PubMed

Front Immunol. 2023 Aug 15;14:1213902. doi: 10.3389/fimmu.2023.1213902. eCollection 2023.ABSTRACTBACKGROUND: Term birth (TB) and preterm birth (PTB) are characterized by uterine contractions, rupture of the chorioamniotic membrane, decidual activation, and other physiological and pathological changes. In this study, we hypothesize that inflammation can cause changes in mRNA expression and metabolic stability in the placenta, decidua, chorioamniotic membrane, uterus and peripheral blood, ultimately leading to PTB.METHODS: To comprehensively assess the effects of inflammation on mRNA expression and metabolite production in different tissues of pregnancy, we used a mouse PTB model by intraperitoneally injecting lipopolysaccharide (LPS) and integrated transcriptomics and metabolomics studies.RESULTS: Our analysis identified 152 common differentially expressed genes (DEGs) and 8 common differentially expressed metabolites (DEMs) in the placenta, decidua, chorioamniotic membrane, uterus, and peripheral blood, or placenta and uterus after LPS injection, respectively. Our bioinformatics analysis revealed significant enrichment of the NOD-like receptor signaling pathway (mmu04621), TNF signaling pathway (mmu04668), IL-17 signaling pathway (mmu04657), and NF-kappa B signaling pathway in the transcriptomics of different tissues, and Hormone synthesis, Lysosome, NOD-like receptor signaling pathway, and Protein digest and absorption pathway in metabolomics. Moreover, we found that several upstream regulators and master regulators, including STAT1, STAT3, and NFKB1, were altered after exposure to inflammation in the different tissues. Interaction network analysis of transcriptomics and metabolomics DEGs and DEMs also revealed functional changes in mice intraperitoneally injected with LPS.CONCLUSIONS: Overall, our study identified significant and biologically relevant alterations in the placenta, decidua, chorioamniotic membrane, uterus, peripheral blood transcriptome and the placenta and uterus metabolome in mice exposed to LPS. Thus, a comprehensive analysis of different pregnancy tissues in mice intraperitoneally injected with LPS by combining transcriptomics and metabolomics may help to systematically understand the local and systemic changes associated with PTB caused by inflammation.PMID:37649476 | PMC:PMC10464907 | DOI:10.3389/fimmu.2023.1213902

Mol Plant. 2023 Aug 29:S1674-2052(23)00248-4. doi: 10.1016/j.molp.2023.08.013. Online ahead of print.ABSTRACTCommon buckwheat (Fagopyrum esculentum Moench) is an ancient crop with a world-wide distribution. Due to its excellent nutritional quality and high economic and ecological value, common buckwheat is becoming increasingly important throughout the world. The availability of a high-quality reference genome sequence and population genomic data will accelerate the breeding of common buckwheat, but the high heterozygosity due to the outcrossing nature has greatly hindered the genome assembly. Here we constructed a chromosome-scale high-quality reference genome of F. esculentum var. homotropicum, a homozygous self-pollinating variant of common buckwheat. Comparative genomics revealed that two cultivated buckwheat species, common buckwheat (F. esculentum) and Tartary buckwheat (F. tataricum), underwent metabolomic divergence and ecotype differentiation. The expansion of several gene families in common buckwheat, including FhFAR genes, is associated with its wider distribution than Tartary buckwheat. Copy number variation of genes involved in the metabolism of flavonoids is associated with the difference of rutin content between common and Tartary buckwheat. We also present a comprehensive atlas of genomic variation based on whole-genome resequencing of 572 accessions of common buckwheat. Population and evolutionary genomics reveal genetic variation associated with environmental adaptability and floral development between Chinese and non-Chinese cultivated groups. Genome-wide association of multi-year agronomic traits and the content of flavonoids were carried out and revealed Fh05G014970 is a potential major regulator of flowering period, a key agronomic trait controlling the yield of outcrossing crops, and Fh06G015130 is a crucial gene underlying flavor-associated flavonoids. Moreover, the gene translocation and sequence variation of FhS-ELF3 contribute to the homomorphic self-compatibility of common buckwheat. Our results elucidate the genetic basis of speciation, ecological adaptation, fertility and unique flavor of common buckwheat, and provide new resource for future genomics-assisted breeding of this economically important crop.PMID:37649255 | DOI:10.1016/j.molp.2023.08.013

