PubMed

Glutamine metabolism in the proliferation of GS-expression pituitary tumor cells. Endocr Connect. 2020 Feb 01;: Authors: Hu J, Chen Q, Ding X, Zheng X, Tang X, Li S, Yang H Abstract OBJECTIVE: Many cancer cells cannot survive without exogenous glutamine (Gln)，however, cancer cells expressed glutamine synthetase (GS) do not have this restriction. Previous metabolomics studies have indicated that glutamine metabolism is altered during pituitary tumorigenesis. However, the main role of Gln in pituitary adenoma (PA) pathophysiology remains unknown. The aim of this study was to evaluate the expression of GS and the main role of Gln in human PAs. METHODS: We used cell proliferation assay and flow cytometry to assess the effect of Gln depletion on three different pituitary cell lines and human primary PA cells. Then investigated the expression level of Gln synthetase (GS) in 24 human PA samples. At last, we used LC-MS/MS to identify the differences in metabolites of PA cells after the blockage of both endogenous and exogenous Gln. RESULTS: PA cell lines showed different sensitivities to Gln starvation, and the sensitivity is correlated with GS expression level. GS expressed in 21 out of the 24 human PA samples. Furthermore, a positive p53 and ki-67 index was correlated with a higher GS expression level (p<0.05). Removal of both endogenous and exogenous Gln from GS-expressing PA cells resulted in blockage of nucleotide metabolism and cell cycle arrest. CONCLUSIONS: Our data indicate that GS is needed for PA cells to proliferation during Gln deprivation, and most human PA cells express GS and might have a negative response to exogenous Gln depletion. Moreover, Gln is mainly responsible for nucleotide metabolism in the proliferation of GS-expressing pituitary tumor cells. PMID: 32069221 [PubMed - as supplied by publisher]

The Aging Metabolome- Biomarkers to Hub Metabolites. Proteomics. 2020 Feb 18;:e1800407 Authors: Sharma R, Ramanathan A Abstract Aging biology is intimately associated with dysregulated metabolism, which is one of the hallmarks of aging. Aging related pathways such as mTOR and AMPK which are major targets of anti-aging interventions including rapamcyin, metformin and exercise, either directly regulate or intersect with metabolic pathways. In this review we outline numerous candidate bio-markers of aging that have emerged using metabolomics. Metabolomics studies also reveal that not all metabolites are created equally. A set of core 'hub' metabolites are emerging as central mediators of aging. The hub metabolites reviewed here are- Nicotinamide adenine dinucleotide (NAD+), reduced nicotinamide dinucleotide phosphate (NADPH), alpha ketoglutarate (aKG) and beta-hydroxybutyrate (βHB). These 'hub' metabolites have signaling and epigenetic roles along with their canonical roles as co-factors or intermediates of carbon metabolism. Together these hub metabolites suggest a central role of the TCA cycle in signaling and metabolic dysregulation associated with aging. This article is protected by copyright. All rights reserved. PMID: 32068959 [PubMed - as supplied by publisher]

Monitoring of the influence of long-term oxidative stress and ischemia on the condition of kidney using solid phase microextraction chemical biopsy coupled with liquid chromatography high resolution mass spectrometry. J Sep Sci. 2020 Feb 18;: Authors: Stryjak I, Warmuzińska N, Bogusiewicz J, Łuczykowski K, Bojko B Abstract The limiting factor in conventional quality assessments of transplanted organs, namely the invasiveness of tissue sample collection, has prompted much research on the field of transplantology to focus on the development of alternative evaluation methods of organ quality. In the present project, we undertake the challenge to address the need for a new analytical solution for graft quality assessments by using a novel metabolomic diagnostic protocol based on low-invasive solid-phase microextraction. Solid-phase microextraction probes of ca. 0.2 mm coated with 4 mm long mixed-mode extraction phase were inserted into rabbit kidneys immediately following euthanasia and after 2, 4, 6, and 21 h of preservation. LC-MS analysis of the extracts was performed with the use of a reversed phase column and a Q-Exactive Focus mass spectrometer operated in positive ionization mode. Statistical analysis of significantly changing compounds revealed metabolic profile changes in kidneys induced by ischemia and oxidative stress as a function of the duration of cold storage. The most pronounced alterations were reflected in levels of essential amino acids and purine nucleosides. Our findings demonstrate that the proposed approach may be successfully used to monitor changes in the metabolic profile of organs over time of preservation. This article is protected by copyright. All rights reserved. PMID: 32068348 [PubMed - as supplied by publisher]

