PubMed

Plant Signal Behav. 2023 Dec 31;18(1):2213934. doi: 10.1080/15592324.2023.2213934.ABSTRACTPiriformospora indica, a plant root-colonizing basidiomycete fungus, exhibits strong growth-promoting activity in symbiosis with a broad range of plants. Here, we report the potential of P. indica to improve growth, yield, and disease resistance in wheat in the field. In the present study, P. indica successfully colonized wheat through chlamydospores and formed dense mycelial networks that covered roots. Plants subjected to the seed soaking (SS) treatment with P. indica chlamydospore suspensions enhanced tillering 2.28-fold compared to the non-inoculated wheat in the tillering stage. In addition, P. indica colonization promoted vegetative growth significantly during the three-leaf, tillering, and jointing stages. Moreover, the P. indica-SS-treatment enhanced wheat yield by 16.37 ± 1.63%, by increasing grains per ear and panicle weight and decreased damage to wheat shoot and root architecture markedly, with high field control effects against Fusarium pseudograminearum (81.59 ± 1.32%), Bipolaris sorokiniana (82.19 ± 1.59%), and Rhizoctonia cerealis (75.98 ± 1.36%). Most of the primary metabolites, such as amino acids, nucleotides, and lipids, involved in vegetative reproduction were increased in P. indica-SS-treatment plants, whereas secondary metabolites, such as terpenoids, polyketides, and alkaloids, decreased following P. indica inoculation. The up-regulated processes of protein, carbohydrate, and lipid metabolism indicated that P. indica colonization increased growth, yield, and disease resistance via the acceleration of plant primary metabolism. In conclusion, P. indica improved morphological, physiological, and metabolic substance levels, and further promoted its growth, yield, and disease resistance in wheat.PMID:37231769 | DOI:10.1080/15592324.2023.2213934

J Nutr. 2022 Dec;152(12):2956-2965. doi: 10.1093/jn/nxac195. Epub 2023 Feb 10.ABSTRACTBACKGROUND: The fecal metabolome is affected by diet and includes metabolites generated by human and microbial metabolism. Advances in -omics technologies and analytic approaches have allowed researchers to identify metabolites and better utilize large data sets to generate usable information. One promising aspect of these advancements is the ability to determine objective biomarkers of food intake.OBJECTIVES: We aimed to utilize a multivariate, machine learning approach to identify metabolite biomarkers that accurately predict food intake.METHODS: Data were aggregated from 5 controlled feeding studies in adults that tested the impact of specific foods (almonds, avocados, broccoli, walnuts, barley, and oats) on the gastrointestinal microbiota. Fecal samples underwent GC-MS metabolomic analysis; 344 metabolites were detected in preintervention samples, whereas 307 metabolites were detected postintervention. After removing metabolites that were only detected in either pre- or postintervention and those undetectable in ≥80% of samples in all study groups, changes in 96 metabolites relative concentrations (treatment postintervention minus preintervention) were utilized in random forest models to 1) examine the relation between food consumption and fecal metabolome changes and 2) rank the fecal metabolites by their predictive power (i.e., feature importance score).RESULTS: Using the change in relative concentration of 96 fecal metabolites, 6 single-food random forest models for almond, avocado, broccoli, walnuts, whole-grain barley, and whole-grain oats revealed prediction accuracies between 47% and 89%. When comparing foods with one another, almond intake was differentiated from walnut intake with 91% classification accuracy.CONCLUSIONS: Our findings reveal promise in utilizing fecal metabolites as objective complements to certain self-reported food intake estimates. Future research on other foods at different doses and dietary patterns is needed to identify biomarkers that can be applied in feeding study compliance and clinical settings.PMID:37230693 | DOI:10.1093/jn/nxac195

