PubMed

J Tissue Eng. 2025 Jan 28;16:20417314241295928. doi: 10.1177/20417314241295928. eCollection 2025 Jan-Dec.ABSTRACTGrowing evidence indicates that type 2 diabetes (T2D) is associated with an increased risk of developing Parkinson's disease (PD) through shared disease mechanisms. Studies show that insulin resistance, which is the driving pathophysiological mechanism of T2D plays a major role in neurodegeneration by impairing neuronal functionality, metabolism and survival. To investigate insulin resistance caused pathological changes in the human midbrain, which could predispose a healthy midbrain to PD development, we exposed iPSC-derived human midbrain organoids from healthy individuals to either high insulin concentration, promoting insulin resistance, or to more physiological insulin concentration restoring insulin signalling function. We combined experimental methods with metabolic modelling to identify the most insulin resistance-dependent pathogenic processes. We demonstrate that insulin resistance compromises organoid metabolic efficiency, leading to increased levels of oxidative stress. Additionally, insulin-resistant midbrain organoids showed decreased neuronal activity and reduced amount of dopaminergic neurons, highlighting insulin resistance as a significant target in PD prevention.PMID:39882547 | PMC:PMC11775974 | DOI:10.1177/20417314241295928

Front Med (Lausanne). 2025 Jan 15;11:1538373. doi: 10.3389/fmed.2024.1538373. eCollection 2024.ABSTRACTAcne vulgaris (AV) is a common inflammatory disorder involving the pilosebaceous unit. Many studies have reported that people with AV have higher levels of total cholesterol (TC), triglycerides (TG), and low-density lipoprotein cholesterol (LDL-c) compared to healthy controls. Hence, they concluded that an unhealthy lipid profile is an independent risk factor for AV. Recent research in metabolomics and lipidomics has been propelled by rapid advancements in technologies including computational methods and mass spectrometry. Using metabolomics and lipidomics approach, a broad range of structurally diverse lipid species were detected and important lipid biomarkers were identified that are vital to the pathogenesis of AV. In this review, we will describe the recent progress in dyslipidemia of AV using metabolomics and lipidomics advances. We will begin with a literature overview of dyslipidemia of AV, followed by a short introduction of metabolomics and lipidomics. Finally, we will focus on applying metabolomics and lipidomics in dyslipidemia of AV.PMID:39882523 | PMC:PMC11774704 | DOI:10.3389/fmed.2024.1538373

BMJ Nutr Prev Health. 2024 Dec 7;7(2):e000883. doi: 10.1136/bmjnph-2024-000883. eCollection 2024.ABSTRACTBACKGROUND: Non-communicable diseases (NCDs), known as chronic diseases, significantly impact patients' quality of life (QoL) and increase medical expenses. The majority of risk factors are modifiable, and metabolomics has been suggested as a promising strategy for their evaluation, though real-world data are scarce. This study evaluated the QoL improvement and cost-effectiveness of a metabolomics-based treatment for NCDs, aiming to restore metabolic dysfunctions and nutritional deficiencies.METHODS: We performed a pre-post intervention analysis using clinical, metabolomics, QoL and economic data obtained from the electronic health records of 765 patients visiting a private practice. The intervention consisted of personalised treatment to restore metabolic dysfunctions and nutritional deficiencies identified by metabolomics alongside the standard treatment for their condition. The mean intervention duration was 401 days.RESULTS: Significant improvement was identified in energy levels, sleep quality, gastrointestinal function and physical activity (p<0.001). 67.9% of participants reported significant improvement in the overall QoL, and the average quality-adjusted life-years (QALYs) increased by 0.064 (95% uncertainty interval 0.050 to 0.078) post-treatment. The incremental cost-effectiveness ratio was estimated at €49.774/QALY (95% CI €40.110 to €61.433). Metabolic profiling demonstrated that 16/35 organic acids and 11/24 total fatty acids were significantly changed post-treatment (p<0.001), participating in key pathways such as energy metabolism, microbiome and neurotransmitter turnover. Vitamin D and 5-methyltetrahydrofolate insufficiency was significantly restored (p=0.036).CONCLUSION: This is the first study providing evidence that the integration of metabolomics in clinical practice can have a clinical benefit for patients' QoL and may be a cost-effective method.PMID:39882279 | PMC:PMC11773651 | DOI:10.1136/bmjnph-2024-000883

