PubMed

bioRxiv [Preprint]. 2025 Feb 7:2024.09.30.615873. doi: 10.1101/2024.09.30.615873.ABSTRACTJoint injury is a risk factor for post-traumatic osteoarthritis. However, metabolic and microarchitectural changes within the joint post-injury in both sexes remain unexplored. This study identified tissue-specific and spatially-dependent metabolic signatures in male and female mice using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and LC-MS metabolomics. Male and female C57Bl/6J mice were subjected to non-invasive joint injury. Eight days post-injury, serum, synovial fluid, and whole joints were collected for metabolomics. Analyses compared between injured, contralateral, and naïve mice, revealing local and systemic responses. Data indicate sex influences metabolic profiles across all tissues, particularly amino acid, purine, and pyrimidine metabolism. MALDI-MSI generated 2D ion images of bone, the joint interface, and bone marrow, highlighting increased lipid species in injured limbs, suggesting physiological changes across injured joints at metabolic and spatial levels. Together, these findings reveal significant metabolic changes after injury, with notable sex differences.SIGNIFICANCE STATEMENT: Osteoarthritis, the leading cause of disability worldwide, disproportionately affects females with sex being one of the strongest predictors of disease. This disparity is partly driven by sex-specific differences in injury susceptibility, increasing the likelihood of traumatic injury to the anterior cruciate ligament (ACL), other ligaments, and menisci. Using a non-invasive injury model, we demonstrate that injury perturbs the local joint environment and has systemic effects in a sex-specific manner. Furthermore, by leveraging matrix-assisted laser desorption ionization-mass spectrometry imaging of the joint, we provide new insight into the composition of osteochondral tissue at the metabolite level. These sexually dimorphic metabolic responses to joint injury advance current understanding of the complex sexual dimorphism in OA pathogenesis providing a foundation for targeted therapeutic strategies and improved patient outcomes for female patients.PMID:39975211 | PMC:PMC11838485 | DOI:10.1101/2024.09.30.615873

bioRxiv [Preprint]. 2025 Feb 8:2025.02.05.636747. doi: 10.1101/2025.02.05.636747.ABSTRACTBACKGROUND: The rumen harbors a diverse and dynamic microbiome vital in digesting vegetation into metabolic byproducts for energy and general biological function. Although previous studies have reported connections between the rumen and the overall health of the sheep, the exact biological process by which this occurs is not well understood. Therefore, our study aimed to quantify sheep rumen metabolites to determine if enriched biological pathways are differentiable across phenotypic features of sex, age, and weight.RESULTS: We collected and quantified metabolites of rumen samples from sixteen sheep using liquid chromatography-tandem mass spectrometry. We performed a series of univariate and multivariate statistical analyses to interpret the rumen metabolomics data. To identify metabolic pathways associated with the phenotypic features of sex, weight, and age, we used MetaboAnalyst, which identified amino acid metabolism as a distinguishing factor. Among the pathways, phenylalanine metabolism emerged as a key pathway differentiating sheep based on sex and age. Additionally, phenylalanine, tyrosine, and tryptophan biosynthesis were exclusively associated with age. In univariate linear models, we also discovered that these amino acid and protein pathways were associated with weight by age-corrected effect. Finally, we identified arginine and proline biosynthesis as a pathway linked to metabolites with weight.CONCLUSION: Our study identified differential pathways based on the sex, age, and weight features of sheep. Metabolites produced by the rumen may act as an indicator for sheep health and other ruminants. These findings encourage further investigation of the differentially produced metabolites to assess overall sheep health.PMID:39975146 | PMC:PMC11839056 | DOI:10.1101/2025.02.05.636747

bioRxiv [Preprint]. 2025 Feb 2:2025.01.28.635396. doi: 10.1101/2025.01.28.635396.ABSTRACTMediation analysis helps uncover how exposures impact outcomes through intermediate variables. Traditional mean-based total mediation effect measures can suffer from the cancellation of opposite component-wise effects and existing methods often lack the power to capture weak effects in high-dimensional mediators. Additionally, most existing work has focused on continuous outcomes, with limited attention to binary outcomes, particularly in case-control studies. To fill in this gap, we propose an R 2 total mediation effect measure under the liability framework, providing a causal interpretation and applicable to various high-dimensional mediation models. We develop a cross-fitted, modified Haseman-Elston regression-based estimation procedure tailored for case-control studies, which can also be applied to cohort studies with reduced efficiency. Our estimator remains consistent with non-mediators and weak effect sizes in extensive simulations. Theoretical justification on consistency is provided under mild conditions. In the Women's Health Initiative of 2150 individuals, we found that 89% (CI: 73% 91%) of the variation in the underlying liability for coronary heart disease associated with BMI can be explained by metabolomics.PMID:39975081 | PMC:PMC11838279 | DOI:10.1101/2025.01.28.635396