J Nutr. 2022 Dec;152(12):2778-2788. doi: 10.1093/jn/nxac228. Epub 2023 Feb 10.ABSTRACTBACKGROUND: Beneficial effects of nut supplementation on cognitive function have previously been demonstrated in young and older adults. Alterations to gut microbiota have also been shown following tree nut consumption. However, no data exists on the effects of nuts on cognition and intestinal microbial communities assessed within the same study.OBJECTIVES: The study aimed to examine the effects of daily consumption of tree nuts for 4 wk on cognitive function (primary outcome), mood, metabolomics, and gut microbial species (secondary outcomes) in healthy, nonelderly adults.METHODS: This randomized, placebo-controlled, double-blind, counterbalanced crossover study assessed the effects of 4 wk of supplementation with 30 g/d mixed tree nuts versus placebo on cognition and mood in 79 healthy adults aged 18-49 y. Metabolic responses, gut bacterial community structure, and the potential for these to impact cognition were explored using a multi-omic approach. Bacterial community analysis was conducted in Quantitative Insights Into Microbial Ecology 2 (QIIME2).RESULTS: Mixed model analysis indicated that nut consumption led to significant improvements to accuracy (placebo M = 92.2% compared with NUTS M = 94.5%; P = 0.019) and speed of response (placebo M = 788 ms compared with NUTS M = 757 ms; P = 0.004) on a picture recognition task. No significant changes to bacterial community α or β diversity were observed when comparing nut consumption to the placebo arm. However, an unclassified Lachnospiraceae amplicon sequence variant (ASV) was significantly enriched in participants when supplemented with nuts (P = 0.015). No correlations were observed between the changes to picture recognition and the changes to the unclassified Lachnospiraceae ASV. There were no significant changes to the urinary metabolome.CONCLUSIONS: These findings indicate a positive effect of nut on cognition following only 4 wk of consumption in a healthy nonelderly sample, as well as upregulation of a microbial taxa associated with gut health. The effects appear to be independent of one another, but further exploration is required in those experiencing cognitive decline and/or gut dysbiosis.PMID:37230675 | DOI:10.1093/jn/nxac228

J Nutr. 2022 Dec;152(12):2643-2644. doi: 10.1093/jn/nxac233. Epub 2023 Feb 10.NO ABSTRACTPMID:37230659 | DOI:10.1093/jn/nxac233

Anal Chim Acta. 2023 Jul 18;1265:341274. doi: 10.1016/j.aca.2023.341274. Epub 2023 May 3.ABSTRACTLipidomics studies strive for a comprehensive identification and quantification of lipids. While reversed phase (RP) liquid chromatography (LC) coupled to high resolution mass spectrometry (MS) offers unrivalled selectivity and thus is the preferred method for lipid identification, accurate lipid quantification remains challenging. The widely adopted one-point lipid class specific quantification (one internal standard per lipid class) suffers from the fact that ionization of internal standard and target lipid occurs under different solvent composition as a consequence of chromatographic separation. To address this issue, we established a dual flow injection and chromatography setup that allows to control solvent conditions during ionization enabling isocratic ionization while running a RP gradient through the use of a counter-gradient. Using this dual LC pump platform, we investigated the impact of solvent conditions within a RP gradient on ionization response and arising quantification biases. Our results confirmed that changing solvent composition significantly influences ionization response. Quantification of human plasma (SRM 1950) lipids under gradient and isocratic ionization conditions further confirmed these findings as significant differences between the two conditions were found for the majority of lipids. While the quantity of sphingomyelins with >40 C atoms was consistently overestimated under gradient ionization, isocratic ionization improved their recovery compared to consensus values. However, the limitation of consensus values was demonstrated as overall only small changes in z-score were observed because of high uncertainties of the consensus values. Furthermore, we observed a trueness bias between gradient and isocratic ionization when quantifying a panel of lipid species standards which is highly dependent on lipid class and ionization mode. Uncertainty calculations under consideration of the trueness bias as RP gradient uncertainty revealed that especially ceramides with >40 C atoms had a high bias leading to total combined uncertainties of up to 54%. The assumption of isocratic ionization significantly decreases total measurement uncertainty and highlights the importance of studying the trueness bias introduced by a RP gradient to reduce quantification uncertainty.PMID:37230568 | DOI:10.1016/j.aca.2023.341274