Front Endocrinol (Lausanne). 2025 Jan 15;15:1398691. doi: 10.3389/fendo.2024.1398691. eCollection 2024.ABSTRACTBACKGROUND: Dyslipidemia is closely related to diabetic neuropathy. This study examined the potential causal relationship involving 179 lipid species and the disease.METHODS: The pooled data on 179 lipid species and diabetic neuropathy were obtained from previous genome-wide association studies (GWAS). A Mendelian Randomization (MR) method was employed to investigate the potential causal link, and the robustness of the findings was confirmed through comprehensive sensitivity analyses.RESULTS: Genetically, phosphatidylcholine might be associated with the risk of diabetic neuropathy. Upon adjusting for multiple comparisons, higher levels of phosphatidylcholine (16:0_20:2) (OR = 0.82, 95%CI: 0.73-0.91; P < 0.001, FDR = 0.033) and phosphatidylcholine (16:1_18:1) (OR = 0.77, 95%CI: 0.67-0.88; P < 0.001, FDR = 0.019) are associated with a decreased risk of diabetic neuropathy. Further multivariable MR (MVMR) analysis demonstrated the effect of genetically predicted phosphatidylcholine (16:1_18:1) remained after adjusting for body mass index (BMI) and glycated hemoglobin (HbA1c). Sensitivity assessments have confirmed the robustness of these findings, revealing no evidence of heterogeneity or pleiotropy.CONCLUSION: Our research linked certain lipid species with diabetic neuropathy risk, suggesting that targeting lipids could be a therapeutic strategy in clinical trials addressing this condition.PMID:39882262 | PMC:PMC11774734 | DOI:10.3389/fendo.2024.1398691

J Anus Rectum Colon. 2025 Jan 25;9(1):20-24. doi: 10.23922/jarc.2024-080. eCollection 2025.ABSTRACTThe tumor microenvironment has recently been well-studied in various gastrointestinal cancers, including colorectal cancer (CRC). The gut microbiota, a collection of microorganisms in the human gastrointestinal tract, is one of the microenvironments associated with colon carcinogenesis. It has been challenging to elucidate the mechanisms by which gut microbiota contributes to carcinogenesis and cancer progression due to complex interactions with the host, including its metabolites and immune and inflammatory responses. Various studies described the influence of diet on reported changes in the composition and microbiota of gut bacteria and its association with CRC. In recent years, metagenomic techniques such as shotgun sequencing and genome-wide association studies focused on understanding the role of the microbiota and the metabolome on early CRCs and colon carcinogenesis to determine if there are modifiable or intervenable targets for CRC. In this review, we will attempt to provide an overview of gut microbiota related to CRC, with particular attention to the findings of recent studies.PMID:39882224 | PMC:PMC11772794 | DOI:10.23922/jarc.2024-080

Front Microbiol. 2025 Jan 15;15:1521719. doi: 10.3389/fmicb.2024.1521719. eCollection 2024.ABSTRACTINTRODUCTION: Diarrhea is a prevalent disease among calves, which significantly hinders their growth and development, thereby impacting farm productivity and revenue. This study aimed to investigate the impact of diarrhea on calf growth.METHODS: Holstein male calves with similar birth weight (39.5 ± 4.2 kg) were included in this study, and key parameters such as fecal score, diarrhea incidence, and growth performance from birth to weaning were measured. Rectal fecal samples from both diarrheic (n = 24) and healthy calves (n = 24) aged 1-4 weeks were analyzed using 16S rRNA gene sequencing and untargeted metabolomics.RESULTS: Our findings indicated a high prevalence of diarrhea among calves between 1-4 weeks of age on pasture, which led to a marked decrease in growth performance, including average daily gain. At the genus level, the relative abundance of GCA-900066575 in one-week-old diarrheic calves was significantly higher; Escherichia-Shigella and Pseudoflavonifractor were more abundant in two-week-old calves; while Tyzzerella and Lachnospiraceae_UCG-004 increased significantly in four-week-old calves, and correlated negatively with average daily gain, suggesting that these bacteria may promote the occurrence of diarrhea. Correlation analysis revealed that fecal metabolites such as arachidonic acid, cis-vaccenic acid, oleic acid, choline, creatinine, and others were significantly negatively correlated with calf growth performance and were significantly increased in diarrheic calves. WGNCA identified that dark magenta module metabolites were significantly associated with diarrhea traits from 1-4 weeks. Thirteen metabolites, including glycerophospholipids (such as 1-stearoyl-2-hydroxy-sn-glycero-3-phosphoethanolamine), fatty acids (such as dodecanoic acid), and arachidonic acid, were positively correlated with GCA-900066575, Escherichia-shigella, Tyzzerella, and Clostridium_butyricum, but negatively correlated with UBA1819, Lachnoclostridium_sp_YL32, and Clostridium_scindens.DISCUSSION: Therefore, GCA-900066575, Escherichia-shigella, Lachnospiraceae_UCG-004, and Tyzzerella are likely key bacterial genera causing diarrhea in calves, while arachidonic acid, glycerol phospholipids, and fatty acids are critical metabolites associated with this condition. These alterations in the fecal microbiota and metabolite composition were found to be the principal contributors to growth retardation in diarrheic calves.PMID:39881985 | PMC:PMC11778179 | DOI:10.3389/fmicb.2024.1521719

