PubMed

bioRxiv [Preprint]. 2024 Nov 17:2024.11.17.624012. doi: 10.1101/2024.11.17.624012.ABSTRACTBACKGROUND: Bacteriophages (phages) and bacteria within the gut microbiome persist in long-term stable coexistence. These interactions are driven by eco-evolutionary dynamics, where bacteria employ a variety of mechanisms to evade phage infection, while phages rely on counterstrategies to overcome these defences. Among the most abundant phages in the gut are the crAss-like phages that infect members of the Bacteroidales, in particular Bacteroides . In this study, we explored some of the mechanisms enabling the co-existence of four phage-Bacteroidales host pairs in vitro using a multi-omics approach (transcriptomics, proteomics and metabolomics). These included three Bacteroides species paired with three crAss-like phages ( Bacteroides intestinalis and ϕcrAss001, Bacteroides xylanisolvens and ϕcrAss002, and an acapsular mutant of Bacteroides thetaiotaomicron with DAC15), and Parabacteroides distasonis paired with the siphovirus ϕPDS1.RESULTS: We show that phase variation of individual capsular polysaccharides (CPSs) is the primary mechanism promoting phage co-existence in Bacteroidales, but this is not the only strategy. Alternative resistance mechanisms, while potentially less efficient than CPS phase variation, can be activated to support bacterial survival by regulating gene expression and resulting in metabolic adaptations, particularly in amino acid degradation pathways. These mechanisms, also likely regulated by phase variation, enable bacterial populations to persist in the presence of phages, and vice versa . An acapsular variant of B. thetaiotaomicron demonstrated broader transcriptomic, proteomic, and metabolomic changes, supporting the involvement of additional resistance mechanisms beyond CPS variation.CONCLUSIONS: This study advances our understanding of long-term phage-host interaction, offering insights into the long-term persistence of crAss-like phages and extending these observations to other phages, such as ϕPDS1. Knowledge of the complexities of phage-bacteria interactions is essential for designing effective phage therapies and improving human health through targeted microbiome interventions.PMID:39605433 | PMC:PMC11601342 | DOI:10.1101/2024.11.17.624012

bioRxiv [Preprint]. 2024 Nov 24:2024.11.23.624981. doi: 10.1101/2024.11.23.624981.ABSTRACTGlioblastoma (GBM) is a highly aggressive primary malignant adult brain tumor that inevitably recurs with a fatal prognosis. This is due in part to metabolic reprogramming that allows tumors to evade treatment. We therefore must uncover the pathways mediating these adaptations to develop novel and effective treatments. We searched for genes that are essential in GBM cells as measured by a whole-genome pan-cancer CRISPR screen available from DepMap and identified the methionine metabolism genes MAT2A and AHCY . We conducted genetic knockdown, evaluated mitochondrial respiration, and performed targeted metabolomics to study the function of these genes in GBM. We demonstrate that MAT2A or AHCY knockdown induces oxidative stress, hinders cellular respiration, and reduces the survival of GBM cells. Furthermore, selective MAT2a or AHCY inhibition reduces GBM cell viability, impairs oxidative metabolism, and changes the metabolic profile of these cells towards oxidative stress and cell death. Mechanistically, MAT2a or AHCY regulates spare respiratory capacity, the redox buffer cystathionine, lipid and amino acid metabolism, and prevents DNA damage in GBM cells. Our results point to the methionine metabolic pathway as a novel vulnerability point in GBM.SIGNIFICANCE: We demonstrated that methionine metabolism maintains antioxidant production to facilitate pro-tumorigenic ROS signaling and GBM tumor cell survival. Importantly, targeting this pathway in GBM can potentially reduce tumor growth and improve survival in patients.PMID:39605416 | PMC:PMC11601785 | DOI:10.1101/2024.11.23.624981

