PubMed

Life Sci Alliance. 2024 Nov 20;8(2):e202403075. doi: 10.26508/lsa.202403075. Print 2025 Feb.ABSTRACTThe brain-related phenotypes observed in 22q11.2 deletion syndrome (DS) patients are highly variable, and their origin is poorly understood. Changes in brain metabolism might contribute to these phenotypes, as many of the deleted genes are involved in metabolic processes, but this is unknown. This study shows for the first time that Tbx1 haploinsufficiency causes brain metabolic imbalance. We studied two mouse models of 22q11.2DS using mass spectrometry, nuclear magnetic resonance spectroscopy, and transcriptomics. We found that Tbx1 +/- mice and Df1/+ mice, with a multigenic deletion that includes Tbx1, have elevated brain methylmalonic acid, which is highly brain-toxic. Focusing on Tbx1 mutants, we found that they also have a more general brain metabolomic imbalance that affects key metabolic pathways, such as glutamine-glutamate and fatty acid metabolism. We provide transcriptomic evidence of a genotype-vitamin B12 treatment interaction. In addition, vitamin B12 treatment rescued a behavioural anomaly in Tbx1 +/- mice. Further studies will be required to establish whether the specific metabolites affected by Tbx1 haploinsufficiency are potential biomarkers of brain disease status in 22q11.2DS patients.PMID:39567195 | DOI:10.26508/lsa.202403075

J Proteome Res. 2024 Nov 20. doi: 10.1021/acs.jproteome.4c00841. Online ahead of print.ABSTRACTHigh-altitude exposure can adversely affect neurocognitive functions; however, the underlying mechanisms remain elusive. Why and how does high-altitude exposure impair neurocognitive functions, particularly sleep? This study seeks to identify the molecular markers and mechanisms involved, with the goal of forming prevention and mitigation strategies for altitude sickness. Using serum proteomics and metabolomics, we analyzed blood samples from 23 Han Chinese plain dwellers before and after six months of high-altitude work in Tibet. The correlation analysis revealed biomarkers associated with cognitive alterations. Six months of high-altitude exposure significantly compromised cognitive function, notably, sleep quality. The key biomarkers implicated include SEPTIN5, PCBP1, STIM1, UBE2L3/I/N, amino acids (l/d-aspartic acid and l-glutamic acid), arachidonic acid, and S1P. Immune and neural signaling were suppressed, with sex-specific differences observed. This study innovatively identified GABA, arachidonic acid, l-glutamic acid, 2-arachidonoyl glycerol, and d-aspartic acid as biomarkers and elucidated the underlying mechanisms contributing to high-altitude-induced neurocognitive decline with a particular focus on sleep disruption. These findings pave the way for developing preventive measures and enhancing adaptation strategies. This study underscores the physiological significance of high-altitude adaptation, raising new questions about sex-specific responses and long-term consequences. It sets the stage for future research exploring individual variability and intervention efficacy.PMID:39566908 | DOI:10.1021/acs.jproteome.4c00841

J Adv Res. 2024 Nov 18:S2090-1232(24)00544-7. doi: 10.1016/j.jare.2024.11.025. Online ahead of print.ABSTRACTINTRODUCTION: A pro-inflammatory diet is positively associated with the risk and progression of inflammatory bowel diseases (IBD). Recently, ferroptosis has been observed in patients with different dietary patterns-associated intestinal inflammation, while the mechanisms underlying the effects of a pro-inflammatory diet and whether it mediates ferroptosis are unknown.OBJECTIVES: This study aims to elucidate the mechanisms underlying pro-inflammatory diet-mediated colitis and explore potential intervention strategies.METHODS: Mice were fed a dietary inflammatory index-based pro-inflammatory diet for 12 weeks. Subsequently, colitis was chemically induced using 2.5 % dextran sulfate sodium. The body weight, pathological score, immune response and mucosal barrier function were evaluated to assess intestinal inflammation. Intestine tissue transcriptomics, fecal microbiome analysis and serum metabolomics were applied to identify diet-microbe-host interactions. Additionally, the dietary inflammatory index (DII) scores and intestinal specimens of 32 patients with Crohn's disease were evaluated. The biological functions of Bacteroides uniformis were observed in vitro and in vivo.RESULTS: Pro-inflammatory diet induces low-grade intestinal inflammation in mice and exacerbates colitis by activating glutathione peroxidase 4-associated ferroptosis in the endoplasmic reticulum stress-mediated pathway. These effects are reversed by ferrostatin-1 treatment. Additionally, the pro-inflammatory diet triggers colitis by modulating the gut microbiota and metabolites. Notably, supplementation with B. uniformis improves the pro-inflammatory diet-aggravated colitis by inhibiting endoplasmic reticulum stress-mediated ferroptosis. Moreover, B. uniformis is non-enterotoxigenic and non-enteroinvasive in co-cultures with intestinal epithelial cells.CONCLUSIONS: Pro-inflammatory diet drives colitis by targeting endoplasmic reticulum stress-mediated ferroptosis, possibly in a gut microbiota-dependent manner. Pro-inflammatory diet restriction and microbial-based therapies may be effective strategies for preventing and treating IBD.PMID:39566817 | DOI:10.1016/j.jare.2024.11.025

