PubMed
Uncovering metabolic signatures in cancer-derived exosomes: LC-MS/MS and NMR profiling
Nanoscale. 2024 Nov 20. doi: 10.1039/d4nr03454f. Online ahead of print.ABSTRACTUnderstanding the intricate interplay between cancer metabolism and intercellular communication within the tumour microenvironment (TME) is crucial for advancing cancer diagnostics and therapeutics. In this study, we investigate the metabolites present in exosomes derived from three distinct cancer cell lines: pancreatic cancer (MiaPaCa-2), lung cancer (A549), and glioma (C6). Exosomes were isolated using ultrafiltration and characterized using a combination of techniques including nanoparticle tracking analysis (NTA), electron microscopy (EM), western blotting (WB) and Fourier-transform infrared (FTIR) spectroscopy. Leveraging state-of-the-art metabolomics techniques, including untargeted LC-MS/MS and NMR analyses, we elucidated the metabolic signatures encapsulated within cancer-derived exosomes. Notably, our investigation represents the first exploration of exosomal metabolites from pancreatic and glioma cells, addressing a significant gap in current knowledge. Furthermore, our study investigates the correlation between metabolites derived from different cancer cells, shedding light on potential metabolic interactions within the TME. Through comprehensive analyses, this study provides insights into dysregulated metabolic pathways driving cancer progression and offers novel perspectives on the diagnostic and therapeutic utility of exosomal metabolites. Importantly, common metabolites identified among cancer types suggest potential markers detectable by multiple techniques, enhancing their clinical applicability.PMID:39565062 | DOI:10.1039/d4nr03454f
Unraveling heterogeneity and treatment of asthma through integrating multi-omics data
Front Allergy. 2024 Nov 5;5:1496392. doi: 10.3389/falgy.2024.1496392. eCollection 2024.ABSTRACTAsthma has become one of the most serious chronic respiratory diseases threatening people's lives worldwide. The pathogenesis of asthma is complex and driven by numerous cells and their interactions, which contribute to its genetic and phenotypic heterogeneity. The clinical characteristic is insufficient for the precision of patient classification and therapies; thus, a combination of the functional or pathophysiological mechanism and clinical phenotype proposes a new concept called "asthma endophenotype" representing various patient subtypes defined by distinct pathophysiological mechanisms. High-throughput omics approaches including genomics, epigenomics, transcriptomics, proteomics, metabolomics and microbiome enable us to investigate the pathogenetic heterogeneity of diverse endophenotypes and the underlying mechanisms from different angles. In this review, we provide a comprehensive overview of the roles of diverse cell types in the pathophysiology and heterogeneity of asthma and present a current perspective on their contribution into the bidirectional interaction between airway inflammation and airway remodeling. We next discussed how integrated analysis of multi-omics data via machine learning can systematically characterize the molecular and biological profiles of genetic heterogeneity of asthma phenotype. The current application of multi-omics approaches on patient stratification and therapies will be described. Integrating multi-omics and clinical data will provide more insights into the key pathogenic mechanism in asthma heterogeneity and reshape the strategies for asthma management and treatment.PMID:39563781 | PMC:PMC11573763 | DOI:10.3389/falgy.2024.1496392
High-fat diet stimulated butyric acid metabolism dysbiosis, altered microbiota, and aggravated inflammatory response in collagen-induced arthritis rats
Nutr Metab (Lond). 2024 Nov 19;21(1):95. doi: 10.1186/s12986-024-00869-x.ABSTRACTBACKGROUND: Research has demonstrated that obesity may be associated with rheumatoid arthritis (RA). In addition, Dysbiosis of intestinal microbiota and their metabolites has been linked to the occurrence and development of RA and obesity. However, the mechanism by which obesity affects RA remains unclear.In this study, we explored the impact of high fat diet(HFD) on collagen-induced arthritis (CIA) rats and revealed its mechanisms based on gut microbiota and metabolomics.METHODS: Based on diet and modeling, rats were divided into normal group (Con), CIA model group, HFD group (HFD), and HFD + CIA group (HCIA). The effect of HFD on arthritis in CIA rats were investigated based on the arthritis index (AI), weight, blood lipid levels, and inflammatory cytokines. Moreover, HE staining and micro-CT were performed to evaluated the effect of HFD on the pathology of joints and synovial tissues in CIA rats.16S rRNA amplicon sequencing and liquid chromatography-mass spectrometry (LC-MS) were employed to explore changes in gut microbiota and short-chain fatty acids (SCFAs).RESULTS: The AI scores, inflammatory cytokines and bone destruction parameters in the HCIA group were significantly higher than those in the other three groups. The results of 16S rRNA amplicon sequencing and metabolomics showed that compared with the other three groups, the expression of g_Muribaculaceae and butyric acid were reduced in the HCIA group. Spearman and linear correlation analyses revealed a positive correlation between g_Muribaculaceae abundance and butyric acid levels.CONCLUSIONS: HFD stimulated butyric acid metabolism dysbiosis, altered microbiota, and aggravated inflammatory response in CIA rats.PMID:39563394 | DOI:10.1186/s12986-024-00869-x
