PubMed

Front Cell Infect Microbiol. 2024 Oct 15;14:1397735. doi: 10.3389/fcimb.2024.1397735. eCollection 2024.ABSTRACTUlcerative colitis (UC) is an inflammatory bowel disease characterized by recurrent inflammatory tissue damage to the intestinal mucosa and forming intestinal epithelial ulcers. It is one of the most intractable diseases in the world. To date, the mechanism is unclear. Causonis japonica (Thunb.) Raf. (Wu Lianmei in Chinese; WLM), a traditional Chinese medicine, which has a long history as an anti-inflammatory, but its effect on UC was unconfirmed yet. Therefore, we established a dextran sodium sulfate (DSS)-induced UC mice model and evaluated the therapeutic effect of WLM extract. The results indicated that WLM inhibits DSS-induced inflammatory response in colitis in vivo, decrease DSS-induced clinical manifestations, reverses colon length shortening, and reduces tissue damage. The results of ELISA kits suggested that WLM could reverse the levels of DSS-induced inflammatory factors. To explore the mechanism of WLM in treating DSS-induced UC, 1H NMR and UHPLC-Q/Orbitrap MS were used to perform non-targeted metabolomics analysis; 21 differential metabolites in colon tissues were closely related to UC. Meanwhile, the pseudo-targeted lipidomics based on UHPLC-Q/Trap MS was used to analyze lipid metabolism disorders, and 60 differential lipid compounds were screened. These differential compounds were mainly involved in glycerophospholipid, arachidonic acid, glycerolipid, citric acid, tyrosine, and ether lipid metabolisms. The analysis of gut microbial showed that WLM may improve the symptoms of UC mice by reducing the abundance of Helicobacter and Streptococcus and increasing the abundance of Limosilactobacillus and Akkermansia. Moreover, the real-time qPCR results showed that WLM extract could decrease the mRNA levels of inflammatory factors and may be associated with protecting the integrity of intestinal mucosal barrier by destroying in vivo metabolic pathways, especially by regulating energy and lipid metabolisms and reducing inflammatory reactions. It provides a beneficial reference for studying WLM to elucidate the therapeutic mechanism of UC.PMID:39473926 | PMC:PMC11518848 | DOI:10.3389/fcimb.2024.1397735

Infect Drug Resist. 2024 Oct 25;17:4665-4683. doi: 10.2147/IDR.S475164. eCollection 2024.ABSTRACTINTRODUCTION: Our study investigated the disparities and correlations between oral microbiota and metabolites in pregnant patients with and without periodontitis.METHODS: Subgingival plaque samples from all subjects were collected for shotgun metagenomic sequencing and broad-target metabolomics analysis.RESULTS: Forty pathogens, including Porphyromonas gingivalis, Fusobacterium nucleatum, Eubacterium saphenum, Gemella morbillorum, Tannerella forsythia, Streptococcus anginosus group, Selenomonas sputigena etc, were significantly enriched in pregnant patients with periodontitis (PPP). Conversely, symbiotic species such as Morococcus cerebrosus, Streptococcus vestibularis, S. salivarius, S. mitis, and S. pneumoniae were significantly more abundant in healthy controls (HCs). A total of 87 predicted functional modules (PFMs) exhibited significant differences between the two groups; eight PFMs showed high enrichment in PPP with involvement of PPP-enriched species within these pathways. The remaining 79 PFMs encompassing ribonucleotide biosynthesis, carbohydrate, and amino acid metabolism were highly abundant in HCs. For oral microbial metabolome, a total of 105 metabolites related to 150 KEGG pathways displayed significant differences between the two groups. Pathways such as pyruvate metabolism, folate biosynthesis, vascular smooth muscle contraction, and AMPK/mTOR signaling pathway along with their associated metabolites were found to be enriched in PPP, while carbohydrate metabolism predominated among HCs. Spearman's rank correlation analysis revealed significant positive associations between species enriched in PPP and metabolites enriched in PPP, but significant negative associations between species enriched in PPP and metabolites enriched in HCs.DISCUSSION: Our findings provide potential biomarkers for distinguishing periodontitis during pregnancy while offering valuable insights into mechanisms exploration and clinical intervention.PMID:39473909 | PMC:PMC11520917 | DOI:10.2147/IDR.S475164

