PubMed

Mol Metab. 2024 Nov 11:102064. doi: 10.1016/j.molmet.2024.102064. Online ahead of print.ABSTRACTOBJECTIVE: The study aimed to investigate the effects of glucagon on metabolic pathways in mouse models of obesity, fatty liver disease, and type 2 diabetes (T2D) to determine the extent and variability of hepatic glucagon resistance in these conditions.METHODS: We investigated glucagon's effects in mouse models of fatty liver disease, obesity, and type 2 diabetes (T2D), including male BKS-db/db, high-fat diet-fed, and western diet-fed C57Bl/6 mice. Glucagon tolerance tests were performed using the selective glucagon receptor agonist acyl-glucagon (IUB288). Blood glucose, serum and liver metabolites include lipids and amino acids were measured. Additionally, liver protein expression related to glucagon signalling and a comprehensive liver metabolomics were performed.RESULTS: Western diet-fed mice displayed impaired glucagon response, with reduced blood glucose and PKA activation. In contrast, high-fat diet-fed and db/db mice maintained normal glucagon sensitivity, showing significant elevations in blood glucose and phospho-PKA motif protein expression. Acyl-glucagon treatment also lowered liver alanine and histidine levels in high-fat diet-fed mice, but not in western diet-fed mice. Additionally, some amino acids, such as methionine, were increased by acyl-glucagon only in chow diet control mice. Despite normal glucagon sensitivity in PKA signalling, db/db mice had a distinct metabolomic response, with acyl-glucagon significantly altering 90 metabolites in db/+ mice but only 42 in db/db mice, and classic glucagon-regulated metabolites, such as cyclic adenosine monophosphate (cAMP), being less responsive in db/db mice.CONCLUSIONS: The study reveals that hepatic glucagon resistance in obesity and T2D is complex and not uniform across metabolic pathways, underscoring the complexity of glucagon action in these conditions.PMID:39536823 | DOI:10.1016/j.molmet.2024.102064

Cell. 2024 Nov 7:S0092-8674(24)01214-5. doi: 10.1016/j.cell.2024.10.032. Online ahead of print.ABSTRACTβ-Hydroxybutyrate (BHB) is an abundant ketone body. To date, all known pathways of BHB metabolism involve the interconversion of BHB and primary energy intermediates. Here, we identify a previously undescribed BHB secondary metabolic pathway via CNDP2-dependent enzymatic conjugation of BHB and free amino acids. This BHB shunt pathway generates a family of anti-obesity ketone metabolites, the BHB-amino acids. Genetic ablation of CNDP2 in mice eliminates tissue amino acid BHB-ylation activity and reduces BHB-amino acid levels. The most abundant BHB-amino acid, BHB-Phe, is a ketosis-inducible congener of Lac-Phe that activates hypothalamic and brainstem neurons and suppresses feeding. Conversely, CNDP2-KO mice exhibit increased food intake and body weight following exogenous ketone ester supplementation or a ketogenic diet. CNDP2-dependent amino acid BHB-ylation and BHB-amino acid metabolites are also conserved in humans. Therefore, enzymatic amino acid BHB-ylation defines a ketone shunt pathway and bioactive ketone metabolites linked to energy balance.PMID:39536746 | DOI:10.1016/j.cell.2024.10.032

Med Princ Pract. 2024 Nov 13:1-21. doi: 10.1159/000542557. Online ahead of print.ABSTRACTAging is an inevitable life process which is accelerated by lifestyle and environmental factors. It is an irreversible accretion of molecular and cellular damage associated with changes in the body composition and deterioration in physiological functions. Each cell (other than stem cells), reaches the limit of its ability to replicate, known as cellular or replicative senescence and consequently, the organs lose their physiological functions resulting in overall impairment. Other factors that promote aging include smoking, alcohol, UV rays, sleep habits, food, stress, sedentary life style and genetic abnormalities. These stress factors, can alter our endogenous clock (the circadian rhythm) and the microbial commensals. As a result of effect of these stressors, the microorganisms that generally support human physiological processes become baleful. The disturbance of natural physiology instigates many age-related pathologies, such as cardiovascular diseases, chronic obstructive pulmonary disorder, cerebrovascular diseases, opportunistic infections, high blood pressure, cancer, diabetes, kidney diseases, dementia, and Alzheimer's disease. The present review covers the three most essential processes of the circadian clock; the circadian gene mechanism and regulation, the mitotic clock (which plays a vital role in the telomere's attrition) and gut microbiota and their metabolome that drive aging and lead to age-related pathologies. In conclusion, maintaining a synchronized circadian rhythm, a healthy gut microbiome and telomere integrity is essential for mitigating the effects of aging and promoting longevity. The interplay among these factors underscores the importance of lifestyle choices in enhancing overall health and lifespan.PMID:39536739 | DOI:10.1159/000542557

