PubMed

Magn Reson Chem. 2023 May 9. doi: 10.1002/mrc.5356. Online ahead of print.ABSTRACTNMR is one of the most powerful techniques for the analysis of biological samples in the field of metabolomics. However, the high complexity of fluids, tissues or other biological materials taken from living organisms is still a challenge for state-of-the-art pulse sequences, thereby limiting the detection, the identification, and the quantification of metabolites. In this context, the resolution enhancement provided by broadband homonuclear decoupling methods, which allows for simplifying 1 H multiplet patterns into singlets, has placed this so-called pure shift technique as a promising approach to perform metabolic profiling with unparalleled level of detail. In recent years, the many advances achieved in the design of pure shift experiments has paved the way to the analysis of a wide range of biological samples with ultra-high resolution. This review leads the reader from the early days of the main pure shift methods that have been successfully developed over the last decades to address complex samples, to the most recent and promising applications of pure shift NMR to the field of NMR-based metabolomics.PMID:37157858 | DOI:10.1002/mrc.5356

Curr Drug Metab. 2023 May 8. doi: 10.2174/1389200224666230508122240. Online ahead of print.ABSTRACTBACKGROUND: Global xenobiotic profiling (GXP) is to detect and structurally characterize all xenobiotics in biological samples using mainly liquid chromatography-high resolution mass spectrometry (LC-HRMS) based methods. GXP is highly needed in drug metabolism study, food safety testing, forensic chemical analysis, and exposome research. For detecting known or predictable xenobiotics, targeted LC-HRMS data processing methods based on molecular weights, mass defects and fragmentations of analytes are routinely employed. For profiling unknown xenobiotics, untargeted and LC-HRMS based metabolomics and background subtraction-based approaches are required.OBJECTIVE: This study aimed to evaluate the effectiveness of untargeted metabolomics and the precise and thorough background subtraction (PATBS) in GXP of rat plasma.METHODS: Rat plasma samples collected from an oral administration of nefazodone (NEF) or Glycyrrhizae Radix et Rhizoma (Gancao, GC) were analyzed by LC-HRMS. NEF metabolites and GC components in rat plasma were thoroughly searched and characterized via processing LC-HRMS datasets using targeted and untargeted methods.RESULTS: PATBS detected 68 NEF metabolites and 63 GC components, while the metabolomic approach (MS-DIAL) found 67 NEF metabolites and 60 GC components in rat plasma. The two methods found 79 NEF metabolites and 80 GC components with 96% and 91% successful rates, respectively.CONCLUSION: Metabolomics methods are capable of GXP and measuring alternations of endogenous metabolites in a group of biological samples, while PATBS is more suited for sensitive GXP of a single biological sample. A combination of metabolomics and PATBS approaches can generate better results in the untargeted profiling of unknown xenobiotics.PMID:37157207 | DOI:10.2174/1389200224666230508122240

Front Immunol. 2023 Apr 20;14:1157702. doi: 10.3389/fimmu.2023.1157702. eCollection 2023.ABSTRACTINTRODUCTION: Although children seem to be less susceptible to COVID-19, some of them develop a rare but serious hyperinflammatory condition called multisystem inflammatory syndrome in children (MIS-C). While several studies describe the clinical conditions of acute MIS-C, the status of convalescent patients in the months after acute MIS-C is still unclear, especially the question of persistence of changes in the specific subpopulations of immune cells in the convalescent phase of the disease.METHODS: We therefore analyzed peripheral blood of 14 children with MIS-C at the onset of the disease (acute phase) and 2 to 6 months after disease onset (post-acute convalescent phase) for lymphocyte subsets and antigen-presenting cell (APC) phenotype. The results were compared with six healthy age-matched controls.RESULTS: All major lymphocyte populations (B cells, CD4 + and CD8+ T cells, and NK cells) were decreased in the acute phase and normalized in the convalescent phase. T cell activation was increased in the acute phase, followed by an increased proportion of γ/δ-double-negative T cells (γ/δ DN Ts) in the convalescent phase. B cell differentiation was impaired in the acute phase with a decreased proportion of CD21 expressing, activated/memory, and class-switched memory B cells, which normalized in the convalescent phase. The proportion of plasmacytoid dendritic cells, conventional type 2 dendritic cells, and classical monocytes were decreased, while the proportion of conventional type 1 dendritic cells was increased in the acute phase. Importantly the population of plasmacytoid dendritic cells remained decreased in the convalescent phase, while other APC populations normalized. Immunometabolic analysis of peripheral blood mononuclear cells (PBMCs) in the convalescent MIS-C showed comparable mitochondrial respiration and glycolysis rates to healthy controls.CONCLUSIONS: While both immunophenotyping and immunometabolic analyzes showed that immune cells in the convalescent MIS-C phase normalized in many parameters, we found lower percentage of plasmablasts, lower expression of T cell co-receptors (CD3, CD4, and CD8), an increased percentage of γ/δ DN Ts and increased metabolic activity of CD3/CD28-stimulated T cells. Overall, the results suggest that inflammation persists for months after the onset of MIS-C, with significant alterations in some immune system parameters, which may also impair immune defense against viral infections.PMID:37153551 | PMC:PMC10157053 | DOI:10.3389/fimmu.2023.1157702

