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Sample records for human alcohol metabolism

  1. A Simplified Model of Human Alcohol Metabolism That Integrates Biotechnology and Human Health into a Mass Balance Team Project

    Science.gov (United States)

    Yang, Allen H. J.; Dimiduk, Kathryn; Daniel, Susan

    2011-01-01

    We present a simplified human alcohol metabolism model for a mass balance team project. Students explore aspects of engineering in biotechnology: designing/modeling biological systems, testing the design/model, evaluating new conditions, and exploring cutting-edge "lab-on-a-chip" research. This project highlights chemical engineering's impact on…

  2. A Simplified Model of Human Alcohol Metabolism That Integrates Biotechnology and Human Health into a Mass Balance Team Project

    Science.gov (United States)

    Yang, Allen H. J.; Dimiduk, Kathryn; Daniel, Susan

    2011-01-01

    We present a simplified human alcohol metabolism model for a mass balance team project. Students explore aspects of engineering in biotechnology: designing/modeling biological systems, testing the design/model, evaluating new conditions, and exploring cutting-edge "lab-on-a-chip" research. This project highlights chemical engineering's impact on…

  3. The secondary alcohol and aglycone metabolites of doxorubicin alter metabolism of human erythrocytes

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    F. Misiti

    2003-12-01

    Full Text Available Anthracyclines, a class of antitumor drugs widely used for the treatment of solid and hematological malignancies, cause a cumulative dose-dependent cardiac toxicity whose biochemical basis is unclear. Recent studies of the role of the metabolites of anthracyclines, i.e., the alcohol metabolite doxorubicinol and aglycone metabolites, have suggested new hypotheses about the mechanisms of anthracycline cardiotoxicity. In the present study, human red blood cells were used as a cell model. Exposure (1 h at 37ºC of intact human red blood cells to doxorubicinol (40 µM and to aglycone derivatives of doxorubicin (40 µM induced, compared with untreated red cells: i a ~2-fold stimulation of the pentose phosphate pathway (PPP and ii a marked inhibition of the red cell antioxidant enzymes, glutathione peroxidase (~20% and superoxide dismutase (~60%. In contrast to doxorubicin-derived metabolites, doxorubicin itself induced a slighter PPP stimulation (~35% and this metabolic event was not associated with any alteration in glutathione reductase, glutathione peroxidase, catalase or superoxide dismutase activity. Furthermore, the interaction of hemoglobin with doxorubicin and its metabolites induced a significant increase (~22% in oxygen affinity compared with hemoglobin incubated without drugs. On the basis of the results obtained in the present study, a new hypothesis, involving doxorubicinol and aglycone metabolites, has been proposed to clarify the mechanisms responsible for the doxorubicin-induced red blood cell toxicity.

  4. Inhibition of human alcohol and aldehyde dehydrogenases by cimetidine and assessment of its effects on ethanol metabolism.

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    Lai, Ching-Long; Li, Yeung-Pin; Liu, Chiu-Ming; Hsieh, Hsiu-Shan; Yin, Shih-Jiun

    2013-02-25

    Previous studies have reported that cimetidine, an H2-receptor antagonist used to treat gastric and duodenal ulcers, can inhibit alcohol dehydrogenases (ADHs) and ethanol metabolism. Human alcohol dehydrogenases and aldehyde dehydrogenases (ALDHs), the principal enzymes responsible for metabolism of ethanol, are complex enzyme families that exhibit functional polymorphisms among ethnic groups and distinct tissue distributions. We investigated the inhibition by cimetidine of alcohol oxidation by recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and aldehyde oxidation by ALDH1A1 and ALDH2 at pH 7.5 and a cytosolic NAD(+) concentration. Cimetidine acted as competitive or noncompetitive inhibitors for the ADH and ALDH isozymes/allozymes with near mM inhibition constants. The metabolic interactions between cimetidine and ethanol/acetaldehyde were assessed by computer simulation using the inhibition equations and the determined kinetic constants. At therapeutic drug levels (0.015 mM) and physiologically relevant concentrations of ethanol (10 mM) and acetaldehyde (10 μM) in target tissues, cimetidine could weakly inhibit (<5%) the activities of ADH1B2 and ADH1B3 in liver, ADH2 in liver and small intestine, ADH4 in stomach, and ALDH1A1 in the three tissues, but not significantly affect ADH1A, ADH1B1, ADH1C1/2, or ALDH2. At higher drug levels, which may accumulate in cells (0.2 mM), the activities of the weakly-inhibited enzymes may be decreased more significantly. The quantitative effects of cimetidine on metabolism of ethanol and other physiological substrates of ADHs need further investigation. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

  5. Ethanol metabolism by HeLa cells transduced with human alcohol dehydrogenase isoenzymes: control of the pathway by acetaldehyde concentration.

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    Matsumoto, Michinaga; Cyganek, Izabela; Sanghani, Paresh C; Cho, Won Kyoo; Liangpunsakul, Suthat; Crabb, David W

    2011-01-01

    Human class I alcohol dehydrogenase 2 isoenzymes (encoded by the ADH1B locus) have large differences in kinetic properties; however, individuals inheriting the alleles for the different isoenzymes exhibit only small differences in alcohol elimination rates. This suggests that other cellular factors must regulate the activity of the isoenzymes. The activity of the isoenzymes expressed from ADH1B*1, ADH1B*2, and ADH1B*3 cDNAs was examined in stably transduced HeLa cell lines, including lines which expressed human low K(m) aldehyde dehydrogenase (ALDH2). The ability of the cells to metabolize ethanol was compared with that of HeLa cells expressing rat class I alcohol dehydrogenase (ADH) (HeLa-rat ADH cells), rat hepatoma (H4IIEC3) cells, and rat hepatocytes. The isoenzymes had similar protein half-lives in the HeLa cells. Rat hepatocytes, H4IIEC3 cells, and HeLa-rat ADH cells oxidized ethanol much faster than the cells expressing the ADH1B isoenzymes. This was not explained by high cellular NADH levels or endogenous inhibitors; but rather because the activity of the β1 and β2 ADHs was constrained by the accumulation of acetaldehyde, as shown by the increased rate of ethanol oxidation by cell lines expressing β2 ADH plus ALDH2. The activity of the human β2 ADH isoenzyme is sensitive to inhibition by acetaldehyde, which likely limits its activity in vivo. This study emphasizes the importance of maintaining a low steady-state acetaldehyde concentration in hepatocytes during ethanol metabolism. Copyright © 2010 by the Research Society on Alcoholism.

  6. Alcohol metabolism by oral streptococci and interaction with human papillomavirus leads to malignant transformation of oral keratinocytes.

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    Tao, Lin; Pavlova, Sylvia I; Gasparovich, Stephen R; Jin, Ling; Schwartz, Joel

    2015-01-01

    Poor oral hygiene, ethanol consumption, and human papillomavirus (HPV) are associated with oral and esophageal cancers. However, the mechanism is not fully known. This study examines alcohol metabolism in Streptococcus and its interaction with HPV-16 in the malignant transformation of oral keratinocytes. The acetaldehyde-producing strain Streptococcus gordonii V2016 was analyzed for adh genes and activities of alcohol and aldehyde dehydrogenases. Streptococcus attachment to immortalized HPV-16 infected human oral keratinocytes, HOK (HPV/HOK-16B), human oral buccal keratinocytes, and foreskin keratinocytes was studied. Acetaldehyde, malondialdehyde, DNA damage, and abnormal proliferation among keratinocytes were also quantified. We found that S. gordonii V2016 expressed three primary alcohol dehydrogenases, AdhA, AdhB, and AdhE, which all oxidize ethanol to acetaldehyde, but their preferred substrates were 1-propanol, 1-butanol, and ethanol, respectively. S. gordonii V2016 did not show a detectable aldehyde dehydrogenase. AdhE is the major alcohol dehydrogenase in S. gordonii. Acetaldehyde and malondialdehyde production from permissible Streptococcus species significantly increased the bacterial attachment to keratinocytes, which was associated with an enhanced expression of furin to facilitate HPV infection and several malignant phenotypes including acetaldehyde adduct formation, abnormal proliferation, and enhanced migration through integrin-coated basement membrane by HPV-infected oral keratinocytes. Therefore, expression of multiple alcohol dehydrogenases with no functional aldehyde dehydrogenase contributes to excessive production of acetaldehyde from ethanol by oral streptococci. Oral Streptococcus species and HPV may cooperate to transform oral keratinocytes after ethanol exposure. These results suggest a significant clinical interaction, but further validation is warranted.

  7. Alcohol abuse and glycoconjugate metabolism

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    Sylwia Chojnowska

    2012-04-01

    Full Text Available The relationship between alcohol consumption and glycoconjugate metabolism is complex and multidimensional. This review summarizes the advances in basic and clinical research on the molecular and cellular events involved in the metabolic effects of alcohol on glycoconjugates (glycoproteins, glycolipids, and proteoglycans. We summarize the action of ethanol, acetaldehyde, reactive oxygen species (ROS, nonoxidative metabolite of alcohol — fatty acid ethyl esters (FAEEs, and the ethanol-water competition mechanism, on glycoconjugate biosynthesis, modification, transport and secretion, as well as on elimination and catabolism processes. As the majority of changes in the cellular metabolism of glycoconjugates are generally ascribed to alterations in synthesis, transport, glycosylation and secretion, the degradation and elimination processes, of which the former occurs also in extracellular matrix, seem to be underappreciated. The pathomechanisms are additionally complicated by the fact that the effect of alcohol intoxication on the glycoconjugate metabolism depends not only on the duration of ethanol exposure, but also demonstrates dose- and regional-sensitivity. Further research is needed to bridge the gap in transdisciplinary research and enhance our understanding of alcohol- and glycoconjugate-related diseases.

  8. Alcohol abuse and glycoconjugate metabolism.

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    Waszkiewicz, Napoleon; Szajda, Sławomir Dariusz; Zalewska, Anna; Szulc, Agata; Kępka, Alina; Minarowska, Alina; Wojewódzka-Żelezniakowicz, Marzena; Konarzewska, Beata; Chojnowska, Sylwia; Ladny, Jerzy Robert; Zwierz, Krzysztof

    2012-04-24

    The relationship between alcohol consumption and glycoconjugate metabolism is complex and multidimensional. This review summarizes the advances in basic and clinical research on the molecular and cellular events involved in the metabolic effects of alcohol on glycoconjugates (glycoproteins, glycolipids, and proteoglycans). We summarize the action of ethanol, acetaldehyde, reactive oxygen species (ROS), nonoxidative metabolite of alcohol--fatty acid ethyl esters (FAEEs), and the ethanol-water competition mechanism, on glycoconjugate biosynthesis, modification, transport and secretion, as well as on elimination and catabolism processes. As the majority of changes in the cellular metabolism of glycoconjugates are generally ascribed to alterations in synthesis, transport, glycosylation and secretion, the degradation and elimination processes, of which the former occurs also in extracellular matrix, seem to be underappreciated. The pathomechanisms are additionally complicated by the fact that the effect of alcohol intoxication on the glycoconjugate metabolism depends not only on the duration of ethanol exposure, but also demonstrates dose- and regional-sensitivity. Further research is needed to bridge the gap in transdisciplinary research and enhance our understanding of alcohol- and glycoconjugate-related diseases.

  9. Inhibition of human alcohol and aldehyde dehydrogenases by acetaminophen: Assessment of the effects on first-pass metabolism of ethanol.

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    Lee, Yung-Pin; Liao, Jian-Tong; Cheng, Ya-Wen; Wu, Ting-Lun; Lee, Shou-Lun; Liu, Jong-Kang; Yin, Shih-Jiun

    2013-11-01

    Acetaminophen is one of the most widely used over-the-counter analgesic, antipyretic medications. Use of acetaminophen and alcohol are commonly associated. Previous studies showed that acetaminophen might affect bioavailability of ethanol by inhibiting gastric alcohol dehydrogenase (ADH). However, potential inhibitions by acetaminophen of first-pass metabolism (FPM) of ethanol, catalyzed by the human ADH family and by relevant aldehyde dehydrogenase (ALDH) isozymes, remain undefined. ADH and ALDH both exhibit racially distinct allozymes and tissue-specific distribution of isozymes, and are principal enzymes responsible for ethanol metabolism in humans. In this study, we investigated acetaminophen inhibition of ethanol oxidation with recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and inhibition of acetaldehyde oxidation with recombinant human ALDH1A1 and ALDH2. The investigations were done at near physiological pH 7.5 and with a cytoplasmic coenzyme concentration of 0.5 mM NAD(+). Acetaminophen acted as a noncompetitive inhibitor for ADH enzymes, with the slope inhibition constants (Kis) ranging from 0.90 mM (ADH2) to 20 mM (ADH1A), and the intercept inhibition constants (Kii) ranging from 1.4 mM (ADH1C allozymes) to 19 mM (ADH1A). Acetaminophen exhibited noncompetitive inhibition for ALDH2 (Kis = 3.0 mM and Kii = 2.2 mM), but competitive inhibition for ALDH1A1 (Kis = 0.96 mM). The metabolic interactions between acetaminophen and ethanol/acetaldehyde were assessed by computer simulation using inhibition equations and the determined kinetic constants. At therapeutic to subtoxic plasma levels of acetaminophen (i.e., 0.2-0.5 mM) and physiologically relevant concentrations of ethanol (10 mM) and acetaldehyde (10 μm) in target tissues, acetaminophen could inhibit ADH1C allozymes (12-26%) and ADH2 (14-28%) in the liver and small intestine, ADH4 (15-31%) in the stomach, and ALDH1A1 (16-33%) and ALDH2 (8.3-19%) in all 3 tissues. The

  10. 人体乙醇代谢模型的制作研究%Observation on human alcohol metabolism model

    Institute of Scientific and Technical Information of China (English)

    潘敏; 谢少龙; 丘慧秋; 谢海萍

    2016-01-01

    目的:制作人体乙醇体内代谢模型供中药配方防治乙醇醉酒实验研究使用。方法:志愿者12名,男女各半,给予53°泸州老窖二曲酒100mL 空腹服用,记录志愿者的人体平衡试验、人体酒后症状(心率、血压、尿量等),然后分别于30min、60min、120min 和180min 时进行呼气乙醇含量检验和人体血液乙醇含量检测,以此作为解酒的效果比较指标。结果:志愿者空腹服用53°泸州老窖二曲酒100mL 后,乙醇呼气含量测定30min、60min、120min、180min 的乙醇平均值是73.58g/100mL、64.72g/100mL、51g/100mL、38.5g/100mL;人体血液乙醇含量60min、120min、180min 的乙醇平均值是86g/100mL、74g/100mL、58g/100mL;志愿者的心率、血压、尿量均较正常值升高。结论:给予53°泸州老窖二曲酒100mL 的志愿者在3h 内仍检测出较高的乙醇浓度,呼气乙醇含量检验和人体血液乙醇含量检测存在差异,血液检测比呼气检测的乙醇浓度高,给予志愿者的乙醇量52g,未出现转氨酶升高的情况,不会造成急性肝损害。%Objective: Treating alcoholic intoxication with TCM medicine was studied by ethanol metabolism in human body model. Methods: 12 volunteers were given high wine (100 mL). Then body balance test and the body symptoms after drinking were observed and recorded. At 30min, 60min, 120min and 180min, breath alcohol content and blood alcohol content were detected. Results: After drinking, breath alcohol content at 30min, 60min, 120min and 180min, average ethanol were 73.58g/100mL, 64.72g/100mL, 51g/100mL, and 38.5g/100 mL respectively. Blood alcohol content at 30min, 60min, 120min and 180min, average ethanol were 86g/100mL, 74g/100mL, and 58g/100mL respectively. Heart rate, blood pressure, urine output were more increased. Conclusion: During 3 hours, a higher concentration of ethanol was detected in 53 volunteers. Difference of human blood of the alcohol content

  11. The Adverse Effects of Alcohol on Vitamin A Metabolism

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    William S. Blaner

    2012-05-01

    Full Text Available The objective of this review is to explore the relationship between alcohol and the metabolism of the essential micronutrient, vitamin A; as well as the impact this interaction has on alcohol-induced disease in adults. Depleted hepatic vitamin A content has been reported in human alcoholics, an observation that has been confirmed in animal models of chronic alcohol consumption. Indeed, alcohol consumption has been associated with declines in hepatic levels of retinol (vitamin A, as well as retinyl ester and retinoic acid; collectively referred to as retinoids. Through the use of animal models, the complex interplay between alcohol metabolism and vitamin A homeostasis has been studied; the reviewed research supports the notion that chronic alcohol consumption precipitates a decline in hepatic retinoid levels through increased breakdown, as well as increased export to extra-hepatic tissues. While the precise biochemical mechanisms governing alcohol’s effect remain to be elucidated, its profound effect on hepatic retinoid status is irrefutable. In addition to a review of the literature related to studies on tissue retinoid levels and the metabolic interactions between alcohol and retinoids, the significance of altered hepatic retinoid metabolism in the context of alcoholic liver disease is also considered.

  12. Inhibition of human alcohol and aldehyde dehydrogenases by aspirin and salicylate: assessment of the effects on first-pass metabolism of ethanol.

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    Lee, Shou-Lun; Lee, Yung-Pin; Wu, Min-Li; Chi, Yu-Chou; Liu, Chiu-Ming; Lai, Ching-Long; Yin, Shih-Jiun

    2015-05-01

    Previous studies have reported that aspirin significantly reduced the first-pass metabolism (FPM) of ethanol in humans thereby increasing adverse effects of alcohol. The underlying causes, however, remain poorly understood. Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), principal enzymes responsible for metabolism of ethanol, are complex enzyme families that exhibit functional polymorphisms among ethnic groups and distinct tissue distributions. We investigated the inhibition profiles by aspirin and its major metabolite salicylate of ethanol oxidation by recombinant human ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, ADH1C2, ADH2, and ADH4, and acetaldehyde oxidation by ALDH1A1 and ALDH2, at pH 7.5 and 0.5 mM NAD(+). Competitive inhibition pattern was found to be a predominant type among the ADHs and ALDHs studied, although noncompetitive and uncompetitive inhibitions were also detected in a few cases. The inhibition constants of salicylate for the ADHs and ALDHs were considerably lower than that of aspirin with the exception of ADH1A that can be ascribed to a substitution of Ala-93 at the bottom of substrate pocket as revealed by molecular docking experiments. Kinetic inhibition equation-based simulations show at higher therapeutic levels of blood plasma salicylate (1.5 mM) that the decrease of activities at 2-10 mM ethanol for ADH1A/ADH2 and ADH1B2/ADH1B3 are predicted to be 75-86% and 31-52%, respectively, and that the activity decline for ALDH1A1 and ALDH2 at 10-50 μM acetaldehyde to be 62-73%. Our findings suggest that salicylate may substantially inhibit hepatic FPM of alcohol at both the ADH and ALDH steps when concurrent intaking aspirin. Copyright © 2015 Elsevier Inc. All rights reserved.

