PubMed

Front Nutr. 2023 Jun 13;10:1169188. doi: 10.3389/fnut.2023.1169188. eCollection 2023.ABSTRACTTyrosine metabolism has an intense role in the synthesis of neurotransmitters. Our study used an untargeted, sportomics-based analysis of urine samples to investigate changes in metabolism during a soccer match in 30 male junior professional soccer players. Samples were collected before and after the match and analyzed using liquid chromatography and mass spectrometry. Results showed significant changes in tyrosine metabolism. Exercise caused a downregulation of the homogentisate metabolites 4-maleylacetoacetate and succinylacetone to 20% (p = 4.69E-5) and 16% (p = 4.25E-14), respectively. 4-Hydroxyphenylpyruvate, a homogentisate precursor, was found to be upregulated by 26% (p = 7.20E-3). The concentration of hawkinsin and its metabolite 4-hydroxycyclohexyl acetate increased ~six-fold (p = 1.49E-6 and p = 9.81E-6, respectively). Different DOPA metabolism pathways were also affected by exercise. DOPA and dopaquinone increased four-to six-fold (p = 5.62E-14 and p = 4.98E-13, respectively). 3-Methoxytyrosine, indole-5,6-quinone, and melanin were downregulated from 1 to 25%, as were dopamine and tyramine (decreasing to up to 5% or 80%; p= 5.62E-14 and p = 2.47E-2, respectively). Blood TCO2 decreased as well as urinary glutathione and glutamate (40% and 10% respectively) associated with a two-fold increase in pyroglutamate. Our study found unexpected similarities between exercise-induced changes in metabolism and the inherited disorder Hawkinsinuria, suggesting a possible transient condition called exercise-induced hawkinsinuria (EIh). Additionally, our research suggests changes in DOPA pathways may be involved. Our findings suggest that soccer exercise could be used as a model to search for potential countermeasures in Hawkinsinuria and other tyrosine metabolism disorders.PMID:37384105 | PMC:PMC10296188 | DOI:10.3389/fnut.2023.1169188

Data Brief. 2023 Apr 18;48:109102. doi: 10.1016/j.dib.2023.109102. eCollection 2023 Jun.ABSTRACTZebrafish (Danio rerio) have the capacity for successful adult optic nerve regeneration. In contrast, mammals lack this intrinsic ability and undergo irreversible neurodegeneration seen in glaucoma and other optic neuropathies. Optic nerve regeneration is often studied using optic nerve crush, a mechanical neurodegenerative model. Untargeted metabolomic studies within successful regenerative models are deficient. Evaluation of tissue metabolomic changes in active zebrafish optic nerve regeneration can elucidate prioritized metabolite pathways that can be targeted in mammalian systems for therapeutic development. Female and male (6 month to 1 year old wild type) right zebrafish optic nerves were crushed and collected three days after. Contralateral, uninjured optic nerves were collected as controls. The tissue was dissected from euthanized fish and frozen on dry ice. Samples were pooled for each category (female crush, female control, male crush, male control) and pooled at n = 31 to obtain sufficient metabolite concentrations for analysis. Optic nerve regeneration at 3 days post crush was demonstrated by microscope visualization of GFP fluorescence in Tg(gap43:GFP) transgenic fish. Metabolites were extracted using a Precellys Homogenizer and a serial extraction method: (1) 1:1 Methanol/Water and (2) 8:1:1 Acetonitrile/Methanol/Acetone. Metabolites were analyzed by untargeted liquid chromatography-mass spectrometry (LC MS-MS) profiling using a Q-Exactive Orbitrap instrument coupled with Vanquish Horizon Binary UHPLC LC-MS system. Metabolites were identified and quantified using Compound Discoverer 3.3 and isotopic internal metabolites standards.PMID:37383800 | PMC:PMC10293924 | DOI:10.1016/j.dib.2023.109102

