Potential Metabolic Pathways Research Articles

Genetic Association Between Blood Metabolites and Craniosynostosis: A Mendelian Randomization Study.

Craniosynostosis is a congenital disorder characterized by the premature fusion of cranial sutures, leading to abnormal skull development and potential neurodevelopmental complications. The role of metabolic influences in craniosynostosis remains underexplored. This study investigates the causal relationship between specific blood metabolites and the risk of craniosynostosis using a 2-sample Mendelian randomization (MR) approach. Genetic instruments were selected from a genome-wide association study on blood metabolites and craniosynostosis data from the FinnGen database. The MR analysis was conducted using inverse variance weighted regression as the primary method, with MR-Egger and weighted median methods as sensitivity analyses. Additional tests for pleiotropy and heterogeneity were performed to validate the robustness of the findings. The analysis identified significant associations between elevated levels of gamma-glutamylglycine [odds ratio (OR) = 2.379, 95% CI = 1.261-4.488, P = 0.007], N6-acetyllysine (OR = 2.731, 95% CI = 1.081-6.901, P = 0.034), phosphocholine (OR = 2.205, 95% CI = 1.226-3.658, P = 0.038) and glycine (OR = 2.118, 95% CI = 1.226-3.658, P = 0.007) with an increased risk of craniosynostosis. Conversely, higher levels of 3-hydroxy-2-methylpyridine sulfate (OR = 0.411, 95% CI = 0.1717-0.988, P = 0.047) and 5,6-dihydrothymine (OR = 0.293, 95% CI = 0.098-0.876, P = 0.028) were associated with reduced risk. Sensitivity analyses confirmed the robustness of these findings, with no significant evidence of pleiotropy or heterogeneity detected. This study provides evidence that specific blood metabolites may causally influence the risk of craniosynostosis, suggesting potential metabolic pathways that could be targeted for therapeutic intervention. These findings help to develop metabolite-based strategies for the prevention and treatment of craniosynostosis.

Self-control study of multi-omics in identification of microenvironment characteristics in urine of uric acid stone

AbstractThe aim of this study is to perform proteomic and metabolomic analyses in bilateral renal pelvis urine of patients with unilateral uric acid kidney stones to identify the specific urinary environment associated with uric acid stone formation. Using cystoscopy-guided insertion of ureteral catheters, bilateral renal pelvis urine samples are collected. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is employed to identify differentially expressed proteins and metabolites in the urine environment. Differentially expressed proteins and metabolites are further analyzed for their biological functions and potential metabolic pathways through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. In the urine from the stone-affected side, eight differential proteins were significantly upregulated, and six metabolites were dysregulated. The uric acid stone urinary environment showed an excess of α-ketoisovaleric acid and 3-methyl-2-oxovaleric acid, which may contribute to the acidification of the urine. Functional and pathway analyses indicate that the dysregulated metabolites are mainly associated with insulin resistance and branched chain amino acid metabolism.

Bacterial phylotypes associated with rock-dwelling Umbilicaria Lichens from Arctic/Subarctic areas in North America and Northern Europe

AbstractThe diversity of bacteria associated with lichens has received increasing attention. However, studies based on next-generation sequencing of microbiomes have not yet been conducted in the Arctic and Subarctic regions. In this study, rock-dwelling lichens belonging to the Umbilicariaceae family were sampled from the Arctic and Subarctic biological zones. The primary research purpose was to undertake a comparative investigation of the bacterial composition and diversity, identify potential indicators, and explore their potential metabolic pathways. 18S rRNA gene sequences of the fungal partner belonging to the genus Umbilicaria (Ascomycota) and the algal partner affiliated with the lineage Trebouxia (Chlorophyta). Comparing Umbilicaria spp. with a previous study in the Antarctic zone, the fungal partners were more inclined to cluster by sampling region. Operational taxonomic units (OTUs) were established based on a predetermined similarity threshold for V3-V4 sequences, which were ascribed to 19 bacterial phyla, and ten of them were consistently present in all samples. The most distinct zonal indicator genera based on OTU frequencies from Arctic and Subarctic lichens were Capsulimonas (Armatimonadota) and Jatrophihabitans (Actinomycota), respectively. Although the Subarctic zone had higher biodiversity and species richness based on alpha-diversity, the beta-diversity showed that the main species of bacterial communities were not significantly different, and the predictions of metabolic pathways based on the bacterial microbiome in lichen samples from the two zones were similar. These findings provide evidence that the geographical and/or bioclimatic environment and the different lichen-forming fungal species mainly and partially influence bacterial microbiomes and metabolic pathways.