  13. ADH single nucleotide polymorphism associations with alcohol metabolism in vivo

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    Birley, Andrew J.; James, Michael R.; Dickson, Peter A.; Montgomery, Grant W.; Heath, Andrew C.; Martin, Nicholas G.; Whitfield, John B.

    2009-01-01

    We have previously found that variation in alcohol metabolism in Europeans is linked to the chromosome 4q region containing the ADH gene family. We have now typed 103 single nucleotide polymorphisms (SNPs) across this region to test for allelic associations with variation in blood and breath alcohol concentrations after an alcohol challenge. In vivo alcohol metabolism was modelled with three parameters that identified the absorption and rise of alcohol concentration following ingestion, and the rate of elimination. Alleles of ADH7 SNPs were associated with the early stages of alcohol metabolism, with additional effects in the ADH1A, ADH1B and ADH4 regions. Rate of elimination was associated with SNPs in the intragenic region between ADH7 and ADH1C, and across ADH1C and ADH1B. SNPs affecting alcohol metabolism did not correspond to those reported to affect alcohol dependence or alcohol-related disease. The combined SNP associations with early- and late-stage metabolism only account for approximately 20% of the total genetic variance linked to the ADH region, and most of the variance for in vivo alcohol metabolism linked to this region is yet to be explained. PMID:19193628

  14. Genetical genomic determinants of alcohol consumption in rats and humans

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    Mangion Jonathan

    2009-10-01

    Full Text Available Abstract Background We have used a genetical genomic approach, in conjunction with phenotypic analysis of alcohol consumption, to identify candidate genes that predispose to varying levels of alcohol intake by HXB/BXH recombinant inbred rat strains. In addition, in two populations of humans, we assessed genetic polymorphisms associated with alcohol consumption using a custom genotyping array for 1,350 single nucleotide polymorphisms (SNPs. Our goal was to ascertain whether our approach, which relies on statistical and informatics techniques, and non-human animal models of alcohol drinking behavior, could inform interpretation of genetic association studies with human populations. Results In the HXB/BXH recombinant inbred (RI rats, correlation analysis of brain gene expression levels with alcohol consumption in a two-bottle choice paradigm, and filtering based on behavioral and gene expression quantitative trait locus (QTL analyses, generated a list of candidate genes. A literature-based, functional analysis of the interactions of the products of these candidate genes defined pathways linked to presynaptic GABA release, activation of dopamine neurons, and postsynaptic GABA receptor trafficking, in brain regions including the hypothalamus, ventral tegmentum and amygdala. The analysis also implicated energy metabolism and caloric intake control as potential influences on alcohol consumption by the recombinant inbred rats. In the human populations, polymorphisms in genes associated with GABA synthesis and GABA receptors, as well as genes related to dopaminergic transmission, were associated with alcohol consumption. Conclusion Our results emphasize the importance of the signaling pathways identified using the non-human animal models, rather than single gene products, in identifying factors responsible for complex traits such as alcohol consumption. The results suggest cross-species similarities in pathways that influence predisposition to consume

  15. Alcohol drinking, mean corpuscular volume of erythrocytes, and alcohol metabolic genotypes in drunk drivers.

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    Pavanello, Sofia; Snenghi, Rossella; Nalesso, Alessandro; Sartore, Daniela; Ferrara, Santo Davide; Montisci, Massimo

    2012-02-01

    Regular and irregular abuse of alcohol are global health priorities associated with diseases at multiple sites, including cancer. Mechanisms of diseases induced by alcohol are closely related to its metabolism. Among conventional markers of alcohol abuse, the mean corpuscular volume (MCV) of erythrocytes is prognostic of alcohol-related cancer and its predictivity increases when combined with functional polymorphisms of alcohol dehydrogenase (ADH1B [rs1229984] and ADH1C [rs698]) and the mitochondrial aldehyde dehydrogenase (ALDH2 [rs671]). Whether these genetic variants can influence abuse in alcohol drinking and MCV has never been examined in drunk-driving traffic offenders. We examined 149 drunk drivers, diagnosed as alcohol abusers according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth edition Text Revision (DSM-IV-TR) and enrolled in a probation program, and 257 social drinkers (controls), all Caucasian males. Alcohol intake was assessed according to self-reported drink-units/d and MCV unadjusted and adjusted for age, smoking, and body mass index. Multivariable models were used to compute MCV adjusted means. Genotype analyses were performed by PCR on DNA from blood. The adjusted MCV mean was higher in drunk-driving abusers than in controls (92 vs. 91fL; Palcohol drinking, and MCV enlargement. This suggests that drunk drivers with augmented MCV modulated by the alcohol metabolic ADH1B*1/*1 genotype may be at higher risk of driving incapability and of alcohol-related cancer.

  16. Contribution of liver alcohol dehydrogenase to metabolism of alcohols in rats.

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    Plapp, Bryce V; Leidal, Kevin G; Murch, Bruce P; Green, David W

    2015-06-05

    The kinetics of oxidation of various alcohols by purified rat liver alcohol dehydrogenase (ADH) were compared with the kinetics of elimination of the alcohols in rats in order to investigate the roles of ADH and other factors that contribute to the rates of metabolism of alcohols. Primary alcohols (ethanol, 1-propanol, 1-butanol, 2-methyl-1-propanol, 3-methyl-1-butanol) and diols (1,3-propanediol, 1,3-butanediol, 1,4-butanediol, 1,5-pentanediol) were eliminated in rats with zero-order kinetics at doses of 5-20 mmol/kg. Ethanol was eliminated most rapidly, at 7.9 mmol/kgh. Secondary alcohols (2-propanol-d7, 2-propanol, 2-butanol, 3-pentanol, cyclopentanol, cyclohexanol) were eliminated with first order kinetics at doses of 5-10 mmol/kg, and the corresponding ketones were formed and slowly eliminated with zero or first order kinetics. The rates of elimination of various alcohols were inhibited on average 73% (55% for 2-propanol to 90% for ethanol) by 1 mmol/kg of 4-methylpyrazole, a good inhibitor of ADH, indicating a major role for ADH in the metabolism of the alcohols. The Michaelis kinetic constants from in vitro studies (pH 7.3, 37 °C) with isolated rat liver enzyme were used to calculate the expected relative rates of metabolism in rats. The rates of elimination generally increased with increased activity of ADH, but a maximum rate of 6±1 mmol/kg h was observed for the best substrates, suggesting that ADH activity is not solely rate-limiting. Because secondary alcohols only require one NAD(+) for the conversion to ketones whereas primary alcohols require two equivalents of NAD(+) for oxidation to the carboxylic acids, it appears that the rate of oxidation of NADH to NAD(+) is not a major limiting factor for metabolism of these alcohols, but the rate-limiting factors are yet to be identified.

  17. Role of alcohol in the regulation of iron metabolism

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Patients with alcoholic liver disease frequently exhibit increased body iron stores, as reflected by elevated serum iron indices (transferrin saturation, ferritin) and hepatic iron concentration. Even mild to moderate alcohol consumption has been shown to increase the prevalence of iron overload. Moreover, increased hepatic iron content is associated with greater mortality from alcoholic cirrhosis, suggesting a pathogenic role for iron in alcoholic liver disease. Alcohol increases the severity of disease in patients with genetic hemochromatosis,an iron overload disorder common in the Caucasian population. Both iron and alcohol individually cause oxidative stress and lipid peroxidation, which culminates in liver injury. Despite these observations, the underlying mechanisms of iron accumulation and the source of the excess iron observed in alcoholic liver disease remain unclear. Over the last decade, several novel iron-regulatory proteins have been identified and these have greatly enhanced our understanding of iron metabolism. For example, hepcidin, a circulatory antimicrobial peptide synthesized by the hepatocytes of the liver is now known to play a central role in the regulation of iron homeostasis. This review attempts to describe the interaction of alcohol and iron-regulatory molecules. Understanding these molecular mechanisms is of considerable clinical importance because both alcoholic liver disease and genetic hemochromatosis are common diseases, in which alcohol and iron appear to act synergistically to cause liver injury.

  18. [Cardiovascular risk parameters, metabolic syndrome and alcohol consumption by workers].

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    Vicente-Herrero, María Teófila; López González, Ángel Arturo; Ramírez-Iñiguez de la Torre, María Victoria; Capdevila-García, Luisa; Terradillos-García, María Jesús; Aguilar-Jiménez, Encarna

    2015-04-01

    Prevalence of alcohol consumption is high in the general population and generates specific problems at the workplace. To establish benchmarks between levels of alcohol consumption and cardiovascular risk variables and metabolic syndrome. A cross-sectional study of 7,644 workers of Spanish companies (2,828 females and 4,816 males). Alcohol consumption and its relation to cardiovascular risk was assessed using Framingham calibrated for the Spanish population (REGICOR) and SCORE, and metabolic syndrome was assessed using modified ATPIII and IDF criteria and Castelli and atherogenic index and triglycerides/HDL ratio. A multivariate analysis was performed using logistic regression and odds ratios were estimated. Statistically significant differences were seen in the mean values of the different parameters studied in prevalence of metabolic syndrome, for both sexes and with modified ATPIII, IDF and REGICOR and SCORE. The sex, age, alcohol, and smoking variables were associated to cardiovascular risk parameters and metabolic syndrome. Physical exercise and stress are only associated to with some of them. The alcohol consumption affects all cardiovascular risk parameters and metabolic syndrome, being more negative the result in high level drinkers. Copyright © 2014 SEEN. Published by Elsevier España, S.L.U. All rights reserved.

  19. Biology, Genetics, and Environment: Underlying Factors Influencing Alcohol Metabolism.

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    Wall, Tamara L; Luczak, Susan E; Hiller-Sturmhöfel, Susanne

    2016-01-01

    Gene variants encoding several of the alcohol-metabolizing enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH), are among the largest genetic associations with risk for alcohol dependence. Certain genetic variants (i.e., alleles)--particularly the ADH1B*2, ADH1B*3, ADH1C*1, and ALDH2*2 alleles--have been associated with lower rates of alcohol dependence. These alleles may lead to an accumulation of acetaldehyde during alcohol metabolism, which can result in heightened subjective and objective effects. The prevalence of these alleles differs among ethnic groups; ADH1B*2 is found frequently in northeast Asians and occasionally Caucasians, ADH1B*3 is found predominantly in people of African ancestry, ADH1C*1 varies substantially across populations, and ALDH2*2 is found almost exclusively in northeast Asians. Differences in the prevalence of these alleles may account at least in part for ethnic differences in alcohol consumption and alcohol use disorder (AUD). However, these alleles do not act in isolation to influence the risk of AUD. For example, the gene effects of ALDH2*2 and ADH1B*2 seem to interact. Moreover, other factors have been found to influence the extent to which these alleles affect a person's alcohol involvement, including developmental stage, individual characteristics (e.g., ethnicity, antisocial behavior, and behavioral undercontrol), and environmental factors (e.g., culture, religion, family environment, and childhood adversity).

  20. Human metabolic atlas: an online resource for human metabolism.

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    Pornputtapong, Natapol; Nookaew, Intawat; Nielsen, Jens

    2015-01-01

    Human tissue-specific genome-scale metabolic models (GEMs) provide comprehensive understanding of human metabolism, which is of great value to the biomedical research community. To make this kind of data easily accessible to the public, we have designed and deployed the human metabolic atlas (HMA) website (http://www.metabolicatlas.org). This online resource provides comprehensive information about human metabolism, including the results of metabolic network analyses. We hope that it can also serve as an information exchange interface for human metabolism knowledge within the research community. The HMA consists of three major components: Repository, Hreed (Human REaction Entities Database) and Atlas. Repository is a collection of GEMs for specific human cell types and human-related microorganisms in SBML (System Biology Markup Language) format. The current release consists of several types of GEMs: a generic human GEM, 82 GEMs for normal cell types, 16 GEMs for different cancer cell types, 2 curated GEMs and 5 GEMs for human gut bacteria. Hreed contains detailed information about biochemical reactions. A web interface for Hreed facilitates an access to the Hreed reaction data, which can be easily retrieved by using specific keywords or names of related genes, proteins, compounds and cross-references. Atlas web interface can be used for visualization of the GEMs collection overlaid on KEGG metabolic pathway maps with a zoom/pan user interface. The HMA is a unique tool for studying human metabolism, ranging in scope from an individual cell, to a specific organ, to the overall human body. This resource is freely available under a Creative Commons Attribution-NonCommercial 4.0 International License.

  1. Redesigned Human Metabolic Simulator

    Science.gov (United States)

    Duffield, Bruce; Jeng, Frank; Lange, Kevin

    2008-01-01

    A design has been formulated for a proposed improved version of an apparatus that simulates atmospheric effects of human respiration by introducing controlled amounts of carbon dioxide, water vapor, and heat into the air. Denoted a human metabolic simulator (HMS), the apparatus is used for testing life-support equipment when human test subjects are not available. The prior version of the HMS, to be replaced, was designed to simulate the respiratory effects of as many as four persons. It exploits the catalytic combustion of methyl acetate, for which the respiratory quotient (the molar ratio of carbon dioxide produced to oxygen consumed) is very close to the human respiratory quotient of about 0.86. The design of the improved HMS provides for simulation of the respiratory effects of as many as eight persons at various levels of activity. The design would also increase safety by eliminating the use of combustion. The improved HMS (see figure) would include a computer that would exert overall control. The computer would calculate the required amounts of oxygen removal, carbon dioxide addition, water addition, and heat addition by use of empirical equations for metabolic profiles of respiration and heat. A blower would circulate air between the HMS and a chamber containing a life-support system to be tested. With the help of feedback from a mass flowmeter, the blower speed would be adjusted to regulate the rate of flow according to the number of persons to be simulated and to a temperature-regulation requirement (the air temperature would indirectly depend on the rate of flow, among other parameters). Oxygen would be removed from the circulating air by means of a commercially available molecular sieve configured as an oxygen concentrator. Oxygen, argon, and trace amounts of nitrogen would pass through a bed in the molecular sieve while carbon dioxide, the majority of nitrogen, and other trace gases would be trapped by the bed and subsequently returned to the chamber. If

  2. Polymorphisms in alcohol metabolism genes ADH1B and ALDH2, alcohol consumption and colorectal cancer.

    Directory of Open Access Journals (Sweden)

    Marta Crous-Bou

    Full Text Available BACKGROUND: Colorectal cancer (CRC is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population. METHODOLOGY/PRINCIPAL FINDINGS: SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC study (OR = 1.47; 95%CI = 1.18-1.81. Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025. A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption. CONCLUSIONS/SIGNIFICANCE: Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants.

  3. Polymorphisms in alcohol metabolism genes ADH1B and ALDH2, alcohol consumption and colorectal cancer.

    Science.gov (United States)

    Crous-Bou, Marta; Rennert, Gad; Cuadras, Daniel; Salazar, Ramon; Cordero, David; Saltz Rennert, Hedy; Lejbkowicz, Flavio; Kopelovich, Levy; Monroe Lipkin, Steven; Bernard Gruber, Stephen; Moreno, Victor

    2013-01-01

    Colorectal cancer (CRC) is a leading cause of cancer death worldwide. Epidemiological risk factors for CRC included alcohol intake, which is mainly metabolized to acetaldehyde by alcohol dehydrogenase and further oxidized to acetate by aldehyde dehydrogenase; consequently, the role of genes in the alcohol metabolism pathways is of particular interest. The aim of this study is to analyze the association between SNPs in ADH1B and ALDH2 genes and CRC risk, and also the main effect of alcohol consumption on CRC risk in the study population. SNPs from ADH1B and ALDH2 genes, included in alcohol metabolism pathway, were genotyped in 1694 CRC cases and 1851 matched controls from the Molecular Epidemiology of Colorectal Cancer study. Information on clinicopathological characteristics, lifestyle and dietary habits were also obtained. Logistic regression and association analysis were conducted. A positive association between alcohol consumption and CRC risk was observed in male participants from the Molecular Epidemiology of Colorectal Cancer study (MECC) study (OR = 1.47; 95%CI = 1.18-1.81). Moreover, the SNPs rs1229984 in ADH1B gene was found to be associated with CRC risk: under the recessive model, the OR was 1.75 for A/A genotype (95%CI = 1.21-2.52; p-value = 0.0025). A path analysis based on structural equation modeling showed a direct effect of ADH1B gene polymorphisms on colorectal carcinogenesis and also an indirect effect mediated through alcohol consumption. Genetic polymorphisms in the alcohol metabolism pathways have a potential role in colorectal carcinogenesis, probably due to the differences in the ethanol metabolism and acetaldehyde oxidation of these enzyme variants.

  4. [Analysis of lipoprotein metabolism in alcoholics].

    Science.gov (United States)

    Mizukami, Yuki; Okazaki, Mitsuyo; Usui, Shinichi; Hosaki, Seijin; Maruyama, Katsuya; Hosokawa, Yu

    2008-04-01

    High density lipoprotein (HDL) is increased by exercise and drinking and is well known as a negative risk factor of coronary heart disease. We analyzed serum lipids of alcoholics from the view points of biochemical examination, remnant like particle (RLP) and particle size of lipoprotein for the purpose of estimated effect of serum lipids, especially HDL quality in alcoholics. Serum levels of total cholesterol, free glycerol, RLP-C and RLP-TG were significantly decreased after hospitalization. The condition of RLP-C/RLP-TG on admission revealed cholesterol-rich composition. In case of HDL-C, the longer period from last drinking to hospitalization affected its decrease. From analytical study of particle size of lipoprotein, quantities of HDL-C in very large size and large size were significantly decreased after hospitalization which means that HDL composition at hospitalization is cholesterol-rich. So, it is speculated that increased serum level of HDL in alcoholics may be caused by expanded cholesterol ester and its quality may be different from that of healthy people. In this meaning, the study of arteriosclerosis in alcoholics will be necessary in relation to high level of serum HDL-C.

  5. Evolution of Metabolic Abnormalities in Alcoholic Patients during Withdrawal

    Directory of Open Access Journals (Sweden)

    X. Vandemergel

    2015-01-01

    Full Text Available Chronic alcohol intoxication is accompanied by metabolic abnormalities. Evolution during the early withdrawal period has been poorly investigated. The aim of this study was to determine the evolution of metabolic parameters during alcohol withdrawal. Patients and Methods. Thirty-three patients admitted in our department for alcohol withdrawal were prospectively included. Results. Baseline hypophosphatemia was found in 24% of cases. FEPO4 was reduced from 14.2 ± 9% at baseline to 7.3 ± 4.2% at day 3 (Pnl, respectively. No correlation was found between the sodium and CPK levels (P=0.75 nor between the CPK level and the amount of alcohol ingested (rs = 0.084, P=0.097. Baseline urate level was elevated and returned to normal after three days. Baseline magnesium concentration was normal and stable over time. Conclusion. Chronic alcohol intoxication was accompanied by phosphaturia, rapidly reversible after alcohol withdrawal and inversely correlated with albuminemia, slight hyponatremia, low levels of 25 hydroxy vitamin D, elevated CPK level in about 30% of women, and hyperuricemia with rapid normalization.