Eur J Pharmacol. 2024 Nov 18:177141. doi: 10.1016/j.ejphar.2024.177141. Online ahead of print.ABSTRACTBACKGROUND: While metformin has shown promise in treating septic myocardial injury (SMI), its underlying mechanisms and impact on metabolic disturbances remain poorly understood.METHODS: This study employed an integrated approach of metabolomics and network pharmacology to identify key targets and pathways through which metformin may act against SMI. Findings were validated using a lipopolysaccharide (LPS)-induced mouse model.RESULTS: Metformin was found to counter myocardial metabolic disruptions, indicated by the reversal of 49 metabolites primarily involved in purine metabolism, pantothenate and CoA biosynthesis, and histidine metabolism. In vivo, metformin significantly improved survival rates and cardiac function, reduced cardiomyocyte apoptosis, and inhibited inflammation and oxidative stress in LPS-induced mice. Integrated analyses identified 27 potential targets for metformin in SMI treatment. KEGG pathway analysis revealed significant enrichment in TNF, HIF-1, IL-17, and PI3K/AKT signaling pathways, while protein-protein interaction analysis pinpointed ten core targets, including IL6, IL1B, CCL2, CASP3, MMP9, HIF1A, IGF1, NOS3, MMP2, and LEP. Molecular docking and dynamics simulations demonstrated metformin's high affinity for these core targets. Further, RT-qPCR and western blot analyses confirmed that metformin modulates core target expression to mitigate SMI. Notably, our data underscore the importance of PI3K/AKT and MMP2/MMP9 signaling pathways in SMI therapy.CONCLUSION: This study elucidates the metabolic and molecular mechanisms of metformin in SMI treatment, supporting its potential repurposing for SMI.PMID:39566813 | DOI:10.1016/j.ejphar.2024.177141

Metabolism. 2024 Nov 18:156082. doi: 10.1016/j.metabol.2024.156082. Online ahead of print.ABSTRACTBACKGROUND: There are no known non-invasive tests (NITs) designed for accurately detecting metabolic dysfunction-associated steatohepatitis (MASH) with liver fibrosis stages F2-F3, excluding cirrhosis-the FDA-defined range for prescribing Resmetirom and other drugs in clinical trials. We aimed to validate and re-optimize known NITs, and most importantly to develop new machine learning (ML)-based NITs to accurately detect MASH F2-F3.METHODS: Clinical and metabolomic data were collected from 443 patients across three countries and two clinic types (metabolic surgery, gastroenterology/hepatology) covering the entire spectrum of biopsy-proven MASLD, including cirrhosis and healthy controls. Three novel types of ML models were developed using a categorical gradient boosting machine pipeline. These were compared with 24 biomarker, imaging, and algorithm-based NITs with both known cutoffs for MASH F2-F4 and re-optimized cutoffs for MASH F2-F3.RESULTS: NFS at a - 1.455 cutoff attained an AUC of 0.59, the highest sensitivity (90.9 %, 95 % CI 84.3-95.4), and NPV of 87.2 %. FIB4 risk stratification followed by elastography (8 kPa) had the best specificity (86.9 %) and PPV (63.3 %), with an AUC of 0.57. NFS followed by elastography improved the PPV to 65.3 % and AUC to 0.62. Re-optimized FibroScan-AST (FAST) at a 0.22 cutoff had the highest PPV (69.1 %). ML models using aminotransferases, metabolic syndrome components, BMI, and 3-ureidopropionate achieved an AUC of 0.89, which further increased to 0.91 following hyperparameter optimization and the addition of alpha-ketoglutarate. These new ML models outperformed all other NITs and displayed accuracy, sensitivity, specificity, PPV, and NPV up to 91.2 %, 85.3 %, 97.0 %, 92.4 %, and 90.7 % respectively. The models were reproduced and validated in a secondary sensitivity analysis, that used one of the cohorts as feature selection/training, and the rest as independent validation, likewise outperforming all other NITs.CONCLUSIONS: We report for the first time the diagnostic characteristics of non-invasive, metabolomics-based biomarker models to detect MASH with fibrosis F2-F3 required for Resmetirom treatment and inclusion in ongoing phase-III trials. These models may be used alone or in combination with other NITs to accurately determine treatment eligibility.PMID:39566717 | DOI:10.1016/j.metabol.2024.156082