Plant J. 2023 Aug 30. doi: 10.1111/tpj.16439. Online ahead of print.ABSTRACTBougainvillea is a typical tropical flower of great ornamental value due to its colorful bracts. The molecular mechanism behind color formation is not well-understood. Therefore, this research conducted metabolome analysis, transcriptome analysis, and multi-flux full-length sequencing in two color bracts of Bougainvillea × buttiana 'Chitra' to investigate the significantly different metabolites (SDMs) and differentially expressed genes (DEGs). Overall, 261 SDMs, including 62 flavonoids and 26 alkaloids, were detected, and flavonols and betalains were significantly differentially accumulated among the two bracts. Furthermore, the complete-length transcriptome of Bougainvillea × buttiana was also developed, which contained 512 493 non-redundant isoforms. Among them, 341 210 (66.58%) displayed multiple annotations in the KOG, GO, NR, KEGG, Pfam, Swissprot, and NT databases. RNA-seq findings revealed that 3610 DEGs were identified between two bracts. Co-expression analysis demonstrated that the DEGs and SDMs involved in flavonol metabolism (such as CHS, CHI, F3H, FLS, CYP75B1, kaempferol, and quercetin) and betacyanin metabolism (DODA, betanidin, and betacyanins) were the main contributors for the canary yellow and red bract formation, respectively. Further investigation revealed that several putative transcription factors (TFs) might interact with the promoters of the genes mentioned above. The expression profiles of the putative TFs displayed that they may positively and negatively regulate the structural genes' expression profiles. The data revealed a potential regulatory network between important genes, putative TFs, and metabolites in the flavonol and betacyanin biosynthesis of Bougainvillea × buttiana 'Chitra' bracts. These findings will serve as a rich genetic resource for future studies that could create new color bracts.PMID:37648415 | DOI:10.1111/tpj.16439

Microb Pathog. 2023 Aug 28:106326. doi: 10.1016/j.micpath.2023.106326. Online ahead of print.ABSTRACTRice remains the primary staple for more than half of the world's population, yet its cultivation faces numerous challenges, including both biotic and abiotic stresses. One significant obstacle is the prevalence of rice blast disease, which substantially diminishes productivity and increases cultivation costs due to frequent fungicide applications. Consequently, the presence of fungicide residues in rice raises concerns about compliance with international Maximum Residue Limits (MRLs). While host resistance has proven effective, it often remains vulnerable to new variants of the Magnaporthe oryzae pathogen. Therefore, there is a critical need to explore innovative management strategies that can complement or enhance existing methods. An unexplored avenue involves harnessing endophytic bacterial communities. To this end, the present study investigates the potential of eleven endophytic Bacillus spp. in suppressing Pyricularia oryzae, promoting plant growth, and eliciting a defense response through phyllobacterization. The results indicate that the secreted metabolome and volatilome of seven tested isolates demonstrate inhibitory effects against Pyricularia oryzae, ranging from a minimum of 40% to a maximum of 70%. Bacillus siamensis L34, B. amyloliquefaciens RA37, B. velezensis L12, and B. subtilis B18 produce antifungal antibiotics targeting Pyricularia oryzae. Additionally, B. subtilis S4 and B. subtilis S6 emerge as excellent inducers of systemic resistance against blast disease, as evidenced by elevated activity of biochemical defense enzymes such as peroxidase, polyphenol oxidase, and total phenol content. However, a balance between primary metabolic activity (e.g., chlorophyll content, chlorophyll fluorescence, and photosynthetic rate) and defense activity is observed. Furthermore, specific endophytic Bacillus spp. significantly stimulates defense-related genes, including OsEDS1, OsFMO1, and OsEDS1. These findings underscore the multifaceted potential of endophytic Bacillus in managing blast disease through antibiosis and induced systemic resistance. In conclusion, this study highlights the promising role of endophytic Bacillus spp. as a viable option for blast disease management. Their ability to inhibit the pathogen and induce systemic resistance makes them a valuable addition to the existing strategies. However, it is crucial to consider the trade-off between primary metabolic activity and defense response when implementing these bacteria-based approaches.PMID:37648175 | DOI:10.1016/j.micpath.2023.106326