  6. Effects of Beverages on Alcohol Metabolism: Potential Health Benefits and Harmful Impacts

    OpenAIRE

    Fang Wang; Yu-Jie Zhang; Yue Zhou; Ya Li; Tong Zhou; Jie Zheng; Jiao-Jiao Zhang; Sha Li; Dong-Ping Xu; Hua-Bin Li

    2016-01-01

    Nonalcoholic beverages are usually consumed accompanying alcoholic drinks, and their effects on alcohol metabolism are unclear in vivo. In this study, the effects of 20 nonalcoholic beverages on alcohol metabolism and liver injury caused by alcohol were evaluated in mice. Kunming mice were orally fed with alcohol (52%, v/v) and beverages. The concentrations of ethanol and acetaldehyde in blood as well as the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in liver ...

  7. Chronic alcoholism-mediated metabolic disorders in albino rat testes

    Directory of Open Access Journals (Sweden)

    Shayakhmetova Ganna M.

    2014-09-01

    Full Text Available There is good evidence for impairment of spermatogenesis and reductions in sperm counts and testosterone levels in chronic alcoholics. The mechanisms for these effects have not yet been studied in detail. The consequences of chronic alcohol consumption on the structure and/or metabolism of testis cell macromolecules require to be intensively investigated. The present work reports the effects of chronic alcoholism on contents of free amino acids, levels of cytochrome P450 3A2 (CYP3A2 mRNA expression and DNA fragmentation, as well as on contents of different cholesterol fractions and protein thiol groups in rat testes. Wistar albino male rats were divided into two groups: I - control (intact animals, II - chronic alcoholism (15% ethanol self-administration during 150 days. Following 150 days of alcohol consumption, testicular free amino acid content was found to be significantly changed as compared with control. The most profound changes were registered for contents of lysine (-53% and methionine (+133%. The intensity of DNA fragmentation in alcohol-treated rat testes was considerably increased, on the contrary CYP3A2 mRNA expression in testis cells was inhibited, testicular contents of total and etherified cholesterol increased by 25% and 45% respectively, and protein SH-groups decreased by 13%. Multidirectional changes of the activities of testicular dehydrogenases were detected. We thus obtained complex assessment of chronic alcoholism effects in male gonads, affecting especially amino acid, protein, ATP and NADPH metabolism. Our results demonstrated profound changes in testes on the level of proteome and genome. We suggest that the revealed metabolic disorders can have negative implication on cellular regulation of spermatogenesis under long-term ethanol exposure.

  8. Oxidative stress and an altered methionine metabolism in alcoholism.

    Science.gov (United States)

    Bleich, S; Spilker, K; Kurth, C; Degner, D; Quintela-Schneider, M; Javaheripour, K; Rüther, E; Kornhuber, J; Wiltfang, J

    2000-11-03

    The exact mechanism of brain atrophy in patients with chronic alcoholism remains unknown. There is growing evidence that chronic alcoholism is associated with oxidative stress and with a derangement in sulphur amino acid metabolism (e.g. ethanol-induced hyperhomocysteinemia). Furthermore, it has been reported that homocysteine induces neuronal cell death by stimulating N-methyl-D-aspartate receptors as well as by producing free radicals. To further evaluate this latter hypothesis we analysed serum levels of both homocysteine and markers of oxidative stress (malondialdehyde) in alcoholic patients who underwent withdrawal from alcohol. Homocysteine and malondialdehyde were quantified by high performance liquid chromatography (HPLC) in serum samples of 35 patients (active drinkers). There was a significant correlation (Pbrain shrinkage.

  9. [Molecular evidences of non-ADH pathway in alcohol metabolism and Class III alcohol dehydrogenase (ADH3)].

    Science.gov (United States)

    Haseba, Takeshi

    2014-06-01

    Class I alcohol dehydrogenase (ADH1), a key enzyme of alcohol metabolism, contributes around 70% to the systemic alcohol metabolism and also to the acceleration of the metabolism due to chronic alcohol consumption by increasing its liver content, if the liver damage or disease is not apparent. However, the contribution of ADH1 to alcohol metabolism decreases in case of acute alcohol poisoning or chronic alcohol consumption inducing liver damage or disease. On the contrary, non-ADH pathway, which is independent of ADH1, increases the contribution to alcohol metabolism in these cases, by complementing the reduced role of ADH1. The molecular substantiality of non-ADH pathway has been still unknown in spite of the long and hot controversy between two candidates of microsomal ethanol oxidizing system (MEOS) and catalase. This research history suggests the existence of other candidates. Among ADH isozymes, Class III (ADH3) has the highest Km for ethanol and the highest resistance to pyrazole reagents of specific ADH inhibitors. This ADH3 was demonstrated to increase the contribution to alcohol metabolism in vivo dose-dependently, therefore, is a potent candidate of non-ADH pathway. Moreover, ADH3 is considered to increase the contribution to alcohol metabolism in case of alcoholic liver diseases, because the enzyme content increases in damaged tissues with increased hydrophobicity or the activity of the liver correlates with the accumulated alcohol consumptions of patients with alcoholic liver diseases. Such adaptation of ADH3 to alcohol metabolism in these pathological conditions makes patients possible to keep drinking a lot in spite of decrease of ADH1 activity and develops alcoholism seriously.

  10. Alcohol-related brain damage in humans.

    Directory of Open Access Journals (Sweden)

    Amaia M Erdozain

    Full Text Available Chronic excessive alcohol intoxications evoke cumulative damage to tissues and organs. We examined prefrontal cortex (Brodmann's area (BA 9 from 20 human alcoholics and 20 age, gender, and postmortem delay matched control subjects. H & E staining and light microscopy of prefrontal cortex tissue revealed a reduction in the levels of cytoskeleton surrounding the nuclei of cortical and subcortical neurons, and a disruption of subcortical neuron patterning in alcoholic subjects. BA 9 tissue homogenisation and one dimensional polyacrylamide gel electrophoresis (PAGE proteomics of cytosolic proteins identified dramatic reductions in the protein levels of spectrin β II, and α- and β-tubulins in alcoholics, and these were validated and quantitated by Western blotting. We detected a significant increase in α-tubulin acetylation in alcoholics, a non-significant increase in isoaspartate protein damage, but a significant increase in protein isoaspartyl methyltransferase protein levels, the enzyme that triggers isoaspartate damage repair in vivo. There was also a significant reduction in proteasome activity in alcoholics. One dimensional PAGE of membrane-enriched fractions detected a reduction in β-spectrin protein levels, and a significant increase in transmembranous α3 (catalytic subunit of the Na+,K+-ATPase in alcoholic subjects. However, control subjects retained stable oligomeric forms of α-subunit that were diminished in alcoholics. In alcoholics, significant loss of cytosolic α- and β-tubulins were also seen in caudate nucleus, hippocampus and cerebellum, but to different levels, indicative of brain regional susceptibility to alcohol-related damage. Collectively, these protein changes provide a molecular basis for some of the neuronal and behavioural abnormalities attributed to alcoholics.

  11. Metabolic Engineering of Oleaginous Yeasts for Fatty Alcohol Production

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Wei; Wei, Hui; Knoshaug, Eric; Van Wychen, Stefanie; Xu, Qi; Himmel, Michael E.; Zhang, Min

    2016-04-25

    To develop pathways for advanced biological upgrading of sugars to hydrocarbons, we are seeking biological approaches to produce high carbon efficiency intermediates amenable to separations and catalytic upgrading to hydrocarbon fuels. In this study, we successfully demonstrated fatty alcohol production by oleaginous yeasts Yarrowia lipolytica and Lipomyces starkeyi by expressing a bacteria-derived fatty acyl-CoA reductase (FAR). Moreover, we find higher extracellular distribution of fatty alcohols produced by FAR-expressing L. starkeyi strain as compared to Y. lipolytica strain, which would benefit the downstream product recovery process. In both oleaginous yeasts, long chain length saturated fatty alcohols were predominant, accounting for more than 85% of the total fatty alcohols produced. To the best of our knowledge, this is the first report of fatty alcohol production in L. starkeyi. Taken together, our work demonstrates that in addition to Y. lipolytica, L. starkeyi can also serve as a platform organism for production of fatty acid-derived biofuels and bioproducts via metabolic engineering. We believe strain and process development both will significantly contribute to our goal of producing scalable and cost-effective fatty alcohols from renewable biomass.

  12. Polymorphisms in the promoter region of the human class II alcohol dehydrogenase (ADH4) gene affect both transcriptional activity and ethanol metabolism in Japanese subjects.

    Science.gov (United States)

    Kimura, Yukiko; Nishimura, Fusae T; Abe, Shuntaro; Fukunaga, Tatsushige; Tanii, Hideji; Saijoh, Kiyofumi

    2009-02-01

    Class II alcohol dehydrogenase (pi-ADH), encoded by alcohol dehydrogenase (ADH4), is considered to contribute to ethanol (EtOH) oxidation in the liver at high concentration. Four single nucleotide polymorphisms (SNPs) were found in the promoter region of this gene. Analysis of genotype distribution in 102 unrelated Japanese subjects revealed that four loci were in strong linkage disequilibrium and could be classified into three haplotypes. The effects of these polymorphisms on transcriptional activity were investigated in HepG2 cells. Transcriptional activity was significantly higher in cells with the -136A allele than in those with the -136C allele. To investigate whether this difference in transcriptional activity caused a difference in EtOH elimination, previous data on blood EtOH changes after 0.4 g/kg body weight alcohol ingestion were analyzed. When analyzed based on aldehyde dehydrogenase-2 gene (ALDH2) (487)Glu/Lys genotype, the significantly lower level of EtOH at peak in subjects with -136C/A and -136A/A genotype compared with subjects with -136C/C genotype indicated that -136 bp was a suggestive locus for differences in EtOH oxidation. This effect was observed only in subjects with ALDH2 (487)Glu/Glu. These results suggested that the SNP at -136bp in the ADH4 promoter had an effect on transcriptional regulation, and that the higher activity of the -136A allele compared with the -136C allele caused a lower level of blood EtOH after alcohol ingestion; that is, individuals with the -136A allele may consume more EtOH and might have a higher risk for development of alcohol dependence than those without the -136A allele.

  13. Metabolism of phthalates in humans

    DEFF Research Database (Denmark)

    Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

    2007-01-01

    on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some......Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Several animal studies have shown that some phthalates possess endocrine disrupting effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects...... phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate...

  14. Metabolism of phthalates in humans

    DEFF Research Database (Denmark)

    Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

    2007-01-01

    phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate...

  15. Metabolic hypothesis for human altriciality.

    Science.gov (United States)

    Dunsworth, Holly M; Warrener, Anna G; Deacon, Terrence; Ellison, Peter T; Pontzer, Herman

    2012-09-18

    The classic anthropological hypothesis known as the "obstetrical dilemma" is a well-known explanation for human altriciality, a condition that has significant implications for human social and behavioral evolution. The hypothesis holds that antagonistic selection for a large neonatal brain and a narrow, bipedal-adapted birth canal poses a problem for childbirth; the hominin "solution" is to truncate gestation, resulting in an altricial neonate. This explanation for human altriciality based on pelvic constraints persists despite data linking human life history to that of other species. Here, we present evidence that challenges the importance of pelvic morphology and mechanics in the evolution of human gestation and altriciality. Instead, our analyses suggest that limits to maternal metabolism are the primary constraints on human gestation length and fetal growth. Although pelvic remodeling and encephalization during hominin evolution contributed to the present parturitional difficulty, there is little evidence that pelvic constraints have altered the timing of birth.

  16. Female alcoholics: electrocardiographic changes and associated metabolic and electrolytic disorders

    Directory of Open Access Journals (Sweden)

    Borini Paulo

    2003-01-01

    Full Text Available OBJECTIVE: To identify the electrocardiographic changes and their associations with metabolic and electrolytic changes in female alcoholics. METHODS: The study comprised 44 female alcoholics with no apparent physical disorder. They underwent the following examinations: conventional electrocardiography; serologic tests for syphilis, Chagas' disease, and hepatitis B and C viruses; urinary pregnancy testing; hematimetric analysis; biochemical measurements of albumin, fibrinogen, fasting and postprandial glycemias, lipids, hepatic enzymes, and markers for tissue necrosis and inflammation. RESULTS: Some type of electrocardiographic change was identified in 33 (75% patients. In 17 (38.6% patients, more than one of the following changes were present: prolonged QTc interval in 24 (54.5%, change in ventricular repolarization in 11(25%, left ventricular hypertrophy in 6 (13.6%, sinus bradycardia in 4 (9.1%, sinus tachycardia in 3 (6.8%, and conduction disorder in 3 (6.8%. The patients had elevated mean serum levels of creatine phosphokinase, aspartate aminotransferases, and gamma glutamyl transferase, as well as hypocalcemia and low levels of total cholesterol and LDL-cholesterol. The patients with altered electrocardiograms had a more elevated age, a lower alcohol consumption, hypopotassemia, and significantly elevated levels of triglycerides, postprandial glucose, sodium and gamma glutamyl transferase than those with normal electrocardiograms. The opposite occurred with fasting glycemia, magnesium, and alanine aminotransferase. CONCLUSION: The electrocardiographic changes found were prolonged QTc interval, change in ventricular repolarization, and left ventricular hypertrophy. Patients with normal and abnormal electrocardiograms had different metabolic and electrolytic changes.

  17. The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans

    Directory of Open Access Journals (Sweden)

    Bin Qiu

    2016-08-01

    Full Text Available FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1 Fkbp5 KO and wild-type (WT EtOH consumption was tested using a two-bottle choice paradigm; (2 The EtOH elimination rate was measured after intraperitoneal (IP injection of 2.0 g/kg EtOH; (3 Blood alcohol concentration (BAC was measured after 3 h limited access of alcohol; (4 Brain region expression of Fkbp5 was identified using LacZ staining; (5 Baseline corticosterone (CORT was assessed. Additionally, two SNPs, rs1360780 (C/T and rs3800373 (T/G, were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162 from 21–26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT. Finally, single nucleotide polymorphisms (SNPs in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans.

  18. The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans.

    Science.gov (United States)

    Qiu, Bin; Luczak, Susan E; Wall, Tamara L; Kirchhoff, Aaron M; Xu, Yuxue; Eng, Mimy Y; Stewart, Robert B; Shou, Weinian; Boehm, Stephen L; Chester, Julia A; Yong, Weidong; Liang, Tiebing

    2016-08-05

    FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21-26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans.

  19. The FKBP5 Gene Affects Alcohol Drinking in Knockout Mice and Is Implicated in Alcohol Drinking in Humans

    Science.gov (United States)

    Qiu, Bin; Luczak, Susan E.; Wall, Tamara L.; Kirchhoff, Aaron M.; Xu, Yuxue; Eng, Mimy Y.; Stewart, Robert B.; Shou, Weinian; Boehm, Stephen L.; Chester, Julia A.; Yong, Weidong; Liang, Tiebing

    2016-01-01

    FKBP5 encodes FK506-binding protein 5, a glucocorticoid receptor (GR)-binding protein implicated in various psychiatric disorders and alcohol withdrawal severity. The purpose of this study is to characterize alcohol preference and related phenotypes in Fkbp5 knockout (KO) mice and to examine the role of FKBP5 in human alcohol consumption. The following experiments were performed to characterize Fkpb5 KO mice. (1) Fkbp5 KO and wild-type (WT) EtOH consumption was tested using a two-bottle choice paradigm; (2) The EtOH elimination rate was measured after intraperitoneal (IP) injection of 2.0 g/kg EtOH; (3) Blood alcohol concentration (BAC) was measured after 3 h limited access of alcohol; (4) Brain region expression of Fkbp5 was identified using LacZ staining; (5) Baseline corticosterone (CORT) was assessed. Additionally, two SNPs, rs1360780 (C/T) and rs3800373 (T/G), were selected to study the association of FKBP5 with alcohol consumption in humans. Participants were college students (n = 1162) from 21–26 years of age with Chinese, Korean or Caucasian ethnicity. The results, compared to WT mice, for KO mice exhibited an increase in alcohol consumption that was not due to differences in taste sensitivity or alcohol metabolism. Higher BAC was found in KO mice after 3 h of EtOH access. Fkbp5 was highly expressed in brain regions involved in the regulation of the stress response, such as the hippocampus, amygdala, dorsal raphe and locus coeruleus. Both genotypes exhibited similar basal levels of plasma corticosterone (CORT). Finally, single nucleotide polymorphisms (SNPs) in FKBP5 were found to be associated with alcohol drinking in humans. These results suggest that the association between FKBP5 and alcohol consumption is conserved in both mice and humans. PMID:27527158

  20. Thiamin metabolism in the rat during long term alcohol administration.

    Science.gov (United States)

    Bitsch, R; Hansen, J; Hötzel, D

    1982-01-01

    In order to test the effect of a long term alcohol administration on the thiamin metabolism in blood, heart and liver under suboptimal supply, an experiment with rats was carried out over a period of 16 weeks. The suboptimal thiamin supply became visible mainly in the liver stores which were lowered during the whole test period. The unphosphorylated thiamin (T) of liver and heart was not detectable after 4 weeks up to the end of experiment. On the other hand the total thiamin concentration in the erythrocytes increased from the beginning due to an enhanced thiamin-diphosphate (TDP) and thiamintriphosphate (TTP) pool and T was lowered to undetectable amounts only after 16 weeks. In contrast, the alpha-TK in blood and liver was enhanced only after 2 and 4 weeks and tended to become normal by the end of the test period indicating an apoenzyme degeneration. Alcohol ingestion resulted in a general diminution of the total thiamin and the thiamin phosphates in blood, heart and liver and a reduced thiamin excretion in urine. An alcohol induced shift of the phosphorylation status could be observed only in the liver, but not in the heart and the erythrocytes, leading to a lowered concentration of T and TMP. The results demonstrate that the level of thiamin and thiamin phosphates in blood and organs under suboptimal thiamin supply seems to be more sensitive to chronic alcohol administration than the transketolase activity and the alpha-TK value.

  1. Energy metabolism during human pregnancy.

    Science.gov (United States)

    Forsum, Elisabet; Löf, Marie

    2007-01-01

    This review summarizes information regarding how human energy metabolism is affected by pregnancy, and current estimates of energy requirements during pregnancy are presented. Such estimates can be calculated using either increases in basal metabolic rate (BMR) or increases in total energy expenditure (TEE). The two modes of calculation give similar results for a complete pregnancy but different distributions of energy requirements in the three trimesters. Recent information is presented regarding the effect of pregnancy on BMR, TEE, diet-induced thermogenesis, and physical activity. The validity of energy intake (EI) data recently assessed in well-nourished pregnant women was evaluated using information regarding energy metabolism during pregnancy. The results show that underreporting of EI is common during pregnancy and indicate that additional longitudinal studies, taking the total energy budget during pregnancy into account, are needed to satisfactorily define energy requirements during the three trimesters of gestation.