Unveiling the molecular mechanisms of Danggui-Shaoyao-San against Alzheimer's disease in APP/PS1 mice via integrating proteomic and metabolomic approaches
Alzheimers Res Ther. 2024 Nov 19;16(1):251. doi: 10.1186/s13195-024-01618-1.ABSTRACTBACKGROUND: Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder for which no effective therapy is currently available. Given that various attempts to target beta-amyloid (Aβ) have been unsuccessful in clinical trials, other potential pathogenic factors such as brain energy metabolism (EM) have attracted increasing attention. Traditional Chinese medicines, including danggui-shaoyao-san (DSS), play a notable role in AD. However, it remains unclear whether DSS exerts therapeutic effects on AD through EM regulation.METHODS: In this study, we conducted behavioural tests, Nissl staining, haematoxylin and eosin staining, and thioflavin S staining, in APP/PS1 mice to assess the pharmacodynamic effect of DSS on AD. Subsequently, we integrated the drug target network of herbal ingredients in DSS and evaluated their absorption, distribution, metabolism, excretion, and toxicity properties to identify the core ingredients. We used proteomic and metabolomic approaches to explore the potential mechanisms of action of DSS against AD. Consequently, we verified the mechanism underlying EM using qPCR, western blotting, and ELISA.RESULTS: In vivo experimental results revealed that DSS ameliorated cognitive impairment in APP/PS1 mice, attenuated neuronal apoptosis, and reduced Aβ burden. Furthermore, the drug-target network comprised 6,514 drug-target interactions involving 1,118 herbal ingredients and 218 AD genes, of which 253 were identified as the core ingredients in DSS. The proteomic results implied that DSS could act on EM to alleviate AD, and targeted energy metabolomics suggested that DSS regulated 47 metabolites associated with EM. Mechanistically, we found that DSS could regulate the GSK3β/PGC1α signalling pathway to improve brain glucose uptake and mitigate mitochondrial dysfunction and oxidative stress, ultimately promoting EM to treat AD.CONCLUSION: Our study is the first to integrate multi-omics approaches to reveal that DSS could regulate the GSK3β/PGC1α signalling pathway to exert therapeutic effects in AD through the promotion of EM, thereby providing new insights into the mechanism of action of DSS against AD.PMID:39563386 | DOI:10.1186/s13195-024-01618-1
Metabolomics and proteomics analyses of Chrysanthemi Flos: a mechanism study of changes in proteins and metabolites by processing methods
Chin Med. 2024 Nov 19;19(1):160. doi: 10.1186/s13020-024-01013-w.ABSTRACTBACKGROUND: Chrysanthemi Flos is a traditional Chinese medicine with a long history of medicinal use. Prior research suggests that the intrinsic composition of Chrysanthemi Flos is affected by shade-drying and oven-drying methods. Nevertheless, the effects of these methods on the proteins and metabolites of Chrysanthemi Flos have not been extensively studied.METHODS: The TMT (tandem mass tag) quantitative proteomics method and the LC-MS/MS (liquid chromatography-tandem mass spectrometry) non-targeted metabolomics method were used to systematically study the differences in the proteins and metabolites during the process of drying Chrysanthemi Flos in the shade and an oven.RESULTS: Differentially accumulated metabolites and abundant proteins were primarily enriched in the purine metabolism, pyrimidine metabolism, cyanogenic amino acid metabolism, phenylpropanoid biosynthesis, and starch and sucrose metabolism pathways. Primary metabolites, such as guanine, xanthine, cytidine 5'-diphosphate serine, L-isoleucine, stearidonic acid, alginate, and inulin, play a crucial role in providing energy for Chrysanthemi Flos to withstand desiccation stress. The upregulation of ferulate-5- hydroxylase (F5H), shikimate O hydroxycinnamoyltransferase (HCT), caffeoyl-CoA O-methyltransferase (CCoAOMT), and chalcone isomerase (CHI) enzymes promotes the synthesis of flavonoids, including sinapic acid, caffeoyl shikimic acid, and naringenin chalcone, which possess antioxidant properties. Despite the notable improvements in energy metabolism and antioxidant capacity, these enhancements proved insufficient in halting the senescence and ultimate demise of Chrysanthemi Flos. Moreover, the shade-drying method can inhibit protein expression and promote the accumulation of bioactive components, but the drying efficiency is low, while the oven-drying method exhibits rapid drying efficiency, it does not effectively preserve the components.CONCLUSION: Our study offers a comprehensive explanation for the changes in protein expression and metabolite conversion observed in shade-dried and oven-dried Chrysanthemi Flos, also providing a foundation for optimizing the drying process of Chrysanthemi Flos.PMID:39563383 | DOI:10.1186/s13020-024-01013-w