Ecotoxicol Environ Saf. 2024 Nov 12;287:117335. doi: 10.1016/j.ecoenv.2024.117335. Online ahead of print.ABSTRACTPesticide residues, resulting from agricultural practices, pose significant health and environmental risks. This review synthesizes the current understanding of pesticide impacts on the immune system, highlighting their role in chronic diseases such as asthma, diabetes, Parkinson's disease (PD) and cancer. We emphasize the significant role of omics technologies in the study of pesticide toxicity mechanisms. The integration of genomics, proteomics, metabolomics, and epigenomics offers a multidimensional strategy for a comprehensive assessment of pesticide effects, facilitating personalized risk management and policy formulation. We advocate for stringent regulatory policies, public education, and global cooperation to enhance food safety and environmental sustainability. By adopting a unified approach, we aim to mitigate the risks of pesticide residues, ensuring human health and ecological balance are preserved.PMID:39536570 | DOI:10.1016/j.ecoenv.2024.117335

Ecotoxicol Environ Saf. 2024 Nov 12;287:117319. doi: 10.1016/j.ecoenv.2024.117319. Online ahead of print.ABSTRACTGiven the reduction of freshwater resources, saline-alkaline aquaculture has emerged as an effective approach to expand the fishery's accessible space. High carbonate alkalinity (CA) is a major stressor for aquatic organisms in saline-alkaline environments. Paramisgurnus dabryanus is a potential species for culture in saline-alkaline water, making it an ideal model for investigating the physiological responses and tolerance mechanisms to CA exposure in freshwater fishes. In the current study, P. dabryanus were exposed to 15 and 30 mmol/L NaHCO3, combining blood biochemical, gill histological, transcriptomic, and metabolomic methods for conjoint analysis of response mechanisms. After 28-d exposure, the gill ventilation frequency of P. dabryanus decreased significantly, gill lamellae twisted and atrophied, and gill filament epithelial cells proliferated, potentially limiting gas exchange, whereas the accessory air-breathing frequency increased significantly, possibly for greater oxygen uptake. Serum osmolality and blood pH remained relatively steady, while serum ammonia levels rose significantly. A total of 3718 differentially expressed genes (DEGs) and 205 differential metabolites (DMs) were identified between the control group and 30 mmol/L NaHCO3 group, involved in ion transport (Na+/K+-ATPase, V-type ATPase, carbonic anhydrase, and ABC transporters), ammonia transport (Rh glycoproteins and Aquaporins), amino acid metabolism, carbohydrate metabolism, and fatty acid metabolism. Furthermore, DEGs were significantly associated with cell-cell/ extracellular matrix interaction and protein synthesis. An integrated multi-omics analysis revealed the activation of carbon metabolism and TCA cycle. These results indicate that in response to CA exposure, P. dabryanus may facilitate carrier-mediated ion and ammonia transport to maintain the internal osmotic equilibrium and lessen the deleterious effects of blocked ammonia excretion. Meanwhile, amino acid metabolism and protein synthesis are disturbed, P. dabryanus can modulate carbohydrate catabolism to maintain energy homeostasis. The above findings provide novel insights into saline-alkaline adaptation in freshwater fishes, paving the way for future research and development of saline-alkaline-tolerant Cobitidae strains.PMID:39536569 | DOI:10.1016/j.ecoenv.2024.117319