Anal Chim Acta. 2023 Jul 18;1265:341271. doi: 10.1016/j.aca.2023.341271. Epub 2023 May 4.ABSTRACTProteins carry a plethora of post-translational modifications (PTMs), such as glycosylation or phosphorylation, which may affect stability and activity. Analytical strategies are needed to investigate these PTMs in their native state to determine the link between structure and function. The coupling of native separation techniques with mass spectrometry (MS) has emerged as a powerful tool for in-depth protein characterization. Yet obtaining high ionization efficiency still can be challenging. Here, we explored the potential of dopant-enriched nitrogen (DEN) gas to improve nano-electrospray ionization (nano-ESI)-MS of native proteins after anion exchange chromatography. The dopant gas was enriched with different dopants (acetonitrile, methanol, and isopropanol) and the effects were compared with the use of solely nitrogen gas for six proteins covering a wide range of physicochemical properties. The use of DEN gas resulted generally in lower charge states, independent of the selected dopant. Moreover, less adduct formation was observed, particularly for the acetonitrile-enriched nitrogen gas. Importantly, striking differences in MS signal intensity and spectral quality were observed for extensively glycosylated proteins, where isopropanol- and methanol-enriched nitrogen appeared to be most beneficial. Altogether, the use of DEN gas improved nano-ESI of native glycoproteins and increased spectral quality for highly glycosylated proteins that normally suffer from low ionization efficiency.PMID:37230565 | DOI:10.1016/j.aca.2023.341271

J Adv Res. 2023 May 23:S2090-1232(23)00144-3. doi: 10.1016/j.jare.2023.05.006. Online ahead of print.ABSTRACTINTRODUCTION: Zearalenone-14-glucoside (Z14G) is a modified mycotoxin that widely contaminates food across the world. Our preliminary experiment showed that Z14G degrades to zearalenone (ZEN) in the intestine exerting toxicity. Notably, oral administration of Z14G in rats induces intestinal nodular lymphatic hyperplasia.OBJECTIVES: To investigate the mechanism of Z14G intestinal toxicity and how it differs from ZEN toxicity. We conducted a precise toxicology study on the intestine of rats exposed to Z14G and ZEN using multi-omics technology.METHODS: Rats were exposed to ZEN (5 mg/kg), Z14G-L (5 mg/kg), Z14G-H (10 mg/kg), and pseudo germ free (PGF)-Z14G-H (10 mg/kg) for 14 days. Histopathological studies were performed on intestines from each group and compared. Metagenomic, metabolomic, and proteomic analyses were performed on rat feces, serum, and intestines, respectively.RESULTS: Histopathological studies showed that Z14G exposure resulted in dysplasia of gut-associated lymphoid tissue (GALT) compared to ZEN exposure. The elimination of gut microbes in the PGF-Z14G-H group alleviated or eliminated Z14G-induced intestinal toxicity and GALT dysplasia. Metagenomic analysis revealed that Z14G exposure significantly promoted the proliferation of Bifidobacterium and Bacteroides compared to ZEN. Metabolomic analysis showed that Z14G exposure significantly reduced bile acid, while proteomic analysis found that Z14G exposure significantly reduced the expression of C-type lectins compared to ZEN.CONCLUSIONS: Our experimental results and previous research suggest that Z14G is hydrolyzed to ZEN by Bifidobacterium and Bacteroides promoting their co-trophic proliferation. This leads to inactivation of lectins by hyperproliferative Bacteroides when ZEN caused intestinal involvement, resulting in abnormal lymphocyte homing and ultimately GALT dysplasia. It is noteworthy that Z14G is a promising model drug to establish rat models of intestinal nodular lymphatic hyperplasia (INLH), which is of great significance for studying the pathogenesis, drug screening and clinical application of INLH.PMID:37230382 | DOI:10.1016/j.jare.2023.05.006

Life Sci. 2023 May 23:121788. doi: 10.1016/j.lfs.2023.121788. Online ahead of print.ABSTRACTAIM: Psoriasis is one of the most common dermatological disorders, characterized by increased epidermal hyperplasia and immune cell infiltration. Psychological stress has been reported to contribute to the severity, aggravation, and relapse of psoriasis. However, the exact mechanism involved in psychological stress's impact on psoriasis is still unclear. We aim to investigate the role of psychological stress in psoriasis from a transcriptomic and metabolomic perspective.MAIN METHOD: We developed a chronic restrain stress (CRS)-imiquimod (IMQ)-induced psoriasis-like mouse model and performed a comprehensive comparative transcriptomic and metabolic analysis with control mice, CRS-treated mice, and IMQ-treated mice to investigate how psychological stress affects psoriasis.KEY FINDING: We found that CRS-IMQ-induced psoriasis-like mice showed significant exacerbation of psoriasis-like skin inflammation compared with mice treated with IMQ only. Mice of the CRS + IMQ group showed increased expression of keratinocyte proliferation and differentiation genes, differential regulation of cytokines, and promotion of linoleic acid metabolism. Correlation analysis of differentially expressed genes in the CRS-IMQ-induced psoriasis-like mice and human psoriasis datasets compared with respective controls revealed 96 overlapping genes of which 30 genes showed consistent induced or repressed expression in all human and mouse datasets.SIGNIFICANCE: Our study provides new insights into the effects of psychological stress on psoriasis pathogenesis and the mechanisms involved, which provides clues for development of therapeutics or biomarkers.PMID:37230377 | DOI:10.1016/j.lfs.2023.121788