Front Microbiol. 2024 Oct 15;15:1456087. doi: 10.3389/fmicb.2024.1456087. eCollection 2024.ABSTRACTBACKGROUND: Low birth weight (LBW; <2,500 g) affects approximately 15 to 20 percent of global births annually and is associated with suboptimal child development. Recent studies suggest a link between the maternal gut microbiome and poor obstetric and perinatal outcomes. The goal of this study was to examine relationships between maternal microbial taxa, fecal metabolites, and maternal anthropometry on incidence of LBW in resource-limited settings.METHODS: This was a secondary analysis of the Women First trial conducted in a semi-rural region of Guatemala. Maternal weight was measured at 12 and 34 weeks (wk) of gestation. Infant anthropometry measures were collected within 48 h of delivery. Maternal fecal samples at 12 and 34 weeks were used for microbiome (16S rRNA gene amplicon sequencing) and metabolomics analysis (34 wk). Linear mixed models using the MaAslin2 package were utilized to assess changes in microbiome associated with LBW. Predictive models using gradient boosted machines (XGBoost) were developed using the H2o.ai engine.RESULTS: No differences in β-diversity were observed at either time point between mothers with LBW infants relative to normal weight (NW) infants. Simpson diversity at 12 and 34 weeks was lower in mothers with LBW infants. Notable differences in genus-level abundance between LBW and NW mothers (p < 0.05) were observed at 12 weeks with increasing abundances of Barnesiella, Faecalibacterium, Sutterella, and Bacterioides. At 34 weeks, there were lower abundances of Magasphaera, Phascolarctobacterium, and Turicibacter and higher abundances of Bacteriodes, and Fusobacterium in mothers with LBW infants. Fecal metabolites related to bile acids, tryptophan metabolism and fatty acid related metabolites changed in mothers with LBW infants. Classification models to predict LBW based on maternal anthropometry and predicted microbial functions showed moderate performance.CONCLUSION: Collectively, the findings indicate that alterations in the maternal microbiome and metabolome were associated with LBW. Future research should target functional and predictive roles of the maternal gut microbiome in infant birth outcomes including birthweight.PMID:39473842 | PMC:PMC11518777 | DOI:10.3389/fmicb.2024.1456087

Adv Mater. 2024 Oct 30:e2409102. doi: 10.1002/adma.202409102. Online ahead of print.ABSTRACTCancer nanomedicine has emerged as a promising approach to overcome the limitations of conventional cancer therapies, offering enhanced efficacy and safety in cancer management. However, the inherent heterogeneity of tumors presents increasing challenges for the application of cancer nanomedicine in both diagnosis and treatment. This heterogeneity necessitates the integration of advanced and high-throughput analytical techniques to tailor nanomedicine strategies to individual tumor profiles. Omics technologies, encompassing genomics, epigenomics, transcriptomics, proteomics, metabolomics, and more, provide unparalleled insights into the molecular and cellular mechanisms underlying cancer. By dissecting tumor heterogeneity across multiple levels, these technologies offer robust support for the development of personalized and precise cancer nanomedicine strategies. In this review, the principles, techniques, and applications of key omics technologies are summarized. Especially, the synergistic integration of omics and nanomedicine in cancer therapy is explored, focusing on enhanced diagnostic accuracy, optimized therapeutic strategies and the assessment of nanomedicine-mediated biological responses. Moreover, this review addresses current challenges and outlines future directions in the field of omics-enhanced nanomedicine. By offering valuable insights and guidance, this review aims to advance the integration of omics with nanomedicine, ultimately driving improved diagnostic and therapeutic strategies for cancer.PMID:39473316 | DOI:10.1002/adma.202409102

