEGG analysis indicated that the differential metabolites between the SS vs. MC groups were enriched in the glycerophospholipid metabolism pathway. The significant metabolic pathways enriched in the SO vs. MC groups were α-linolenic acid metabolism, citric acid cycle, and glucagon signaling pathway. In the CV vs. MC groups, metabolic pathways related to insulin secretion, carbohydrate digestion and absorption, inositol phosphate metabolism, and C-type lectin receptor signaling pathway were also identified. In addition, the intervention of Se-enriched peptides regulated alcohol-induced dysbiosis of the gut microbiota and upgraded the levels of short-chain fatty acids. In the CV group, differential taxa included unidentified_Bacteria, unidentified_Bacteria family and unidentified_Bacteria genus. The dominant species in the SO group included the Atopobiaceae and Turicibiacter. In conclusion, these findings revealed the important role of the gut-liver axis in the protective effects of Se-containing compounds against alcoholic liver injury. Se-enriched peptides, particularly those from CV with selenocystine as the main Se specie, hold great promise as a novel functional food ingredient for the prevention of alcoholic liver injury.PMID:40192491 | DOI:10.1039/d5fo00469a