PubMed

Metabolomics. 2024 Nov 3;20(6):124. doi: 10.1007/s11306-024-02182-3.ABSTRACTBACKGROUND: The global incidence of hypertension, a condition of elevated blood pressure, is rising alarmingly. According to the World Health Organization's Qatar Hypertension Profile for 2023, around 33% of adults are affected by hypertension. This is a significant public health concern that can lead to serious health complications if left untreated. Metabolic dysfunction is a primary cause of hypertension. By studying key biomarkers, we can discover new treatments to improve the lives of those with high blood pressure.AIMS: This study aims to use explainable artificial intelligence (XAI) to interpret novel metabolite biosignatures linked to hypertension in Qatari Population.METHODS: The study utilized liquid chromatography-mass spectrometry (LC/MS) method to profile metabolites from biosamples of Qatari nationals diagnosed with stage 1 hypertension (n = 224) and controls (n = 554). Metabolon platform was used for the annotation of raw metabolite data generated during the process. A comprehensive series of analytical procedures, including data trimming, imputation, undersampling, feature selection, and biomarker discovery through explainable AI (XAI) models, were meticulously executed to ensure the accuracy and reliability of the results.RESULTS: Elevated Vanillylmandelic acid (VMA) levels are markedly associated with stage 1 hypertension compared to controls. Glycerophosphorylcholine (GPC), N-Stearoylsphingosine (d18:1/18:0)*, and glycine are critical metabolites for accurate hypertension prediction. The light gradient boosting model yielded superior results, underscoring the potential of our research in enhancing hypertension diagnosis and treatment. The model's classification metrics: accuracy (78.13%), precision (78.13%), recall (78.13%), F1-score (78.13%), and AUROC (83.88%) affirm its efficacy. SHapley Additive exPlanations (SHAP) further elucidate the metabolite markers, providing a deeper understanding of the disease's pathology.CONCLUSION: This study identified novel metabolite biomarkers for precise hypertension diagnosis using XAI, enhancing early detection and intervention in the Qatari population.PMID:39489869 | DOI:10.1007/s11306-024-02182-3

Sci Rep. 2024 Nov 3;14(1):26494. doi: 10.1038/s41598-024-78359-6.ABSTRACTMyocarditis is a common disease of the cardiovascular and immune systems, but the relationship between relevant blood metabolites and the risk of myocarditis has not been well-established. To identify potential biometabolic markers associated with myocarditis, we conducted a two-sample Mendelian randomization (MR) study. We performed preliminary MR analysis using the inverse variance weighted (IVW) method, supplemented by MR-Egger, weighted median, and weighted mode methods to adjust for false discovery rate (FDR). Confounders were screened using the GWAS Catalog website. Sensitivity analyses included Cochrane Q-test, Egger regression, Mendelian Randomization Pleiotropy RESidual Sum and Outlier (MR-PRESSO), scatterplots, funnel plots, and forest plots. For genetic and directional analysis, we employed co-localization analysis and the Steiger test. MR analysis was performed using the FinnGen database and meta-analysis was performed using the IEU database. MR analysis identified significant correlations for five metabolic biomarkers after FDR correction. These included four known metabolites: kynurenine, 1-stearoyl-GPE (18:0), deoxycarnitine, and 5-acetylamino-6-formylamino-3-methyluracil, as well as one unknown metabolite, X-25,422. Among these, kynurenine (OR = 1.441, 95%CI = 1.089-1.906, p-value = 0.018) and 1-stearoyl-GPE (18:0) (OR = 1.263, 95%CI = 1.029-1.550, p-value = 0.029) were identified as risk factors for myocarditis, while deoxycarnitine (OR = 0.813, 95%CI = 0.676-0.979, p-value = 0.029), 5-acetylamino-6-formylamino-3-methyluracil (OR = 0.864, 95% CI = 0.775-0.962, p-value = 0.018), and X-25,422 (OR = 0.721, 95%CI = 0.587-0.886, p-value = 0.009) were found to be protective factors. No evidence of heterogeneity, horizontal pleiotropy, or sensitivity issues was observed, and no shared genetic factors between exposure and outcome were detected. The causality was in the correct direction. Meta-analysis further confirmed the causal relationship between the five metabolites and myocarditis. This study identifies a causal relationship between five circulating metabolites and myocarditis. Kynurenine, 1-stearoyl-GPE (18:0), deoxycarnitine, X-25,422, and 5-acetylamino-6-formylamino-3-methyluracil may serve as potential drug targets for myocarditis, providing a theoretical basis for the prevention, diagnosis, and treatment of the condition.PMID:39489852 | DOI:10.1038/s41598-024-78359-6