Taurocholic acid inhibits features of age-related macular degeneration in vitro. Exp Eye Res. 2020 Feb 14;:107974 Authors: Warden C, Barnett J, Brantley MA Abstract Previous metabolomics studies from our lab found altered plasma levels of bile acids in patients with age-related macular degeneration (AMD) compared to controls. In this study, we investigated the ability of the bile acid taurocholic acid (TCA) to inhibit features of AMD modeled in vitro. Paraquat was used to induce oxidative stress in HRPEpiC primary retinal pigment epithelial (RPE) cells. Cells were treated with 300 μM paraquat alone or with TCA (10, 50, 100, 200, or 500 μM). RPE tight junction integrity was assessed via ZO-1 immunofluorescence and transepithelial electrical resistance (TEER) measurements. RF/6A macaque choroidal endothelial cells were treated with 100 ng/mL vascular endothelial growth factor (VEGF) to induce angiogenesis. The effect of TCA on VEGF-induced angiogenesis was evaluated with cell proliferation, cell migration, and tube formation assays. Addition of TCA at 100 (P = 8.6 × 10-4), 200 (P = 0.0035), and 500 (P = 2.1 × 10-4) μM resulted in significant preservation of TEER in paraquat treated cells. In RF/6A cells, TCA did not significantly affect VEGF-induced cell proliferation. VEGF-induced migration of RF/6A cells was significantly inhibited at TCA concentrations of 100 (P = 0.010), 200 (P = 0.023) and 500 (P = 0.0049) μM. VEGF-induced tube formation was significantly inhibited when treated with 200 (P = 0.014) and 500 (P = 7.1 × 10-4) μM TCA. In vitro, TCA promoted RPE cell and diminished VEGF-induced choroidal endothelial cell migration and tube formation. This suggests that TCA may have protective effects against both degenerative and neovascular AMD. PMID: 32067977 [PubMed - as supplied by publisher]

Precision Medicine Approach in Prostate Cancer. Curr Pharm Des. 2020 Feb 17;: Authors: Assadi M, Jokar N, Ghasemi M, Nabipour I, Gholamrezanezhad A, Ahmadzadehfar H Abstract Prostate cancer is the most prevalent form of cancer and the second cause of death in men worldwide. Various diagnostic and treatment procedures are available for this type of malignancy, but High-risk or locally advanced prostate cancers showed the potential to develop to lethal phase that can be causing dead. Therefore, new approaches are needed to prolong patient survival and provide a better quality of life. Precision medicine is a novel emerging field that has an essential role in identifying new sub-classifications of disease and guiding treatment based on individual multi-omics data. Multi-omics approaches include the use of genomics, transcriptomics, proteomics, metabolomics, epigenomics and phenomics data to unravel the complexity of a disease-associated biological network, to predict prognostic biomarkers, and to identify new targeted drugs for individual cancer patients. We review the impact of multi-omics data in the framework of systems biology in the era of precision medicine, emphasising the combination of molecular imaging modalities with high-throughput techniques and the new treatments that target metabolic pathways involved in prostate cancer. PMID: 32067601 [PubMed - as supplied by publisher]