J Hepatol. 2023 May 23:S0168-8278(23)00341-0. doi: 10.1016/j.jhep.2023.05.012. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Roux-en-Y gastric bypass (RYGB), the most weight-loss effective surgical procedure, decreases obesity and comorbidities, such as non-alcoholic fatty liver (NAFLD) and cardiovascular (CVD) diseases. Cholesterol is a major CVD risk factor and modulator of NAFLD development, and the liver tightly controls its metabolism. How RYGB surgery modulates systemic and hepatic cholesterol metabolism is still unclear.METHODS: We studied the hepatic transcriptome of 26 non-diabetic obese patients undergoing RYGB before and one-year post-surgery. In parallel, we measured quantitative changes in plasma cholesterol metabolites and bile acids (BA).RESULTS: RYGB surgery improved systemic cholesterol metabolism and increased plasma total and primary BA levels. Transcriptomic analysis revealed specific alterations in the liver after RYGB, with the down-regulation of a module of genes implicated in inflammation and the up-regulation of three modules, one associated with BA metabolism. A dedicated analysis of hepatic genes related to cholesterol homeostasis pointed towards increased biliary cholesterol elimination after RYGB, associated with enhancement of the alternate, but not the classical, BA synthesis pathway. In parallel, alterations in the expression of genes involved in cholesterol uptake and intracellular trafficking indicate improved hepatic free cholesterol handling. Finally, RYGB decreased plasma markers of cholesterol synthesis, which correlated with post-surgery liver disease status improvement.CONCLUSIONS: Our results identify specific regulatory effects of RYGB on inflammation and cholesterol metabolism. RYGB alters the hepatic transcriptome signature, likely improving liver cholesterol homeostasis. These gene regulatory effects are reflected by systemic post-surgery changes of cholesterol-related metabolites, corroborating the beneficial effects of RYGB on both hepatic and systemic cholesterol homeostasis.IMPACTS AND IMPLICATION: Roux-en-Y gastric bypass (RYGB) is a widely used bariatric surgery procedure with proven efficacy in body weight management, combatting cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD). RYGB exerts many beneficial metabolic effects, by lowering plasma cholesterol and improving atherogenic dyslipidemia. Using a cohort of RYGB patients, studied before and one year after surgery, we analyzed how RYGB modulates hepatic and systemic cholesterol and bile acid metabolism. The results of our study provide important insights on the regulation of cholesterol homeostasis after RYGB and open avenues that could guide future monitoring and treatment strategies targeting CVD and NAFLD in obesity.PMID:37230231 | DOI:10.1016/j.jhep.2023.05.012

