PubMed

Macrophages and Metabolism in the Tumor Microenvironment. Cell Metab. 2019 Jul 02;30(1):36-50 Authors: Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L Abstract Tumor-associated macrophages (TAMs) constitute a plastic and heterogeneous cell population of the tumor microenvironment (TME) that can account for up to 50% of some solid neoplasms. Most often, TAMs support disease progression and resistance to therapy by providing malignant cells with trophic and nutritional support. However, TAMs can mediate antineoplastic effects, especially in response to pharmacological agents that boost their phagocytic and oxidative functions. Thus, TAMs and their impact on the overall metabolic profile of the TME have a major influence on tumor progression and resistance to therapy, de facto constituting promising targets for the development of novel anticancer agents. Here, we discuss the metabolic circuitries whereby TAMs condition the TME to support tumor growth and how such pathways can be therapeutically targeted. PMID: 31269428 [PubMed - in process]

Cell-Based Metabolomics for Untargeted Screening and Prioritization of Vertebrate-Active Stressors in Streams Across the United States. Environ Sci Technol. 2019 Jul 03;: Authors: Collette TW, Ekman D, Zhen H, Nguyen H, Bradley PM, Teng Q Abstract The U.S. Geological Survey and the U.S. Environmental Protection Agency have assessed contaminants in 38 streams across the U.S., using an extensive suite of target-chemical analysis methods along with a variety of biological effects tools. Here we report zebrafish liver (ZFL) cell-culture based NMR metabolomic analysis of these split stream samples. We used this untargeted approach to evaluate the sites according to overall impact on the ZFL metabolome and found that neither the total number of organics detected at the sites, nor their cumulative concentrations, were good predictors of these impacts. Further, we used partial-least squares regression to compare ZFL endogenous metabolite profiles to values for 455 potential stressors (organics, inorganics, and physical properties) measured in these waters and found that the profiles covaried with at most 280 of the stressors, which were subsequently ranked into quartiles based on the strength of their covariance. While contaminants of emerging concern (CECs) were well represented in the top, most strongly, covarying quartile - suggesting considerable potential for eliciting biological responses at these sites - there was even higher representation of various well-characterized legacy contaminants (e.g., PCBs). These results emphasize the importance of complementing chemical analysis with untargeted bioassays to help focus regulatory efforts on the most significant ecosystem threats. PMID: 31268696 [PubMed - as supplied by publisher]

A Digital Method to Quantify Type I IFN. J Interferon Cytokine Res. 2019 Jul 03;: Authors: Rius-Rocabert S, Presa JL, Esteban-Rubio S, Ayuso-Sacido A, Nistal-Villan E Abstract Interferon (IFN), the first ever-described cytokine, has a potent activity against viruses. Soon since its discovery, quantification of IFN has been an important issue. Most of the traditional methods to measure IFN biological activity rely on indirect methods that quantify dyes retained by IFN-protected cells against a lytic virus, or by techniques that indirectly quantify viral replication by measuring the expression level of viral-encoded reporter proteins such as the green fluorescent protein (GFP). In both cases, the IFN units are determined by the quantification of an effective dose 50, defined as the IFN dose that prevents 50% cell death of 50% reduction of the maximal amount of GFP intensity. In this study we propose the use of an alternative approach to measure IFN activity by calculating the minimal IFN dose 50 as the amount of IFN able to completely protect 50% of the cells from infection measured by the total absence of virus-dependent GFP signal in a cell culture plate. This sensitive approach could be used to easily quantify the Z value to determine IFN bioassay robustness. We believe that this approximation could be interesting to be considered by the IFN community. PMID: 31268382 [PubMed - as supplied by publisher]