  2. Effect of dissolved oxygen in alcoholic beverages and drinking water on alcohol elimination in humans.

    Science.gov (United States)

    Rhee, Su-jin; Chae, Jung-woo; Song, Byung-jeong; Lee, Eun-sil; Kwon, Kwang-il

    2013-02-01

    Oxygen plays an important role in the metabolism of alcohol. An increased dissolved oxygen level in alcoholic beverages reportedly accelerates the elimination of alcohol. Therefore, we evaluated the effect of dissolved oxygen in alcohol and the supportive effect of oxygenated water on alcohol pharmacokinetics after the excessive consumption of alcohol, i.e., 540 ml of 19.5% alcohol (v/v). Fifteen healthy males were included in this randomized, 3 × 3 crossover study. Three combinations were tested: X, normal alcoholic beverage and normal water; Y, oxygenated alcoholic beverage and normal water; Z, oxygenated alcoholic beverage and oxygenated water. Blood alcohol concentrations (BACs) were determined by conversion of breath alcohol concentrations. Four pharmacokinetic parameters (C(max), T(max), K(el), and AUCall) were obtained using non-compartmental analysis and the times to reach 0.05% and 0.03% BAC (T(0.05%) and T(0.03%)) were compared using one-way analysis of variance (ANOVA) and Duncan's post hoc test. With combination Z, the BAC decreased to 0.05% significantly faster (p water augments the effect of oxygen in the alcoholic beverage in alcohol elimination. Therefore, it is necessary to investigate the supportive effect of ingesting additional oxygenated water after heavy drinking of normal alcoholic beverages.

  3. Metabolism of phthalates in humans.

    Science.gov (United States)

    Frederiksen, Hanne; Skakkebaek, Niels E; Andersson, Anna-Maria

    2007-07-01

    Phthalates are synthetic compounds widely used as plasticisers, solvents and additives in many consumer products. Several animal studies have shown that some phthalates possess endocrine disrupting effects. Some of the effects of phthalates seen in rats are due to testosterone lowering effects on the foetal testis and they are similar to those seen in humans with testicular dysgenesis syndrome. Therefore, exposure of the human foetus and infants to phthalates via maternal exposure is a matter of concern. The metabolic pathways of phthalate metabolites excreted in human urine are partly known for some phthalates, but our knowledge about metabolic distribution in the body and other biological fluids, including breast milk, is limited. Compared to urine, human breast milk contains relatively more of the hydrophobic phthalates, such as di-n-butyl phthalate and the longer-branched, di(2-ethylhexyl) phthalate (DEHP) and di-iso-nonyl phthalate (DiNP); and their monoester metabolites. Urine, however, contains relatively more of the secondary metabolites of DEHP and DiNP, as well as the monoester phthalates of the more short-branched phthalates. This differential distribution is of special concern as, in particular, the hydrophobic phthalates and their metabolites are shown to have adverse effects following in utero and lactational exposures in animal studies.

  4. Association between in vivo alcohol metabolism and genetic variation in pathways that metabolize the carbon skeleton of ethanol and NADH reoxidation in the alcohol challenge twin study.

    Science.gov (United States)

    Lind, Penelope A; Macgregor, Stuart; Heath, Andrew C; Madden, Pamela A F; Montgomery, Grant W; Martin, Nicholas G; Whitfield, John B

    2012-12-01

    Variation in alcohol metabolism affects the duration of intoxication and alcohol use. While the majority of genetic association studies investigating variation in alcohol metabolism have focused on polymorphisms in alcohol or aldehyde dehydrogenases, we have now tested for association with genes in alternative metabolic pathways that catalyze the carbon skeleton of ethanol (EtOH) and NADH reoxidation. Nine hundred fifty single nucleotide polymorphisms (SNPs) spanning 14 genes (ACN9, ACSS1, ACSS2, ALDH1A1, CAT, CYP2E1, GOT1, GOT2, MDH1, MDH2, SLC25A10, SLC25A11, SLC25A12, SLC25A13) were genotyped in 352 young adults who participated in an alcohol challenge study. Traits tested were blood alcohol concentration (BAC), breath alcohol concentration (BrAC), peak alcohol concentration, and rates of alcohol absorption and elimination. Allelic association was tested using quantitative univariate and multivariate methods. A CYP2E1 promoter SNP (rs4838767, minor allele frequency 0.008) exceeded the threshold for study-wide significance (4.01 × 10(-5) ) for 2 early BAC, 8 BrAC measures, and the peak BrAC. For each phenotype, the minor C allele was related to a lower alcohol concentration, most strongly for the fourth BrAC (p = 2.07 × 10(-7) ) explaining ~8% of the phenotypic variance. We also observed suggestive patterns of association with variants in ALDH1A1 and on chromosome 17 near SLC25A11 for aspects of blood and breath alcohol metabolism. An SNP upstream of GOT1 (rs2490286) reached study-wide significance for multivariate BAC metabolism (p = 0.000040). Overall, we did not find strong evidence that variation in genes coding for proteins that further metabolize the carbon backbone of acetaldehyde, or contribute to mechanisms for regenerating NAD from NADH, affects alcohol metabolism in our European-descent subjects. However, based on the breath alcohol data, variation in the promoter of CYP2E1 may play a role in preabsorptive or early hepatic alcohol metabolism

  5. Effects of Beverages on Alcohol Metabolism: Potential Health Benefits and Harmful Impacts

    Directory of Open Access Journals (Sweden)

    Fang Wang

    2016-03-01

    Full Text Available Nonalcoholic beverages are usually consumed accompanying alcoholic drinks, and their effects on alcohol metabolism are unclear in vivo. In this study, the effects of 20 nonalcoholic beverages on alcohol metabolism and liver injury caused by alcohol were evaluated in mice. Kunming mice were orally fed with alcohol (52%, v/v and beverages. The concentrations of ethanol and acetaldehyde in blood as well as the activities of alcohol dehydrogenase (ADH and aldehyde dehydrogenase (ALDH in liver were assessed to indicate alcohol metabolism. The levels of aspartate aminotransferase (AST and alanine transaminase (ALT in serum as well as the levels of malonaldehyde (MDA and superoxide dismutase (SOD in liver were measured to reflect the alcohol-induced liver injury. The results showed that the treatment of soda water, green tea and honey chrysanthemum tea could accelerate ethanol metabolism and prevent liver injuries caused by alcohol when companied with excessive alcohol drinking. They might be potential dietary supplements for the alleviation of harmful effects from excessive alcohol consumption. On the contrary, some beverages such as fresh orange juice and red bull are not advised to drink when companied with alcohol consumption due to their adverse effects on ethanol induced liver injury.

  6. Effects of Beverages on Alcohol Metabolism: Potential Health Benefits and Harmful Impacts.

    Science.gov (United States)

    Wang, Fang; Zhang, Yu-Jie; Zhou, Yue; Li, Ya; Zhou, Tong; Zheng, Jie; Zhang, Jiao-Jiao; Li, Sha; Xu, Dong-Ping; Li, Hua-Bin

    2016-03-09

    Nonalcoholic beverages are usually consumed accompanying alcoholic drinks, and their effects on alcohol metabolism are unclear in vivo. In this study, the effects of 20 nonalcoholic beverages on alcohol metabolism and liver injury caused by alcohol were evaluated in mice. Kunming mice were orally fed with alcohol (52%, v/v) and beverages. The concentrations of ethanol and acetaldehyde in blood as well as the activities of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) in liver were assessed to indicate alcohol metabolism. The levels of aspartate aminotransferase (AST) and alanine transaminase (ALT) in serum as well as the levels of malonaldehyde (MDA) and superoxide dismutase (SOD) in liver were measured to reflect the alcohol-induced liver injury. The results showed that the treatment of soda water, green tea and honey chrysanthemum tea could accelerate ethanol metabolism and prevent liver injuries caused by alcohol when companied with excessive alcohol drinking. They might be potential dietary supplements for the alleviation of harmful effects from excessive alcohol consumption. On the contrary, some beverages such as fresh orange juice and red bull are not advised to drink when companied with alcohol consumption due to their adverse effects on ethanol induced liver injury.

  7. Influence of dissolved oxygen concentration on the pharmacokinetics of alcohol in humans.

    Science.gov (United States)

    Baek, In-hwan; Lee, Byung-yo; Kwon, Kwang-il

    2010-05-01

    Ethanol oxidation by the microsomal ethanol oxidizing system requires oxygen for alcohol metabolism, and a higher oxygen uptake increases the rate of ethanol oxidation. We investigated the effect of dissolved oxygen on the pharmacokinetics of alcohol in healthy humans (n = 49). The concentrations of dissolved oxygen were 8, 20, and 25 ppm in alcoholic drinks of 240 and 360 ml (19.5% v/v). Blood alcohol concentrations (BACs) were determined by converting breath alcohol concentrations. Breath samples were collected every 30 min when the BAC was higher than 0.015%, 20 min at BAC dissolved oxygen groups (20, 25 ppm) descended to 0.000% and 0.050% BAC faster than the normal dissolved oxygen groups (8 ppm; p oxygen groups were lower than in the normal oxygen group, while C(max) and T(max) were not significantly affected. In a Monte Carlo simulation, the lognormal distribution of mean values of AUC(inf) and t(1/2) was expected to be reduced in the high oxygen group compared to the normal oxygen group. In conclusion, elevated dissolved oxygen concentrations in alcoholic drinks accelerate the metabolism and elimination of alcohol. Thus, enhanced dissolved oxygen concentrations in alcohol may have a role to play in reducing alcohol-related side effects and accidents.

  8. The role of ethanol metabolism in development of alcoholic steatohepatitis in the rat

    Science.gov (United States)

    The importance of ethanol metabolism in the development of alcoholic liver disease remains controversial. The present study examined the effects of selective inhibition of the cytochrome P450 enzyme CYP2E1, compared with the inhibition of overall ethanol metabolism on the development of alcoholic st...

  9. Polymorphism of alcohol metabolizing gene ADH3 predisposes to development of alcoholic pancreatitis in North Indian population

    Directory of Open Access Journals (Sweden)

    Divya eSingh

    2015-12-01

    Full Text Available Background and aim- Genetic factors regulating alcohol metabolism could predispose in developing alcoholic pancreatitis (ACP. Studies revealed that alcohol could be metabolized by both ways, oxidative and non-oxidative. The main oxidative pathway includes alcohol dehydrogenase (ADH, aldehyde dehydrogenase (ALDH and cytochrome P450 enzyme. We investigated whether polymorphism in these alcohol metabolizing enzyme genes could be associated with alcoholic pancreatitis and is the purpose of our study. Method- Patients with alcoholic pancreatitis (ACP (n=72, tropical calcific pancreatitis (TCP (n=75, alcoholic controls (AC (n=40 and healthy controls (HC (n=100 were included in the study. Blood samples were collected from the subjects in EDTA coated vials. DNA was extracted and genotyping for ADH3, ALDH2 and CYP2E1 was done by PCR-RFLP (polymerase chain reaction- restriction fragment length polymorphism. The products were analyzed by gel electrophoresis. Result- The frequency distribution of ADH3*1/*1 genotype was significantly higher in ACP group (59.7% compared with TCP (38.7%, HC (42% and AC (37.5% and was found to be associated with increased risk of alcoholic pancreatitis. There was no statistically significant difference between the frequency distribution of ADH3*1/*1, ADH3*1/*2 and ADH3*2/*2 genotype between TCP and HC and healthy alcoholics. ALDH2 gene was monomorphic in our population, and the frequencies for CYP2E1 intron 6 Dra I polymorphism were comparable in all four groups. Conclusion- This study shows that carriers of ADH3*1/*1 individuals consuming alcohol are at higher risk for alcoholic pancreatitis than those with other genotypes such as ADH3*1/*2 and ADH3*2/*2.

  10. Plasma proteomic alterations in non-human primates and humans after chronic alcohol self-administration.

    Science.gov (United States)

    Freeman, Willard M; Vanguilder, Heather D; Guidone, Elizabeth; Krystal, John H; Grant, Kathleen A; Vrana, Kent E

    2011-08-01

    Objective diagnostics of excessive alcohol use are valuable tools in the identification and monitoring of subjects with alcohol use disorders. A number of potential biomarkers of alcohol intake have been proposed, but none have reached widespread clinical usage, often due to limited diagnostic sensitivity and specificity. In order to identify novel potential biomarkers, we performed proteomic biomarker target discovery in plasma samples from non-human primates that chronically self-administer high levels of ethanol. Two-dimensional difference in-gel electrophoresis (2D-DIGE) was used to quantify plasma proteins from within-subject samples collected before exposure to ethanol and after 3 months of excessive ethanol self-administration. Highly abundant plasma proteins were depleted from plasma samples to increase proteomic coverage. Altered plasma levels of serum amyloid A4 (SAA4), retinol-binding protein, inter-alpha inhibitor H4, clusterin, and fibronectin, identified by 2D-DIGE analysis, were confirmed in unmanipulated, whole plasma from these animals by immunoblotting. Examination of these target plasma proteins in human subjects with excessive alcohol consumption (and control subjects) revealed increased levels of SAA4 and clusterin and decreased levels of fibronectin compared to controls. These proteins not only serve as targets for further development as biomarker candidates or components of biomarker panels, but also add to the growing understanding of dysregulated immune function and lipoprotein metabolism with chronic, excessive alcohol consumption.

  11. Expression pattern, ethanol-metabolizing activities, and cellular localization of alcohol and aldehyde dehydrogenases in human large bowel: association of the functional polymorphisms of ADH and ALDH genes with hemorrhoids and colorectal cancer.

    Science.gov (United States)

    Chiang, Chien-Ping; Jao, Shu-Wen; Lee, Shiao-Pieng; Chen, Pei-Chi; Chung, Chia-Chi; Lee, Shou-Lun; Nieh, Shin; Yin, Shih-Jiun

    2012-02-01

    Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are principal enzymes responsible for metabolism of ethanol. Functional polymorphisms of ADH1B, ADH1C, and ALDH2 genes occur among racial populations. The goal of this study was to systematically determine the functional expressions and cellular localization of ADHs and ALDHs in human rectal mucosa, the lesions of adenocarcinoma and hemorrhoid, and the genetic association of allelic variations of ADH and ALDH with large bowel disorders. Twenty-one surgical specimens of rectal adenocarcinoma and the adjacent normal mucosa, including 16 paired tissues of rectal tumor, normal mucosae of rectum and sigmoid colon from the same individuals, and 18 surgical mixed hemorrhoid specimens and leukocyte DNA samples from 103 colorectal cancer patients, 67 hemorrhoid patients, and 545 control subjects recruited in previous study, were investigated. The isozyme/allozyme expression patterns of ADH and ALDH were identified by isoelectric focusing and the activities were assayed spectrophotometrically. The protein contents of ADH/ALDH isozymes were determined by immunoblotting using the corresponding purified class-specific antibodies; the cellular activity and protein localizations were detected by immunohistochemistry and histochemistry, respectively. Genotypes of ADH1B, ADH1C, and ALDH2 were determined by polymerase chain reaction-restriction fragment length polymorphisms. At 33mM ethanol, pH 7.5, the activity of ADH1C*1/1 phenotypes exhibited 87% higher than that of the ADH1C*1/*2 phenotypes in normal rectal mucosa. The activity of ALDH2-active phenotypes of rectal mucosa was 33% greater than ALDH2-inactive phenotypes at 200μM acetaldehyde. The protein contents in normal rectal mucosa were in the following order: ADH1>ALDH2>ADH3≈ALDH1A1, whereas those of ADH2, ADH4, and ALDH3A1 were fairly low. Both activity and content of ADH1 were significantly decreased in rectal tumors, whereas the ALDH activity remained

  12. Evidence of metabolic transformations of amino acids into higher alcohols through (13)C NMR studies of wine alcoholic fermentation.

    Science.gov (United States)

    López-Rituerto, Eva; Avenoza, Alberto; Busto, Jesús H; Peregrina, Jesús M

    2010-04-28

    Because the metabolite transformations in wine fermentation processes play a crucial role in the organoleptic and hygienic quality of wines, the nuclear magnetic resonance (NMR) technique is presented as a significant tool to follow metabolic pathways. In this paper, we investigated the transformation of several amino acids into their corresponding higher alcohols during the alcoholic fermentation, showing that the amino acids are totally consumed in the first stages of the process.

  13. Optical Spectra of Hemoglobin Taken from Alcohol Dependent Humans

    OpenAIRE

    Dudok K.; Dudok T.; Vlokh I.; Vlokh R.

    2005-01-01

    Optical spectra of CNMetHb and CNMetHb-Coomassi G-250, taken from the blood of humans with alcohol dependence, are studied in the spectral range of 450–750nm. The shifts in the spectral absorption maxima of CNMetHb-Coomassi G-250 complexes are observed for the diseased persons with alcohol dependence. The obtained results show that the hemoglobin structure of alcohol dependent humans is changed.

  14. Alcohol consumption and metabolic syndrome among Shanghai adults: A randomized multistage stratified cluster sampling investigation

    Institute of Scientific and Technical Information of China (English)

    Jian-Gao Fan; Xiao-Bu Cai; Lui Li; Xing-Jian Li; Fei Dai; Jun Zhu

    2008-01-01

    AIM: To examine the relations of alcohol consumption to the prevalence of metabolic syndrome in Shanghai adults.METHODS: We performed a cross-sectional analysis of data from the randomized multistage stratified cluster sampling of Shanghai adults, who were evaluated for alcohol consumption and each component of metabolic syndrome, using the adapted U.S. National Cholesterol Education Program criteria. Current alcohol consumption was defined as more than once of alcohol drinking per month.RESULTS: The study population consisted of 3953participants (1524 men) with a mean age of 54.3 ± 12.1years. Among them, 448 subjects (11.3%) were current alcohol drinkers, including 405 males and 43 females.After adjustment for age and sex, the prevalence of current alcohol drinking and metabolic syndrome in the general population of Shanghai was 13.0% and 15.3%,respectively. Compared with nondrinkers, the prevalence of hypertriglyceridemia and hypertension was higher while the prevalence of abdominal obesity, low serum high-density-lipoprotein cholesterol (HDL-C) and diabetes mellitus was lower in subjects who consumed alcohol twice or more per month, with a trend toward reducing the prevalence of metabolic syndrome. Among the current alcohol drinkers, systolic blood pressure, HDL-C, fasting plasma glucose, and prevalence of hypertriglyceridemia tended to increase with increased alcohol consumption.However, Iow-density-lipoprotein cholesterol concentration,prevalence of abdominal obesity, low serum HDL-C andmetabolic syndrome showed the tendency to decrease.Moreover, these statistically significant differences were independent of gender and age.CONCLUSION: Current alcohol consumption is associatedwith a lower prevalence of metabolic syndrome irrespe-ctive of alcohol intake (g/d), and has a favorable influence on HDL-C, waist circumference, and possible diabetes mellitus. However, alcohol intake increases the likelihoodof hypertension, hypertriglyceridemia and hyperglycemia

  15. Kinetics of homocysteine metabolism after moderate alcohol consumption

    NARCIS (Netherlands)

    Beulens, J.W.J.; Sierksma, A.; Schaafsma, G.; Kok, F.J.; Struys, E.A.; Jakobs, C.; Hendriks, H.F.J.