Front Cardiovasc Med. 2023 Jun 13;10:1118796. doi: 10.3389/fcvm.2023.1118796. eCollection 2023.ABSTRACTINTRODUCTION: Right ventricular (RV) function is a major determinant of outcome in patients with precapillary pulmonary hypertension (PH). We studied the effect of ranolazine on RV function over 6 months using multi-modality imaging and biochemical markers in patients with precapillary PH (groups I, III, and IV) and RV dysfunction [CMR imaging ejection fraction (EF) < 45%] in a longitudinal, randomized, double-blinded, placebo-controlled, multicenter study of ranolazine treatment.METHODS: Enrolled patients were assessed using cardiac magnetic resonance (CMR) imaging, 11C-acetate and 18-F-FDG positron emission tomography (PET), and plasma metabolomic profiling, at baseline and at the end of treatment.RESULTS: Twenty-two patients were enrolled, and 15 patients completed all follow-up studies with 9 in the ranolazine arm and 6 in the placebo arm. RVEF and RV/Left ventricle (LV) mean glucose uptake were significantly improved after 6 months of treatment in the ranolazine arm. Metabolomic changes in aromatic amino acid metabolism, redox homeostasis, and bile acid metabolism were observed after ranolazine treatment, and several changes significantly correlated with changes in PET and CMR-derived fluid dynamic measurements.DISCUSSION: Ranolazine may improve RV function by altering RV metabolism in patients with precapillary PH. Larger studies are needed to confirm the beneficial effects of ranolazine.PMID:37383703 | PMC:PMC10293744 | DOI:10.3389/fcvm.2023.1118796

World J Diabetes. 2023 Jun 15;14(6):846-861. doi: 10.4239/wjd.v14.i6.846.ABSTRACTBACKGROUND: Lomatogonium rotatum (LR) is traditionally used in Mongolian folk medicine as a hypoglycemic agent, but its evidence-based pharmacological effects and me-chanisms of action have not been fully elucidated.AIM: To emphasize the hypoglycemic action mechanism of LR in a type 2 diabetic rat model and examine potential biomarkers to obtain mechanistic understanding regarding serum metabolite modifications.METHODS: A high-fat, high-sugar diet and streptozotocin injection-induced type 2 diabetic rat model was established. The chemical composition of the LR was identified by high performance liquid chromatography. LR extract administrated as oral gavage at 0.5 g/kg, 2.5 g/kg, and 5 g/kg for 4 wk. Anti-diabetic effects of LR extract were evaluated based on histopathological examination as well as the measurement of blood glucose, insulin, glucagon-like peptide 1 (GLP-1), and lipid levels. Serum metabolites were analyzed using an untargeted metabolomics approach.RESULTS: According to a chemical analysis, swertiamarin, sweroside, hesperetin, coumarin, 1.7-dihydroxy-3,8-dimethoxyl xanthone, and 1-hydroxy-2,3,5 trimethoxanone are the principal active ingredients in LR. An anti-diabetic experiment revealed that the LR treatment significantly increased plasma insulin and GLP-1 levels while effectively lowering blood glucose, total cholesterol, triglycerides, low-density lipoprotein cholesterol, and oral glucose tolerance test compared to the model group. Furthermore, untargeted metabolomic analysis of serum samples detected 236 metabolites, among which 86 were differentially expressed between the model and the LR group. It was also found that LR considerably altered the levels of metabolites such as vitamin B6, mevalonate-5P, D-proline, L-lysine, and taurine, which are involved in the regulation of the vitamin B6 metabolic pathway, selenium amino acid metabolic pathway, pyrimidine metabolic pathway, and arginine and proline metabolic pathways.CONCLUSION: These findings indicated that LR may have a hypoglycemic impact and that its role may be related to changes in the serum metabolites and to facilitate the release of insulin and GLP-1, which lower blood glucose and lipid profiles.PMID:37383587 | PMC:PMC10294064 | DOI:10.4239/wjd.v14.i6.846