Mitochondrial activity contributes to impaired renal metabolic homeostasis and renal pathology in STZ-induced diabetic mice. Am J Physiol Renal Physiol. 2019 Jul 03;: Authors: Wu M, Li S, Yu X, Chen W, Ma H, Shao C, Zhang Y, Zhang A, Huang S, Jia Z Abstract Diabetic nephropathy (DN) has become the main cause of end-stage renal disease worldwide while the efficacy of current therapeutic strategies on DN remains unsatisfactory. Recent researches reported the involvement of metabolic re-arrangement in the pathological process of DN, and of all the disturbances in metabolism, mitochondria serve as key regulatory hubs. In the present study, high-resolution mass spectrometry-based none-target metabolomics was employed to uncover the metabolic characteristics of early diabetic kidney with or without the inhibition of mitochondrial activity. At first, we observed a moderate enhancement of mitochondrial complex-1 activity in diabetic kidney, which was completely normalized by a specific mitochondrial complex-1 inhibitor rotenone (ROT). Meanwhile, metabolomics data indicated over-activated pentose phosphate pathway, purine and pyrimidine metabolism, hexosamine biosynthetic pathway, and Kreb cycle, which were strikingly corrected by ROT. In addition, ROT also strikingly corrected imbalanced redox homeostasis possibly by increasing the ratio of antioxidant metabolites GSH and NAPDH against their oxidative form. In agreement with the improved metabolic status and oxidative response, ROT attenuated glomerular and tubular injury efficiently. The fibrotic markers (fibronectin, α-SMA, collagen I and collagen III), inflammatory factors (TNF-ᵯC;, IL-1ᵯD;, and ICAM-1) and oxidative stress were all markedly blocked by ROT. In vitro, ROT dose-dependently attenuated high glucose-induced proliferation and extracellular matrix production in mesangial cells. Collectively, these findings revealed that the overactivation of mitochondrial activity in kidney could contribute to the metabolic disorders and the pathogenesis of early diabetic nephropathy. PMID: 31268353 [PubMed - as supplied by publisher]

The negative impact of antibiotics on outcomes in cancer patients treated with immunotherapy: a new independent prognostic factor? Ann Oncol. 2019 Jul 03;: Authors: Elkrief A, Derosa L, Kroemer G, Zitvogel L, Routy B Abstract Immune checkpoint inhibitors (ICI) now represent the standard of care for several cancer types. In pre-clinical models, absence of an intact gut microbiome negatively impacted ICI efficacy and these findings permitted to unravel the importance of the commensal microbiota in immuno-oncology. Recently, multiple clinical studies including more than 1800 patients in aggregate demonstrated the negative predictive impact of treatments with broad-spectrum antibiotics (ATB) on cancer patients receiving ICI. Altogether, these results have led to the hypothesis that ATB-induced symbiosis might influence the clinical response through the modulation of the gut microbiome. Controversy still remains, as ATB treatment might simply constitute a surrogate marker of unfit or immunodeficient patients. In this review, we summarize recent publications addressing the impact of the gut microbiome on ICI efficacy, discuss currently available data on the effect of ATB administered in different time-frames respect to ICI initiation, and finally evoke the therapeutic implications of these findings. PMID: 31268133 [PubMed - as supplied by publisher]

Triterpenoids Extracted from Rhus chinensis Mill Act Against Colorectal Cancer by Inhibiting Enzymes in Glycolysis and Glutaminolysis: Network Analysis and Experimental Validation. Nutr Cancer. 2019 Jul 03;:1-27 Authors: Wang G, Wang YZ, Yu Y, Wang JJ, Yin PH, Xu K Abstract Background: Rhus chinensis Mill is a traditional Chinese medicine (TCM) mostly used to treat several cancer types. Although previous studies have found that certain ingredients of R. chinensis such as flavonoids can inhibit tumor cell proliferation [e.g. colorectal cancer (CRC)], systematic research on the mechanism underlying anticancer effect of active compounds like triterpenoids (TER) is lacking. Study Design: Herein, the concept of "network pharmacology primarily based on active compounds" was applied to explore the anticancer mechanisms of TER extract from R. chinensis. In this regard, potential targets and pathways of glycolysis and glutaminolysis form the basis for the anti-CRC effect of triterpenoids. Network pharmacology was used to predict several key proteins in the metabolic pathways, which were further verified via western blot and metabolomics methods. Results: Our results showed that the total TER in R. chinensis remarkably inhibited the proliferation and apoptosis of SW620 cells. The top 4 compounds of TER (viz., betulinic acid-BTA, betulonic acid-BTOA, betulin-BT, and semialactic acid-SA) were confirmed through the detection of UPLC-MS and analysis of cell proliferation assays. Mechanistically, this study revealed that TER plays an anti-CRC role through key targets, such as ENO1, ALDOA, PFKFB3, PKM2, and LDHA, as well as key glycolytic and glutaminolytic pathways. Conclusion: Collectively, these results have provided new insights into the mechanism underlying anti-CRC effect of triterpenoids extract obtained from R. chinensis, mainly through combination of compositional quantitative analysis, network pharmacology, and experimental verification. PMID: 31267795 [PubMed - as supplied by publisher]

