PubMed

Hypertension. 2023 May 10. doi: 10.1161/HYPERTENSIONAHA.123.20901. Online ahead of print.ABSTRACTBACKGROUND: The DASH (Dietary Approaches to Stop Hypertension) diets reduced blood pressure (BP) in the DASH and DASH-Sodium trials, but the underlying mechanisms are unclear. We identified metabolites associated with systolic BP or diastolic BP (DBP) changes induced by dietary interventions (DASH versus control arms) in 2 randomized controlled feeding studies-the DASH and DASH-Sodium trials.METHODS: Metabolomic profiling was conducted in serum and urine samples collected at the end of diet interventions: DASH (n=219) and DASH-Sodium (n=395). Using multivariable linear regression models, associations were examined between metabolites and change in systolic BP and DBP. Tested for interactions between diet interventions and metabolites were the following comparisons: (1) DASH versus control diets in the DASH trial (serum), (2) DASH high-sodium versus control high-sodium diets in the DASH-Sodium trial (urine), and (3) DASH low-sodium versus control high-sodium diets in the DASH-Sodium trial (urine).RESULTS: Sixty-five significant interactions were identified (DASH trial [serum], 12; DASH high sodium [urine], 35; DASH low sodium [urine], 18) between metabolites and systolic BP or DBP. In the DASH trial, serum tryptophan betaine was associated with reductions in DBP in participants consuming the DASH diets but not control diets (P interaction, 0.023). In the DASH-Sodium trial, urine levels of N-methylglutamate and proline derivatives (eg, stachydrine, 3-hydroxystachydrine, N-methylproline, and N-methylhydroxyproline) were associated with reductions in systolic BP or DBP in participants consuming the DASH diets but not control diets (P interaction, <0.05 for all tests).CONCLUSIONS: We identified metabolites that were associated with BP lowering in response to dietary interventions.REGISTRATION: URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT03403166 (DASH trial). URL: https://www.CLINICALTRIALS: gov; Unique identifier: NCT00000608 (DASH-Sodium trial).PMID:37161796 | DOI:10.1161/HYPERTENSIONAHA.123.20901

Diabetes Obes Metab. 2023 May 10. doi: 10.1111/dom.15104. Online ahead of print.ABSTRACTAIMS: To evaluate the associations of plasma bile acid metabolites, especially in early pregnancy, with gestational diabetes mellitus (GDM) risk among pregnant women.MATERIALS AND METHODS: Plasma concentrations of 15 bile acid metabolites were measured in 645 women at early pregnancy from the Jiashan Birth Cohort using a liquid chromatography-tandem mass spectrometry metabolomics platform. Using logistic and cubic spline models, we examined associations between baseline plasma bile acid metabolites and GDM risk during mid-late pregnancy. A meta-analysis of prospective studies of bile acid and GDM risk was performed.RESULTS: The linear and nonlinear univariate models identified eight metabolites associated with GDM, including cholic acid, taurocholic acid (TCA), glycocholic acid, glycochenodeoxycholic acid, deoxycholic acid, lithocholic acid (LCA), ursodeoxycholic acid and taurolithocholic acid (all P <0.05). Multivariable analysis indicated that TCA and LCA levels were positively (odds ratio [OR] 2.07, 95% confidential interval [CI] 1.05, 3.96; P = 0.030) and negatively (OR 0.83, 95% CI 0.68, 1.01; P = 0.065) associated with GDM, respectively, after adjusting for confounders. The TCA-GDM association showed a positive linear shaped relationship (OR 2.07, 95% CI 1.05, 3.96; P = 0.030); while LCA was negatively related with GDM risk in linearity (OR 0.83, 95% CI 0.68, 1.01; P = 0.065). The meta-analysis of five studies showed a consistent bile acid and GDM association, with a risk ratio (RR) of 2.43 (1.95, 3.03).CONCLUSIONS: This study indicated that, the levels of circulating bile acids in early pregnancy were associated with risk of GDM, independent of GDM risk factors. Most GDM-associated bile acids were primary conjugated and secondary unconjugated bile acids.PMID:37161712 | DOI:10.1111/dom.15104