Cardiovasc Drugs Ther. 2023 Jun 29. doi: 10.1007/s10557-023-07482-9. Online ahead of print.ABSTRACTPURPOSE: Diastolic dysfunction is an increasingly common cardiac pathology linked to heart failure with preserved ejection fraction. Previous studies have implicated glucagon-like peptide 1 (GLP-1) receptor agonists as potential therapies for improving diastolic dysfunction. In this study, we investigate the physiologic and metabolic changes in a mouse model of angiotensin II (AngII)-mediated diastolic dysfunction with and without the GLP-1 receptor agonist liraglutide (Lira).METHODS: Mice were divided into sham, AngII, or AngII+Lira therapy for 4 weeks. Mice were monitored for cardiac function, weight change, and blood pressure at baseline and after 4 weeks of treatment. After 4 weeks of treatment, tissue was collected for histology, protein analysis, targeted metabolomics, and protein synthesis assays.RESULTS: AngII treatment causes diastolic dysfunction when compared to sham mice. Lira partially prevents this dysfunction. The improvement in function in Lira mice is associated with dramatic changes in amino acid accumulation in the heart. Lira mice also have improved markers of protein translation by Western blot and increased protein synthesis by puromycin assay, suggesting that increased protein turnover protects against fibrotic remodeling and diastolic dysfunction seen in the AngII cohort. Lira mice also lost lean muscle mass compared to the AngII cohort, raising concerns about peripheral muscle scavenging as a source of the increased amino acids in the heart.CONCLUSIONS: Lira therapy protects against AngII-mediated diastolic dysfunction, at least in part by promoting amino acid uptake and protein turnover in the heart. Liraglutide therapy is associated with loss of mean muscle mass, and long-term studies are warranted to investigate sarcopenia and frailty with liraglutide therapy in the setting of diastolic disease.PMID:37382868 | DOI:10.1007/s10557-023-07482-9

J Am Heart Assoc. 2023 Jun 29:e028540. doi: 10.1161/JAHA.122.028540. Online ahead of print.ABSTRACTBackground This study was performed to identify metabolites associated with incident acute coronary syndrome (ACS) and explore causality of the associations. Methods and Results We performed nontargeted metabolomics in a nested case-control study in the Dongfeng-Tongji cohort, including 500 incident ACS cases and 500 age- and sex-matched controls. Three metabolites, including a novel one (aspartylphenylalanine), and 1,5-anhydro-d-glucitol (1,5-AG) and tetracosanoic acid, were identified as associated with ACS risk, among which aspartylphenylalanine is a degradation product of the gut-brain peptide cholecystokinin-8 rather than angiotensin by the angiotensin-converting enzyme (odds ratio [OR] per SD increase [95% CI], 1.29 [1.13-1.48]; false discovery rate-adjusted P=0.025), 1,5-AG is a marker of short-term glycemic excursions (OR per SD increase [95% CI], 0.75 [0.64-to 0.87]; false discovery rate-adjusted P=0.025), and tetracosanoic acid is a very-long-chain saturated fatty acid (OR per SD increase [95% CI], 1.26 [1.10-1.45]; false discovery rate-adjusted P=0.091). Similar associations of 1,5-AG (OR per SD increase [95% CI], 0.77 [0.61-0.97]) and tetracosanoic acid (OR per SD increase [95% CI], 1.32 [1.06-1.67]) with coronary artery disease risk were observed in a subsample from an independent cohort (152 and 96 incident cases, respectively). Associations of aspartylphenylalanine and tetracosanoic acid were independent of traditional cardiovascular risk factors (P-trend=0.015 and 0.034, respectively). Furthermore, the association of aspartylphenylalanine was mediated by 13.92% from hypertension and 27.39% from dyslipidemia (P<0.05), supported by its causal links with hypertension (P<0.05) and hypertriglyceridemia (P=0.077) in Mendelian randomization analysis. The association of 1,5-AG with ACS risk was 37.99% mediated from fasting glucose, and genetically predicted 1,5-AG level was negatively associated with ACS risk (OR per SD increase [95% CI], 0.57 [0.33-0.96], P=0.036), yet the association was nonsignificant when further adjusting for fasting glucose. Conclusions These findings highlighted novel angiotensin-independent involvement of the angiotensin-converting enzyme in ACS cause, and the importance of glycemic excursions and very-long-chain saturated fatty acid metabolism.PMID:37382146 | DOI:10.1161/JAHA.122.028540