J Hepatol. 2023 May 23:S0168-8278(23)00339-2. doi: 10.1016/j.jhep.2023.04.040. Online ahead of print.ABSTRACTBACKGROUND & AIMS: Temporal oscillations in intestinal nutrient processing and absorption are coordinated by the local clock, which leads to the hypothesis that intestine clock has major impact on shaping peripheral rhythms via diurnal nutritional signals. Here we investigate the role of intestine clock in controlling liver rhythmicity and metabolism.METHODS: Transcriptomic analysis, metabolomics, metabolic assays, histology, qPCR, and immunoblotting were performed with Bmal1-iKO (intestine-specific knockout of Bmal1), Rev-erbα-iKO and control mice.RESULTS: Bmal1-iKO causes a large-scale reprogramming of the rhythmic transcriptome of mouse liver with a limited effect on its clock. In the absence of intestinal Bmal1, liver clock is resistant to the entrainment by inverted feeding and high-fat diet. Importantly, Bmal1-iKO remodels diurnal hepatic metabolism by shifting to gluconeogenesis from lipogenesis in the dark phase, leading to elevated glucose production (hyperglycemia) and insulin insensitivity. Conversely, Rev-erbα-iKO causes a diversion to lipogenesis from gluconeogenesis in the light phase, resulting in enhanced lipogenesis and an increased susceptibility to alcoholic liver injury. These temporal diversions are attributed to a disruption of hepatic SREBP-1c rhythmicity, which is maintained via gut-derived polyunsaturated fatty acids produced by intestinal FADS1/2 under the control of local clock.CONCLUSION: Our findings establish a pivotal role of intestine clock in dictating liver rhythmicity and diurnal metabolism, and suggest targeting intestinal rhythms as a new avenue for improving metabolic health.IMPACT AND IMPLICATIONS: Our findings establish the centrality of the intestine clock amongst peripheral tissue clocks, and associate liver-related pathologies with malfunction of intestine clock. Clock modifiers in the intestine are shown to modulate liver metabolism with improved metabolic parameters. The knowledge will help the clinicians improve the diagnosis and treatment of metabolic diseases by incorporating intestinal circadian factors.PMID:37230230 | DOI:10.1016/j.jhep.2023.04.040

Plant Sci. 2023 May 23:111748. doi: 10.1016/j.plantsci.2023.111748. Online ahead of print.ABSTRACTIn the last decades, linkage mapping has help in the location of metabolite quantitative trait loci (QTL) in many species; however, this approach shows some limitations. Recently, thanks to the most recent advanced in high-throughput genotyping technologies like next-generation sequencing, metabolite genome-wide association study (mGWAS) has been proposed a powerful tool to identify the genetic variants in polygenic agrinomic traits. Fruit flavor is a complex interaction of aroma volatiles and taste being sugar and acid ratio key parameter for flavor acceptance. Here, we review recent progress of mGWAS in pinpoint gene polymorphisms related to flavor-related metabolites in fruits. Despite clear successes in discovering novel genes or regions associated with metabolite accumulation affecting sensory attributes in fruits, GWAS incurs in several limitations summarized in this review. In addition, in our own work, we performed mGWAS on 194 Citrus grandis accessions to investigate the genetic control of individual primary and lipid metabolites in ripe fruit. We have identified a total of 667 associations for 14 primary metabolites including amino acids, sugars, and organic acids, and 768 associations corresponding to 47 lipids. Furthermore, candidate genes related to important metabolites related to fruit quality such as sugars, organic acids and lipids were discovered.PMID:37230189 | DOI:10.1016/j.plantsci.2023.111748

Theriogenology. 2023 May 5;206:189-196. doi: 10.1016/j.theriogenology.2023.05.003. Online ahead of print.ABSTRACTOvarian fluid is essential for successful fertilization by maintaining the viability, motility, and velocity of sperm. The organic compounds and inorganic ions in ovarian fluid significantly influence spermatozoa's motility, velocity, and longevity. However, the effect of ovarian fluid on sperm performance is limited in teleost fish. In this study, the effect of ovarian fluid on sperm performance and its components in external fertilization species (Scophthalmus maximus, turbot) and internal fertilization species (Sebastes schlegelii, black rockfish) was investigated using computer-assisted sperm analysis, high-performance liquid chromatography, and metabolome analysis. The ovarian fluid had a distinct and species-specific effect on both species. In the black rockfish, the ovarian fluid from turbot significantly increased sperm motility (74.07% ± 4.09%), as well as VCL (45 ± 1.67 μm/s), VAP (40.17 ± 1.6 μm/s), and VSL (36.67 ± 1.86 μm/s), and longevity (352 ± 11.31 min) (P < 0.05). In the turbot, only the longevity (71.33 ± 5.69 min) and fertilization rate (65.27% ± 11.59%) showed significantly improvement (P < 0.05). The ovarian fluid was rich in organic compounds, suggesting enrichment in the glycolysis/gluconeogenesis pathways. The results suggest that glycometabolism plays a crucial role in improving sperm performance in teleost with internal fertilization. Thus, incorporating ovarian fluid into the sperm activation medium can enhance artificial fertilization in fish breeding.PMID:37229958 | DOI:10.1016/j.theriogenology.2023.05.003