Ecotoxicol Environ Saf. 2024 Nov 12;287:117275. doi: 10.1016/j.ecoenv.2024.117275. Online ahead of print.ABSTRACTBisphenol A (BPA) exposure is linked to multiple adverse health outcomes, prompting the rise of "BPA-free" products. However, substitutes like Bisphenol S (BPS) and Bisphenol F (BPF) are equally prevalent, with detection frequencies and concentrations rivaling BPA. Our research previously identified BPA as an endocrine disruptor affecting reproductive and developmental systems. This study explores the impact of BPA, BPS, and BPF on endometrial decidualization and receptivity. We detected these bisphenols in serum samples from infertile women undergoing assisted reproductive technology (ART) treatment whose average age was 31.58 years. Human endometrial stromal cells were exposed to varying concentrations (0, 1 nM, 10 nM, 100 nM, and 1 µM) of BPA, BPS, and BPF, following hormonal induction of decidualization (10 nM E2 (Estradiol) + 0.5 mM cAMP (Cyclic adenosine monophosphate) + 1 µM MPA (Medroxyprogesterone acetate) for 6 days). Methods including CCK-8, RT-qPCR, untargeted metabolomics, and transcriptome sequencing assessed cell proliferation, molecular markers, gene expression, and metabolites. BPS levels in the serum of infertile patients were significantly higher than BPA (14.52 vs. 2.58 ng/mL) and even more pronounced in the recurrent implantation failure (RIF) group compared to the Control group (23.46 vs. 5.57 ng/mL). Findings revealed that BPA and its substitutes inhibited endometrial stromal cell proliferation and reduced decidualization markers. Differential metabolites (25, 66, 104) and gene expressions (3260, 9686, 10357) were observed with BPA, BPF, and BPS exposure, respectively. Enriched pathways included glutathione metabolism, arginine biosynthesis, ABC transporters, cAMP signaling, and glucagon signaling. Metabolomics and transcriptome analyses unveiled the reproductive toxic effects of BPA and its substitutes, suggesting significant impacts on endometrial decidualization through diverse signaling pathways.PMID:39536566 | DOI:10.1016/j.ecoenv.2024.117275

Microbiol Res. 2024 Nov 9;290:127968. doi: 10.1016/j.micres.2024.127968. Online ahead of print.ABSTRACTDrought is a significant abiotic stress that adversely affects the physiological and biochemical processes in crops, posing a considerable challenge to agricultural productivity. The present study explored the efficacy of plant-derived biostimulant (PDB) and plant growth-promoting rhizobacteria (PGPR) strains Pseudomonas putida (RA) and Paenibacillus lentimorbus CHM12) in the management of negative impacts of drought stress in Zea mays (maize). Adathoda vasica leaf extracts (ADLE) emerged as the most potent biostimulant of the seven evaluated medicinal plant extracts. The synergetic effect of ADLE and RA enhances plant vegetative growth (root length, shoot length, fresh weight and dry weight) as well as significantly modulates drought-induced oxidative stress, as indicated by higher chlorophyll content and increased sugar and phenolic levels and reduction of proline level. The expression of defence-related (ZmAPX, ZmSOD, and ZmCAT) and transcription factor (ZmNAC, ZmWRKY, and ZmMYB) genes further supported the beneficial effects of this synergism under drought conditions. Furthermore, metabolite profiling through GC-MS analysis showed significant alterations in metabolites such as glucose, galactose, mannose, hexopyranose, linolenic acid, hexadecenoic acid, and butanedioic acid when PDB and PGPR were applied together. Overall, the findings of the present study affirm that the combined application of plant-derived biostimulant ADLE and plant-beneficial rhizobacteria RA can effectively alleviate the adverse effects of drought on maize, providing an eco-friendly and sustainable solution for improving productivity under stress.PMID:39536514 | DOI:10.1016/j.micres.2024.127968