Mol Nutr Food Res. 2024 Oct 30:e2400500. doi: 10.1002/mnfr.202400500. Online ahead of print.ABSTRACTSCOPE: This multi-omic study investigates the bidirectional interactions between gut microbiota and silymarin metabolism, highlighting the differential effects across various age groups. Silymarin, the extract from Silybum marianum (milk thistle), is commonly used for its hepatoprotective effects.METHODS AND RESULTS: An in vitro fermentation colon model was used with microbiota from 20 stool samples obtained from healthy donors divided into two age groups. A combination of three analytical advanced techniques, namely proton nuclear magnetic resonance (1H NMR), next-generation sequencing (NGS), and liquid chromatography-mass spectrometry (LC-MS) was used to determine silymarin microbial metabolites over 24 h, overall metabolome, and microbiota composition. Silymarin at a low diet-relevant dose of 50 µg mL-1 significantly altered gut microbiota metabolism, reducing short-chain fatty acid (acetate, butyrate, propionate) production, glucose utilization, and increasing alpha-diversity. Notably, the study reveals age-related differences in silymarin catabolism. Healthy elderly donors (70-80 years) exhibited a significant increase in a specific catabolite associated with Oscillibacter sp., whereas healthy young donors (12-45 years) showed a faster breakdown of silymarin components, particularly isosilybin B, which is associated with higher abundance of Faecalibacterium and Erysipelotrichaceae UCG-003.CONCLUSION: This study provides insights into microbiome functionality in metabolizing dietary flavonolignans, highlighting implications for age-specific nutritional strategies, and advancing our understanding of dietary (poly)phenol metabolism.PMID:39473280 | DOI:10.1002/mnfr.202400500

J Neurochem. 2024 Oct 30. doi: 10.1111/jnc.16244. Online ahead of print.ABSTRACTAlzheimer's disease (AD) pathogenesis involves dysregulation in diverse biochemical processes. Nevertheless, plasma tau phosphorylated at threonine 181 (P-tau181), a recognised AD biomarker, has been described to reflect early-stage cortical amyloid-β (Aβ) deposition in cognitively normal (CN) adults. Therefore, identifying changes in plasma metabolites associated with plasma P-tau181 at the pre-clinical stage may provide insights into underlying biochemical mechanisms to better understand initial AD pathogenesis. In the current study, plasma P-tau181, quantified via single molecule array (Simoa) technology, and plasma metabolites, quantified via targeted-mass spectrometry, were investigated for associations in CN older adults and upon stratification by positron emission tomography (PET)-Aβ load. In addition, the P-tau181-linked metabolites were evaluated for cognitive performance and neuroimaging markers of AD and the potential to distinguish between CN Aβ- and CN Aβ+ individuals. Significant positive associations of medium- and long-chain acylcarnitines (ACs) were observed with P-tau181 in the entire cohort, CN Aβ- and CN Aβ+, suggesting a link between initial Aβ pathology and fatty acid oxidation-mediated energy metabolism pathways. However, in CN Aβ-, additional linear associations of P-tau181 were observed with muscle metabolism and nitric oxide homeostasis-associated metabolites. Upon investigating the P-tau181-linked metabolites for cognitive performance, significant inverse correlations of the verbal and visual episodic memory and the global composite score were noted in CN Aβ+ with medium- and long-chain ACs, suggesting prognostic value of ACs accompanying weaker cognitive performance. While investigating neuroimaging markers, ACs had positive associations with PET-Aβ load and inverse associations with hippocampal volume in CN Aβ+, indicating connections of ACs with initial AD pathogenesis. Furthermore, based on receiver operating characteristics analysis, the associated ACs potentially classified PET-Aβ status in older adults. Therefore, plasma P-tau181-linked circulating ACs may serve as potential prognostic markers for initial AD pathogenesis in CN older adults. However, further cross-sectional and longitudinal research in highly characterised AD cohorts is needed to validate current findings.PMID:39473263 | DOI:10.1111/jnc.16244