Related Articles Transcriptional coactivator with PDZ-binding motif suppresses the expression of steroidogenic enzymes by nuclear receptor 4 A1 in Leydig cells. FASEB J. 2020 Feb 17;: Authors: Shin JH, Lee G, Jeong MG, Kim HK, Won HY, Choi Y, Lee JH, Nam M, Choi CS, Hwang GS, Hwang ES Abstract Transcriptional coactivator with PDZ-binding motif (TAZ) plays crucial role in maintaining testicular structure and function via regulation of senescence of spermatogenic cells. However, it remains unclear whether TAZ is involved in testosterone biosynthesis in testicular Leydig cells. We found that TAZ deficiency caused aberrant Leydig cell expansion and increased lipid droplet formation, which was significantly associated with increased lipogenic enzyme expression. Additionally, the expression of key steroidogenic enzymes, including steroidogenic acute regulatory protein, cytochrome P450 (CYP) 11A1, CYP17A1, and 3β-hydroxysteroid dehydrogenase, was greatly increased in TAZ-deficient testes and primary Leydig cells. Interestingly, the transcriptional activity of nuclear receptor 4 A1 (NR4A1) was dramatically suppressed by TAZ; however, the protein expression and the subcellular localization of NR4A1 were not affected by TAZ. TAZ directly associated with the N-terminal region of NR4A1 and substantially suppressed its DNA-binding and transcriptional activities. Stable expression of TAZ in the mouse Leydig TM3 cell line decreased the expression of key steroidogenic enzymes, whereas knockdown of endogenous TAZ in TM3 cells increased transcripts of steroidogenic genes induced by NR4A1. Consistently, testosterone production was enhanced within TAZ-deficient Leydig cells. However, TAZ deficiency resulted in decreased testosterone secretion caused by dysfunctional mitochondria and lysosomes. Therefore, TAZ plays essential role in NR4A1-induced steroidogenic enzyme expression and testosterone production in Leydig cells. PMID: 32067268 [PubMed - as supplied by publisher]

Related Articles Germinal center B cells selectively oxidize fatty acids for energy while conducting minimal glycolysis. Nat Immunol. 2020 Feb 17;: Authors: Weisel FJ, Mullett SJ, Elsner RA, Menk AV, Trivedi N, Luo W, Wikenheiser D, Hawse WF, Chikina M, Smita S, Conter LJ, Joachim SM, Wendell SG, Jurczak MJ, Winkler TH, Delgoffe GM, Shlomchik MJ Abstract Germinal center B cells (GCBCs) are critical for generating long-lived humoral immunity. How GCBCs meet the energetic challenge of rapid proliferation is poorly understood. Dividing lymphocytes typically rely on aerobic glycolysis over oxidative phosphorylation for energy. Here we report that GCBCs are exceptional among proliferating B and T cells, as they actively oxidize fatty acids (FAs) and conduct minimal glycolysis. In vitro, GCBCs had a very low glycolytic extracellular acidification rate but consumed oxygen in response to FAs. [13C6]-glucose feeding revealed that GCBCs generate significantly less phosphorylated glucose and little lactate. Further, GCBCs did not metabolize glucose into tricarboxylic acid (TCA) cycle intermediates. Conversely, [13C16]-palmitic acid labeling demonstrated that GCBCs generate most of their acetyl-CoA and acetylcarnitine from FAs. FA oxidation was functionally important, as drug-mediated and genetic dampening of FA oxidation resulted in a selective reduction of GCBCs. Hence, GCBCs appear to uncouple rapid proliferation from aerobic glycolysis. PMID: 32066950 [PubMed - as supplied by publisher]

