PubMed

Am J Physiol Gastrointest Liver Physiol. 2023 May 2. doi: 10.1152/ajpgi.00017.2023. Online ahead of print.ABSTRACTThe use of probiotics, prebiotics and synbiotics has become an important therapy in numerous gastrointestinal diseases in recent years. Modifying the gut microbiota, this therapeutic approach helps to restore a healthy microbiome. Nonalcoholic fatty liver disease and alcohol-associated liver disease are among the leading causes of chronic liver disease worldwide. A disrupted intestinal barrier, microbial translocation and an altered gut microbiome metabolism, or metabolome, are crucial in the pathogenesis of these chronic liver diseases. As pro-, pre- and synbiotics modulate these targets, they were identified as possible new treatment options in liver disease. In this review, we highlight the current findings on clinical and mechanistic effects of this therapeutic approach in nonalcoholic fatty liver disease and alcohol-associated liver disease.PMID:37129252 | DOI:10.1152/ajpgi.00017.2023

J Proteome Res. 2023 May 2. doi: 10.1021/acs.jproteome.2c00430. Online ahead of print.ABSTRACTGestational Diabetes Mellitus (GDM) results in complications affecting both mothers and their offspring. Metabolomic analysis across pregnancy provides an opportunity to better understand GDM pathophysiology. The objective was to conduct a metabolomics analysis of first and third trimester plasma samples to identify metabolic differences associated with GDM development. Forty pregnant women with overweight/obesity from a multisite clinical trial of a lifestyle intervention were included. Participants who developed GDM (n = 20; GDM group) were matched with those who did not develop GDM (n = 20; Non-GDM group). Plasma samples collected at the first (10-16 weeks) and third (28-35 weeks) trimesters were analyzed with ultra-performance liquid chromatography-mass spectrometry (UPLC-MS). Cardiometabolic risk markers, dietary recalls, and physical activity metrics were also assessed. Four medium-chain acylcarnitines, lauroyl-, octanoyl-, decanoyl-, and decenoylcarnitine, significantly differed over the course of pregnancy in the GDM vs Non-GDM group in a group-by-time interaction (p < 0.05). Hypoxanthine and inosine monophosphate were elevated in the GDM group (p < 0.04). In both groups over time, bile acids and sorbitol increased while numerous acylcarnitines and α-hydroxybutyrate decreased (p < 0.05). Metabolites involved in fatty acid oxidation and purine degradation were altered across the first and third trimesters of GDM-affected pregnancies, providing insight into metabolites and metabolic pathways altered with GDM development.PMID:37129248 | DOI:10.1021/acs.jproteome.2c00430

Anal Chem. 2023 May 2. doi: 10.1021/acs.analchem.2c05783. Online ahead of print.ABSTRACTAs metabolomics grows into a high-throughput and high demand research field, current metrics for the identification of small molecules in gas chromatography-mass spectrometry (GC-MS) still require manual verification. Though steps have been taken to improve scoring metrics by combining spectral similarity (SS) and retention index (RI), the problem persists. A large body of literature has analyzed and refined SS scores, but few studies have explicitly studied improvements to RI scores. Here, we examined whether uninvestigated assumptions of the RI score are valid and propose ways to improve them. Query RIs were matched to library RI with a generous window of ±35 to avoid unintentional removal of valid compound identifications. Each match was manually verified as a true positive (TP), true negative, or unknown. Metabolites with at least 30 TP identifications were included in downstream analyses, resulting in a total of 87 metabolites from samples of varying complexity and type (e.g., amino acid mixtures, human urine, fungal species, and so on.). Our results showed that the RI score assumptions of normality, consistent variance across metabolites, and a mean error centered at 0 are often violated. We demonstrated through a cross-validation analysis that modifying these underlying assumptions according to empirical metabolite-specific distributions improved the TP and negative rankings. Further, we statistically determined the minimum number of samples required to estimate distributional parameters for scoring metrics. Overall, this work proposes a robust statistical pipeline to reduce the time bottleneck of metabolite identification by improving RI scores and thus minimize the effort to complete manual verification.PMID:37129113 | DOI:10.1021/acs.analchem.2c05783

