PubMed

Food Res Int. 2025 Jan;199:115385. doi: 10.1016/j.foodres.2024.115385. Epub 2024 Nov 19.ABSTRACTGut dysbiosis is a characteristic feature of obesity and targeting gut microbiota presents a promising approach to attenuate obesity. Euglena gracilis polysaccharide (EGP) has emerged as a potential prebiotic capable of promoting health-beneficial bacteria. However, its effects on the gut dysbiosis of obese individuals remain unclear. This study investigated the impacts of EGP on gut microbiota from both non-obese and obese individuals using an in vitro fermentation model. Results showed that EGP significantly altered the gut microbiota composition and metabolism. Specifically, EGP improved the relative abundance of Paeniclostridium, Clostridium_sensu_stricto_1 and Paraclostridium of the non-obese individuals and Providencia, Enterococcus and Bacteroides of the obese individuals. Metabolomics results showed EGP significantly altered the lipid metabolism especially in the obese group with enriched bile secretion and cholesterol metabolism pathways. Noting that acetic acid was significantly increased in both groups, these acetic acid favorable microbiota from non-obese individuals was collected with acetic acid supplementation. Transplantation of these acetic acid-induced microbiota (AAiM) notably improved the richness and diversity of fecal microbiota of the obese individuals, enhancing the growth of probiotics like Bacteroides and Bifidobacterium. Consequently, AAiM significantly restructured macronutrients (including amino acids, carbohydrates and lipids) metabolism of the gut microbiota from obese individuals. Altogether, this study underscores the potential of EGP and acetic acid favorable microbiota in manipulating obesity-associated gut dysbiosis via acetic acid production.PMID:39658176 | DOI:10.1016/j.foodres.2024.115385

Int J Biol Macromol. 2024 Dec 8:138400. doi: 10.1016/j.ijbiomac.2024.138400. Online ahead of print.ABSTRACTHigh molecular weight polysaccharides (GLPH, ≥300 kDa) are the major compounds of Ganoderma lucidum with improving liver function. However, the effect of GLPH on improving acute liver injury (ALI) wasn't revealed. Herein, the ameliorating effects and mechanisms of GLPH were revealed in lipopolysaccharide (LPS)-ALI mice. The results indicated that GLPH intervention (100 mg/kg day) reduced the serum ALT (22.67 ± 6.48 U/L), AST (21.19 ± 7.08 U/L), ALP (56.98 ± 12.71 U/L), GGT (1.48 ± 0.22 U/L) levels in ALI mice (p < 0.01). GLPH activated the hepatic antioxidant enzymes activity [SOD (3.75 ± 1.17 U/mg prot.) and CAT (3.01 ± 0.85 U/mg prot.)] and suppressed the hepatic inflammatory cytokines production [TNF-α (40.14 ± 8.15 pg/mg prot.), IL-1β (35.47 ± 10.90 pg/mg prot.), and IL-6 (8.44 ± 1.71 pg/mg prot.)] by regulating the Nrf2/OH-1 and Tlr4/NF-κB pathway (p < 0.05). Furthermore, GLPH regulated the abundance of Bifidobacterium, Akkermansia, Anaerovorax, and Tyzzerella, which associated with cecal SCFAs, hepatic inflammatory cytokines and antioxidant enzymes. GLPH significantly changed 85 liver metabolites (p < 0.01), which is beneficial for prevent the development of ALI. These results suggested GLPH displayed promising prebiotic properties in relieving ALI, regulating gut microbiota and liver metabolism.PMID:39657883 | DOI:10.1016/j.ijbiomac.2024.138400