Related Articles Dl-3-n-butylphthalide attenuates mouse behavioral deficits to chronic social defeat stress by regulating energy metabolism via AKT/CREB signaling pathway. Transl Psychiatry. 2020 Feb 03;10(1):49 Authors: Wang W, Wang T, Bai S, Chen Z, Qi X, Xie P Abstract Major depressive disorder (MDD) is a severe mental disorder associated with high rates of morbidity and mortality. Current first-line pharmacotherapies for MDD are based on enhancement of monoaminergic neurotransmission, but these antidepressants are still insufficient and produce significant side-effects. Consequently, the development of novel antidepressants and therapeutic targets is desired. Dl-3-n-butylphthalide (NBP) is a compound with proven efficacy in treating ischemic stroke, yet its therapeutic effects and mechanisms for depression remain unexplored. The aim of this study was to investigate the effect of NBP in a chronic social defeat stress model of depression and its underlying molecular mechanisms. Here, we examined depression-related behavior and performed a targeted metabolomics analysis. Real-time quantitative polymerase chain reaction and western blotting were used to examine key genes and proteins involved in energy metabolism and the AKT/cAMP response element-binding protein (CREB) signaling pathway. Our results reveal NBP attenuates stress-induced social deficits, anxiety-like behavior and despair behavior, and alters metabolite levels of glycolysis and tricarboxylic acid (TCA) cycle components. NBP affected gene expression of key enzymes of the TCA cycle, as well as protein expression of p-AKT and p-CREB. Our findings provide the first evidence showing that NBP can attenuate stress-induced behavioral deficits by modulating energy metabolism by regulating activation of the AKT/CREB signaling pathway. PMID: 32066705 [PubMed - in process]

Related Articles Metabolomic analyses of the bio-corona formed on TiO2 nanoparticles incubated with plant leaf tissues. J Nanobiotechnology. 2020 Feb 17;18(1):28 Authors: Kurepa J, Shull TE, Smalle JA Abstract BACKGROUND: The surface of a nanoparticle adsorbs molecules from its surroundings with a specific affinity determined by the chemical and physical properties of the nanomaterial. When a nanoparticle is exposed to a biological system, the adsorbed molecules form a dynamic and specific surface layer called a bio-corona. The present study aimed to identify the metabolites that form the bio-corona around anatase TiO2 nanoparticles incubated with leaves of the model plant Arabidopsis thaliana. RESULTS: We used an untargeted metabolomics approach and compared the metabolites isolated from wild-type plants with plants deficient in a class of polyphenolic compounds called flavonoids. CONCLUSIONS: These analyses showed that TiO2 nanoparticle coronas are enriched for flavonoids and lipids and that these metabolite classes compete with each other for binding the nanoparticle surface. PMID: 32066442 [PubMed - in process]

Related Articles Feature selection for OPLS discriminant analysis of cancer tissue lipidomics data. J Mass Spectrom. 2020 Jan;55(1):e4457 Authors: Tokareva AO, Chagovets VV, Starodubtseva NL, Nazarova NM, Nekrasova ME, Kononikhin AS, Frankevich VE, Nikolaev EN, Sukhikh GT Abstract The mass spectrometry-based molecular profiling can be used for better differentiation between normal and cancer tissues and for the detection of neoplastic transformation, which is of great importance for diagnostics of a pathology, prognosis of its evolution trend, and development of a treatment strategy. The aim of the present study is the evaluation of tissue classification approaches based on various data sets derived from the molecular profile of the organic solvent extracts of a tissue. A set of possibilities are considered for the orthogonal projections to latent structures discriminant analysis: all mass spectrometric peaks over 300 counts threshold, subset of peaks selected by ranking with support vector machine algorithm, peaks selected by random forest algorithm, peaks with the statistically significant difference of the intensity determined by the Mann-Whitney U test, peaks identified as lipids, and both identified and significantly different peaks. The best predictive potential is obtained for OPLS-DA model built on nonpolar glycerolipids (Q2 = 0.64, area under curve [AUC] = 0.95); the second one is OPLS-DA model with lipid peaks selected by random forest algorithm (Q2 = 0.58, AUC = 0.87). Moreover, models based on particular molecular classes are more preferable from biological point of view, resulting in new explanatory mechanisms of pathophysiology and providing a pathway analysis. Another promising features for OPLS-DA modeling are phosphatidylethanolamines (Q2 = 0.48, AUC = 0.86). PMID: 31661719 [PubMed - indexed for MEDLINE]