    2005-01-01

    Background: Moderate alcohol consumption is associated with a decreased risk of cardiovascular disease. Because plasma homocysteine (tHcy) is considered an independent risk factor for cardiovascular disease and associated with alcohol consumption, the authors investigated the effect of moderate

  16. Water metabolism in rats subjected to chronic alcohol administration

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Pohl, C.; Bode, J.C.;

    2004-01-01

    AIM: While the diuretic action of acute ingestion of alcohol has been studied extensively, the effect of chronic alcohol consumption has received less attention. The aim of the present study was to investigate the effect of chronic alcohol consumption on the balance of water intake and excretion ...

  17. MAMMALIAN METABOLISM AND DISTRIBUTION OF PERFLUOROOCTYL ETHANOL (8-2 TELOMER ALCOHOL) AND ITS OXIDATION METABOLITES

    Science.gov (United States)

    Perfluorinated compounds have been shown to be globally distributed, bioaccumulative, persistent and potentially toxic. It has been hypothesized that many precursor fluorinated compounds, including the telomer alcohols, degrade or metabolize to the common metabolite PFOA.

  18. Alcohol consumption, genetic variants in the alcohol- and folate metabolic pathways and colorectal cancer risk: the JPHC Study.

    Science.gov (United States)

    Svensson, Thomas; Yamaji, Taiki; Budhathoki, Sanjeev; Hidaka, Akihisa; Iwasaki, Motoki; Sawada, Norie; Inoue, Manami; Sasazuki, Shizuka; Shimazu, Taichi; Tsugane, Shoichiro

    2016-11-09

    The association between alcohol intake and colorectal cancer (CRC) may vary secondary to single nucleotide polymorphisms (SNPs) in two pathways related to alcohol intake. 375 cases of CRC were identified among 38 373 Japan Public Health Center-based prospective Study (JPHC Study) participants who had returned a baseline questionnaire, reported no diagnosis of any cancer and provided blood samples. For each case, two controls were selected on matching variables. Logistic regression models were used to determine matched Odds Ratios (OR) and 95% Confidence Intervals (CI) for the association between alcohol consumption, genetic polymorphisms of enzymes in the alcohol- and folate metabolic pathways (e.g. methylenetetrahydrofolate reductase (MTHFR) rs1801133) and CRC risk. Compared to never/occasional alcohol intake, moderate to heavy alcohol intake was associated with CRC (OR = 2.12, 95% CI, 1.34-3.36). When compared to the CC genotype, the MTHFR rs1801133 CT/TT genotype was inversely associated with CRC (OR = 0.72, 95% CI, 0.54-0.97). Never/occasional consumers of alcohol with the MTHFR rs1801133 CT/TT genotype were also at a reduced risk of CRC compared to never/occasional drinkers with the CC genotype (OR = 0.68, 95% CI, 0.47-0.98) (P for interaction = 0.27). The results indicate that the folate pathway is likely to be involved in alcohol-related CRC development.

  19. Combined effects of smoking and alcohol on metabolic syndrome : the LifeLines cohort study

    NARCIS (Netherlands)

    Slagter, Sandra N; van Vliet-Ostaptchouk, Jana V; Vonk, Judith M; Boezen, Hendrika; Dullaart, Robin P F; Muller Kobold, Anna; Feskens, Edith J M; van Beek, André P; van der Klauw, Melanie M; Wolffenbuttel, Bruce H R

    2014-01-01

    INTRODUCTION: The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. METHODS: 64,046 participants aged 18-80 years from the LifeLines

  20. Comined effects of smoking and alcohol on metabolic syndrome: the lifelines cohort study

    NARCIS (Netherlands)

    Slagter, S.N.; Vliet-Ostaptchouk, J.V.; Vonk, J.M.; Boezen, H.M.; Dullaart, R.P.F.; Muller Kobold, A.C.; Feskens, E.J.M.; Beek, van A.P.; Klauw, van der M.M.; Wolffenbuttel, B.H.R.

    2014-01-01

    Introduction - The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. Methods - 64,046 participants aged 18–80 years from the LifeLin

  1. The metabolic syndrome in patients with alcohol dependency: Current research and clinical implications.

    Science.gov (United States)

    Kahl, Kai G; Hillemacher, Thomas

    2016-10-01

    The relationship between alcohol dependency and disorders such as liver disease and cancer has been thoroughly researched. However, the effects of alcohol on cardiometabolic health remain controversial. Several reports found low to moderate alcohol consumption to be associated with a lower risk for cardiometabolic disorders. In contrast, excessive alcohol consumption has been related to an increased risk. Most of these studies were performed in non-clinical populations, therefore limiting the explanatory power to non-dependent patients. Only a few studies examined cardiovascular disorders and cardiovascular risk factors, in particular the metabolic syndrome (MetS), in alcohol dependent patients. We here present a narrative review of studies performed so far on the MetS in alcohol dependency, and provide current hypotheses on the association of alcohol dependency, appetite regulation and the development of the MetS.

  2. Applying the nursing theory of human relatedness to alcoholism and recovery in alcoholics anonymous.

    Science.gov (United States)

    Strobbe, Stephen; Hagerty, Bonnie; Boyd, Carol

    2012-12-01

    Alcohol misuse is a global health risk, and Alcoholics Anonymous (AA) is the largest and most popular mutual-help program for individuals with alcohol-related problems. In recent years, researchers and clinicians have become increasingly interested in specific mechanisms of action that may contribute to positive outcomes through involvement with this 12-step program for recovery, yet few have applied a theoretical framework to these efforts. We examined the phenomena of alcoholism and recovery in AA, using the nursing Theory of Human Relatedness (THR). THR addresses a pervasive human concern: "establishing and maintaining relatedness to others, objects, environments, society and self." The theory describes four states of relatedness (connectedness, disconnectedness, parallelism, and enmeshment) and four relatedness competencies (sense of belonging, reciprocity, mutuality, and synchrony). Both alcoholism and recovery in AA can be viewed primarily in terms of relatedness. In active alcoholism, an individual's involvement with alcohol (enmeshment) can limit, impair, or preclude healthy or adaptive relatedness toward virtually all other referents, including self. As a program of recovery, each of the 12 Steps of Alcoholics Anonymous addresses an individual's relatedness to one or more identified referents while simultaneously enhancing and expanding each of the four relatedness competencies. THR provides a theoretical framework to help direct patient care, research, and education and has the potential to serve as a unifying theory in the study of alcoholism and recovery in AA.

  3. Elderly Alcoholism: Implications for Human Service Education

    Science.gov (United States)

    Beechem, Michael

    2004-01-01

    Incumbent upon those faculty who teach substance abuse courses is the need to integrate elderly alcoholism-related course content to encourage and adequately prepare university students to serve this "hidden" population. Course content would ideally include theories specific to loss-grief, aging, and alcoholism. In addition, field placement…

  4. Effects of Alcohol on Human Aggression.

    Science.gov (United States)

    Parrott, Dominic J; Eckhardt, Christopher I

    2018-02-01

    There is little debate that alcohol is a contributing cause of aggressive behavior. The extreme complexity of this relation, however, has been the focus of extensive theory and research. And, likely due to this complexity, evidence-based programs to prevent or reduce alcohol-facilitated aggression are quite limited. We integrate I(3) Theory and Alcohol Myopia Theory to provide a framework that (1) organizes the myriad instigatory and inhibitory factors that moderate the effect of alcohol on aggression, and (2) highlights the mechanisms by which alcohol facilitates aggression among at-risk individuals. This integrative framework provides the basis for understanding the appropriate targets for prevention and intervention efforts and may serve as a catalyst for future research that seeks to inform intervention development.

  5. Genetic polymorphisms in alcohol-metabolizing enzymes and chronic pancreatitis.

    NARCIS (Netherlands)

    Verlaan, M.; Morsche, R.H.M. te; Roelofs, H.M.J.; Laheij, R.J.F.; Jansen, J.B.M.J.; Peters, W.H.M.; Drenth, J.P.H.

    2004-01-01

    AIMS: Alcohol misuse is now regarded as an important risk factor for development of chronic pancreatitis (CP). However, not every alcohol misuser develops CP and it therefore might be suggested that susceptibility could be further influenced by inter-individual variations in the activities of alcoho

  6. Kinetics of homocysteine metabolism after moderate alcohol consumption

    NARCIS (Netherlands)

    Beulens, J.W.J.; Sierksma, A.; Schaafsma, G.; Kok, F.J.; Struys, E.A.; Jakobs, C.; Hendriks, H.F.J.

    2005-01-01

    Background: Moderate alcohol consumption is associated with a decreased risk of cardiovascular disease. Because plasma homocysteine (tHcy) is considered an independent risk factor for cardiovascular disease and associated with alcohol consumption, the authors investigated the effect of moderate alco

  7. Metabolic interactions of agrochemicals in humans.

    Science.gov (United States)

    Hodgson, Ernest; Rose, Randy L

    2008-06-01

    Agrochemicals and other xenobiotics are metabolized by xenobiotic-metabolizing enzymes (XMEs) to products that may be more or less toxic than the parent chemical. In this regard, phase-I XMEs such as cytochrome P450s (CYPs) are of primary importance. Interactions at the level of metabolism may take place via either inhibition or induction of XMEs. Such interactions have often been investigated, in vitro, in experimental animals, using subcellular fractions such as liver microsomes, but seldom in humans or at the level of individual XME isoforms. The authors have been investigating the metabolism of a number of agrochemicals by human liver microsomes and recombinant CYP isoforms and have recently embarked on studies of the induction of XMEs in human hepatocytes. The insecticides chlorpyrifos, carbaryl, carbofuran and fipronil, as well as the repellant DEET, are all extensively metabolized by human liver microsomes and, although a number of CYP isoforms may be involved, CYP2B6 and CYP3A4 are usually the most important. Permethrin is hydrolyzed by esterase(s) present in both human liver microsomes and cytosol. A number of metabolic interactions have been observed. Chlorpyrifos and other phosphorothioates are potent inhibitors of the CYP-dependent metabolism of both endogenous substrates, such as testosterone and estradiol, and exogenous substrates, such as carbaryl, presumably as a result of the interaction of highly reactive sulfur, released during the oxidative desulfuration reaction, with the heme iron of CYP. The hydrolysis of permethrin in human liver can be inhibited by chlorpyrifos oxon and by carbaryl. Fipronil can inhibit testosterone metabolism by CYP3A4 and is an effective inducer of CYP isoforms in human hepatocytes.

  8. Metabolism of liriodendrin and syringin by human intestinal bacteria and their relation to in vitro cytotoxicity.

    Science.gov (United States)

    Kim, D H; Lee, K T; Bae, E A; Han, M J; Park, H J

    1999-02-01

    When liriodendrin or syringin was incubated for 24 h with human intestinal bacteria, two metabolites, (+)-syringaresinol-beta-D-glucopyranoside and (+)-syringaresinol, from liriodendrin and one metabolite, synapyl alcohol, from syringin were produced. The metabolic time course of liriodendrin was as follows: at early time, liriodendrin was converted to (+)-syringaresinol-beta-D-glucopyranoside, and then (+)-syringaresinol. The in vitro cytotoxicities of these metabolites, (+)-syringaresinol and synapyl alcohol, were superior to those of liriodendrin and syringin.

  9. Human metabolic interactions of environmental chemicals.

    Science.gov (United States)

    Hodgson, Ernest; Rose, Randy L

    2007-01-01

    Investigations utilizing recombinant human xenobiotic-metabolizing enzymes as well as human hepatocytes have revealed a number of interactions not only between different environmental chemicals (ECs) but also between ECs and endogenous metabolites. Organophosphorus insecticides (OPs) are potent inhibitors of the human metabolism of carbaryl, carbofuran, DEET and fipronil, as well as the jet fuel components, nonane and naphthalene. OPs are potent irreversible inhibitors of testosterone metabolism by cytochrome P450 (CYP) 3A4 and of estradiol metabolism by CYP3A4 and CYP1A2. All of these CYP inhibitions are believed to be due to the release of reactive sulfur during CYP-catalyzed oxidative desulfuration. It has also been shown that the esterase(s) responsible for the initial step in permethrin metabolism in human liver is inhibited by both chlorpyrifos oxon and carbaryl. A number of pesticides, including chlorpyrifos, fipronil and permethrin, and the repellent, DEET, have been shown to be inducers of CYP isoforms in human hepatocytes, with fipronil being the most potent. Several agrochemicals, including fipronil and the pyrethroids, permethrin and deltamethrin, show toxicity toward human hepatocytes with fipronil being the most potent in this regard. Endosulfan-alpha, which has shown promise as a model substrate for phenotyping CYP3A4 and CYP2B6 in human liver microsomes, is also an inducer of CYP2B6, acting through the PXR receptor.

  10. Assessing the Metabolic Effects of Aromatherapy in Human Volunteers

    Directory of Open Access Journals (Sweden)

    Yinan Zhang

    2013-01-01

    Full Text Available Aromatherapy, a form of complementary and alternative medicine (CAM that uses essential oils through inhalation, is believed to enhance physical and spiritual conditions. Although clinical studies suggest that the use of essential oils may have therapeutic potential, evidence for the efficacy of aromatherapy in treating medical conditions remains poor, with a particular lack of studies employing rigorous analytical methods that capture its identifiable impact on human biology. Here, we report a comprehensive metabolomics study that reveals metabolic changes in people after exposed to aroma inhalation for 10 continuous days. In this study, the metabolic alterations in urine of 31 females with mild anxiety symptoms exposed to aerial diffusion of aromas were measured by GC-TOF-MS and UPLC-Q-TOF-MS analyses. A significant alteration of metabolic profile in subjects responsive to essential oil was found, which is characterized by the increased levels of arginine, homocysteine, and betaine, as well as decreased levels of alcohols, carbohydrates, and organic acids in urine. Notably, the metabolites from tricarboxylic acid (TCA cycle and gut microbial metabolism were significantly altered. This study demonstrates that the metabolomics approach can capture the subtle metabolic changes resulting from exposure to essential oils, which may lead to an improved mechanistic understanding of aromatherapy.

  11. Effects of alcohol ingestion on lipids and lipoproteins in normal men: isocaloric metabolic studies.

    Science.gov (United States)

    Glueck, C J; Hogg, E; Allen, C; Gartside, P S

    1980-11-01

    To investigate metabolic relationships between alcohol ingestion and fasting plasma high density lipoprotein cholesterol (C-HDL) and triglycerides, seven young normal males were assessed with isocaloric substitution of alcohol for carbohydrate in the diet. For a 5-week study period, an isocaloric low cholesterol diet containing 20% of the calories as protein, 40% as fat, and 40% as carbohydrate, with alcohol for dietary carbohydrate during these study weeks. In week 5, 1.35 g/day of lecithin linoleate was added to assess another putative nutritional approach to increasing C-HDL levels. By two-way analysis of variance and Scheffe's paired t tests, there were no significant differences in either C-HDL or triglyceride levels for any of the five metabolic diet, alcohol substitution diet periods; additionally, there were no significant effects of lecithin on plasma lipids or lipoproteins. The general question asked, "Does alcohol affect C-HDL levels?" is answered negatively for isocaloric alcohol substitution, on a cholesterol-poor, high P/S, and relatively carbohydrate restricted diet, for a 2-week period of moderate alcohol intake. Alcohol's effect on C-HDL and triglyceride probably involves an interaction with total calories, and perhaps with dietary composition (cholesterol, saturated fat, carbohydrate content), as well as the amount of ethanol ingested, and duration of intake.

  12. Metabolic heterogeneity in human lung tumors

    Science.gov (United States)

    Hensley, Christopher T.; Faubert, Brandon; Yuan, Qing; Lev-Cohain, Naama; Jin, Eunsook; Kim, Jiyeon; Jiang, Lei; Ko, Bookyung; Skelton, Rachael; Loudat, Laurin; Wodzak, Michelle; Klimko, Claire; McMillan, Elizabeth; Butt, Yasmeen; Ni, Min; Oliver, Dwight; Torrealba, Jose; Malloy, Craig R.; Kernstine, Kemp; Lenkinski, Robert E.; DeBerardinis, Ralph J.

    2015-01-01

    SUMMARY Non-small cell lung cancer (NSCLC) is heterogeneous in the genetic and environmental parameters that influence cell metabolism in culture. Here, we assessed the impact of these factors on human NSCLC metabolism in vivo using intra-operative 13C-glucose infusions in nine NSCLC patients to compare metabolism between tumors and benign lung. While enhanced glycolysis and glucose oxidation were common among these tumors, we observed evidence for oxidation of multiple nutrients in each of them, including lactate as a potential carbon source. Moreover, metabolically heterogeneous regions were identified within and between tumors, and surprisingly, our data suggested potential contributions of non-glucose nutrients in well-perfused tumor areas. Our findings not only demonstrate the heterogeneity in tumor metabolism in vivo but also highlight the strong influence of the microenvironment on this feature. PMID:26853473

  13. [Carnitine: function, metabolism and value in hepatic failure during chronic alcohol intoxication].

    Science.gov (United States)

    Kępka, Alina; Szajda, Sławomir Dariusz; Waszkiewicz, Napoleon; Płudowski, Paweł; Chojnowska, Sylwia; Rudy, Michał; Szulc, Agata; Ladny, Jerzy Robert; Zwierz, Krzysztof

    2011-10-07

    Alcoholism is one of the most frequent dependences among people, leading to damage of the liver and death of the person. Chronic alcohol consumption decreases fatty acid oxidation by interfering with carnitine metabolism and citric acid cycle activity. Block in activity of the citric acid cycle caused by alcohol and its metabolites is partially compensated by increased ketone body production, which results in ketosis. Chronic administration of alcohol induces liver injury, inflammation, cirrhosis, focal necrosis and steatosis. L-carnitine (L-3-hydroxy-4-N, N, N-trimethylaminebutyric acid) is an essential factor in fatty acid metabolism, which plays a major role in transport of activated long-chain fatty acids to sites of β-oxidation in mitochondria. Carnitine also stabilizes cell membranes by removing long-chain acyl-CoA and excess of the acyl group from the body. L-carnitine can be a useful and safe drug in the liver pathology induced by chronic ethanol exposure.