J Infect Dis. 2024 Dec 9:jiae532. doi: 10.1093/infdis/jiae532. Online ahead of print.ABSTRACTBACKGROUND: Persons with HIV (PWH) on contemporary antiretroviral therapy (ART) are at elevated risk for developing age-related cardiometabolic diseases. We hypothesized that integrative analysis of cross-tissue, multimodal data from PWH could provide insight into molecular programming that defines cardiometabolic phenotypes in this high-risk group.METHODS: We enrolled 93 PWH without diabetes who were virologically suppressed on contemporary ART and obtained measures of insulin resistance, glucose intolerance, and adiposity. We performed circulating lipidomics, proteomics, and metabolomics, as well as subcutaneous adipose tissue (SAT) bulk transcriptomics, and used multiomics factor analysis (MOFA) to perform integrative analyses of these datasets.RESULTS: The median age was 43 years, median body mass index 30.8 kg/m2, 81% were male, and 56% were self-identified non-Hispanic White. We identified a specific MOFA factor associated with visceral adipose tissue volume (ρ = -0.43), homeostasis model assessment 2 insulin resistance score (ρ = -0.52), liver density (ρ = 0.43), and other cardiometabolic risk factors, which explained more variance in the SAT transcriptome and circulating lipidome compared with the circulating proteome and metabolome. Gene set enrichment analysis of this factor showed extracellular matrix and inflammatory pathways that primarily mapped to SAT myeloid cells and adipose progenitor cells using single-cell deconvolution. Lipidomic analysis showed that this factor was significantly enriched for triacylglycerol and diacylglycerol species.CONCLUSIONS: Our multiomic analysis demonstrated coordinated, multitissue molecular reprogramming in virologically suppressed PWH with elevated cardiometabolic disease risk. Longitudinal studies of PWH with assessments of adipose tissue and lipid handling are necessary to understand mechanisms of cardiometabolic disease in PWH. Clinical Trials Registration. NCT04451980.PMID:39657693 | DOI:10.1093/infdis/jiae532

Cell Metab. 2024 Dec 5:S1550-4131(24)00453-4. doi: 10.1016/j.cmet.2024.11.007. Online ahead of print.ABSTRACTChronological age is a crucial risk factor for diseases and disabilities among older adults. However, individuals of the same chronological age often exhibit divergent biological aging states, resulting in distinct individual risk profiles. Chronological age estimators based on omics data and machine learning techniques, known as aging clocks, provide a valuable framework for interpreting molecular-level biological aging. Metabolomics is an intriguing and rapidly growing field of study, involving the comprehensive profiling of small molecules within the body and providing the ultimate genome-environment interaction readout. Consequently, leveraging metabolomics to characterize biological aging holds immense potential. The aim of this review was to provide an overview of metabolomics approaches, highlighting the establishment and interpretation of metabolomic aging clocks while emphasizing their strengths, limitations, and applications, and to discuss their underlying biological significance, which has the potential to drive innovation in longevity research and development.PMID:39657675 | DOI:10.1016/j.cmet.2024.11.007

Cell Rep Med. 2024 Dec 5:101853. doi: 10.1016/j.xcrm.2024.101853. Online ahead of print.ABSTRACTMetabolic dysfunction-associated steatotic liver disease (MASLD) is a major public health threat globally. Management of patients afflicted with MASLD and research in this domain are limited by the lack of robust well-established non-invasive biomarkers for diagnosis, prognostication, and monitoring. The circulating metabolome reflects both the systemic metabo-inflammatory milieu and changes in the liver in affected individuals. In this review we summarize the available literature on changes in the different components of the metabolome in MASLD with a focus on changes that are linked to the presence of underlying steatohepatitis, severity of disease activity, and fibrosis stage. We further summarize the existing literature around biomarker panels that are derived from interrogation of the metabolome. Their relevance to disease biology and utility in practice are also discussed. We further highlight potential direction for future studies particularly to ensure they are fit for purpose and suitable for widespread use.PMID:39657668 | DOI:10.1016/j.xcrm.2024.101853

Biomed Pharmacother. 2024 Dec 9;181:117731. doi: 10.1016/j.biopha.2024.117731. Online ahead of print.ABSTRACTThe interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and RORγt inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reverses disease severity and RORγt activation induced by a RORγt agonist and IL-23, a Th17 inducing cytokine. These results demonstrated that intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and RORγt inverse agonist, is reduced in IBD and in models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.PMID:39657506 | DOI:10.1016/j.biopha.2024.117731