bioRxiv [Preprint]. 2024 Nov 13:2024.11.11.623108. doi: 10.1101/2024.11.11.623108.ABSTRACTAlzheimer's disease (AD) affects more women than men. Although women live longer than men, it is not longevity alone, but other factors, including metabolic changes, that contribute to the higher risk of AD in women. Metabolic pathways have been implicated in AD progression, but studies to date examined targeted pathways, leaving many metabolites unmeasured. Sex is often a neglected biological variable, and most metabolomic studies were not designed to investigate sex differences in metabolomic profiles. Here, we performed untargeted metabolomic profiling of sera from male and female patients with mild cognitive impairment (MCI), a common precursor to AD, and matched controls. We discovered significant metabolic changes in individuals with MCI, and found several pathways that were strongly associated with sex. Peptide energy metabolism demonstrated sexual dimorphism. Lipid pathways exhibited the strongest differences between female and male MCI patients, including specific phosphatidylcholine lipids, lysophospholipids, long-chain fatty acids, and monoacylglycerols. 1-palmitoleoyl glycerol and 1-arachidonoyl glycerol were higher in female MCI subjects than in male MCI subjects with no differences between control males and females. Conversely, specific dicarboxylic fatty acids were lower in female MCI subjects than male MCI subjects. In cultured astrocytes, 1-arachidonoyl glycerol promoted phosphorylation of the transcriptional regulator sphingosine kinase 2, which was inhibited by the transient receptor potential vanilloid 1 receptor antagonists, as well as chromatin remodelling. Overall, we identified novel sex-specific metabolites in MCI patients that could serve as biomarkers of MCI in both sexes, help further define AD etiology, and reveal new potential prevention strategies for AD.HIGHLIGHTS: Individuals with MCI experience significant metabolic changes.Lipid pathways demonstrated the strongest sexual dimorphism in MCI.1-monoacylglycerols showed a robust sex association, being higher in MCI females.Sex-specific metabolites may be MCI biomarkers in each sex.PMID:39605322 | PMC:PMC11601308 | DOI:10.1101/2024.11.11.623108

Chin Med. 2024 Nov 28;19(1):165. doi: 10.1186/s13020-024-01009-6.ABSTRACTBACKGROUND: Heart failure (HF) is associated with high mortality and rehospitalization rates, highlighting the need for novel therapeutic approaches. Jianxin (JX) granules, a Traditional Chinese Medicine formulation, have been patented for the treatment of HF. However, the specific therapeutic effects and underlying mechanisms of JX granules have not been fully elucidated. This study aimed at investigating the effects and mechanism of JX granules in the treatment of HF based on proteomics and metabolomic profiling.METHODS: HF model was established in rats by ligation of left coronary artery. The successfully modeled rats were randomly divided into three groups: the model group, the JX granules group, and Sacubitril/Valsartan (S/V) group. Four weeks after treatment, left ventricular (LV) function was evaluated via echocardiography. LV fibrosis and apoptosis were examined through histological analyses, while mitochondrial morphology was assessed using transmission electron microscopy. Quantitative assessment of oxidative stress was also conducted. Proteomics was used to identify the differentially expressed proteins and potential pathways. Metabolomics was utilized to elucidate the variations in metabolism. Then western blotting and in vitro analyses were performed.RESULTS: A rat model of HF was established, evidenced by a decrease in left ventricular ejection fraction (LVEF), stroke volume (SV), and left ventricular fractional shortening (LVFS), alongside diminished adenosine triphosphate (ATP) content, elevated oxidative stress, augmented apoptosis, and disrupted pyruvate metabolism. Treatment with JX granules ameliorated these effects, improving systolic function, reducing ventricular chamber size, and increasing LVEF, SV, and LVFS, as assessed by echocardiography. Additionally, JX granules attenuated cardiac fibrosis and improved mitochondrial structure, as evidenced by less vacuolation and clearer mitochondrial cristae, when compared to the model group. The treatment also regulated apoptosis-related protein expression, partially reversing the increase in cleaved Caspase-9, cleaved Caspase-3, and Bax and the suppression of Bcl-2 observed in the heart failure rats. All of these effects were similar to S/V. Proteomic and metabolomic analyses identified key differential genes, such as triosephosphate isomerase 1 (TPI1), lactate dehydrogenase B (LDHB), pyruvate kinase M (PKM), protein kinase B (Akt), Pyruvate Dehydrogenase Beta (PDHB) and lactate dehydrogenase A (LDHA), as well as vital pathways including carbon metabolism, the PI3K-Akt signaling pathway, pyruvate metabolism, and HIF-1α signaling pathway. Moreover, JX granules mitigated oxidative stress, inhibited apoptosis, and activated Akt in H9c2 cells exposed to angiotensin II, which could be reversed by the PI3K inhibitor LY294002.CONCLUSION: JX granules improve HF in parallel to the efficacy of S/V, at least in part, through enhancing pyruvate metabolism, inhibiting oxidative stress and activating PI3K/Akt pathway.PMID:39605071 | DOI:10.1186/s13020-024-01009-6