Investigating the causal relationship between human blood metabolites and pulmonary hypertension: a two-sample Mendelian randomization study.

Several recent investigations have posited that distinct metabolites in the bloodstream may be correlated with the pathogenesis of Pulmonary Hypertension (PH). Nonetheless, the interrelationship between the pathogenesis of PH and metabolite fluctuations remains incompletely elucidated, and findings may differ across studies. In the extant research, data from 486 metabolite-and PH-related genetic variants in human subjects were procured based on Genome-Wide Association Studies (GWAS) and Finnish databases. Univariate Mendelian Randomization analyses were deployed to evaluate the causal relationships between them. The utilization of the randomized Inverse Variance weighted(IVW) method served as the primary analytic framework in this Mendelian Randomization (MR) study. Additionally, four alternative computational strategies, encompassing MR-Egger, were employed as auxiliary methods. A myriad of tests, including Cochran's Q Test, MR-Egger intercept test, MR-PRESSO, leave-one-out analysis, and linkage disequilibrium score were incorporated to assess the robustness of the study outcomes. Metabolite pathway analysis was also executed to identify potential metabolic pathways. After a series of validations and corrected for False discovery rate (FDR), we found a significant association between 1,5-anhydroglucitol (OR = 2.00, 95% CI: 1.39-2.89, P = 0.0002) and PH, and a significant association between pyridoxalate (OR = 0.59, 95% CI: 0.43-0.81, P = 0.0009) and 1-a achidonoylglycerophosphocholine (OR = 1.78, 95% CI: 1.22-2.58, P = 0.0026) had a suggested association with PH. In addition, the vitamin B6 metabolic pathway was also determined to be associated with PH. Conclusively, we isolated 1,5-anhydroglucitol, 1-arachidonoylglycerophosphocholine, and pyridoxate as causally implicated in PH, thereby proffering substantial theoretical substantiation for the formulation of future PH prevention and screening paradigms.

To Drink or Not to Drink? Investigating Alcohol’s Impact on Prostate Cancer Risk

Background/Objectives: Prostate cancer (PCa) is a significant global health issue. The relationship between alcohol consumption and PCa risk has been the subject of extensive research, yet findings remain inconsistent. This review aims to clarify the association between alcohol intake and PCa risk, its aggressiveness, and the potential metabolic pathways involved in PCa onset. Methods: A comprehensive literature search was conducted across multiple databases, including PubMed and MEDLINE, focusing on epidemiological studies, meta-analyses, cohort studies, and case–control studies. Studies evaluating alcohol consumption, prostate-specific antigen (PSA) levels, and PCa risk were included. The review also explored the roles of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in alcohol metabolism. Results: The analysis reveals a complex relationship between alcohol consumption and PCa. Heavy alcohol intake is associated with an increased risk of PCa, particularly more aggressive forms, and higher mortality rates. However, studies also show weak or no association between moderate alcohol consumption and PCa. The variability in findings may be attributed to differences in alcohol types, regional factors, and study methodologies. Conclusions: The link between alcohol consumption and PCa risk is multifaceted. While heavy drinking appears to increase the risk of aggressive PCa, the overall relationship remains unclear. Further research is needed to better understand these associations and inform public health recommendations and cancer prevention strategies.

Physical activity, metabolites, and breast cancer associations.

The effects of usual physical activity on physiology and disease prevention are not fully understood. We examined the associations between physical activity, metabolites, and breast cancer risk. Physical activity levels were assessed using doubly labeled water, accelerometers, and 24-hr recalls in the IDATA study (N = 707 participants, ages 50-74 years, 51% women), with 1-6 assessments over 12 months and two blood sample collections. Partial Spearman correlations were used to estimate associations between physical activity and 843 serum metabolites, corrected for multiple testing. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of metabolites with postmenopausal breast cancer in a nested case-control study (621 cases, 621 controls), all statistical tests were 2-sided. Physical activity was associated with 164 metabolites spanning numerous pathways, including amino acid and fatty acid metabolism. Twelve of these metabolites were also associated with breast cancer risk, ten of which supported a protective role of physical activity. Notably, higher physical activity was associated with lower 16alpha-hydroxy DHEA 3-sulfate (androgen) and adipoylcarnitine (fatty acid), both of which were associated with increased breast cancer risk (OR per 1 standard deviation (SD)=1.34, 95% CI = 1.16-1.55 and 1.26,1.11-1.42, respectively). Higher physical activity energy expenditure was also associated with lower sphingomyelin (d18:1/20:1, d18:2/20:0), which was associated with a reduced breast cancer risk (0.82,0.73-0.93). Physical activity is associated with a broad range of metabolites, many of which are consistent with a protective effect against breast cancer. Our findings highlight potential metabolic pathways for cancer prevention.