J Hazard Mater. 2024 Dec 7;485:136818. doi: 10.1016/j.jhazmat.2024.136818. Online ahead of print.ABSTRACTResidual concentrations of antibiotics in water can reach ng mL-1 - µg mL-1 levels, which pose high risks to crops during irrigation; however, the interactions between rice and antibiotics, as well as the defense mechanisms of rice at their early growth phase remain unclear. In this study, we investigated the uptake dynamics of a ubiquitously found antibiotic, ciprofloxacin (CIP) at 0.1, 1, 6.5, and 20 µg mL-1 in rice seedlings. We found gradually bioaccumulated CIP induced significant physiological changes including inhibited growth of roots and leaves of rice seedlings, and decreased pigment contents, which can be caused by disrupted homeostasis of reactive oxygen species. Integrating roots transcriptomics, metabolomics, and validation experiments, we found that rice seedlings synthesized more gibberellins to trigger the expression of transcription factors such as group VII ethylene response factors, which induced metabolic reprogramming to yield more fatty acids derivates. These compounds including eicosanoids, isoprenoids, and fatty acids and conjugates can act as signaling molecules, as well as antioxidants and energy sources to achieve rice recovery. This conclusion is supported by the evidence showing that adding gibberellins in rice seedlings culture decreased the accumulated CIP and improved rice growth; whilst, disrupting gibberellin signaling pathway using paclobutrazol as an inhibitor increased uptaken CIP in both roots and leaves with augmenting the antibiotic stress on rice. This study has demonstrated a gibberellin-based defense mechanism in rice for defense of CIP stress, which might have significant environmental applications since we can add minor gibberellins to reduce bioaccumulated CIP with simultaneously promoting rice growth at their early phases.PMID:39657495 | DOI:10.1016/j.jhazmat.2024.136818

Microbiol Res. 2024 Dec 6;292:127995. doi: 10.1016/j.micres.2024.127995. Online ahead of print.ABSTRACTThis review provides a comprehensive analysis of the intricate architecture of bacterial sensing systems, with a focus on signal transduction mechanisms and their critical roles in microbial physiology. It highlights quorum sensing (QS), quorum quenching (QQ), and quorum sensing interference (QSI) as fundamental processes driving bacterial communication, influencing gene expression, biofilm formation, and interspecies interactions. The analysis explores the importance of diffusible signal factors (DSFs) and secondary messengers such as cAMP and c-di-GMP in modulating microbial behaviors. Additionally, cross-kingdom signaling, where bacterial signals impact host-pathogen dynamics and ecological balance, is systematically reviewed. This review introduces "signalomics", an novel interdisciplinary framework integrating genomics, proteomics, and metabolomics to offer a holistic framework for understanding microbial communication and evolution. These findings hold significant implications for various domains, including food preservation, agriculture, and human health.PMID:39657399 | DOI:10.1016/j.micres.2024.127995

Ecotoxicol Environ Saf. 2024 Dec 9;289:117491. doi: 10.1016/j.ecoenv.2024.117491. Online ahead of print.ABSTRACTThe increasing exposure to biomass-burning emissions underscores the need to understand their toxicological impacts on human health. In this study, we developed a laboratory model to evaluate the effects of single and repeated sub-acute exposures to water-soluble wood tar (WT) extracts, a product of biomass burning, on human lung, liver, and immune cells. Using representative cell lines for different tissues, we examined the cytotoxic effects under conditions mimicking sub-acute environmental exposure levels relevant to humans. Our findings indicate that repeated sub-acute exposures to water-soluble WT extracts significantly enhance the inflammatory response, evidenced by increased IL6, IL8, and TNFa cytokine levels, compared to a single exposure. Additionally, oxidative stress responses were more pronounced with increased lipid peroxidation and HMOX1, GCLC and CYP1A1 gene expression following repeated exposures. Metabolomics analyses of polar and lipid metabolites revealed changes related to energy production and consumption that emerge even after a single exposure at sub-acute levels and vary across different cell types representing the different tissues. Impaired cellular respiration, measured by oxygen consumption rate, corroborates the observed changes. These results provide important insights into the cellular mechanisms driving the response to biomass-burning exposure and highlight the potential health risks associated with sub-acute exposure to environmental pollutants.PMID:39657377 | DOI:10.1016/j.ecoenv.2024.117491