Front Endocrinol (Lausanne). 2023 Apr 20;14:1143755. doi: 10.3389/fendo.2023.1143755. eCollection 2023.ABSTRACTBACKGROUND: Vitamin D affects adipogenesis, oxidative stress, inflammation, secretion of adipocytokines, lipid metabolism and thermogenesis. Some researchers postulate that those effects could be exerted by the influence of vitamin D on chemerin levels.AIM OF THE STUDY: We aimed to investigate if there is a link between serum 25-hydroksyvitamin D [25(OH)D], chemerin and metabolic profile in overweight and obese children before and after vitamin D supplementation.MATERIAL AND METHODS: The prospective study included 65 overweight and obese children aged 9.08-17.5 years and 26 peers as a control. None of the patients in the study group had received vitamin D within the last twelve months before the study.RESULTS: The study group had lower baseline 25(OH)D (p<0.001) and higher chemerin (p<0.001), triglycerides (TG, p<0.001), triglycerides/high density lipoprotein cholesterol (TG/HDL-C, p<0.001), C-reactive protein (CRP, p<0.05), fasting insulin (p<0.001), Homeostasis Model Assessment - Insulin Resistance (HOMA-IR, p<0.001), alanine aminotransferase (ALT, p<0.001) and uric acid (p<0.001) compared to the control group. Baseline vitamin D was related to fasting insulin (R=-0.29, p=0.021), HOMA-IR (R=-0.30, p=0.016), HDL-C (R=0.29, p=0.020) and uric acid (R=-0.28, p=0.037) in the study group. Baseline chemerin was related to insulin at 30' (R=0.27, p=0.030), 60' (R=0.27, p=0.033), 90' (R=0.26, p=0.037) and 120' (R=0.26, p=0.040) during the oral glucose tolerance test (OGTT) and ALT (R=0.25, p=0.041) in the study group. Correlation between vitamin D and chemerin (R=-0.39, p=0.046) was found only in the control group. After six months of vitamin D supplementation a decrease in CRP (p<0.01), total cholesterol (p<0.05), ALT (p<0.01), glucose at 150' OGTT (p<0.05) was observed. Moreover, we noticed a tendency for negative association between 25(OH)D and chemerin levels (p=0.085). Multivariable backward linear regression models were build using baseline vitamin D, baseline chemerin and six months chemerin as the dependent variables.CONCLUSIONS: Our study confirmed that vitamin D has positive effect on metabolic profile in overweight and obese children. The relationship between vitamin D and chemerin is not clear, nevertheless we have observed a tendency to decrease chemerin concentrations after improving vitamin D status, even without a significant reduction in body fat mass.PMID:37152969 | PMC:PMC10159269 | DOI:10.3389/fendo.2023.1143755

Phytochemistry. 2023 May 6:113715. doi: 10.1016/j.phytochem.2023.113715. Online ahead of print.ABSTRACTL'Hér. (Myrtaceae) is one of the economically most important and widely cultivated trees for wood crop purposes worldwide. Climatic changes together with the constant need to expand plantations to areas that do not always provide optimal conditions for plant growth highlight the need to assess the impact of abiotic stresses on eucalypt trees. We aimed to unveil the drought effect on the leaf metabolome of commercial clones with differential phenotypic response to this stress. For this, seedlings of 13 clones were grown at well-watered (WW) and water-deficit (WD) conditions and their leaf extracts were subjected to comparative analysis using ultra-high performance liquid chromatography coupled to mass spectrometry (UPLC-MS) and nuclear magnetic resonance spectroscopy (NMR). UPLC-MS and NMR analyses led to the annotation of over 100 molecular features of classes such as cyclitols, phenolics, flavonoids, formylated phloroglucinol compounds (FPCs) and fatty acids. Multivariate data analysis was employed for specimens' classifications and markers identification from both platforms. The results obtained in this work allowed us to classify clones differing in drought tolerance. Classification models were validated using an extra subset of samples. Tolerant plants exposed to water deficit accumulated arginine, gallic acid derivatives, caffeic acid and tannins at higher levels. In contrast, stressed drought-sensitive clones were characterised by a significant reduction in glucose, inositol and shikimic acid levels. These changes in contrasting drought response eucalypt pave ways for differential outcomes of tolerant and susceptible phenotypes. Under optimal growth conditions, all clones were rich in FPCs. These results can be used for early screening of tolerant clones and to improve our understanding of the role of these biomarkers in Eucalyptus tolerance to drought stress.PMID:37156433 | DOI:10.1016/j.phytochem.2023.113715