Biomed Chromatogr. 2023 May 9:e5683. doi: 10.1002/bmc.5683. Online ahead of print.ABSTRACTRheumatoid arthritis (RA) is an autoimmune disease with a 0.5% prevalence worldwide. Inflammation, periosteal proliferation, and joint destruction are the main clinical symptoms of RA. Typhonii Rhizoma (TR) is the dry tuber of the Araceae plant Typhonium giganteum Engl, and possesses many uses such as dispelling obstructive wind-phlegm, and relieving pain. TR is used for the clinical treatment of arthromyodynia and RA. However, the mechanism of action remains unclear. In this study, we first evaluated the effects of TR in type II collagen-induced RA model rats. Secondly, in serum metabolomics, TR could ameliorate 11 potential metabolites in RA model rats and reversed RA through pentose and glucuronate interconversions, sphingolipid metabolism, glycerophospholipid metabolism, and tryptophan metabolism. To further explore the mechanisms of TR, 40 chemical constituents in TR were used to established a component-target interaction network. Some key genes were verified by in vitro pharmacological tests by integrating the results from the network pharmacology and metabolomics. The verification results showed that the mechanisms of TR against RA may be related to the inhibition of the production of inflammatory cytokines and the expression and function of HIF1-α. This study serves as a theoretical basis for the treatment of RA with TR.PMID:37161606 | DOI:10.1002/bmc.5683

J Exp Clin Cancer Res. 2023 May 10;42(1):118. doi: 10.1186/s13046-023-02686-1.ABSTRACTBACKGROUND: The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic.METHODS: Syngeneic G422TN-GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422TN-GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action.RESULTS: Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422TN) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422TN-tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422TN-mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3+/CD4+/CD8+ T-lymphocytes in G422TN-tumor on the basis of RT/TMZ regimen.CONCLUSION: Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials.PMID:37161450 | DOI:10.1186/s13046-023-02686-1

BMC Plant Biol. 2023 May 10;23(1):245. doi: 10.1186/s12870-023-04258-z.ABSTRACTBACKGROUND: Cotton is an important industrial crop and a pioneer crop for saline-alkali land restoration. However, the molecular mechanism underlying the cotton response to salt is not completely understood.METHODS: Here, we used metabolome data and transcriptome data to analyze the salt tolerance regulatory network of cotton and metabolic biomarkers.RESULTS: In this study, cotton was stressed at 400 m M NaCl for 0 h, 3 h, 24 h and 48 h. NaCl interfered with cotton gene expression, altered metabolite contents and affected plant growth. Metabolome analysis showed that NaCl stress increased the contents of amino acids, sugars and ABA, decreased the amount of vitamin and terpenoids. K-means cluster analysis of differentially expressed genes showed that the continuously up-regulated genes were mainly enriched in metabolic pathways such as flavonoid biosynthesis and amino acid biosynthesis.CONCLUSION: The four metabolites of cysteine (Cys), ABA(Abscisic acid), turanose, and isopentenyladenine-7-N-glucoside (IP7G) were consistently up-regulated under salt stress, which may indicate that they are potential candidates for cotton under salt stress biomarkers. Combined transcriptome and metabolome analysis revealed accumulation of cysteine, ABA, isopentenyladenine-7-N-glucoside and turanose were important for salt tolerance in cotton mechanism. These results will provide some metabolic insights and key metabolite biomarkers for salt stress tolerance, which may help to understanding of the metabolite response to salt stress in cotton and develop a foundation for cotton to grow better in saline soil.PMID:37161359 | DOI:10.1186/s12870-023-04258-z