bioRxiv [Preprint]. 2025 Feb 6:2025.02.05.636675. doi: 10.1101/2025.02.05.636675.ABSTRACTThe recent ICH M12 guidance on Drug Interaction Studies encourages the use of alternate approaches for predicting drug-drug interaction (DDI) potential of new chemical entities. One approach involves biomarkers, which are endogenous substrates of drug metabolizing enzymes and transporters (DMET) and can be used to assess the inhibitory potential of new chemical entities during Phase 1 clinical studies. Thus, biomarkers could potentially eliminate the need for dedicated DDI studies with exogenous probe substrates. Metabolomics, in conjunction with in vitro and/or in vivo preclinical models or clinical studies, can be used for biomarker discovery. We developed and applied a novel metabolomics-based DMET biomarker discovery (MDBD) approach to identify and qualify biomarkers of renal organic anion transporter 1 (OAT1) and OAT3. Untargeted metabolomics of pooled plasma and urine samples from a pharmacokinetic DDI study using the OAT1/3 inhibitor, probenecid, yielded 153 features identified as putative OAT1/3 biomarkers. Subsequently, in vitro transporter uptake assays using processed urine samples confirmed 57 of these features as OAT1 and/or OAT3 substrates. Finally, 23 features were clinically validated as OAT1/3 biomarkers through a detailed pharmacokinetic analysis (0-24 h) of plasma and urine samples. These biomarkers, either alone or as part of a panel, can predict OAT1/3-mediated DDIs and interindividual variability in the renal secretory clearance of organic anions across different populations, thereby enabling translational utility in clinical settings. The novel MDBD approach can be extended to discover biomarkers of other transporters and enzymes.SUMMARY: Using clinical and mechanistic in vitro approaches, 23 endogenous substrates of OAT1/3 were identified as potential clinical biomarkers of renal secretary elimination of organic anions.PMID:39975069 | PMC:PMC11838602 | DOI:10.1101/2025.02.05.636675

Food Nutr Res. 2025 Jan 22;69. doi: 10.29219/fnr.v69.10677. eCollection 2025.ABSTRACTOBJECTIVE: Myricetin is a bioactive compound in many edible plants. We have previously demonstrated that myricetin could significantly protect mice against colitis by regulating Treg/Th17 balance, while underlying mechanism remains unclear. The current study aimed to unravel the potential regulating mechanism of myricetin.METHODS: The concentrations of 22 amino acids in colon were determined using HPLC-MS/MS and principal component analysis (PCA) was performed on the data. MetaboAnalyst was used to detect potential biological pathway influenced by myricetin. The results were further verified using qPCR, molecular docking method, and AhR inhibitor.RESULTS: Studies had found that the biosynthesis of phenylalanine, tyrosine, and tryptophan; phenylalanine metabolism; and histidine metabolism were the most important pathways related to myricetin. Therefore, the aryl hydrocarbon receptor (AhR), which is closely related to the metabolism of tryptophan, phenylalanine, and tyrosine, was postulated to be the underlying signaling pathways. Furthermore, administration of myricet in significantly increased the relative expressions of CYP1A1 and CYP1B1, whereas AhR inhibitor abolished the amelioration of myricetin on DSS-induced colitis. Moreover, AhR inhibitor weakened the regulatory effect of myricetin on Treg/Th17 balance. Furthermore, the results obtained by the molecular docking method speculated that myricetin could bind to AhR as a ligand and activate AhR.CONCLUSION: The results suggested that myricetin could exert its protection against dextran sulfate sodium (DSS)-induced colitis by activating AhR signaling pathway.PMID:39974840 | PMC:PMC11836776 | DOI:10.29219/fnr.v69.10677