Related Articles Regulation of MAGE-A3/6 by the CRL4-DCAF12 ubiquitin ligase and nutrient availability. EMBO Rep. 2019 Jul;20(7):e47352 Authors: Ravichandran R, Kodali K, Peng J, Potts PR Abstract Melanoma antigen genes (MAGEs) are emerging as important oncogenic drivers that are normally restricted to expression in male germ cells but are aberrantly expressed in cancers and promote tumorigenesis. Mechanistically, MAGEs function as substrate specifying subunits of E3 ubiquitin ligases. Thus, the activation of germline-specific genes in cancer can drive metabolic and signaling pathways through altered ubiquitination to promote tumorigenesis. However, the mechanisms regulating MAGE expression and activity are unclear. Here, we describe how the MAGE-A3/6 proteins that function as repressors of autophagy are downregulated in response to nutrient deprivation. Short-term cellular starvation promotes rapid MAGE-A3/6 degradation in a proteasome-dependent manner. Proteomic analysis reveals that degradation of MAGE-A3/6 is controlled by the CRL4-DCAF12 E3 ubiquitin ligase. Importantly, the degradation of MAGE-A3/6 by CRL4-DCAF12 is required for starvation-induced autophagy. These findings suggest that oncogenic MAGEs can be dynamically controlled in response to stress to allow cellular adaptation, autophagy regulation, and tumor growth and that CRL4-DCAF12 activity is responsive to nutrient status. PMID: 31267705 [PubMed - in process]

Related Articles Phytochelatin database: a resource for phytochelatin complexes of nutritional and environmental metals. Database (Oxford). 2019 Jan 01;2019: Authors: Dennis KK, Uppal K, Liu KH, Ma C, Liang B, Go YM, Jones DP Abstract Phytochelatins (PyCs) are a diverse set of plant compounds that chelate metals, protect against metal toxicity and function in metal homeostasis. PyCs are present in plants consumed as food by humans and could, in principle, impact absorption and utilization of essential and toxic metals such as selenium and cadmium, respectively. PyCs vary in terminal amino acid composition and chain length, exist in multiple oxidation states and reversibly bind multiple metals; consequently, PyCs include a large set of possible structures. Although individual PyC-metal complexes have been studied, no resource exists to characterize the diversity of PyCs and PyC-metal complexes. We used the scientific literature to develop a database of elemental formulas for polymer forms varying in chain length from 2 to 11 glutamyl-cysteine repeats. Using elemental formulas, we calculated monoisotopic masses using the most abundant isotopes of each element and calculated masses for complexes with 13 metals of nutritional and toxicological significance. The resulting phytochelatin database (PyCDB) contains 46 260 unique elemental formulas for PyC and PyC-metal complexes. The database is available online for download as well as for direct mass queries for mass spectrometry using an accurate mass annotation tool for user-selected PyC types, metals and adducts of interest. We performed studies of a commonly consumed food-onion-to validate the database and test utility of the tool. Onion samples were analyzed using ultra-high resolution mass spectrometry-based metabolomics. Mass spectral features were annotated using the PyCDB web tool and the R package, xMSannotator; annotated features were further validated by collision-induced dissociation mass spectrometry. The results establish use and a workflow for PyCDB as a resource for characterization of PyCs and PyC-metal complexes. PMID: 31267134 [PubMed - in process]