Oncogene. 2023 May 9. doi: 10.1038/s41388-023-02703-9. Online ahead of print.ABSTRACTVimentin is highly expressed in metastatic cancers, and its expression correlates with poor patient prognoses. However, no causal in vivo studies linking vimentin and non-small cell lung cancer (NSCLC) progression existed until now. We use three complementary in vivo models to show that vimentin is required for the progression of NSCLC. First, we crossed LSL-KrasG12D; Tp53fl/fl mice (KPV+/+) with vimentin knockout mice (KPV-/-) to demonstrate that KPV-/- mice have attenuated tumor growth and improved survival compared with KPV+/+ mice. Next, we therapeutically treated KPV+/+ mice with withaferin A (WFA), an agent that disrupts vimentin intermediate filaments (IFs). We show that WFA suppresses tumor growth and reduces tumor burden in the lung. Finally, luciferase-expressing KPV+/+, KPV-/-, or KPVY117L cells were implanted into the flanks of athymic mice to track cancer metastasis to the lung. In KPVY117L cells, vimentin forms oligomers called unit-length filaments but cannot assemble into mature vimentin IFs. KPV-/- and KPVY117L cells fail to metastasize, suggesting that cell-autonomous metastasis requires mature vimentin IFs. Integrative metabolomic and transcriptomic analysis reveals that KPV-/- cells upregulate genes associated with ferroptosis, an iron-dependent form of regulated cell death. KPV-/- cells have reduced glutathione peroxidase 4 (GPX4) levels, resulting in the accumulation of toxic lipid peroxides and increased ferroptosis. Together, our results demonstrate that vimentin is required for rapid tumor growth, metastasis, and protection from ferroptosis in NSCLC.PMID:37161053 | DOI:10.1038/s41388-023-02703-9

Sci Rep. 2023 May 9;13(1):7489. doi: 10.1038/s41598-023-34593-y.ABSTRACTSample preparation in untargeted metabolomics should allow reproducible extractions of as many molecules as possible. Thus, optimizing sample preparation is crucial. This study compared six different extraction procedures to find the most suitable for extracting zebrafish larvae in the context of an infection model. Two one-phase extractions employing methanol (I) and a single miscible phase of methanol/acetonitrile/water (II) and two two-phase methods using phase separation between chloroform and methanol/water combinations (III and IV) were tested. Additional bead homogenization was used for methods III and IV (III_B and IV_B). Nine internal standards and 59 molecules of interest (MoInt) related to mycobacterial infection were used for method evaluation. Two-phase methods (III and IV) led to a lower feature count, higher peak areas of MoInt, especially amino acids, and higher coefficients of variation in comparison to one-phase extractions. Adding bead homogenization increased feature count, peak areas, and CVs. Extraction I showed higher peak areas and lower CVs than extraction II, thus being the most suited one-phase method. Extraction III and IV showed similar results, with III being easier to execute and less prone to imprecisions. Thus, for future applications in zebrafish larvae metabolomics and infection models, extractions I and III might be chosen.PMID:37161044 | DOI:10.1038/s41598-023-34593-y

Nat Commun. 2023 May 9;14(1):2682. doi: 10.1038/s41467-023-38072-w.ABSTRACTFormate can be envisioned at the core of a carbon-neutral bioeconomy, where it is produced from CO2 by (electro-)chemical means and converted into value-added products by enzymatic cascades or engineered microbes. A key step in expanding synthetic formate assimilation is its thermodynamically challenging reduction to formaldehyde. Here, we develop a two-enzyme route in which formate is activated to formyl phosphate and subsequently reduced to formaldehyde. Exploiting the promiscuity of acetate kinase and N-acetyl-γ-glutamyl phosphate reductase, we demonstrate this phosphate (Pi)-based route in vitro and in vivo. We further engineer a formyl phosphate reductase variant with improved formyl phosphate conversion in vivo by suppressing cross-talk with native metabolism and interface the Pi route with a recently developed formaldehyde assimilation pathway to enable C2 compound formation from formate as the sole carbon source in Escherichia coli. The Pi route therefore offers a potent tool in expanding the landscape of synthetic formate assimilation.PMID:37160875 | DOI:10.1038/s41467-023-38072-w