Front Med (Lausanne). 2025 Feb 5;11:1492383. doi: 10.3389/fmed.2024.1492383. eCollection 2024.ABSTRACTOBJECTIVES: To explore the mechanism underlying the effect of Fructus Akebiae (FAE) against hepatic fibrosis in mice through combined network pharmacology, liver metabolomics, and 16S rDNA analyses of the gut microbiota.METHODS: In this study, we randomly divided mice into the control, model, FAE high-dose, FAE medium-dose, and FAE low-dose groups to analyze the pathological changes in the hepatic fibrosis and levels of the α-SMA, collagen 1, Nuclear Factor Kappa B (NF-κ B), Toll Like Receptor 4 (TLR4). The gut microbiota was analyzed through 16S rDNA sequencing analysis of liver metabolites using liquid chromatography-mass spectrometry. Furthermore, network pharmacology was used to determine the specific molecular regulation mechanism of FAE in hepatic fibrosis treatment.RESULTS: FAE treatment markedly improved the pathological changes in the hepatic fibrosis. Analysis revealed that FAE administration reversed the carbon tetrachloride (CCl4)-induced dysbiosis by increasing the abundance of Akkermansia and reducing that of Cyanobacteria. Additionally, metabolomic analysis showed that FAE treatment reversed the CCl4-induced metabolic disorders by regulating amino and nucleotide sugar metabolism. Furthermore, correlation analysis showed that Akkermansia and Verrucomicobiota were closely related to D-tolasaccharide and maltotetraose saccharide. Moreover, network pharmacology indicated that FAE might regulate the signaling pathway through the JUN/CASP3/NOS3/PTGS2/HSP90AA1 during treatment.CONCLUSION: FAE may be a promising treatment for hepatic fibrosis, and its protective effects are associated with improvements in the microbiome and metabolic disorders.PMID:39974825 | PMC:PMC11835924 | DOI:10.3389/fmed.2024.1492383

Front Endocrinol (Lausanne). 2025 Feb 5;16:1558561. doi: 10.3389/fendo.2025.1558561. eCollection 2025.NO ABSTRACTPMID:39974823 | PMC:PMC11835697 | DOI:10.3389/fendo.2025.1558561

J Anim Sci Technol. 2025 Jan;67(1):164-178. doi: 10.5187/jast.2023.e135. Epub 2025 Jan 31.ABSTRACTTraditionally, velvet antler (VA) has been used as a medicine or dietary supplement in East Asia. It contains biologically active compounds that exert anti-inflammatory, anti-fatigue, anti-aging, and anticancer effects. Although demand for VA has increased globally, its supply and consumption are limited due to the low recovery of its bioactive compounds from traditional decoctions. Therefore, alternative extraction methods are required to enrich the active compounds and enhance their biological efficacy. The extract has been reported to protect against neuropathological conditions in brain cells and suppress oxidative stress and neuroinflammation-crucial for the initiation or progression of neurodegenerative diseases. Therefore, VA is a potential therapeutic agent for neurodegenerative diseases. However, the beneficial effects of VA on astrocytes, which are the predominant glial cells in the brain, remain unclear. In the present study, we investigated the protective effects of enzymatically digested VA extract (YC-1101) on the mitochondria in astrocytes, which are essential organelles regulating oxidative stress. Proteomic and metabolomic results using liquid chromatography-mass spectrometry (LC-MS/MS) identified enriched bioactive ingredients in YC-1101 compared to hot water extract of VA. YC-1101 displayed significant protective effects against mitochondrial stressors in astrocytes compared with other health functional ingredients. Altogether, our results showed improved bioactive efficacy of YC-1101 and its protective role against mitochondrial stressors in astrocytes.PMID:39974783 | PMC:PMC11833196 | DOI:10.5187/jast.2023.e135