Transcriptomics integrated with targeted metabolomics reveals endogenous hormone changes in tuberous root expansion of Pueraria
BMC Genomics. 2024 Nov 19;25(1):1112. doi: 10.1186/s12864-024-11010-w.ABSTRACTBACKGROUND: Pueraria is a widely cultivated medicinal and edible homologous plant in Asia, and its tuberous roots are commonly used in the food, nutraceutical, and pharmaceutical industries. "Gange No. 5" is a local variety of Pueraria montana var. thomsonii (Bentham) M.R. Almeida (PMT) in Jiangxi Province, China. After optimizing its cultivation technique, we shortened the cultivation cycle of this variety from two years to one year, suggesting that the regulatory mechanism of the endogenous hormone system during tuberous root expansion may have changed significantly. In this study, we focused on the molecular mechanisms of endogenous hormones in promoting tuberous root expansion during one-year cultivation of "Gange No. 5".RESULTS: The mid-late expansion period (S4) is critical for the rapid swelling of "Gange No. 5" tuberous roots during annual cultivation. At S4, the number of cells increased dramatically and their volume enlarged rapidly in the tuberous roots, the fresh weight of a single root quickly increased, and the contents of multiple nutrients (total protein, total phenol, isoflavones) and medicinal components (puerarin, puerarin apigenin, and soy sapogenin) were at their peak values. We compared the transcriptomes and metabolomes of S1 (the pre-expansion period), S4, and S6 (the final expansion period), and screened 42 differentially accumulated hormone metabolites and 1,402 differentially expressed genes (DEGs) associated with hormone biosynthesis, metabolism, and signaling. Most Auxin, cytokinins (CKs), jasmonic acids (JAs), salicylic acid (SA), melatonin (MLT), and ethylene (ETH), reached their maximum levels at S1 and then gradually decreased; however, abscisic acid (ABA) appeared in S6, indicating that most of the endogenous hormones may play a key role in regulating the initiation of tuberous root expansion, while ABA mainly promotes tuberous root maturation. Notably, multiple key genes of the 'Tryptophan metabolism' pathway (ko00380) were significantly differentially expressed, and COBRA1, COBRA2, YUCCA10, IAA13, IAA16, IAA20, IAA27, VAN3, ACAA2, and ARF were also identified to be significantly correlated with the expansion of "Gange No. 5" tuberous roots.CONCLUSIONS: Our study has revealed how endogenous hormone regulation affects the expansion of "Gange No. 5" tuberous roots. These findings offer a theoretical foundation for improving the yield of PMT tuberous roots.PMID:39563238 | DOI:10.1186/s12864-024-11010-w
PyINETA: Open-Source Platform for INADEQUATE-JRES Integration in NMR Metabolomics
Anal Chem. 2024 Nov 19. doi: 10.1021/acs.analchem.4c03966. Online ahead of print.ABSTRACTRobust annotation of compounds is a critical element in metabolomics. The 13C-detection NMR experiment incredible natural abundance double-quantum transfer experiment (INADEQUATE) stands out as a powerful tool for structural elucidation, but this valuable experiment is not often included in metabolomics studies. This is partly due to the lack of a community platform that provides structural information based on INADEQUATE. Also, it is often the case that a single study uses various NMR experiments synergistically to improve the quality of information or balance total NMR experiment time, but there is no public platform that can integrate the outputs of INADEQUATE with other NMR experiments. Here, we introduce PyINETA, a Python-based INADEQUATE network analysis. PyINETA is an open-source platform that provides structural information on molecules using INADEQUATE, conducts database searches using an INADEQUATE library, and integrates information on INADEQUATE and a complementary NMR experiment 13C J-resolved experiment (13C-JRES). 13C-JRES was chosen because of its ability to efficiently provide relative quantification in a study of the 13C-enriched samples. Those steps are carried out automatically, and PyINETA keeps track of all the pipeline parameters and outputs, ensuring the transparency of annotation in metabolomics. Our evaluation of PyINETA using a model mouse study showed that PyINETA successfully integrated INADEQUATE and 13C-JRES. The results showed that 13C-labeled amino acids that were fed to mice were transferred to different tissues and were transformed to other metabolites. The distribution of those compounds was tissue-specific, showing enrichment of specific metabolites in the liver, spleen, pancreas, muscle, or lung. PyINETA is freely available on NMRbox.PMID:39563064 | DOI:10.1021/acs.analchem.4c03966