J Exp Clin Cancer Res. 2023 May 26;42(1):134. doi: 10.1186/s13046-023-02713-1.ABSTRACTBACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal cancer. Large-scale metabolomic data have associated metabolic alterations with the pathogenesis and progression of renal carcinoma and have correlated mitochondrial activity with poor survival in a subset of patients. The aim of this study was to determine whether targeting mitochondria-lysosome interaction could be a novel therapeutic approach using patient-derived organoids as avatar for drug response.METHODS: RNAseq data analysis and immunohistochemistry were used to show overexpression of Purinergic receptor 4 (P2XR4) in clear cell carcinomas. Seahorse experiments, immunofluorescence and fluorescence cell sorting were used to demonstrate that P2XR4 regulates mitochondrial activity and the balance of radical oxygen species. Pharmacological inhibitors and genetic silencing promoted lysosomal damage, calcium overload in mitochondria and cell death via both necrosis and apoptosis. Finally, we established patient-derived organoids and murine xenograft models to investigate the antitumor effect of P2XR4 inhibition using imaging drug screening, viability assay and immunohistochemistry.RESULTS: Our data suggest that oxo-phosphorylation is the main source of tumor-derived ATP in a subset of ccRCC cells expressing P2XR4, which exerts a critical impact on tumor energy metabolism and mitochondrial activity. Prolonged mitochondrial failure induced by pharmacological inhibition or P2XR4 silencing was associated with increased oxygen radical species, changes in mitochondrial permeability (i.e., opening of the transition pore complex, dissipation of membrane potential, and calcium overload). Interestingly, higher mitochondrial activity in patient derived organoids was associated with greater sensitivity to P2XR4 inhibition and tumor reduction in a xenograft model.CONCLUSION: Overall, our results suggest that the perturbed balance between lysosomal integrity and mitochondrial activity induced by P2XR4 inhibition may represent a new therapeutic strategy for a subset of patients with renal carcinoma and that individualized organoids may be help to predict drug efficacy.PMID:37231503 | DOI:10.1186/s13046-023-02713-1

Respir Res. 2023 May 25;24(1):138. doi: 10.1186/s12931-023-02441-2.ABSTRACTElectronic cigarette (Ecig) use has become more common, gaining increasing acceptance as a safer alternative to tobacco smoking. However, the 2019 outbreak of Ecig and Vaping-Associated Lung Injury (EVALI) alerted the community to the potential for incorporation of deleterious ingredients such as vitamin E acetate into products without adequate safety testing. Understanding Ecig induced molecular changes in the lung and systemically can provide a path to safety assessment and protect consumers from unsafe formulations. While vitamin E acetate has been largely removed from commercial and illicit products, many Ecig products contain additives that remain largely uncharacterized. In this study, we determined the lung-specific effects as well as systemic immune effects in response to exposure to a common Ecig base, propylene glycol and vegetable glycerin (PGVG), with and without a 1% addition of phytol, a diterpene alcohol that has been found in commercial products. We exposed animals to PGVG with and without phytol and assessed metabolite, lipid, and transcriptional markers in the lung. We found both lung-specific as well as systemic effects in immune parameters, metabolites, and lipids. Phytol drove modest changes in lung function and increased splenic CD4 T cell populations. We also conducted multi-omic data integration to better understand early complex pulmonary responses, highlighting a central enhancement of acetylcholine responses and downregulation of palmitic acid connected with conventional flow cytometric assessments of lung, systemic inflammation, and pulmonary function. Our results demonstrate that Ecig exposure not only leads to changes in pulmonary function but also affects systemic immune and metabolic parameters.PMID:37231407 | DOI:10.1186/s12931-023-02441-2