Phytochem Anal. 2023 May 2. doi: 10.1002/pca.3229. Online ahead of print.ABSTRACTINTRODUCTION: Natural products and metabolomics are intrinsically linked through efforts to analyze complex mixtures for compound annotation. Although most studies that aim for compound identification in mixtures use MS as the main analysis technique, NMR has complementary advances that are worth exploring for enhanced structural confidence.OBJECTIVE: This review aimed to showcase a portfolio of the main tools available for compound identification using NMR.MATERIALS AND METHODS: COLMAR, SMART-NMR, MADByTE, and NMRfilter are presented using examples collected from real samples from the perspective of a natural product chemist. Data are also made available through Zenodo so that readers can test each case presented here.CONCLUSION: The acquisition of 1 H NMR, HSQC, TOCSY, HSQC-TOCSY, and HMBC data for all samples and fractions from a natural products study is strongly suggested. The same is valid for MS analysis to create a bridged analysis between both techniques in a complementary manner. The use of NOAH supersequences has also been suggested and demonstrated to save NMR time.PMID:37128872 | DOI:10.1002/pca.3229

Exp Physiol. 2023 May 1. doi: 10.1113/EP091127. Online ahead of print.NO ABSTRACTPMID:37128718 | DOI:10.1113/EP091127

Biotechnol J. 2023 May 1:e2300052. doi: 10.1002/biot.202300052. Online ahead of print.ABSTRACTIn order to find a more effective way to obtain docosahexaenoic acid (DHA) rich lipid from Schizochytrium sp., a widespread propionate wastewater (PW) is used. PW is a common industrial and domestic wastewater, and transforming it into valuable products is a potential treatment method. Schizochytrium sp. is a rapidly growing oleaginous organism, which has been used commercially for DHA production. Herein, PW is completely used for DHA production by Schizochytrium sp. by genetic engineering and fermentation optimization, which can alleviate the increasingly tense demand for water resources and environmental pollution caused by industrial wastewater. Firstly, the methylmalonyl-CoA mutase (MCM) was overexpressed in Schizochytrium sp. to enhance the metabolism of propionate, then the engineered strain of OMCM can effectively use propionate. Then, the effects of PW with different concentration of propionate were investigated, and results showed that OMCM can completely replace clean water with PW containing 5 g/L propionate. Furthermore, in the fed-batch fermentation, the OMCM obtained the highest biomass of 113.4 g/L and lipid yield of 64.4 g/L in PW condition, which is 26.8% and 51.7% higher than that of WT in PW condition. Moreover, to verify why overexpression of MCM can promote DHA and lipid accumulation, the comparative metabolomics, ATP production level, the antioxidant system, and the transcription of key genes were investigated. Results showed that ATP induced by PW condition could drive the synthesis of DHA, and remarkably improve the antioxidant capacity of cells by enhancing the carotenoids production. Therefore, PW can be used as an effective and economical substrate and water source for Schizochytrium sp. to accumulate biomass and DHA. This article is protected by copyright. All rights reserved.PMID:37128672 | DOI:10.1002/biot.202300052

iScience. 2023 Apr 6;26(5):106578. doi: 10.1016/j.isci.2023.106578. eCollection 2023 May 19.ABSTRACTCaloric deprivation interventions such as intermittent fasting and caloric restriction ameliorate metabolic and inflammatory disease. As a human model of caloric deprivation, a 24-h fast blunts innate and adaptive immune cell responsiveness relative to the refed state. Isolated serum at these time points confers these same immunomodulatory effects on transformed cell lines. To identify serum mediators orchestrating this, metabolomic and lipidomic analysis was performed on serum extracted after a 24-h fast and re-feeding. Bioinformatic integration with concurrent peripheral blood mononuclear cells RNA-seq analysis implicated key metabolite-sensing GPCRs in fasting-mediated immunomodulation. The putative GPR18 ligand N-arachidonylglycine (NAGly) was elevated during fasting and attenuated CD4+T cell responsiveness via GPR18 MTORC1 signaling. In parallel, NAGly reduced inflammatory Th1 and Th17 cytokines levels in CD4+T cells isolated from obese subjects, identifying a fasting-responsive metabolic intermediate that may contribute to the regulation of nutrient-level dependent inflammation associated with metabolic disease.PMID:37128607 | PMC:PMC10148119 | DOI:10.1016/j.isci.2023.106578