Curr Mol Med. 2024 Oct 28. doi: 10.2174/0115665240296536240603112525. Online ahead of print.ABSTRACTBACKGROUND: Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. According to Traditional Chinese Medicine (TCM) syndromes theory, moist heat arthralgia spasm syndrome is the most prevalent syndrome of RA patients in the active period. However, the mechanism of alteration of gut microbiota in RA with moist heat arthralgia spasm syndrome has not been reported until now.OBJECTIVE: This study focused on the alteration of gut microbiota in adjuvant-induced arthritis rats with moist heat arthralgia spasm syndrome, elaborated its regulation mechanism, and analyzed the associations between gut microbiota and microbial metabolites.METHODS: The disease-syndrome combination rat model of RA with moist heat arthralgia spasm syndrome was constructed with Adjuvant-Induced Arthritis (AIA) under damp-heat stimulating. Enzyme-Linked Immunosorbent Assay (ELISA) was used to measure serum biochemical indicators. Damages of ankle joints were observed using hematoxylin and eosin (H&E). 16 small ribosomal subunit RNA (16S rRNA) gene sequencing was conducted to assess the gut microbiota composition and function on feces from rats. Alterations in fecal metabolites profiling were evaluated by fecal metabolomics through Liquid Chromatography-Mass Spectrometry (LC-MS) and Gas Chromatography-Mass Spectrometry (GC-MS). Pearson correlation analysis was performed to explore the associations of altered gut microbiota and microbial metabolites in Model rats.RESULTS: The imbalance of gut microbiota in Model rats was accompanied by metabolic disorders. Lactobacillus, Prevotellaceae_NK3B31_group, Allobaculum, Prevotellaceae_UCG_001, Alloprevotella, and Dubosiella were found to be dominant genera in Model rats. In total, 357 metabolites were significantly altered in Model rats and predominantly enriched into fatty acid degradation and glycerophospholipid metabolism. Pearson correlation analysis showed that TNF-α and IL-1β were associated with Prevotellaceae_Ga6A1_group and 3R-hydroxy-docosan-5S-olide, alpha-N-(3-hydroxy-14-methyl-pentadecanoyl)-ornithine, 17-methyl-trans-4,5- methylenenona-decanoic acid, Semiplenamide F.CONCLUSION: The key differential microbiota genera and differential microbial metabolites may become important targets for the treatment of RA and provide the theoretical basis for exploring the pathogenesis of RA.PMID:39473257 | DOI:10.2174/0115665240296536240603112525

Gut Microbes. 2024 Jan-Dec;16(1):2416928. doi: 10.1080/19490976.2024.2416928. Epub 2024 Oct 29.ABSTRACTBACKGROUND: The importance of gut microbes in mediating the benefits of lifestyle intervention is increasingly recognized. However, compared to the bacterial microbiome, the role of intestinal fungi in exercise remains elusive. With our established randomized controlled trial of exercise intervention in Chinese males with prediabetes (n = 39, ClinicalTrials.gov:NCT03240978), we investigated the dynamics of human gut mycobiome and further interrogated their associations with exercise-elicited outcomes using multi-omics approaches.METHODS: Clinical variations and biological samples were collected before and after training. Fecal fungal composition was analyzed using the internal transcribed spacer 2 (ITS2) sequencing and integrated with paired shotgun metagenomics, untargeted metabolomics, and Olink proteomics.RESULTS: Twelve weeks of exercise training profoundly promoted fungal ecological diversity and intrakingdom connection. We further identified exercise-responsive genera with potential metabolic benefits, including Verticillium, Sarocladium, and Ceratocystis. Using multi-omics approaches, we elucidated comprehensive associations between changes in gut mycobiome and exercise-shaped metabolic phenotypes, bacterial microbiome, and circulating metabolomics and proteomics profiles. Furthermore, a machine-learning algorithm built using baseline microbial signatures and clinical characteristics predicted exercise responsiveness in improvements of insulin sensitivity, with an area under the receiver operating characteristic (AUROC) of 0.91 (95% CI: 0.85-0.97) in the discovery cohort and of 0.79 (95% CI: 0.74-0.86) in the independent validation cohort (n = 30).CONCLUSIONS: Our findings suggest that intense exercise training significantly remodels the human fungal microbiome composition. Changes in gut fungal composition are associated with the metabolic benefits of exercise, indicating gut mycobiome is a possible molecular transducer of exercise. Moreover, baseline gut fungal signatures predict exercise responsiveness for diabetes prevention, highlighting that targeting the gut mycobiome emerges as a prospective strategy in tailoring personalized training for diabetes prevention.PMID:39473051 | DOI:10.1080/19490976.2024.2416928