Food Chem X. 2024 Oct 5;24:101871. doi: 10.1016/j.fochx.2024.101871. eCollection 2024 Dec 30.ABSTRACTFeeding sheep with high-concentrate diet (HCD) to shorten production cycle is a well-developed feeding strategy to increase lamb production. Here, metabolomics were performed to explore the mechanism that HCD changes lamb nutrition composition. Differential metabolites were enriched in primary bile acid biosynthesis. Significantly higher content of bile acids including taurodeoxycholic acid sodium salt (TDCA), taurochenodeoxycholic acid sodium salt (TCDCA) and taurocholic acid (TCA) was observed in lamb of HCD, while the content of lithocholic acid (LCA), cholic acid (CA), chenodeoxycholic acid (CDCA) and Chenodeoxycholic acid-3-beta-D-glucuronide (CDCA-3Gln) were higher in the controls. Furthermore, a significantly decreased content of fatty acids was observed in lamb of HCD group. Finally, primary skeletal cells treated with CA or TCA showed a significant decrease in contents of fatty acids, while TCA showed a stronger effect in decreasing fatty acid contents. Collectively, we suggest that HCD decreases lamb fatty acid contents by regulating bile acid composition.PMID:39974716 | PMC:PMC11838137 | DOI:10.1016/j.fochx.2024.101871

Food Chem X. 2024 Oct 9;24:101884. doi: 10.1016/j.fochx.2024.101884. eCollection 2024 Dec 30.ABSTRACTIn order to ensure the quality of saozi and expand its usage scenarios, it is necessary to determine the appropriate dose of irradiation. Non-targeted metabonomics method was used to explore the influence of changes in composition induced by different irradiation doses on the sensory characteristics of saozi. With increased irradiation dose (0, 2, 5, and 8 kGy), the TBARS value of saozi increased, whereas aroma, taste, and overall acceptability scores of saozi significantly decreased (p < 0.05). A total of 147 differential components including amino acids, organic acids, fatty acids, purines, and pyrimidines were screened from different irradiation doses of saozi. Twenty significant change pathways were identified in the KEGG enrichment results, most of which involve amino acids, nucleotide substances, acidic substances, among others, indicating that radiation-induced changes in these substances were one of the main reasons affecting the sensory scores of saozi. Considering the sensory scores and changes in the composition of saozi, when using cobalt 60 for the irradiation treatment of saozi, the optimal irradiation dose should be less than 5 kGy.PMID:39974712 | PMC:PMC11838134 | DOI:10.1016/j.fochx.2024.101884

Med Rev (2021). 2024 Aug 29;5(1):76-82. doi: 10.1515/mr-2024-0056. eCollection 2025 Feb.ABSTRACTAdipose-derived mesenchymal stem cells (ADSCs) and bone marrow-derived mesenchymal stem cells (BMSCs) have shown great potential in clinical applications. However, the similarities and differences between these two cell types have not been fully elucidated. Recent advances in transcriptomic and metabolomic research have provided valuable insight into the characteristics and functions of ADSCs and BMSCs. In this perspective article, we review the key findings from these studies, including cellular heterogeneity as well as differences in metabolic and secretory properties. We discuss how these insights can help guide the selection of the most suitable cell source for the clinic, and the optimization of preconditioning strategies prior to clinical deployment. Furthermore, we analyze the current landscape of products and clinical trials involving ADSCs and BMSCs, highlighting their therapeutic potential. We propose that the integration of multi-omics datasets will be crucial for establishing a comprehensive understanding of ADSC and BMSC identity and potency, and the provision of quality-assured stem cell-derived products for the clinic.PMID:39974562 | PMC:PMC11834745 | DOI:10.1515/mr-2024-0056

Food Chem X. 2024 Dec 17;25:102089. doi: 10.1016/j.fochx.2024.102089. eCollection 2025 Jan.ABSTRACTHighland barley β-glucan (HBG) has attracted increasing attention due to its excellent biological activities. However, the effects of HBG on gut flora and metabolites are unknown. Therefore, the effects of HBG on the gut microbiota during fermentation were analyzed by 16 s rRNA sequencing and untargeted metabolomics. The results showed that HBG could enrich microbial diversity, increase the abundance of beneficial bacteria, and inhibit the biology of pathogenic bacteria. In addition, HBG increased the content of short-chain fatty acids and decreased fermentation broth pH. Metabolomics analyses showed that HBG also increased the content of beneficial metabolites such as taurine and affected amino acid metabolism, among other pathways. This study lays the foundation for the application of HBG in functional foods.PMID:39974532 | PMC:PMC11838092 | DOI:10.1016/j.fochx.2024.102089