BMC Med. 2024 Nov 27;22(1):561. doi: 10.1186/s12916-024-03779-0.ABSTRACTBACKGROUND: It is not clear if conventional liver fat cutoff of 5.56% weight which has been used for identifying fatty liver in western populations is also applicable for Asians. In Asian women of reproductive age, we evaluate the optimum metabolic syndrome (MetS)-linked liver fat cutoff, the specific metabolomic alterations apparent at this cutoff, as well as prospective associations of preconception liver fat levels with gestational dysglycemia.METHODS: Liver fat (measured by magnetic resonance spectroscopy), MetS, and nuclear magnetic resonance (NMR)-based plasma metabolomic profiles were assessed in 382 Asian women, who were planning to conceive. Ninety-eight women went on to become pregnant and received an oral glucose tolerance test at week 26 of gestation.RESULTS: The optimum liver fat cutoff for diagnosing MetS was 2.07%weight. Preconception liver fat was categorized into Low (liver fat < 2.07%), Moderate (2.07% ≤ liver fat < 5.56%), and High (liver fat ≥ 5.56%) groups. Individual MetS traits showed worsening trends, going from Low to Moderate to High groups. Multiple plasma metabolomic alterations, previously linked to incident type 2 diabetes (T2D), were already evident in the Moderate group (adjusted for ethnicity, age, parity, educational attainment, and BMI). Both a cross-sectional multi-metabolite score for incident T2D and mid-gestational glucose area under the curve showed increasing trends, going from Low to Moderate to High groups (p < 0.001 for both). Gestational diabetes incidence was 2-fold (p = 0.23) and 7-fold (p < 0.001) higher in the Moderate and High groups relative to the Low group.CONCLUSIONS: In Asian women of reproductive age, moderate liver fat accumulation below the conventional fatty liver cutoff was not metabolically benign and was linked to gestational dysglycemia. The newly derived cutoff can aid in screening individuals before adverse metabolic phenotypes have consolidated, which provides a longer window for preventive strategies.PMID:39605006 | DOI:10.1186/s12916-024-03779-0

J Transl Med. 2024 Nov 27;22(1):1072. doi: 10.1186/s12967-024-05764-w.ABSTRACTBACKGROUND: Acute pancreatitis (AP) is an inflammatory condition with potentially life-threatening complications. This study investigates the therapeutic potential of Clostridium butyricum for modulating the inflammatory cascade through the AMPK/NF-κB signaling pathway, focusing on inflammation induced by AP. LC-MS analysis of serum samples from AP patients highlighted the regulation of lipid metabolism and inflammation, and found that metabolites involved in the inhibition of NF-κB phosphorylation and the AMPK activation pathway were downregulated. We hypothesized that pre-administration of Clostridium butyricum and its culture supernatant could mitigate AP-induced damage by modulating the AMPK/NF-κB pathway.METHODS: Lipopolysaccharide (LPS)-induced cell inflammation models. LPS combined with CAE induced acute pancreatitis in mice. We divided mice into four groups: Con, AP, AP + C.Buty (AP with Clostridium butyricum treatment), and AP + CFS (AP with culture supernatant treatment). Analyses were performed using WB, RT-qPCR, Elisa, flow cytometry, IHC, and HE, respectively.RESULTS: Our study shows that CFS can reduce the apoptosis of LPS-induced cellular inflammation and reduce the release of LPS-induced cytoinflammatory factors through the AMPK/NF-κB pathway in vitro. In vivo, Clostridium butyricum and its supernatant significantly reduced inflammatory markers, and corrected histopathological alterations in AP mice. Gut microbiota analysis further supported these results, showing that Clostridium butyricum and its supernatant could restore the balance of intestinal flora disrupted by AP.CONCLUSIONS: Mechanistically, our results indicated that the therapeutic effects of Clostridium butyricum are mediated through the activation of AMPK, leading to the inhibition of the NF-κB pathway, thereby reducing the production of pro-inflammatory cytokines. Clostridium butyricum and its culture supernatant exert a protective effect against AP-induced damage by modulating the AMPK/NF-κB signaling pathway. Future studies will further elucidate the molecular mechanisms underlying the beneficial effects of Clostridium butyricum in AP and explore its clinical applicability in human subjects.PMID:39604956 | DOI:10.1186/s12967-024-05764-w

Food Funct. 2024 Nov 28. doi: 10.1039/d4fo03809f. Online ahead of print.ABSTRACTRecent studies confirmed that host-gut microbiota interactions modulate disease-linked metabolite TMA production via TMA lyase. However, microbial enzyme production mechanisms remain unclear. In the present study, we investigated the impact of dietary and intervention factors on gut microbiota, microbial gene expression, and the interplay between TMA lyase and glycolytic pathways in mice. Using 16S rRNA gene sequencing, metagenomics, and metabolomics, the gut microbiota composition and microbial functional gene expression profiles related to TMA lyase and glycolytic enzymes were determined. The results revealed that distinct diets and intervention factors altered gut microbiota, gene expression, and metabolites linked to glycine metabolism and glycolysis. Notably, an arabinoxylan-rich diet suppressed genes linked to choline, glycine, glycolysis, and TMA lyase, favoring glycine utilization via pyruvate pathways. Glycolytic inhibitors amplified these effects, mainly inhibiting pyruvate kinase. Our findings underscored the crosstalk between TMA lyase and glycolytic pathways, regulating glycine levels, and suggested avenues for targeted interventions and personalized diets to curb choline TMA lyase production.PMID:39604809 | DOI:10.1039/d4fo03809f