Biochem Biophys Res Commun. 2024 Dec 3;742:151119. doi: 10.1016/j.bbrc.2024.151119. Online ahead of print.ABSTRACTEndometrial carcinoma (EC), a prevalent gynecological cancer, is characterized by rising incidence and mortality rates, highlighting the need for novel treatments to improve patient outcomes. Maackiain (MA) is a natural compound isolated from common herbal medicines, that has been reported to have anti-cancer effects. However, the underlying roles and mechanisms concerning EC remain unclear. This study focused on deeply exploring the potential roles and mechanisms of MA against EC by network pharmacology, experimentally validated, metabolomics, and molecular docking. A total of 86 potential targets of MA against EC were identified by network pharmacology. In vitro experiments further confirmed network pharmacology' predictions. In addition to suppressing EC cell proliferation, MA also paused the cell cycle at the G2/M phase in a dose-dependent manner. This effect is accompanied by increased p21 and phospho-p53 expression, as well as reduced expression of CDK1 and CCNB1. Furthermore, cell metabolomics analysis revealed that 285 metabolites were changed after MA administration, which majorly affects glycerophospholipid metabolism, nucleotide metabolism, choline metabolism in cancer, and purine metabolism. Combination network pharmacology, metabolomics, and molecular docking, PLA2G10, PDE4D, and PDE5A were found to be potential targets for therapeutic intervention. These findings underlined that MA has anti-EC potential by modulating multiple targets including PLA2G10, PDE4D, and PDE5A, inhibiting EC cell proliferation, inducing G2/M phase arrest, and causing metabolic shifts. This study provides theoretical support for advanced experimental research on its clinical applications.PMID:39657356 | DOI:10.1016/j.bbrc.2024.151119

Lett Appl Microbiol. 2024 Dec 6:ovae126. doi: 10.1093/lambio/ovae126. Online ahead of print.ABSTRACTVibrio alginolyticus, the causative agent of aquatic vertebrates and invertebrates, can cause severe infections (e.g., septicaemia, gill necrosis, and surface ulcers) and high mortality in aquatic organisms, leading to serious economic losses in global aquaculture. Small non-coding RNAs (sRNAs), emerging modulators of gene expression, played vital regulatory roles in virulence, pathogenicity and physiological metabolism of bacteria. In this work, the modulation of physiological functions and metabolome of V. alginolyticus by the quorum-regulatory sRNA, Qrr1, was figured out. We found that the deletion of qrr1 induced significant cell shape elongation. Meanwhile, Qrr1 could inhibit the production of alkaline serine protease by weakening the expression of main regulator LuxR in the quorum sensing (QS) system. Moreover, the untargeted metabolomics and lipidomics approaches showed most of nucleotides, organic acids, carbohydrates, and lipidome (both lipid content and category) were significantly altered in response to the qrr1 deletion. Spearman correlation analysis demonstrated that most of the intermediates involved in glutamate metabolism, sphingolipid metabolism and glycerolipid metabolism displayed high correlations with cell virulence factors. These findings illuminate the mechanism of bacterial virulence regulation and further exploit potential therapeutic targets for virulence prevention in V. alginolyticus.PMID:39657312 | DOI:10.1093/lambio/ovae126

J Pharm Biomed Anal. 2024 Dec 6;255:116624. doi: 10.1016/j.jpba.2024.116624. Online ahead of print.ABSTRACTThe pathogenesis of cold-dampness syndrome (CDS) is closely related to intestinal inflammation and immune disorders induced by cold-dampness pathogen. CDS is the root cause of a variety of chronic inflammatory and immune diseases. Jingfang granule (JF) was widely used to treat a variety of diseases closely related to CDS. JF is well known for its clinical effect of dispelling cold and eliminating dampness, but the pharmacological effect and mechanism of JF on the improvement of CDS are still unclear. This study aimed to explore the efficacy and mechanism of JF in improving CDS from the perspective of intestinal immunity. In this study, mass spectrometry (CyTOF), metabolomics, network pharmacology, proteomics and molecular biology experiments were performed to investigate the therapeutic effects and underlying mechanisms of JF on intestinal inflammation and immune disorders in CDS mice. These results showed that JF could improve the clinical symptoms and increase the thymus index of CDS mice. Most strikingly, JF ameliorated intestinal inflammation and immune disorders in CDS mice, as indicated by increased frequency of TH1, CD8 + Tem, CD8 + TEFF, gdT and iNK cells and decreased frequency of Naive B cells, M1-macrophages, DCs and eosinophils. Metabolomics results showed that JF reversed the content of docosahexaenoic acid, arachidonic acid, linoleic acid, inosine and hypoxanthine in CDS mice. Correlation analysis showed that these metabolites were strongly correlated with a variety of intestinal immune cells, indicating that there was a certain regulatory effect between them. Then, 271 JF targets, 316 metabolite targets and 18374 disease targets were integrated to obtain 75 common targets and 138 pathways (such as PI3K/AKT and MAPK pathway, etc). Furthermore, molecular docking, proteomics and western blotting demonstrated that PI3K/AKT signaling pathway might be the key molecular mechanism by which JF regulated intestinal immune disorders in CDS mice. These results suggested that JF may act on the PI3K/AKT pathways to further regulate the levels of metabolites to exert intestinal immunomodulatory effects. In summary, we confirmed the beneficial effects of JF on intestinal immune disorders in CDS mice.PMID:39657279 | DOI:10.1016/j.jpba.2024.116624