Proteomic and metabolomic profiling of aged pork loin chops reveals molecular phenotypes linked to pork tenderness
J Anim Sci. 2024 Nov 20:skae355. doi: 10.1093/jas/skae355. Online ahead of print.ABSTRACTThe ability to predict fresh pork tenderness and quality is hindered by an incomplete understanding of molecular factors that influence these complex traits. It is hypothesized that a comprehensive description of the metabolomic and proteomic phenotypes associated with variation in pork tenderness and quality will enhance the understanding and inform the development of rapid and non-destructive methods to measure pork quality. The objective of this investigation was to examine the proteomic and metabolomic profiles of approximately 2-week aged pork chops categorized across instrumental tenderness groups. One hundred pork loin chops from a larger sample (N=120) were assigned to one of four categories (n=25) based on instrumental star probe value. (Category A, x = 4.23 kg, 3.43-4.55 kg; Category B, x = 4.79 kg, 4.66-5.00 kg; Category C, x = 5.43 kg, 5.20-5.64 kg; Category D, x = 6.21 kg, 5.70-7.41 kg;). Soluble protein from approximately two week aged pork loin was prepared using a low ionic strength buffer. Proteins were digested with trypsin, labeled with 11-plex isobaric TMT reagents, and identified and quantified using a Q-Exactive Mass Spectrometer. Metabolites were extracted in 80 % methanol from lyophilized and homogenized tissue samples. Derivatized metabolites were identified and quantified using GC-MS. Between Categories A and D, 84 proteins and 22 metabolites were differentially abundant (Adjusted P < 0.05). Fewer differences were detected in comparison between categories with less divergent tenderness measures. The molecular phenotype of the more tender (Category A) aged chops is consistent with a slower and less extended pH decline and markedly less abundance of glycolytic metabolites. The presence and greater abundance of proteins in the low ionic strength extract, including desmin, filamin C, calsequestrin, and fumarate hydratase, indicates a greater disruption of sarcoplasmic reticulum and mitochondrial membranes and the degradation and release of structural proteins from the continuous connections of myofibrils and the sarcolemma.PMID:39563021 | DOI:10.1093/jas/skae355
Implementation of multi-omics in diagnosis of pediatric rare diseases
Pediatr Res. 2024 Nov 19. doi: 10.1038/s41390-024-03728-w. Online ahead of print.ABSTRACTThe rapid and accurate diagnosis of rare diseases is paramount in directing clinical management. In recent years, the integration of multi-omics approaches has emerged as a potential strategy to overcome diagnostic hurdles. This review examines the application of multi-omics technologies, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics, in relation to the diagnostic journey of rare diseases. We explore how these combined approaches enhance the detection of pathogenic genetic variants and decipher molecular mechanisms. This review highlights the groundbreaking potential of multi-omics in advancing the precision medicine paradigm for rare diseases, offering insights into future directions and clinical applications. IMPACT: This review discusses using current tests and emerging technologies to diagnose pediatric rare diseases. We describe the next steps after inconclusive molecular testing and a structure for using multi-omics in further investigations. The use of multi-omics is expanding, and it is essential to incorporate it into clinical practice to enhance individualized patient care.PMID:39562738 | DOI:10.1038/s41390-024-03728-w
Arsenic-induced enhancement of diazotrophic recruitment and nitrogen fixation in Pteris vittata rhizosphere
Nat Commun. 2024 Nov 19;15(1):10003. doi: 10.1038/s41467-024-54392-x.ABSTRACTHeavy metal contamination poses an escalating global challenge to soil ecosystems, with hyperaccumulators playing a crucial role in environmental remediation and resource recovery. The enrichment of diazotrophs and resulting nitrogen accumulation promoted hyperaccumulator growth and facilitated phytoremediation. Nonetheless, the regulatory mechanism of hyperaccumulator biological nitrogen fixation has remained elusive. Here, we report the mechanism by which arsenic regulates biological nitrogen fixation in the arsenic-hyperaccumulator Pteris vittata. Field investigations and greenhouse experiments, based on multi-omics approaches, reveal that elevated arsenic stress induces an enrichment of key diazotrophs, enhances plant nitrogen acquisition, and thus improves plant growth. Metabolomic analysis and microfluidic experiments further demonstrate that the upregulation of specific root metabolites plays a crucial role in recruiting key diazotrophic bacteria. These findings highlight the pivotal role of nitrogen-acquisition mechanisms in the arsenic hyperaccumulation of Pteris vittata, and provide valuable insights into the plant stress resistance.PMID:39562570 | DOI:10.1038/s41467-024-54392-x