Zhongguo Zhong Yao Za Zhi. 2023 Jun;48(12):3327-3344. doi: 10.19540/j.cnki.cjcmm.20230117.705.ABSTRACTUltra-performance liquid chromatography-quadrupole time of fight/mass spectrometry(UPLC-Q-TOF-MS) and UNIFI were employed to rapidly determine the content of the components in Liangxue Tuizi Mixture. The targets of the active components and Henoch-Schönlein purpura(HSP) were obtained from SwissTargetPrediction, Online Mendelian Inheritance in Man(OMIM), and GeneCards. A &quot;component-target-disease&quot; network and a protein-protein interaction(PPI) network were constructed. Gene Ontology(GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis were performed for the targets by Omishare. The interactions between the potential active components and the core targets were verified by molecular docking. Furthermore, rats were randomly assigned into a normal group, a model group, and low-, medium-, and high-dose Liangxue Tuizi Mixture groups. Non-targeted metabolomics was employed to screen the differential metabolites in the serum, analyze possible metabolic pathways, and construct the &quot;component-target-differential metabolite&quot; network. A total of 45 components of Liangxue Tuizi Mixture were identified, and 145 potential targets for the treatment of HSP were predicted. The main signaling pathways enriched included resistance to epidermal growth factor receptor tyrosine kinase inhibitors, phosphatidylinositol 3-kinase/protein kinase B(PI3K-AKT), and T cell receptor. The results of molecular docking showed that the active components in Liangxue Tuizi Mixture had strong binding ability with the key target proteins. A total of 13 differential metabolites in the serum were screened out, which shared 27 common targets with active components. The progression of HSP was related to metabolic abnormalities of glycerophospholipid and sphingolipid. The results indicate that the components in Liangxue Tuizi Mixture mainly treats HSP by regulating inflammation and immunity, providing a scientific basis for rational drug use in clinical practice.PMID:37382017 | DOI:10.19540/j.cnki.cjcmm.20230117.705

Zhongguo Zhong Yao Za Zhi. 2023 Jun;48(12):3317-3326. doi: 10.19540/j.cnki.cjcmm.20230119.401.ABSTRACTIn recent years, reports of adverse reactions related to traditional Chinese medicine(TCM) have been on the rise, especially some traditionally considered &quot;non-toxic&quot; TCM(such as Dictamni Cortex). This has aroused the concern of scholars. This study aims to explore the metabolomic mechanism underlying the difference in liver injury induced by dictamnine between males and females through the experiment on 4-week-old mice. The results showed that the serum biochemical indexes of liver function and organ coefficients were significantly increased by dictamnine(P&lt;0.05), and hepatic alveolar steatosis was mainly observed in female mice. However, no histopathological changes were observed in the male mice. Furthermore, a total of 48 differential metabolites(such as tryptophan, corticosterone, and indole) related to the difference in liver injury between males and females were screened out by untargeted metabolomics and multivariate statistical analysis. According to the receiver operating characteristic(ROC) curve, 14 metabolites were highly correlated with the difference. Finally, pathway enrichment analysis indicated that disorders of metabolic pathways, such as tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis(linoleic acid metabolism and arachidonic acid metabolism), may be the potential mechanism of the difference. Liver injury induced by dictamnine is significantly different between males and females, which may be caused by the disorders of tryptophan metabolism, steroid hormone biosynthesis, and ferroptosis pathways.PMID:37382016 | DOI:10.19540/j.cnki.cjcmm.20230119.401

Arterioscler Thromb Vasc Biol. 2023 Jun 29. doi: 10.1161/ATVBAHA.122.318684. Online ahead of print.ABSTRACTBACKGROUND: Impairments in carbohydrate, lipid, and amino acid metabolism drive features of plaque instability. However, where these impairments occur within the atheroma remains largely unknown. Therefore, we sought to characterize the spatial distribution of metabolites within stable and unstable atherosclerosis in both the fibrous cap and necrotic core.METHODS: Atherosclerotic tissue specimens from 9 unmatched individuals were scored based on the Stary classification scale and subdivided into stable and unstable atheromas. After performing mass spectrometry imaging on these samples, we identified over 850 metabolite-related peaks. Using MetaboScape, METASPACE, and Human Metabolome Database, we confidently annotated 170 of these metabolites and found over 60 of these were different between stable and unstable atheromas. We then integrated these results with an RNA-sequencing data set comparing stable and unstable human atherosclerosis.RESULTS: Upon integrating our mass spectrometry imaging results with the RNA-sequencing data set, we discovered that pathways related to lipid metabolism and long-chain fatty acids were enriched in stable plaques, whereas reactive oxygen species, aromatic amino acid, and tryptophan metabolism were increased in unstable plaques. In addition, acylcarnitines and acylglycines were increased in stable plaques whereas tryptophan metabolites were enriched in unstable plaques. Evaluating spatial differences in stable plaques revealed lactic acid in the necrotic core, whereas pyruvic acid was elevated in the fibrous cap. In unstable plaques, 5-hydroxyindoleacetic acid was enriched in the fibrous cap.CONCLUSIONS: Our work here represents the first step to defining an atlas of metabolic pathways involved in plaque destabilization in human atherosclerosis. We anticipate this will be a valuable resource and open new avenues of research in cardiovascular disease.PMID:37381983 | DOI:10.1161/ATVBAHA.122.318684