Related Articles Non-invasive assessment of hepatic lipid subspecies matched with non-alcoholic fatty liver disease phenotype. Nutr Metab Cardiovasc Dis. 2019 11;29(11):1197-1204 Authors: Erickson ML, Haus JM, Malin SK, Flask CA, McCullough AJ, Kirwan JP Abstract BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic fat accumulation. Increased hepatic saturated fats and decreased hepatic polyunsaturated fats may be particularly lipotoxic, contributing to metabolic dysfunction. We compared hepatic lipid subspecies in adults with and without NAFLD, and examined links with hallmark metabolic and clinical characteristics of NAFLD. METHODS AND RESULTS: Nineteen adults with NAFLD (total hepatic fat:18.8 ± 0.1%) were compared to sixteen adults without NAFLD (total hepatic fat: 2.1 ± 0.01%). 1H-MRS was used to assess hepatic lipid subspecies. Methyl, allylic, methylene, and diallylic proton peaks were measured. Saturation, unsaturation, and polyunsaturation indices were calculated. Whole-body phenotyping in a subset of participants included insulin sensitivity (40 mU/m2 hyperinsulinemic-euglycemic clamps), CT-measured abdominal adipose tissue depots, exercise capacity, and serum lipid profiles. Participants with NAFLD exhibited more saturated and less unsaturated hepatic fat, accompanied by increased insulin resistance, total and visceral adiposity, triglycerides, and reduced exercise capacity compared to controls (all P < 0.05). All proton lipid peaks were related to insulin resistance and hypertriglyceridemia (P < 0.05). CONCLUSION: Participants with NAFLD preferentially stored excess hepatic lipids as saturated fat, at the expense of unsaturated fat, compared to controls. This hepatic lipid profile was accompanied by an unhealthy metabolic phenotype. PMID: 31371265 [PubMed - indexed for MEDLINE]

Related Articles Secretome Profiling Reveals Virulence-Associated Proteins of Fusarium proliferatum during Interaction with Banana Fruit. Biomolecules. 2019 06 23;9(6): Authors: Li T, Wu Y, Wang Y, Gao H, Gupta VK, Duan X, Qu H, Jiang Y Abstract Secreted proteins are vital for the pathogenicity of many fungi through manipulating their hosts for efficient colonization. Fusarium proliferatum is a phytopathogenic fungus infecting many crops, vegetables, and fruit, including banana fruit. To access the proteins involved in pathogen-host interaction, we used label-free quantitative proteomics technology to comparatively analyze the secretomes of F. proliferatum cultured with and without banana peel in Czapek's broth medium. By analyzing the secretomes of F. proliferatum, we have identified 105 proteins with 40 exclusively secreted and 65 increased in abundance in response to a banana peel. These proteins were involved in the promotion of invasion of banana fruit, and they were mainly categorized into virulence factors, cell wall degradation, metabolic process, response to stress, regulation, and another unknown biological process. The expressions of corresponding genes confirmed the existence of these secreted proteins in the banana peel. Furthermore, expression pattern suggested variable roles for these genes at different infection stages. This study expanded the current database of F. proliferatum secreted proteins which might be involved in the infection strategy of this fungus. Additionally, this study warranted the further attention of some secreted proteins that might initiate infection of F. proliferatum on banana fruit. PMID: 31234604 [PubMed - indexed for MEDLINE]

Related Articles Associations among tourist camp management, high and low tourist seasons, and welfare factors in female Asian elephants in Thailand. PLoS One. 2019;14(6):e0218579 Authors: Norkaew T, Brown JL, Thitaram C, Bansiddhi P, Somgird C, Punyapornwithaya V, Punturee K, Vongchan P, Somboon N, Khonmee J Abstract This study investigated how camp management and tourist activities affect body condition, adrenocortical function, lipid profiles and metabolic status in female tourist elephants. We compared twice monthly serum insulin, glucose, fructosamine, total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), high density lipoprotein (HDL), and fecal glucocorticoid metabolite (FGM) concentrations to body condition scores (BCS) at five camps with different management styles (e.g., tourist activities, work type, diet) between the High (November-February) and Low (March-October) tourist seasons. There were significant camp effects on health parameters, with BCS, TC, HDL, insulin and glucose being among the highest, and G:I being the lowest (less heathy) in elephants at an observation camp compared to those at camps where elephants received exercise by providing rides to tourists. Differences between High and Low tourist season months also were found for all measures, except TG and FGM concentrations. Both work time and walking distance were negatively correlated to glucose, fructosamine and insulin, while walking distance was negatively related to FGM concentrations. By contrast, positive associations were found between tourist number and BCS, TG, and insulin, perhaps related to tourists feeding elephants. Quantity of supplementary diet items (e.g., bananas, sugar cane, pumpkin) were positively correlated with FGM concentrations, glucose, fructosamine, and insulin. This study provides evidence that body condition, adrenal activity, metabolic markers, and lipid profiles in captive elephants may be affected by visitor numbers, work activities, and the amount of supplementary foods offered by tourists. Some activities appear to have negative (e.g., feeding), while others (e.g., exercise) may have positive effects on health and welfare. We conclude that camps adopting a more hands-off approach to tourism need to ensure elephants remain healthy by providing environments that encourage activity and rely on more natural diets or foraging. PMID: 31206564 [PubMed - indexed for MEDLINE]