Clin Chim Acta. 2024 Nov 1:120020. doi: 10.1016/j.cca.2024.120020. Online ahead of print.ABSTRACTOne of the essential factors in the appropriate treatment of infections is accurate and timely laboratory diagnosis. The correct diagnosis of infections plays a vital role in determining desirable therapy and controlling the spread of pathogens. Traditional methods of infection diagnosis are limited by several factors such as insufficient sensitivity and specificity, being time-consuming and laborious, having a low ability to distinguish infection from non-infectious inflammatory conditions and a low potential to predict treatment outcomes. Therefore, it is necessary to find innovative strategies for detecting specific biomarkers in order to diagnose infections. The rapid advancement of metabolomics makes it possible to determine the pattern of metabolite changes in the both of pathogen and the host during an infection. Metabolomics is a method used to assess the levels and type of metabolites in an organism. Metabolites are of low-molecular-weight compounds produced as a result of metabolic processes and pathways within cells. Metabolomics provides valuable data to detect accurate biomarkers of specific biochemical features directly related to certain phenotypes or conditions. This study aimed to review the applications and progress of metabolomics as a biomarker for the diagnosis of bacterial infections.PMID:39489271 | DOI:10.1016/j.cca.2024.120020

Int J Biol Macromol. 2024 Nov 1:137112. doi: 10.1016/j.ijbiomac.2024.137112. Online ahead of print.ABSTRACTHyperuricemia (HUA) is a common metabolic disorder that often accompanies kidney diseases such as tubule damage and renal interstitial fibrosis. The preventive and therapeutic effects of Dioscorea septemloba, an anti-HUA herb, polysaccharide of which was considered as the main active ingredient on HUA, need to be explored. The major polysaccharide component, BXP, was purified from Dioscorea septemloba, with an average molecular weight of 10.432 kDa. Structural analysis inferred that BXP backbone was composed of t-β-D-Glcp-(1 → 4)-α-D-Glcp-(1 → 4)-α-D-Glcp-(1 → 4, 3)-β-D-Glcp-(1→, along with the side chain of →1)-α-D-Glcp-(6, 4 → 3, 4)-β-D-Glcp-(1→. The HUA mouse model was further established to clarify the underlying effect of BXP on HUA alleviation. As results shown, BXP decreased serum uric acid by inhibiting XOD and regulating urate transporter expression (GLUT9, OAT3, OAT1, URAT1 and ABCG2) in HUA mice, as well as relieving kidney and liver damage. Moreover, results of microbiome and metabolomics indicated that BXP improved the abundance of gut bacteria and reversed the Lipids-related metabolism disorder caused by HUA. This study indicated that BXP had potential to alleviate HUA and kidney disease through the gut-kidney axis in mice.PMID:39489240 | DOI:10.1016/j.ijbiomac.2024.137112

Gene. 2024 Nov 1:149050. doi: 10.1016/j.gene.2024.149050. Online ahead of print.ABSTRACTAminopeptidase N (ANPEP), a membrane-associated ectoenzyme, has been identified as a susceptibility gene for type 2 diabetes (T2D) by genome-wide association and transcriptome studies; however, the mechanisms by which this gene contributes to disease pathogenesis remain unclear. The aim of this study was to determine the comprehensive contribution of ANPEP polymorphisms to T2D risk and annotate the underlying mechanisms. A total of 3206 unrelated individuals including 1579 T2D patients and 1627 controls were recruited for the study. Twenty-three common functional single nucleotide polymorphisms (SNP) of ANPEP were genotyped by the MassArray-4 system. Six polymorphisms, rs11073891, rs12898828, rs12148357, rs9920421, rs7111, and rs25653, were found to be associated with type 2 diabetes (Pperm ≤ 0.05). Common haplotype rs9920421G-rs4932143G-rs7111T was strongly associated with increased risk of T2D (Pperm = 5.9 × 10-12), whereas two rare haplotypes such as rs9920421G-rs4932143C-rs7111T (Pperm = 6.5 × 10-40) and rs12442778A-rs12898828A-rs6496608T-rs11073891C (Pperm = 1.0 × 10-7) possessed strong protection against disease. We identified 38 and 109 diplotypes associated with T2D risk in males and females, respectively (FDR ≤ 0.05). ANPEP polymorphisms showed associations with plasma levels of fasting blood glucose, aspartate aminotransferase, total protein and glutathione (P < 0.05), and several haplotypes were strongly associated with the levels of reactive oxygen species and uric acid (P < 0.0001). A deep literature analysis has facilitated the formulation of a hypothesis proposing that increased plasma levels of ANPEP as well as liver enzymes such as aspartate aminotransferase, alanine aminotransferase and gammaglutamyltransferase serve as an adaptive response directed towards the restoration of glutathione deficiency in diabetics by stimulating the production of amino acid precursors for glutathione biosynthesis.PMID:39489227 | DOI:10.1016/j.gene.2024.149050