Environ Pollut. 2024 Nov 18:125339. doi: 10.1016/j.envpol.2024.125339. Online ahead of print.ABSTRACTA major alternative to bisphenol A (BPA), fluorene-9-bisphenol (BHPF) has been shown to cause multiorgan toxicity. However, its reproductive toxicity and the underlying biological mechanism remain largely unknown. Recently, changes in the gut microbiota and metablome caused by environmental contaminant exposure and their potential impact on male reproductive health have been of great concern. Therefore, we aimed to elucidate the underlying mechanism of BHPF-related fertility impairment by integrating metabolome and microbiome analysis. In the present study, we showed that BHPF exposure caused testicular dysfunction with impaired spermatogenesis and disrupted steroid hormone synthesis. Mechanistically, altered gut microbiota and metabolites were revealed by 16S rDNA sequencing and untargeted metabolomics analysis. Subsequent multi-omics combination analysis revealed a strong correlation between altered microbiota and lipid metabolites. We also found a strong relationship between lipid metabolites and sperm parameters such as sperm concentration, sperm motility, etc. Most importantly, these findings provide new insights into the mechanistic scenario underlying BHPF-induced fertility toxicity, that disrupted lipid metabolism caused by gut microbiota dysbiosis may be a reason for reproductive impairment caused by BHPF exposure.PMID:39566706 | DOI:10.1016/j.envpol.2024.125339

Bioresour Technol. 2024 Nov 18:131848. doi: 10.1016/j.biortech.2024.131848. Online ahead of print.ABSTRACTDopamine (DA) has attracted attention because of its effects on Haematococcus lacustris biomass, astaxanthin production, and physiological responses. The alga treated with 25 μM DA combined with 1 g L-1 sodium chloride exhibited 7.63 %, 41.25 %, and 52.04 % increases in biomass (1.41 g L-1), astaxanthin content (32.37 mg/g), and astaxanthin productivity (3.51 mg L-1 d-1) respectively, compared with the salinity stress and high light. Exogenous DA treatment promoted lipid synthesis while reducing carbohydrate and protein contents. Moreover, carotenogenesis and lipogenesis-associated genes were upregulated under DA induction. Inhibition of reactive oxygen species and autophagy, along with mitogen-activated protein kinase activation, promoted astaxanthin accumulation under DA. Furthermore, DA application boosted astaxanthin biosynthesis by regulating the levels of respiratory metabolic intermediates, the γ-aminobutyric acid shunt, and important phytohormones. These findings present a potential and successful biotechnological approach for enhancing biomass and astaxanthin production in H. lacustris under stressful conditions.PMID:39566692 | DOI:10.1016/j.biortech.2024.131848