Related Articles Elevated O-GlcNAcylation enhances pro-inflammatory Th17 function by altering the intracellular lipid microenvironment. J Biol Chem. 2019 05 31;294(22):8973-8990 Authors: Machacek M, Saunders H, Zhang Z, Tan EP, Li J, Li T, Villar MT, Artigues A, Lydic T, Cork G, Slawson C, Fields PE Abstract Chronic, low-grade inflammation increases the risk for atherosclerosis, cancer, and autoimmunity in diseases such as obesity and diabetes. Levels of CD4+ T helper 17 (Th17) cells, which secrete interleukin 17A (IL-17A), are increased in obesity and contribute to the inflammatory milieu; however, the relationship between signaling events triggered by excess nutrient levels and IL-17A-mediated inflammation is unclear. Here, using cytokine, quantitative real-time PCR, immunoprecipitation, and ChIP assays, along with lipidomics and MS-based approaches, we show that increased levels of the nutrient-responsive, post-translational protein modification, O-GlcNAc, are present in naive CD4+ T cells from a diet-induced obesity murine model and that elevated O-GlcNAc levels increase IL-17A production. We also found that increased binding of the Th17 master transcription factor RAR-related orphan receptor γ t variant (RORγt) at the IL-17 gene promoter and enhancer, as well as significant alterations in the intracellular lipid microenvironment, elevates the production of ligands capable of increasing RORγt transcriptional activity. Importantly, the rate-limiting enzyme of fatty acid biosynthesis, acetyl-CoA carboxylase 1 (ACC1), is O-GlcNAcylated and necessary for production of these RORγt-activating ligands. Our results suggest that increased O-GlcNAcylation of cellular proteins may be a potential link between excess nutrient levels and pathological inflammation. PMID: 31010828 [PubMed - indexed for MEDLINE]

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Metabolism and Effects on Endogenous Metabolism of Paracetamol (Acetaminophen) in a Porcine Model of Liver Failure. Toxicol Sci. 2020 Feb 15;: Authors: Dargue R, Zia R, Lau C, Nicholls AW, Dare TO, Lee K, Jalan R, Coen M, Wilson ID Abstract The metabolic fate, toxicity and effects on endogenous metabolism of paracetamol (acetaminophen, APAP) in 22 female Landrace cross large white pigs were evaluated in a model of acute liver failure (ALF). Anaesthetized pigs were initially dosed at 250 mg/kg via an oroduodenal tube with APAP serum concentrations maintained above 300 mg/L using maintenance doses of 0.5-4g/h until ALF. Studies were undertaken to determine both the metabolic fate of APAP and its effects on the endogenous metabolic phenotype of ALF in using 1H NMR spectroscopy. Increased concentrations of citrate combined with pre-ALF increases in circulating lactate, pyruvate and alanine in plasma suggest mitochondrial dysfunction and a switch in hepatic energy metabolism to glycolysis in response to APAP treatment. A specific liquid chromatography-tandem mass spectrometry assay was used to quantify APAP and metabolites. The major circulating and urinary metabolite of APAP was the phenolic glucuronide (APAP-G), followed by p-aminophenol glucuronide (PAP-G) formed from N-deacetylated APAP. The PAP produced by N-deacetylation was the likely cause of the methaemoglobinemia and kidney toxicity observed in this, and previous, studies in the pig. The phenolic sulfate of APAP, and the glutathione-derived metabolites of the drug were only found as minor components (with the cysteinyl conjugate detected but not the mercapturate). Given its low sulfation, combined with significant capacity for N-deacetylation the pig may represent a poor translational model for toxicology studies for compounds undergoing significant metabolism by sulfation, or which contain amide bonds which when hydrolysed to unmask an aniline lead to toxicity. However, the pig may provide a useful model where extensive amide hydrolysis is seen for drugs or environmental chemicals in humans, but not in e.g., the rat and dog which are the pre-clinical species normally employed for safety assessment. PMID: 32061126 [PubMed - as supplied by publisher]