Related Articles Metabolic regulatory oscillations in intertidal green seaweed Ulva lactuca against tidal cycles. Sci Rep. 2017 11 27;7(1):16430 Authors: Gupta V, Kushwaha HR Abstract The survival of wetland plant species largely relies on physiological adaptations essential for submergence and desiccation. Intertidal seaweeds, unlike terrestrial plants, have unique adaptations to submergence and can also sustain desiccation arising from tidal rhythms. This study determined the differential metabolic regulations in the inter-tidal seaweed species Ulva lactuca against the submergence and desiccation. During desiccation, the relative water content of the algal thalli declined with concomitant increase in reactive oxygen species (ROS) and lipid peroxidation. Nevertheless, the trends reversed during recovery on re-submergence and attained homeostasis. Metabolite profiling of U. lactuca revealed desiccation induced balance in energy reserve utilization by adjusting carbohydrate metabolism and switch over to ammonia metabolism. Upon re-submergence, thalli showed an increase in fermentative metabolites, pyruvate-alanine conversion, and the GABA shunt. Prolonged submergence induced substrate level phosphorylation mediated sugar biosynthesis while continuing the alternative carbon flux through fermentative metabolism, an increase in osmoprotectants glycine and betaine, sulfur bearing compounds cysteine and hypotaurine, and phenolic compound coniferaldehyde. The determined metabolic regulations in U. lactuca for submergence tolerance provide insights into potential evolutionarily conserved protective mechanisms across the green lineage and also highlights the possible role of sulfur oxoforms as strong free radical scavengers. PMID: 29180713 [PubMed - indexed for MEDLINE]

Related Articles Transcriptome and metabolite analyses reveal the complex metabolic genes involved in volatile terpenoid biosynthesis in garden sage (Salvia officinalis). Sci Rep. 2017 11 22;7(1):16074 Authors: Ali M, Li P, She G, Chen D, Wan X, Zhao J Abstract A large number of terpenoid compounds have been extracted from different tissues of S. officinalis. However, the molecular genetic basis of terpene biosynthesis pathways is virtually unknown. In this study, approximately 6.6 Gb of raw data were generated from the transcriptome of S. officinalis leaves using Illumina HiSeq 2000 sequencing. After filtering and removing the adapter sequences from the raw data, the number of reads reached 21 million, comprising 98 million of high-quality nucleotide bases. 48,671 unigenes were assembled de novo and annotated for establishing a valid database for studying terpenoid biosynthesis. We identified 135 unigenes that are putatively involved in terpenoid metabolism, including 70 mevalonate and methyl-erythritol phosphate pathways, terpenoid backbone biosynthesis genes, and 65 terpene synthase genes. Moreover, five terpene synthase genes were studied for their functions in terpenoid biosynthesis by using transgenic tobacco; most transgenic tobacco plants expressing these terpene synthetic genes produced increased amounts of terpenoids compared with wild-type control. The combined data analyses from the transcriptome and metabolome provide new insights into our understanding of the complex metabolic genes in terpenoid-rich sage, and our study paves the way for the future metabolic engineering of the biosynthesis of useful terpene compounds in S. officinalis. PMID: 29167468 [PubMed - indexed for MEDLINE]

Related Articles Metabolic Profiling of healthy and cancerous tissues in 2D and 3D. Sci Rep. 2017 11 10;7(1):15285 Authors: Russell S, Wojtkowiak J, Neilson A, Gillies RJ Abstract Metabolism is a compartmentalized process, and it is apparent in studying cancer that tumors, like normal tissues, demonstrate metabolic cooperation between different cell types. Metabolic profiling of cells in 2D culture systems often fails to reflect the metabolism occurring within tissues in vivo due to lack of other cell types and 3D interaction. We designed a tooling and methodology to metabolically profile and compare 2D cultures with cancer cell spheroids, and microtissue slices from tumors, and normal organs. We observed differences in the basal metabolism of 2D and 3D cell cultures in response to metabolic inhibitors, and chemotherapeutics. The metabolic profiles of microtissues derived from normal organs (heart, kidney) were relatively consistent when comparing microtissues derived from the same organ. Treatment of heart and kidney microtissues with cardio- or nephro-toxins had early and marked effects on tissue metabolism. In contrast, microtissues derived from different regions of the same tumors exhibited significant metabolic heterogeneity, which correlated to histology. Hence, metabolic profiling of complex microtissues is necessary to understand the effects of metabolic co-operation and how this interaction, not only can be targeted for treatment, but this method can be used as a reproducible, early and sensitive measure of drug toxicity. PMID: 29127321 [PubMed - indexed for MEDLINE]