Zhongguo Zhong Yao Za Zhi. 2023 Jun;48(11):2868-2875. doi: 10.19540/j.cnki.cjcmm.20230227.601.ABSTRACTWith the advances in medicine, people have deeply understood the complex pathogenesis of diseases. Revealing the mechanism of action and therapeutic effect of drugs from an overall perspective has become the top priority of drug design. However, the traditional drug design methods cannot meet the current needs. In recent years, with the rapid development of systems biology, a variety of new technologies including metabolomics, genomics, and proteomics have been used in drug research and development. As a bridge between traditional pharmaceutical theory and modern science, computer-aided drug design(CADD) can shorten the drug development cycle and improve the success rate of drug design. The application of systems biology and CADD provides a methodological basis and direction for revealing the mechanism and action of drugs from an overall perspective. This paper introduces the research and application of systems biology in CADD from different perspectives and proposes the development direction, providing reference for promoting the application.PMID:37381949 | DOI:10.19540/j.cnki.cjcmm.20230227.601

J Inherit Metab Dis. 2023 Jun 29. doi: 10.1002/jimd.12646. Online ahead of print.ABSTRACTGM1 gangliosidosis is a rare lysosomal storage disorder associated with β-galactosidase enzyme deficiency. There are three types of GM1 gangliosidosis based on age of symptom onset, which correlate with disease severity. In 2019, we performed a retrospective multicentric study including all patients diagnosed with GM1 gangliosidosis in France since 1998. We had access to data for 61 of the 88 patients diagnosed between 1998 and 2019. There were 41 patients with type 1 (symptom onset ≤6 months), 11 with type 2a (symptom onset from 7 months to 2 years), 5 with type 2b (symptom onset from 2 to 3 years), and 4 with type 3 (symptom onset >3 years). The estimated incidence in France was 1/210,000. In patients with type 1, the first symptoms were hypotonia (26/41, 63%), dyspnea (7/41, 17%), and nystagmus (6/41, 15%), whereas in patients with type 2a these were psychomotor regression (9/11, 82%) and seizures (3/11, 27%). In types 2b and 3, the initial symptoms were mild, such as speech difficulties, school difficulties, and progressive psychomotor regression. Hypotonia was observed in all patients, except type 3. The mean overall survival was 23 months (95% confidence interval [CI]: 7, 39) for type 1 and 9.1 years (95% CI: 4.5, 13.5) for type 2a. To the best of our knowledge, this is one of the largest historical cohorts reported, which provides important information on the evolution of all types of GM1 gangliosidosis. These data could be used as a historical cohort in studies assessing potential therapies for this rare genetic disease. This article is protected by copyright. All rights reserved.PMID:37381921 | DOI:10.1002/jimd.12646

Ren Fail. 2023 Dec;45(1):2228419. doi: 10.1080/0886022X.2023.2228419.ABSTRACTBACKGROUND: The kidney transplant recipients (KTRs) were diagnosed with Chronic Kidney Disease after transplantation (CKD-T). CKD-T can be affected by the microbial composition and metabolites. The present study integrates the analysis of gut microbiome and metabolites to further identify the characteristics of CKD-T.METHODS: We collected 100 fecal samples of KTRs and divided them into two groups according to the stage progression of CKD-T. Among them, 55 samples were analyzed by Hiseq sequencing, and 100 samples were used for non-targeted metabolomics analysis. The gut microbiome and metabolomics of KTRs were comprehensively characterized.RESULTS: As well as significant differences in gut microbiome diversity between the CKD G1-2T group and CKD G3T group. Eight flora including Akkermansia were found to be enriched in CKD G3T group. As compared with CKD G1-2T group, the relative abundance of some amino acid metabolism, glycerophospholipid metabolism, amino acid biosynthesis, carbohydrate metabolism and purine metabolism in CKD G3T group were differential expressed significantly. In addition, fecal metabolome analysis indicated that CKD G3T group had a unique metabolite distribution characteristic. Two differentially expressed metabolites, N-acetylornithine and 5-deoxy-5'-(Methylthio) Adenosine, were highly correlated with serum creatinine, eGFR and cystatin C. The enrichment of gut microbial function in CKD-T is correlated with the expression of gut metabolites.CONCLUSION: Gut microbiome and metabolites in the progression of CKD-T display some unique distribution and expression characteristics. The composition of the gut microbiome and their metabolites appears to be different between patients with CKD G3T and those with CKD G1-2T.PMID:37381833 | DOI:10.1080/0886022X.2023.2228419