Endocrinol Metab (Seoul). 2024 Nov 28. doi: 10.3803/EnM.2024.2117. Online ahead of print.ABSTRACTBACKGROUND: Sarcopenia, a multifactorial disorder involving metabolic disturbance, suggests potential for metabolite biomarkers. Carnitine (CN), essential for skeletal muscle energy metabolism, may be a candidate biomarker. We investigated whether CN metabolites are biomarkers for sarcopenia.METHODS: Associations between the CN metabolites identified from an animal model of sarcopenia and muscle cells and sarcopenia status were evaluated in men from an age-matched discovery (72 cases, 72 controls) and a validation (21 cases, 47 controls) cohort.RESULTS: An association between CN metabolites and sarcopenia showed in mouse and cell studies. In the discovery cohort, plasma C5-CN levels were lower in sarcopenic men (P=0.005). C5-CN levels in men tended to be associated with handgrip strength (HGS) (P=0.098) and were significantly associated with skeletal muscle mass (P=0.003). Each standard deviation increase in C5-CN levels reduced the odds of low muscle mass (odd ratio, 0.61; 95% confidence interval [CI], 0.42 to 0.89). The area under the receiver operating characteristic curve (AUROC) of CN score using a regression equation of C5-CN levels, for sarcopenia was 0.635 (95% CI, 0.544 to 0.726). In the discovery cohort, addition of CN score to HGS significantly improved AUROC from 0.646 (95% CI, 0.575 to 0.717; HGS only) to 0.727 (95% CI, 0.643 to 0.810; P=0.006; HGS+CN score). The improvement was confirmed in the validation cohort (AUROC=0.563; 95% CI, 0.470 to 0.656 for HGS; and AUROC=0.712; 95% CI, 0.569 to 0.855 for HGS+CN score; P=0.027).CONCLUSION: C5-CN, indicative of low muscle mass, is a potential circulating biomarker for sarcopenia in men. Further studies are required to confirm these results and explore sarcopenia-related metabolomic changes.PMID:39604802 | DOI:10.3803/EnM.2024.2117

Sci Rep. 2024 Nov 27;14(1):29489. doi: 10.1038/s41598-024-80556-2.ABSTRACTResults of artificial insemination (AI) are affected by changes in sperm quality and the function throughout collection and preservation procedures. Proteome and metabolome alterations of sperm treated with the different procedures in goat, however, aren't fully understood. To this end, we sought to investigate the impacts of rectal probe electrostimulation (EE) and artificial vagina (AV) semen collection methods on the quality and the cryotolerance of goat sperm, with additional focus on proteomic and metabolomic analyses. Semen samples were collected from Yunshang black goats and categorized into four groups: fresh sperm collected via AV (XAZ), fresh sperm collected via EE (XEZ), frozen sperm post-AV collection (DAZ) and frozen sperm post-EE collection (DEZ). Four comparisons (XAZ vs. XEZ, DAZ vs. XAZ, DEZ vs. XEZ, DAZ vs. DEZ) were performed, respectively. This study first evaluated sperm motility, acrosome integrity, plasma membrane integrity, mitochondrial activity, and reactive oxygen species (ROS) levels. The results indicated that there were no significant differences in fresh sperm quality parameters between the EE and AV methods. However, notable differences emerged post-cryopreservation. Specifically, the AV method proved more advantageous in preserving the motility, integrities of acrosome and plasma membrane, mitochondrial activity of frozen sperm compared to the EE method. Through the multi-omics approaches, a total of 210 differentially abundant proteins (DAPs) related to sperm characteristics and function were identified across the four comparations. Moreover, 32 differentially abundant metabolites (DAMs) were detected. Comprehensive bioinformatics analysis underscored significant molecular pathways in the co-enrichment of DAPs and DAMs, particularly focusing on the citrate cycle, ROS, oxidative phosphorylation, and glycine, serine, and threonine metabolism etc. We elucidated the differential impacts of AV and EE collection methods on the quality and cryotolerance of goat semen from omics perspectives, which offer a critical foundation for further exploration into optimizing semen collection and cryopreservation techniques in goat breeding program.PMID:39604559 | DOI:10.1038/s41598-024-80556-2