Correction to: Studying Plant Specialized Metabolites Using Computational Metabolomics Strategies
Methods Mol Biol. 2024;2788:C1-C2. doi: 10.1007/978-1-0716-3782-1_24.NO ABSTRACTPMID:39562475 | DOI:10.1007/978-1-0716-3782-1_24
Structural characteristics and potential antidepressant mechanism of a water-insoluble β-1,3-glucan from an edible fungus Wolfiporia cocos
Carbohydr Polym. 2025 Jan 15;348(Pt A):122779. doi: 10.1016/j.carbpol.2024.122779. Epub 2024 Sep 25.ABSTRACTA water-insoluble β-1,3-glucan (Wβ) with a molecular weight of 8.12 × 104 Da was extracted from an edible fungus Wolfiporia cocos. Its backbone was composed of 1,3-β-linked Glcp branched at the C-2, C-4, and C-6 positions, connecting more 1,3-β-linked Glcp with a triple helical structure. Wβ effectively ameliorated depressive symptoms, abnormality of neurotransmitters and inflammatory factors in chronic unpredictable mild stress (CUMS)-induced rats. Wβ also altered the composition of gut microbiota, especially Romboutsia, norank_f_Muribaculaceae and Ruminococcus. Integration of untargeted and targeted metabolomics and Western blotting analysis suggested that the short-chain fatty acids (SCFAs) and tryptophan metabolites were the most important metabolites involved in Wβ mediation. Wβ significantly modulated the levels of 7 SCFAs and 7 tryptophan metabolites, as well as the protein expression of two related enzymes (indoleamine-2,3-dioxygenase: IDO; kynurenine-3-monooxygenase: KMO). Our results suggest that Wβ exerts its antidepressant effect by influencing neurotransmitters and inflammatory factors through interactions between the gut microbiota, SCFA and tryptophan metabolites. The findings offer new insights into water-insoluble polysaccharides, especially β-glucan in structure analysis and utilization, and provide evidence that Wβ, a novel glucan from the often-discarded water-insoluble part of Wolfiporia cocos, has potential application in antidepressant health products.PMID:39562060 | DOI:10.1016/j.carbpol.2024.122779
Ferroptosis Induces gut microbiota and metabolic dysbiosis in Collagen-Induced arthritis mice via PAD4 enzyme
Gene. 2024 Nov 17:149106. doi: 10.1016/j.gene.2024.149106. Online ahead of print.ABSTRACTRheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation and joint destruction, with emerging evidence implicating gut microbiota dysbiosis in its pathogenesis. The current study explores the role of ferroptosis, a form of regulated cell death driven by iron-dependent lipid peroxidation, in modulating gut microbiota and metabolic dysregulation through the enzyme peptidyl arginine deiminase 4 (PAD4) in collagen-induced arthritis (CIA) mouse model. Our findings demonstrate that ferroptosis exacerbates RA-related inflammatory responses and joint damage by upregulating PAD4 expression, which, in turn, influences the gut microbial composition and associated metabolite profiles. Erastin, a known ferroptosis agonist, significantly increased the relative abundance of pro-inflammatory bacteria such as Proteobacteria while reducing beneficial taxa like Firmicutes and Bacteroidetes. This microbial shift was associated with heightened oxidative stress and an imbalance in key metabolites, such as lysophosphatidyl ethanolamine 14:0 (LysoPE 14:0), further exacerbated by ferroptosis. Co-treatment with GSK484, a PAD4 inhibitor, reversed these effects, restoring microbial homeostasis and reducing joint inflammation. This study suggests that ferroptosis-mediated PAD4 activity contributes to RA pathogenesis by disrupting the gut-joint axis, providing novel insights into potential therapeutic targets for RA. Our results highlight the intricate interplay between immune-mediated cell death, gut microbiota, and systemic inflammation, emphasizing the importance of ferroptosis as a therapeutic target in mitigating RA progression.PMID:39561902 | DOI:10.1016/j.gene.2024.149106
Validation of urine p-cresol glucuronide as renal cell carcinoma non-invasive biomarker