CNS Neurosci Ther. 2023 Jun 28. doi: 10.1111/cns.14312. Online ahead of print.ABSTRACTAIMS: Status epilepticus (SE) is the most common neurological emergency in pediatric patients. This study aimed to screen for prognostic biomarkers of SE in the cerebrospinal fluid (CSF) using metabolomics.METHODS: Ultra-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry (UPLC-QTOF-MS) was conducted to identify prognostic biomarkers in CSF metabolomics by comparing the poor outcome group (N = 13) with the good outcome group (N = 15) of children with SE. Differentially expressed metabolites were identified using Mann-Whitney U test corrected by Benjamini-Hochberg and partial least squares discriminant analysis (PLS-DA).RESULTS: The PLS-DA model identified and validated significant metabolic differences between the poor and good outcome groups of children with SE (PLS-DA with R2 Y = 0.992 and Q2 = 0.798). A total of 49 prognosis-related metabolites were identified. Of these metabolites, 20 including glutamyl-glutamine, 3-iodothyronamine, and L-fucose had an area under the curve (AUC) ≥ 80% in prognostic prediction of SE. The logistic regression model combining glutamyl-glutamine and 3-iodothyronamine produced an AUC value of 0.976, with a sensitivity of 0.863 and specificity of 0.956. Pathway analysis revealed that dysregulation of the citrate cycle (TCA) and arginine biosynthesis may contribute to poor SE prognosis.CONCLUSIONS: This study highlighted the prognosis-related metabolomic disturbances in the CSF of children with SE and identified potential prognostic biomarkers. A prognostic prediction model combining glutamyl-glutamine and 3-iodothyronamine with high predictive value was established.PMID:37381696 | DOI:10.1111/cns.14312

Acta Orthop. 2023 Jun 27;94:300-306. doi: 10.2340/17453674.2023.12359.ABSTRACTBACKGROUND AND PURPOSE: Mesenchymal stem cells (MSCs), both endogenous and exogenous, enhance chondrocyte proliferation by stimulating collagen type II. Secretome, an MSC derivate, has shown to also provide this mechanism through a paracrine effect. We aimed to evaluate the use of secretome and MSC in the management of early osteoarthritis (OA).ANIMALS AND METHODS: 19 (1 control) male sheep (Ovies aries), which were operated on with total lateral meniscectomy to induce knee OA, were divided into 3 groups: the secretome group, hyaluronic acid group, and MSC group. Each group was injected with the respective substances and was evaluated macroscopically and microscopically. The Osteoarthritis Research Society International (OARSI) score was calculated for all subjects and a descriptive and comparative statistical analysis was undertaken.RESULTS: The macroscopic analysis of the treated groups revealed better OARSI score in the secretome group compared with the other 2 groups. The secretome group showed a significantly better microscopic score compared with the hyaluronic acid group (mean difference [MD] 6.0, 95% confidence interval [CI] 0.15-12), but no significant difference compared with the MSC group (MD 1.0, CI -4.8 to 6.8).CONCLUSION: Intra-articular injection of secretome is effective in managing early-stage osteoarthritis in the animal model compared with hyaluronic acid and has similar efficacy to MSC injection.PMID:37377012 | PMC:PMC10301849 | DOI:10.2340/17453674.2023.12359