Heliyon. 2023 Apr 17;9(4):e15573. doi: 10.1016/j.heliyon.2023.e15573. eCollection 2023 Apr.ABSTRACTThe regulation of sugar and organic acid metabolism during fruit development has a major effect on high-quality fruit production. The reduction of leaf area is a common feature in plant growth, induced by abiotic and biotic stresses and disturbing source/sink ratio, thus impacting fruit quality. Here, we induced carbohydrate limitation by partial leaf defoliation at the beginning of the second stage of mandarin development (before the citrate peak). Resulting changes were monitored in the short-term (48 h and 1 week) and long-term (7 weeks) after the defoliation. Short-term response to early defoliation implied metabolic settings to re-feed TCA for sustaining respiration rate. These features involved (i) vacuolar sucrose degradation (high acid invertase activity and mRNA expression level) and enhanced glycolytic flux (high ATP-phosphofructokinase activity), (ii) malic and citric acid utilization (increased phosphoenolpyruvate kinase and NADP-Isocitrate dehydrogenase) associated with vacuolar citric acid release (high mRNA expression of the transporter CsCit1) and (iii) stimulation of GABA shunt pathway (low GABA content and increased mRNA expression of succinate semialdehyde dehydrogenase). A steady-state proline level was found in ED fruits although an increase in P5CS mRNA expression level. These results contribute to a better knowledge of the molecular basis of the relationship between defoliation and sugar and organic acid metabolism in mandarin fruit.PMID:37128327 | PMC:PMC10148037 | DOI:10.1016/j.heliyon.2023.e15573

Nat Rev Chem. 2020 May;4(5):229-242. doi: 10.1038/s41570-020-0174-3. Epub 2020 Mar 17.ABSTRACTProteins can undergo glycosylation during and/or after translation to afford glycoconjugates, which are often secreted by a cell or populate cell surfaces. Changes in the glycan portion can have a strong influence on a glycoconjugate and are associated with a multitude of human pathologies. Of particular interest are sialylated glycoconjugates, which exist as constitutional isomers that differ in their linkages (α2,3, α2,6, α2,8 or α2,9) between sialic acids and their neighbouring monosaccharides. In general, mass spectrometry enables the rapid and sensitive characterization of glycosylation, but there are challenges specific to identifying and (relatively) quantifying sialic acid isomers. These challenges can be addressed using linkage-specific methodologies for sialic acid derivatization, after which mass spectrometry can enable product identification. This Review is concerned with the new and important derivatization approaches reported in the past decade, which have been implemented in various mass-spectrometry-glycomics workflows and have found clinical glycomics applications. The convenience and wide applicability of the approaches make them attractive for studies of sialylation in different types of glycoconjugate.PMID:37127981 | DOI:10.1038/s41570-020-0174-3