J Med Toxicol. 2023 May 25. doi: 10.1007/s13181-023-00951-5. Online ahead of print.ABSTRACTBACKGROUND: Acetaminophen (APAP) is the most common cause liver injury following alcohol in US patients. Predicting liver injury and subsequent hepatic regeneration in patients taking therapeutic doses of APAP may be possible using new 'omic methods such as metabolomics and genomics. Multi'omic techniques increase our ability to find new mechanisms of injury and regeneration.METHODS: We used metabolomic and genomic data from a randomized controlled trial of patients administered 4 g of APAP per day for 14 days or longer with blood samples obtained at 0 (baseline), 4, 7, 10, 13 and 16 days. We used the highest ALT as the clinical outcome to be predicted in our integrated analysis. We used penalized regression to model the relationship between genetic variants and day 0 metabolite level, and then performed a metabolite-wide colocalization scan to associate the genetically regulated component of metabolite expression with ALT elevation. Genome-wide association study (GWAS) analyses were conducted for ALT elevation and metabolite level using linear regression, with age, sex, and the first five principal components included as covariates. Colocalization was tested via a weighted sum test.RESULTS: Out of the 164 metabolites modeled, 120 met the criteria for predictive accuracy and were retained for genetic analyses. After genomic examination, eight metabolites were found to be under genetic control and predictive of ALT elevation due to therapeutic acetaminophen. The metabolites were: 3-oxalomalate, allantoate, diphosphate, L-carnitine, L-proline, maltose, and ornithine. These genes are important in the tricarboxylic acid cycle (TCA), urea breakdown pathway, glutathione production, mitochondrial energy production, and maltose metabolism.CONCLUSIONS: This multi'omic approach can be used to integrate metabolomic and genomic data allowing identification of genes that control downstream metabolites. These findings confirm prior work that have identified mitochondrial energy production as critical to APAP induced liver injury and have confirmed our prior work that demonstrate the importance of the urea cycle in therapeutic APAP liver injury.PMID:37231244 | DOI:10.1007/s13181-023-00951-5

Genes Immun. 2023 May 25. doi: 10.1038/s41435-023-00206-x. Online ahead of print.ABSTRACTIn order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.PMID:37231189 | DOI:10.1038/s41435-023-00206-x

J Pharm Biomed Anal. 2023 May 22;233:115473. doi: 10.1016/j.jpba.2023.115473. Online ahead of print.ABSTRACTBladder cancer (BC) is frequent cancer affecting the urinary tract and is one of the most prevalent malignancies worldwide. No biomarkers that can be used for effective monitoring of therapeutic interventions for this cancer have been identified to date. This study investigated polar metabolite profiles in urine samples from 100 BC patients and 100 normal controls (NCs) using nuclear magnetic resonance (NMR) and two methods of high-resolution nanoparticle-based laser desorption/ionization mass spectrometry (LDI-MS). Five urine metabolites were identified and quantified using NMR spectroscopy to be potential indicators of bladder cancer. Twenty-five LDI-MS-detected compounds, predominantly peptides and lipids, distinguished urine samples from BC and NCs individuals. Level changes of three characteristic urine metabolites enabled BC tumor grades to be distinguished, and ten metabolites were reported to correlate with tumor stages. Receiver-Operating Characteristics analysis showed high predictive power for all three types of metabolomics data, with the area under the curve (AUC) values greater than 0.87. These findings suggest that metabolite markers identified in this study may be useful for the non-invasive detection and monitoring of bladder cancer stages and grades.PMID:37229797 | DOI:10.1016/j.jpba.2023.115473