Neoplasia. 2024 Nov 19;59:101089. doi: 10.1016/j.neo.2024.101089. Online ahead of print.ABSTRACTMonocytes and monocyte-derived macrophages facilitate cancer progression and metastasis. Inflammatory monocytes expressing CCR2 are actively recruited to metastatic lungs, where they promote tumor cell extravasation, metastatic outgrowth, and an immunosuppressive environment. The role of CCR1 in this process has remained unclear. We used Ccr1- and Ccr2-deficient mice and two different tumor cells lines, MC38 and LLC1 with and without Ccl2-deficiency in vitro and in vivo. The recruitment of both Ccr1- and Ccr2-deficient monocytes towards the Ccl2 chemokine was significantly impaired, while no substantial recruitment was observed towards Ccl5 in vitro. MC38 and LLC1 Ccl2-deficient tumor cells showed reduced lung metastasis in both Ccr1- and Ccr2-deficient mice when compared to wild-type mice. We detected reduced numbers of macrophages and myeloid cells in both chemokine receptor-deficient mice. Lung metastasis in both Ccr1- and Ccr2-deficient mice could be rescued to the same levels as in wild-type mice by an adoptive transfer of Ccr2-deficient but not Ccr1-deficient monocytic cells. Accumulation of Ccr1-deficient monocytes in the lungs was severely impaired upon intravenous monocyte injection, indicating the importance of this axis in cell recruitment. Moreover, the efficient recruitment of adoptive transferred Ccr2-deficient monocytes to the lungs and the restoration of lung metastasis suggests an involvement of an additional, Ccr2-independent chemokine pathway. This data defines the non-redundant functions of the Ccr1- and Ccr2-chemokine axes in monocyte recruitment and macrophage presence during lung metastasis. While Ccr2 is essential for the release of monocytes from the bone marrow, Ccr1 is primarily responsible for monocyte presence at metastatic sites.PMID:39566333 | DOI:10.1016/j.neo.2024.101089

Redox Biol. 2024 Nov 12;78:103353. doi: 10.1016/j.redox.2024.103353. Online ahead of print.ABSTRACTSepsis is a critical condition characterized by a systemic inflammatory response to infection, often leading to severe vascular dysfunction and high mortality. One of the hallmarks of vascular dysfunction in sepsis is increased vascular permeability and the loss of pericytes, which are essential for maintaining vascular integrity. Despite the significance of pericyte loss in sepsis, the primary type of cell death responsible and the underlying molecular mechanisms remain incompletely understood. This study aims to elucidate these mechanisms by focusing on ferroptosis, a form of programmed cell death, and its regulation through the Hippo/ACSL4 axis. Our research confirmed significant pericyte loss in patients with sepsis. Through advanced single-cell analysis and proteomics, ferroptosis was identified as a key differentiating cell death type between sepsis and sham samples. Further metabolomics analysis revealed that Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) plays a pivotal role in the ferroptosis of pericytes during sepsis. In vitro experiments demonstrated that downregulation of ACSL4 effectively reduced lipopolysaccharide (LPS)-induced lipid peroxidation, restored pericyte viability, and improved endothelial permeability. In vivo studies with pericyte-specific ACSL4 knockout mice showed a marked decrease in pericyte loss and enhanced vascular barrier function following sepsis induction. To translate these findings into potential therapeutic strategies, we developed pericyte-targeting liposomes encapsulating ACSL4 shRNA adenovirus. These liposomes successfully restored pulmonary vascular barrier function and significantly reduced pericyte loss in septic conditions. The results of this study underscore the crucial role of ACSL4 in mediating ferroptosis in pericytes and highlight the therapeutic potential of targeting ACSL4 to mitigate vascular dysfunction in sepsis.PMID:39566164 | DOI:10.1016/j.redox.2024.103353