  14. Genetic determinants of both ethanol and acetaldehyde metabolism influence alcohol hypersensitivity and drinking behaviour among Scandinavians

    DEFF Research Database (Denmark)

    Linneberg, A; Gonzalez-Quintela, A; Vidal, C

    2010-01-01

    Although hypersensitivity reactions following intake of alcoholic drinks are common in Caucasians, the underlying mechanisms and clinical significance are not known. In contrast, in Asians, alcohol-induced asthma and flushing have been shown to be because of a single nucleotide polymorphism (SNP......), the acetaldehyde dehydrogenase 2 (ALDH2) 487lys, causing decreased acetaldehyde (the metabolite of ethanol) metabolism and high levels of histamine. However, the ALDH2 487lys is absent in Caucasians....

  15. The human metabolic reconstruction Recon 1 directs hypotheses of novel human metabolic functions

    Directory of Open Access Journals (Sweden)

    Thiele Ines

    2011-10-01

    Full Text Available Abstract Background Metabolic network reconstructions formalize our knowledge of metabolism. Gaps in these networks pinpoint regions of metabolism where biological components and functions are "missing." At the same time, a major challenge in the post genomic era involves characterisation of missing biological components to complete genome annotation. Results We used the human metabolic network reconstruction RECON 1 and established constraint-based modelling tools to uncover novel functions associated with human metabolism. Flux variability analysis identified 175 gaps in RECON 1 in the form of blocked reactions. These gaps were unevenly distributed within metabolic pathways but primarily found in the cytosol and often caused by compounds whose metabolic fate, rather than production, is unknown. Using a published algorithm, we computed gap-filling solutions comprised of non-organism specific metabolic reactions capable of bridging the identified gaps. These candidate solutions were found to be dependent upon the reaction environment of the blocked reaction. Importantly, we showed that automatically generated solutions could produce biologically realistic hypotheses of novel human metabolic reactions such as of the fate of iduronic acid following glycan degradation and of N-acetylglutamate in amino acid metabolism. Conclusions The results demonstrate how metabolic models can be utilised to direct hypotheses of novel metabolic functions in human metabolism; a process that we find is heavily reliant upon manual curation and biochemical insight. The effectiveness of a systems approach for novel biochemical pathway discovery in mammals is demonstrated and steps required to tailor future gap filling algorithms to mammalian metabolic networks are proposed.

  16. Thermodynamic Significance of Human Basal Metabolism

    Institute of Scientific and Technical Information of China (English)

    WangCuncheng

    1993-01-01

    The human basal state,a non-equilibrium steady state,is analysed in this paper in the light of the First and Second Laws of Thermodynamics whereby the thermodynamic significance of the basal metabolic rate and its distinction to the dissipation function and exergy loss are identified.The analysis demonstrates the correct expression of the effects of the blood flow on the heat balance in a human-body bio-heat model and the relationship between the basal metabolic rate and the blood perfusion.

  17. Timing and Type of Alcohol Consumption and the Metabolic Syndrome - ELSA-Brasil.

    Science.gov (United States)

    Vieira, Bruna Angelo; Luft, Vivian Cristine; Schmidt, Maria Inês; Chambless, Lloyd Ellwood; Chor, Dora; Barreto, Sandhi Maria; Duncan, Bruce Bartholow

    2016-01-01

    The prevalence of the metabolic syndrome is rising worldwide. Its association with alcohol intake, a major lifestyle factor, is unclear, particularly with respect to the influence of drinking with as opposed to outside of meals. We investigated the associations of different aspects of alcohol consumption with the metabolic syndrome and its components. In cross-sectional analyses of 14,375 active or retired civil servants (aged 35-74 years) participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), we fitted logistic regression models to investigate interactions between the quantity of alcohol, the timing of its consumption with respect to meals, and the predominant beverage type in the association of alcohol consumption with the metabolic syndrome. In analyses adjusted for age, sex, educational level, income, socioeconomic status, ethnicity, smoking, body mass index, and physical activity, light consumption of alcoholic beverages with meals was inversely associated with the metabolic syndrome (≤4 drinks/week: OR = 0.85, 95%CI 0.74-0.97; 4 to 7 drinks/week: OR = 0.75, 95%CI 0.61-0.92), compared to abstention/occasional drinking. On the other hand, greater consumption of alcohol consumed outside of meals was significantly associated with the metabolic syndrome (7 to 14 drinks/week: OR = 1.32, 95%CI 1.11-1.57; ≥14 drinks/week: OR = 1.60, 95%CI 1.29-1.98). Drinking predominantly wine, which occurred mostly with meals, was significantly related to a lower syndrome prevalence; drinking predominantly beer, most notably when outside of meals and in larger quantity, was frequently associated with a greater prevalence. In conclusion, the alcohol-metabolic syndrome association differs markedly depending on the relationship of intake to meals. Beverage preference-wine or beer-appears to underlie at least part of this difference. Notably, most alcohol was consumed in metabolically unfavorable type and timing. If further investigations extend these

  18. [Comparative characteristics of glucose metabolism in the liver of rats under acute alcohol and morphine intoxication].

    Science.gov (United States)

    Lelevich, S V

    2011-01-01

    The comparative analysis effect of acute alcohol and morphine intoxications on rats on hepatic glycolysis and pentose phosphate pathway was done. The dose-dependent inhibitory effect of ethanol on activity of limiting enzymes of these metabolic ways, as well as anaerobic reorientation of glucose metabolism was recognised with the increase of the dose of the intake alcohol. Morfine (10 mg/kg) activated enymes of glycolysis and pentose phosphate pathway, but in contrast to ethanol it did not influence these parameters at the dose 20 or 40 mg/kg.

  19. Spirulina improves non-alcoholic steatohepatitis, visceral fat macrophage aggregation, and serum leptin in a mouse model of metabolic syndrome.

    Science.gov (United States)

    Fujimoto, Makoto; Tsuneyama, Koichi; Fujimoto, Takako; Selmi, Carlo; Gershwin, M Eric; Shimada, Yutaka

    2012-09-01

    Nutritional approaches are sought to overcome the limits of pioglitazone in metabolic syndrome and non-alcoholic fatty liver disease. Spirulina, a filamentous unicellular alga, reduces serum lipids and blood pressure while exerting antioxidant effects. To determine whether Spirulina may impact macrophages infiltrating the visceral fat in obesity characterizing our metabolic syndrome mouse model induced by the subcutaneous injection treatment of monosodium glutamate. Mice were randomized to receive standard food added with 5% Spirulina, 0.02% pioglitazone, or neither. We tested multiple biochemistry and histology (both liver and visceral fat) readouts at 24 weeks of age. Data demonstrate that both the Spirulina and the pioglitazone groups had significantly lower serum cholesterol and triglyceride levels and liver non-esterified fatty acid compared to untreated mice. Spirulina and pioglitazone were associated with significantly lower leptin and higher levels, respectively, compared to the control group. At liver histology, non-alcoholic fatty liver disease activity score and lipid peroxide were significantly lower in mice treated with Spirulina. Spirulina reduces dyslipidaemia in our metabolic syndrome model while ameliorating visceral adipose tissue macrophages. Human studies are needed to determine whether this safe supplement could prove beneficial in patients with metabolic syndrome. Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

  20. Timing and Type of Alcohol Consumption and the Metabolic Syndrome - ELSA-Brasil

    Science.gov (United States)

    Vieira, Bruna Angelo; Luft, Vivian Cristine; Schmidt, Maria Inês; Chambless, Lloyd Ellwood; Chor, Dora; Barreto, Sandhi Maria; Duncan, Bruce Bartholow

    2016-01-01

    The prevalence of the metabolic syndrome is rising worldwide. Its association with alcohol intake, a major lifestyle factor, is unclear, particularly with respect to the influence of drinking with as opposed to outside of meals. We investigated the associations of different aspects of alcohol consumption with the metabolic syndrome and its components. In cross-sectional analyses of 14,375 active or retired civil servants (aged 35–74 years) participating in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), we fitted logistic regression models to investigate interactions between the quantity of alcohol, the timing of its consumption with respect to meals, and the predominant beverage type in the association of alcohol consumption with the metabolic syndrome. In analyses adjusted for age, sex, educational level, income, socioeconomic status, ethnicity, smoking, body mass index, and physical activity, light consumption of alcoholic beverages with meals was inversely associated with the metabolic syndrome (≤4 drinks/week: OR = 0.85, 95%CI 0.74–0.97; 4 to 7 drinks/week: OR = 0.75, 95%CI 0.61–0.92), compared to abstention/occasional drinking. On the other hand, greater consumption of alcohol consumed outside of meals was significantly associated with the metabolic syndrome (7 to 14 drinks/week: OR = 1.32, 95%CI 1.11–1.57; ≥14 drinks/week: OR = 1.60, 95%CI 1.29–1.98). Drinking predominantly wine, which occurred mostly with meals, was significantly related to a lower syndrome prevalence; drinking predominantly beer, most notably when outside of meals and in larger quantity, was frequently associated with a greater prevalence. In conclusion, the alcohol—metabolic syndrome association differs markedly depending on the relationship of intake to meals. Beverage preference—wine or beer—appears to underlie at least part of this difference. Notably, most alcohol was consumed in metabolically unfavorable type and timing. If further investigations

  1. Smoking, alcoholism and genetic polymorphisms alter CYP2B6 levels in human brain.

    Science.gov (United States)

    Miksys, Sharon; Lerman, Caryn; Shields, Peter G; Mash, Deborah C; Tyndale, Rachel F

    2003-07-01

    CYP2B6 metabolizes drugs such as nicotine and bupropion, and many toxins and carcinogens. Nicotine induces CYP2B1 in rat brain and in humans polymorphic variation in CYP2B6 affects smoking cessation rates. The aim of this study was to compare CYP2B6 expression in brains of human smokers and non-smokers and alcoholics and non-alcoholics (n=26). CYP2B6 expression was brain region-specific, and was observed in both neurons and astrocytes. CYP2B6 levels were higher in brains of smokers and alcoholics, particularly in cerebellar Purkinje cells and hippocampal pyramidal neurons, cells known to be damaged in alcoholics. Significantly more (penzyme levels, stability and activity. Preliminary genotyping of this small sample (n=24) suggested that individuals with the CC genotype had higher brain CYP2B6 than those with the CT or TT genotype. Higher brain CYP2B6 activity in smokers and alcoholics may cause altered sensitivity to centrally acting drugs, increased susceptibility to neurotoxins and carcinogenic xenobiotics and contribute to central tolerance to nicotine.

  2. Metabolic syndrome in alcohol-dependent men: A cross-sectional study

    Directory of Open Access Journals (Sweden)

    Jitender Aneja

    2013-01-01

    Full Text Available Background: In the context to mental illness metabolic syndrome (MS has gained significant attention in the last decade. The present research aimed to study the prevalence of MS and its correlates among the alcohol-dependent men at a deaddiction center in Northern India. Materials and Methods: A cross-sectional analysis was done for consecutive male subjects who met the diagnosis of alcohol-dependence syndrome currently using alcohol according to the International Clinical Diagnostic criteria- tenth revision mental and behavioral disorder- Clinical description and diagnostic guidelines criteria (ICD-10. The subjects were evaluated for alcohol consumption and the components of MS as per the International Diabetic Federation (IDF and National Cholesterol Education Program Adult Treatment Panel-III (NCEP ATP-III. Results: A total of 200 male subjects were studied: 100 subjects meeting ICD-10 criteria for alcohol dependence currently using alcohol; 50 each of genetically related controls and nongenetically related healthy controls. As per the IDF (with ethnicity specific modifications for waist circumference and NCEP ATP- III definitions, respectively, MS was found to be less prevalent in alcohol-dependent subjects (27% and 18% in comparison the healthy controls (30% and 20%. Conclusion: Findings of the study suggest that irrespective of the amount the current alcohol intake is associated with a lower prevalence of MS and a favorable effect on serum high density lipoproteins and waist circumference. However, the cross-sectional nature of our study does not allow any definitive causal inference.

  3. Effect of alcohol consumption on hormones involved in carbohydrate and lipid metabolism in premenopausal women

    Energy Technology Data Exchange (ETDEWEB)

    Law, J.S.; Bhathena, S.J.; Kim, Y.C.; Berlin, E.; Judd, J.T.; Reichman, M.E.; Taylor, P.R.; Schatzkin, A. (Dept. of Agriculture, Beltsville, MD (United States) NCI, Bethesda, MD (United States))

    1991-03-15

    Alcohol consumption alters carbohydrate and lipid metabolism which are in part regulated by pancreatic and adrenal hormones. The menstrual cycle per se produces changes in several peptide and steroid hormones besides the sex hormones. The authors investigated the effect of moderate alcohol consumption on plasma hormone levels in 40 premenopausal women. The subjects were fed controlled diets containing 35% of calories from fat. In a random crossover design women were given either alcohol or a soft-drink of equal caloric value for 3 menstrual cycles. Fasting blood samples were collected in the third cycle during follicular, ovulatory and luteal phases. Plasma dehydroepiandrosterone-sulphate (DHEA-S), insulin, glucagon and cortisol levels were measured by radioimmunoassay. Moderate alcohol consumption had no effect on plasma insulin and DHEA-S levels but significantly increased glucagon and cortisol levels. Menstrual cycle per se affected plasma glucagon level in that the levels were higher during follicular phase than luteal phase. Thus, changes in carbohydrate and lipid metabolism following alcohol consumption are mediated in part by alterations in hormones involved in their metabolism.

  4. Metabolic engineering of Corynebacterium crenatium for enhancing production of higher alcohols

    Science.gov (United States)

    Su, Haifeng; Lin, Jiafu; Wang, Guangwei

    2016-12-01

    Biosynthesis approaches for the production of higher alcohols as a source of alternative fossil fuels have garnered increasing interest recently. However, there is little information available in the literature about using undirected whole-cell mutagenesis (UWCM) in vivo to improve higher alcohols production. In this study, for the first time, we approached this question from two aspects: first preferentially improving the capacity of expression host, and subsequently optimizing metabolic pathways using multiple genetic mutations to shift metabolic flux toward the biosynthetic pathway of target products to convert intermediate 2-keto acid compounds into diversified C4~C5 higher alcohols using UWCM in vivo, with the aim of improving the production. The results demonstrated the production of higher alcohols including isobutanol, 2-methyl-1-butanol, 3-methyl-1-butanol from glucose and duckweed under simultaneous saccharification and fermentation (SSF) scheme were higher based on the two aspects compared with only the use of wild-type stain as expression host. These findings showed that the improvement via UWCM in vivo in the two aspects for expression host and metabolic flux can facilitate the increase of higher alcohols production before using gene editing technology. Our work demonstrates that a multi-faceted approach for the engineering of novel synthetic pathways in microorganisms for improving biofuel production is feasible.

  5. Hesperidin Protects against Acute Alcoholic Injury through Improving Lipid Metabolism and Cell Damage in Zebrafish Larvae

    Directory of Open Access Journals (Sweden)

    Zhenting Zhou

    2017-01-01

    Full Text Available Alcoholic liver disease (ALD is a series of abnormalities of liver function, including alcoholic steatosis, steatohepatitis, and cirrhosis. Hesperidin, the major constituent of flavanone in grapefruit, is proved to play a role in antioxidation, anti-inflammation, and reducing multiple organs damage in various animal experiments. However, the underlying mechanism of resistance to alcoholic liver injury is still unclear. Thus, we aimed to investigate the protective effects of hesperidin against ALD and its molecular mechanism in this study. We established an ALD zebrafish larvae model induced by 350 mM ethanol for 32 hours, using wild-type and transgenic line with liver-specific eGFP expression Tg (lfabp10α:eGFP zebrafish larvae (4 dpf. The results revealed that hesperidin dramatically reduced the hepatic morphological damage and the expressions of alcohol and lipid metabolism related genes, including cyp2y3, cyp3a65, hmgcra, hmgcrb, fasn, and fads2 compared with ALD model. Moreover, the findings demonstrated that hesperidin alleviated hepatic damage as well, which is reflected by the expressions of endoplasmic reticulum stress and DNA damage related genes (chop, gadd45αa, and edem1. In conclusion, this study revealed that hesperidin can inhibit alcoholic damage to liver of zebrafish larvae by reducing endoplasmic reticulum stress and DNA damage, regulating alcohol and lipid metabolism.

  6. Phytophenols in whisky lower blood acetaldehyde level by depressing alcohol metabolism through inhibition of alcohol dehydrogenase 1 (class I) in mice.

    Science.gov (United States)

    Haseba, Takeshi; Sugimoto, Junichi; Sato, Shigeo; Abe, Yuko; Ohno, Youkichi

    2008-12-01

    We recently reported that the maturation of whisky prolongs the exposure of the body to a given dose of alcohol by reducing the rate of alcohol metabolism and thus lowers the blood acetaldehyde level (Alcohol Clin Exp Res. 2007;31:77s-82s). In this study, administration of the nonvolatile fraction of whisky was found to lower the concentration of acetaldehyde in the blood of mice by depressing alcohol metabolism through the inhibition of liver alcohol dehydrogenase (ADH). Four of the 12 phenolic compounds detected in the nonvolatile fraction (caffeic acid, vanillin, syringaldehyde, ellagic acid), the amounts of which increase during the maturation of whisky, were found to strongly inhibit mouse ADH 1 (class I). Their inhibition constant values for ADH 1 were 0.08, 7.9, 15.6, and 22.0 mumol/L, respectively, whereas that for pyrazole, a well-known ADH inhibitor, was 5.1 mumol/L. The 2 phenolic aldehydes and ellagic acid exhibited a mixed type of inhibition, whereas caffeic acid showed the competitive type. When individually administered to mice together with ethanol, each of these phytophenols depressed the elimination of ethanol, thereby lowering the acetaldehyde concentration of blood. Thus, it was demonstrated that the enhanced inhibition of liver ADH 1 due to the increased amounts of these phytophenols in mature whisky caused the depression of alcohol metabolism and a consequent lowering of blood acetaldehyde level. These substances are commonly found in various food plants and act as antioxidants and/or anticarcinogens. Therefore, the intake of foods rich in them together with alcohol may not only diminish the metabolic toxicity of alcohol by reducing both the blood acetaldehyde level and oxidative stress, but also help limit the amount of alcohol a person drinks by depressing alcohol metabolism.