Food Chem X. 2024 Dec 9;25:102075. doi: 10.1016/j.fochx.2024.102075. eCollection 2025 Jan.ABSTRACTThis study investigated the impact of steaming on the flavor and metabolic profile of Antarctic krill, aiming to elucidate the pathways responsible for flavor development and metabolic shifts during processing. HS-SPME-GC-MS identified key volatile compounds, including alcohols, aldehydes, ketones and so on. The results demonstrated a significant increase in nonanal content from 2.23 ± 0.06 μg/kg to 8.14 ± 1.26 μg/kg after steaming. The formation pathways of two key flavor compounds, nonanal and 1-octen-3-ol, were attributed to fatty acid degradation. Hierarchical clustering and volcano plot showed metabolic shifts between raw and steamed krill, with differential metabolites like hydroquinone and gamma-aminobutyric acid emerging as key contributors to flavor changes. Furthermore, metabolic network further linked these shifts to reactions involving amino acids, nucleotide and other compounds during steaming, impacting the overall taste.PMID:39974529 | PMC:PMC11838135 | DOI:10.1016/j.fochx.2024.102075

Biochem Med (Zagreb). 2025 Feb 15;35(1):010707. doi: 10.11613/BM.2025.010708.ABSTRACTINTRODUCTION: Sphingolipids, essential to trophoblast and endothelial function, may impact inflammation in preeclampsia. However, their specific role in late-onset preeclampsia remains unclear. To address this research gap, we analyzed sphingolipid profiles in pregnancies at high risk for preeclampsia development to identify potential biomarkers and clarify their role in disease pathogenesis.MATERIALS AND METHODS: We monitored 90 pregnant women at high risk for preeclampsia development across four gestational points. These women were later categorized into the group of women with high risk who did not develop preeclampsia (HRG) (70 women) or the preeclampsia group (PG) (20 women). Sphingolipids (sphingosine, sphinganine, sphingosine-1-phosphate (S1P), ceramides C16:0/C24:0, and sphingomyelin C16:0) were quantified via liquid chromatography-tandem mass spectrometry.RESULTS: Sphingolipid profiles revealed distinct patterns between groups. Concentrations of S1P in the HRG increased from the 1st trimester to delivery (P < 0.001). We did not notice significant changes in S1P during pregnancy in the PG but compared with the HRG we found significantly lower concentrations at each test point from the 2nd trimester until delivery (P = 0.020, P = 0.013, P = 0.011, respectively). Ceramides C16:0 and C24:0 demonstrated significant increases over time in HRG (P < 0.001, both). Sphingomyelin C16:0 increased significantly across pregnancy in both groups (P < 0.001 in HRG and P = 0.006 in PG), with no significant differences between groups.CONCLUSIONS: We identified S1P as a potential biomarker for late-onset preeclampsia, with lower concentrations observed in PG compared to HRG. Rising sphingomyelin concentrations in both cohorts might serve as a relevant cardiovascular risk indicator in pregnancies at high risk for preeclampsia.PMID:39974194 | PMC:PMC11838718 | DOI:10.11613/BM.2025.010708

medRxiv [Preprint]. 2025 Jan 25:2025.01.23.25320909. doi: 10.1101/2025.01.23.25320909.ABSTRACTExtracellular vesicles (EVs) released by neurons (nEVs) provide an opportunity to measure biomarkers from the brain circulating in the periphery. No study yet has directly compared molecular cargo in brain tissue to nEVs found in circulation in humans. We compared the levels microRNAs and environmental chemicals because microRNAs are one of the most studied nEV cargoes and offer great potential as biomarkers and environmental chemical load in nEVs is understudied and could reveal levels of chemicals in the brain. To do so, we leveraged matched sets of brain tissue and serum, and isolated serum total EVs and serum nEVs. We also generated and compared metabolomic profiles in a different set of matched serum, serum total EVs, and serum nEVs since metabolite cargo in nEVs is also understudied but could offer potential biomarkers. Highly expressed brain tissue miRNAs showed stronger correlations with nEVs than serum or total EVs. We detected several environmental chemical pollutant classes in nEVs. The chemical pollutant concentrations in nEVs were more strongly correlated with brain tissue levels than those observed between brain tissue and serum or total EVs. We also detected several endogenous metabolite classes in nEVs. Compared to serum and total EVs, there was enrichment of metabolites with known signaling roles, such as bile acids, oleic acid, phosphatidylserine, and isoprenoids. We provide evidence that nEV cargo is closely correlated to brain tissue content, further supporting their utility as a brain liquid biopsy.PMID:39974146 | PMC:PMC11839008 | DOI:10.1101/2025.01.23.25320909