J Cachexia Sarcopenia Muscle. 2023 May 1. doi: 10.1002/jcsm.13244. Online ahead of print.ABSTRACTBACKGROUND: Sarcopenia is characterized by a progressive decrease in skeletal muscle mass and function with age. Given that sarcopenia is associated with various metabolic disorders, effective metabolic biomarkers for its early detection are required. We aimed to investigate the metabolic biomarkers related to sarcopenia in elderly men and perform experimental studies using metabolomics.METHODS: Plasma metabolites from 142 elderly men, comprising a sarcopenia group and an age-matched control group, were measured using global metabolome profiling. Muscle and plasma samples from an aging mouse model of sarcopenia, as well as cell media and cell lysates during myoblast differentiation, were analysed based on targeted metabolome profiling. Based on these experimental results, fatty acid amides were quantified from human plasma as well as human muscle tissues. The association of fatty acid amide levels with sarcopenia parameters was evaluated.RESULTS: Global metabolome profiling showed that fatty acid amide levels were significantly different in the plasma of elderly men with sarcopenia (all Ps < 0.01). Consistent with these results in human plasma, targeted metabolome profiling in an aging mouse model of sarcopenia showed decreased levels of fatty acid amides in plasma but not in muscle tissue. In addition, the levels of fatty acid amides increased in cell lysates during muscle cell differentiation. Targeted metabolome profiling in men showed decreased docosahexaenoic acid ethanolamide (DHA EA) levels in the plasma (P = 0.016) but not in the muscle of men with sarcopenia. DHA EA level was positively correlated with sarcopenia parameters such as skeletal muscle mass index (SMI) and handgrip strength (HGS) (P = 0.001, P = 0.001, respectively). The area under the receiver-operating characteristic curve (AUC) for DHA EA level ≤ 4.60 fmol/μL for sarcopenia was 0.618 (95% confidence interval [CI]: 0.532-0.698). DHA EA level ≤ 4.60 fmol/μL was associated with a significantly greater likelihood of sarcopenia (odds ratio [OR]: 2.11, 95% CI: 1.03-4.30), independent of HGS. The addition of DHA EA level to age and HGS significantly improved the AUC from 0.620 to 0.691 (P = 0.0497).CONCLUSIONS: Our study demonstrated that fatty acid amides are potential circulating biomarkers in elderly men with sarcopenia. DHA EA, in particular, strongly related to muscle mass and strength, can be a key metabolite to become a reliable metabolic biomarker for sarcopenia. Further research on fatty acid amides will provide insights into the metabolomic changes relevant to sarcopenia from an aging perspective.PMID:37127296 | DOI:10.1002/jcsm.13244

Environ Pollut. 2023 Apr 29:121741. doi: 10.1016/j.envpol.2023.121741. Online ahead of print.ABSTRACTHumans are exposed to a growing list of synthetic chemicals, some of them becoming a major public health concern due to their capacity to impact multiple biological endpoints and contribute to a range of chronic diseases. The integration of endogenous (omic) biomarkers of effect in environmental health studies has been growing during the last decade, aiming to gain insight on the potential mechanisms linking the exposures and the clinical conditions. The emergence of high-throughput omic platforms has raised a list of statistical challenges posed by the large dimension and complexity of data generated. Thus, the aim of the present study was to critically review the current state-of-the-science about statistical approaches used to integrate endogenous biomarkers in environmental-health studies linking chemical exposures with health outcomes. The present review specifically focused on internal exposure to environmental chemical pollutants, involving both persistent organic pollutants (POPs), non-persistent pollutants like phthalates or bisphenols, and metals. We identified 42 eligible articles published since 2016, reporting 48 different statistical workflows, mostly focused on POPs and using metabolomic profiling in the intermediate layer. The outcomes were mainly binary and focused on metabolic disorders. A large diversity of statistical strategies were reported to integrate chemical mixtures and endogenous biomarkers to characterize their associations with health conditions. Multivariate regression models were the most predominant statistical method reported in the published workflows, however some studies applied latent based methods or multipollutant models to overcome the specific constraints of omic or exposure of data. A minority of studies used formal mediation analysis to characterize the indirect effects mediated by the endogenous biomarkers. The principles of each specific statistical method and overall workflow set-up are summarized in the light of highlighting their applicability, strengths and weaknesses or interpretability to gain insight into the causal structures underlying the triad: exposure, effect-biomarker and outcome.PMID:37127239 | DOI:10.1016/j.envpol.2023.121741