Front Nutr. 2023 May 9;10:1135343. doi: 10.3389/fnut.2023.1135343. eCollection 2023.ABSTRACTThe occurrence and development of type 2 diabetes mellitus (T2DM) are closely related to gut microbiota. Jiaotai pill (JTP) is used to treat type 2 diabetes mellitus, with definite efficacy in clinical practice. However, it is not clear whether the therapeutic effect is produced by regulating the changes in gut microbiota and its metabolism. In this study, T2DM rat models were established by a high-fat diet and low-dose streptozotocin (STZ). Based on the pharmacodynamic evaluation, the mechanism of JTP in the treatment of type 2 diabetes mellitus was investigated by fecal metabolism and 16S rRNA gene sequencing. The results showed that JTP decreased blood glucose (FBG, HbA1c) and blood lipid (TC, TG, and LDL) levels and alleviated insulin resistance (FINS, IL-10) in T2DM rats. 16S rRNA gene sequencing results revealed that JTP increased microbiota diversity and reversed the disorder of gut microbiota in T2DM rats, and therefore achieved the therapeutic effect in T2DM. JTP regulated 13 differential flora, which were Actinobacteria, Bacteroidetes, Firmicutes, Proteobacteria, Eubacteriaceae, Prevotellaceae, Ruminococcaceae, Clostridium_IV, Clostridium_XlVa, Eubacterium, Fusicatenibacter, Romboutsia, and Roseburia. Metabolomics analysis showed that JTP interfered with 13 biomarkers to play a therapeutic role in type 2 diabetes mellitus. They were L-Valine, Choline, L-Aspartic acid, Serotonin, L-Lysine, L-Histidine, 3-Hydroxybutyric acid, Pyruvic acid, N-Acetylornithine, Arachidonic acid, L-Tryptophan, L-Alanine, and L-Methionine. KEGG metabolic pathway analysis of the above differential metabolites and gut microbiota by using the MetaboAnalyst database and Picrust software. It was found that JTP treated type 2 diabetes mellitus by affecting metabolic pathways such as amino acid metabolism, carbohydrate metabolism, and lipid metabolism. Spearman correlation analysis revealed high correlations for 7 pharmacological indicators, 12 biomarkers, and 11 gut microbiota. In this study, the therapeutic effect and potential mechanism of JTP on type 2 diabetes mellitus were preliminarily demonstrated by gut microbiota and metabolomics, which could provide a theoretical basis for the treatment of T2DM with JTP.PMID:37229468 | PMC:PMC10203393 | DOI:10.3389/fnut.2023.1135343

Front Endocrinol (Lausanne). 2023 May 9;14:1172290. doi: 10.3389/fendo.2023.1172290. eCollection 2023.ABSTRACTOBJECTIVE: This study aimed to explore the relationship between the plasma metabolites of adolescent obesity and hypertension and whether metabolite alterations had a mediating effort between adolescent obesity and hypertension.METHODS: We applied untargeted ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) to detect the plasma metabolomic profiles of 105 adolescents. All participants were selected randomly based on a previous cross-sectional study. An orthogonal partial least squares- discriminant analysis (OPLS-DA), followed by univariate statistics and enrichment analysis, was used to identify differential metabolites. Using logistic regression for variable selection, an obesity-related metabolite score (OMS, OMS=∑k=1nβnmetabolite n) was constructed from the metabolites identified, and hypertension risk was estimated.RESULTS: In our study, based on P< 0.05, variable importance in projection (VIP) > 1.0, and impact value > 0.1, we identified a total of 12 differential metabolites. Significantly altered metabolic pathways were the sphingolipid metabolism, purine metabolism, pyrimidine metabolism, phospholipid metabolism, steroid hormone biosynthesis, tryptophan, tyrosine, and phenylalanine biosynthesis. The logistic regression selection resulted in a four-metabolite score (thymidine, sphingomyelin (SM) d40:1, 4-hydroxyestradiol, and L-lysinamide), which was positively associated with hypertension risk (odds ratio: 7.79; 95% confidence interval: 2.13, 28.47; for the quintile 4 compared with quartile 1 of OMS) after multivariable adjustment.CONCLUSIONS: The OMS constructed from four differential metabolites was used to predict the risk of hypertension in adolescents. These findings could provide sensitive biomarkers for the early recognition of hypertension in adolescents with obesity.PMID:37229452 | PMC:PMC10203610 | DOI:10.3389/fendo.2023.1172290

Front Plant Sci. 2023 May 9;14:1099375. doi: 10.3389/fpls.2023.1099375. eCollection 2023.ABSTRACTMetal presence in the aquatic ecosystem has increased and diversified over the last decades due to anthropogenic sources. These contaminants cause abiotic stress on living organisms that lead to the production of oxidizing molecules. Phenolic compounds are part of the defense mechanisms countering metal toxicity. In this study, the production of phenolic compounds by Euglena gracilis under three different metal stressors (i.e. cadmium, copper, or cobalt) at sub-lethal concentration was assessed using an untargeted metabolomic approach by mass spectrometry combined with neuronal network analysis (i.e. Cytoscape). The metal stress had a greater impact on molecular diversity than on the number of phenolic compounds. The prevalence of sulfur- and nitrogen-rich phenolic compounds were found in Cd- and Cu-amended cultures. Together these results confirm the impact of metallic stress on phenolic compounds production, which could be utilized to assess the metal contamination in natural waters.PMID:37229138 | PMC:PMC10203486 | DOI:10.3389/fpls.2023.1099375