Free Radic Biol Med. 2024 Nov 1:S0891-5849(24)01020-7. doi: 10.1016/j.freeradbiomed.2024.10.312. Online ahead of print.ABSTRACTDecreased nicotinamide adenine dinucleotide (NAD+) content has been shown to contribute to metabolic dysfunction during aging, including polycystic ovary syndrome (PCOS). However, the effect of NAD+ on ovulatory dysfunction in PCOS by regulating glycolysis has not been reported. Based on the observations of granulosa cells (GCs) transcriptome data from the Gene Expression Omnibus (GEO) database, the signal pathways including glycolysis and nicotinate-nicotinamide metabolism were significantly enriched, and most genes of the above pathway like LDHA and SIRT2 were down-regulated in PCOS patients. Therefore, the PCOS rat model was established by combining letrozole with a high-fat diet (HFD), we demonstrate that in vivo supplementation of nicotinamide mononucleotide (NMN) significantly improves the ovulatory dysfunction by facilitating the follicular development, promoting luteal formation, as well the fertility in PCOS rats. Furthermore, target energy metabolomics and transcriptome results showed that NMN supplementation ameliorates the lactate production by activating glycolytic process in the ovary. In vitro, when NAD+ synthesis and SIRT2 expression were inhibited, lactate content in KGN cells was decreased and LDHA expression was significantly inhibited. We confirmed that FK866 can enhance the acetylation of LDHA on 293T cells by Co-immunoprecipitation (Co-IP) assay. We also observed that inhibition of NAD+ synthesis can reduce the activity and increase the apoptosis of KGN cells. Overall, these benefits of NMN were elucidated and the Nampt/SIRT2/LDHA pathway mediated lactate production in granulosa cells played an important role in the improvement of follicular development disorders in PCOS. This study will provide experimental evidence for the clinical application of NMN in the treatment of PCOS in the future.PMID:39489197 | DOI:10.1016/j.freeradbiomed.2024.10.312

Poult Sci. 2024 Oct 19;103(12):104433. doi: 10.1016/j.psj.2024.104433. Online ahead of print.ABSTRACTAccompanied by the accelerated growth rate of chickens, the quality of chicken meat has deteriorated in recent years. Wooden breast (WB) is a severe myopathy affecting meat quality, and its pathophysiology depends on gene expression and intercellular interactions of various cell types, which are not yet fully understood. We have performed a comprehensive transcriptomic and metabolomic atlas of chicken WB muscle. Our data showed a significant increase in the number of immune cells, WB muscle displayed a unique cluster of macrophages (cluster 11), distinct from the M1 and M2 macrophages. Regarding the myocytes, the most significant differences were the decrease in cell number and the intensification of fatty deposits. Satellite cells were involved in muscle repair and regeneration producing more collagen. Interestingly, the interaction network in the WB group was weaker compared to that in normal breast muscle. Additionally, we found six key differential metabolites across 22 pathways. When WB occurs, myocytes and endothelial cells undergo apoptosis, macrophages are activated and exert immune functions, satellite cells participate in muscle rebuilding and repair, and the content of metabolites undergoes significant changes. This cell transcriptome profile provides an essential reference for future studies on the development and remodeling of WB.PMID:39489032 | DOI:10.1016/j.psj.2024.104433