  7. Metabolic syndrome and risk factors for non-alcoholic fatty liver disease

    Directory of Open Access Journals (Sweden)

    Mônica Rodrigues de Araújo Souza

    2012-03-01

    Full Text Available CONTEXT: Non-alcoholic fatty liver disease (NAFLD, hepatic manifestation of metabolic syndrome, has been considered the most common liver disease nowadays, which is also the most frequent cause of elevated transaminases and cryptogenic cirrhosis. The greatest input of fatty acids into the liver and consequent increased beta-oxidation contribute to the formation of free radicals, release of inflammatory cytokines and varying degrees of hepatocytic aggression, whose histological expression may vary from steatosis (HS to non-alcoholic steatohepatitis (NASH. The differentiation of these forms is required by the potential risk of progression to cirrhosis and development of hepatocellular carcinoma. OBJECTIVE: To review the literature about the major risk factors for NAFLD in the context of metabolic syndrome, focusing on underlying mechanisms and prevention. METHOD: PubMed, MEDLINE and SciELO data basis analysis was performed to identify studies describing the link between risk factors for metabolic syndrome and NAFLD. A combination of descriptors was used, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, metabolic syndrome and risk factors. At the end, 96 clinical and experimental studies, cohorts, meta-analysis and systematic reviews of great impact and scientific relevance to the topic, were selected. RESULTS: The final analysis of all these data, pointed out the central obesity, type 2 diabetes, dyslipidemia and hypertension as the best risk factors related to NAFLD. However, other factors were highlighted, such as gender differences, ethnicity, genetic factors and the role of innate immunity system. How these additional factors may be involved in the installation, progression and disease prognosis is discussed. CONCLUSION: Risk factors for NAFLD in the context of metabolic syndrome expands the prospects to 1 recognize patients with metabolic syndrome at high risk for NAFLD, 2 elucidate pathways common to other co-morbidities, 3

  8. Human Metabolic Network: Reconstruction, Simulation, and Applications in Systems Biology

    Science.gov (United States)

    Wu, Ming; Chan, Christina

    2012-01-01

    Metabolism is crucial to cell growth and proliferation. Deficiency or alterations in metabolic functions are known to be involved in many human diseases. Therefore, understanding the human metabolic system is important for the study and treatment of complex diseases. Current reconstructions of the global human metabolic network provide a computational platform to integrate genome-scale information on metabolism. The platform enables a systematic study of the regulation and is applicable to a wide variety of cases, wherein one could rely on in silico perturbations to predict novel targets, interpret systemic effects, and identify alterations in the metabolic states to better understand the genotype-phenotype relationships. In this review, we describe the reconstruction of the human metabolic network, introduce the constraint based modeling approach to analyze metabolic networks, and discuss systems biology applications to study human physiology and pathology. We highlight the challenges and opportunities in network reconstruction and systems modeling of the human metabolic system. PMID:24957377

  9. Human health risk assessment of long chain alcohols (LCOH)

    DEFF Research Database (Denmark)

    Veenstra, Gauke; Sanderson, Hans; Webb, Catherine

    2009-01-01

    Representative chemicals from the long chain alcohols category have been extensively tested to define their toxicological hazard properties. These chemicals show low acute and repeat dose toxicity with high-dose effects (if any) related to minimal liver toxicity. These chemicals do not show evide...... of human health are documented for the uses of these chemicals. © 2008....

  10. Protective effect of alcohol consumption for fatty liver but not metabolic syndrome

    Institute of Scientific and Technical Information of China (English)

    Masahide Hamaguchi; Takao Kojima; Akihiro Ohbora; Noriyuki Takeda; Michiaki Fukui; Takahiro Kato

    2012-01-01

    AIM: To investigate the effect of alcohol on the metabolic syndrome (MS) and fatty liver in Japanese men and women. METHODS: A cross-sectional study was conducted in a medical health checkup program at a general hospital. This study involved 18 571 Japanese men and women, 18-88 years of age, with a mean body mass index of 22.6 kg/m2. A standardized questionnaire was administered. The total amount of alcohol consumed per week was calculated, and categorized into four grades. Fatty liver was examined by ultrasound modified criteria of the revised National Cholesterol Education Program Adult Treatment Panel Ⅲ and the new International Diabetes Federation. RESULTS: The prevalence of fatty liver decreased in men and women with light to moderate alcohol consumption, whereas the prevalence of MS was not so changed. The prevalence of fatty liver of any grade in men was lower than that in those with no or minimal alcohol consumption. In women with light to moderate alcohol consumption, prevalence of fatty liver was lower than that in women with no or minimal alcohol consumption. By logistic regression analysis, the odds ratio (OR) for MS in women with light alcohol consumption was decreased to < 1.0, but this change was not clear in men. The OR for fatty liver was clearly < 1.0 in men with any level of alcohol consumption and in women with light to moderate consumption. CONCLUSION: Light to moderate alcohol consumption has a favorable effect for fatty liver, but not for MS in Japanese men and women.

  11. Metabolic Consequences of Chronic Alcohol Abuse in Non-Smokers: A Pilot Study.

    Directory of Open Access Journals (Sweden)

    Obiamaka Obianyo

    Full Text Available An alcohol use disorder (AUD is associated with an increased susceptibility to respiratory infection and injury and, upon hospitalization, higher mortality rates. Studies in model systems show effects of alcohol on mitochondrial function, lipid metabolism and antioxidant systems. The present study applied high-resolution metabolomics to test for these changes in bronchoalveolar lavage fluid (BALF of subjects with an AUD. Smokers were excluded to avoid confounding effects and compliance was verified by cotinine measurements. Statistically significant metabolic features, differentially expressed by control and AUD subjects, were identified by statistical and bioinformatic methods. The results show that fatty acid and acylcarnitine concentrations were increased in AUD subjects, consistent with perturbed mitochondrial and lipid metabolism. Decreased concentrations of methyl-donor compounds suggest altered one-carbon metabolism and oxidative stress. An accumulation of peptides suggests proteolytic activity, which could reflect altered epithelial barrier function. Two metabolites of possible microbial origin suggest subclinical bacterial infection. Furthermore, increased diacetylspermine suggests additional metabolic perturbations, which could contribute to dysregulated alveolar macrophage function and vulnerability to infection. Together, the results show an extended metabolic consequence of AUD in the bronchoalveolar space.

  12. 饮酒与代谢综合征%Alcohol consumption in metabolic syndrome.

    Institute of Scientific and Technical Information of China (English)

    俞慧宏; 沈薇

    2011-01-01

    代谢综合征是一组包括超重或腹型肥胖、高血糖、高血压、高甘油三酯及低高密度脂蛋白血症等的代谢紊乱症候群,也是多重心脑血管疾病危险因素聚集的表现.过去20年来的研究发现饮酒对体内多元代谢有着复杂影响,对代谢综合征具有保护和促进的双重矛盾效应.本文从饮酒与代谢综合征中各种组分的关系出发,分析饮酒对代谢综合征的利与弊.%Metabolic syndrome is a group of metabolic disorders including overweight/abdominal obesity, hy-perglycemia, hypertension, hypertriglyceridemia and low high-density lipoprotein, a clustering of multiple risk factors for cardio- and cerebro-vascular diseases. Over the past two decades, there have been a number of studies linking the complex effects of alcohol consumption to metabolic syndrome as a paradox of protection and deterioration. This article addresses the relationship between alcohol and a variety of components in metabolic syndrome,thereby providing pros and cons for alcohol consumption in this condition.

  13. Alpha adrenergic receptor mediation of cardiovascular and metabolic responses to alcohol

    Energy Technology Data Exchange (ETDEWEB)

    Brackett, D.J.; Gauvin, D.V.; Lerner, M.R.; Holloway, F.H.; Wilson, M.F. (Univ. of Oklahoma, Oklahoma City (United States) Veterans Affairs Medical Center, Oklahoma City, OK (United States))

    1992-02-26

    The role of alpha adrenergic receptors in acute cardiovascular and metabolic responses to alcohol (ETOH) have not been clearly defined. In this study two groups of male Sprague-Dawley rats were given intravenous phentolamine mesylate or saline prior to intragastric alcohol to blockade of alpha receptors during alcohol intoxication in conscious rats. ETOH alone evoked an increase in systemic vascular resistance (SVR), heart rate (HR), and blood glucose concentrations (G) and a decrease in mean arterial pressure (MAP), cardiac output (CO), central venous pressure (CVP), respiration rate (RR) and cardiac stroke volume (SV). Blood alcohol concentration (BAC) peaked at 30 min and remained elevated for the four hrs of monitoring. Phentolamine pretreatment produced a decrease in MAP and SV and an increase in HR. However, antagonism of the alpha receptor blocked the decrease in CO and the increase in SVR and G. The decrease in CVP was unaffected. Surprisingly, the early rise and peak in BAC in the phentolamine treated group was attenuated, but was the same as the untreated group during the final 3 hrs. These data suggest that alpha receptors are significant mediators of cardiovascular and glucoregulatory responses elicited by alcohol. Furthermore, alpha receptor blockade appears to effect the absorption and/or distribution of intragastrically administered alcohol.

  14. Vague relationship between alcohol consumption and metabolic syndrome in nonobese people

    Institute of Scientific and Technical Information of China (English)

    Kei Nakajima; Masafumi Saito

    2012-01-01

    Fatty liver,including non-alcoholic fatty liver disease,is closely associated with metabolic syndrome (MS).Thus,the presence of fatty liver without MS in some conditions may be clinically important.Many studies have shown that compared with no or occasional alcohol intake,moderate alcohol consumption is associated with lower prevalence rates of hypertension and type 2 diabetes,and lower levels of circulating C-reactive protein,a valuable marker for MS and insulin resistance.Considering these findings,light to moderate alcohol consumption has theoretical benefits on fatty liver and MS.Fatty liver,including non-alcoholic fatty liver disease,may be more clinically important than MS,particularly in non-obese individuals,because fatty liver can develop before MS in several conditions,such as regular alcohol consumers.Furthermore,most of the currently used MS criteria are unable to detect "true MS" because of variations in multiple factors such as age,height,medications,and complications.

  15. Effect of the allelic variant of alcohol dehydrogenase ADH1B*2 on ethanol metabolism.

    Science.gov (United States)

    Kang, Gaeun; Bae, Kyung-Yeol; Kim, Sung-Wan; Kim, Jin; Shin, Hee-Young; Kim, Jae-Min; Shin, Il-Seon; Yoon, Jin-Sang; Kim, Jong-Keun

    2014-06-01

    It has been known that ADH1B*2 allele has a protective effect against the development of alcohol dependence. However, the protection mechanism is still unknown. We investigated whether ADH1B gene polymorphism affects ethanol (EtOH) metabolism. In a parent study, we conducted a randomized crossover trials on 24 healthy male subjects who were selected by genotyping: 12 with ALDH2*1/*1 (active form) and 12 with ALDH2*1/*2 (inactive form). In the present study, the 24 subjects were reclassified into 2 groups of 11 with ADH1B*1/*2 and 13 with ADH1B*2/*2 according to the ADH1B genotypes. Each subject was administered 1 of 3 doses of EtOH (0.25, 0.5, 0.75 g/kg) or a placebo in 4 trials. After the administration of alcohol, blood EtOH and acetaldehyde concentrations were measured 9 times over 4 hours. In the case of EtOH, the area under the concentration-time curve from 0 to 4 hours (AUC0-4 ) and the peak blood concentration of EtOH (Cmax ) in subjects with ADH1B*2/*2 were significantly higher than those in subjects with ADH1B*1/*2 at all 3 dosages before stratifying by ALDH2 genotype. However, after stratifying by ALDH2 genotype, a statistically significant difference between ADH1B*2/*2 and ADH1B*1/*2 was found only at the 0.5 g/kg dosage regardless of ALDH2 genotype. In the case of acetaldehyde, the AUC0-4 and Cmax of acetaldehyde of ADH1B*2/*2 after administration of 0.25 g/kg alcohol and the AUC0-4 of acetaldehyde of ADH1B*2/*2 at 0.5 g/kg were significantly higher than corresponding values of ADH1B*1/*2 only in the group of ALDH2*1/*2. Our findings indicate that the blood EtOH concentrations of ADH1B*2/*2 group are higher than those of ADH1B*1/*2 group regardless of ALDH2 genotype, and the blood acetaldehyde concentrations of ADH1B*2/*2 are also higher than those of ADH1B*1/*2 only in the ALDH2*1/*2 group. To our knowledge, this is the first report to demonstrate the association of ADH1B*2 allele with blood EtOH and acetaldehyde levels in humans, and these results

  16. Human liver microsomal metabolism of (+)-discodermolide.

    Science.gov (United States)

    Fan, Yun; Schreiber, Emanuel M; Day, Billy W

    2009-10-01

    The polyketide natural product (+)-discodermolide is a potent microtubule stabilizer that has generated considerable interest in its synthetic, medicinal, and biological chemistry. It progressed to early clinical oncology trials, where it showed some efficacy in terms of disease stabilization but also some indications of causing pneumotoxicity. Remarkably, there are no reports of its metabolism. Here, we examined its fate in mixed human liver microsomes. Due to limited availability of the agent, we chose a nanoflow liquid chromatography-electrospray ionization-mass spectrometry analytical approach employing quadrupolar ion trap and quadrupole-quadrupole-time-of-flight instruments for these studies. (+)-Discodermolide was rapidly converted to eight metabolites, with the left-side lactone (net oxidation) and the right-side diene (epoxidation followed by hydrolysis, along with an oxygen insertion product) being the most metabolically labile sites. Other sites of metabolism were the allylic and pendant methyl moieties in the C12-C14 region of the molecule. The results provide information on the metabolic soft spots of the molecule and can be used in further medicinal chemistry efforts to optimize discodermolide analogues.

  17. Human adipose dynamics and metabolic health.

    Science.gov (United States)

    Feng, Bin; Zhang, Tracy; Xu, Haiyan

    2013-04-01

    The two types of adipose tissue in humans, white and brown, have distinct developmental origins and functions. Human white adipose tissue plays a pivotal role in maintaining whole-body energy homeostasis by storing triglycerides when energy is in surplus, releasing free fatty acids as a fuel during energy shortage, and secreting adipokines that are important for regulating lipid and glucose metabolism. The size of white adipose mass needs to be kept at a proper set point. Dramatic expansion of white fat mass causes obesity--now become a global epidemic disease--and increases the risk for the development of many life-threatening diseases. The absence of white adipose tissue or abnormal white adipose tissue redistribution leads to lipodystrophy, a condition often associated with metabolic disorders. Brown adipose tissue is a thermogenic organ whose mass is inversely correlated with body mass index and age. Therapeutic approaches targeting adipose tissue have been proven to be effective in improving obesity-related metabolic disorders, and promising new therapies could be developed in the near future. © 2013 New York Academy of Sciences.

  18. Understanding alcoholism through microRNA signatures in brains of human alcoholics

    Directory of Open Access Journals (Sweden)

    R. Dayne eMayfield

    2012-04-01

    Full Text Available Advances in the fields of genomics and genetics in the last decade have identified a large number of genes that can potentially influence alcohol-drinking behavior in humans as well as animal models. Consequently, the task of identifying efficient molecular targets that could be used to develop effective therapeutics against the disease has become increasingly daunting. One of the reasons for this is the fact that each of the many alcohol-responsive genes only contributes a small effect to the overall mechanism and disease phenotype, as is characteristic of complex traits. Current research trends are hence shifting towards the analysis of gene networks rather than emphasizing individual genes. The discovery of microRNAs and their mechanisms of action on regulation of transcript level and protein translation have made evident the utility of these small non-coding RNA molecules that act as central coordinators of multiple cross-communicating cellular pathways. Cells exploit the fact that a single microRNA can target hundreds of mRNA transcripts and that a single mRNA transcript can be simultaneously targeted by distinct microRNAs, to ensure fine-tuned and/or redundant control over a large number of cellular functions. By the same token, we can use these properties of microRNAs to develop novel, targeted strategies to combat complex disorders. In this review, we will focus on recent discoveries of microRNA signatures in brain of human alcoholics supporting the hypothesis that changes in gene expression and regulation by microRNAs are responsible for long-term neuroadaptations occurring during development of alcoholism. We also discuss insights into the potential modulation of epigenetic regulators by a subset of microRNAs. Taken together, microRNA activity may be controlling many of the cellular mechanisms already known to be involved in the development of alcoholism, and suggests potential targets for the development of novel therapeutic

  19. Alcohol

    Science.gov (United States)

    ... that's how many accidents occur. continue What Is Alcoholism? What can be confusing about alcohol is that ... develop a problem with it. Sometimes, that's called alcoholism (say: al-kuh-HOL - ism) or being an ...

  20. Alcohol

    Science.gov (United States)

    If you are like many Americans, you drink alcohol at least occasionally. For many people, moderate drinking ... risky. Heavy drinking can lead to alcoholism and alcohol abuse, as well as injuries, liver disease, heart ...

  1. Influence of metabolic indicators, smoking, alcohol and socioeconomic position on mortality after breast cancer

    DEFF Research Database (Denmark)

    Larsen, Signe Benzon; Kroman, Niels; Ibfelt, Else Helene

    2015-01-01

    BACKGROUND: Factors differently distributed among social groups like obesity, metabolic syndrome, diabetes, smoking, and alcohol intake predict survival after breast cancer diagnosis and therefore might mediate part of the observed social inequality in survival. MATERIAL AND METHODS: We conducted...... as outcome. RESULTS: Median follow-up was 9.6 years [interquartile range (IQR), 2.2-17.0 years]. The hazard ratio (HR) for death from all causes increased with lower education (p for trend, 0.01). Adjustment for disease-related prognostic factors, comorbidity and metabolic indicators measured as BMI, waist...... circumference and diabetes, and smoking and alcohol affected but did not explain the social gradient. CONCLUSION: The findings indicate that these factors explain some but not all the social inequality in survival after breast cancer and that improvement of lifestyle to some extent would improve survival among...

  2. Non-Alcoholic Fatty Liver Disease and Metabolic Syndrome after Liver Transplant.

    Science.gov (United States)

    Gitto, Stefano; Villa, Erica

    2016-04-02

    Liver transplant is the unique curative therapy for patients with acute liver failure or end-stage liver disease, with or without hepatocellular carcinoma. Increase of body weight, onset of insulin resistance and drug-induced alterations of metabolism are reported in liver transplant recipients. In this context, post-transplant diabetes mellitus, hyperlipidemia, and arterial hypertension can be often diagnosed. Multifactorial illnesses occurring in the post-transplant period represent significant causes of morbidity and mortality. This is especially true for metabolic syndrome. Non-alcoholic steatosis and steatohepatitis are hepatic manifestations of metabolic syndrome and after liver transplant both recurrent and de novo steatosis can be found. Usually, post-transplant steatosis shows an indolent outcome with few cases of fibrosis progression. However, in the post-transplant setting, both metabolic syndrome and steatosis might play a key role in the stratification of morbidity and mortality risk, being commonly associated with cardiovascular disease. The single components of metabolic syndrome can be treated with targeted drugs while lifestyle intervention is the only reasonable therapeutic approach for transplant patients with non-alcoholic steatosis or steatohepatitis.