J Biol Eng. 2024 Oct 29;18(1):61. doi: 10.1186/s13036-024-00457-w.ABSTRACTType 2 diabetes mellitus (T2DM) is a major public health concern with significant cardiovascular complications (CVD). Despite extensive epidemiological data, the molecular mechanisms relating hyperglycemia to CVD remain incompletely understood. We here investigated the impact of chronic hyperglycemia on human aortic smooth muscle cells (HASMCs) cultured under varying glucose conditions in vitro, mimicking normal (5 mmol/L), pre-diabetic (10 mmol/L), and diabetic (20 mmol/L) conditions, respectively. Normal HASMC cultures served as baseline controls, and patient-derived T2DM-SMCs served as disease controls. Results showed significant increases in cellular proliferation, area, perimeter, and F-actin expression with increasing glucose concentration (p < 0.01), albeit not exceeding the levels in T2DM cells. Atomic force microscopy analysis revealed significant decreases in Young's moduli, membrane tether forces, membrane tension, and surface adhesion in SMCs at higher glucose levels (p < 0.001), with T2DM-SMCs being the lowest among all the cases (p < 0.001). T2DM-SMCs exhibited elevated levels of selected pro-inflammatory markers (e.g., ILs-6, 8, 23; MCP-1; M-CSF; MMPs-1, 2, 3) compared to glucose-treated SMCs (p < 0.01). Conversely, growth factors (e.g., VEGF-A, PDGF-AA, TGF-β1) were higher in SMCs exposed to high glucose levels but lower in T2DM-SMCs (p < 0.01). Pathway enrichment analysis showed significant increases in the expression of inflammatory cytokine-associated pathways, especially involving IL-10, IL-4 and IL-13 signaling in genes that are up-regulated by elevated glucose levels. Differentially regulated gene analysis showed that compared to SMCs receiving normal glucose, 513 genes were upregulated and 590 genes were downregulated in T2DM-SMCs; fewer genes were differentially expressed in SMCs receiving higher glucose levels. Finally, the altered levels in genes involved in ECM organization, elastic fiber synthesis and formation, laminin interactions, and ECM proteoglycans were identified. Growing literature suggests that phenotypic switching in SMCs lead to arterial wall remodeling (e.g., change in stiffness, calcific deposits formation), with direct implications in the onset of CVD complications. Our results suggest that chronic hyperglycemia is one such factor that leads to morphological, biomechanical, and functional alterations in vascular SMCs, potentially contributing to the pathogenesis of T2DM-associated arterial remodeling. The observed differences in gene expression patterns between in vitro hyperglycemic models and patient-derived T2DM-SMCs highlight the complexity of T2DM pathophysiology and underline the need for further studies.PMID:39473010 | DOI:10.1186/s13036-024-00457-w

BMC Genomics. 2024 Oct 29;25(1):1014. doi: 10.1186/s12864-024-10785-2.ABSTRACTBACKGROUND: Ophiocordyceps sinensis (O. sinensis) is the dominant bacterium in the asexual stage of Chinese cordyceps, and its growth usually suffers from water stress. Thus, simulating its ecological growth environment is crucial for artificial cultivation. This study aimed to reveal the mechanism underlying the water stress tolerance of Ophiocordyceps sinensis (O. sinensis) by combining metabolomic and transcriptome analyses to identify crucial pathways related to differentially expressed genes (DEGs) and metabolites (DEMs) involved in the response to water stress.RESULTS: Gene coexpression analysis revealed that many genes related to 'betalain biosynthesis', 'tyrosine metabolism', 'linoleic acid metabolism', 'fructose and mannose metabolism', and 'starch and sucrose metabolism' were highly upregulated after 20d-water stress. Metabolomic analysis revealed that many metabolites regulated by these genes in these metabolic pathways were markedly decreased. On the one hand, we surmised that carbohydrate metabolism and the β-oxidation pathway worked cooperatively to generate enough acyl-CoA and then entered the TCA cycle to provide energy when exposed to water stress. On the other hand, the betalain biosynthesis and tyrosine metabolism pathway might play crucial roles in response to water stress in O. sinensis by enhancing cell osmotic potential and producing osmoregulatory substances (betaine) and antioxidant pigments (eumelanin).CONCLUSIONS: Overall, our findings provide important information for further exploration of the mechanism underlying the water stress tolerance of O. sinensis for the industrialization of artificial cultivation of Chinese cordyceps.PMID:39472792 | DOI:10.1186/s12864-024-10785-2

BMC Plant Biol. 2024 Oct 29;24(1):1025. doi: 10.1186/s12870-024-05700-6.ABSTRACTBACKGROUND: Mango is a tropical fruit with high economic value. The selection of suitable dwarf mango varieties is an important aspect of mango breeding. However, the mechanisms that regulate mango dwarfing remain unclear.RESULTS: In this study, we compared the transcriptomes and metabolomes of mango varieties Guiqi (a dwarfed variety) and Jinhuang (an arborized variety). A total of 4,954 differentially expressed genes and 317 differentially abundant metabolites were identified between the two varieties, revealing the molecular mechanism of the gibberellin 3β-hydroxylase gene GA3ox in regulating dwarfing traits in mangoes using joint transcriptome and metabolome analyses. The results showed that differentially expressed genes were enriched in the diterpenoid biosynthesis pathway and that differentially abundant metabolites were annotated to their upstream pathway, the terpenoid backbone biosynthesis. A gene regulation network based on these two pathways was constructed, indicating the upregulation of the GA3ox gene and the accumulation of gibberellin in dwarfed mangoes. We then transferred the GA3ox gene to tobacco plants following the application of gibberellin, and the morphology and height of the transgenic tobacco plants largely recovered the phenotype.CONCLUSIONS: These results demonstrated that GA3ox plays a role in the regulation of dwarf traits. Our study provides an important theoretical basis for studying the regulatory mechanisms underlying mango dwarfism to facilitate mango breeding.PMID:39472789 | DOI:10.1186/s12870-024-05700-6