Metabolism. 2023 May 6:155587. doi: 10.1016/j.metabol.2023.155587. Online ahead of print.ABSTRACTBACKGROUND: Systemic sclerosis (SSc) is a chronic and systemic autoimmune disease marked by the skin and visceral fibrosis. Metabolic alterations have been found in SSc patients; however, serum metabolomic profiling has not been thoroughly conducted. Our study aimed to identify alterations in the metabolic profile in both SSc patients before and during treatment, as well as in mouse models of fibrosis. Furthermore, the associations between metabolites and clinical parameters and disease progression were explored.METHODS: High-performance liquid chromatography quadrupole time-of-flight mass spectrometry (HPLC-Q-TOF-MS)/MS was performed in the serum of 326 human samples and 33 mouse samples. Human samples were collected from 142 healthy controls (HC), 127 newly diagnosed SSc patients without treatment (SSc baseline), and 57 treated SSc patients (SSc treatment). Mouse serum samples were collected from 11 control mice (NaCl), 11 mice with bleomycin (BLM)-induced fibrosis and 11 mice with hypochlorous acid (HOCl)-induced fibrosis. Both univariate analysis and multivariate analysis (orthogonal partial least-squares discriminate analysis (OPLS-DA)) were conducted to unravel differently expressed metabolites. KEGG pathway enrichment analysis was performed to characterize the dysregulated metabolic pathways in SSc. Associations between metabolites and clinical parameters of SSc patients were identified by Pearson's or Spearman's correlation analysis. Machine learning (ML) algorithms were applied to identify the important metabolites that have the potential to predict the progression of skin fibrosis.RESULTS: The newly diagnosed SSc patients without treatment showed a unique serum metabolic profile compared to HC. Treatment partially corrected the metabolic changes in SSc. Some metabolites (phloretin 2'-O-glucuronide, retinoyl b-glucuronide, all-trans-retinoic acid, and betaine) and metabolic pathways (starch and sucrose metabolism, proline metabolism, androgen and estrogen metabolism, and tryptophan metabolism) were dysregulated in new-onset SSc, but restored upon treatment. Some metabolic changes were associated with treatment response in SSc patients. Metabolic changes observed in SSc patients were mimicked in murine models of SSc, indicating that they may reflect general metabolic changes associated with fibrotic tissue remodeling. Several metabolic changes were associated with SSc clinical parameters. The levels of allysine and all-trans-retinoic acid were negatively correlated, while D-glucuronic acid and hexanoyl carnitine were positively correlated with modified Rodnan skin score (mRSS). In addition, a panel of metabolites including proline betaine, phloretin 2'-O-glucuronide, gamma-linolenic acid and L-cystathionine were associated with the presence of interstitial lung disease (ILD) in SSc. Specific metabolites identified by ML algorithms, such as medicagenic acid 3-O-b-D-glucuronide, 4'-O-methyl-(-)-epicatechin-3'-O-beta-glucuronide, valproic acid glucuronide, have the potential to predict the progression of skin fibrosis.CONCLUSIONS: Serum of SSc patients demonstrates profound metabolic changes. Treatment partially restored the metabolic changes in SSc. Moreover, certain metabolic changes were associated with clinical manifestations such as skin fibrosis and ILD, and could predict the progression of skin fibrosis.PMID:37156409 | DOI:10.1016/j.metabol.2023.155587