J Hazard Mater. 2024 Nov 7;480:136423. doi: 10.1016/j.jhazmat.2024.136423. Online ahead of print.ABSTRACTMulching has been demonstrated to improve the soil environment and promote plant growth. However, the effects of mulching and mulch-derived microplastics (MPs) on nitrogen fixation by root nodules remain unclear. In this study, we investigated the effects of polyethylene (PE) and polylactic acid-polybutylene adipate-co-terephthalate (PLA-PBAT) film mulching on nitrogen fixation by root nodules after 4 years of continuous mulching using 15N tracer technology. Additionally, we examined the relationship between nitrogen fixation and MPs. We found a reduction in the proportion of nitrogen fixation by nodules (54.3 %-58.7 %) due to mulching. This decrease may be attributed to reduced dinitrogenase activity and flavonoid content at the seedling stage caused by mulching, and mulching with PLA-PBAT films significantly decreased the abundance of Bradyrhizobium at maturity. Furthermore, combined analysis of nitrogen-fixing bacteria (nifH) and metabolomes indicated that N-lauroylethanolamine may act as a regulatory signal influencing the root nodule nitrogen fixation process and that mulching resulted in significant changes in its content. The mantel test and PLS-PM suggest that microplastic from mulching may harm root nodule nitrogen fixation. This study reveals the influence of mulching on plant nitrogen uptake and the potential threat of mulch-derived microplastics, with a special focus on root nodule nitrogen fixation.PMID:39536342 | DOI:10.1016/j.jhazmat.2024.136423

J Agric Food Chem. 2024 Nov 13. doi: 10.1021/acs.jafc.4c07913. Online ahead of print.ABSTRACTAs a traditional drug-food homologous plant, Dendrobium officinale is widely recognized for its nutritional and medicinal value. Specifically, D. officinale polysaccharide (DOP) has garnered attention as a potential prebiotic for its protective effects on gut microbiota and the nervous system. However, the underlying mechanism by which DOP improves cognitive dysfunction in Alzheimer's disease (AD) remains unclear. This study intends to elucidate the beneficial effects of DOP on AD mice from the perspectives of metabolomics and the intestinal microbiome. The results showed that DOP significantly ameliorated cognitive dysfunction, attenuated hippocampal neuronal damage and Aβ plaque deposition, and restored intestinal barrier integrity in AD mice. The antibiotic-cocktail-induced germ-free mouse model confirmed that the neuroprotective effect of DOP was dependent on gut microbiota. Further investigations demonstrated that DOP influenced the composition of gut microbiota and restored its diversity. Additionally, DOP reshaped metabolic profile disorders in AD mice and increased the short-chain fatty acids (SCFAs) content. Correlation analysis further highlighted that specific gut microbiota was associated with the metabolism of AD mice. In conclusion, this study sheds light on the positive impact of DOP in reshaping the gut microbiota and enhancing cognitive function, offering important perspectives for the possible advancement and utilization of DOP.PMID:39536176 | DOI:10.1021/acs.jafc.4c07913

Environ Sci Technol. 2024 Nov 13. doi: 10.1021/acs.est.4c10434. Online ahead of print.ABSTRACTKnowledge of the biotransformation of tetrabromobisphenol A (TBBPA) and its related contaminants by human gut microbiota (GM) remains unexplored. Here, TBBPA and its four analogs were incubated with mixed GM strains, and nine rhamnosylated or debrominated transformation products (TPs) were discovered. Remarkably, rhamnosylation was identified as a common and unique microbial transformation pathway for these contaminants, and six of the seven rhamnosylated TPs were reported for the first time. Additionally, a kinetic transformation study also showed a rapid and strong bioaccumulation of TBBPA and TPs by Clostridium manihotivorum. Genomic analysis and phylogenetic studies identified C1.1_02053 as the gene encoding the C. manihotivorum working rhamnosyltransferase (CmRT), showing elevated gene expression with higher TBBPA exposure. Molecular docking identified five critical amino acid residues in CmRT that catalyze TBBPA rhamnosylation, and molecular dynamics simulations further confirmed the stability of the CmRT-TBBPA complex. Dynamic metabolomics analysis showed microbial growth-dependent disturbing effects in C. manihotivorum upon TBBPA exposure, and key metabolic pathways related to rhamnosyltransferase showed changes closely related to the transformation process. These findings provide insights into the unique transformation of environmental contaminants by the GM and highlight the disturbing effects of exogenous chemicals on the GM, as well as the potential impacts on overall human health.PMID:39536133 | DOI:10.1021/acs.est.4c10434