Chemosphere. 2023 Aug 28:139997. doi: 10.1016/j.chemosphere.2023.139997. Online ahead of print.ABSTRACTBACKGROUND: Environmental exposure to dicofol (DCF), one of common organochlorine pesticides (OCPs) widely used for controlling agricultural pests, elicits a potential risk for human health due to its toxicity. However, potential physiological hazards of oral DCF exposure remain largely unknown.METHODS: Mice were exposed to relatively chronic and subacute DCF at different doses (5, 20 and 100 mg/kg) by gavage for 2 weeks. 1H NMR-based metabolomics was used to explore alterations of metabolic profiling induced by DCF exposure. Targeted metabolomics was subsequently employed to investigate the dose-dependent effects of oral DCF exposure on lipid metabolism and the gut microbiota-derived metabolites of mice. 16S rRNA gene sequencing was further employed to evaluate the changes of gut community of mice exposed to DCF.RESULTS: Oral exposure to DCF dose-dependently induced liver injury, manifested by hepatic lipogenesis, inflammation and liver dysfunction of mice. Typically, DCF exposure disrupted host fatty acids metabolism that were confirmed by marked alteration in the levels of related genes. DCF exposure also dose-dependently caused dysbiosis of the gut bacteria and its metabolites including altered microbial composition accompanied by inhibition of bacterial fermentation.CONCLUSION: These results provide metabolic evidence that DCF exposure dose-dependently induces liver lipidosis and disruption of the gut microbiota in mice, which enrich our views of molecular mechanism of DCF hepatoxicity.PMID:37648173 | DOI:10.1016/j.chemosphere.2023.139997

Chemosphere. 2023 Aug 28:140009. doi: 10.1016/j.chemosphere.2023.140009. Online ahead of print.ABSTRACTIncreasing studies have linked air pollution to kidney dysfunction, however, the associations between mixture of air pollutants and kidney function and potential effect modifiers remain unclear. We aimed to investigate whether obese adults were more susceptible than normal-weight ones to joint effects of multiple air pollutants on kidney function and further to explore effect modification by free fatty acids (FFAs). Forty obese and 49 normal-weight adults were recruited from a panel study (252 follow-up visits). Individual exposure levels to air pollutants (PM2.5, PM10, O3, NO2, SO2 and CO) were estimated. Glomerular function (cystatin C (CysC) and estimated glomerular filtration rate (eGFR)) and tubular function (neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1) were evaluated. Plasma levels of FFAs including trans fatty acids (TFAs) and essential fatty acids (EFAs) were quantified using targeted metabolomics. Bayesian kernel machine regression model was applied to estimate associations between mixture of air pollutants and kidney function. The results showed significant joint effects of air pollutants on kidney function indicators. In the normal-weight group, the mixture of air pollutants was significantly associated with CysC and eGFRcr-cys when the mixture was at its 70 percentile or above it compared with the median, where O3 was identified the key pollutant. In the obese group, a significantly positive association between pollutant mixture and NGAL was observed in addition to trends in CysC and eGFRcr-cys, mainly driven by SO2. Interaction analysis suggested that the associations of air pollutants with kidney function were augmented with TFAs in both groups and weakened with EFAs in the normal-weight group. This study highlighted the renal adverse effects of air pollutants and modification of FFAs, which has implications for target prevention for kidney dysfunction associated with air pollution, especially among vulnerable population.PMID:37648166 | DOI:10.1016/j.chemosphere.2023.140009

Brain Behav Immun. 2023 Aug 28:S0889-1591(23)00250-7. doi: 10.1016/j.bbi.2023.08.021. Online ahead of print.ABSTRACTEpidemiological investigations show that noise exposure in early life is associated with health and cognitive impairment. The gut microbiome established in early life plays a crucial role in modulating developmental processes that subsequently affect brain function and behavior. Here, we examined the impact of early-life exposure to noise on cognitive function in adolescent rats by analyzing the gut microbiome and metabolome to elucidate the underlying mechanisms. Chronic noise exposure during early life led to cognitive deficits, hippocampal injury, and neuroinflammation. Early-life noise exposure showed significant difference on the composition and function of the gut microbiome throughout adolescence, subsequently causing axis-series changes in fecal short-chain fatty acid (SCFA) metabolism and serum metabolome profiles, as well as dysregulation of endothelial tight junction proteins, in both intestine and brain. We also observed sex-dependent effects of microbiota depletion on SCFA-related beneficial bacteria in adolescence. Experiments on microbiota transplantation and SCFA supplementation further confirmed the role of intestinal bacteria and related SCFAs in early-life noise-exposure-induced impairments in cognition, epithelial integrity, and neuroinflammation. Overall, these results highlight the homeostatic imbalance of microbiota-gut-brain axis as an important physiological response toward environmental noise during early life and reveals subtle differences in molecular signaling processes between male and female rats.PMID:37648006 | DOI:10.1016/j.bbi.2023.08.021