J Infect Dev Ctries. 2023 Apr 30;17(4):507-517. doi: 10.3855/jidc.16921.ABSTRACTINTRODUCTION: This present study aimed to isolate beneficial bacteria from honey bee pollen microbiota and to investigate the metabolite profiles of postbiotics exhibiting anti-microbial and anti-oxidant properties.METHODOLOGY: Pour plate technique was used to isolate bacteria from honey bee (Apis mellifera L.) pollen samples. Different colonies grown on agar plates were selected and screened for their anti-microbial activity against important pathogens using agar well diffusion assay. The isolates that exhibited remarkable inhibitory effects against all tested pathogens were identified by 16S rRNA sequence analysis. DPPH (2, 2-diphenyl-1-picrylhydrazil) free radical scavenging assays were used to assess the antioxidant capacity of their postbiotics. Besides, the total phenolic and total flavonoid compounds in postbiotics were determined as gallic acid and quercetin equivalents, respectively. The valuable metabolites in postbiotics were also profiled using chromatographic tools and Mass Spectrophotometry (MS) analysis.RESULTS: Twenty-seven strains were isolated from different honey bee pollen samples. 16 out of the 27 strains exhibited antagonistic activity against at least one reference strain of pathogens, tested. The most effective strains belonging to the genus Weissella were identified as W. cibaria and W. confusa. Postbiotics above 10 mg/mL exhibited higher radical scavenging activity and high total phenolic and total flavonoid contents. MS analysis demonstrated that metabolites in postbiotics derived from Weissella spp. were found very similar to the metabolites found in honeybee pollen.CONCLUSIONS: The outcomes of this study revealed that honey bee pollen could be considered a potential source for the bacteria which produce anti-microbial and anti-oxidant agents. The similarity with the nutritional dynamics of honey bee pollen also indicated that postbiotics could also be used as novel and sustainable food supplements.PMID:37159891 | DOI:10.3855/jidc.16921

Pest Manag Sci. 2023 May 9. doi: 10.1002/ps.7534. Online ahead of print.ABSTRACTBACKGROUND: Thiamethoxam (TMX) is insecticidal, but also can trigger physiological and metabolic reactions of plant cycles. The objective of this work was to evaluate the physiological and metabolic effect of TMX on tea plant and its potential benefits.RESULTS: In this study, dose of TMX (0.09, 0.135 and 0.18 kg a.i./ha) were tested. Except for peroxidase (POD) and glutathione S-transferase (GST), chlorophyll, carotenoid, catalase (CAT) and malondialdehyde (MDA) were significantly affected compared with the controls. The CAT activity was increased by 3.38, 1.71, 2.91 times respectively under 3 doses of TMX treatment. The metabolic response between TMX treatment and control groups on the 3rd day was compared using a widely targeted metabolomics. A total of 97 different metabolites were identified, including benzenoids, flavonoids, lipids and lipid-like molecules, organic acids and derivatives, organic nitrogen compounds, organic oxygen compounds, organoheterocyclic compounds, phenylpropanoids and polyketides, and others. Those metabolites were mapped on the perturbed metabolic pathways. The results demonstrated that the most perturbation occurred in flavone and flavonol biosynthesis. The beneficial secondary metabolites luteolin and kaempferol were upregulated 1.46 and 1.31 times respectively, which protect plants from biotic and abiotic stresses. Molecular docking models suggest interactions between TMX and flavonoid 3-O glucosyltransferase.CONCLUSION: Thiamethoxam spray positively promoted the physiological and metabolic response of tea plant. And this work also provided the useful information of TMX metabolism in tea plants as well as rational application of insecticides.PMID:37160655 | DOI:10.1002/ps.7534