Integration of metabolomics and transcriptomics to reveal metabolic characteristics and key targets associated with lncRNA Vof-16 in H19-7 cells

Cognitive disorders represent one of the most common chronic complications of diabetes. Our previous study has demonstrated that long non-coding RNA (lncRNA) Vof-16 is upregulated in the hippocampal tissue of streptozotocin (STZ)-induced diabetic rats. Despite this finding, the specific roles and underlying mechanisms of lncRNA Vof-16 in diabetes-related cognitive dysfunction remain largely unexplored. To elucidate the mechanism involved, lncRNA Vof-16 was overexpressed in rat hippocampal cell line H19-7 through lentivirus transfection. We integrated metabolomics and transcriptomics approaches to identify potential targets and metabolic pathways influenced by lncRNA Vof-16. Key proteins and pathways were subsequently validated using western blotting and immunofluorescence staining. Transcriptomics indicated that lncRNA Vof-16 overexpression may modulate autophagic activity in H19-7 cells. Metabolomic profiling revealed that the primary differential metabolic pathways included trehalose degradation, tryptophan metabolism, vitamin B6 metabolism, glycolysis, pterine biosynthesis, and the pentose phosphate pathway. Ingenuity Pathway Analysis (IPA) of gene-metabolite networks demonstrated that the high lncRNA Vof-16 expression group exhibited a significantly higher association with autophagy compared to the low lncRNA Vof-16 expression group. Western blot results confirmed that lncRNA Vof-16 overexpression led to decreased protein expression levels of ATG3 and ATG12. Specifically, lncRNA Vof-16 reduces autophagy in hippocampal neurons by targeting the elevated levels of phospho-p70S6K, a downstream effector of mTORC1, potentially contributing to the pathogenesis of diabetic cognitive impairment. The construction of gene-metabolite networks may offer promising new strategies for addressing the growing issue of diabetic cognitive impairment.

Multi-omics and bioinformatics for the investigation of therapeutic mechanism of roucongrong pill against postmenopausal osteoporosis

Ethnopharmacological relevanceThe Roucongrong Pill (RCRP), originating from the historical General Medical Collection of Royal Benevolence, is frequently used to treat postmenopausal osteoporosis (PMOP). Despite its prevalent application, the specific anti-osteoporotic mechanisms of RCRP remain to be elucidated. Aim of the studyThis study aims to elucidate the therapeutic mechanism of RCRP in the context of ovariectomy (OVX)-induced PMOP in rats. By employing an integrative approach, the research combines medicinal chemistry, gut microbiota (GM) profiling, metabolomics, MetOrigin traceability, network pharmacology, molecular docking, and molecular dynamics simulations to deliver a comprehensive analysis. Materials and methodsSprague-Dawley (SD) rats underwent bilateral OVX to establish a PMOP model. The therapeutic efficacy of RCRP was evaluated through bone metrics (BMD, bone strength, BV/TV, Tb.Sp), hematoxylin and eosin (H&E) histological assessment, and bone metabolism markers (OPG, BALP, TRACP-5b, β-CTX, RANKL). Fecal metabolomics and 16S rDNA sequencing were employed to assess the influence of RCRP on GM and metabolite profiles. Furthermore, MetOrigin facilitated the traceability analysis of relevant metabolites. Molecular docking identified potential RCRP compounds with anti-PMOP activity, while their stability and protein interactions were assessed through molecular dynamics simulations. Network pharmacology further confirms the targets of action. ResultsRCRP alleviated PMOP in rats, enhancing bone strength, cortical and trabecular BMD, BV/TV, and serum OPG levels, while reducing Tb.Sp, serum BALP, TRACP-5b, β-CTX, and RANKL concentrations. A total of twenty-six distinct metabolites were identified, of which ten—tribufos, sulfoacetic acid, betamethasone dipropionate, 9-oxooctadeca-10,12,15-trienoic acid, menatetrenone, piperlongumine, maltopentaose, enol-phenylpyruvate, catechol, pentaacetate, and (+)-2-methylpropanoic acid—exhibited correlations with six GM species: Turicibacter, Roseburia, Colidextribacter, Helicobacter, Odoribacter, and Lachnoclostridium, as determined by Spearman's correlation analysis. Notably, MetOrigin revealed the microbial metabolism of taurine and hypotaurine, along with host-specific steroid hormone synthesis. Computational docking studies demonstrated robust interactions between five RCRP-derived steroids (hydroxyecdysone, corticosterone, trilostane, 5α-androstan-3,6,17-trione, and cortisol) and key enzymes (estradiol 17α-dehydrogenase and UDP-glucuronosyltransferase), suggesting a potential enhancement of therapeutic efficacy against PMOP. Furthermore, molecular dynamics simulations indicated stable interactions between hydroxyecdysone and two proteins, with binding free energies of −67.427 kJ/mol and −156.948 kJ/mol, respectively. Through network pharmacology and molecular docking approaches, potential targets of these metabolites were identified, including estrogen receptors ESR1 and ESR2, dual specificity phosphatase 6 (DUSP6), sex hormone-binding globulin (SHBG), prostaglandin E receptor 4 (PTGER4), cannabinoid receptor 2 (CNR2), cathepsin K (CTSK), and androgen receptor (AR). ConclusionsRCRP effectively mitigates OVX-induced bone loss in PMOP rats by modulating GM and associated metabolites, along with their potential targets and key metabolic pathways, including taurine and hypotaurine metabolism, as well as steroid hormone biosynthesis. These findings offer new insights into the therapeutic mechanisms by which RCRP may alleviate PMOP.