J Hazard Mater. 2024 Oct 28;480:136342. doi: 10.1016/j.jhazmat.2024.136342. Online ahead of print.ABSTRACTThe ecological safety of copper oxide nanoparticles (CuO NPs) in the environment determines the advancement of nano-agriculture owing to breakthroughs in nanotechnology; however, the release of Cu2+ is an uncontrollable factor. Currently, the trade-off mechanisms of CuO NPs and Cu2+ dominating the potential hazards of plant-nano systems remain unclear. This study proposed the trade-off strategy for reconstructing physiological responses and metabolic profiles and deciphered the differential regulation of dominant CuO NPs and Cu2+ in plants. The results showed that 100 and 500 mg/kg CuO NPs promoted root fresh weight but reduced shoot fresh weight, while 1000 mg/kg Cu2+ demonstrated the strongest inhibition on both roots and shoots. The net photosynthetic perturbation in photosynthetic disorders is accompanied by superoxide anion and hydrogen peroxide accumulation, which are severe under 1000 mg/kg CuO NPs and Cu2+ stress. Metabolomics revealed that CuO NPs significantly altered coumaric acid and derivatives, for example, down-regulating coumaroyl hexoside (isomers of 690 and 691) by 40.79 %. Additionally, Cu2+ treatment severely interfered with the dominant metabolic response, activating plant hormone signal transduction and α-linolenic acid metabolism. The trade-off strategies of galactose metabolism, amino sugar and nucleotide sugar metabolism, pantothenate and coenzyme A (CoA) biosynthesis, and β-alanine metabolism as differential metabolism were confirmed by comparing the CuO NPs and Cu2+ exposure. Protein secondary structure analysis revealed specific regulation of protein conformation upon exposure to CuO NPs and Cu2+. These findings provide new insights into differential metabolism and environmental effects in plant-nano systems.PMID:39488971 | DOI:10.1016/j.jhazmat.2024.136342

J Environ Manage. 2024 Nov 2;371:123122. doi: 10.1016/j.jenvman.2024.123122. Online ahead of print.ABSTRACTThe escalation of major ion concentrations in freshwater and soil poses diverse effects on ecosystems and the environment. Excessive ions can exhibit toxicity to aquatic organisms and terrestrial plants. Currently, research on ion toxicity primarily focuses on cation toxicity. Notably, there is a noticeable research gap in understanding the impact of chloride ion (Cl-) on plant growth and development, as well as on the defense mechanisms against Cl- toxicity. In the present study, sampling was conducted on major rivers in China to measure Cl- concentrations. The results revealed that certain rivers exhibited excessive levels of Cl-, emphasizing the critical need to address Cl- toxicity issues. Subsequently, when salt-tolerant cotton seedlings were subjected to various chloride treatments, it was observed that excessive Cl- severely hindered plant growth and development. A combined analysis of transcriptomic and metabolomic data shed light on significantly enriched pathways related to galactose metabolism, arginine and proline metabolism, carotenoid metabolism, and alpha-linolenic acid metabolism under chloride stress. In summary, this research provides a scientific foundation and references for environmental management and water resource protection and offers novel insights for mitigating the adverse impacts of Cl-, thereby contributing to the preservation of ecosystem health.PMID:39488955 | DOI:10.1016/j.jenvman.2024.123122

Int Immunopharmacol. 2024 Nov 2;143(Pt 3):113535. doi: 10.1016/j.intimp.2024.113535. Online ahead of print.ABSTRACTColorectal cancer (CRC) ranks as China's second most common cancer and fifth top cancer death cause. The study highlights the role of Natural Killer (NK) cells in targeting cancer stem cells (CSCs) that evade immune responses in CRC. Colorectal cancer stem cells (CCSCs) were stem from HT-29 cells and co-cultured with NK cells under normoxic or hypoxic conditions. The impact of this co-culture was evaluated using CCK8 assays for NK cell viability, ELISA for cytokine level changes, and flow cytometry for assessing NK cell apoptosis and activation. Comprehensive metabolomic and transcriptomic analyses were also performed to identify key genes and metabolites involved in the interaction between CCSCs and NK cells Co-culture of CCSCs with NK cells under hypoxia reduced NK cytotoxicity, increased NK apoptosis, and altered cytokine secretion by decreasing IFN-γ and TNF-α levels while increasing IL-6. Transcriptomic and metabolomic analysis identified 4 genes (FADS1, ALDH3A2, GCSH, MTCL1) and 3 metabolites (glyoxylic acid, spermine, DDA) as significant. Interfering with FADS1 counteracted the suppression of IFN-γ and TNF-α induced by CSC cells. Curiously, this inhibition caused by si-FADS1 could be neutralized by the addition of exogenous DDA. Co-culturing with NK cells notably increased spermine levels. Exogenous spermine resulted in a significant reduction in HT-29 cell death rates at 32 µM, 64 µM, and 128 µM, compared to NK cells without spermine. Our research explored CCSCs employed the FADS1/DDA axis to evade NK cell-mediated immunosuppression after co-cultured with NK cells under hypoxia.PMID:39488917 | DOI:10.1016/j.intimp.2024.113535