J Proteomics. 2024 Nov 17:105357. doi: 10.1016/j.jprot.2024.105357. Online ahead of print.ABSTRACTRenal cell carcinoma (RCC) stands among the most lethal urological malignancies. Most RCCs are incidentally diagnosed as initial symptoms are unspecific. Novel, minimally-invasive diagnostic and prognostic methods for RCC are needed, ideally in urine. Using UPLC-Q-ToF MS untargeted metabolomic analysis in urine, we previously revealed p-cresol glucuronide as potential RCC diagnostic marker. Additionally, urine samples one-year post-nephrectomy revealed isobutyryl-l-carnitine and L-proline betaine as potential RCC prognostic markers. Our present aim was to validate these differences in an independent cohort of RCC patients and healthy controls to strengthen their value as non-invasive biomarkers. In an independent cohort of 69 RCC patients and 52 controls we validated an increase in p-cresol glucuronide in urine from patients at diagnosis compared to controls (P = 0.0043). It remained increased one-year post-nephrectomy (P = 0.0288). The value of p-cresol glucuronide for RCC diagnosis was assessed with ROC curves analysis (AUC = 0.66, 95 % Confidence Interval 0.56-0.76). The role of isobutyryl-l-carnitine and L-proline betaine as prognostic markers could not be validated and will require a larger cohort. Our findings confirm the value of p-cresol glucuronide in urine as diagnostic marker for RCC in an independent cohort. This non-invasive method holds promise for enhancing patient care by reducing the need for potentially risky diagnostic procedures. Further metaproteomics-oriented approaches towards the tyrosine oxidation pathway and microbiota metagenomics studies may promote a holistic management of RCC. SIGNIFICANCE: Current imaging techniques available to diagnose and monitor renal cell carcinoma (RCC) are harmful for the patient given the high-radiation dose, and unspecific in low-grade tumors. Thus, novel non-invasive biomarkers with diagnostic and prognostic capabilities are of utmost importance. Herein, we have validated urine p-cresol glucuronide as diagnostic marker for RCC. This novel non-invasive biomarker could improve accurate assessments of tumor behavior, while enhancing patient outcomes by reducing discomfort and detrimental side effects.PMID:39561853 | DOI:10.1016/j.jprot.2024.105357
Time-restricted eating reveals a "younger" immune system and reshapes the intestinal microbiome in human
Redox Biol. 2024 Nov 9;78:103422. doi: 10.1016/j.redox.2024.103422. Online ahead of print.ABSTRACTTime-restricted eating (TRE) has been shown to extent lifespans in drosophila and mouse models by affecting metabolic and anti-inflammatory activities. However, the effect of TRE on the human immune system, especially on immunosenescence, intestinal microbiome, and metabolism remains unclear. We conducted a 30-day 16:8 TRE single-arm clinical trial with 49 participants. Participants consumed daily meals from 9 a.m. to 5 p.m., provided by a nutrition canteen with a balanced, calorie-appropriate nutrition, which is designed by clinical nutritionists (ChiCTR2200058137). We monitored weight changes and weight-related parameters and focused on changes in the frequency of CD4+ senescent T cells, immune repertoire from peripheral blood, as well as serum metabolites and gut microbiota. We found that up to 95.9 % of subjects experienced sustained weight loss after TRE. The frequency of circulating senescent CD4+ T cells was decreased, while the frequency of Th1, Treg, Tfh-like, and B cells was increased. Regarding the immune repertoire, the proportions of T cell receptor alpha and beta chains were increased, whereas B cell receptor kappa and lambda chains were reduced. In addition, a reduced class switch recombination from immunoglobulin M (IgM) to immunoglobulin A (IgA) was observed. TRE upregulated the levels of anti-inflammatory and anti-aging serum metabolites named sphingosine-1-phosphate and prostaglandin-1. Additionally, several anti-inflammatory bacteria and probiotics were increased, such as Akkermansia and Rikenellaceae, and the composition of the gut microbiota tended to be "younger". Overall, TRE showed multiple anti-aging effects, which may help humans maintain a healthy lifestyle to stay "young". Clinical Trial Registration URL: https://www.chictr.org.cn/showproj.html?proj=159876.PMID:39561680 | DOI:10.1016/j.redox.2024.103422
Ginsenoside compound K restrains hepatic fibrotic response by dual-inhibition of GLS1 and LDHA
Phytomedicine. 2024 Nov 8;135:156223. doi: 10.1016/j.phymed.2024.156223. Online ahead of print.ABSTRACTBACKGROUND: Liver fibrosis is a dynamic process marked by the accumulation of extracellular matrix due to hepatic stellate cells (HSCs) activation. Ginsenoside compound K (CK), a rare derivative of its parent ginsenosides, is known to significantly ameliorate metabolic disorders.PURPOSE: The aim of this study was to elucidate the protective effects of CK against liver fibrosis with a focus on metabolic regulation.METHODS: We established liver fibrosis models in mice using carbon tetrachloride (CCl4) challenge, bile duct ligation, or a methionine-choline deficient diet, with continuous oral administration of CK at specified doses and intervals. Simultaneously, we examined the impact of CK on metabolic regulation in cultured HSCs and investigated the associated mechanisms.RESULTS: CK was found to alleviate liver injury and curb fibrotic responses in mouse models, as well as decrease elevated levels of liver enzyme. Metabolomic