Related Articles Zdhhc13-dependent Drp1 S-palmitoylation impacts brain bioenergetics, anxiety, coordination and motor skills. Sci Rep. 2017 10 16;7(1):12796 Authors: Napoli E, Song G, Liu S, Espejo A, Perez CJ, Benavides F, Giulivi C Abstract Protein S-palmitoylation is a reversible post-translational modification mediated by palmitoyl acyltransferase enzymes, a group of Zn2+-finger DHHC-domain-containing proteins (ZDHHC). Here, for the first time, we show that Zdhhc13 plays a key role in anxiety-related behaviors and motor function, as well as brain bioenergetics, in a mouse model (luc) carrying a spontaneous Zdhhc13 recessive mutation. At 3 m of age, mutant mice displayed increased sensorimotor gating, anxiety, hypoactivity, and decreased motor coordination, compared to littermate controls. Loss of Zdhhc13 in cortex and cerebellum from 3- and 24 m old hetero- and homozygous male mutant mice resulted in lower levels of Drp1 S-palmitoylation accompanied by altered mitochondrial dynamics, increased glycolysis, glutaminolysis and lactic acidosis, and neurotransmitter imbalances. Employing in vivo and in vitro models, we identified that Zdhhc13-dependent Drp1 S-palmitoylation, which acting alone or in concert, enables the normal occurrence of the fission-fusion process. In vitro and in vivo direct Zdhhc13-Drp1 protein interaction was observed, confirming Drp1 as a substrate of Zdhhc13. Abnormal fission-fusion processes result in disrupted mitochondria morphology and distribution affecting not only mitochondrial ATP output but neurotransmission and integrity of synaptic structures in the brain, setting the basis for the behavioral abnormalities described in the Zdhhc13-deficient mice. PMID: 29038583 [PubMed - indexed for MEDLINE]

21 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/07/03PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

24 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results: metabolomics These pubmed results were generated on 2019/07/02PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Related Articles Identification of urine biomarkers for calcium-oxalate urolithiasis in adults based on UPLC-Q-TOF/MS. J Chromatogr B Analyt Technol Biomed Life Sci. 2019 Jun 21;1124:290-297 Authors: Wang X, Wang M, Ruan J, Zhao S, Xiao J, Tian Y Abstract Urolithiasis is a common urological disease with a high morbidity and recurrence rate, of which calcium oxalate (CaOx) is the most common type of stone that underlies the disease. However, the potential metabolic mechanisms of CaOx urolithiasis remain unclear. The present study aimed to seek potential biomarkers and metabolic mechanisms of CaOx urolithiasis in adults. Urine samples were collected from 36 healthy individuals and 36 patients diagnosed with bilateral upper-urinary-tract stones. All of the stones were composed of CaOx. Ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to perform a metabolic fingerprinting analysis. Principal component analysis (PCA) and orthogonal partial least-squares determinant analysis (OPLS-DA) were carried out to analyze the multivariate data. There were 18 differential metabolites identified, which mainly involved caffeine, phenylalanine, galactose, and tyrosine metabolism. The results revealed potential urinary biomarkers, via metabolic fingerprinting of adults with CaOx urolithiasis, which may help to improve future metabolic evaluation of urolithiasis. The elucidated metabolic pathways may have potential applications as novel treatment targets of CaOx urolithiasis. Additionally, our study suggests that the UPLC-Q-TOF/MS platform may offer new insights into the pathobiology of urolithiasis. PMID: 31255901 [PubMed - as supplied by publisher]