Environ Res. 2023 May 6:116043. doi: 10.1016/j.envres.2023.116043. Online ahead of print.ABSTRACTWildlife is exposed to mixtures of environmental contaminants that affect health and population dynamics. Exposure to toxic heavy metals originating from anthropogenic sources may exert metabolic effects at even low exposure concentrations. Here we investigated the relationships between heavy metal exposure and metabolic changes in the migratory bird pink-footed goose (Anser brachyrhynchus). We used blood pellet and blood plasma samples from 27 free-ranging pink-footed geese to study heavy metal (Cd, Cr, Hg, and Pb) exposure in relation to the metabolome. The results relate blood concentrations of Cd (range: 0.218-1.09 ng/g), Cr (range: 0.299-5.60 ng/g), and Hg (range: 2.63-6.00 ng/g) to signal areas of fatty acids and other lipids, while no correlations were identified for Pb level (range: 21.0-64.2 ng/g) exposure. Lipid signal areas were negatively associated with concentrations of Cr and positively associated with Hg exposure (both p < 0.05). α-Linolenic acid and 9-oxononanoic acid were negatively correlated to Cr exposure (both p < 0.05) and were related in the α-linolenic acid metabolism pathway. Compared to known thresholds for aviary species, the heavy metal concentrations are below levels of toxicity, which may explain the low number of metabolites that significantly change. Nevertheless, the heavy metal exposure is still correlated to changes in the lipid metabolism that may reduce migrating birds' breeding success and increase mortality for an exposed part of the population.PMID:37156351 | DOI:10.1016/j.envres.2023.116043

Chemosphere. 2023 May 6:138864. doi: 10.1016/j.chemosphere.2023.138864. Online ahead of print.ABSTRACTHair has recently emerged as a biospecimen for characterizing the long-term chemical exposome in biomonitoring investigations spanning several months, as chemical compounds circulating in the bloodstream accumulate in hair. Although there has been interest in using human hair as a biospecimen for exposome studies, it has yet to be widely adopted compared to blood and urine. Here, we applied a high-resolution mass spectrometry (HRMS)-based suspect screening strategy to characterize the long-term chemical exposome in human hair. Hair samples were collected from 70 subjects and cut into 3 cm segments, which were then mixed to prepare pooled samples. The pooled hair samples underwent a sample preparation procedure, and the hair extracts were further analyzed using an HRMS-based suspect screening approach. An in-house chemical suspect list containing 1227 chemical entries from National Report on Human Exposure to Environmental Chemicals (Report) published by the U.S. CDC and the Exposome-Explorer 3.0 database developed by the WHO was subsequently used to screen and filter the suspect features against the HRMS dataset. Overall, we matched 587 suspect features in the HRMS dataset to 246 unique chemical formulas in the suspect list, and the structures of 167 chemicals were further identified through a fragmentation analysis. Among these, chemicals such as mono-2-ethylhexyl phthalate, methyl paraben, and 1-naphthol, which have been detected in the urine or blood for exposure assessment, were also identified in human hair. This suggests that hair reflects the accumulation of environmental compounds to which an individual is exposed. Exposure to exogenous chemicals may exert adverse effects on cognitive function, and we discovered 15 chemicals in human hair that may contribute to the pathogenesis of Alzheimer's disease. This finding suggests that human hair may be a promising biospecimen for monitoring long-term exposure to multiple environmental chemicals and perturbations in endogenous chemicals in biomonitoring investigations.PMID:37156292 | DOI:10.1016/j.chemosphere.2023.138864

J Gerontol A Biol Sci Med Sci. 2023 May 9:glad122. doi: 10.1093/gerona/glad122. Online ahead of print.ABSTRACTBiological mechanisms that lead to multimorbidity are mostly unknown, and metabolomic profiles are promising to explain different pathways in the aging process. The aim of this study was to assess the prospective association between plasma fatty acids and other lipids, and multimorbidity in older adults. Data were obtained from the Spanish Seniors-ENRICA 2 cohort, comprising non-institutionalized adults ≥65 years old. Blood samples were obtained at baseline and after a two-year follow-up period for a total of 1488 subjects. Morbidity was also collected at baseline and end of the follow-up from electronic health records. Multimorbidity was defined as a quantitative score, after weighting morbidities (from a list of 60 mutually exclusive chronic conditions) by their regression coefficients on physical functioning. Generalized estimating equation models were employed to assess the longitudinal association between fatty acids and other lipids, and multimorbidity, and stratified analyses by diet quality, measured with the Alternative Healthy Eating Index-2010, were also conducted. Among study participants, higher concentrations of omega-6 fatty acids [coef. per 1-SD increase (95% CI) = -0.76 (-1.23, -0.30)], phosphoglycerides [-1.26 (-1.77, -0.74)], total cholines [-1.48 (-1.99, -0.96)], phosphatidylcholines [-1.23 (-1.74, -0.71)], and sphingomyelins [-1.65 (-2.12, -1.18)], were associated with lower multimorbidity scores. The strongest associations were observed for those with a higher diet quality. Higher plasma concentrations of omega-6 fatty acids, phosphoglycerides, total cholines, phosphatidylcholines, and sphingomyelins were prospectively associated with lower multimorbidity in older adults, while diet quality could modulate the associations found. These lipids may serve as risk markers for multimorbidity.PMID:37156635 | DOI:10.1093/gerona/glad122