Aquat Toxicol. 2023 Aug 25;262:106669. doi: 10.1016/j.aquatox.2023.106669. Online ahead of print.ABSTRACTThe mussels are species with high socio-economic weights and are often used as bioindicators of biological and chemical contamination. In the field and aquaculture, they can intake microplastics during filter-feeding, and the microplastics can have a negative impact on their health, even at low concentrations. The effects of microplastics have yet to be fully examined on the blue mussel (Mytilus edulis), considering the factors of ageing and sorption of some polyaromatic hydrocarbons (PAHs), ubiquitous environmental contaminants. In this work, 5 different exposure conditions were studied: pristine microplastics, microplastics aged for 1000 days under UV radiation, microplastics sorbing PAHs, as well as microplastics both aged and sorbing PAHs, in parallel to controls. The microplastic changes after ageing were studied with spectroscopic and chromatographic methods. Then, 8-day laboratory exposures of mussels at 10 µg/L of microplastics were performed. The oxidative stress, as well as neurotoxic and immunological responses of M. edulis, were measured using a battery of biomarkers (catalase/CAT, superoxide dismutase/SOD, glutathione S-transferases/GST, acetylcholinesterase/AChE) in 3 different organs (digestive gland, gills and mantle), and acid phosphatase in hemolymph. Then, a study of lipid impairments on the digestive gland was performed through the use of lipidomic tools. No significant difference of oxidative stress activity was observed for all the tissues of mussels exposed to pristine microplastics at 10 µg/L, compared to controls. The ageing and the PAH soption onto microplastics were influencing factors of the oxydative stress in mussels with increased CAT activities in the digestive glands and decreased SOD activities in the mantles. The neurotoxicity was highlighted by higher AChE activities measured in the mantle of mussels exposed to all the microplastic treatments, compared to controls. Concerning lipidomics, no compound was determined as a biomarker of microplastic exposure. The study demonstrated a low toxicity of microplastics at environmental relevant concentration with a 8-day exposure and using the chosen biomarkers. However, some microplastic changes seemed to lead to specific effects on mussels.PMID:37647752 | DOI:10.1016/j.aquatox.2023.106669

Food Chem. 2023 Aug 23;432:137247. doi: 10.1016/j.foodchem.2023.137247. Online ahead of print.ABSTRACTPinecone substrate offers an eco-friendly and cost-effective alternative for cultivating edible fungi. This pioneering study explores the 94 amino acids metabolic profiles of Auricularia cornea grown on various pinecone substrates. To our knowledge, this is the first study of quantify A. cornea on an oleaginous substrate (pinecone) using targeted LC-MS /MS-based metabolomics approaches. Five different pinecone substrate percentages (0%, 7%, 14%, 21%, and 28% respectively) were used for A. cornea culture, and the resulting fruiting bodies were analyzed for amino acids metabolic profiles. Detected 79 amino acids metabolites, 15 undetected. High contents of succinic-acid and γ-aminobutyric acid. Thirty-three amino acid metabolites showed significant differences between groups, primarily related to protein synthesis. KEGG analysis revealed that seven major metabolic pathways were significantly enriched. The findings provide valuable insights into the metabolite composition of A. cornea grown on a pinecone substrate, potentially contribute to the understanding of its nutritional and medicinal properties.PMID:37647707 | DOI:10.1016/j.foodchem.2023.137247