Ecotoxicol Environ Saf. 2023 Jun 26;262:115182. doi: 10.1016/j.ecoenv.2023.115182. Online ahead of print.ABSTRACTThe relationships between fine particulate matter (PM2.5) exposure and health effects are complex and incompletely understood. Evidence suggests that PM2.5 exposure alters gut microbiota composition and metabolites, but the connections between these changes remain unclear. The aim of our study was to investigate how gut microbiota are involved in the systemic metabolic changes following PM2.5 gastrointestinal exposure. We used multi-omics approaches, including 16S rRNA sequencing and serum metabolomics, to identify alterations in gut microbes and metabolites of PM2.5-exposed rats. We then explored correlations between perturbed gut microbiota and metabolic changes, and conducted pathway analyses to determine critical metabolic pathways impacted by PM2.5 exposure. To verify links between gut microbiome and metabolome disruptions, we performed fecal microbiota transplantation (FMT) experiment. A total of 30 differential gut microbe taxa were identified between PM2.5 and control groups, primarily in Firmicutes, Acidobacteria, and Proteobacteria phyla. We also identified 30 differential metabolites, including glycerophospholipids, fatty acyls, amino acids and others. Pathway analysis revealed disruptions in glycerophospholipid metabolism, steroid hormone biosynthesis, and linoleic acid metabolism. Through FMT, we confirmed PM2.5 altered phosphatidylcholine and linoleic acid metabolism by changing specific gut bacteria. Our results suggest that PM2.5 gastrointestinal exposure triggers systemic metabolic changes by disrupting the gut microbiome, especially glycerophospholipid and linoleic acid metabolism pathways.PMID:37379664 | DOI:10.1016/j.ecoenv.2023.115182

J Transl Med. 2023 Jun 28;21(1):419. doi: 10.1186/s12967-023-04294-1.ABSTRACTBACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe syndrome with high short-term mortality, but the pathophysiology still remains largely unknown. Immune dysregulation and metabolic disorders contribute to the progression of ACLF, but the crosstalk between immunity and metabolism during ACLF is less understood. This study aims to depict the immune microenvironment in the liver during ACLF, and explore the role of lipid metabolic disorder on immunity.METHODS: Single-cell RNA-sequencing (scRNA-seq) was performed using the liver non-parenchymal cells (NPCs) and peripheral blood mononuclear cells (PBMCs) from healthy controls, cirrhosis patients and ACLF patients. A series of inflammation-related cytokines and chemokines were detected using liver and plasma samples. The lipid metabolomics targeted free fatty acids (FFAs) in the liver was also detected.RESULTS: The scRNA-seq analysis of liver NPCs showed a significant increase of monocytes/macrophages (Mono/Mac) infiltration in ACLF livers, whereas the resident Kupffer cells (KCs) were exhausted. A characterized TREM2+ Mono/Mac subpopulation was identified in ACLF, and showed immunosuppressive function. Combined with the scRNA-seq data from PBMCs, the pseudotime analysis revealed that the TREM2+ Mono/Mac were differentiated from the peripheral monocytes and correlated with lipid metabolism-related genes including APOE, APOC1, FABP5 and TREM2. The targeted lipid metabolomics proved the accumulation of unsaturated FFAs associated with α-linolenic acid (α-LA) and α-LA metabolism and beta oxidation of very long chain fatty acids in the ACLF livers, indicating that unsaturated FFAs might promote the differentiation of TREM2+ Mono/Mac during ACLF.CONCLUSIONS: The reprogramming of macrophages was found in the liver during ACLF. The immunosuppressive TREM2+ macrophages were enriched in the ACLF liver and contributed to the immunosuppressive hepatic microenvironment. The accumulation of unsaturated FFAs in the ACLF liver promoted the reprogramming of the macrophages. It might be a potential target to improve the immune deficiency of ACLF patients through regulating lipid metabolism.PMID:37380987 | DOI:10.1186/s12967-023-04294-1