Food Chem. 2023 Feb 17;422:135716. doi: 10.1016/j.foodchem.2023.135716. Online ahead of print.ABSTRACTYunnan pickled tea is produced from fresh tea-leaves through fixation, rolling, anaerobic fermentation and sun-drying. In this study, widely targeted metabolomics using UHPLC-QQQ-MS/MS and HPLC analysis were carried out to elaborate its quality formation during the whole process. Results confirmed the contribution of preliminary treatments and anaerobic fermentation to the quality formation. A total of 568 differential metabolites (VIP > 1.0, P < 0.05, FC > 1.50 or < 0.67) were screened through OPLS-DA. (-)-Epigallocatechin and (-)-epicatechin significantly (P < 0.05) increased from the hydrolyzation of ester catechins, such as (-)-epigallocatechin gallate and (-)-epicatechin gallate in anaerobic fermentation. Additionally, the anaerobic fermentation promoted vast accumulations of seven essential amino acids, four phenolic acids, three flavones and flavone glycosides, pelargonidin and pelargonidin glycosides, flavonoids and flavonoid glycosides (i.e. kaempferol, quercetin, taxifolin, apigenin, myricetin, luteolin and their glycosides) through relevant N-methylation, O-methylation, hydrolyzation, glycosylation and oxidation.PMID:37156017 | DOI:10.1016/j.foodchem.2023.135716

Anal Chem. 2023 May 8. doi: 10.1021/acs.analchem.3c01109. Online ahead of print.ABSTRACTMetabolic footprinting as a convenient and non-invasive cell metabolomics strategy relies on monitoring the whole extracellular metabolic process. It covers nutrient consumption and metabolite secretion of in vitro cell culture, which is hindered by low universality owing to pre-treatment of the cell medium and special equipment. Here, we report the design and a variety of applicability, for quantifying extracellular metabolism, of fluorescently labeled single-stranded DNA (ssDNA)-AuNP encoders, whose multi-modal signal response is triggered by extracellular metabolites. We constructed metabolic response profiling of cells by detecting extracellular metabolites in different tumor cells and drug-induced extracellular metabolites. We further assessed the extracellular metabolism differences using a machine learning algorithm. This metabolic response profiling based on the DNA-AuNP encoder strategy is a powerful complement to metabolic footprinting, which significantly applies potential non-invasive identification of tumor cell heterogeneity.PMID:37155931 | DOI:10.1021/acs.analchem.3c01109

Anal Chem. 2023 May 8. doi: 10.1021/acs.analchem.3c00804. Online ahead of print.ABSTRACTTargeted metabolomics has been broadly used for metabolite measurement due to its good quantitative linearity and simple metabolite annotation workflow. However, metabolite interference, the phenomenon where one metabolite generates a peak in another metabolite's MRM setting (Q1/Q3) with a close retention time (RT), may lead to inaccurate metabolite annotation and quantification. Besides isomeric metabolites having the same precursor and product ions that may interfere with each other, we found other metabolite interferences as the result of inadequate mass resolution of triple-quadruple mass spectrometry and in-source fragmentation of metabolite ions. Characterizing the targeted metabolomics data using 334 metabolite standards revealed that about 75% of the metabolites generated measurable signals in at least one other metabolite's MRM setting. Different chromatography techniques can resolve 65-85% of these interfering signals among standards. Metabolite interference analysis combined with the manual inspection of cell lysate and serum data suggested that about 10% out of ∼180 annotated metabolites were mis-annotated or mis-quantified. These results highlight that a thorough investigation of metabolite interference is necessary for accurate metabolite measurement in targeted metabolomics.PMID:37155916 | DOI:10.1021/acs.analchem.3c00804

Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2220334120. doi: 10.1073/pnas.2220334120. Epub 2023 May 8.ABSTRACTEsophageal squamous cell carcinoma (ESCC) is a deadly disease with few prevention or treatment options. ESCC development in humans and rodents is associated with Zn deficiency (ZD), inflammation, and overexpression of oncogenic microRNAs: miR-31 and miR-21. In a ZD-promoted ESCC rat model with upregulation of these miRs, systemic antimiR-31 suppresses the miR-31-EGLN3/STK40-NF-κB-controlled inflammatory pathway and ESCC. In this model, systemic delivery of Zn-regulated antimiR-31, followed by antimiR-21, restored expression of tumor-suppressor proteins targeted by these specific miRs: STK40/EGLN3 (miR-31), PDCD4 (miR-21), suppressing inflammation, promoting apoptosis, and inhibiting ESCC development. Moreover, ESCC-bearing Zn-deficient (ZD) rats receiving Zn medication showed a 47% decrease in ESCC incidence vs. Zn-untreated controls. Zn treatment eliminated ESCCs by affecting a spectrum of biological processes that included downregulation of expression of the two miRs and miR-31-controlled inflammatory pathway, stimulation of miR-21-PDCD4 axis apoptosis, and reversal of the ESCC metabolome: with decrease in putrescine, increase in glucose, accompanied by downregulation of metabolite enzymes ODC and HK2. Thus, Zn treatment or miR-31/21 silencing are effective therapeutic strategies for ESCC in this rodent model and should be examined in the human counterpart exhibiting the same biological processes.PMID:37155893 | DOI:10.1073/pnas.2220334120

Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2219953120. doi: 10.1073/pnas.2219953120. Epub 2023 May 8.ABSTRACTThe Golgi is a membrane-bound organelle that is essential for protein and lipid biosynthesis. It represents a central trafficking hub that sorts proteins and lipids to various destinations or for secretion from the cell. The Golgi has emerged as a docking platform for cellular signaling pathways including LRRK2 kinase whose deregulation leads to Parkinson disease. Golgi dysfunction is associated with a broad spectrum of diseases including cancer, neurodegeneration, and cardiovascular diseases. To allow the study of the Golgi at high resolution, we report a rapid Golgi immunoprecipitation technique (Golgi-IP) to isolate intact Golgi mini-stacks for subsequent analysis of their content. By fusing the Golgi-resident protein TMEM115 to three tandem HA epitopes (GolgiTAG), we purified the Golgi using Golgi-IP with minimal contamination from other compartments. We then established an analysis pipeline using liquid chromatography coupled with mass spectrometry to characterize the human Golgi proteome, metabolome, and lipidome. Subcellular proteomics confirmed known Golgi proteins and identified proteins not previously associated with the Golgi. Metabolite profiling established the human Golgi metabolome and revealed the enrichment of uridine-diphosphate (UDP) sugars and their derivatives, which is consistent with their roles in protein and lipid glycosylation. Furthermore, targeted metabolomics validated SLC35A2 as the subcellular transporter for UDP-hexose. Finally, lipidomics analysis showed that phospholipids including phosphatidylcholine, phosphatidylinositol, and phosphatidylserine are the most abundant Golgi lipids and that glycosphingolipids are enriched in this compartment. Altogether, our work establishes a comprehensive molecular map of the human Golgi and provides a powerful method to study the Golgi with high precision in health and disease.PMID:37155866 | DOI:10.1073/pnas.2219953120

Proc Natl Acad Sci U S A. 2023 May 16;120(20):e2214942120. doi: 10.1073/pnas.2214942120. Epub 2023 May 8.ABSTRACTAberrant accumulation of succinate has been detected in many cancers. However, the cellular function and regulation of succinate in cancer progression is not completely understood. Using stable isotope-resolved metabolomics analysis, we showed that the epithelial mesenchymal transition (EMT) was associated with profound changes in metabolites, including elevation of cytoplasmic succinate levels. The treatment with cell-permeable succinate induced mesenchymal phenotypes in mammary epithelial cells and enhanced cancer cell stemness. Chromatin immunoprecipitation and sequence analysis showed that elevated cytoplasmic succinate levels were sufficient to reduce global 5-hydroxymethylcytosinene (5hmC) accumulation and induce transcriptional repression of EMT-related genes. We showed that expression of procollagen-lysine,2-oxoglutarate 5-dioxygenase 2 (PLOD2) was associated with elevation of cytoplasmic succinate during the EMT process. Silencing of PLOD2 expression in breast cancer cells reduced succinate levels and inhibited cancer cell mesenchymal phenotypes and stemness, which was accompanied by elevated 5hmC levels in chromatin. Importantly, exogenous succinate rescued cancer cell stemness and 5hmC levels in PLOD2-silenced cells, suggesting that PLOD2 promotes cancer progression at least partially through succinate. These results reveal the previously unidentified function of succinate in enhancing cancer cell plasticity and stemness.PMID:37155842 | DOI:10.1073/pnas.2214942120