Related Articles Non-targeted metabolomics reveals diagnostic biomarker in the tongue coating of patients with chronic gastritis. J Pharm Biomed Anal. 2019 Jun 20;174:541-551 Authors: Mu X, Ji C, Wang Q, Liu K, Hao X, Zhang G, Shi X, Zhang Y, Gonzalez FJ, Wang Q, Wang Y Abstract Analysis of the properties of the tongue has been used in traditional Chinese medicine for disease diagnosis. Notably, tongue analysis, which is non-invasive and convenient compared with gastroscopy and pathological examination, can be used to assess chronic gastritis (CG). In order to find potential diagnostic biomarkers and study the metabolic mechanisms of the endogenous small molecules in the tongue coating related to CG, a non-targeted metabolomic analysis method was developed using ultra high performance liquid chromatography combined with quadrupole time-of-flight mass spectrometry (UHPLC-Q/TOF-MS). It was performed using two different columns in positive and negative ion scanning modes separately. The stability of the samples was evaluated and the age and gender factors of the subjects were excluded to ensure the reliability of the data in this study. Finally, under the four analysis models, 130, 229, 113 and 92 differential compounds were found using multivariate statistical methods respectively. 37 potential biomarkers were putatively identified after removing the duplicate compounds and five potential diagnostic biomarkers were putatively identified by receiver operating characteristic (ROC) curve analysis, including inosine, oleamide, adenosine, N-acetylglucosamine (GlcNAc) and xanthine. The main metabolic pathways associated with CG were purine metabolism, amino acid metabolism, sphingolipid metabolism and energy metabolism, which suggested that oxygen free radicals and energy metabolism were altered in patients with CG. These results provided a potential new basis for the quantitative diagnosis and pathogenesis of CG. PMID: 31255854 [PubMed - as supplied by publisher]

Related Articles Metabolomics in plasma of Malawian children 7 years after surviving severe acute malnutrition: "ChroSAM" a cohort study. EBioMedicine. 2019 Jun 26;: Authors: Bourdon C, Lelijveld N, Thompson D, Dalvi PS, Gonzales GB, Wang D, Alipour M, Wine E, Chimwezi E, Wells JC, Kerac M, Bandsma R, Nyirenda MJ Abstract BACKGROUND: More children are now surviving severe acute malnutrition (SAM), but evidence suggests that early-life malnutrition is associated with increased risk of long-term cardio-metabolic disorders. To better understand potential mechanisms, we studied the metabolite profiles of children seven years after treatment for SAM. METHODS: We followed-up children (n = 352) treated for SAM in 2006-2007, at Queen Elizabeth Central Hospital, in Malawi. Using nuclear magnetic resonance spectroscopy, tandem mass spectrometry and enzyme-linked immunosorbent assay, we measured circulating metabolites in fasting blood in a subset of SAM survivors (n = 69, 9·6 ± 1·6 years), siblings (n = 44, 10·5 ± 2·7 years), and age and sex-matched community controls (n = 37, 9·4 ± 1·8 years). Data were analysed using univariate and sparse partial least square (sPLS) methods. Differences associated with SAM survival, oedema status, and anthropometry were tested, adjusting for age, sex, HIV, and wealth index. FINDINGS: Based on 194 measured metabolites, the profiles of SAM survivors were similar to those of siblings and community controls. IGF1, creatinine, and FGF21, had loading values >0·3 and ranked stably in the top 10 distinguishing metabolites, but did not differ between SAM survivors and controls with univariate analysis. Current stunting was associated with IGF1 (β = 15·2, SE = 3·5, partial R2 = 12%, p < 0·0001) and this relationship could be influenced by early childhood SAM (β = 17·4, SE = 7·7, partial R2 = 2·8%, p = 0·025). No metabolites were associated with oedema status, duration of hospital stay, anthropometry measured during hospitalization, nor with changes in anthropometry since hospitalization. INTERPRETATION: In this group of survivors, SAM was not associated with longer-term global metabolic changes 7 years after treatment. However, SAM may influence the relationship between current stunting and IGF1. Further risk markers for NCDs in SAM survivors may only be revealed by direct metabolic challenge or later in life. PMID: 31255658 [PubMed - as supplied by publisher]