Clin Transl Med. 2023 Sep;13(9):e1369. doi: 10.1002/ctm2.1369.ABSTRACTBACKGROUND: The imbalance between osteoblasts and osteoclasts may lead to osteoporosis. Osteoblasts and osteoclasts have different energy requirements, with aerobic glycolysis being the prominent metabolic feature of osteoblasts, while osteoclast differentiation and fusion are driven by oxidative phosphorylation.METHODS: By polymerase chain reaction as well as Western blotting, we assayed coactivator-associated arginine methyltransferase 1 (CARM1) expression in bone tissue, the mouse precranial osteoblast cell line MC3T3-E1 and the mouse monocyte macrophage leukaemia cell line RAW264.7, and expression of related genes during osteogenic differentiation and osteoclast differentiation. Using gene overexpression (lentivirus) and loss-of-function approach (CRISPR/Cas9-mediated knockout) in vitro, we examined whether CARM1 regulates osteogenic differentiation and osteoblast differentiation by metabolic regulation. Transcriptomic assays and metabolomic assays were used to find the mechanism of action of CARM1. Furthermore, in vitro methylation assays were applied to clarify the arginine methylation site of PPP1CA by CARM1.RESULTS: We discovered that CARM1 reprogrammed glucose metabolism in osteoblasts and osteoclasts from oxidative phosphorylation to aerobic glycolysis, thereby promoting osteogenic differentiation and inhibiting osteoclastic differentiation. In vivo experiments revealed that CARM1 significantly decreased bone loss in osteoporosis model mice. Mechanistically, CARM1 methylated R23 of PPP1CA, affected the dephosphorylation of AKT-T450 and AMPK-T172, and increased the activities of phosphofructokinase-1 and pructose-2,6-biphosphatase3, causing an up-regulation of glycolytic flux. At the same time, as a transcriptional coactivator, CARM1 regulated the expression of pyruvate dehydrogenase kinase 3, which resulted in the inhibition of pyruvate dehydrogenase activity and inhibition of the tricarboxylic acid cycle, leading to a subsequent decrease in the flux of oxidative phosphorylation.CONCLUSIONS: These findings reveal for the first time the mechanism by which CARM1 affects both osteogenesis and osteoclast differentiation through metabolic regulation, which may represent a new feasible treatment strategy for osteoporosis.PMID:37649137 | DOI:10.1002/ctm2.1369

Parasit Vectors. 2023 Aug 30;16(1):304. doi: 10.1186/s13071-023-05881-3.ABSTRACTBACKGROUND: Leishmaniasis is one of the most neglected tropical diseases and is spread mainly in impoverished regions of the world. Although many studies have focused on the host's response to Leishmania invasion, relatively less is known about the complex processes at the metabolic level, especially the metabolic alterations in the infected hosts.METHODS: In this study, we conducted metabolomics analysis on the urine of golden hamsters in the presence or absence of visceral leishmaniasis (VL) using the ultra-performance liquid chromatography (UPLC) system tandem high-resolution mass spectrometer (HRMS). The metabolic characteristics of urine samples, along with the histopathological change and the parasite burden of liver and spleen tissues, were detected at 4 and 12 weeks post infection (WPI), respectively.RESULTS: Amino acid metabolism was extensively affected at both stages of VL progression. Meanwhile, there were also distinct metabolic features at different stages. At 4 WPI, the significantly affected metabolic pathways involved alanine, aspartate and glutamate metabolism, the pentose phosphate pathway (PPP), histidine metabolism, tryptophan metabolism and tyrosine metabolism. At 12 WPI, the markedly enriched metabolic pathways were almost concentrated on amino acid metabolism, including tyrosine metabolism, taurine and hypotaurine metabolism and tryptophan metabolism. The dysregulated metabolites and metabolic pathways at 12 WPI were obviously less than those at 4 WPI. In addition, seven metabolites that were dysregulated at both stages through partial least squares-discriminant analysis (PLS-DA) and receiver-operating characteristic (ROC) tests were screened to be of diagnostic potential. The combination of these metabolites as a potential biomarker panel showed satisfactory performance in distinguishing infection groups from control groups as well as among different stages of infection.CONCLUSION: Our findings could provide valuable information for further understanding of the host response to Leishmania infection from the aspect of the urine metabolome. The proposed urine biomarker panel could help in the development of a novel approach for the diagnosis and prognosis of VL.PMID:37649093 | DOI:10.1186/s13071-023-05881-3