Cell Rep Methods. 2023 Apr 18;3(4):100455. doi: 10.1016/j.crmeth.2023.100455. eCollection 2023 Apr 24.ABSTRACTBrain glucose metabolism is highly heterogeneous among brain regions and continues postmortem. In particular, we demonstrate exhaustion of glycogen and glucose and an increase in lactate production during conventional rapid brain resection and preservation by liquid nitrogen. In contrast, we show that these postmortem changes are not observed with simultaneous animal sacrifice and in situ fixation with focused, high-power microwave. We further employ microwave fixation to define brain glucose metabolism in the mouse model of streptozotocin-induced type 1 diabetes. Using both total pool and isotope tracing analyses, we identified global glucose hypometabolism in multiple brain regions, evidenced by reduced 13C enrichment into glycogen, glycolysis, and the tricarboxylic acid (TCA) cycle. Reduced glucose metabolism correlated with a marked decrease in GLUT2 expression and several metabolic enzymes in unique brain regions. In conclusion, our study supports the incorporation of microwave fixation for more accurate studies of brain metabolism in rodent models.PMID:37159672 | PMC:PMC10163000 | DOI:10.1016/j.crmeth.2023.100455

J Agric Food Chem. 2023 May 9. doi: 10.1021/acs.jafc.2c09013. Online ahead of print.ABSTRACTWhen bushfires occur near wine regions, vineyards are frequently exposed to environmental smoke, which can negatively affect grapes and wine. For evaluating the severity of smoke exposure, volatile phenols and their glycosides are commonly used as biomarkers of smoke exposure. While critical to refining smoke taint diagnostics, few studies have comprehensively assessed the compositional impact of smoke exposure of grapes. In this study, Merlot grapevines were exposed to smoke post-véraison, with grapes being sampled both pre-smoke exposure and repeatedly post-smoke exposure, for analysis by liquid chromatography-high-resolution mass spectrometry. Volatile phenol glycosides were detected in control and smoke-affected grapes at ≤22 μg/kg and up to 160 μg/kg, respectively. The metabolite profiles of control and smoke-affected grapes were then compared using an untargeted metabolomics approach and compounds differentiating the sample types tentatively identified. The results demonstrate the presence of novel phenolic glycoconjugates as putative metabolites from environmental smoke together with stress-related grapevine metabolites and highlight the need to further characterize the consequences of grapevine smoke exposure with respect to the regulation of abiotic stress and plant defense mechanisms.PMID:37159503 | DOI:10.1021/acs.jafc.2c09013

J Agric Food Chem. 2023 May 9. doi: 10.1021/acs.jafc.3c00850. Online ahead of print.ABSTRACTCadmium (Cd) pollution reduces rice production and quality, putting food security and human health at risk. We conducted comparative physiology and metabolomic analyses in two indica rice ('NH199' and 'NH224') to elucidate the Cd-tolerance mechanism. Cd hampered rice growth, induced oxidative stress, and changed the metabolomics profiling of the root. The biochemical and physiological analysis demonstrated that NH224 exhibited a more potent Cd-tolerance ability than NH199. Cd was primarily distributed in root, and NH224 had a lower Cd translocation factor than NH199 by about 24%. The metabolomic analysis revealed 180 and 177 differentially accumulated metabolites between Cd-stressed seedlings and the controls in NH224 and NH199, respectively. In NH224, amino acids biosynthesis, hormone metabolism, lipids-related metabolism, phenylalanine metabolism, and phenylpropanoid biosynthesis pathways were more active and highly associated with antioxidant defense system, biosynthesis of the cell wall and phytochelatins, and maintenance of plasma membrane stability. These findings provide insights into the metabolic profiles of rice following Cd stress and the screening and breeding of Cd-tolerant rice varieties.PMID:37159413 | DOI:10.1021/acs.jafc.3c00850