J Pharm Biomed Anal. 2024 Oct 28;253:116551. doi: 10.1016/j.jpba.2024.116551. Online ahead of print.ABSTRACTOphiocordyceps sinensis is widely used to treat various diseases and as a health supplement. The present study comprehensively compared the metabolic differences between wild and cultivated O. sinensis through 2D 1H-13C HSQC-based metabolomics, and assessed their anti-lung cancer activity on A549 cells. To characterize the global metabolic profile, sample preparation was scrutinously optimized, and both polar (1:4 methanol-water) and non-polar (1:4 methanol-chloroform) extracts of O. sinensis were investigated. A total of 47 and 10 metabolites were identified in the polar and non-polar extracts, respectively. Principal Component Analysis (PCA) revealed greater differences between the two types of O. sinensis in the polar extracts than in the non-polar extracts. Orthogonal Partial Least Squares-Discriminant Analysis (OPLS-DA) together with univariate tests captured 23 and 19 differential spectral features (with 22 and 11 of them assigned) between wild and cultivated O. sinensis in the polar and non-polar extracts, respectively. Meanwhile, the anti-lung cancer activities of both polar and non-polar extracts of wild and cultivated O. sinensis were assessed by MTS assay on A549 cells, and the sterols found in non-polar extracts, such as ergosterol, ergosterol peroxide, and 9,11-dehydroergosterol peroxide, and β-sitosterol, are the active ingredients with potential anti-lung cancer properties. In this study, we introduced a comprehensive strategy integrating 2D NMR-based metabolomics with in vitro assays for comparing the chemical composition and assessing the pharmacological activity of wild and cultivated O. sinensis. Our results provided a scientific basis for the potential viability of cultivated O. sinensis as an alternative to the wild counterpart.PMID:39488908 | DOI:10.1016/j.jpba.2024.116551

Comp Biochem Physiol Part D Genomics Proteomics. 2024 Oct 29;52:101346. doi: 10.1016/j.cbd.2024.101346. Online ahead of print.ABSTRACTGlobal warming has multi-dimensional and complex impacts on the Earth's system, among which changes in light intensities cannot be overlooked. Sea cucumbers are a marine biological resource with significant economic and ecological value. Their presence and activity help maintain the balance and stability of marine ecosystems. The variation in light intensities have important ecological effects on sea cucumbers. Light intensities can alter the synthesis and degradation of metabolic substances within the bodies of Apostichopus japonicus by changing their body color. Their changes affect the production of microorganisms in the environment, thereby achieving the goal of bioremediation. This study investigated metabolic variations in green, purple, and white sea cucumber Apostichopus japonicus under different light conditions (0 lx and 910 lx) with a 12-h light and 12-h dark photoperiod. The findings indicated that the sea cucumbers displayed more diverse metabolic alterations under 910 lx illumination compared to 0 lx. Specifically, these color morphs primarily responded to changes in light intensities through "tryptophan metabolism" and "biosynthesis of steroid hormones". Additionally, high light intensities environment exacerbated the consumption of fatty acids by sea cucumbers. Different color morphs of sea cucumbers have differences in key metabolites in response to changes in light intensities. Green and white sea cucumbers primarily adapt to environment through phospholipids, while purple sea cucumbers mainly utilize fatty acids. These results enhance our comprehension of how sea cucumbers adapt ecologically to varying light intensities, and they offer valuable insights for systematically uncovering the regulatory processes that marine animals employ in response to environmental changes.PMID:39488885 | DOI:10.1016/j.cbd.2024.101346