Front Med (Lausanne). 2025 Jan 15;12:1522503. doi: 10.3389/fmed.2025.1522503. eCollection 2025.ABSTRACTINTRODUCTION: Recurrent spontaneous abortion (RSA) represents a significant clinical challenge, with its underlying mechanisms yet to be fully elucidated. Despite advances in understanding, the precise pathophysiology driving RSA remains unclear. Angelica sinensis, a traditional herbal remedy, is frequently used as an adjunctive treatment for miscarriage. However, it remains uncertain whether its primary active component, Angelica sinensis polysaccharide (ASP), plays a definitive role in its therapeutic effects. The specific function and mechanism of ASP in the context of RSA require further investigation.METHODS: In this study, we sought to evaluate autophagy levels at the maternal-fetal interface in RSA patients and in an RSA mouse model treated with ASP, complemented by a comprehensive metabolomic analysis. Autophagy flux in the decidua was compared between eight RSA patients and eight healthy pregnant women. Additionally, changes in autophagy flux were assessed in an RSA mouse model following ASP treatment, with embryos and placental tissues collected for subsequent metabolomic profiling.RESULTS: Our results revealed a significant reduction in Beclin 1 protein levels in the decidua of RSA patients compared to the normal pregnancy group. Conversely, ASP treatment in the RSA mouse model restored autophagy-related protein expression, including ATG7, ATG16L, and Beclin 1, to levels higher than those observed in the untreated RSA group. Metabolomic analyses further identified significant changes in phosphatidylethanolamine levels between ASP-treated and control groups, with differential metabolites enriched in pathways related to glycolysis/gluconeogenesis, glycerolipid metabolism, and glycine, serine, and threonine metabolism. Functional assays revealed that ASP enhances trophoblast cell proliferation, migration, and invasion.CONCLUSION: In summary, our findings demonstrate diminished autophagy activity in RSA patients, while ASP appears to restore autophagy and regulate key metabolic pathways, including glycolysis/gluconeogenesis. These results provide new insights into the protective mechanisms of ASP in RSA, suggesting its potential as a therapeutic intervention for this condition.PMID:39881843 | PMC:PMC11774876 | DOI:10.3389/fmed.2025.1522503

Front Mol Biosci. 2025 Jan 15;11:1452312. doi: 10.3389/fmolb.2024.1452312. eCollection 2024.ABSTRACTINTRODUCTION: Gestational diabetes mellitus (GDM) is a global health concern with significant short and long-term complications for both mother and baby. Early prediction of GDM, particularly late-onset, is crucial for implementing timely interventions to mitigate adverse outcomes. In this study, we conducted a comprehensive metabolomic analysis to explore potential biomarkers for early GDM prediction.METHODS: Plasma samples were collected during the first trimester from 60 women: 20 with early-onset GDM, 20 with late-onset GDM, and 20 with normal glucose tolerance. Using advanced analytical techniques, including liquid chromatography-tandem mass spectrometry (LC-MS/MS) and gas chromatography-mass spectrometry (GC-MS), we profiled over 150 lipid species and central carbon metabolism intermediates.RESULTS: Significant metabolic alterations were observed in both early- and late-onset GDM groups compared to healthy controls, with a specific focus on glycerolipids, fatty acids, and glucose metabolism. Key findings revealed a 4.0-fold increase in TG(44:0), TG(46:0), TG(46:1) with p-values <0.001 and TG(46:2) with 4.7-fold increase and p-value <0.0001 as well as changes in several phospholipids as PC(38:3), PC(40:4) with 1.4-fold increase, p < 0.001 and PE(34:1), PE(34:2) and PE(36:2) with 1.5-fold change, p < 0.001 in late-onset GDM.DISCUSSION: Observed lipid changes highlight disruptions in energy metabolism and inflammatory pathways. It is suggested that lipid profiles with distinct fatty acid chain lengths and degrees of unsaturation can serve as early biomarkers of GDM risk. These findings underline the importance of integrating metabolomic insights with clinical data to develop predictive models for GDM. Such models could enable early risk stratification, allowing for timely dietary, lifestyle, or medical interventions aimed at optimizing glucose regulation and preventing complications such as preeclampsia, macrosomia, and neonatal metabolic disorders. By focusing on metabolic disruptions evident in the first trimester, this approach addresses a critical window for improving maternal and fetal outcomes. Our study demonstrates the value of metabolomics in understanding the metabolic perturbations associated with GDM. Future research is needed to validate these biomarkers in larger cohorts and assess their integration into clinical workflows for personalized pregnancy care.PMID:39881810 | PMC:PMC11774710 | DOI:10.3389/fmolb.2024.1452312