Effects of different fermentation modes on tea leaves: Revealing the metabolites modification by quasi-targeted metabolomics

To investigate the effects of aerobic and anaerobic fermentation on tea leaves and to compare the differences between different fermentation modes, the metabolite profiles of pre-fermented tea, anaerobic-fermented tea, and aerobic-fermented tea from the same batch were comprehensively analyzed by quasi-targeted metabolomics. The results showed that the two fermentation modes altered tea metabolites significantly differently based on 1162 identified metabolites. A total of 611 differential metabolites were screened in different fermented teas, of which phenolics were the most critical compounds. Both fermentation modes reduced the levels of phenolic esters/glucosides in tea, accompanied by the accumulation of free phenolic. Notably, aerobic fermentation was more conducive for flavonoid glycosides and phenolic acid esters/glycosides reduction, while anaerobic fermentation better for free phenolic acids enhancement, especially gallic acid and its derivatives. Additionally, potential metabolic pathways of tea phenolics during fermentation were depicted, primarily involving the hydrolysis, methylation, and glycosylation of flavonoids, as well as the hydrolysis, esterification, degradation, and amination of phenolic acids. Furthermore, there were also some differences in the metabolism of amino acids, sugars, organic acids and lipids between the two fermentation modes. This study will advance our insights into the fermentation metabolism of post-fermented tea.

Prenatal exposure to per- and polyfluoroalkyl substances and sex-specific associations with offspring adiposity at 10 years of age: Metabolic perturbation plays a role

BackgroundPer- and polyfluoroalkyl substances (PFAS) have been suspected as potential environmental obesogens, with several mechanisms being proposed, including the role of metabolomics. However, current epidemiological studies have yielded inconclusive findings. ObjectivesWe aimed to estimate the associations of prenatal exposure to PFAS with offspring adiposity measures, and to explore the potential metabolic pathways underlying these associations. MethodsA total of 464 mother–child pairs from the Sheyang Mini Birth Cohort Study (SMBCS) were included in this study. Cord serum concentrations of 12 PFAS and urine metabolite profiles at age 10 were obtained from the SMBCS database. Adiposity-related anthropometric measurements and body composition estimates of children aged 10 were used to assess offspring obesity. Multiple linear regression models and quantile g-computation were conducted to estimate the associations of prenatal exposure to individual and multiple PFAS with obesity at 10 years old. Metabolomics analysis was performed to characterize the biological pathways associated with PFAS exposure or obesity, subsequently identifying the overlapping metabolic pathways underlying the PFAS-obesity relationship. ResultsPrenatal exposure to several PFAS was significantly associated with elevated obesity-related markers in 10-year-old children. After stratification by sex, the effects were more pronounced in girls. Quantile g-computation results indicated that exposure to higher levels of PFAS mixtures during pregnancy was associated with increased odds of obesity in girls, with PFNA emerging as the predominant driving compound. Untargeted metabolomics results showed that several amino acid metabolic pathways were characterized as the overlapping pathways underlying the above associations. ConclusionsTaken together, our findings suggested the potential obesogenic effects of prenatal exposure to PFAS and offered insight into the possible metabolic mechanisms underlying PFAS-related offspring obesity.

16S rRNA based metagenomic analysis unveils unique oral microbial signatures in oral squamous cell carcinoma cases from Coastal Karnataka, India.