Neuropsychopharmacology. 2023 Jun 28. doi: 10.1038/s41386-023-01633-0. Online ahead of print.ABSTRACTBrain metabolism is a fundamental process involved in the proper development of the central nervous system and in the maintenance of the main higher functions in humans. As consequence, energy metabolism imbalance has been commonly associated to several mental disorders, including depression. Here, by employing a metabolomic approach, we aimed to establish if differences in energy metabolite concentration may underlie the vulnerability and resilience in an animal model of mood disorder named chronic mild stress (CMS) paradigm. In addition, we have investigated the possibility that modulation of metabolite concentration may represent a pharmacological target for depression by testing whether repeated treatment with the antidepressant venlafaxine may normalize the pathological phenotype by acting at metabolic level. The analyses were conducted in the ventral hippocampus (vHip) for its key role in the modulation of anhedonia, a core symptom of patients affected by depression. Interestingly, we showed that a shift from glycolysis to beta oxidation seems to be responsible for the vulnerability to chronic stress and that vHip metabolism contributes to the ability of the antidepressant venlafaxine to normalize the pathological phenotype, as shown by the reversal of the changes observed in specific metabolites. These findings may provide novel perspectives on metabolic changes that could serve as diagnostic markers and preventive strategies for the early detection and treatment of depression as well as for the identification of potential drug targets.PMID:37380799 | DOI:10.1038/s41386-023-01633-0

Commun Biol. 2023 Jun 28;6(1):676. doi: 10.1038/s42003-023-05057-w.ABSTRACTKidney metabolism may be greatly altered in chronic kidney disease. Here we report that arginine metabolism is the most altered in unilateral ureteral obstruction (UUO)-induced fibrosis of the kidneys in metabolomic analysis. Spermidine is the most increased metabolite of arginine. In human glomerulonephritis, the amount of spermidine shown by immunostaining is associated with the amount of fibrosis. In human proximal tubule cells, spermidine induces nuclear factor erythroid 2-related factor 2 (Nrf2). Subsequently, fibrotic signals, such as transforming growth factor β1 secretion, collagen 1 mRNA, and oxidative stress, represented by a decrease in the mitochondrial membrane potential is suppressed by spermidine. UUO kidneys of Arg2 knockout mice show less spermidine and significantly exacerbated fibrosis compared with wild-type mice. Nrf2 activation is reduced in Arg2 knockout UUO kidneys. Spermidine treatment prevents significant fibrotic progression in Arg2 knockout mice. Spermidine is increased in kidney fibrosis, but further increases in spermidine may reduce fibrosis.PMID:37380734 | DOI:10.1038/s42003-023-05057-w

Sci Rep. 2023 Jun 28;13(1):10461. doi: 10.1038/s41598-023-36535-0.ABSTRACTRespiratory infections are a leading cause of morbidity and mortality in early life, and recurrent infections increase the risk of developing chronic diseases. The maternal environment during pregnancy can impact offspring health, but the factors leading to increased infection proneness have not been well characterized during this period. Steroids have been implicated in respiratory health outcomes and may similarly influence infection susceptibility. Our objective was to describe relationships between maternal steroid levels and offspring infection proneness. Using adjusted Poisson regression models, we evaluated associations between sixteen androgenic and corticosteroid metabolites during pregnancy and offspring respiratory infection incidence across two pre-birth cohorts (N = 774 in VDAART and N = 729 in COPSAC). Steroid metabolites were measured in plasma samples from pregnant mothers across all trimesters of pregnancy by ultrahigh-performance-liquid-chromatography/mass-spectrometry. We conducted further inquiry into associations of steroids with related respiratory outcomes: asthma and lung function spirometry. Higher plasma corticosteroid levels in the third trimester of pregnancy were associated with lower incidence of offspring respiratory infections (P = 4.45 × 10-7 to 0.002) and improved lung function metrics (P = 0.020-0.036). Elevated maternal androgens were generally associated with increased offspring respiratory infections and worse lung function, with some associations demonstrating nominal significance at P < 0.05, but these trends were inconsistent across individual androgens. Increased maternal plasma corticosteroid levels in the late second and third trimesters were associated with lower infections and better lung function in offspring, which may represent a potential avenue for intervention through corticosteroid supplementation in late pregnancy to reduce offspring respiratory infection susceptibility in early life.Clinical Trial Registry information: VDAART and COPSAC were originally conducted as clinical trials; VDAART: ClinicalTrials.gov identifier NCT00920621; COPSAC: ClinicalTrials.gov identifier NCT00798226.PMID:37380711 | DOI:10.1038/s41598-023-36535-0

Nat Commun. 2023 Jun 28;14(1):3823. doi: 10.1038/s41467-023-38921-8.ABSTRACTPancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies the suppressive effect of forced hyperglycemia in mouse models of PDAC, while rescuing this pathway mitigates anti-tumor effects observed with chemotherapy and high glucose.PMID:37380658 | DOI:10.1038/s41467-023-38921-8