Front Vet Sci. 2025 Jan 15;11:1521544. doi: 10.3389/fvets.2024.1521544. eCollection 2024.ABSTRACTINTRODUCTION: A small number of soybean allergens [including Glycinin (11S) and β-Conglycinin (7S)] in the commercially available corn-soybean meal diet can still cause allergy in some weaned piglets, which may be the result of the interaction of genetic, and nutrition, but the specific mechanism is still unclear.METHODS: In this study, 20 allergic piglets and 20 non-allergic piglets were selected from 92 weaned piglets by skin sensitization tests, which were used to examine the whole sequence genome. The indicators related to humoral and cellular immunity, transcriptomics, and metabolomics analysis were determined by randomly selecting 5 boars in the allergic group and non-allergic group and then performing a validation in vitro.RESULTS: The sensitization rate of soybean antigen in the corn-soybean meal diet was 21.74% and there was a gender difference with the sensitization rate of female pigs (31.34%) being higher than that of male pigs (13.23%). Moreover, the levels of inflammatory factors (IL-1β, IL-4, TNF-α) and antibodies (IgG, IgE, and specific IgG) in allergic piglets were significantly higher than those in non-allergic piglets (P < 0.05). Whole genome re-sequencing analysis revealed specific mutations in the exons and URT5 of TRAPPC2, PIR, CFP, and SOWAHD genes and showed significantly higher expression levels of related genes in the spleen of allergic piglets (P < 0.05). Transcriptome analysis identified IL17REL, CCL19, CD1E, CD1.1, etc. immune differential genes, metabolomics results showed that soybean antigen affected the utilization and metabolism of intestinal nutrients in piglets, mainly the digestion and absorption of protein and the synthesis and metabolism of amino acids. Transfection of CFP/TRAPPC2/CCL19 siRNA could partially alleviate the injury of RAW264.7 cells or IPEC-J2 cells induced by β-Conglycinin.CONCLUSION: Therefore, the individual differences in intestinal damage induced by soybean antigen protein in the corn-soybean meal diet are closely related to PIR, CFP, TRAPPC2, SOWAHD, and CCL19 genes. Soybean antigens affect the intestinal nutrient utilization and metabolism of piglets, which provides a scientific reference for the study of soybean antigen sensitization mechanisms, precision nutrition, disease prevention, and control of piglets, and also lays a foundation for human foodborne diseases.PMID:39881721 | PMC:PMC11774947 | DOI:10.3389/fvets.2024.1521544

J Proteome Res. 2025 Jan 29. doi: 10.1021/acs.jproteome.4c00872. Online ahead of print.ABSTRACTLiquid chromatography-mass spectrometry (LC-MS) is an indispensable analytical technique in proteomics, metabolomics, and other life sciences. While OpenMS provides advanced open-source software for MS data analysis, its complexity can be challenging for nonexperts. To address this, we have developed OpenMS WebApps, a framework for creating user-friendly MS web applications based on the Streamlit Python package. OpenMS WebApps simplifies MS data analysis through an intuitive graphical user interface, interactive result visualizations, and support for both local and online execution. Key features include workspace management, automatic generation of input widgets, and parallel execution of tools, resulting in high performance and ready-to-use solutions for online and local deployment. This framework benefits both researchers and developers: scientists can focus on their research without the burden of complex software setups, and developers can rapidly create and distribute custom WebApps with novel algorithms. Several applications built on the OpenMS WebApps template demonstrate its utility across diverse MS-related fields, enhancing the OpenMS ecosystem for developers and a wider range of users. Furthermore, it integrates seamlessly with third-party software, extending its benefits to developers beyond the OpenMS community.PMID:39881492 | DOI:10.1021/acs.jproteome.4c00872