Phytomedicine. 2024 Oct 28;135:156184. doi: 10.1016/j.phymed.2024.156184. Online ahead of print.ABSTRACTBACKGROUND: Gui-Ling-Ji (GLJ) described in the ancient medical book 'Yunji Qijian' is a traditional Chinese medicine formula used to improve male fertility. It is now available for the treatment of oligoasthenoteratozoospermia (OAT). However, the active ingredients and mechanism of GLJ are not clear.PURPOSE: The aim of this study was to clarify the active ingredients and mechanism of GLJ in OAT.METHODS: Firstly, the cyclophosphamide-induced OAT rat model was established to evaluate the efficacy of GLJ. Secondly, serum/urine-based metabolomics and lipidomics and tissue-based transcriptomics were performed to discover the differential metabolites and genes in rats. Furthermore, network pharmacology was constructed to explore the associated mechanisms based on the results of multi-omics analysis. Finally, cellular experiment on testicular mesenchymal stromal cells (TM3) was used to validate the active ingredients and the key metabolic pathway.RESULTS: Rats were administered GLJ by gavage every day for 3 weeks. Testicular damage and weight loss caused by cyclophosphamide were restored in rats, the sperm count and motility were improved, and levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and testosterone (T) secretion were also elevated. Compared to the metabolites of OAT rats, 51 and 37 differential metabolites regulated by GLJ were identified from serum and urine respectively, 54 lipid differential metabolites regulated by GLJ were identified by lipidomics. At the same time, 23 of the 258 differential genes were found to be regulated by OAT rats and then reverse-regulated by GLJ. Network pharmacology has identified 13 pathways (Steroid hormone biosynthesis, Taurine and hypotaurine metabolism, Primary bile acid biosynthesis, Linoleic acid metabolism, Retinol metabolism, Glycerophospholipid metabolism, Ether lipid metabolism, Sphingolipid metabolism, Arachidonic acid metabolism, Glutathione metabolism, Arginine biosynthesis, Arginine and proline metabolism, D-Arginine and D-ornithine metabolism), four metabolites (arachidonic acid, oestrone sulphate, phosphatidylglycerol choline and sphingomyelin) and 15 targets (ABCB11, ALDH18A1, CCL3, CD244, CIITA, CYP2C8, DLL1, ITGA4, ESR1, AR, ABCB1, ABCC1, ALB, PLA2G1B and NOS2). GLJ, psoralen, isopsoralen, liquiritin, isoliquiritin, liquiritigenin, and ginsenoside Ro could significantly promote T secretion from TM3 cells. Additionally, arachidonic acid metabolism particularly the cyclooxygenase pathway, is closely related to the promotion of testosterone secretion by GLJ in TM3.CONCLUSION: GLJ has a therapeutic efficacy in cyclophosphamide-induced OAT rats, which can modulate the disorders of lipid metabolism and amino acid metabolism. Arachidonic acid metabolism may be a key pathway, and six prototype compounds are potential key active ingredients for GLJ.PMID:39488872 | DOI:10.1016/j.phymed.2024.156184

STAR Protoc. 2024 Nov 2;5(4):103430. doi: 10.1016/j.xpro.2024.103430. Online ahead of print.ABSTRACTSingle-cell analysis of human peripheral blood cells provides insights into innate and adaptive immune systems. However, robust protocols are essential to ensuring single-cell sequencing data quality and cell viability. Here, we present a protocol for acquiring high-quality single-cell multi-omics data from human peripheral blood mononuclear cells (PBMCs). We describe steps for collecting human blood followed by single-cell sequencing, whole-genome sequencing, and metabolome and proteome analysis of PBMCs using modified multi-omics sample processing.PMID:39488839 | DOI:10.1016/j.xpro.2024.103430

Inflammopharmacology. 2024 Nov 3. doi: 10.1007/s10787-024-01594-w. Online ahead of print.ABSTRACTBACKGROUND: Osteoarthritis (OA) is a common age-related disease that causes pain and impaired mobility. Various blood metabolites are reportedly associated with bone health; however, their impact on OA remains unclear. Therefore, we conducted a metabolome-wide Mendelian randomization (MR) study to identify causal metabolites and therapeutic targets in OA.METHODS: Genetic associations of metabolites were derived from the largest genome-wide association study (GWAS) of the blood metabolome, which provided summary-level data on 1091 blood metabolites. Genetic associations with OA were obtained from four large-scale GWAS: McDonald's study (140,025 cases, 344,349 controls), Zengini's study (12,658 cases, 50,898 controls), Dönertaş's study (39,515 cases, 445,083 controls), and Tachmazidou's study (39,427 cases, 378,169 controls). MR and colocalization analyses were performed to validate the causal roles of the candidate metabolites. Further analyses were conducted using expression quantitative trait locus-based MR, single-cell sequencing data, protein-protein interaction networks, and druggability assessments. These analyses aimed to identify the differentially expressed genes and prioritize them as potential therapeutic targets.RESULTS: The genetically predicted levels of 10 metabolites were associated with OA. Elevated levels of five metabolites and reduced levels of another five metabolites were associated with an increased OA risk. Among these, five metabolites were prioritized based on the most compelling evidence. Seven genes were identified as potentially involved and could serve as novel therapeutic targets for OA.CONCLUSION: Several blood metabolites were associated with OA, providing new insights into the etiology of OA and highlighting promising therapeutic targets.PMID:39488818 | DOI:10.1007/s10787-024-01594-w