Invest Ophthalmol Vis Sci. 2024 Dec 2;65(14):19. doi: 10.1167/iovs.65.14.19.ABSTRACTPURPOSE: To identify the role of lipocalin-2 (LCN2) in diabetic cataract (DC) and diabetic retinopathy (DR), diabetes models were established in wild-type (WT) and LCN2 gene knockout (LCN2-/-) mice by streptozotocin (STZ), this study aimed to investigate the metabolic alterations and underlying pathways in the lens and retina.METHODS: Untargeted metabolomic analysis was performed on the lenses and retinas of WT and LCN2-/- diabetic mice, and relevant pathways were predicted through bioinformatics analysis.RESULTS: LCN2 was notably elevated in the anterior capsules of DC and the vitreous humor of DR. Metabolic profiling of the lenses and retinas of diabetic mice indicated that the differential metabolites were mostly amino acids, fatty acids, carbohydrates, and their derivatives. In the lenses of STZ-induced WT mice, the differential abundance score (DA-score) revealed an increase in metabolites associated with the citrate (or TCA) cycle and glucagon signaling pathway, whereas a decrease was observed in metabolites related to cholesterol metabolism. After the knockout of LCN2, the DA-score indicated that the majority of metabolites involved in cholesterol metabolism, cysteine and methionine metabolism, and tryptophan metabolism were diminished. In the STZ-induced retina, there was an increase in metabolites associated with the mTOR signaling pathway, and this increase was inhibited by the knockout of LCN2.CONCLUSIONS: Numerous metabolites exhibited substantial alterations in the lenses and retinas of diabetic mice. Untargeted metabolomics has provided insights into the function of LCN2 in DC and DR. These changes in metabolites, along with their related pathways, could be the mechanisms by which LCN2 modulated DC and DR.PMID:39656472 | DOI:10.1167/iovs.65.14.19

United European Gastroenterol J. 2024 Dec 10. doi: 10.1002/ueg2.12720. Online ahead of print.ABSTRACTThe heterogeneity and suboptimal efficacy of biological treatments and small molecule drugs necessitate their precise selection based on biomarkers that predict therapeutic responses in inflammatory bowel disease. Recent studies have identified numerous novel biomarkers predictive of responses to biologics and small molecule modulators, utilizing a variety of omics approaches in inflammatory bowel disease. In this review, we systematically examine baseline omics biomarkers that predict responses to biological therapies and small molecule drugs, drawing on literature from PubMed. Our analysis spans multiple omics disciplines, including genomics, transcriptomics (both bulk RNA and single-cell RNA sequencing), proteomics, microbiomics, and metabolomics, with particular emphasis on the impact of models integrating multiple omics datasets. Additionally, to further the field of precision medicine, we evaluated specific biomarkers that may exhibit distinct effects on responses to multiple therapeutic interventions.PMID:39656426 | DOI:10.1002/ueg2.12720

Planta. 2024 Dec 10;261(1):10. doi: 10.1007/s00425-024-04587-9.ABSTRACTBrassica vegetables are one of the possible solutions to tackle the emerging human diseases and malnutrition due to their rich content of phyto-nutraceutaical compounds. The genomics enabled tools have facilitated the elucidation of molecular regulation, mapping of genes/QTLs governing nutraceutical compounds, and development of nutrient-rich Brassica vegetables. The enriched food products or foods as whole termed as functional foods are intended to provide health benefits. The 2500 year old Hippocratic phrase 'let thy food be thy medicine and thy medicine be thy food' remained in anonymity due to lack of sufficient evidence. However, today, we are facing reappraisal of healthy nutritious functional foods in battling diseases. In this context, the Brassica vegetables represent the most extensively investigated class of functional foods. An optimal consumption of Brassica vegetables is associated with lowering the risks of several types of cancer, chronic diseases, cardiovascular disease, and help in autism. In the post-genomic era, the integration of genetic and neoteric omics tools like transcriptomics, metabolomics, and proteomics have illuminated the downstream genetic mechanisms governing functional food value of Brassica vegetables. In this review, we have summarized in brief the phyto-nutraceutical profile and their functionality in Brassica vegetables. This review also highlights the progress made in identification of candidate genes/QTLs for accumulation of bioactive compounds in Brassica vegetables. We summarize the molecular regulation of major phytochemicals and breeding triumphs in delivering multifunctional Brassica vegetables.PMID:39656314 | DOI:10.1007/s00425-024-04587-9