J Clin Endocrinol Metab. 2024 Nov 20:dgae812. doi: 10.1210/clinem/dgae812. Online ahead of print.ABSTRACTOBJECTIVE: This study aimed to investigate serum metabolomic biomarkers associated with incident type 2 diabetes mellitus (T2DM) and evaluate their performance in improving T2DM risk prediction.METHODS: Untargeted proton nuclear magnetic resonance (1H NMR) spectroscopy-based metabolomics analyses were conducted in the Multi-Ethnic Study of Atherosclerosis (MESA; n=3460; discovery cohort) and Rotterdam Study (RS; n=1556; replication cohort). Multivariable cause-specific hazards models were used to analyze the associations between 23,571 serum metabolomic spectral variables and incident T2DM. Replicated metabolites required an FDR-adjusted P<0.01 in MESA, P<0.05 in RS, and consistent direction of association. Pathway and network analyses were conducted to elucidate biological mechanisms underlying T2DM development. Utility of the replicated metabolites in improving T2DM risk prediction was assessed based on the Framingham Diabetes Risk Score. A 2-sample Mendelian randomization was conducted to assess causal associations.RESULTS: Nineteen metabolites were significantly associated with incident T2DM. Pathway analyses revealed disturbances in aminoacyl-tRNA biosynthesis, metabolism of branched-chain amino acids (BCAAs), glycolysis/gluconeogenesis, and glycerolipid metabolism. Network analyses identified interactions with upstream regulators including p38 MAPK, c-JNK, and mTOR signaling pathways. Adding replicated metabolites to the Framingham Diabetes Risk Score showed modest to moderate improvements in prediction performance in MESA and RS, with Δ c-statistic of 0.05 (95% CI, 0.04-0.07) in MESA and 0.03 (95% CI, 0.01-0.05) in RS. Genetically increased BCAAs and mannose were associated with T2DM.CONCLUSIONS: 1H NMR measured metabolites involved in aminoacyl-tRNA biosynthesis, BCAA metabolism, glycolysis/gluconeogenesis, and glycerolipid metabolism were significantly associated with incident T2DM and provided modest to moderate predictive utility beyond traditional risk factors.PMID:39566105 | DOI:10.1210/clinem/dgae812

Phytopathology. 2024 Nov 20. doi: 10.1094/PHYTO-09-24-0277-R. Online ahead of print.ABSTRACTIn several plant species, thiamin foliar application primes plant immunity and can be effective in controlling various diseases. However, the effectiveness of thiamin against potato pathogens has seldom been investigated. Additionally, the transcriptomics and metabolomics of immune priming by thiamin have not previously been investigated. Here, we tested the effect of thiamin application against Alternaria solani, the causal agent of early blight in potato, and identified associated changes in gene expression and metabolite content. Thiamin applied on foliage at an optimal concentration of 10 mM reduced lesion size by ~33%. However, prevention of lesion growth was temporally limited, as a reduction of lesion size occurred when leaves were inoculated 4 h, but not 24 h, following thiamin treatment. Additionally, the effect of thiamin on lesion size was restricted to the application site and was not systemic. RNA-seq analysis showed that thiamin affected the expression of 308 genes involved in the synthesis of salicylic acid, secondary metabolites, fatty acid, chitin, and primary metabolism, and photosynthesis, which were also amongst the thousands of genes differentially regulated in the response to pathogen alone. Several of these genes and pathways were more differentially expressed and enriched when thiamin and the pathogen were combined. Thiamin also delayed the downregulation of photosynthesis-associated genes in plants inoculated with A. solani. Metabolite analyses revealed that thiamin treatment in the absence of pathogen decreased the amounts of several organic compounds involved in the citric acid cycle. We hypothesize that thiamin primes plant defenses through perturbation of primary metabolism.PMID:39565900 | DOI:10.1094/PHYTO-09-24-0277-R

Sci Adv. 2024 Nov 22;10(47):eadr5807. doi: 10.1126/sciadv.adr5807. Epub 2024 Nov 20.ABSTRACTTuberous sclerosis complex (TSC) is targeted to the lysosomal membrane, where it hydrolyzes RAS homolog-mTORC1 binding (RHEB) from its GTP-bound to GDP-bound state, inhibiting mechanistic target of rapamycin complex 1 (mTORC1). Loss-of-function mutations in TSC cause TSC disease, marked by excessive tumor growth. Here, we overcome a high degree of continuous conformational heterogeneity to determine the 2.8-Å cryo-electron microscopy (cryo-EM) structure of the complete human TSC in complex with the lysosomal recruitment factor WD repeat domain phosphoinositide-interacting protein 3 (WIPI3). We discover a previously undetected amino-terminal TSC1 HEAT repeat dimer that clamps onto a single TSC wing and forms a phosphatidylinositol phosphate (PIP)-binding pocket, which specifically binds monophosphorylated PIPs. These structural advances provide a model by which WIPI3 and PIP-signaling networks coordinate to recruit TSC to the lysosomal membrane to inhibit mTORC1. The high-resolution TSC structure reveals previously unrecognized mutational hotspots and uncovers crucial insights into the mechanisms of TSC dysregulation in disease.PMID:39565846 | DOI:10.1126/sciadv.adr5807