Metabolomics. 2023 May 8;19(5):50. doi: 10.1007/s11306-023-02012-y.ABSTRACTINTRODUCTION: Gestational hypertension (GH) is defined as the presence of systolic blood pressure (BP) ≥ 140 mm Hg and/or diastolic BP ≥ 90 mm Hg, measured at least 4 h apart after 20 weeks of gestation. Early identification of women at high-risk of developing GH could contribute significantly towards improved maternal and fetal outcomes.OBJECTIVES: To determine early metabolic biomarkers in women with GH as compared with normotensive women.METHODS: Serum samples were collected from subjects during three stages of their pregnancy: 8-12 weeks, 18-20 weeks and after 28 weeks (< 36 weeks) of gestation and studied using nuclear magnetic resonance (NMR) metabolomics approach. Multivariate and univariate analyses were performed to determine the significantly altered metabolites in GH women.RESULTS: A total of 10 metabolites, including isoleucine, glutamine, lysine, proline, histidine, phenylalanine, alanine, carnitine, N-acetyl glycoprotein and lactic acid were observed to be significantly downregulated during all pregnancy stages in women with GH as compared with controls. Furthermore, expression of 5 metabolites in the first trimester i.e., phenylalanine [area under the curve (AUC) = 0.745], histidine [AUC = 0.729], proline [AUC = 0.722], lactic acid [AUC = 0.722], and carnitine [AUC = 0.714] exhibited highest potential in discriminating GH from normotensive women.CONCLUSION: The present study is the first of its kind to identify significantly altered metabolites that have the potential to discriminate between women at risk of developing GH and normotensive women across three trimesters of pregnancy. This opens up the possibility of exploring these metabolites as potential early predictive markers of GH.PMID:37154845 | DOI:10.1007/s11306-023-02012-y

Mol Nutr Food Res. 2023 May 8:e2300056. doi: 10.1002/mnfr.202300056. Online ahead of print.ABSTRACTSCOPE: The aging biomarkers are alternatives and none of them could act as a strong predictor of frailty during the progression of aging. Several studies revealed the relationship between metabolites and frailty or gut microbiota and frailty. However, the connection between metabolites and gut microbiota in non-robust older adults hasn't been discussed yet. Our study aims to combine the findings of serum metabolites and gut microbiota in non-robust subjects as a possible diagnostic biomarker.METHODS AND RESULTS: Frailty-related assessments were conducted to ensure the discrimination of non-robustness. The serum and fecal were collected for serum metabolomics and gut microbiota analysis. Robust and non-robust subjects showed very different gut microbial compositions. Among the gut microbial differences, Escherichia/Shigella and its higher taxonomic ranks were found to have the most discriminative abundance among compared groups. More importantly, the abundance of Escherichia/Shigella was found to be positively correlated (p<0.05) with the level of discriminant metabolites, such as serum oxoglutarate, glutamic acid, and 1-methyladenosine.CONCLUSION: These results indicate that the obvious interrelation between gut microbiota and serum metabolites in non-robust older adults. Besides, our findings suggested that Escherichia/Shigella could be a potential biomarker candidate for robustness sub-phenotypic identification. This article is protected by copyright. All rights reserved.PMID:37154673 | DOI:10.1002/mnfr.202300056