medRxiv [Preprint]. 2025 Feb 4:2025.02.03.25321363. doi: 10.1101/2025.02.03.25321363.ABSTRACTBACKGROUND: Towards improving outcomes for adolescents with obesity, we aimed to define metabolic and microbiome phenotypes at baseline and post-weight loss intervention.METHODS: The Pediatric Obesity Microbiome and Metabolism Study enrolled 220 adolescents aged 10-18 with severe obesity (OB) and 67 healthy weight controls (HWC). Blood, stool, and clinical measures were collected at baseline and after a 6-month intervention for the OB group. Serum metabolomic and fecal microbiome data were analyzed for associations with BMI, insulin resistance, and inflammation. Fecal microbiome transplants were performed on germ-free mice using samples from both groups to assess weight gain and metabolomic changes.RESULTS: Adolescents with OB exhibited elevated serum branched-chain amino acids (BCAA) but reduced ketoacid metabolites (BCKA) compared to HWC. This pattern was sex- and age-dependent, unlike adults with OB, who showed elevated levels of both. The fecal microbiomes of adolescents with OB and HWC had similar diversity but differed in membership and functional potential. FMT from OB and HWC donors had similar effects on mouse body weight, with specific taxa linked to weight gain in FMT recipients. Longitudinal analysis identified metabolic and microbial features correlated with changes in health measures during the intervention.CONCLUSION: Adolescents with OB have unique metabolomic adaptations and microbiome signatures compared to their HWC counterparts and adults with OB.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03139877 (Observational Study) and NCT02959034 (Repository).FUNDING SOURCES: American Heart Association Grants: 17SFRN33670990, 20PRE35180195National Institute of Diabetes and Digestive and Kidney Diseases Grant: R24-DK110492.PMID:39974080 | PMC:PMC11838640 | DOI:10.1101/2025.02.03.25321363

medRxiv [Preprint]. 2025 Feb 6:2025.02.05.25321733. doi: 10.1101/2025.02.05.25321733.ABSTRACTBACKGROUND: Preclinical literature and behavioral human data suggest that diet profoundly impacts the human gut microbiome and energy absorption-a key determinant of energy balance. To determine whether these associations are causal, domiciled controlled feeding studies with precise measurements of dietary intake and energy balance are needed. Metabolomics-a functional readout of microbiome modulation-can help identify putative mechanisms mediating these effects. We previously demonstrated that a high-fiber, minimally processed Microbiome Enhancer Diet (MBD) fed at energy balance decreased energy absorption and increased microbial biomass relative to a calorie-matched fiber-poor, highly processed Western Diet (WD).OBJECTIVE: To identify metabolic signatures distinguishing MBD from WD feeding and potential metabolomic mechanisms mediating the MBD-induced negative energy balance.METHODS: We deployed global metabolomics in feces, serum, and urine using samples collected at the end of a randomized crossover controlled feeding trial delivering 22 days of an MBD and a WD to 17 persons without obesity. Samples were collected while participants were domiciled on a metabolic ward and analyzed using Ultrahigh Performance Liquid Chromatography-Tandem Mass Spectroscopy. Linear mixed effects models tested metabolite changes by diet. Weighted gene network correlation analysis identified metabolite modules correlated with energy balance phenotypes.RESULTS: Numerous metabolites consistently altered in the feces, fasting serum, and/or urine may serve as putative dietary biomarkers of MBD feeding. Fecal diet-microbiota co-metabolites decreased by an MBD correlated with reduced energy absorption and increased microbial biomass. An MBD shifted the urinary metabolome from sugar degradation to ketogenesis-evidence of negative energy balance.CONCLUSIONS: Precisely controlled diets disparate in microbiota-accessible substrates led to distinct metabolomic signatures in feces, fasting serum, and/or urine. These diet-microbiota co-metabolites may be biomarkers of a "fed" (MBD) or "starved" (WD) gut microbiota associated with energy balance. These findings lay the foundation for unveiling causal pathways linking diet-microbiota co-metabolism to energy absorption.PMID:39974023 | PMC:PMC11838622 | DOI:10.1101/2025.02.05.25321733