Related Articles Inhibition of human CYP1 enzymes by a classical inhibitor α-naphthoflavone and a novel inhibitor N-(3, 5- dichlorophenyl)cyclopropanecarboxamide - an in vitro and in silico study. Chem Biol Drug Des. 2020 Feb 14;: Authors: Juvonen RO, Jokinen EM, Javaid A, Lehtonen M, Raunio H, Pentikäinen OT Abstract Enzymes in the cytochrome P450 family 1 (CYP1) catalyze metabolic activation of procarcinogens and deactivation of certain anticancer drugs. Inhibition of these enzymes is a potential approach for cancer chemoprevention and treatment of CYP1-mediated drug resistance. We characterized inhibition of human CYP1A1, CYP1A2 and CYP1B1 enzymes by the novel inhibitor N-(3,5-dichlorophenyl) cyclopropanecarboxamide (DCPCC) and α-naphthoflavone (ANF). Depending on substrate, IC50 values of DCPCC for CYP1A1 or CYP1B1 were 10-95 times higher than for CYP1A2. IC50 of DCPCC for CYP1A2 was 100-fold lower than for enzymes in CYP2 and CYP3 families. DCPCC IC50 values were 10-680 times higher than the ones of ANF. DCPCC was a mixed type inhibitor of CYP1A2. ANF was a competitive tight-binding inhibitor of CYP1A1, CYP1A2 and CYP1B1. CYP1A1 oxidized DCPCC more rapidly than CYP1A2 or CYP1B1 to the same metabolite. Molecular dynamics simulations and binding free energy calculations explained the differences of binding of DCPCC and ANF to the active sites of all three CYP1 enzymes. We conclude that DCPCC is a more selective inhibitor for CYP1A2 than ANF. DCPCC is a candidate structure to modulate CYP1A2 mediated metabolism of procarcinogens and anticancer drugs. PMID: 32060993 [PubMed - as supplied by publisher]