Allergy Asthma Clin Immunol. 2024 Nov 2;20(1):59. doi: 10.1186/s13223-024-00921-8.ABSTRACTBACKGROUND AND METHODS: The Zéro allergie research clinic (Saguenay, Canada) is a clinical and research initiative in oral immunotherapy (OIT) for managing IgE-mediated food allergy (FA). A total of 183 children with FA and 27 non-allergic siblings were recruited to date in the Zéro allergie cohort (ZAC) to better understand biological mechanisms underlying FA and OIT prognosis. The primary aims are to (a) better understand the genetic, epigenetic, transcriptomic, metabolomic, and microbial diversity associated with FA; (b) establish the multi-omics and microbial diversity profiles of children following OIT to identify predictive prognosis biomarkers, (c) make OIT more accessible to the population of the Saguenay-Lac-Saint-Jean region, and (d) build a biobank of data and biological material.RESULTS: The ZAC constitutes a unique and rich biobank of biological samples (blood, buccal swabs, microbiota samples [intestinal, buccal, nasal, and cutaneous]) combined with clinical data and more than 75 phenotypic characteristics.CONCLUSIONS: This represents an innovative interdisciplinary initiative by researchers, allergists, and paediatricians to make FA care accessible to a greater number of children with IgE-mediated FA. Ultimately, it will contribute to provide more accessible treatment options with greater chances of success through a better understanding of the biological nature of FA and OIT.PMID:39488713 | DOI:10.1186/s13223-024-00921-8

Microb Cell Fact. 2024 Nov 2;23(1):295. doi: 10.1186/s12934-024-02570-3.ABSTRACTBACKGROUND: Myceliophthora thermophila has been engineered as a significant cell factory for malic acid production, yet strategies to further enhance production remain unclear and lack rational guidance. 13C-MFA (13C metabolic flux analysis) offers a means to analyze cellular metabolic mechanisms and pinpoint critical nodes for improving product synthesis. Here, we employed 13C-MFA to investigate the metabolic flux distribution of a high-malic acid-producing strain of M. thermophila and attempted to decipher the crucial bottlenecks in the metabolic pathways.RESULTS: Compared with the wild-type strain, the high-Malic acid-producing strain M. thermophila JG207 exhibited greater glucose uptake and carbon dioxide evolution rates but lower oxygen uptake rates and biomass yields. Consistent with these phenotypes, the 13C-MFA results showed that JG207 displayed elevated flux through the EMP pathway and downstream TCA cycle, along with reduced oxidative phosphorylation flux, thereby providing more precursors and NADH for malic acid synthesis. Furthermore, based on the 13C-MFA results, we conducted oxygen-limited culture and nicotinamide nucleotide transhydrogenase (NNT) gene knockout experiments to increase the cytoplasmic NADH level, both of which were shown to be beneficial for malic acid accumulation.CONCLUSIONS: This work elucidates and validates the key node for achieving high malic acid production in M. thermophila. We propose effective fermentation strategies and genetic modifications for enhancing malic acid production. These findings offer valuable guidance for the rational design of future cell factories aimed at improving malic acid yields.PMID:39488710 | DOI:10.1186/s12934-024-02570-3

J Nanobiotechnology. 2024 Nov 2;22(1):671. doi: 10.1186/s12951-024-02952-0.ABSTRACTBladder cancer (BCa) exhibits the escalating incidence and mortality due to the untimely and inaccurate early diagnosis. Urinary exosome metabolites, carrying critical tumor cell information and directly related to bladder, emerge as promising non-invasive diagnostic biomarkers of BCa. Herein, the magnetic 3D ordered macroporous zeolitic imidazolate framework-8 (magMZIF-8) is synthesized and used for efficient urinary exosome isolation. Notably, beyond retaining the single crystals and micropores of conventional ZIF-8, MZIF-8 is further enhanced with highly oriented and ordered macropores (150 nm) and the large specific surface area (973 m2·g-1), which could enable the high purity and yield separation of exosomes via leveraging the combination of size exclusion, affinity, and electrostatic interactions between magMZIF-8 and the surfaces of exosome. Furthermore, the magnetic and hydrophilic properties of magMZIF-8 will further simplify the process and enhance the efficiency of separation. After conditional optimization, a 50 mL of urine is sufficient for exosome metabolomics analysis, and the time for isolating exosomes from 42 urine samples was 2 hours only. Incorporating machine learning algorithms with LC-MS/MS analysis of the metabolic patterns obtained from isolated exosomes, early-stage BCa patients were differentiated from healthy controls, with area under the curve (AUC) value of 0.844-0.9970 in the training set and 0.875-1.00 in the test set, signifying its potential as a reliable diagnostic tool. This study offers a promising approach for the non-invasive and efficient diagnosis of BCa on a large scale via exosome metabolomics.PMID:39488699 | DOI:10.1186/s12951-024-02952-0