Environ Pollut. 2023 Apr 29:121744. doi: 10.1016/j.envpol.2023.121744. Online ahead of print.ABSTRACTThe capacity of Spanish moss (Tillandsia usneoides), an aerial plant, to adsorb radon (Rn) and absorb CO2 was assessed to analyze its capacity to remove pollutants from indoor air and to determine its radon (Rn) tolerance mechanism. Transcriptomics and metabolomics techniques were used to analyze the response of the plant to Rn exposure. Spanish moss absorbed indoor CO2 at night using the type of photosynthesis termed crassulacean acid metabolism. The CO2 absorption efficiency of the plant was mainly affected by the light duration and diurnal temperature differences. The highest purification efficiency was 48.25%, and the scales on the Spanish moss leaf surface were the key sites for Rn adsorption. Metabolome analysis showed that Rn exposure induced differential metabolites significantly enriched in the metabolism of lipids, amino acids, nucleotides, and carbohydrates. Transcriptome analysis showed significantly upregulated expression levels of functional genes in Rn-exposed leaves. Rn had significant effects on respiratory metabolism, as indicated by upregulated expression of metabolites and functional genes related to the glycolysis pathway, pyruvate oxidation, tricarboxylic acid cycle, and oxidative phosphorylation pathway. These responses indicated that the internal mechanism by which Spanish moss alleviates Rn stress involves an enhancement of cellular energy supplies and regulation of respiratory metabolic pathways to allow adaptation to Rn pollution.PMID:37127238 | DOI:10.1016/j.envpol.2023.121744

Mol Biochem Parasitol. 2023 Apr 29:111573. doi: 10.1016/j.molbiopara.2023.111573. Online ahead of print.ABSTRACTClonorchis sinensis (C. sinensis) is a fish-borne trematode that inhabits the bile duct of mammals including humans, cats, dogs, rats, and so on. In the complex life cycle of C. sinensis, the worm develops successively in two intermediate hosts in fresh water and one definitive host. What's more, it undergoes eight developmental stages with a distinct morphology. Clonorchiasis, caused by C. sinensis infection, is an important food-borne parasitic disease and one of the most common zoonoses. C. sinensis infection could result in hyperplasia of the bile duct epithelium, obstructive jaundice, gall-stones, cholecystitis and cholangitis, even liver cirrhosis and cholangiocarcinoma. Thus, clonorchiasis is a serious public health problem in endemic areas. Integrated strategies should be adopted in the prevention and control of clonorchiasis due to the epidemiological characteristics. The recent advances in high-throughput technologies have made available the profiling of multiple layers of a biological system, genomics, transcriptomics, proteomics, and metabolomics. These data can help us to get more information about the development, physiology, metabolism, and reproduction of the parasite as well as pathogenesis and parasite-host interactions in clonorchiasis. In the present study, we summarized recent progresses in omics studies on C. sinensis providing insights into the studies and future directions on treating and preventing C. sinensis associated diseases.PMID:37127222 | DOI:10.1016/j.molbiopara.2023.111573

Biochim Biophys Acta Mol Basis Dis. 2023 Apr 29:166725. doi: 10.1016/j.bbadis.2023.166725. Online ahead of print.ABSTRACTIntermittent fasting (IF) is an ecological strategy to control various metabolic disorder symptoms, but its protective effect on type 1 diabetes (T1D)-induced cognitive dysfunction and the underlying mechanisms remain poorly defined. Herein, we examined the efficacy of IF in altering the behaviors and brain metabolome in T1D mice and investigated the potential molecular mechanisms. We demonstrated that IF remarkably improved frontal cortical-dependent memory in T1D mice and reduced the loss of neuronal cells. Metabolomics and targeted mass spectrometry assay showed that IF reprogrammed the frontal cortical metabolome composition, including activated the aspartate and glutamate pathway and reversed glycerophospholipid and sphingolipid depositions in T1D mice. Mechanistically, IF attenuated the levels of oxidative stress proteins, such as NOX2, NOX4, 8-OHdG, 4-HNE, and inhibited the levels of pro-apoptotic factors Bax and cleaved Caspase-3, finally improved the memory ability of T1D mice. In vitro studies confirmed the protective effect of the supplemented N-acetylaspartate, a pivotal metabolite involved in IF-regulated T1D-induced cognitive dysfunction, in high glucose-stimulated SH-SY5Y cells by eliminating toxic lipids accumulation, oxidative stress and apoptosis. To conclude, the frontal cortical metabolites mediated the protective effects of IF against T1D-induced cognitive dysfunction by attenuating oxidative stress and apoptotic signaling. Thus, IF can be a potential therapeutic strategy for T1D-induced cognitive dysfunction.PMID:37127173 | DOI:10.1016/j.bbadis.2023.166725