Ann Clin Microbiol Antimicrob. 2025 Jan 29;24(1):9. doi: 10.1186/s12941-025-00777-9.ABSTRACTBACKGROUND: Highly frequent colorectal cancer (CRC) is predicted to have 3.2 million novel cases by 2040. Tumor microenvironment (TME) bacteriome and metabolites are proposed to be involved in CRC development. In this regard, we aimed to investigate the bacteriome and metabolites of healthy, adenomatous polyp, and CRC tissues.METHODS: Sixty samples including healthy (H), adenomatous polyps (AP), adenomatous polyps-adjacent (APA), cancer tumor (CT), and cancer tumor-adjacent (CA) tissues were collected and analyzed by 16 S rRNA sequencing and 1H NMR spectroscopy.RESULTS: Our results revealed that the bacteriome and metabolites of the H, AP, and CT groups were significantly different. We observed that the Lachnospiraceae family depleted concomitant with acetoacetate and beta-hydroxybutyric acid (BHB) accumulations in the AP tissues. In addition, some bacterial species including Gemella morbillorum, and Morganella morganii were enriched in the AP compared to the H group. Furthermore, fumarate was accumulated concomitant to Aeromonas enteropelogenes, Aeromonas veronii, and Fusobacterium nucleatum subsp. animalis increased abundance in the CT compared to the H group.CONCLUSION: These results proposed that beneficial bacteria including the Lachnospiraceae family depletion cross-talk with acetoacetate and BHB accumulations followed by an increased abundance of driver bacteria including G. morbillorum, and M. morganii may reprogram polyp microenvironment leading to tumor initiation. Consequently, passenger bacteria accumulation like A. enteropelogenes, A.veronii, and F. nucleatum subsp. animalis cross-talking fumarate in the TME may aggravate cancer development. So, knowledge of TME bacteriome and metabolites might help in cancer prevention, early diagnosis, and a good prognosis.PMID:39881353 | DOI:10.1186/s12941-025-00777-9

Nat Chem Biol. 2025 Jan 29. doi: 10.1038/s41589-025-01836-0. Online ahead of print.ABSTRACTDiverse bacteria and archaea use atmospheric CO as an energy source for long-term survival. Bacteria use [MoCu]-CO dehydrogenases (Mo-CODH) to convert atmospheric CO to carbon dioxide, transferring the obtained electrons to the aerobic respiratory chain. However, it is unknown how these enzymes oxidize CO at low concentrations and interact with the respiratory chain. Here, we use cryo-electron microscopy and structural modeling to show how Mo-CODHMs (CoxSML) from Mycobacterium smegmatis interacts with its partner, the membrane-bound menaquinone-binding protein CoxG. We provide electrochemical, biochemical and genetic evidence that Mo-CODH transfers CO-derived electrons to the aerobic respiratory chain through CoxG. Lastly, we show that Mo-CODH and CoxG genetically and structurally associate in diverse bacteria and archaea. These findings reveal the basis of the biogeochemically and ecologically important process of atmospheric CO oxidation, while demonstrating that long-range quinone transport is a general mechanism of energy conservation, which convergently evolved on multiple occasions.PMID:39881213 | DOI:10.1038/s41589-025-01836-0

Transl Psychiatry. 2025 Jan 29;15(1):35. doi: 10.1038/s41398-025-03239-0.ABSTRACTRising studies have consistently reported gut bacteriome alterations in schizophrenia (SCZ). However, little is known about the role of the gut virome on shaping the gut bacteriome in SCZ. Here in, we sequenced the fecal virome, bacteriome, and host peripheral metabolome in 49 SCZ patients and 49 health controls (HCs). We compared the gut bacterial community composition and specific abundant bacteria in SCZ patients and HCs. Specific gut viruses and host peripheral metabolites co-occurring with differential bacteria were identified using Multiple Co-inertia Analysis (MCIA). Additionally, we construct a latent serial mediation model (SMM) to investigate the effect of the gut virome on SCZ through the bacteriome and host metabolic profile. SCZ patients exhibited a decreased gut bacterial β-diversity compared to HCs, with seven differentially abundant bacteria, including Coprobacillaceae, Enterococcaceae etc. Gut viruses including Suoliviridae and Rountreeviridae, co-occur with these SCZ-related bacteria. We found that the viral-bacterial transkingdom correlations observed in HCs were dramatically lost in SCZ. The altered correlations profile observed in SCZ may impact microbiota-derived peripheral metabolites enriched in the bile acids pathway, eicosanoids pathway, and others, contributing to host immune dysfunction and inflammation. The SMM model suggested potential causal chains between gut viruses and SCZ, indicating that the effect of gut virome on SCZ is significantly mediated by bacteriome and metabolites. In conclusion, these findings provide a comprehensive perspective on the role of gut microbiota in the pathogenesis of SCZ. They reveal that patients with schizophrenia harbor an abnormal virome-bacteriome ecology, shedding light on the potential development of microbial therapeutics.PMID:39880843 | DOI:10.1038/s41398-025-03239-0