Related Articles Investigation of betaine as a novel psychotherapeutic for schizophrenia. EBioMedicine. 2019 Jun 06;: Authors: Ohnishi T, Balan S, Toyoshima M, Maekawa M, Ohba H, Watanabe A, Iwayama Y, Fujita Y, Tan Y, Hisano Y, Shimamoto-Mitsuyama C, Nozaki Y, Esaki K, Nagaoka A, Matsumoto J, Hino M, Mataga N, Hayashi-Takagi A, Hashimoto K, Kunii Y, Kakita A, Yabe H, Yoshikawa T Abstract BACKGROUND: Betaine is known to act against various biological stresses and its levels were reported to be decreased in schizophrenia patients. We aimed to test the role of betaine in schizophrenia pathophysiology, and to evaluate its potential as a novel psychotherapeutic. METHODS: Using Chdh (a gene for betaine synthesis)-deficient mice and betaine-supplemented inbred mice, we assessed the role of betaine in psychiatric pathophysiology, and its potential as a novel psychotherapeutic, by leveraging metabolomics, behavioral-, transcriptomics and DNA methylation analyses. FINDINGS: The Chdh-deficient mice revealed remnants of psychiatric behaviors along with schizophrenia-related molecular perturbations in the brain. Betaine supplementation elicited genetic background-dependent improvement in cognitive performance, and suppressed methamphetamine (MAP)-induced behavioral sensitization. Furthermore, betaine rectified the altered antioxidative and proinflammatory responses induced by MAP and in vitro phencyclidine (PCP) treatments. Betaine also showed a prophylactic effect on behavioral abnormality induced by PCP. Notably, betaine levels were decreased in the postmortem brains from schizophrenia, and a coexisting elevated carbonyl stress, a form of oxidative stress, demarcated a subset of schizophrenia with "betaine deficit-oxidative stress pathology". We revealed the decrease of betaine levels in glyoxylase 1 (GLO1)-deficient hiPSCs, which shows elevated carbonyl stress, and the efficacy of betaine in alleviating it, thus supporting a causal link between betaine and oxidative stress conditions. Furthermore, a CHDH variant, rs35518479, was identified as a cis-expression quantitative trait locus (QTL) for CHDH expression in postmortem brains from schizophrenia, allowing genotype-based stratification of schizophrenia patients for betaine efficacy. INTERPRETATION: The present study revealed the role of betaine in psychiatric pathophysiology and underscores the potential benefit of betaine in a subset of schizophrenia. FUND: This study was supported by the Strategic Research Program for Brain Sciences from AMED (Japan Agency for Medical Research and Development) under Grant Numbers JP18dm0107083 and JP19dm0107083 (TY), JP18dm0107129 (MM), JP18dm0107086 (YK), JP18dm0107107 (HY), JP18dm0107104 (AK) and JP19dm0107119 (KH), by the Grant-in-Aid for Scientific Research on Innovative Areas from the MEXT under Grant Numbers JP18H05435 (TY), JP18H05433 (AH.-T), JP18H05428 (AH.-T and TY), and JP16H06277 (HY), and by JSPS KAKENHI under Grant Number JP17H01574 (TY). In addition, this study was supported by the Collaborative Research Project of Brain Research Institute, Niigata University under Grant Numbers 2018-2809 (YK) and RIKEN Epigenetics Presidential Fund (100214-201801063606-340120) (TY). PMID: 31255657 [PubMed - as supplied by publisher]