Microbiol Spectr. 2024 Dec 10:e0099624. doi: 10.1128/spectrum.00996-24. Online ahead of print.ABSTRACTThe Amazon, an important biodiversity hotspot, remains poorly explored in terms of its microbial diversity and biotechnological potential. The present study characterized the metabolic potential of Gram-positive strains of the Actinomycetes and Bacilli classes isolated from soil samples of an Amazon Conservation Unit. The sequencing of the 16S rRNA gene classified the strains ACT015, ACT016, and FIR094 within the genera Streptomyces, Rhodococcus, and Brevibacillus, respectively. Genome mining identified 33, 17, and 14 biosynthetic gene clusters (BGCs) in these strains, including pathways for the biosynthesis of antibiotic and antitumor agents. Additionally, 40 BGCs (62,5% of the total BGCs) were related to unknown metabolites. The OSMAC approach and untargeted metabolomics analysis revealed a plethora of metabolites under laboratory conditions, underscoring the untapped chemical diversity and biotechnological potential of these isolates. Our findings illustrated the efficacy of the metabologenomics approach in elucidating secondary metabolism and selecting BGCs with chemical novelty.IMPORTANCEThe largest rainforest in the world is globally recognized for its biodiversity. However, until now, few studies have been conducted to prospect natural products from the Amazon microbiome. In this work, we isolated three free-living bacterial species from the microbiome of pristine soils and used two high-throughput technologies to reveal the vast unexplored repertoire of secondary metabolites produced by these microorganisms.PMID:39656018 | DOI:10.1128/spectrum.00996-24

J Am Heart Assoc. 2024 Dec 10:e036906. doi: 10.1161/JAHA.124.036906. Online ahead of print.ABSTRACTBACKGROUND: Contemporary risk assessment in patients with coronary atherosclerotic disease (CAD) often relies on invasive angiography. However, we aimed to explore the potential of metabolomic biomarkers in reflecting residual risk in patients with CAD after moderate lipid-lowering therapy.METHODS AND RESULTS: We analyzed serum metabolomic profile among 2560 patients with newly diagnosed CAD undergoing moderate lipid-lowering therapy, through nuclear magnetic resonance spectroscopy and quantified 175 metabolites, predominantly lipoproteins and their components. CAD severity was evaluated using Gensini score for plaque burden and circulating cardiac troponin T levels for plaque instability. The association of metabolites with CAD severity was examined using multivariate linear regression, and the underlying potential causality was explored using a 2-sample Mendelian randomization approach. Two composite metabolomic indices were constructed to reflect CAD severity using least absolute shrinkage and selection operator linear regression, and their associations with risk of major adverse cardiac events during a median follow-up of 3.8 years were evaluated using Cox models. Our investigation revealed that triglycerides and apolipoprotein B in low-density lipoprotein particles displayed stronger associations with CAD severity compared with the clinically used low-density lipoprotein cholesterol marker. In large high-density lipoprotein, components like cholesterol, cholesterol esters, triglyceride, apolipoprotein A1/A2 showed inverse associations with CAD severity. Certain metabolites, including apolipoprotein B and dihydrothymine, showed a putative causal link with Gensini score. Notably, per standard deviation increase in Gensini score-based metabolomic index was associated with 14.8% higher major adverse cardiac event risk (hazard ratio, 1.148 [95% CI, 1.018-1.295]) independent of demographic factors, medication use, and disease status.CONCLUSIONS: Our findings highlight the potential of nuclear magnetic resonance-based metabolomics in identifying novel biomarkers of plaque burden and instability. Metabolites related to plaque burden may facilitate noninvasive assessment of CAD prognosis.PMID:39655754 | DOI:10.1161/JAHA.124.036906