Neurotherapeutics. 2025 Jan 28:e00530. doi: 10.1016/j.neurot.2025.e00530. Online ahead of print.ABSTRACTDL-3-n-butylphthalide (NBP) exhibits promising pharmacological efficacy against ischemia-reperfusion injury, but its protective effects may involve many mechanisms that are yet to be fully understood. This study aimed to profile the metabolic alterations induced by NBP during the process of ischemia-reperfusion using spatial metabolomics. Our study found that NBP could significantly reduce the ischemic area and restore physical function by potentially modulating pathways of the citrate cycle, pyruvate metabolism, autophagy, and unsaturated fatty acid biosynthesis. During the process of ischemia-reperfusion, NBP played a therapeutic role in improving energy supply, decreasing autophagy, and improving unsaturated fatty acid biosynthesis. Subsequent studies confirmed improvements in relevant indices of mitochondrial morphology, autophagy, and ferroptosis after treatment with NBP. These findings shed light on novel mechanisms underlying the efficacy of NBP in treating cerebral ischemia/reperfusion injury associated with ischemic stroke.PMID:39880748 | DOI:10.1016/j.neurot.2025.e00530

J Clin Endocrinol Metab. 2025 Jan 29:dgaf057. doi: 10.1210/clinem/dgaf057. Online ahead of print.ABSTRACTCONTEXT: PCOS pregnancies are linked to metabolic disorders affecting maternal and fetal outcomes, with maternal metabolites differing from those in normal pregnancies.OBJECTIVE: To investigate the metabolic communication at the maternal-fetal interface in PCOS pregnancies.DESIGN: Placenta and umbilical cord serum were analyzed using gas chromatography-mass spectrometry. In-depth analysis was performed with clinical characteristics.SETTING: Placenta and umbilical cord serum were analyzed using gas chromatography-mass spectrometry, alongside clinical characteristics.PARTICIPANTS: 45 uncomplicated PCOS pregnancies and 50 normal pregnancies.INTERVENTION(S): None.MAIN OUTCOME MEASURE(S): The metabolic characteristics at the maternal-fetal interface in PCOS pregnancies and the underlying mechanisms.RESULTS: A total of 79 metabolites in the placenta and 25 in umbilical cord serum showed significant differences between polycystic ovary syndrome (PCOS) and normal pregnancies. The 10 most significant placental metabolites were identified through receiver operating characteristic (ROC) analysis, 9 of which correlated significantly with maternal serum testosterone levels. Lasso regression analysis identified 4 key placental metabolite combinations: gamma-aminobutyric acid, proline, glycine, and isoleucine, achieving an area under the curve (AUC) of 93.24%. In umbilical cord serum, 6 metabolites differed significantly between PCOS and normal pregnancies, with the highest AUC reaching 76.07%, and 5 of these metabolites showed significant correlations with maternal serum testosterone levels. Nine differential metabolites were shared between the placenta and umbilical cord serum, which also shared metabolic pathways, including ABC transporters and aminoacyl-tRNA biosynthesis, potentially influencing maternal-fetal interactions.CONCLUSION: This study identifies the metabolomic profile and key pathways in maternal-fetal communication during PCOS pregnancies.PMID:39880380 | DOI:10.1210/clinem/dgaf057

Environ Pollut. 2025 Jan 27:125759. doi: 10.1016/j.envpol.2025.125759. Online ahead of print.ABSTRACTCr(VI) is widely used in industry and has high toxicity, making it one of the most common environmental pollutants. Long-term exposure to Cr(VI) can cause metabolic disorders and tissue damage. However, the effects of Cr(VI) on liver and gut microbes in fish have rarely been reported. In this study, 240 fish were randomly divided into 3 groups: the control group, low-dose Cr(VI) group (0.5 mg/L), and high-dose Cr(VI) group (2 mg/L). The mechanism by which Cr(VI) affects the enterohepatic axis of common carp was elucidated via multiomic analysis, serology, histomorphology, and physiological and biochemical indices. The results revealed that Cr(VI) stress led to hepatocyte damage, nuclear lysis, inflammatory cell infiltration, and vacuolated degeneration. The structure of the intestinal villi was severely damaged, and the length and width of the intestinal villi were significantly reduced. We also found that the accumulation of Cr(VI) in tissues increased in a concentration-dependent manner, and the content of Cr(VI) in each tissue increased in the order of gut > gill > liver > muscle. Multiple omics studies have revealed that chronic Cr(VI) stress leads to disturbances in the intestinal flora, with a significant reduction in the abundance of the beneficial bacterium Akkermansia and a significant increase in the abundance of the harmful bacterium Escherichia/Shigella. Intestinal injury and dysbiosis lead to an increase in blood LPS levels, further inducing metabolic disorders in the liver. The metabolites in the liver, including geniposide, leucine, C17 sphingosine, and 9,10-DiHODE, were significantly increased, whereas the beneficial metabolites, such as carnitine propionate and palmitoyl ethanolamide, were significantly reduced. In conclusion, our results suggest that chronic Cr(VI) stress leads to disturbances in gut microbial homeostasis and disturbed fatty acid and amino acid metabolism in the liver. LPS released into the bloodstream reaches the liver through the portal circulation, further exacerbating Cr(VI) stress-induced hepatotoxicity. This study revealed the mechanism of Cr(VI) toxicity to the liver-microbiota-gut axis of common carp. Our study provides new insights into the effects of Cr(VI) on the liver-microbiota-gut axis.PMID:39880355 | DOI:10.1016/j.envpol.2025.125759