Oral Squamous cell carcinoma (OSCC) is the 14th most frequent cancer with 300,000 new cases and 100,000 deaths reported annually. Even with advanced therapy, the treatment outcomes are poor at advanced stages of the disease. The diagnosis of early OSCC is of paramount clinical value given the high mortality rate associated with the late stages of the disease. Recently, the role of microbiome inthedisease manifestation, including oral cancer, has garnered considerable attention. But, to establish the role of bacteria in oral cancer, it is important to determine the differences in the colonization patternin non-tumour and tumour tissues. In this study, 16S rRNA based metagenomic analyses of 13tumorous and contralateral anatomically matched normal tissue biopsies, obtained from patients with advanced stage of OSCC were evaluated to understand the correlation between OSCC and oral microbiome. In this study we identified Fusobacterium, Prevotella, Capnocytophaga, Leptotrichia, Peptostreptococcus, Parvimonas and Bacteroidetes as the most significantly enriched taxa in OSCC lesions compared to the non-cancerous tissues. Further, PICRUSt2 analysis unveiled enhanced expression of metabolic pathways associated with L-lysine fermentation, pyruvate fermentation, and isoleucine biosynthesis in those microbes associated with OSCC tissues. These findings provide valuable insights into the distinctive microbial signatures associated with OSCC, offering potential biomarkers and metabolic pathways underlying OSCC pathogenesis. While our focus has primarily centred onmicrobial signatures, it is essential to recognize the pivotal role of host factors such as immune responses, genetic predisposition, and the oral microenvironment in shaping OSCC development and microbiome composition.

LC-MS/MS-based metabolomics and proteomics reveal the intervention of Kangnian decoction on the postoperative intestinal adhesion of rats.

Postoperative Intestinal Adhesions (PIAs) remain a significant complication of abdominal surgery that can cause pain, infertility, and a potentially lethal bowel obstruction. Kangnian (KN) decoction, a Traditional Chinese Medicine prescription, has been shown to be effective in treating PIAs. Nevertheless, its underlying mechanisms remain unclear. This study aims to explore the therapeutic effects of KN decoction in a PIA rat model, as well as its potential mechanisms via metabolomics and proteomics analyses. 60 rats were randomly assigned to six groups: Normal Control (NC), PIA model, Dexamethasone, KN-Low, KN-Medium, and KN-High. The PIA model was created by abdominal surgery under anesthesia. Pathological damage was evaluated through H&E staining and adhesion grading of affected tissues. The levels of serum cytokines (IL-1β, IL-6, TNF-α, and TGF-1), Connective Tissue Growth Factor (CTGF), and Motilin (MTL) in adherent intestinal tissues were detected using ELISA kits. Untargeted metabolomics was used to investigate potential metabolic pathways of the KN decoction intervention in intestinal adhesions and to screen for differential biomarkers. The label-free quantitative proteomics technique was employed to detect Differentially Expressed Proteins and for biological function and pathway enrichment analyses. In PIA rats, KN decoction significantly improved the pathological injury associated with intestinal adhesions and effectively regulated the blood inflammation indicators. Furthermore, KN presented a favorable anti-fibrotic and protective effect against abdominal adhesions, effectively modifying gastrointestinal motility disorders in PIA rats. We identified 58 variables as potential biomarkers and discovered seven main pathological pathways that may be associated with PIAs. Proteomics analysis revealed 75 DEPs that were primarily involved in Valine, leucine, and isoleucine degradation, the MAPK signaling pathway, and retrograde endocannabinoid signaling. This study proved that KN reduces intestinal mucosal injury, downregulates inflammatory factors, and alleviates intestinal adhesions, thus protecting the intestinal barrier function in PIA rats. The combination of proteomics and metabolomics provided a feasible approach for unraveling the therapeutic mechanism of KN decoction in PIAs.

Probiotic Lactobacillus plantarum 299v supplementation in patients with major depression in a double-blind, randomized, placebo-controlled trial: A metabolomics study