PLoS Genet. 2024 Nov 20;20(11):e1011467. doi: 10.1371/journal.pgen.1011467. Online ahead of print.ABSTRACTThe quality of meat is important to the consumer. Color is a primary indicator of meat quality and is characterized mainly into lightness, redness, and yellowness. Here, we used the genome-wide association study (GWAS) and gene-based association analysis with whole-genome resequencing of 230 fast-growing white-feathered chickens to map genes related to meat lightness and redness to a 6.24 kb QTL region (Chr15: 6298.34-6304.58 kb). This analysis revealed that only the protein phosphatase 1 catalytic subunit gamma (PPP1CC) was associated with meat color (P = 8.65E-08). The causal relationships between PPP1CC expression and meat lightness/redness were further validated through Mendelian randomization analyses (P < 2.9E-12). Inducible skeletal muscle-specific PPP1CC knockout (PPP1CC-SSKO) mice were generated and these mice showed increased lightness and decreased myoglobin content in the limb muscles. In addition, the predominant myofiber shifted from slow-twitch to fast-twitch myofibers. Through transcriptome and targeted metabolome evidence, we found that inhibition of PPP1CC decreased the expression of typical slow-twitch myofiber and myofiber-type specification genes and enhanced the glycolysis pathway. Functional validation through a plasmid reporter assay revealed that a SNP (rs315520807, C > T) located in the intron of PPP1CC could regulate the gene transcription activity. The differences in meat color phenotypes, myoglobin content, frequency of rs315520807 variant, expression of PPP1CC and fast-twitch fiber marker genes were detected between fast-growing white-feathered chickens and local chickens. In this study, PPP1CC was identified as the causative gene for meat color, and the novel target gene and variant that can aid in the innovation of meat improvement technology were detected.PMID:39565795 | DOI:10.1371/journal.pgen.1011467

Invest Ophthalmol Vis Sci. 2024 Nov 4;65(13):44. doi: 10.1167/iovs.65.13.44.ABSTRACTPURPOSE: The purpose of this study was to investigate biologically meaningful endotypes of open-angle glaucoma (OAG) by applying unsupervised machine learning to plasma metabolites.METHODS: This retrospective longitudinal cohort study enrolled consecutive patients aged ≥20 years with OAG at Tohoku University Hospital from January 2017 to January 2020. OAG was confirmed based on comprehensive ophthalmic examinations. Among the 523 patients with OAG with available clinical metabolomic data, 173 patients were longitudinally followed up for ≥2 years, with available data from ≥5 reliable visual field (VF) tests without glaucoma surgery. We collected fasting blood samples and clinical data at enrollment and nuclear magnetic resonance spectroscopy to profile 45 plasma metabolites in a targeted approach. After computing a distance matrix of preprocessed metabolites with Pearson distance, gap statistics determined the optimal number of OAG endotypes. Its risk factors, clinical presentations, metabolomic profiles, and progression rate of sector-based VF loss were compared across endotypes.RESULTS: Five distinct OAG endotypes were identified. The highest-risk endotype (endotype B) showed a significant faster progression of central VF loss (P = 0.007). Compared with patients with other endotypes, those with endotype B were more likely to have a high prevalence of dyslipidemia, cold extremities, oxidative stress, and low OAG genetic risk scores. Pathway analysis of metabolomic profiles implicated altered fatty acid and ketone body metabolism in this endotype, with 34 differentially enriched pathways (false discovery rate [FDR] < 0.05).CONCLUSIONS: Integrated metabolomic profiles identified five distinct etiologic endotypes of OAG, suggesting pathological mechanisms related with a high-risk group of central vision loss progression in the Japanese population.PMID:39565301 | DOI:10.1167/iovs.65.13.44

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

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

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

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

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

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