Alcohol Alcohol. 2023 May 8:agad034. doi: 10.1093/alcalc/agad034. Online ahead of print.ABSTRACTAIM: Differentiating alcoholic hepatitis (AH) from acute decompensation of alcoholic cirrhosis (DC) is challenging, as the presentation and biochemistry are similar. We aimed to identify potential metabolomic biomarkers to differentiate between AH and DC, and to predict short-term mortality.METHODS: We included consecutive biopsy proven AH and DC patients, which were managed according to current guidelines and followed up until the end of the study. Untargeted metabolomics was assessed in all patients at baseline. Specific analyses were successively performed to identify potential biomarkers, which were further semi-quantitatively analysed against relevant clinical endpoints.RESULTS: Thirty-four patients with AH and 37 with DC were included. UHPLC-MS analysis identified 83 molecules potentially differentiating between AH and DC. C16-Sphinganine-1P (S1P) was the most increased, whereas Prostaglandin E2 (PGE2) was the most decreased. The PGE2/S1P ratio < 1.03 excellently discriminates between AH and DC: AUC 0.965 (p < 0.001), Se 90%, Sp 100%, PPV 0.91, NPV 1, and diagnostic accuracy 95%. This ratio is not influenced by the presence of infection (AUC 0.967 vs. 0.962), correlates with the Lille score at 7 days (r = -0.60; P = 0.022) and tends to be lower in corticosteroid non-responders as compared with patients who responded [0.85(±0.02) vs. 0.89(±0.05), P = 0.069]. Additionally, decreased ursodeoxycholic acid levels are correlated with MELD and Maddrey scores and predict mortality with a 77.27% accuracy (NPV = 100%).CONCLUSION: This study suggests the PGE2 (decreased)/S1P (increased) ratio as a biomarker to differentiate AH from DC. The study also finds that low levels of ursodeoxycholic acid could predict increased mortality in AH.PMID:37154612 | DOI:10.1093/alcalc/agad034

Oral Dis. 2023 May 8. doi: 10.1111/odi.14594. Online ahead of print.ABSTRACTOBJECTIVES: The transforming growth factor-Beta (TGF-ß) pathway may be involved in the radioresistance of head and neck squamous cell carcinoma (HNSCC). This study analyzed TGF-ß receptor 1 (TGFBR1) expression in HNSCC patients and evaluated the antineoplastic and radiosensitizing effects of vactosertib, a novel TGFBR1 inhibitor, in vitro.MATERIALS AND METHODS: TGFBR1 expression was examined in HNSCC patients at the mRNA level in silico and the protein level by immunohistochemistry, including surgical specimens of primary tumors, matched lymph node metastasis, and recurrent disease. Furthermore, a novel small molecule TGFBR1 inhibitor was evaluated in HNSCC cell lines. Finally, an indirect coculture model using patient-derived cancer-associated fibroblasts was applied to mimic the tumor microenvironment.RESULTS: Patients with high TGFBR1 mRNA levels showed significantly worse overall survival in silico (OS, p = 0.024). At the protein level, an association between TGFBR1+ tumor and OS was observed for the subgroup with TGFBR1-stroma (p = 0.001). Those results prevailed in multivariable analysis. Inhibition of TGFBR1 showed antineoplastic effects in vitro. In combination with radiation, vactosertib showed synergistic effects.CONCLUSION: Our results indicate a high risk of death in tumorTGFBR1+ |stromaTGFBR1- expressing patients. In vitro data suggest a potential radiosensitizing effect of TGFBR1 inhibition by vactosertib.PMID:37154295 | DOI:10.1111/odi.14594

J Agric Food Chem. 2023 May 8. doi: 10.1021/acs.jafc.2c08372. Online ahead of print.ABSTRACTIn China, the endemic species Garcinia yunnanensis and native Garcinia xanthochymus are known as edible and medicinal plants. However, a systematic metabolomic and bioactivity evaluation of different plant parts from both species is lacking. In this study, comprehensive investigations of 11 plant parts of G. yunnanensis and 10 of G. xanthochymus employing UPLC-ESI-QTOF-MSE-based metabolomic analysis in conjunction with three bioactivity assays were undertaken. A customized chemotaxonomic-based in-house library containing 6456 compounds was constructed and coupled to the Progenesis QI informatic platform for metabolite annotations. From these two species, a total of 235 constituents were characterized using multiple criteria. Differences in metabolite profiles between the plant parts within each species were uncovered using multivariate analysis. Based on orthogonal partial least-squares discriminant analysis (OPLS-DA), 23 markers were identified as highly differential metabolites from G. xanthochymus and 20 from G. yunnanensis. Comparative assessment of the biological assays revealed the activity variations among different plant parts. The seeds of both species and G. yunnanensis latex exhibited excellent cytotoxic and antibacterial activities, while G. xanthochymus roots and G. yunnanensis arils showed strong anti-inflammatory effects. S-plot analysis identified 26 potential biomarkers for the observed activities, including the known cytotoxic agent cycloxanthochymol and the anti-inflammatory compound garcimultiflorone B, which likely explains some of the potent observed bioactivity.PMID:37154236 | DOI:10.1021/acs.jafc.2c08372