Related Articles Identifying metabolomic profiles of inflammatory diets in postmenopausal women. Clin Nutr. 2019 Jun 17;: Authors: Tabung FK, Liang L, Huang T, Balasubramanian R, Zhao Y, Chandler PD, Manson JE, Cespedes Feliciano EM, Hayden KM, Van Horn L, Clish CB, Giovannucci EL, Rexrode KM Abstract BACKGROUND: We previously showed that a food-based empirical dietary inflammatory pattern (EDIP) score is associated with circulating inflammatory biomarkers. Metabolomic profiling of inflammatory diets may therefore provide insights on mechanisms contributing to disease etiology and prognosis. We aimed to elucidate metabolites associated with inflammatory diets among postmenopausal women, utilizing a robust study design that incorporates independent discovery and validation datasets. METHODS: This baseline cross-sectional investigation evaluated associations between continuous EDIP scores calculated from food frequency questionnaires and 448 log-transformed plasma metabolites as outcomes in multivariable-adjusted linear regression analyses. Metabolites were measured with liquid chromatography tandem mass spectroscopy. Metabolite discovery was conducted among 1109 Women's Health Initiative (WHI) Hormone Therapy trial participants and results were replicated in an independent dataset of 810 WHI Observational Study participants. Secondary analyses were stratified by standard body mass index (BMI, kg/m2) categories. In discovery and replication datasets statistical significance was based on false-discovery rate adjusted P < 0.05. RESULTS: After adjusting for energy intake, BMI, physical activity, and other confounding variables, 23 metabolites were significantly associated with EDIP score in the discovery dataset. Of these, the following ten were replicated: trigonelline, caffeine, acethylamino-6-amino-3-methyluracil, 7-methylxanthine, 1,7-dimethyluric acid, 3-methylxanthine, C18:3CE, glycine, associated with lower dietary inflammatory potential; whereas C52:3 triacylglycerol and linoleate associated with higher dietary inflammatory potential. Four of the ten were associated [glycine (inversely), caffeine, 1,7-dimethyluric acid, C52:3 triacylglycerol, (positively)], with C-reactive protein levels. In secondary analyses, associations showed differences by BMI category. Four metabolites, related to coffee/caffeine metabolism were inversely associated among normal weight women, and 83 metabolites associated with EDIP among overweight/obese women, including 40 (48%) that were also associated with C-reactive protein. CONCLUSION: Metabolites associated with coffee/caffeine and lipid metabolism may reflect the inflammatory potential of diet. Potential differences by BMI and the linkage to disease outcomes, require further study. PMID: 31255351 [PubMed - as supplied by publisher]

Related Articles Lymphocytes exposed to vegetables grown in waters contaminated by anticancer drugs: metabolome alterations and genotoxic risks for human health. Mutat Res. 2019 Jun;842:125-131 Authors: Russo C, Graziani V, Lavorgna M, D'Abrosca B, Piscitelli C, Fiorentino A, Scognamiglio M, Isidori M Abstract Wastewater irrigation of crops may be effective to avoid depletion (about 70%) of freshwater resources. However, the use of reclaimed waters containing persistent microcontaminants such as antineoplastic drugs is of high environmental concern. These active compounds may affect human health with potentially severe adverse effects. To better understand the impact on human health following irrigation of crops with reused contaminated waters, we exposed four edible plants, Brassica rapa, Lactuca sativa, Raphanus sativus, and Triticum durum, to two commonly used antitumoral drugs: 5-fluorouracil (5-FU), and Cisplatin (CDDP), using metabolomics as a potential functional genomics tool to combine with genotoxicity experiments. The metabolome of the treated and untreated plants was analysed to detect biochemical alterations associated to the exposure, and the potential genotoxic damage related to human exposure to the treated plants was evaluated using the comet assay in human lymphocytes, which are characterized by high sensitivity to genotoxic substances. The edible species were able to assimilate 5-FU and CDDP during the treatment, affecting the biochemical pathways of these plants with subsequent metabolome modifications. These metabolic alterations differed according to the specific species used for the test. Furthermore, all vegetables treated with two concentrations of the selected drugs (10 and 100 μg/L) caused significant (p < 0.0001) genotoxic damage in the cells of the immune system at a higher level than in the lymphocytes directly exposed to single antineoplastic drugs. PMID: 31255220 [PubMed - in process]