BackgroundUnderstanding the multifactorial nature of major depressive disorder (MDD) is crucial for tailoring treatments. However, the complex interplay of various factors underlying the development and progression of MDD poses significant challenges. Our previous study demonstrated improvements in cognitive functions in MDD patients undergoing treatment with selective serotonin reuptake inhibitors (SSRIs) supplemented with Lactobacillus plantarum 299v (LP299v). MethodsTo elucidate the biochemical mechanisms underlying cognitive functions improvements, we explored underlying metabolic changes. We employed multi-platform metabolomics, including LC-QTOF-MS and CE-TOF-MS profiling, alongside chiral LC-QqQ-MS analysis for amino acids. ResultsSupplementation of SSRI treatment with LP299v intensified the reduction of long-chain acylcarnitines, potentially indicating improved mitochondrial function. LP299v supplementation reduced N-acyl taurines more than four times compared to the placebo, suggesting a substantial impact on restoring biochemical balance. The LP299v-supplemented group showed increased levels of oxidized glycerophosphocholine (oxPC). Additionally, LP299v supplementation led to higher levels of sphingomyelins, L-histidine, D-valine, and p-cresol. LimitationsThis exploratory study suggests potential metabolic pathways influenced by LP299v supplementation. However, the need for further research hinders the ability to draw definitive conclusions. ConclusionsObserved metabolic changes were linked to mitochondrial dysfunction, inflammation, oxidative stress, and gut microbiota disruption. Despite the subtle nature of this alterations, our research successfully detected these differences and connected them to the metabolic disruptions associated with MDD. Our findings emphasise the intricate relationship between metabolism, gut microbiota, and mental health prompting further research into the mechanisms of action of probiotics in MDD treatment.

HADH suppresses clear cell renal cell carcinoma progression through reduced NRF2-dependent glutathione synthesis

BackgroundClear cell renal cell carcinoma (ccRCC) is a serious threat to human life. It is very important to clarify the pathogenesis of ccRCC. In this study we evaluated the clinical value of HADH and explored its role and mechanism in the malignant progression of ccRCC. MethodsHADH expression and its relationship with prognosis were analyzed using bioinformatics database. RT-PCR, Western blot and immunohistochemistry were used to examine the expression of HADH in ccRCC tissues and tissue microarrays. To examine the cell proliferation, apoptosis, migration and invasion ability, ccRCC cells with HADH overexpressed were constructed. Xenograft experiments were performed to determine the role of HADH. Non-target metabolomics was applied to explore the potential metabolic pathway by which HADH inhibited ccRCC progression. Plasmid pcDNA3.1-NRF2 was used to confirm whether HADH inhibited the process of ccRCC cells through NRF2-related glutathione (GSH) synthesis. ResultsBioinformatics database analysis showed that HADH expression was significantly decreased in ccRCC tissues, and its low expression predicted a poor prognosis. Both ccRCC tissues and tissue microarrays exhibited a significantly decreased HADH level compared with adjacent normal renal tissues. HADH overexpression inhibited the malignant behaviors of ccRCC cells. Furthermore, HADH overexpression attenuated GSH synthesis and induced oxidative stress damage. Exogenously increased NRF2 effectively attenuated the inhibitive effect of HADH overexpression on ccRCC cells. ConclusionOur data revealed that HADH suppressed the malignant behaviors of ccRCC cells by attenuating GSH synthesis through inhibition of NRF2 nuclear translocation, and HADH might be a novel therapeutic target for ccRCC treatment.

Insights into the role of GhCYP and GhTPS in the gossypol biosynthesis pathway via a multiomics and functional-based approach in cotton

Two Cotton Research Institute (CRI) near-isogenic lines, CRI-12 glanded and CRI-12 glandless, were used to pinpoint potential genes and metabolic pathways linked to gossypol biosynthesis through transcriptome sequencing. We discovered more than 235 million clean reads and 1,184 differentially expressed genes (DEGs). Consecutively, we conducted a weighted gene co-expression network analysis and found strong correlation of white and yellow modules containing GhTPS (GH_D09G0090) and GhCYP (GH_D05G2016) hub genes with the gossypol content. The importance of the GhTPS and GhCYP genes was demonstrated using RT-qPCR, virus-induced gene silencing (VIGS) and target metabolite analysis. Silencing of these genes resulted in fewer glands on both leaves and stems two weeks after the infection, as compared to the wild type. In addition, a total of 152 metabolites were identified through targeted metabolite profiling. Differential metabolite screening revealed 12 and 18 significantly different metabolites in TRV:GhTPS and TRV:GhCYP plants vs. control group, respectively, showing reduction in accumulation of metabolites compared to the control. The content of hemigossypol, the final product of gossypol biosynthesis, was also reduced, as revealed by target metabolite analysis, suggesting the role of these genes in the gossypol biosynthetic pathway. Furthermore, a highly significant difference in gossypol content between the glanded and glandless lines was recorded. The findings of this study reveal a strong link between the gossypol content and GhTPS and GhCYP hub genes, suggesting their role in the gossypol biosynthetic pathway to reduce the accumulation of hemigossypol, which may offer new comprehension into the regulatory checkpoints of the gossypol biosynthesis pathway in cotton.