Commun Biol. 2024 Oct 29;7(1):1411. doi: 10.1038/s42003-024-07075-8.NO ABSTRACTPMID:39472761 | DOI:10.1038/s42003-024-07075-8

Cell Death Differ. 2024 Oct 29. doi: 10.1038/s41418-024-01406-2. Online ahead of print.ABSTRACTOxaliplatin-based therapeutics is a widely used treatment approach for hepatocellular carcinoma (HCC) patients; however, drug resistance poses a significant clinical challenge. Epigenetic modifications have been implicated in the development of drug resistance. In our study, employing siRNA library screening, we identified that silencing the m6A writer METTL3 significantly enhanced the sensitivity to oxaliplatin in both in vivo and in vitro HCC models. Further investigations through combined RNA-seq and non-targeted metabolomics analysis revealed that silencing METTL3 impeded the pentose phosphate pathway (PPP), leading to a reduction in NADPH and nucleotide precursors. This disruption induced DNA damage, decreased DNA synthesis, and ultimately resulted in cell cycle arrest. Mechanistically, METTL3 was found to modify E3 ligase TRIM21 near the 3'UTR with N6-methyladenosine, leading to reduced RNA stability upon recognition by YTHDF2. TRIM21, in turn, facilitated the degradation of the rate-limiting enzyme of PPP, G6PD, through the ubiquitination-proteasome pathway. Importantly, high expression of METTL3 was significantly associated with adverse prognosis and oxaliplatin resistance in HCC patients. Notably, treatment with the specific METTL3 inhibitor, STM2457, significantly improved the efficacy of oxaliplatin. These findings underscore the critical role of the METTL3/TRIM21/G6PD axis in driving oxaliplatin resistance and present a promising strategy to overcome chemoresistance in HCC.PMID:39472692 | DOI:10.1038/s41418-024-01406-2

Sci Rep. 2024 Oct 29;14(1):25948. doi: 10.1038/s41598-024-77436-0.ABSTRACTAlthough ethyl formate (EF) fumigant and low temperature applications are widely used for pest management, studies related to their mechanisms of action and subsequent metabolic changes in Drosophila suzukii models are still unclear. In this study, a comparative metabolome analysis was performed to investigate the major metabolites modified by EF and low temperature and how they are related to and affect insect physiology. Most of the identified metabolites function in metabolic pathways related to the biosynthesis of amino acids, nucleotides and cofactors. In addition, a combined treatment with EF and low temperature significantly altered the tricarboxylic acid cycle (TCA) and the levels of the purine and pyrimidine classes of metabolites. Interestingly, the levels of cytochrome P450 and glutathione metabolites involved in detoxification dramatically changed under stress conditions compared to those in the control group.PMID:39472532 | DOI:10.1038/s41598-024-77436-0

Oncogene. 2024 Oct 29. doi: 10.1038/s41388-024-03191-1. Online ahead of print.ABSTRACTSystemic levels of methylmalonic acid (MMA), a byproduct of propionate metabolism, increase with age and MMA promotes tumor progression via its direct effects in tumor cells. However, the role of MMA in modulating the tumor ecosystem remains to be investigated. The proliferation and function of CD8+ T cells, key anti-tumor immune cells, declines with age and in conditions of vitamin B12 deficiency, which are the two most well-established conditions that lead to increased systemic levels of MMA. Thus, we hypothesized that increased circulatory levels of MMA would lead to a suppression of CD8+ T cell immunity. Treatment of primary CD8+ T cells with MMA induced a dysfunctional phenotype characterized by robust immunosuppressive transcriptional reprogramming and marked increases in the expression of the exhaustion regulator, TOX. Accordingly, MMA treatment upregulated exhaustion markers in CD8+ T cells and decreased their effector functions, which drove the suppression of anti-tumor immunity in vitro and in vivo. Mechanistically, MMA-induced CD8+ T cell exhaustion was associated with a suppression of NADH-regenerating reactions in the TCA cycle and concomitant defects in mitochondrial function. Thus, MMA has immunomodulatory roles, thereby highlighting MMA as an important link between aging, immune dysfunction, and cancer.PMID:39472497 | DOI:10.1038/s41388-024-03191-1