BMC Microbiol. 2023 Aug 30;23(1):242. doi: 10.1186/s12866-023-02993-9.ABSTRACTBACKGROUND: As substitutes for antibiotics, probiotic bacteria protect against digestive infections caused by pathogenic bacteria. Ligilactobacillus salivarius is a species of native lactobacillus found in both humans and animals. Herein, a swine-derived Ligilactobacillus salivarius was isolated and shown to colonize the ileal mucous membrane, thereby promoting nutritional digestion, absorption, and immunity. To evaluate its probiotic role, the entire genome was sequenced, the genetic information was annotated, and the metabolic information was analyzed.RESULTS: The phylogenetic relationship indicated that the bacteria was closer to L. salivarius MT573555.1 and MT585431.1. Functional genes included transporters, membrane proteins, enzymes, heavy metal resistance proteins, and putative proteins; metabolism-related genes were the most abundant. The six types of metabolic pathways secreted by L. salivarius were mainly composed of secretory transmembrane proteins and peptides. The secretory proteins of L. salivarius were digestive enzymes, functional proteins that regulate apoptosis, antibodies, and hormones. Non-targeted metabolomic analysis of L. salivarius metabolites suggested that ceramide, pyrrolidone- 5- carboxylic acid, N2-acetyl-L-ornithine, 2-ethyl-2-hydroxybutyric acid, N-lactoyl-phenylalanine, and 12 others were involved in antioxidation, repair of the cellular membrane, anticonvulsant, hypnosis, and appetite inhibition. Metabolites of clavaminic acid, antibiotic X14889C, and five other types of bacteriocins were identified, namely phenyllactic acid, janthitrem G, 13-demethyl tacrolimus, medinoside E, and tertonasin. The adherence and antioxidation of L. salivarius were also predicted. No virulence genes were found.CONCLUSION: The main probiotic properties of L. salivarius were identified using genomic, metabonomic, and biochemical assays, which are beneficial for porcine feeding. Our results provided deeper insights into the probiotic effects of L. salivarius.PMID:37648978 | DOI:10.1186/s12866-023-02993-9

Geroscience. 2023 Aug 30. doi: 10.1007/s11357-023-00918-y. Online ahead of print.ABSTRACTThe identification of metabolic biomarkers for aging-related diseases and mortality is of significant interest in the field of longevity. In this study, we investigated the associations between nuclear magnetic resonance (NMR) metabolomics biomarkers and aging-related diseases as well as mortality using the UK Biobank dataset. We analyzed NMR samples from approximately 110,000 participants and used multi-head machine learning classification models to predict the incidence of aging-related diseases. Cox regression models were then applied to assess the relevance of NMR biomarkers to the risk of death due to aging-related diseases. Additionally, we conducted survival analyses to evaluate the potential improvements of NMR in predicting survival and identify the biomarkers most strongly associated with negative health outcomes by dividing participants into health, disease, and death groups for all age groups. Our analysis revealed specific metabolomics profiles that were associated with the incidence of age-related diseases, and the most significant biomarker was intermediate density lipoprotein cholesteryl (IDL-CE). In addition, NMR biomarkers could provide additional contributions to relevant mortality risk prediction when combined with conventional risk factors, by improving the C-index from 0.813 to 0.833, with 17 NMR biomarkers significantly contributing to disease-related death, such as monounsaturated fatty acids (MUFA), linoleic acid (LA), glycoprotein acetyls (GlycA), and omega-3. Moreover, the value of free cholesterol in very large HDL particles (XL-HDL-FC) in the healthy control group demonstrated significantly higher values than the disease and death group across all age groups. This study highlights the potential of NMR metabolomics profiling as a valuable tool for identifying metabolic biomarkers associated with aging-related diseases and mortality risk, which could have practical implications for aging-related disease risk and mortality prediction.PMID:37648937 | DOI:10.1007/s11357-023-00918-y