JCI Insight. 2023 May 9:e167274. doi: 10.1172/jci.insight.167274. Online ahead of print.ABSTRACTBACKGROUND: Current studies suggest mitochondrial dysfunction is a major contributor to impaired physical performance and exercise intolerance in chronic kidney disease (CKD). We conducted a clinical trial of coenzyme Q10 (CoQ10) and nicotinamide riboside (NR) to determine their impact on exercise tolerance and metabolic profile in CKD patients.METHODS: We conducted a randomized placebo-controlled, double blind, cross-over trial comparing CoQ10, NR, and placebo in 25 patients with eGFR of <60ml/min/1.73m2. Subjects received NR (1000 mg/day), CoQ10 (1200 mg/day), or placebo for 6 weeks each. Primary outcomes were aerobic capacity (VO2 peak) and work efficiency measured using graded cycle ergometry testing. We performed semi-targeted plasma metabolomics and lipidomics.RESUTS: Participant mean age was 61.0 ± 11.6 years and mean eGFR was 36.9±9.2 ml/min/1.73m2. Compared to placebo, we found no differences in VO2 peak (P=0.30, 0.17), total work (P=0.47, 0.77), and total work efficiency (P=0.46, 0.55) post NR or CoQ10 supplementation. NR decreased submaximal VO2 at 30W (P=0.03) and VO2 at 60W (P=0.07) compared to placebo. No changes in eGFR were observed post-NR or CoQ10 (P=0.14, 0.88). CoQ10 increased free fatty acids and decreased complex medium/long chain triglycerides. NR supplementation significantly altered TCA cycle intermediates and glutamate that are involved in reactions that exclusively use NAD+ and NADP+ as cofactors. NR decreased a broad range of lipid groups including triglycerides and ceramides.CONCLUSIONS: Six-weeks of treatment with NR or CoQ10 improved markers of systemic mitochondrial metabolism and lipid profiles but did not improve VO2 peak or total work efficiency.CLINICALTRIALS: gov (NCT03579693)FUNDING. This study was supported by National Institutes of Diabetes and Digestive Kidney Diseases R01 DK101509 (to BK), R03 DK114502 (to BR), R01 DK125794 (to BR), R01 DK101509 (to JG), Dialysis Clinics Incorporated C-4112 (to BR), Northern California VA Health Care System (BR).PMID:37159264 | DOI:10.1172/jci.insight.167274

Microbiome. 2023 May 8;11(1):100. doi: 10.1186/s40168-023-01518-w.ABSTRACTBACKGROUND AND AIMS: The gut microbiota is implicated in the pathogenesis of colorectal cancer (CRC). We aimed to map the CRC mucosal microbiota and metabolome and define the influence of the tumoral microbiota on oncological outcomes.METHODS: A multicentre, prospective observational study was conducted of CRC patients undergoing primary surgical resection in the UK (n = 74) and Czech Republic (n = 61). Analysis was performed using metataxonomics, ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), targeted bacterial qPCR and tumour exome sequencing. Hierarchical clustering accounting for clinical and oncological covariates was performed to identify clusters of bacteria and metabolites linked to CRC. Cox proportional hazards regression was used to ascertain clusters associated with disease-free survival over median follow-up of 50 months.RESULTS: Thirteen mucosal microbiota clusters were identified, of which five were significantly different between tumour and paired normal mucosa. Cluster 7, containing the pathobionts Fusobacterium nucleatum and Granulicatella adiacens, was strongly associated with CRC (PFDR = 0.0002). Additionally, tumoral dominance of cluster 7 independently predicted favourable disease-free survival (adjusted p = 0.031). Cluster 1, containing Faecalibacterium prausnitzii and Ruminococcus gnavus, was negatively associated with cancer (PFDR = 0.0009), and abundance was independently predictive of worse disease-free survival (adjusted p = 0.0009). UPLC-MS analysis revealed two major metabolic (Met) clusters. Met 1, composed of medium chain (MCFA), long-chain (LCFA) and very long-chain (VLCFA) fatty acid species, ceramides and lysophospholipids, was negatively associated with CRC (PFDR = 2.61 × 10-11); Met 2, composed of phosphatidylcholine species, nucleosides and amino acids, was strongly associated with CRC (PFDR = 1.30 × 10-12), but metabolite clusters were not associated with disease-free survival (p = 0.358). An association was identified between Met 1 and DNA mismatch-repair deficiency (p = 0.005). FBXW7 mutations were only found in cancers predominant in microbiota cluster 7.CONCLUSIONS: Networks of pathobionts in the tumour mucosal niche are associated with tumour mutation and metabolic subtypes and predict favourable outcome following CRC resection. Video Abstract.PMID:37158960 | DOI:10.1186/s40168-023-01518-w