Nat Commun. 2024 Oct 29;15(1):9330. doi: 10.1038/s41467-024-52909-y.ABSTRACTDietary restriction (DR) is a potent method to enhance lifespan and healthspan, but individual responses are influenced by genetic variations. Understanding how metabolism-related genetic differences impact longevity and healthspan are unclear. To investigate this, we used metabolites as markers to reveal how different genotypes respond to diet to influence longevity and healthspan traits. We analyzed data from Drosophila Genetic Reference Panel (DGRP) strains raised under AL and DR conditions, combining metabolomic, phenotypic, and genome-wide information. We employed two computational and complementary methods across species-random forest modeling within the DGRP as our primary analysis and Mendelian randomization in human cohorts as a secondary analysis. We pinpointed key traits with cross-species relevance as well as underlying heterogeneity and pleiotropy that influence lifespan and healthspan. Notably, orotate was linked to parental age at death in humans and blocked the DR lifespan extension in flies, while threonine supplementation extended lifespan, in a strain- and sex-specific manner. Thus, utilizing natural genetic variation data from flies and humans, we employed a systems biology approach to elucidate potential therapeutic pathways and metabolomic targets for diet-dependent changes in lifespan and healthspan.PMID:39472442 | DOI:10.1038/s41467-024-52909-y

Chem Biodivers. 2024 Oct 29:e202402227. doi: 10.1002/cbdv.202402227. Online ahead of print.ABSTRACTOcotea is an important genus of Lauraceae plant family that comprises over 400 species, many of which pose challenges in taxonomic differentiation due to their complex botanical characteristics. Chemosystematics, and more recently, chemophenetics, have emerged as valuable tools to address these challenges based on their natural products (NPs) composition. O. diospyrifolia (Meisn.) Mez is a poorly studied species with known pharmacological potential. Here, we applied ultra-high performance liquid chromatography coupled with high-resolution tandem mass spectrometry (UHPLC-HRMS) allied to a curated in-house database with all previous isolated NPs from the Ocotea genus (OcoteaDB), gas phase fragmentations reactions, and biosynthesis. The strategy resulted in compounds annotated in confidence levels 2 (n=27), 3 (n=231), and 4 (n=21) according to the Metabolomics Standards Initiative (MSI). Additional annotations based on fragmentation proposals (n=16) were also included. The study revealed that O. diospyrifolia is a great alkaloid producer, even though different lignoids, which also comes from the shikimate pathway, were annotated. Additionally, the flavonoid profile predominantly consists of flavonol glycosides, complementing prior reports. This study provides the first comprehensive chemical profile of O. diospyrifolia leaves, which corroborates the chemotaxonomy of the species, and also contributes to further characterization studies, as the UHPLC-HRMS data is publicly available.PMID:39472301 | DOI:10.1002/cbdv.202402227

Sci Total Environ. 2024 Oct 27:177135. doi: 10.1016/j.scitotenv.2024.177135. Online ahead of print.ABSTRACTDrylands are home to over 38 % of the world's population and are among the areas most sensitive to climate change and human activity. Most xerophytes rely on arbuscular mycorrhizal fungi (AMF) for improved drought tolerance. Although research has focused on crops and economically significant plants, the response of sand-fixation shrubs to AMF under drought conditions remains underexplored. This study aims to investigate how AMF affects the drought adaptation strategies of the sand-fixation shrub Artemisia ordosica. A culture system for A. ordosica and the main symbiotic partner Funneliformis mosseae was established, and phenotypic, metabolomic, and transcriptomic analyses were conducted to assess physiological changes induced by arbuscular mycorrhizal symbiosis (AMS) under varying drought stress conditions. AMS influenced A. ordosica's metabolic pathways and its drought adaptation strategies, promoted the redistribution of sugars and flavonoids, and shaped different metabolic patterns of seedlings and adult A. ordosica. AMS had an important shaping ability in the accumulation of proline at A. ordosica seedlings, but had a significant influence on the accumulation of sugars of A. ordosica at the adult growth stage. AMS enhanced the ability of the host to adapt to extreme drought by modulating metabolites at the adult growth stage of A. ordosica. AMS also facilitated an accumulation of key metabolites under well-watered conditions but also intensified interactions with pathogens, leading to a trade-off between drought adaptation and immune capacity under extreme drought of A. ordosica during the adult growth stage. This study uses metabolome and transcriptome methods to explore AMS effects on A. ordosica's drought adaptation strategies, revealing a significant trade-off between drought adaptation and immune capacity. The findings highlight AMS's role in modifying the drought adaptation strategies of A. ordosica in desert ecosystems, and enhance our understanding of key species for sand fixation and ecological restoration, and maintain ecological security.PMID:39471960 | DOI:10.1016/j.scitotenv.2024.177135