Nature. 2023 Aug 30. doi: 10.1038/s41586-023-06483-w. Online ahead of print.ABSTRACTTissue resident memory CD8+ T (TRM) cells offer rapid and long-term protection at sites of reinfection1. Tumour-infiltrating lymphocytes with characteristics of TRM cells maintain enhanced effector functions, predict responses to immunotherapy and accompany better prognoses2,3. Thus, an improved understanding of the metabolic strategies that enable tissue residency by T cells could inform new approaches to empower immune responses in tissues and solid tumours. Here, to systematically define the basis for the metabolic reprogramming supporting TRM cell differentiation, survival and function, we leveraged in vivo functional genomics, untargeted metabolomics and transcriptomics of virus-specific memory CD8+ T cell populations. We found that memory CD8+ T cells deployed a range of adaptations to tissue residency, including reliance on non-steroidal products of the mevalonate-cholesterol pathway, such as coenzyme Q, driven by increased activity of the transcription factor SREBP2. This metabolic adaptation was most pronounced in the small intestine, where TRM cells interface with dietary cholesterol and maintain a heightened state of activation4, and was shared by functional tumour-infiltrating lymphocytes in diverse tumour types in mice and humans. Enforcing synthesis of coenzyme Q through deletion of Fdft1 or overexpression of PDSS2 promoted mitochondrial respiration, memory T cell formation following viral infection and enhanced antitumour immunity. In sum, through a systematic exploration of TRM cell metabolism, we reveal how these programs can be leveraged to fuel memory CD8+ T cell formation in the context of acute infections and enhance antitumour immunity.PMID:37648857 | DOI:10.1038/s41586-023-06483-w

Nature. 2023 Aug 30. doi: 10.1038/s41586-023-06466-x. Online ahead of print.ABSTRACTInsulin resistance is the primary pathophysiology underlying metabolic syndrome and type 2 diabetes1,2. Previous metagenomic studies have described the characteristics of gut microbiota and their roles in metabolizing major nutrients in insulin resistance3-9. In particular, carbohydrate metabolism of commensals has been proposed to contribute up to 10% of the host's overall energy extraction10, thereby playing a role in the pathogenesis of obesity and prediabetes3,4,6. Nevertheless, the underlying mechanism remains unclear. Here we investigate this relationship using a comprehensive multi-omics strategy in humans. We combine unbiased faecal metabolomics with metagenomics, host metabolomics and transcriptomics data to profile the involvement of the microbiome in insulin resistance. These data reveal that faecal carbohydrates, particularly host-accessible monosaccharides, are increased in individuals with insulin resistance and are associated with microbial carbohydrate metabolisms and host inflammatory cytokines. We identify gut bacteria associated with insulin resistance and insulin sensitivity that show a distinct pattern of carbohydrate metabolism, and demonstrate that insulin-sensitivity-associated bacteria ameliorate host phenotypes of insulin resistance in a mouse model. Our study, which provides a comprehensive view of the host-microorganism relationships in insulin resistance, reveals the impact of carbohydrate metabolism by microbiota, suggesting a potential therapeutic target for ameliorating insulin resistance.PMID:37648852 | DOI:10.1038/s41586-023-06466-x

Phytomedicine. 2023 Aug 16;120:155033. doi: 10.1016/j.phymed.2023.155033. Online ahead of print.ABSTRACTBACKGROUND: Hypertension is a serious global public health issue. Blood pressure (BP) is still not effectively controlled in about 20 - 30% of hypertensive patients. Therefore, it is imperative to develop new treatments for hypertension. Veratrum alkaloids were once used for the clinical treatment of hypertension, the mechanism of which is still unclear. It was gradually phased out due to adverse reactions.PURPOSE: This study aimed to investigate the short-term and long-term hypotensive profiles of different components of Veratrum alkaloids in spontaneously hypertensive rats (SHRs) to unveil their mechanisms of action.RESULTS: Total Veratrum alkaloid (V), component A (A), and veratramine (M) quickly decreased BP within 30 min of treatment, reduced renal and cardiovascular damage, and improved relevant biochemical indicators (nitric oxide [NO], endothelin-1 [ET-1], angiotensin II [Ang II)], noradrenaline [NE], etc) in SHRs to delay stroke occurrence. Thereinto, A exhibited excellent protective effects in cardiovascular disease. The metabolomic profiles of SHRs treated with V, A, and M were significantly different from those of SHRs treated with vehicle. Thirteen metabolites were identified as potential pharmacodynamic biomarkers. Through Kyoto Encyclopedia of Genes and Genomes analysis, V, A, and M-induced hypotension was mainly related to alterations in nicotinate and nicotinamide metabolism, GABAergic synapses, linoleic acid metabolism, ketone body synthesis and degradation, arginine and proline metabolism, and urea cycle, of which nicotinate and nicotinamide metabolism was the key metabolic pathway to relieve hypertension.CONCLUSION: This work shows that A is an effective and promising antihypertensive agent for hypertension treatment to reduce BP and hypertensive target organ damage, which is mainly mediated through modulating nicotinate and nicotinamide metabolism, RAS, and NO-ET homeostasis.PMID:37647672 | DOI:10.1016/j.phymed.2023.155033