Proc Natl Acad Sci U S A. 2024 Nov 19;121(47):e2413837121. doi: 10.1073/pnas.2413837121. Epub 2024 Nov 13.ABSTRACTTyrosine phosphorylation of metabolic enzymes is an evolutionarily conserved posttranslational modification that facilitates rapid and reversible modulation of enzyme activity, localization, or function. Despite the high abundance of tyrosine phosphorylation events detected on metabolic enzymes in high-throughput mass spectrometry-based studies, functional characterization of tyrosine phosphorylation sites has been limited to a subset of enzymes. Since tyrosine phosphorylation is dysregulated across human diseases, including cancer, understanding the consequences of metabolic enzyme tyrosine phosphorylation events is critical for informing disease biology and therapeutic interventions. To globally identify metabolic enzyme tyrosine phosphorylation events and simultaneously assign functional significance to these sites, we performed parallel phosphoproteomics and polar metabolomics in nontumorigenic mammary epithelial cells (MCF10A) stimulated with epidermal growth factor (EGF) in the absence or presence of the EGF receptor inhibitor erlotinib. We performed an integrated analysis of the phosphoproteomic and metabolomic datasets to identify tyrosine phosphorylation sites on metabolic enzymes with functional consequences. We identified two previously characterized (pyruvate kinase muscle isozyme, phosphoglycerate mutase 1) and two uncharacterized (glutathione S-transferase Pi 1, glutamate dehydrogenase 1) tyrosine phosphorylation sites on metabolic enzymes with purported functions based on metabolomic analyses. We validated these hits using a doxycycline-inducible CRISPR interference system in MCF10A cells, in which target metabolic enzymes were depleted with simultaneous reexpression of wild-type, phosphomutant, or phosphomimetic isoforms. Together, these data provide a framework for identification, prioritization, and characterization of tyrosine phosphorylation sites on metabolic enzymes with functional significance.PMID:39536083 | DOI:10.1073/pnas.2413837121

PLoS One. 2024 Nov 13;19(11):e0312416. doi: 10.1371/journal.pone.0312416. eCollection 2024.ABSTRACTThe petroleum hydrocarbons in seawater have been worldwide concern contaminants. Biological method, with the advantages of low cost, minimal environmental impact, and no secondary pollution, is a promising method for petroleum hydrocarbon treatment. In this study, two strains, identified as Stenotrophomonas acidaminiphila and Ochrobactrum, were demonstrated to possess the ability to degrade petroleum hydrocarbons. The mixed culture composed of Stenotrophomonas acidaminiphila and Ochrobactrum at a 2:1 ratio was able to achieve 79.41% degradation of the total petroleum hydrocarbons after 5 days. Besides, the average removal efficiencies of C10-C30 components in petroleum hydrocarbons by Stenotrophomonas acidaminiphila, Ochrobactrum, and mixed culture were 62.98%, 59.14% and 73.30%, respectively. The possible degradation pathways of petroleum hydrocarbons had been speculated through gas chromatography-mass spectrometry (GC-MS) and differential gene expression metabolomics analyses. The toxicity of products from the biodegradation of petroleum hydrocarbons was greatly reduced.PMID:39535996 | DOI:10.1371/journal.pone.0312416