analysis in vitro highlighted the crucial roles of pyruvate and glutamine metabolism in metabolic remodeling. Immunohistochemical staining indicated significantly elevated expressions of lactate dehydrogenase A (LDHA) (p = 0.014) and glutaminase 1 (GLS1) (p = 0.024) in liver cirrhosis patients. Comparable alterations were noted in the liver of model mice and in cultured HSCs. Molecular docking and bio-layer interferometry demonstrated that CK interacts with and inhibits the activities of LDHA and GLS1. As expected, CK attenuated glycolysis and glutaminolysis, reducing HSC growth dependently on lactate and α-ketoglutarate (α-KG). Upon HSC activation, metabolism is reprogrammed with Myc as a key regulator, transcriptionally controlling LDHA, GLS1, and glutamine transporters SLC1A5 and SLC38A5. CK inhibited Myc induction, integrating glycolysis and glutaminolysis regulation to counteract the fibrotic response.CONCLUSION: CK inhibited LDHA and GLS1 activities, thereby inhibiting hepatic fibrosis. These findings offer new insights into the role of ginsenosides in liver protection, especially regarding metabolic disorders.PMID:39561660 | DOI:10.1016/j.phymed.2024.156223
Integrated physiological, energy metabolism, and metabonomic responses indicate the stress response in the hepatopancreas of Litopenaeus vannamei to nitrite stress
Aquat Toxicol. 2024 Nov 13;277:107164. doi: 10.1016/j.aquatox.2024.107164. Online ahead of print.ABSTRACTNitrite is a toxic substance found in rearing water that affects shrimp health. The hepatopancreas is an important digestive, immune, and metabolic organ in the shrimp. In this study, shrimps (Litopenaeus vannamei) were separately exposed to 1 and 5 mg/L nitrite stress for 48 h, and the toxicity of nitrite in the hepatopancreas was explored by integrating histology, physiological indicators, energy metabolism, and metabolomics. Nitrite stress induced morphological changes and stress responses in the hepatopancreas. Specifically, physiology-related indices, such as the relative gene expression levels of antioxidants (ROMO1, Nrf2, GPx), endoplasmic reticulum stress (Bip, IRE1 and XBP1), and immune genes (ALF, Pen-3, Lys) were decreased, whereas the gene expression of apoptosis (Casp-3), detoxification (CYP450), and glutamic oxaloacetic transaminase (GOT) activity were increased. The activities of osmotic adjustment-related enzymes (NKA, CMA, and ATPase) also decreased. Energy metabolism-related indices, such as pyruvate and hepatic glycogen contents, increased, whereas glucose, lactic acid, triglyceride, and ATP contents and ATPase activity decreased, and the relative gene expression levels of carbohydrate metabolism (PDH, HK, and LDH) and electron-transport chain genes (CytC, COI and CCO) decreased, and the expressions of lipid metabolism (AMPK, SREBP, and FAS), tricarboxylic acid cycle (MDH, CS, IDH and FH) genes were also disturbed. The metabolic pattern of the hepatopancreas was affected by nitrite stress. Glycine, serine, and threonine metabolism were highly affected, and more functional amino acids varied in the 5 mg/L nitrite stress group. These results reveal the toxic effects of nitrite stress on the stress response, physiology, energy metabolism, and metabolite homeostasis in the hepatopancreas of shrimp. Several potential metabolite biomarker candidates were identified for toxicological evaluation.PMID:39561610 | DOI:10.1016/j.aquatox.2024.107164
Effects of acetochlor on the interaction between Scenedesmus and Microcystis: Integrated perspectives on toxicity, biotransformation, and competition strategies
J Hazard Mater. 2024 Nov 12;481:136470. doi: 10.1016/j.jhazmat.2024.136470. Online ahead of print.ABSTRACTTo reveal the disruption caused by herbicides and the mechanisms of algal interactions on interspecific competitive strategies at a metabolic and population level, this study established short-term (7 d) and long-term (21 d) Scenedesmus-Microcystis competition coculture systems and investigated the toxicity of acetochlor (ACT) on algae competition. Scenedesmus obliquus (EC50 6.586 μg/L) is three orders of magnitude more sensitive to ACT than Microcystis aeruginosa (EC50 19,539 μg/L), placing it at a competitive disadvantage in environments with ACT pollution. Short-term coculture tests (ACT concentrations from 0 to 12.5 μg/L) showed that ACT suppresses S. obliquus growth and competition, while M. aeruginosa initially showed compensatory growth, which was negated by ACT. Metabolomics revealed that interspecies competition and ACT affect fatty acid synthesis and nitrogen assimilation metabolism of both microalgae, suggesting species differences in the mode of action (MOA) of ACT toxicity and resource competition strategies, respectively. ACT weakens the ability of M. aeruginosa to compete for nitrogen and synthesize microcystin under competitive stress. ACT biotransformation can be conducted across species. In an algal culture system with equal initial biomass, the 7 d ACT degradation rate increased by 24.9 % and 123.8 % with coculture of the two algae compared with monocultures of S. obliquus and M. aeruginosa, respectively. In long-term experiments, the degradation rate increased by 19.0 % and 8.9 % in cocultures compared with the monocultures. Lotka-Volterra models showed that competitive inhabitation was alleviated, implying that the competition interspecies relationship is beneficial for the coexistence of both algal populations under ACT stress.PMID:39561538 | DOI:10.1016/j.jhazmat.2024.136470