Cardiovasc Diabetol. 2024 Nov 2;23(1):393. doi: 10.1186/s12933-024-02470-1.ABSTRACTBACKGROUND: Dysglycemia and insulin resistance increase type 2 diabetes (T2D) and cardiovascular disease (CVD) risk, yet associations with specific glucose-insulin homeostatic biomarkers have been inconsistent. Vitamin D and marine omega-3 fatty acids (n-3 FA) may improve insulin resistance. We sought to examine the association between baseline levels of insulin, C-peptide, HbA1c, and a novel insulin resistance score (IRS) with incident cardiometabolic diseases, and whether randomized vitamin D or n-3 FA modify these associations.METHODS: VITamin D and OmegA-3 TriaL (NCT01169259) was a randomized clinical trial testing vitamin D and n-3 FA for the prevention of CVD and cancer over a median of 5.3 years. Incident cases of T2D and CVD (including cardiovascular death, myocardial infarction, stroke, and coronary revascularization) were matched 1:1 on age, sex, and fasting status to controls. Conditional logistic regressions adjusted for demographic, clinical, and adiposity-related factors were used to assess the adjusted odds ratio (aOR) per-standard deviation (SD) and 95%CI of baseline insulin, C-peptide, HbA1c, and IRS (Insulin×0.0295 + C-peptide×0.00372) with risk of T2D, CVD, and coronary heart disease (CHD).RESULTS: We identified 218 T2D case-control pairs and 715 CVD case-control pairs including 423 with incident CHD. Each of the four biomarkers at baseline was separately associated with incident T2D, aOR (95%CI) per SD increment: insulin 1.46 (1.03, 2.06), C-peptide 2.04 (1.35, 3.09), IRS 1.72 (1.28, 2.31) and HbA1c 7.00 (3.76, 13.02), though only HbA1c remained statistically significant with mutual adjustments. For cardiovascular diseases, we only observed significant associations of HbA1c with CVD (1.19 [1.02, 1.39]), and IRS with CHD (1.25 [1.04, 1.50]), which persisted after mutual adjustment. Randomization to vitamin D and/or n-3 FA did not modify the association of these biomarkers with the endpoints.CONCLUSIONS: Each of insulin, C-peptide, IRS, and HbA1c were associated with incident T2D with the strongest association noted for HbA1c. While HbA1c was significantly associated with CVD risk, a novel IRS appears to be associated with CHD risk. Neither vitamin D nor n-3 FA modified the associations between these biomarkers and cardiometabolic outcomes.PMID:39488682 | DOI:10.1186/s12933-024-02470-1

Discov Oncol. 2024 Nov 2;15(1):614. doi: 10.1007/s12672-024-01467-2.ABSTRACTBACKGROUND: Gliomas are the most common malignant brain tumors characterized by angiogenesis and invasive growth. A detailed understanding of its molecular characteristics could provide potential therapeutic targets. In the present study, we sought to explore the key gene CXCL8 in methionine metabolism in gliomas and its potential role in angiogenesis.METHODS: U251 glioma cells were divided into control and methionine-restriction tolerant (constructed with 1/4 of the standard level of methionine in the culture medium) groups for transcriptome and metabolome analysis. To confirm the functions and mechanism of CXCL8 in glioma, heat map, volcano map, Go enrichment, gene set enrichment analysis (GSEA), protein-protein interaction network analysis, RT-PCR, western blotting assays, chicken embryo chorioallantoic membrane (CAM) test, chicken embryo yolk sac membrane (YSM) test and transplantation tumor nude mice model were performed. The TCGA database, CGGA database and clinical tissue samples were used to analyze CXCL8's significance on prognosis for patients with glioma.RESULTS: CXCL8 expression was significantly up-regulated in methionine-restricted tolerance cells, it also activated vascular system development and triggered angiogenesis. CXCL8 expression is negatively correlated with survival prognosis in gliomas.CONCLUSIONS: Glioma cells promote angiogenesis in methionine-restricted environments through the activation of CXCL8, compensating for nutrient deprivation, and possibly contributing to the failure of antiangiogenic therapy.PMID:39488622 | DOI:10.1007/s12672-024-01467-2