Gut Microbes. 2024 Jan-Dec;16(1):2424913. doi: 10.1080/19490976.2024.2424913. Epub 2024 Nov 13.ABSTRACTThe gut microbiota has been implicated in onset and progression of ulcerative colitis (UC). Here, we assess potential causal involvement of the microbiota and -associated fecal water (FW) metabolome in altering key functional parameters of the colonic epithelium. Fecal samples were collected from N = 51 healthy controls (HC), N = 36 patients with active UC (UC-A), and N = 41 subjects in remission N = 41 (UC-R). Using in vitro incubation experiments, the FW metabolome's impact on butyrate oxidation rates/gene expression and cell death (cytotoxicity) of HT-29 cells, cytokine production by PBMC, and barrier integrity of Caco2 monolayers was evaluated. The FW metabolome from patients and individuals hosting the Bacteroides 2 (Bact2) enterotype (69% of UC-A, 31% of UC-R, 3% of HC), characterized by lower levels of median- and short-chain fatty acids and furan compounds, left butyrate oxidation rates unaltered but affected associated gene expression profiles. UC patients/Bact2-carriers' FW lowered PBMC IL-8 production and increased IL-1β production. Patients' FW increased cytotoxicity, associated with sulfide compound levels. Bact2 carriers' FW, displaying higher levels of bile acids, lowered barrier function upon incubation of monolayers. The FW metabolome of patients and individuals hosting a dysbiotic microbiota could contribute to the disruption of functional processes of the colonic epithelium as observed in UC.PMID:39535140 | DOI:10.1080/19490976.2024.2424913

Int J Tryptophan Res. 2024 Nov 11;17:11786469241284423. doi: 10.1177/11786469241284423. eCollection 2024.ABSTRACTBACKGROUND: The kynurenine pathway (KP) is an important hub in neuroimmune crosstalk that is dysregulated in persons with multiple sclerosis (pwMS) and modulated by exercise in a modality-specific manner.OBJECTIVES: To compare changes in the KP metabolite profile of pwMS (1) following combined treatments including either high-intensity interval training (HIIT) or moderate-intensity continuous training (MICT) during a 3-week multimodal rehabilitation, (2) to evaluate exercise response in relation to baseline systemic inflammation, and (3) to investigate associations of kynurenines with physical capacity and clinical outcomes.METHODS: For this secondary analysis of a randomized controlled trial, serum concentrations of kynurenines at baseline and after 3 weeks were determined using targeted metabolomics (LC-MS/MS). Exercise-induced changes in the KP metabolite profile according to treatment and baseline systemic inflammation (neutrophil-to-lymphocyte ratio (NLR) <3.12 versus ⩾3.12) were investigated using covariance analyses.RESULTS: Regardless of treatment, concentrations of tryptophan and most kynurenines decreased over time. Quinolinic acid concentration increased (p < .001). Participants with low and high NLR revealed differential exercise-induced changes in concentrations of kynurenines and NLR. The systemic inflammation markers neopterin (p = .015) and NLR (p < .001) decreased in the whole group and in participants with high NLR, respectively.CONCLUSIONS: Combined treatments including HIIT or MICT do not differentially modulate the KP metabolite profile, with both reducing concentrations of most kynurenines. Baseline systemic inflammation may impact exercise-induced changes in the KP metabolite profile and anti-inflammatory effects of exercise in pwMS.TRIAL REGISTRATION: clinicaltrials.gov (identifier: NCT04356248).PMID:39534856 | PMC:PMC11555752 | DOI:10.1177/11786469241284423

MedComm (2020). 2024 Nov 11;5(11):e792. doi: 10.1002/mco2.792. eCollection 2024 Nov.ABSTRACTIdentification of therapeutic targets can directly elucidate the mechanism and effect of drug therapy, which is a central step in drug development. The disconnect between protein targets and phenotypes under complex mechanisms hampers comprehensive target understanding. Metabolomics, as a systems biology tool that captures phenotypic changes induced by exogenous compounds, has emerged as a valuable approach for target identification. A comprehensive overview was provided in this review to illustrate the principles and advantages of metabolomics, delving into the application of metabolomics in target identification. This review outlines various metabolomics-based methods, such as dose-response metabolomics, stable isotope-resolved metabolomics, and multiomics, which identify key enzymes and metabolic pathways affected by exogenous substances through dose-dependent metabolite-drug interactions. Emerging techniques, including single-cell metabolomics, artificial intelligence, and mass spectrometry imaging, are also explored for their potential to enhance target discovery. The review emphasizes metabolomics' critical role in advancing our understanding of disease mechanisms and accelerating targeted drug development, while acknowledging current challenges in the field.PMID:39534557 | PMC:PMC11555024 | DOI:10.1002/mco2.792