BMC Med. 2023 May 9;21(1):176. doi: 10.1186/s12916-023-02886-8.ABSTRACTBACKGROUND: Childhood obesity is a global health concern and can lead to lifetime cardiometabolic disease. New advances in metabolomics can provide biochemical insights into the early development of obesity, so we aimed to characterize serum metabolites associated with overweight and adiposity in early childhood and to stratify associations by sex.METHODS: Nontargeted metabolite profiling was conducted in the Canadian CHILD birth cohort (discovery cohort) at age 5 years (n = 900) by multisegment injection-capillary electrophoresis-mass spectrometry. Clinical outcome was defined using novel combined measures of overweight (WHO-standardized body mass index ≥ 85th percentile) and/or adiposity (waist circumference ≥ 90th percentile). Associations between circulating metabolites and child overweight/adiposity (binary and continuous outcomes) were determined by multivariable linear and logistic regression, adjusting for covariates and false discovery rate, and by subsequent sex-stratified analysis. Replication was assessed in an independent replication cohort called FAMILY at age 5 years (n = 456).RESULTS: In the discovery cohort, each standard deviation (SD) increment of branched-chain and aromatic amino acids, glutamic acid, threonine, and oxoproline was associated with 20-28% increased odds of overweight/adiposity, whereas each SD increment of the glutamine/glutamic acid ratio was associated with 20% decreased odds. All associations were significant in females but not in males in sex-stratified analyses, except for oxoproline that was not significant in either subgroup. Similar outcomes were confirmed in the replication cohort, where associations of aromatic amino acids, leucine, glutamic acid, and the glutamine/glutamic acid ratio with childhood overweight/adiposity were independently replicated.CONCLUSIONS: Our findings show the utility of combining measures of both overweight and adiposity in young children. Childhood overweight/adiposity at age 5 years has a specific serum metabolic phenotype, with the profile being more prominent in females compared to males.PMID:37158942 | DOI:10.1186/s12916-023-02886-8

J Anim Sci Biotechnol. 2023 May 9;14(1):63. doi: 10.1186/s40104-023-00862-z.ABSTRACTBACKGROUND: Dairy cows' lactation performance is the outcome of the crosstalk between ruminal microbial metabolism and host metabolism. However, it is still unclear to what extent the rumen microbiome and its metabolites, as well as the host metabolism, contribute to regulating the milk protein yield (MPY).METHODS: The rumen fluid, serum and milk of 12 Holstein cows with the same diet (45% coarseness ratio), parity (2-3 fetuses) and lactation days (120-150 d) were used for the microbiome and metabolome analysis. Rumen metabolism (rumen metabolome) and host metabolism (blood and milk metabolome) were connected using a weighted gene co-expression network (WGCNA) and the structural equation model (SEM) analyses.RESULTS: Two different ruminal enterotypes, with abundant Prevotella and Ruminococcus, were identified as type1 and type2. Of these, a higher MPY was found in cows with ruminal type2. Interestingly, [Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae (the differential bacteria) were the hub genera of the network. In addition, differential ruminal, serum and milk metabolome between enterotypes were identified, where the cows with type2 had higher L-tyrosine of rumen, ornithine and L-tryptophan of serum, and tetrahydroneopterin, palmitoyl-L-carnitine, S-lactoylglutathione of milk, which could provide more energy and substrate for MPY. Further, based on the identified modules of ruminal microbiome, as well as ruminal serum and milk metabolome using WGCNA, the SEM analysis indicated that the key ruminal microbial module1, which contains the hub genera of the network ([Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae) and high abundance of bacteria (Prevotella and Ruminococcus), could regulate the MPY by module7 of rumen, module2 of blood, and module7 of milk, which contained L-tyrosine and L-tryptophan. Therefore, in order to more clearly reveal the process of rumen bacterial regulation of MPY, we established the path of SEM based on the L-tyrosine, L-tryptophan and related components. The SEM based on the metabolites suggested that [Ruminococcus] gauvreauii group could inhibit the energy supply of serum tryptophan to MPY by milk S-lactoylglutathione, which could enhance pyruvate metabolism. Norank_f_Ruminococcaceae could increase the ruminal L-tyrosine, which could provide the substrate for MPY.CONCLUSION: Our results indicated that the represented enterotype genera of Prevotella and Ruminococcus, and the hub genera of [Ruminococcus] gauvreauii group and norank_f_Ruminococcaceae could regulate milk protein synthesis by affecting the ruminal L-tyrosine and L-tryptophan. Moreover, the combined analysis of enterotype, WGCNA and SEM could be used to connect rumen microbial metabolism with host metabolism, which provides a fundamental understanding of the crosstalk between host and microorganisms in regulating the synthesis of milk composition.PMID:37158919 | DOI:10.1186/s40104-023-00862-z