J Lipid Res. 2025 Jan 27:100750. doi: 10.1016/j.jlr.2025.100750. Online ahead of print.ABSTRACTThe environmental pollutant cadmium (Cd) poses a threat to human health through consumption of contaminated foodstuffs culminating in chronic nephrotoxicity. Mitochondrial dysfunction and excessive reactive oxygen species (ROS) are key to Cd cellular toxicity. Cd-lipid interactions have been less considered. We hypothesized Cd binding to the inner mitochondrial membrane (IMM) phospholipid cardiolipin (CL) and membrane rigidification underlies defective electron transfer by disrupted respiratory supercomplexes (SCs). In Cd-treated rat kidney cortex (rKC) mitoplasts, laurdan (lipid-water interface) and diphenylhexatriene (hydrophobic core) revealed increased and decreased membrane fluidity, respectively. Laurdan-loaded pure CL or IMM biomimetic (40mol% POPC, 35mol% DOPE, 20mol% TOCL, 5mol% SAPI) nanoliposomes were rigidified by 25μM Cd, which was confirmed in live-cell imaging of laurdan or di-4-ANEPPDHQ loaded human proximal convoluted tubule (HPCT) cells. Blue native gel electrophoresis evidenced ∼30% loss of I+III2+IVn SC formation after 5μM Cd for 6h in HPCTs, which was reversed by CL-binding drug MTP-131/SS-31/elamipretide (0.1μM), yet α-tocopherol-insensitive. Moreover, MTP131 attenuated Cd-induced H2O2 (∼30%) and cytochrome c release (∼25%), but not osmotic swelling, in rKC mitochondria as well as Cd-induced ROS (∼25%) in HPCTs. MTP-131 binding to IMM biomimetic nanoliposomes decreased zeta potential, prevented Cd-induced liposome size increase, and membrane rigidification reported by laurdan. Heterologous CRLS1 expression reversed Cd (5μM, 24h) cytotoxicity (∼25%) by MTT assay, Cd (5μM, 3h)-induced ROS and mitochondrial membrane rigidification by Cd (1μM, 1h) in HPCT cells. In summary, we report a novel mechanism for Cd toxicity in which Cd-CL interactions cause IMM rigidification, thereby disrupting correct SC assembly and increasing ROS.PMID:39880166 | DOI:10.1016/j.jlr.2025.100750

Biochim Biophys Acta Bioenerg. 2025 Jan 27:149542. doi: 10.1016/j.bbabio.2025.149542. Online ahead of print.ABSTRACTCircadian rhythms driven by biological clocks regulate physiological processes in all living organisms by anticipating daily geophysical changes, thus enhancing environmental adaptation. Time-resolved serial multi-omic analyses in vivo, ex vivo, and in synchronized cell cultures have revealed rhythmic changes in the transcriptome, proteome, and metabolome, involving up to 50 % of the mammalian genome. Mitochondrial oxidative metabolism is central to cellular bioenergetics, and many nuclear genes encoding mitochondrial proteins exhibit both circadian and ultradian oscillatory expression. However, studies on mitochondrial DNA (mtDNA) gene expression remain incomplete. Using a well-established in vitro synchronization protocol, we investigated the time-resolved expression of mtDNA genes coding for respiratory chain complex subunits, revealing a rhythmic profile dependent on BMAL1, the master circadian clock transcription factor. Additionally, the expression of genes coding for key mitochondrial biogenesis transcription factors, PGC1a, NRF1, and TFAM, showed BMAL1-dependent circadian oscillations. Notably, LC3-II, involved in mitophagy, displayed a similar in-phase circadian expression, thereby maintaining stable respiratory chain complex levels. Moreover, we found that simultaneous mitochondrial biogenesis and degradation occur in a coordinated manner with cycles in organelle dynamics, leading to rhythmic changes in mitochondrial fission and fusion. This study provides new insights into circadian clock regulation of mitochondrial turnover, emphasizing the importance of temporal regulation in cellular metabolism. Understanding these mechanisms opens potential therapeutic avenues for targeting mitochondrial dysfunctions and related metabolic disorders.PMID:39880150 | DOI:10.1016/j.bbabio.2025.149542