Eur J Nutr. 2024 Nov 28;64(1):29. doi: 10.1007/s00394-024-03511-x.ABSTRACTBACKGROUND: Diet is an important modifiable lifestyle factor for human health, and plant-rich dietary patterns are associated with lower risk of non-communicable diseases in numerous studies. However, objective assessment of plant-rich dietary exposure in nutritional epidemiology remains challenging.OBJECTIVES: This study aimed to develop and evaluate metabolic signatures of the most widely used plant-rich dietary patterns using a targeted metabolomics method comprising 108 plant food metabolites.METHODS: A total of 218 healthy participants were included, aged 51.5 ± 17.7 years, with 24 h urine samples measured using ultra-high-performance liquid chromatography-mass spectrometry. The validation dataset employed three sample types to test the robustness of the signature, including 24 h urine (n = 88), plasma (n = 195), and spot urine (n = 198). Adherence to the plant-rich diet was assessed using a priori plant-rich dietary patterns calculated using Food Frequency Questionnaires. A combination of metabolites evaluating the adherence to a specific diet was identified as metabolic signature. We applied linear regression analysis to select the metabolites significantly associated with dietary patterns (adjusting energy intake), and ridge regression to estimate penalized weights of each candidate metabolite. The correlation between metabolic signature and the dietary pattern was assessed by Spearman analysis (FDR < 0.05).RESULTS: The metabolic signatures consisting of 42, 22, 35, 15, 33, and 33 predictive metabolites across different subclasses were found to be associated with adherence to Amended Mediterranean Score (A-MED), Original MED (O-MED), Dietary Approaches to Stop Hypertension (DASH), Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND), healthy Plant-based Diet Index (hPDI) and unhealthy PDI (uDPI), respectively. The overlapping and distinct predictive metabolites across six dietary patterns predominantly consisted of phenolic acids (n = 38), including 14 cinnamic acids, 14 hydroxybenzoic acids, seven phenylacetic acids, and three hippuric acids. Six metabolites were included in all signatures, including two lignans: enterolactone-glucuronide, enterolactone-sulfate, and four phenolic acids: cinnamic acid, cinnamic acid-4'-sulfate, 2'-hydroxycinnamic acid, and 4-methoxybenzoic acid-3-sulfate. The established signatures were robustly correlated with dietary patterns in the validation datasets (r = 0.13-0.40, FDR < 0.05).CONCLUSIONS: We developed and evaluated a set of metabolic signatures that reflected the adherence to plant-rich dietary patterns, suggesting the potential of these signatures to serve as an objective assessment of free-living eating habits.PMID:39604558 | DOI:10.1007/s00394-024-03511-x

Sci Rep. 2024 Nov 27;14(1):29466. doi: 10.1038/s41598-024-80865-6.ABSTRACTCurrently, the diagnosis of delirium is solely based on clinical observation, lacking objective diagnostic tools, and the regulatory networks and pathological mechanisms behind it are not yet fully understood. Exosomes have garnered considerable interest as potential biomarkers for a variety of illnesses. This research aimed to delineate both the proteomic and metabolomic landscapes inherent to exosomes, assessing their diagnostic utility in postoperative delirium (POD) and understanding the underlying pathophysiological frameworks. Integrated analyses of proteomics and metabolomics were conducted on exosomes derived from plasma of individuals from both the non-postoperative delirium (NPOD) control group and the POD group. Subsequently, the study utilized the Connectivity Map (CMap) methodology for the identification of promising small-molecule drugs and carried out molecular docking assessments to explore the binding affinities with the enzyme MMP9 of these identified molecules. We identified significant differences in exosomal metabolites and proteins between the POD and control groups, highlighting pathways related to neuroinflammation and blood-brain barrier (BBB) integrity. Our CMap analysis identified potential small-molecule therapeutics, and molecular docking studies revealed two compounds with high affinity to MMP9, suggesting a new therapeutic avenue for POD. This study highlights MMP9, TLR2, ICAM1, S100B, and glutamate as key biomarkers in the pathophysiology of POD, emphasizing the roles of neuroinflammation and BBB integrity. Notably, molecular docking suggests mirin and orantinib as potential inhibitors targeting MMP9, providing new therapeutic avenues. The findings broaden our understanding of POD mechanisms and suggest targeted strategies for its management, reinforcing the importance of multidimensional biomarker analysis and molecular targeting in POD intervention.PMID:39604493 | DOI:10.1038/s41598-024-80865-6