Multi-Omic characterization of the effects of Ocrelizumab in patients with relapsing-remitting multiple sclerosis
J Neurol Sci. 2024 Nov 10;467:123303. doi: 10.1016/j.jns.2024.123303. Online ahead of print.ABSTRACTThe study examined changes in the plasma proteome, metabolome, and lipidome of N = 14 patients with relapsing-remitting multiple sclerosis (RRMS) initiating treatment with ocrelizumab, assayed at baseline, 6 months, and 12 months. Analyses of >4000 circulating biomarkers identified depletion of B-cell associated proteins as the early effect observed following ocrelizumab (OCR) initiation, accompanied by the reduction in plasma abundance of cytokines and cytotoxic proteins, markers of neuronaxonal damage, and biologically active lipids including ceramides and lysophospholipids, at 6 months. B-cell depletion was accompanied by decreases in B-cell receptor and cytokine signaling but a pronounced increase in circulating plasma B-cell activating factor (BAFF). This was followed by an upregulation of a number of signaling and metabolic pathways at 12 months. Patients with higher baseline brain MRI lesion load demonstrated both higher levels of cytotoxic and structural proteins in plasma at baseline and more pronounced biomarker change trajectories over time. Digital cytometry identified a putative increase in myeloid cells and a pro-inflammatory subset of T-cells. Therapeutic effects of ocrelizumab extend beyond CD20-mediated B-cell lysis and implicate metabolic reprogramming, juxtaposing the early normalization of immune activation, cytokine signaling and metabolite and lipid turnover in periphery with changes in the dynamics of immune cell activation or composition. We identify BAFF increase following CD20 depletion as a tentative compensatory mechanism that contributes to the reconstitution of targeted B-cells, necessitating further research.PMID:39561535 | DOI:10.1016/j.jns.2024.123303
Unraveling the molecular mechanism of aqueous extract of Sargentodoxa cuneata against ulcerative colitis from serum metabolomics and bioinformatics perspectives
J Chromatogr B Analyt Technol Biomed Life Sci. 2024 Nov 13;1249:124372. doi: 10.1016/j.jchromb.2024.124372. Online ahead of print.ABSTRACTSymptoms of ulcerative colitis (UC) are like "intestinal carbuncle" in Chinese medicine. The aqueous extract of Sargentodoxa cuneata (AESc) has good therapeutic effects on UC, but the underlying mechanism needs to be further elucidated. The mechanism of AESc against UC was studied based on metabolomics and bioinformatics in mice with UC. Dextran sodium sulfate was applied to induce a mouse model of UC. After the intervention of AESc, the general condition of the animals was recorded, and efficacy-related indicators were measured. Information on serum metabolites was determined. Multivariate analysis combined with bioinformatics methods were used to identify the differential metabolites. Furthermore, "metabolite-target-disease" network was obtained, and differential metabolites of UC were screened, and further analysis of the metabolites were performed. Molecular docking validation was also carried out. AESc improved general conditions such as blood in stool, hair of animals, and weight loss, reduced disease activity index scores and shortening of colon length in mice with UC. A total of 3445 serum metabolites were obtained, and 64 differentiated metabolites of AESc against UC were screened. Enrichment analysis showed that arachidonic acid metabolism, bile secretion, drug metabolism-other enzymes, and tyrosine metabolism were associated with AESc in the treatment of UC. In addition, based on "metabolite-target-disease" network, the serum metabolites cholylleucine, 9,10,13-TriHOME, birabresib, anthramycin methyl ether, trans-hexadec-2-enoyl carnitine, and lucidumol A were found to have the therapeutic potential for UC. Further, 14 core targets were obtained, and lipids and atherosclerosis, rheumatoid arthritis and multiple immune-inflammatory pathways were associated with AESc for the treatment of UC. AESc corrects serum metabolic disturbances in UC mice, and multiple serum metabolites have therapeutic potential for UC. AESc may treat UC by regulating biological processes such as lipid metabolism, amino acid metabolism, thereby restoring normal physiological function of the intestine.PMID:39561468 | DOI:10.1016/j.jchromb.2024.124372