Mol Cell Proteomics. 2025 Jan 27:100920. doi: 10.1016/j.mcpro.2025.100920. Online ahead of print.ABSTRACTUnder stress conditions, cells reprogram their molecular machineries to mitigate damage and promote survival. Ubiquitin signaling is globally increased during oxidative stress, controlling protein fate and supporting stress defenses at several subcellular compartments. However, the rules driving subcellular ubiquitin localization to promote concerted response mechanisms remain understudied. Here, we show that K63-linked polyubiquitin chains, known to promote proteasome-independent pathways, accumulate primarily in non-cytosolic compartments during oxidative stress induced by sodium arsenite in mammalian cells. Our subcellular ubiquitin proteomic analyses of non-cytosolic compartments expanded 2.5-fold the pool of proteins (2,494) and provided a comprehensive number of sites (10,157) known to be ubiquitinated during arsenite stress, suggesting their involvement in a myriad of cellular pathways. Moreover, subcellular proteome analyses revealed proteins that are recruited to non-cytosolic compartments under stress, including a significant enrichment of helper ubiquitin-binding adaptors of the ATPase VCP that processes ubiquitinated substrates for downstream signaling. We further show that VCP recruitment to non-cytosolic compartments under arsenite stress occurs in a ubiquitin-dependent manner mediated by its adaptor NPLOC4. Additionally, we show that VCP and NPLOC4 activities are critical to sustain low levels of non-cytosolic K63-linked ubiquitin chains, supporting a cyclical model of ubiquitin conjugation and removal that is disrupted by reactive oxygen species. This work deepens our understanding of the role of localized ubiquitin and VCP signaling in the basic mechanisms of stress response and highlights new pathways and molecular players that are essential to reshape the composition and function of the human subcellular proteome under dynamic environments.PMID:39880084 | DOI:10.1016/j.mcpro.2025.100920

J Ethnopharmacol. 2025 Jan 27:119418. doi: 10.1016/j.jep.2025.119418. Online ahead of print.ABSTRACTETHNOPHARMACOLOGICAL RELEVANCE: Xinbao pill (XBP) is a renowned Chinese patent medicine, primarily efficacious in warming and nourishing the heart and kidneys, supplementing Qi to boost Yang, and promoting blood circulation to remove blood stasis. XBP has been utilized for the treatment of chronic heart failure (CHF) for nearly 30 years, but the lack of clarity regarding the active ingredients of XBP against CHF has hindered its clinical application and further promotion.AIM OF THE STUDY: To comprehensively elucidate the efficacy-specific ingredients and potential mechanism of XBP against CHF.METHODS: The efficacy, chemical profiling and pharmacokinetics of XBP was assessed in a CHF model rat. The anti-CHF mechanism of the mixture of the likely active ingredients was clarified by targeted metabolomics and western blotting analysis.RESULTS: XBP alleviated CHF by enhancing cardiac function, reducing NT-pro BNP, mitigating myocardial damage and degrading extracellular collagen. Following XBP administration, ginsenosides exposed relatively abundant in sham or CHF rats. Ginsenoside Rg1 and notoginsenoside R1 showed downward trends in AUC0-t values in CHF group, accompanied by increasing trends in Vz/F values. Moreover, CHF rats presented significantly elevated levels of ginsenoside Rg1, ginsenoside Rg2 and notoginsenoside R1 in heart. The mixture of ginsenoside Rg1, ginsenoside Rg2 and notoginsenoside R1 demonstrated remarkable efficacy in ameliorating CHF as XBP did. Notably, these three compounds were predominantly localized in mitochondria and exhibited significant potential to enhance mitochondrial homeostasis by inhibiting heme synthesis pathway-mediated decomposition of succinyl CoA.CONCLUSIONS: Our research provides valuable insights that ginsenoside Rg1, ginsenoside Rg2 and notoginsenoside R1 may constitute the anti-CHF active ingredients of XBP for facilitating mitochondrial homeostasis by the suppression of heme synthesis to increase succinyl CoA.PMID:39880064 | DOI:10.1016/j.jep.2025.119418