Sci Total Environ. 2023 Apr 29:163793. doi: 10.1016/j.scitotenv.2023.163793. Online ahead of print.ABSTRACTCrop diseases significantly threaten global food security and will worsen with a changing climate. Elemental sulfur nanomaterials (S NMs) were used to suppress bacterial pathogen Pectobacterium carotovorum on lettuce (Lactuca sativa L.). Foliar application with S NMs at 10-100 mg/L statistically decreased the occurrence of bacterial soft rot, where 100 mg/L exhibited the best performance with alleviating disease severity by 94.1 % as relative to infected controls. The disease suppression efficiency of S based materials (100 mg/L) and a conventional pesticide (thiophanate-methyl) followed the order of S NMs ≈ pesticide > S bulk particles (BPs) > sulfate. The disease control efficiency of S NMs was 1.33- and 3.20-fold that of S BPs and sulfate, respectively, and the shoot and root biomass with S NMs was 1.25- and 1.17-fold that of the pesticide treated plants. Mechanistically, S NMs (1) triggered jasmonic acid (JA) and salicylic acid (SA) mediated systematic induced resistance and systemic acquired resistance, thereby upregulating pathogenesis-related gene expression (enhanced by 29.3-259.7 %); (2) enhanced antioxidative enzyme activity and antioxidative gene expression (improved by 67.5-326.6 %), thereby alleviating the oxidative stress; and (3) exhibited direct in vivo antibacterial activity. Metabolomics analysis demonstrated that S NMs also promoted the tricarboxylic acid cycle and increased SA and JA metabolite biosynthesis. Moreover, S NMs application increased nutritive quality of lettuce by 20.8-191.7 %. These findings demonstrate that S NMs have potential to manage crop disease, thereby reducing the environmental burden due to decreasing use of conventional pesticides.PMID:37127166 | DOI:10.1016/j.scitotenv.2023.163793

J Invertebr Pathol. 2023 Apr 29:107929. doi: 10.1016/j.jip.2023.107929. Online ahead of print.ABSTRACTSpodoptera frugiperda is a pest that poses serious threat to the production of food and crops. Entopathogenic fungi, represented by Beauveria bassiana, has shown potential for S. frugiperda control. However, the mechanism of this biological control of pathogens is not fully understood, such as how antioxidant enzyme activities and metabolic profiles in S. frugiperda larvae are affected when infected by entomopathogenic fungi. This study assessed the antioxidant enzyme activities and shift in metabolomic profile in the S. frugiperda larvae infected with B.bassiana. The results indicate a pattern of initial increase and subsequent decrease in the activities of superoxide dismutase, catalase, and peroxidase in the B.bassiana-infected larvae. And the enzyme activities at 60 h of infection ended significantly lower than those of the uninfected larvae. A total of 93 differential metabolites were identified in the B.bassiana-infected larvae, of which 41 metabolites were up-regulated and 52 were down-regulated. These metabolites mainly included amino acids, nucleotides, lipids, carbohydrates, and their derivatives. Among the changed metabolites, cystathionine, L-tyrosine, L-dopa, arginine, alpha-ketoglutaric acid, D-sedoheptulose-7-phosphate and citric acid were significantly decreased in B. bassiana-infected larvae. This indicated that the fungal infection might impair the ability of S. frugiperda larvae to cope with oxidative stress, leading to a negative impact of organism fitness. Further analyses of key metabolic pathways reveal that B. bassiana infection might affect purine metabolism, arginine biosynthesis, butanoate metabolism, and phenylalanine metabolism of S. frugiperda larvae. The findings from this study will contribute to our understanding of oxidative stress on immune defense in insects, and offer fundamental support for the biological control of S. frugiperda.PMID:37127135 | DOI:10.1016/j.jip.2023.107929