medRxiv [Preprint]. 2025 Feb 3:2025.01.29.25321260. doi: 10.1101/2025.01.29.25321260.ABSTRACTBiological age (BA), shaped by genetics, lifestyle, and environmental exposures, reflects physiological changes and mediates the effects of social determinants of health (SDoH) in diseases other than multiple sclerosis (MS). We investigated BA acceleration through metabolic profiling in people with MS (PwMS) and its association with SDoH, measured by the area deprivation index. Accelerated BA was observed in PwMS compared to healthy controls in independent adult and pediatric-onset MS cohorts. Greater social deprivation correlated with greater BA acceleration in PwMS. These findings highlight BA as a potential mediator linking SDoH to MS outcomes and a target to reduce health disparities.PMID:39974014 | PMC:PMC11838630 | DOI:10.1101/2025.01.29.25321260

Biostatistics. 2024 Dec 31;26(1):kxaf001. doi: 10.1093/biostatistics/kxaf001.ABSTRACTThere is still more to learn about the pathobiology of coronavirus disease (COVID-19) despite 4 years of the pandemic. A multiomics approach offers a comprehensive view of the disease and has the potential to yield deeper insight into the pathogenesis of the disease. Previous multiomics integrative analysis and prediction studies for COVID-19 severity and status have assumed simple relationships (ie linear relationships) between omics data and between omics and COVID-19 outcomes. However, these linear methods do not account for the inherent underlying nonlinear structure associated with these different types of data. The motivation behind this work is to model nonlinear relationships in multiomics and COVID-19 outcomes, and to determine key multidimensional molecules associated with the disease. Toward this goal, we develop scalable randomized kernel methods for jointly associating data from multiple sources or views and simultaneously predicting an outcome or classifying a unit into one of 2 or more classes. We also determine variables or groups of variables that best contribute to the relationships among the views. We use the idea that random Fourier bases can approximate shift-invariant kernel functions to construct nonlinear mappings of each view and we use these mappings and the outcome variable to learn view-independent low-dimensional representations. We demonstrate the effectiveness of the proposed methods through extensive simulations. When the proposed methods were applied to gene expression, metabolomics, proteomics, and lipidomics data pertaining to COVID-19, we identified several molecular signatures for COVID-19 status and severity. Our results agree with previous findings and suggest potential avenues for future research. Our algorithms are implemented in Pytorch and interfaced in R and available at: https://github.com/lasandrall/RandMVLearn.PMID:39973130 | DOI:10.1093/biostatistics/kxaf001

Brain Behav. 2025 Feb;15(2):e70352. doi: 10.1002/brb3.70352.ABSTRACTOBJECTIVE: This study aimed to explore the causal effects of lipidome on Alzheimer's disease (AD) and the mediated effects of the metabolites using Mendelian randomization (MR).METHODS: Data were obtained in genome-wide association studies, and single-nucleotide polymorphisms were screened according to the underlying assumptions of MR. Subsequently, weighted inverse variance was used to analyze the causality of lipidome with AD as well as the mediated effects of metabolites. Finally, MR-Egger, Cochran's Q, and sensitivity analysis were used to assess horizontal pleiotropy, heterogeneity, and robustness of the results, respectively.RESULTS: The MR analysis showed that phosphatidylcholine (PC) (15:0_18:2) (mediated proportion: 18.30%, p = 0.024) and phosphatidylethanolamine (PE) (18:0_18:2) (mediated proportion: 14.60%, p = 0.028) mediated the reduction of AD risk by lowering betaine levels, which revealed lipidomic susceptibility. The MR-Egger intercept showed no horizontal pleiotropy for all results (p ≥ 0.05). Cochran's Q showed heterogeneity in some of the results. Sensitivity analysis indicated that all results were robust.CONCLUSION: Our findings reveal the pathways through which PC (15:0_18:2) and PE (18:0_18:2) mediated the reduction of AD risk by lowering betaine levels.PMID:39972983 | DOI:10.1002/brb3.70352