Elife. 2023 May 9;12:e85307. doi: 10.7554/eLife.85307. Online ahead of print.ABSTRACTBackground: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism.Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins.Results: CSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis.Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy.Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).PMID:37158692 | DOI:10.7554/eLife.85307

Food Funct. 2023 May 9. doi: 10.1039/d2fo03224d. Online ahead of print.ABSTRACTThe abnormal accumulation of fused in sarcoma (FUS) is a pathological hallmark in a proportion of patients with frontotemporal dementia and amyotrophic lateral sclerosis. Therefore, the clearance of FUS aggregates is a possible therapeutic strategy for FUS-associated neurodegenerative diseases. This study reports that curcumin can strongly suppress FUS droplet formation and stress granule aggregation of FUS. Fluorescence spectra and isothermal titration calorimetry showed that curcumin can bind FUS through hydrophobic interactions, thereby reducing the β-sheet content of FUS. Aggregated FUS sequesters pyruvate kinase, leading to reduced ATP levels. However, results from a metabolomics study revealed that curcumin changed the metabolism pattern and differentially expressed metabolites were enriched in glycolysis. Curcumin attenuated FUS aggregation-mediated sequestration of pyruvate kinase and restored cellular metabolism, consequently increasing ATP levels. These results indicate that curcumin is a potent inhibitor of FUS liquid-liquid phase separation and provide novel insights into the effect of curcumin in ameliorating abnormal metabolism.PMID:37158592 | DOI:10.1039/d2fo03224d

Mol Omics. 2023 May 9. doi: 10.1039/d2mo00317a. Online ahead of print.ABSTRACTInfrared spectroscopy is a crucial tool to achieve the origin traceability of rice, but it is constrained by data mining. In this study, a novel infrared spectroscopy-based metabolomics analytical method was proposed to discriminate rice products from 14 Chinese cities by seeking 'wave number markers'. Principal component analysis (PCA), cluster analysis and orthogonal partial least squares discriminant analysis (OPLS-DA) were employed to separate all rice groups. The S-plot, permutation test and variable importance in projection (VIP) are used to screen eligible 'markers', which were further verified by a pairwise t-test. There are 55-265 'markers' picked out from 14 rice groups, with their characteristic wave number bands to be 2935.658-3238.482, 3851.846-4000.364, 3329.136-3518.160, 1062.778-1213.225, 1161.147-1386.819, 3348.425-3560.594, 3115.038-3624.245, 2567.254-2872.007, 3334.923-3560.594, 3282.845-3543.235, 3338.780-3518.160, 3197.977-3560.594, 3163.258-3267.414 and 3292.489-3477.655 cm-1, respectively. All but No. 5 rice groups show significantly low absorbance on their 'marker' bands. A mixed rice containing congenial No. 5 and No. 6 rice (80 : 20, m/m) was employed to test the validity of the method, and found that the 'marker' band of the mixed rice is the range of 1170.791-1338.598 cm-1, implying the existence of considerable discrepancy between the mixed rice and other rice. The results indicate that infrared spectroscopy coupled with metabolomics analysis is competent for origin traceability of rice; thus, it provides a novel and workable approach for the accurate and rapid discrimination of rice from different geographical origins, and a distinctive perspective of metabolomics to explore infrared spectroscopy and beyond, especially not confined in the field of origin traceability.PMID:37158208 | DOI:10.1039/d2mo00317a