Sci Rep. 2024 Nov 27;14(1):29517. doi: 10.1038/s41598-024-80921-1.ABSTRACTThe goal of this study is to develop a non-invasive approach for early detection of oral squamous cell carcinoma (OSCC) using our established mouse model that faithfully recapitulates the human disease. We present for the first time a comparative metabolomic profiling of saliva samples of the tobacco smoke constituent, dibenzo[def, p]pyrene, (DB[a, l]P) vs. DMSO (control)-treated mice using an established and highly sensitive LC-MS/MS approach. DB[a, l]P was administered by topical application into the mouse oral cavity (25 µmol, 3x week for 6 weeks) and saliva was collected 24 h after the last dose of carcinogen administration. Using an untargeted metabolomics approach (negative and positive modes), we found that DB[a, l]P differentially altered several metabolites known to be involved in the carcinogenesis process when compared to DMSO. Of particular significance, we found that DB[a, l]P significantly enriched the levels of phosphatidic acid, known to bind and activate mTORC which can enhance proliferation and promote carcinogenesis. Pathway enrichment analysis revealed that DB[a, l]P altered two major lipid metabolism pathways (phospholipid biosynthesis and glycerolipid metabolism). Collectively, our results using saliva as a safe and non-invasive approach, provide additional mechanistic insights on DB[a, l]P-induced OSCC and potential biomarkers for early detection and an opportunity for cancer interception via reprogramming lipid metabolism.PMID:39604478 | DOI:10.1038/s41598-024-80921-1

Sci Rep. 2024 Nov 27;14(1):29488. doi: 10.1038/s41598-024-80633-6.ABSTRACTFabry disease is an X-linked lysosomal storage disorder caused by deficiency of the lysosomal enzyme ⍺-galactosidase-A (⍺-Gal A), resulting in widespread accumulation of terminal galactose-containing glycosphingolipids (GSLs) and the impairment of multiple organ systems. Thrombotic events are common in Fabry patients, with strokes and heart attacks being significant contributors to a shortened lifespan in patients of both genders. Previously, we developed an ⍺-Gal A-knockout (KO) murine model that recapitulates most Fabry symptomologies and demonstrated that platelets from KO males become sensitized to agonist-mediated activation. In the current report, we used mass spectrometry, platelet-based assays and histology to define further the mechanisms linking GSL accumulation with thrombotic phenotypes in both sexes. Sera and platelets from ⍺-Gal A-KO females have elevated levels of Fabry-associated GSLs relative to wild-type females, but accumulated less of these GSLs than KO males. Correspondingly, KO females demonstrate a less severe thrombotic phenotypes than KO males. Notably, treatment of platelets from wild-type animals with globotriaosylceramide (Gb3) increased baseline platelet activation and aggregation. In contrast, several control GSLs did not stimulate platelet responses. These data suggest that chronically high concentrations of the Fabry-associated GSL, Gb3, contributes to the prothrombotic phenotypes experienced by Fabry patients by directly stimulating platelet activation.PMID:39604471 | DOI:10.1038/s41598-024-80633-6

Sci Rep. 2024 Nov 27;14(1):29523. doi: 10.1038/s41598-024-80985-z.ABSTRACTAcute respiratory distress syndrome (ARDS), with high morbidity and mortality, is a common clinical syndrome of acute respiratory failure caused by diffuse lung inflammation and edema. ARDS can precipitate in various ways. The complex pathophysiology of ARDS involves the activation and dysregulation of multiple metabolisms and immune responses. Using summary-level data from a genome-wide association study (GWAS), a two-sample Mendelian randomization (MR) analysis of 179 genetically predicted lipid species and ARDS (375 cases, 406,518 controls) was performed and validated in plasma and pulmonary edema fluid from 24 patients. Furthermore, we used a two-step MR to quantify the effect of immune cell-mediated lipids on ARDS. We identified 8 lipids (Cholesterol, Phosphatidylcholine (14:0_16:0), Phosphatidylcholine (16:0_20:5), Phosphatidylcholine (18:0_18:2), Phosphatidylethanolamine (18:1_18:1), Triacylglycerol (51:2), Triacylglycerol (52:4), and Triacylglycerol (54:3) ) associated with ARDS. The proportions of genetically-predicted lipids mediated by the four types of immune cells were determined. Sensitivity analysis did not reveal any obvious pleiotropy or heterogeneity. Our study demonstrates the power of multivariate genetic analysis in correlated lipidomic data and reveals genetic links between ARDS and lipid species beyond standard lipids.PMID:39604464 | DOI:10.1038/s41598-024-80985-z

Sci Data. 2024 Nov 27;11(1):1293. doi: 10.1038/s41597-024-04066-6.ABSTRACTMost of the species in Paris have important medicinal values in China. Polyphyllins are the key components in Paris, with varying levels and compositions among different species. This study investigated polyphyllin compositions of 206 Paris samples from 16 different producing areas. 9 Paris polyphylla var. yunnanensis, 3 Paris fargesii, and 3 Paris forrestii were selected based on polyphyllin levels and composition for metabolome and transcriptome analysis. A total of 1,243 metabolites were identified among these samples, along with 92.11 Gb of full-length transcriptome data. This study provides potential candidate genes involved in polyphyllins synthesis in Paris, aiming to facilitate the biosynthesis of different polyphyllins.PMID:39604406 | DOI:10.1038/s41597-024-04066-6