Am J Clin Nutr. 2023 Apr 29:S0002-9165(23)48892-2. doi: 10.1016/j.ajcnut.2023.04.034. Online ahead of print.ABSTRACTBACKGROUND: While substantial evidence reveals that healthy lifestyle behaviors are associated with a lower risk of rheumatoid arthritis (RA), the underlying metabolic mechanisms remain unclear.OBJECTIVES: This study aimed to identify the metabolic signature reflecting a healthy lifestyle and investigate its observational and genetic linkage with RA risk.METHODS: This study included 87,258 UK Biobank participants (557 cases of incident RA) aged 37 to 73 years with complete lifestyle, genotyping and nuclear magnetic resonance (NMR) metabolomics data. A healthy lifestyle was assessed based on five factors: healthy diet, regular exercise, not smoking, moderate alcohol consumption, and normal body mass index. The metabolic signature was developed by summing selected metabolites' concentrations weighted by the coefficients using elastic net regression. We used multivariate Cox model to assess the associations between metabolic signatures and RA risk, and examined the mediating role of the metabolic signature in the impact of a healthy lifestyle on RA. We performed genome-wide association analysis (GWAS) to obtain genetic variants associated with the metabolic signature, then conducted Mendelian randomization (MR) analyses to detect causality.RESULTS: The metabolic signature comprised of 81 metabolites, robustly correlated with healthy lifestyle ( r = 0.45, P = 4.2 × 10-15). The metabolic signature was inversely associated with RA risk (HR per SD increment: 0.76, 95% CI: 0.70-0.83), and largely explained protective effects of healthy lifestyle on RA with 64% (95%CI: 50.4-83.3) mediation proportion. One and two-sample MR analyses also consistently showed the associations of genetically inferred per SD increment in metabolic signature with a reduction in RA risk (HR: 0.84, 95% CI: 0.75-0.94, P = 0.002 and OR: 0.84, 95% CI: 0.73-0.97, P = 0.02 respectively).CONCLUSION: Our findings implicate the metabolic signature reflecting healthy lifestyle as a potential causal mediator in the development of RA, highlighting the importance of early lifestyle intervention and metabolic tracking for precise prevention of RA.PMID:37127109 | DOI:10.1016/j.ajcnut.2023.04.034

Biomed Pharmacother. 2023 Apr 29;163:114787. doi: 10.1016/j.biopha.2023.114787. Online ahead of print.ABSTRACTBACKGROUND AND PURPOSE: Cisplatin-induced nephrotoxicity manifests as acute kidney injury (AKI) in approximately one third of patients receiving cisplatin therapy. Current measures of AKI are inadequate in detecting AKI prior to significant renal injury, and better biomarkers are needed for early diagnosis of cisplatin-induced AKI.EXPERIMENTAL APPROACH: C57BL/6 and FVB/N mice were treated with a single intraperitoneal injection of cisplatin (15 mg kg-1) or saline. Plasma, urine, and kidney samples were collected prior to cisplatin injection and 24-, 48-, 72-, and 96-hours following cisplatin injection. Untargeted metabolomics was employed using liquid chromatography-mass spectrometry to identify early diagnostic biomarkers for cisplatin nephrotoxicity.PRINCIPAL RESULTS: There was clear metabolic discrimination between saline and cisplatin-treated mice at all timepoints (day 1 to day 4). In total, 26 plasma, urine, and kidney metabolites were identified as exhibiting early alterations following cisplatin treatment. Several of the metabolites showing early alterations were associated with mitochondrial function and energetics, including intermediates of the tricarboxylic acid cycle, regulators of mitochondrial function and indicators of fatty acid β-oxidation dysfunction. Furthermore, several metabolites were derived from the gut microbiome.MAJOR CONCLUSIONS: Our results highlight the detrimental effects of cisplatin on mitochondrial function and demonstrate potential involvement of the gut microbiome in the pathophysiology of cisplatin-induced AKI. We provide a panel of metabolites to guide future clinical studies of cisplatin-induced AKI and provide insight into potential mechanisms behind cisplatin nephrotoxicity.PMID:37126930 | DOI:10.1016/j.biopha.2023.114787