Related Articles Targeted Metabolomics Analysis Reveals that Dietary Supranutritional Selenium Regulates Sugar and Acylcarnitine Metabolism Homeostasis in Pig Liver. J Nutr. 2020 Feb 14;: Authors: Zhang K, Han Y, Zhao Q, Zhan T, Li Y, Sun W, Li S, Sun D, Si X, Yu X, Qin Y, Tang C, Zhang J Abstract BACKGROUND: The association between high selenium (Se) intake and metabolic disorders such as type 2 diabetes has raised great concern, but the underlying mechanism remains unclear. OBJECTIVE: Through targeted metabolomics analysis, we examined the liver sugar and acylcarnitine metabolism responses to supranutritional selenomethionine (SeMet) supplementation in pigs. METHODS: Thirty-six castrated male pigs (Duroc-Landrace-Yorkshire, 62.0 ± 3.3 kg) were fed SeMet adequate (Se-A, 0.25 mg Se/kg) or SeMet supranutritional (Se-S, 2.5 mg Se/kg) diets for 60 d. The Se concentration, biochemical, gene expression, enzyme activity, and energy-targeted metabolite profiles were analyzed. RESULTS: The Se-S group had greater fasting serum concentrations of glucose (1.9-fold), insulin (1.4-fold), and free fatty acids (FFAs,1.3-fold) relative to the Se-A group (P < 0.05). The liver total Se concentration was 4.2-fold that of the Se-A group in the Se-S group (P < 0.05), but expression of most selenoprotein genes and selenoenzyme activity did not differ between the 2 groups. Seven of 27 targeted sugar metabolites and 4 of 21 acylcarnitine metabolites significantly changed in response to high SeMet (P < 0.05). High SeMet supplementation significantly upregulated phosphoenolpyruvate carboxy kinase (PEPCK) activity by 64.4% and decreased hexokinase and succinate dehydrogenase (SDH) activity by 46.5-56.7% (P < 0.05). The relative contents of glucose, dihydroxyacetone phosphate, α-ketoglutarate, fumarate, malate, erythrose-4-phosphate, and sedoheptulose-7-phosphate in the Se-S group were 21.1-360% greater than those in the Se-A group (P < 0.05). The expression of fatty acid synthase (FASN) and the relative contents of carnitine, hexanoyl-carnitine, decanoyl-carnitine, and tetradecanoyl-carnitine in the Se-S group were 35-97% higher than those in the Se-A group (P < 0.05). CONCLUSIONS: Dietary high SeMet-induced hyperglycemia and hyperinsulinemia were associated with suppression of sugar metabolism and elevation of lipid synthesis in pig livers. Our research provides novel insights into high SeMet intake-induced type 2 diabetes. PMID: 32060554 [PubMed - as supplied by publisher]

Related Articles Glycolysis/gluconeogenesis- and tricarboxylic acid cycle-related metabolites, Mediterranean diet, and type 2 diabetes. Am J Clin Nutr. 2020 Feb 14;: Authors: Guasch-Ferré M, Santos JL, Martínez-González MA, Clish CB, Razquin C, Wang D, Liang L, Li J, Dennis C, Corella D, Muñoz-Bravo C, Romaguera D, Estruch R, Santos-Lozano JM, Castañer O, Alonso-Gómez A, Serra-Majem L, Ros E, Canudas S, Asensio EM, Fitó M, Pierce K, Martínez JA, Salas-Salvadó J, Toledo E, Hu FB, Ruiz-Canela M Abstract BACKGROUND: Glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear. OBJECTIVES: We aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions. METHODS: We included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil, MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC-tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-one-out cross-validation approach. RESULTS: Baseline circulating concentrations of hexose monophosphate, pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T2D risk (17-44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1 y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons. CONCLUSIONS: We identified a panel of glycolysis/gluconeogenesis-related metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites.This trial was registered at controlled-trials.com as ISRCTN35739639. PMID: 32060497 [PubMed - as supplied by publisher]

Related Articles Genomic determinants of hypertension with a focus on metabolomics and the gut microbiome. Am J Hypertens. 2020 Feb 15;: Authors: Louca P, Menni C, Padmanabhan S Abstract Epidemiologic and genomic studies have progressively improved our understanding of the causation of hypertension and the complex relationship with diet and environment. The majority of mendelian forms of syndromic hypotension and HTN have all been linked to mutations in genes whose encoded proteins regulate salt-water balance in the kidney, supporting the primacy of the kidneys in BP regulation. There are over 1,477 single nucleotide polymorphisms associated with blood pressure and hypertension and the challenge is establishing a causal role for these variants. Hypertension is a complex multifactorial phenotype and it is likely to be influenced by multiple factors including interactions between diet and lifestyle factors, microbiome and epigenetics. Given the finite genetic variability that is possible in humans, it is likely that incremental gains from single marker analyses have now plateaued and a greater leap in our understanding of the genetic basis of disease will come from integration of other omics and the interacting environmental factors. In this review, we focus on emerging results from the microbiome and metabolomics and discuss how leveraging these findings may facilitate a deeper understanding of the interrelationships between genomics, diet and microbial ecology in humans in the causation of essential hypertension. PMID: 32060494 [PubMed - as supplied by publisher]