NPJ Aging. 2024 Nov 27;10(1):58. doi: 10.1038/s41514-024-00183-z.ABSTRACTThis study investigates why individuals with multimorbidity-two or more chronic conditions-are more prone to adverse outcomes after surgery. In our cohort, ninety-eight of 144 participants had multimorbidity. The myocardial transcriptome and metabolites involved in energy production were measured in 53 and 57 sequential participants, respectively. Untargeted analysis of the metabolome in blood and myocardium was performed in 30 sequential participants. Mitochondrial respiration in circulating mononuclear cells was measured in 70 participants. Results highlighted four main biological processes associated with multimorbidity: DNA damage with epigenetic changes, mitochondrial energy disruption, cellular aging (senescence) and innate immune response. Histone 2B, its ubiquitination enzymes and AKT3 were upregulated in the multimorbid group. Plasma senescence-associated proteins (IL-1β, GM-CSF) increased with more comorbidities. DNA damage and nucleolar instability were specifically apparent in multimorbid myocardium. We conclude that multimorbidity in cardiovascular patients accelerates biological aging, making them more vulnerable to metabolic stress.PMID:39604391 | DOI:10.1038/s41514-024-00183-z

Phytochem Anal. 2024 Nov 27. doi: 10.1002/pca.3483. Online ahead of print.ABSTRACTINTRODUCTION: Polygoni Multiflori Radix (PMR) is commonly used in traditional medicine as both raw and processed forms. Raw PMR was prepared into processed PMR via processing procedure; however, there is a lack of standardized protocols ensuring the completeness of processing.OBJECTIVE: This aims to develop a strategy based on a metabolomics approach for the comprehensive chemical profiling and comparison of raw and processed PMR and establish a basis for PMR processing standardization.MATERIALS AND METHODS: Methanol extracts of raw and processed PMR were fractionated by centrifugal partition chromatography (CPC) with an optimized two-phase solvent system based on the partition coefficient calculated from the shake-flask method to produce primary (1°Ms)- and secondary metabolites (2°Ms)-enriched fractions. These fractions were profiled by 1D and 2D and selective 1D NMR experiments, spectral fitting, and comparison with reference standards. The profiled compounds were quantified via quantitative 1H NMR (qHNMR) to show the chemical changes, which were correlated with changes in antioxidant effects on H2452 cells.RESULTS: A CPC method was developed to efficiently separate 1°Ms- and 2°Ms-enriched fractions. This method achieved high purity of the major stilbene in PMR in a single run. qHNMR effectively quantified four 2°Ms and twenty-one 1°Ms in both raw and processed PMR, including meso-butane-2,3-diol, which was first reported from processed PMR. Changes in chemical composition of PMR because of processing are highly correlated to the increase of antioxidant activity.CONCLUSION: A convenient and cost-effective strategy for the comprehensive chemical profiling of raw and processed PMR was developed by combining countercurrent separation and qHNMR. This approach will contribute to the standardization of medicinal herbal materials.PMID:39604055 | DOI:10.1002/pca.3483

J Agric Food Chem. 2024 Nov 27. doi: 10.1021/acs.jafc.4c07851. Online ahead of print.ABSTRACTUnderstanding the impacts of pile-fermentation on the taste quality of dark tea (DT) is crucial. Although the large-leaf DT, Yinghong 9 DT, was successfully developed, its taste quality was not systematically studied. This research aims to analyze how pile-fermentation affects taste. Our taste evaluations indicated that pile-fermentation reduces astringency while slightly increasing bitterness. Through untargeted metabolomic analysis, we identified 16 key metabolites associated with these taste changes. The analysis of the dose-overthreshold values affirmed that rutin, isoquercetin, myricetin 3-galactoside, EGCG, DL-C, and ECG were found to lower astringency, while caffeine contributed to the slight increase in bitterness. Additionally, the changes in these metabolites are closely linked to the catalytic effects of microbial extracellular enzymes. These findings provide a theoretical foundation for a deeper understanding of how pile fermentation influences the taste quality of large-leaf DT.PMID:39604007 | DOI:10.1021/acs.jafc.4c07851