Plant Physiol Biochem. 2023 Apr 24;199:107713. doi: 10.1016/j.plaphy.2023.107713. Online ahead of print.ABSTRACTCassava (Manihot esculenta Crantz) is a predominant food security crop in several developing countries. Its storage roots, rich in carbohydrate, are deficient in essential micronutrients, including provitamin A carotenoids. Increasing carotenoid content in cassava storage roots is important to reduce the incidence of vitamin A deficiency, a public health problem in sub-Saharan Africa. However, cassava improvement advances slowly, mainly due to limited information on the molecular factors influencing β-carotene accumulation in cassava. To address this problem, we performed comparative transcriptomic and untargeted metabolic analyses of roots and leaves of eleven African cassava landraces ranging from white to deep yellow colour, to uncover regulators of carotenoid biosynthesis and accumulation with conserved function in yellow cassava roots. Sequence analysis confirmed the presence of a mutation, known to influence β-carotene content, in PSY transcripts of deep yellow but not of pale yellow genotypes. We identified genes and metabolites with expression and accumulation levels significantly associated with β-carotene content. Particularly an increased activity of the abscisic acid catabolism pathway together with a reduced amount of L-carnitine, may be related to the carotenoid pathway flux, higher in yellow than in white storage roots. In fact, NCED_3.1 was specifically expressed at a lower level in all yellow genotypes suggesting that it could be a potential target for increasing carotenoid accumulation in cassava. These results expand the knowledge on metabolite compositions and molecular mechanisms influencing carotenoid biosynthesis and accumulation in cassava and provide novel information for biotechnological applications and genetic improvement of cassava with high nutritional values.PMID:37126903 | DOI:10.1016/j.plaphy.2023.107713

Nat Metab. 2023 May 1. doi: 10.1038/s42255-023-00799-7. Online ahead of print.ABSTRACTDiet-induced weight loss is associated with improved beta-cell function in people with type 2 diabetes (T2D) with remaining secretory capacity. It is unknown if adding exercise to diet-induced weight loss improves beta-cell function and if exercise volume is important for improving beta-cell function in this context. Here, we carried out a four-armed randomized trial with a total of 82 persons (35% females, mean age (s.d.) of 58.2 years (9.8)) with newly diagnosed T2D (<7 years). Participants were randomly allocated to standard care (n = 20), calorie restriction (25% energy reduction; n = 21), calorie restriction and exercise three times per week (n = 20), or calorie restriction and exercise six times per week (n = 21) for 16 weeks. The primary outcome was beta-cell function as indicated by the late-phase disposition index (insulin secretion multiplied by insulin sensitivity) at steady-state hyperglycemia during a hyperglycemic clamp. Secondary outcomes included glucose-stimulated insulin secretion and sensitivity as well as the disposition, insulin sensitivity, and secretion indices derived from a liquid mixed meal tolerance test. We show that the late-phase disposition index during the clamp increases more in all three intervention groups than in standard care (diet control group, 58%; 95% confidence interval (CI), 16 to 116; moderate exercise dose group, 105%; 95% CI, 49 to 182; high exercise dose group, 137%; 95% CI, 73 to 225) and follows a linear dose-response relationship (P > 0.001 for trend). We report three serious adverse events (two in the control group and one in the diet control group), as well as adverse events in two participants in the diet control group, and five participants each in the moderate and high exercise dose groups. Overall, adding an exercise intervention to diet-induced weight loss improves glucose-stimulated beta-cell function in people with newly diagnosed T2D in an exercise dose-dependent manner (NCT03769883).PMID:37127822 | DOI:10.1038/s42255-023-00799-7