Ameliorative effects of Trichosanthes kirilowii Maxim. seed oil on hyperlipidemia rats associated with the regulation of gut microbiology and metabolomics

The mechanisms underlying the ameliorative effects of polyunsaturated fatty acids (PUFAs) on metabolic disorders induced by a high-fat diet (HFD) remain poorly unclear. In this study, we investigated the anti-hyperlipidemic effects of Trichosanthes kirilowii Maxim. (T. kirilowii) seed oil rich in conjugated linolenic acid in HFD-induced hyperlipidemic rats, by the gut microbiome, cecum bile acids (BAs), and serum metabolomics. The results showed that T. kirilowii seed oil improved dyslipidemia, hepatic steatosis, oxidative stress, and inflammatory responses in HFD-induced rats. Meanwhile, T. kirilowii seed oil inhibited sterol regulatory element-binding protein 1c (SREBP-1c) mediated fatty acid synthesis and upregulated cholesterol 7-alpha hydroxylase (CYP7A1) mediated hepatic cholesterol metabolism to exert hypolipidemic effects. The administration of high dose T. kirilowii seed oil (THD) improved gut microbiota dysbiosis, increased the relative abundance of beneficial bacteria Romboutsia and unidentified_Oscillospiraceae, and decreased the relative abundance of Christensenellaceae_R-7 group, Phascolarctobacterium, and Bacteroides in HFD-induced rats. T. kirilowii seed oil reduced the accumulation of cecum primary BAs in HFD-induced rats. In addition, THD reversed the HFD-induced changes in 24 serum metabolites including leucine, isoleucine, acetylcarnitine, and glucose. Metabolic pathway enrichment analysis of the differential metabolites revealed that valine, leucine and isoleucine metabolism, butanoate metabolism, citrate cycle, and glycolysis were potential metabolic pathways involved in the anti-hyperlipidemic effects of T. kirilowii seed oil. In conclusion, this study found that dietary T. kirilowii seed oil alleviated gut microbiota dysbiosis and improved metabolic disorders in hyperlipidemic rats. This provides new insights into the anti-hyperlipidemic mechanism by which other families of PUFAs are derived from different plants.

Engineered Bimetallic MOF-Crafted Bullet Aids in Penetrating Serum Metabolic Traits of Chronic Obstructive Pulmonary Disease.

Metabolomics analysis based on body fluids, combined with high-throughput laser desorption and ionization mass spectrometry (LDI-MS), holds great potential and promising prospects for disease diagnosis and screening. On the other hand, chronic obstructive pulmonary disease (COPD) currently lacks innovative and powerful diagnostic and screening methods. In this work, CoFeNMOF-D, a metal-organic framework (MOF)-derived metal oxide nanomaterial, was synthesized and utilized as a matrix to assist LDI-MS for extracting serum metabolic fingerprints of COPD patients and healthy controls (HC). Through machine learning algorithms, successful discrimination between the COPD and HC was achieved. Furthermore, four potential biomarkers significantly downregulated in COPD were screened out. The disease diagnostic models based on the biomarkers demonstrated excellent diagnostic performance across different algorithms, with area under the curve (AUC) values reaching 0.931 and 0.978 in the training and validation sets, respectively. Finally, the potential metabolic pathways and disease mechanisms associated with the identified markers were explored. This work advances the application of LDI-based molecular diagnostics in clinical settings.

Genetic liability to human serum metabolites is causally linked to telomere length: insights from genome-wide Mendelian randomization and metabolic pathways analysis.

Telomere has been recognized as a biomarker of accelerating aging, and telomere length (TL) shortening is closely related to diverse chronic illnesses. Human serum metabolites have demonstrated close correlations with TL maintenance or shortening in observational studies. Nevertheless, little is known about the underlying pathological mechanisms, and Mendelian randomization (MR) analysis of serum metabolites may provide a more comprehensive understanding of the potential biological process. We employed a two-sample MR analysis method to assess the causal links between 486 serum metabolites and TL. We applied the inverse-variance weighted (IVW) approach as our primary analysis, and to assure the stability and robustness of our results, additional analysis methods including the weighted median, MR-Egger, and weighted mode were conducted. MR-Egger intercept test was utilized to detect the pleiotropy. Cochran's Q test was implemented to quantify the extent of heterogeneity. Furthermore, the pathway analysis was conducted to identify potential metabolic pathways. We identified 11 known blood metabolites associated with TL. Among these metabolites, four were lipid (taurocholate, dodecanedioate, 5,8-tetradecadienoate, and 15-methylpalmitate), one amino acid (levulinate (4-oxovaleate)), one carbohydrate (lactate), one nucleotide (pseudouridine), one energy (phosphate), and three xenobiotics (2-hydroxyacetaminophen sulfate, paraxanthine, and ergothioneine). The known protective metabolites included levulinate (4-oxovaleate), dodecanedioate, 5,8-tetradecadienoate, lactate, phosphate, paraxanthine, and ergothioneine. Multiple metabolic pathways have been identified as being implicated in the maintenance of telomere length. Our MR analysis provided suggestive evidence supporting the causal relationships between 11 identified blood metabolites and TL, necessitating further exploration to clarify the mechanisms by which these serum metabolites and metabolic pathways may affect the progression of telomeres.