J Sci Food Agric. 2023 Aug 30. doi: 10.1002/jsfa.12951. Online ahead of print.ABSTRACTBACKGROUND: The commercial value of red wine is strongly linked to the geographical origin. Given the large global market, there is great demand for high-throughput screening methods to authenticate the geographical source of red wine. However, only limited techniques have been established up to now.RESULTS: Herein, a sensitive and robust method, namely probe electrospray ionization mass spectrometry (μ-PESI-MS), was established to achieve the rapid analysis at approximately 1.2 mins/sample without any pretreatment. A scotch near the needle tip provides a fixed micro-volume for each analysis to achieve satisfactory ion signal reproducibility (RSD < 26.7%). In combining with machine learning algorithm, 16 characteristic ions were discovered from thousands detected ions and were utilized for differentiating the red wine origins. Among them, the relative abundances of two characteristic metabolites (trigonelline and proline) correlated to geographical conditions (sun exposure and water stress) were identified, providing the rationale for the differentiation of the geographical origins.CONCLUSION: The proposed μ-PESI-MS based method demonstrates promising high-throughput determination capability in red wine traceability. This article is protected by copyright. All rights reserved.PMID:37647550 | DOI:10.1002/jsfa.12951

Sci Adv. 2023 Sep;9(35):eadi4029. doi: 10.1126/sciadv.adi4029. Epub 2023 Aug 30.ABSTRACTThe metabolome is the biochemical basis of plant form and function, but we know little about its macroecological variation across the plant kingdom. Here, we used the plant functional trait concept to interpret leaf metabolome variation among 457 tropical and 339 temperate plant species. Distilling metabolite chemistry into five metabolic functional traits reveals that plants vary on two major axes of leaf metabolic specialization-a leaf chemical defense spectrum and an expression of leaf longevity. Axes are similar for tropical and temperate species, with many trait combinations being viable. However, metabolic traits vary orthogonally to life-history strategies described by widely used functional traits. The metabolome thus expands the functional trait concept by providing additional axes of metabolic specialization for examining plant form and function.PMID:37647404 | DOI:10.1126/sciadv.adi4029

Cell Rep. 2023 Aug 29;42(9):113043. doi: 10.1016/j.celrep.2023.113043. Online ahead of print.ABSTRACTThe malate-aspartate shuttle (MAS) is a redox shuttle that transports reducing equivalents across the inner mitochondrial membrane while recycling cytosolic NADH to NAD+. We genetically disrupted each MAS component to generate a panel of MAS-deficient HEK293 cell lines in which we performed [U-13C]-glucose tracing. MAS-deficient cells have reduced serine biosynthesis, which strongly correlates with the lactate M+3/pyruvate M+3 ratio (reflective of the cytosolic NAD+/NADH ratio), consistent with the NAD+ dependency of phosphoglycerate dehydrogenase in the serine synthesis pathway. Among the MAS-deficient cells, those lacking malate dehydrogenase 1 (MDH1) show the most severe metabolic disruptions, whereas oxoglutarate-malate carrier (OGC)- and MDH2-deficient cells are less affected. Increasing the NAD+-regenerating capacity using pyruvate supplementation resolves most of the metabolic disturbances. Overall, we show that the MAS is important for de novo serine biosynthesis, implying that serine supplementation could be used as a therapeutic strategy for MAS defects and possibly other redox disorders.PMID:37647199 | DOI:10.1016/j.celrep.2023.113043

J Plant Res. 2023 Aug 30. doi: 10.1007/s10265-023-01489-x. Online ahead of print.NO ABSTRACTPMID:37646870 | DOI:10.1007/s10265-023-01489-x