Clin Chim Acta. 2024 Oct 27:120022. doi: 10.1016/j.cca.2024.120022. Online ahead of print.ABSTRACTBACKGROUND: Bladder cancer (BC) is a common malignant tumour of the urinary system. Currently, the gold standard for diagnosing BC is cystoscopy, but it is an invasive examination that can lead to a certain psychological burden on the patient. In this study, we aimed to identify non-invasive potential metabolic biomarkers that could improve the diagnostic accuracy of bladder cancer.METHODS: Urine from 30 healthy people and 50 BC patients, including 40 non-muscle-invasive bladder cancer (NMIBC) patients and 10 muscle-invasive bladder cancer (MIBC) patients, were analyzed by liquid chromatography coupled with mass spectrometry to identify potential diagnostic metabolites. Binary Logistic regression was used to construct biomarker panels. Correlation analysis and construction of compound-reaction-enzyme-gene network were also performed to explore the possible mechanisms of BC development.RESULTS: Twenty-six metabolites were identified for differentiating BC patients from healthy controls, and eight metabolites were identified for differentiating NMIBC patients form MIBC patients. The biomarker panel consisting of urate, 4-Androstene-3α, 17β-diol and 3-Indoxyl sulfate can distinguish well between BC patients and healthy controls, with an area under the ROC curve (AUC) value of 0.983. And the biomarker panel consisting of L-Octanoylcarnitine, γ-Glutamylleucine, and heptanoylcarnitine for distinguishing NMIBC patients from MIBC patients had an AUC value of 0.941.CONCLUSIONS: The diagnostic capability of the biomarker panels are superior to that of any single potential biomarker. This panel significantly benefits bladder cancer diagnostics and reveals insight into bladder cancer pathogenesis.PMID:39471892 | DOI:10.1016/j.cca.2024.120022

Benef Microbes. 2024 Oct 25:1-15. doi: 10.1163/18762891-bja00048. Online ahead of print.ABSTRACTCow's milk protein allergy (CMPA) in infancy is associated with intestinal microbial dysbiosis, characterised by low Bifidobacteriaceae levels. The present study aimed to investigate the impact of two human milk oligosaccharides (HMO), lactose (L), and their combination on the faecal microbiome and metabolome of infants with CMPA. Stool samples of 12 term infants with probable CMPA (mean age 4.3 months) were analysed using a validated intestinal fermentation assay (SIFR® technology). For each substrate (i.e. HMO (2'-fucosyllactose [2'-FL] and lacto-N-neotetraose [LNnT]), L and HMO + L), taxonomic microbiome characterisation and untargeted metabolite profiling were performed at multiple timepoints. At baseline, the tested faecal microbiota overall displayed low abundances of Bifidobacteriaceae. Fermentation with either HMO or lactose significantly enriched Bifidobacterium breve, Bifidobacterium longum, Bifidobacterium pseudocatenulatum and, for HMO + L, also Bifidobacterium bifidum. The increase in HMO-utilising bifidobacteria was associated with a significant rise in levels of short-chain fatty acids, aromatic lactic acids and N-acetylated amino acids, with additive effects being observed for HMO + L. The above data suggest that the combination of 2'-FL, LNnT and lactose helps to alleviate the previously reported CMPA-associated intestinal bacterial dysbiosis and induces the production of several beneficial metabolites. The clinical significance of these findings for infants with CMPA requires further investigation.PMID:39471839 | DOI:10.1163/18762891-bja00048