Assessing the causal relationship between metabolic biomarkers and coronary artery disease by Mendelian randomization studies

The development of coronary artery disease (CAD) is significantly affected by impaired endocrine and metabolic status. Under this circumstance, improved prevention and treatment of CAD may result from knowing the connection between metabolites and CAD. This study aims to delve into the causal relationship between human metabolic biomarkers and CAD by using two-sample Mendelian randomization (MR). Utilizing two-sample bidirectional MR analysis, we assessed the correlation between 1400 blood metabolites and CAD, and the metabolites data from the CLSA, encompassing 8299 participants. Metabolite analysis identified 1091 plasma metabolites and 309 ratios as instrumental variables. To evaluate the causal link between metabolites and CAD, we analyzed three datasets: ebi-a-GCST005195 (547,261 European & East Asian samples), bbj-a-159 (29,319 East Asian CAD cases & 183,134 East Asian controls), and ebi-a-GCST005194 (296,525 European & East Asian samples). To estimate causal links, we utilized the IVW method. To conduct sensitivity analysis, we used MR-Egger, Weighted Median, and MR-PRESSO. Additionally, we employed MR-Egger interception and Cochran’s Q statistic to assess potential heterogeneity and pleiotropy. What’s more, replication and reverse analyses were performed to verify the reliability of the results and the causal order between metabolites and disease. Furthermore, we conducted a pathway analysis to identify potential metabolic pathways. 59 blood metabolites and 27 metabolite ratios nominally associated with CAD (P < 0.05) were identified by IVW analysis method. A total of four known blood metabolites, namely beta-hydroxyisovaleroylcarnitine (OR 1.06, 95% CI 1.027–1.094, FDR 0.07), 1-palmitoyl-2-arachidonoyl (OR 1.07, 95% CI 1.029–1.110, FDR 0.09), 1-stearoyl-2- docosahexaenoyl (OR 1.07, 95% CI 1.034–1.113, FDR 0.07) and Linoleoyl-arachidonoyl-glycerol, (OR 1.07, 95% CI 1.036–1.105, FDR 0.05), and two metabolite ratios, namely spermidine to N-acetylputrescine ratio (OR 0.94, 95% CI 0.903–0.972, FDR 0.09) and benzoate to linoleoyl-arachidonoyl-glycerol ratio (OR 0.87, 95% CI 0.879–0.962, FDR 0.07), were confirmed as having a significant causal relationship with CAD, after correcting for the FDR method (p < 0. 1). A causal relationship was found to be established between beta -hydroxyisovalerylcarnitine and CAD with the validation in other two datasets. Moreover, multiple metabolic pathways were discovered to be associated with CAD. Our study supports the hypothesis that metabolites have an impact on CAD by demonstrating a causal relationship between human metabolites and CAD. This study is important for new strategies for the prevention and treatment of CAD.

Metabolic pathways altered by air pollutant exposure in association with coagulation function among the rural elderly

Air pollution exposure has been linked with coagulation function. However, evidence is limited for the relationships between air pollution, coagulation function and metabolomics in humans. We recruited a panel of 130 rural elderly from the Chayashan township in China, all of whom were free of pre-existing cardiovascular diseases and had provided residential address information. We conducted clinical examinations and collected blood samples from these rural elderly for the detection of coagulation biomarkers (e.g, activated partial thromboplastin time, fibrinogen, thrombin time, and prothrombin time) and untargeted metabolites in both December 2021 and August 2022. We used mini ambient air quality monitor to measure the mean levels of five air pollutants (e.g., PM2.5, SO2, NO2, CO and O3) during 1 to 2 weeks before blood sample collection. The Mummichog pathway analysis was used to identified potential metabolic features and pathways. In this study, we identified 5 pathways associated with both air pollution and coagulation function, and further pinpointed eight metabolic features within these pathways. The majority of these features were lipids, including arachidonic acid and linoleic acid. Overall, the findings of this study offer insights into potential mechanisms, particularly lipid metabolism, that may underlie the association between air pollution and coagulation function.