Front Cardiovasc Med. 2024 Oct 29;11:1433643. doi: 10.3389/fcvm.2024.1433643. eCollection 2024.ABSTRACTINTRODUCTION: Aspirin and indobufen are commonly used therapeutic drugs for the prevention of vascular restenosis (VR) after percutaneous transluminal angioplasty surgery. They both exhibited antiplatelet effects but molecular mechanisms underlying metabolic changes induced by them remain unclear.METHODS: In this study, we collected plasma samples from patients on aspirin medication (n = 5), patients on indobufen medication, patients with no medication after PTA, and healthy controls (CKs) (n = 5). Our investigation aimed to reveal the metabolic processes in patients during vascular restenosis and its amelioration through drug therapy using liquid chromatography-tandem mass spectrometry (LC-MS/MS).RESULTS: Our data showed significant alterations in amino acid and choline metabolism in patients without medication after PTA. Aspirin and indobufen were able to regulate these metabolic pathways to alleviate VR symptoms. We identified several characteristic amino acids, including pro-leu, L-citrulline, his-glu, and L-glutamate, as important biomarkers for VR assessment in patients without medication after PTA. A total of 17 and 4 metabolites involved in arginine and phenylalanine metabolism were specifically induced by aspirin and indobufen, respectively. Their expression levels were significantly regulated by aspirin or indobufen, nearly reaching normal levels.DISCUSSION: Taken together, our identification of metabolites involved in metabolic changes affected by aspirin and indobufen medication enhances the understanding of VR pathology after PTA. This may help identify early diagnostic biomarkers and therapeutic targets.PMID:39534497 | PMC:PMC11554490 | DOI:10.3389/fcvm.2024.1433643

Hortic Res. 2024 Aug 30;11(11):uhae243. doi: 10.1093/hr/uhae243. eCollection 2024 Nov.ABSTRACTRose (Rosa rugosa) petals are rich in diverse secondary metabolites, which have important physiological functions as well as great economic values. Currently, it remains unclear how saline and/or alkaline stress(es) influence the accumulation of secondary metabolites in rose. In this study, we analyzed the transcriptome and metabolite profiles of rose petals under aline-alkali stress and uncovered the induction mechanism underlying major metabolites. Dramatic changes were observed in the expression of 1363 genes and the abundances of 196 metabolites in petals in response to saline-alkali stress. These differentially expressed genes (DEGs) and differentially accumulated metabolites (DAMs) are mainly associated with flavonoid and terpenoid metabolism and the reconstruction of cell walls. Of them, TERPENE SYNTHASE 31 (TPS31) overexpression in tobacco leaves driven by its own promoter resulted in significant alterations in the levels of diverse terpenoids, which were differentially influenced by saline-alkali stress. An integrated analysis of metabolomic and transcriptomic data revealed a high correlation between the abundances of flavonoids/terpenoids and the expression of the transcription factor MYB5. MYB5 may orchestrate the biosynthesis of sesquiterpenoids and proanthocyanidins through direct regulation of TPS31 and ANR expression under aline-alkali stress. Our finding facilitates improving the bioactive substance accumulation of rose petals by metabolic engineering.PMID:39534410 | PMC:PMC11554761 | DOI:10.1093/hr/uhae243