Phytomedicine. 2024 Nov 8:156200. doi: 10.1016/j.phymed.2024.156200. Online ahead of print.ABSTRACTBACKGROUND: Chinese yam polysaccharide (SYDT) has been reported to protect renal function and mitigate renal fibrosis in mice with diabetic nephropathy. Based on a multi-omics analysis, the objectives of this study were to determine the effect of SYDT on cisplatin (CDDP)-induced chronic renal interstitial fibrosis (RIF) and the underlying molecular mechanisms using an in vivo model.METHODS: Rats were intraperitoneally injected with a single dose of CDDP and then treated with SYDT or amifostine (AMF). The levels of urinary N-acetyl-β-d-glucosaminidase (NAG), blood urea nitrogen (BUN) and serum creatinine (Scr) were detected to assess renal function. Renal tissue damage and fibrosis were evaluated using hematoxylin and eosin (H&E) and Masson's trichrome staining, respectively. In addition, this study applied transcriptomics and metabolomics to predict the possible mechanism of SYDT action, which was verified by several relevant examinations.RESULTS: SYDT significantly protected the renal function, alleviated renal tissue damage and fibrosis, as well as decreased the protein levels of vimentin, α-SMA and CTGF, whereas SYDT significantly increased MMP-1 protein level in renal tissues from rats treated with CDDP. There were 1130 differently expressed genes (DEGs) between the CDDP model and SYDT-M groups proved by transcriptome analysis, indicating that metabolic pathways were likely the primary targets of relevance. Consistent with the transcriptome analysis, metabolome analysis identified 276 differentially expressed metabolites (DEMs) between the SYDT-M and CDDP model groups, with predominant clustering within glycerophospholipid metabolism. Integrative analysis of the transcriptome and metabolome indicated that SYDT inhibited the glycerophospholipid metabolism pathway by regulating the target genes Gpd2, Gpam, Agpat3, Lcat, and Pla2g4b. Notably, integrative analysis showed that the Phospholipase D (PLD) signaling pathway may be the most relevant target. Moreover, related signaling pathway analysis confirmed that SYDT inhibited CDDP-induced RIF in rats by down-regulating the PLD pathway.CONCLUSION: Our study showed that the alleviation of CDDP-induced RIF in vivo can be achieved through the inhibition of glycerophospholipid metabolism and PLD signaling pathways by SYDT.PMID:39603894 | DOI:10.1016/j.phymed.2024.156200

Clin Ther. 2024 Nov 26:S0149-2918(24)00324-2. doi: 10.1016/j.clinthera.2024.10.015. Online ahead of print.ABSTRACTPURPOSE: Females are at increased lifetime risk of stroke and experience worse outcomes compared with males. Tryptophan metabolism through the kynurenine pathway, resulting in decreased tryptophan concentrations, is associated with poor outcomes (larger infarct volume, higher National Institutes of Health Stroke Scale [NIHSS] score, and increased early mortality). This metabolic pathway activity varies by sex in healthy adults. However, evaluation of potential sex differences in tryptophan metabolism after an acute ischemic stroke (AIS) is lacking and could contribute to the disparate outcomes by sex. This study characterized sex differences in tryptophan metabolism via the kynurenine pathway in patients with AIS.METHODS: Whole blood from patients with AIS enrolled in the University of Colorado Health Emergency Medicine Specimen Bank was analyzed using high-throughput mass spectrometry-based metabolomics at the time of arrival to the emergency department and at 12, 24, and 48 hours thereafter. Descriptive statistics characterized the cohort and metabolite levels. Potential sex differences in tryptophan metabolites at individual time points and their change over time were estimated using linear regression models to control for known factors influencing metabolite levels, initial NIHSS score, therapeutic interventions, and time to last known well (or symptom onset). A multivariable linear regression model examined the interaction effect between sex and metabolite level (at 12 hours after admission) on 24-hour NIHSS score while controlling for initial metabolite level, initial NIHSS score, time to last known well, factors influencing metabolite level, and factors influencing neurologic outcomes.FINDINGS: After adjusting for covariates, females with AIS had significantly lower levels of tryptophan at 12 hours after admission compared with males (point estimate, -5.80; P = 0.03). Females and males neither differ in levels of tryptophan, kynurenine, quinolinic acid, or kynurenic acid at any other time point nor did they differ in change in metabolite concentration over time. Only increased quinolinic acid levels across both sexes at 12 hours after admission were associated with increased 24-hour NIHSS scores (point estimate, 0.49; P = 0.0002).IMPLICATIONS: Overall, females and males have similar levels and changes in tryptophan and kynurenine pathway metabolites after an AIS. However, females have lower levels of tryptophan early after a stroke. Increased quinolinic acid levels across both sexes were associated with worsening neurologic function as measured by an NIHSS score. Future evaluation of alternative metabolic pathways downstream of tryptophan is needed to explain differences in tryptophan levels but similar levels of downstream kynurenine metabolites in females and males with AIS.PMID:39603869 | DOI:10.1016/j.clinthera.2024.10.015