J Proteome Res. 2024 Dec 10. doi: 10.1021/acs.jproteome.4c00747. Online ahead of print.ABSTRACTPeg-IFNα is one of the current therapeutic strategies for Hepatitis B virus (HBV) seroclearance. Nevertheless, the underlying mechanisms are not yet adequately understood. The objective of this study was to explore the potential mechanisms using multiomics approach. For the first time, we revealed the transcriptomic, proteomic, and metabolomic characterizations of Peg-IFNα-induced HBsAg seroclearance. We found that Peg-IFNα caused significant changes during the treatment. Patients who achieved HBsAg seroclearance were characterized as having decreased transcriptional activity of genes involved in fatty acid metabolism and the glycolysis/gluconeogenesis pathway, with up-regulated expression of fatty acid degradation-related proteins. Consistently, mitochondrial TCA cycle metabolites, including citric, isocitric, and malic acids, were significantly elevated in patients who achieved HBsAg seroclearance. We also observed up-regulated transcriptional activity of NK cell-mediated cytotoxicity, positive regulation of B cell activation, immunoglobulin production, and T cell receptor complex in functional-cured patients. Conversely, the metabolites associated with unsaturated fatty acid biosynthesis were increased in HBsAg persistent patients, and the transcriptional activity of immunoglobulin production and T cell receptor complex was down-regulated after 48 weeks of Peg-IFNα treatment. Our findings provided valuable resources to better understand the process of HBsAg seroclearance and shed new light on the pathways to facilitate higher functional cure rates for CHB.PMID:39655723 | DOI:10.1021/acs.jproteome.4c00747

FASEB J. 2024 Dec 15;38(23):e70240. doi: 10.1096/fj.202401771R.ABSTRACTThe nutritional contents of breastmilk (BM) directly participate in neonatal metabolism via breastfeeding. Currently, there is limited research on BM metabolites and proteins compositions, and their alterations during the long lactation period in Hong Kong mothers. In this study, liquid chromatography-mass spectrometry-based metabolomics, lipidomics and proteomics studies were applied to compare the compositions in BM of Hong Kong lactating mothers at the 2nd, 6th, and 12th months after delivery. Distinct metabolomics and lipidomics signatures in 6th month versus 2nd month and 12th month versus 2nd month were observed, and a total of 19 differential metabolites and 105 lipids were identified. Metabolomics study showed the significant alterations in key pathways involved in biotin metabolism, amino acid, and fatty acid-associated metabolisms. Lipidomics analysis indicated the accumulation of triglyceride and ceramide during the lactation period. The remodeling of glycerophospholipids was also observed during 12-month period. Moreover, 28 differentially expressed proteins were identified and mainly associated with GO functions and KEGG pathways of ribosome and complement and coagulation cascades, which were validated by network analysis. Our research contributes to the understanding of the BM compositions and differences during the long lactation period in postpartum women of Hong Kong.PMID:39655667 | DOI:10.1096/fj.202401771R

Antioxid Redox Signal. 2024 Dec 10. doi: 10.1089/ars.2024.0557. Online ahead of print.ABSTRACTAims: Alterations of mitochondrial bioenergetics and arginine metabolism are universally present and mechanistically linked to pulmonary arterial hypertension (PAH), but there is little knowledge of arginine metabolism and mitochondrial functions across the different pulmonary hypertension (PH) groups. We hypothesize that abnormalities in mitochondrial functions are present across all PH groups and associated with clinical phenotypes. We test the hypothesis in PH patients and healthy controls from the Pulmonary Vascular Disease Phenomics Program cohort, who had comprehensive clinical phenotyping and follow-up for at least 4 years for death or transplant status. Mitochondrial transmembrane potential, superoxide production, and mass were measured by flow cytometry in fresh platelets. Metabolomics analysis was performed on plasma samples. Global arginine bioavailability was calculated as the ratio of arginine/(ornithine+citrulline). Results: Global arginine bioavailability is consistently lower than controls in all PH groups. Although the mitochondrial mass is similar across all PH groups and controls, superoxide production and transmembrane potential vary across groups. Mitochondrial superoxide is higher in group 1 PAH and lowest in group 3 compared with other groups, while transmembrane potential is lower in group 1 PAH than controls or group 3. The alterations in mitochondrial functions of group 1 PAH are associated with changes in fatty acid metabolism. Mitochondrial transmembrane potential in group 1 PAH is associated with transplant-free survival. Conclusion: While alterations in mitochondrial function are found in all PH groups, group 1 PAH has a unique mitochondrial phenotype with greater superoxide and lower transmembrane potential linked to fatty acid metabolism, and clinically to survival. Antioxid. Redox Signal. 00, 000-000.PMID:39655485 | DOI:10.1089/ars.2024.0557