Front Endocrinol (Lausanne). 2024 Oct 29;15:1438405. doi: 10.3389/fendo.2024.1438405. eCollection 2024.ABSTRACTOBJECTIVE: This study integrates network pharmacology and metabolomics techniques to explore the potential regulatory mechanisms of Res on gouty arthritis (GA).METHODS: Network pharmacology was used to predict the mechanism of Res in regulating GA, and methods such as HE staining, ELISA, immunohistochemistry, Real-time PCR, Western blot, and molecular docking were used to verify the role of NF-κB, MAPK, and JAK/STAT inflammatory signaling pathways in the MSU-induced GA rat model. In addition, non-targeted metabolomics techniques were combined to further investigate the mechanism of Res in treating GA.RESULTS: The results of network pharmacology showed that Res may exert its therapeutic effects through the NF-κB signaling pathway. Animal experiments demonstrated that in the MSU-induced GA rat model, pathological damage, serum biochemical indicators, and levels of inflammatory factors were significantly increased, and the NF-κB signaling pathway was activated. The intervention of Res significantly reduced pathological damage, serum biochemical indicators, levels of inflammatory factors, and the activation of NF-κB, MAPK, and JAK/STAT signaling pathways in the model rats. Metabolomics results showed that Res could improve the metabolic trajectory deviations in serum and joint fluid of GA model rats. Through related metabolic pathway analysis, the most affected metabolic pathways were found to be Sphingolipid metabolism, Glycerophospholipid metabolism, Phenylalanine, tyrosine and tryptophan biosynthesis, Pantothenate and CoA, Citrate cycle (TCA cycle), and Arachidonic acid metabolism.CONCLUSION: Resveratrol can regulate the biosynthetic pathways of arachidonic acid, phenylalanine, tyrosine, and tryptophan, pantothenic acid and CoA biosynthesis pathways, TCA cycle, and other metabolic pathways, thereby regulating the NF-κB, MAPK, and JAK/STAT3 signaling pathways, and inhibiting the acute inflammatory response during GA attacks, showing characteristics of multi-pathway and multi-target action.PMID:39534253 | PMC:PMC11555470 | DOI:10.3389/fendo.2024.1438405

Psychiatry Clin Neurosci. 2024 Nov 12. doi: 10.1111/pcn.13761. Online ahead of print.ABSTRACTAIM: Methamphetamine use disorders (MUDs) cause widespread disruptions in metabolomic and immunologic processes, highlighting the need for new therapeutic approaches. The purpose of this study was to find molecular and neuroimaging biomarkers for methamphetamine addiction.METHODS: In this study, we recruited 231 patients with MUD at varying stages of withdrawal and 40 healthy controls to quantify the blood levels of 52 molecules using enzyme-linked immunosorbent assay.RESULTS: The overall molecular disruption caused by methamphetamine was inversely related to withdrawal time (P = 0.0008), with partial recovery observed after 1 year of follow-up (P = 2.20 × 10-5). Molecules related to stress, immune activation, oxidative products, and cardiac injury were significantly elevated in all MUD groups, while antioxidation enzymes were downregulated. Additionally, the blood level of brain-derived neurotrophic factor was significantly correlated with gray matter volumes in nine brain regions (fusiform gyrus, orbitofrontal cortex, temporal pole, caudate, cerebellum crus, and vermis, adjusted P < 0.05) among patients with MUD.CONCLUSION: These findings suggest that patients with MUD exhibit elevated levels of immune response, stress, and oxidative stress, which are associated with brain structural abnormalities.PMID:39533760 | DOI:10.1111/pcn.13761

EMBO J. 2024 Nov 12. doi: 10.1038/s44318-024-00301-3. Online ahead of print.ABSTRACTUbiquitin-conjugating enzymes (E2) play a crucial role in the attachment of ubiquitin to proteins. Together with ubiquitin ligases (E3), they catalyze the transfer of ubiquitin (Ub) onto lysines with high chemoselectivity. A subfamily of E2s, including yeast Ubc6 and human Ube2J2, also mediates noncanonical modification of serines, but the structural determinants for this chemical versatility remain unknown. Using a combination of X-ray crystallography, molecular dynamics (MD) simulations, and reconstitution approaches, we have uncovered a two-layered mechanism that underlies this unique reactivity. A rearrangement of the Ubc6/Ube2J2 active site enhances the reactivity of the E2-Ub thioester, facilitating attack by weaker nucleophiles. Moreover, a conserved histidine in Ubc6/Ube2J2 activates a substrate serine by general base catalysis. Binding of RING-type E3 ligases further increases the serine selectivity inherent to Ubc6/Ube2J2, via an allosteric mechanism that requires specific positioning of the ubiquitin tail at the E2 active site. Our results elucidate how subtle structural modifications to the highly conserved E2 fold yield distinct enzymatic activity.PMID:39533056 | DOI:10.1038/s44318-024-00301-3