  3. Impaired alcohol metabolism after gastric bypass surgery: a case-crossover trial.

    Science.gov (United States)

    Woodard, Gavitt A; Downey, John; Hernandez-Boussard, Tina; Morton, John M

    2011-02-01

    Severe obesity remains the leading public health crisis of the industrialized world, with bariatric surgery the only effective and enduring treatment. Poor psychological adjustment has been occasionally reported postoperatively. In addition, evidence suggests that patients can metabolize alcohol differently after gastric bypass. Preoperatively and at 3 and 6 months postoperatively, 19 Roux-en-Y gastric bypass (RYGB) patients' breath alcohol content (BAC) was measured every 5 minutes after drinking 5 oz red wine to determine peak BAC and time until sober in a case-crossover design preoperatively and at 6 months postoperatively. Patients reported symptoms experienced when intoxicated and answered a questionnaire of drinking habits. The peak BAC in patients after RYGB was considerably higher at 3 months (0.059%) and 6 months (0.088%) postoperatively than matched preoperative levels (0.024%). Patients also took considerably more time to return to sober at 3 months (61 minutes) and 6 months (88 minutes) than preoperatively (49 minutes). Postoperative intoxication was associated with lower levels of diaphoresis, flushing, and hyperactivity and higher levels of dizziness, warmth, and double vision. Postoperative patients reported drinking considerably less alcohol, fewer preferred beer, and more preferred wine than before surgery. This is the first study to match preoperative and postoperative alcohol metabolism in gastric bypass patients. Post-RYGB patients have much higher peak BAC after ingesting alcohol and require more time to become sober. Patients who drink alcohol after gastric bypass surgery should exercise caution. Copyright © 2011 American College of Surgeons. Published by Elsevier Inc. All rights reserved.

  4. Combined effects of smoking and alcohol on metabolic syndrome: the LifeLines cohort study.

    Directory of Open Access Journals (Sweden)

    Sandra N Slagter

    Full Text Available INTRODUCTION: The development of metabolic syndrome (MetS is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. METHODS: 64,046 participants aged 18-80 years from the LifeLines Cohort study were categorized into three body mass index (BMI classes (BMI1 drink/day and tobacco showed higher triglycerides levels. Up to 2 drinks/day was associated with a smaller waist circumference in overweight and obese individuals. Consumption of >2 drinks/day increased blood pressure, with the strongest associations found for heavy smokers. The overall metabolic profile of wine drinkers was better than that of non-drinkers or drinkers of beer or spirits/mixed drinks. CONCLUSION: Light alcohol consumption may moderate the negative associations of smoking with MetS. Our results suggest that the lifestyle advice that emphasizes smoking cessation and the restriction of alcohol consumption to a maximum of 1 drink/day, is a good approach to reduce the prevalence of MetS.

  5. Identification of gene targets eliciting improved alcohol tolerance in Saccharomyces cerevisiae through inverse metabolic engineering.

    Science.gov (United States)

    Hong, Min-Eui; Lee, Ki-Sung; Yu, Byung Jo; Sung, Young-Je; Park, Sung Min; Koo, Hyun Min; Kweon, Dae-Hyuk; Park, Jae Chan; Jin, Yong-Su

    2010-08-20

    The economic production of biofuels from renewable biomass using Saccharomyces cerevisiae requires tolerance to high concentrations of sugar and alcohol. Here we applied an inverse metabolic engineering approach to identify endogenous gene targets conferring improved alcohol tolerance in S. cerevisiae. After transformation with a S. cerevisiae genomic library, enrichment of the transformants exhibiting improved tolerance was performed by serial subculture in the presence of iso-butanol (1%). Through sequence analysis of the isolated plasmids from the selected transformants, four endogenous S. cerevisiae genes were identified as overexpression targets eliciting improved tolerance to both iso-butanol and ethanol. Overexpression of INO1, DOG1, HAL1 or a truncated form of MSN2 resulted in remarkably increased tolerance to high concentrations of iso-butanol and ethanol. Overexpression of INO1 elicited the highest ethanol tolerance, resulting in higher titers and volumetric productivities in the fermentation experiments performed with high glucose concentrations. In addition, the INO1-overexpressing strain showed a threefold increase in the specific growth rate as compared to that of the control strain under conditions of high levels of glucose (10%) and ethanol (5%). Although alcohol tolerance in yeast is a complex trait affected by simultaneous interactions of many genes, our results using a genomic library reveal potential target genes for better understanding and possible engineering of metabolic pathways underlying alcohol tolerance phenotypes. Crown Copyright 2010. Published by Elsevier B.V. All rights reserved.

  6. Carnitine: function, metabolism and value in hepatic failure during chronic alcohol intoxication

    Directory of Open Access Journals (Sweden)

    Alina Kępka

    2011-10-01

    Full Text Available Alcoholism is one of the most frequent dependences among people, leading to damage of the liver and death of the person. Chronic alcohol consumption decreases fatty acid oxidation by interfering with carnitine metabolism and citric acid cycle activity. Block in activity of the citric acid cycle caused by alcohol and its metabolites is partially compensated by increased ketone body production, which results in ketosis. Chronic administration of alcohol induces liver injury, inflammation, cirrhosis, focal necrosis and steatosis.L-carnitine (L-3-hydroxy-4-N, N, N-trimethylaminebutyric acid is an essential factor in fatty acid metabolism, which plays a major role in transport of activated long-chain fatty acids to sites of β-oxidation in mitochondria. Carnitine also stabilizes cell membranes by removing long-chain acyl-CoA and excess of the acyl group from the body. L-carnitine can be a useful and safe drug in the liver pathology induced by chronic ethanol exposure.

  7. Elucidation of xenobiotic metabolism pathways in human skin and human skin models by proteomic profiling.

    Directory of Open Access Journals (Sweden)

    Sven van Eijl

    Full Text Available BACKGROUND: Human skin has the capacity to metabolise foreign chemicals (xenobiotics, but knowledge of the various enzymes involved is incomplete. A broad-based unbiased proteomics approach was used to describe the profile of xenobiotic metabolising enzymes present in human skin and hence indicate principal routes of metabolism of xenobiotic compounds. Several in vitro models of human skin have been developed for the purpose of safety assessment of chemicals. The suitability of these epidermal models for studies involving biotransformation was assessed by comparing their profiles of xenobiotic metabolising enzymes with those of human skin. METHODOLOGY/PRINCIPAL FINDINGS: Label-free proteomic analysis of whole human skin (10 donors was applied and analysed using custom-built PROTSIFT software. The results showed the presence of enzymes with a capacity for the metabolism of alcohols through dehydrogenation, aldehydes through dehydrogenation and oxidation, amines through oxidation, carbonyls through reduction, epoxides and carboxylesters through hydrolysis and, of many compounds, by conjugation to glutathione. Whereas protein levels of these enzymes in skin were mostly just 4-10 fold lower than those in liver and sufficient to support metabolism, the levels of cytochrome P450 enzymes were at least 300-fold lower indicating they play no significant role. Four epidermal models of human skin had profiles very similar to one another and these overlapped substantially with that of whole skin. CONCLUSIONS/SIGNIFICANCE: The proteomics profiling approach was successful in producing a comprehensive analysis of the biotransformation characteristics of whole human skin and various in vitro skin models. The results show that skin contains a range of defined enzymes capable of metabolising different classes of chemicals. The degree of similarity of the profiles of the in vitro models indicates their suitability for epidermal toxicity testing. Overall, these

  8. Metabolic syndrome and non-alcoholic fatty liver disease:Asian deifnitions and Asian studies

    Institute of Scientific and Technical Information of China (English)

    Jian-Gao Fan; Yong-De Peng

    2007-01-01

    BACKGROUND:Non-alcoholic fatty liver disease (NAFLD), as conventionally recognized, is a metabolic disorder largely conifned to residents of aflfuent industrialized Western countries. However, obesity and insulin resistance are not restricted to the West, as witnessed by their increasingly universal distribution. In particular, there has been an upsurge in metabolic syndrome in the Asia-Paciifc region, although there are critical differences in the extent of adiposity between Eastern and Western populations. DATA SOURCES:An English-language literature search using PubMed (1999-2007) on obesity, metabolic syndrome and NAFLD, focusing on Asian deifnitions and Asian studies. RESULTS:NAFLD appears to be of long-standing insulin resistance and likely represents the hepatic manifestation of the metabolic syndrome. With insulin resistance as a common factor, the disease is associated with atherosclerosis and cardiovascular risk. All features of the metabolic syndrome and related events are assessed for practical management of NAFLD, although the criteria for the diagnosis of obesity and central obesity differ across racial groups. CONCLUSIONS:The increasing prevalence of obesity, coupled with diabetes, dyslipidemia, hypertension and ultimately metabolic syndrome, puts a very large population at risk of developing NAFLD in the coming decades. The simultaneous identiifcation and appropriate treatment of the components of metabolic syndrome are crucial to reduce hepatic as well as cardiovascular morbidity and mortality.

  9. A New View of Alcohol Metabolism and Alcoholism—Role of the High-Km Class Ⅲ Alcohol Dehydrogenase (ADH3

    Directory of Open Access Journals (Sweden)

    Youkichi Ohno

    2010-03-01

    Full Text Available The conventional view is that alcohol metabolism is carried out by ADH1 (Class I in the liver. However, it has been suggested that another pathway plays an important role in alcohol metabolism, especially when the level of blood ethanol is high or when drinking is chronic. Over the past three decades, vigorous attempts to identify the enzyme responsible for the non-ADH1 pathway have focused on the microsomal ethanol oxidizing system (MEOS and catalase, but have failed to clarify their roles in systemic alcohol metabolism. Recently, using ADH3-null mutant mice, we demonstrated that ADH3 (Class III, which has a high Km and is a ubiquitous enzyme of ancient origin, contributes to systemic alcohol metabolism in a dose-dependent manner, thereby diminishing acute alcohol intoxication. Although the activity of ADH3 toward ethanol is usually low in vitro due to its very high Km, the catalytic efficiency (kcat/Km is markedly enhanced when the solution hydrophobicity of the reaction medium increases. Activation of ADH3 by increasing hydrophobicity should also occur in liver cells; a cytoplasmic solution of mouse liver cells was shown to be much more hydrophobic than a buffer solution when using Nile red as a hydrophobicity probe. When various doses of ethanol are administered to mice, liver ADH3 activity is dynamically regulated through induction or kinetic activation, while ADH1 activity is markedly lower at high doses (3–5 g/kg. These data suggest that ADH3 plays a dynamic role in alcohol metabolism, either collaborating with ADH1 or compensating for the reduced role of ADH1. A complex two-ADH model that ascribes total liver ADH activity to both ADH1 and ADH3 explains the dose-dependent changes in the pharmacokinetic parameters (b, CLT, AUC of blood ethanol very well, suggesting that alcohol metabolism in mice is primarily governed by these two ADHs. In patients with alcoholic liver disease, liver ADH3 activity increases, while ADH1 activity decreases

  10. Altered gut microbial energy and metabolism in children with non-alcoholic fatty liver disease.

    Science.gov (United States)

    Michail, Sonia; Lin, Malinda; Frey, Mark R; Fanter, Rob; Paliy, Oleg; Hilbush, Brian; Reo, Nicholas V

    2015-02-01

    Obesity is becoming the new pediatric epidemic. Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity and has become the most common cause of pediatric liver disease. The gut microbiome is the major metabolic organ and determines how calories are processed, serving as a caloric gate and contributing towards the pathogenesis of NAFLD. The goal of this study is to examine gut microbial profiles in children with NAFLD using phylogenetic, metabolomic, metagenomic and proteomic approaches. Fecal samples were obtained from obese children with or without NAFLD and healthy lean children. Stool specimens were subjected to 16S rRNA gene microarray, shotgun sequencing, mass spectroscopy for proteomics and NMR spectroscopy for metabolite analysis. Children with NAFLD had more abundant Gammaproteobacteria and Prevotella and significantly higher levels of ethanol, with differential effects on short chain fatty acids. This group also had increased genomic and protein abundance for energy production with a reduction in carbohydrate and amino acid metabolism and urea cycle and urea transport systems. The metaproteome and metagenome showed similar findings. The gut microbiome in pediatric NAFLD is distinct from lean healthy children with more alcohol production and pathways allocated to energy metabolism over carbohydrate and amino acid metabolism, which would contribute to development of disease. © FEMS 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  11. Human KATP channelopathies: diseases of metabolic homeostasis

    Science.gov (United States)

    2009-01-01

    Assembly of an inward rectifier K+ channel pore (Kir6.1/Kir6.2) and an adenosine triphosphate (ATP)-binding regulatory subunit (SUR1/SUR2A/SUR2B) forms ATP-sensitive K+ (KATP) channel heteromultimers, widely distributed in metabolically active tissues throughout the body. KATP channels are metabolism-gated biosensors functioning as molecular rheostats that adjust membrane potential-dependent functions to match cellular energetic demands. Vital in the adaptive response to (patho)physiological stress, KATP channels serve a homeostatic role ranging from glucose regulation to cardioprotection. Accordingly, genetic variation in KATP channel subunits has been linked to the etiology of life-threatening human diseases. In particular, pathogenic mutations in KATP channels have been identified in insulin secretion disorders, namely, congenital hyperinsulinism and neonatal diabetes. Moreover, KATP channel defects underlie the triad of developmental delay, epilepsy, and neonatal diabetes (DEND syndrome). KATP channelopathies implicated in patients with mechanical and/or electrical heart disease include dilated cardiomyopathy (with ventricular arrhythmia; CMD1O) and adrenergic atrial fibrillation. A common Kir6.2 E23K polymorphism has been associated with late-onset diabetes and as a risk factor for maladaptive cardiac remodeling in the community-at-large and abnormal cardiopulmonary exercise stress performance in patients with heart failure. The overall mutation frequency within KATP channel genes and the spectrum of genotype–phenotype relationships remain to be established, while predicting consequences of a deficit in channel function is becoming increasingly feasible through systems biology approaches. Thus, advances in molecular medicine in the emerging field of human KATP channelopathies offer new opportunities for targeted individualized screening, early diagnosis, and tailored therapy. PMID:20033705

  12. Characterizing metabolic changes in human colorectal cancer.

    Science.gov (United States)

    Williams, Michael D; Zhang, Xing; Park, Jeong-Jin; Siems, William F; Gang, David R; Resar, Linda M S; Reeves, Raymond; Hill, Herbert H

    2015-06-01

    Colorectal cancer (CRC) remains a leading cause of cancer death worldwide, despite the fact that it is a curable disease when diagnosed early. The development of new screening methods to aid in early diagnosis or identify precursor lesions at risk for progressing to CRC will be vital to improving the survival rate of individuals predisposed to CRC. Metabolomics is an advancing area that has recently seen numerous applications to the field of cancer research. Altered metabolism has been studied for many years as a means to understand and characterize cancer. However, further work is required to establish standard procedures and improve our ability to identify distinct metabolomic profiles that can be used to diagnose CRC or predict disease progression. The present study demonstrates the use of direct infusion traveling wave ion mobility mass spectrometry to distinguish metabolic profiles from CRC samples and matched non-neoplastic epithelium as well as metastatic and primary tumors at different stages of disease (T1-T4). By directly infusing our samples, the analysis time was reduced significantly, thus increasing the speed and efficiency of this method compared to traditional metabolomics platforms. Partial least squares discriminant analysis was used to visualize differences between the metabolic profiles of sample types and to identify the specific m/z features that led to this differentiation. Identification of the distinct m/z features was made using the human metabolome database. We discovered alterations in fatty acid biosynthesis and oxidative, glycolytic, and polyamine pathways that distinguish tumors from non-malignant colonic epithelium as well as various stages of CRC. Although further studies are needed, our results indicate that colonic epithelial cells undergo metabolic reprogramming during their evolution to CRC, and the distinct metabolites could serve as diagnostic tools or potential targets in therapy or primary prevention. Graphical Abstract

  13. Characterization of an Arxula adeninivorans alcohol dehydrogenase involved in the metabolism of ethanol and 1-butanol.

    Science.gov (United States)

    Kasprzak, Jakub; Rauter, Marion; Riechen, Jan; Worch, Sebastian; Baronian, Kim; Bode, Rüdiger; Schauer, Frieder; Kunze, Gotthard

    2016-05-01

    In this study, alcohol dehydrogenase 1 from Arxula adeninivorans (Aadh1p) was identified and characterized. Aadh1p showed activity with short and medium chain length primary alcohols in the forward reaction and their aldehydes in the reverse reaction. Aadh1p has 64% identity with Saccharomyces cerevisiae Adh1p, is localized in the cytoplasm and uses NAD(+) as cofactor. Gene expression analysis showed a low level increase in AADH1 gene expression with ethanol, pyruvate or xylose as the carbon source. Deletion of the AADH1 gene affects growth of the cells with 1-butanol, ethanol and glucose as the carbon source, and a strain which overexpressed the AADH1 gene metabolized 1-butanol more rapidly. An ADH activity assay indicated that Aadh1p is a major enzyme for the synthesis of ethanol and the degradation of 1-butanol in A. adeninivorans. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  14. Regulation of Metabolic Signaling in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Albers, Peter Hjorth

    Regulation of glucose metabolism, despite intense research through decades, is still not clear. Skeletal muscle is highly important for maintaining glucose homeostasis. Regulation of skeletal muscle glucose metabolism is influenced by protein signaling and changes in the activity of metabolic enz...... interval exercise). The abundance of signaling proteins and metabolic enzymes are in most cases different in type I and type II muscle fibers, indicating that their glucose metabolism is different.......Regulation of glucose metabolism, despite intense research through decades, is still not clear. Skeletal muscle is highly important for maintaining glucose homeostasis. Regulation of skeletal muscle glucose metabolism is influenced by protein signaling and changes in the activity of metabolic...... enzymes. Skeletal muscle consists of thousands of muscle fibers. These fibers can roughly be classified into type I and type II muscle fibers. The overall aim of this PhD thesis was to investigate the effect of insulin and exercise on human muscle fiber type specific metabolic signaling. The importance...

  15. Immune response to acetaldehyde-human serum albumin adduct among healthy subjects related to alcohol intake.

    Science.gov (United States)

    Romanazzi, Valeria; Schilirò, Tiziana; Carraro, Elisabetta; Gilli, Giorgio

    2013-09-01

    Acetaldehyde (AA) is the main metabolic product in ethanol metabolism, although it can also derive from sources of airborne pollution. As a typical aldehyde, AA is able to react with a variety of molecular targets, including DNA and protein. This property justifies the hypothesis of a immune reaction against this kind of adduct, to be studied by a seroprevalence screening approach. In this study, the correlation between drinking habits and the amount of circulating AA-human serum albumin adduct (AA-HSA) was evaluated in a group of healthy subjects, non alcohol-addicted. Daily ethanol intake (grams) was inferred for each subject using the information collected through a questionnaire, and AA-HSA antibodies (AA-HSA ab) analyses were performed using the Displacement Assay on whole blood samples. The findings showed a correlation between ethanol intake and immune response to molecular adduct. These results underscore the evaluation of AA-HSA ab amount as a suitable molecular marker for alcohol intake that can be applied in future investigations on a large scale for prevention screening.

  16. Short-term salivary acetaldehyde increase due to direct exposure to alcoholic beverages as an additional cancer risk factor beyond ethanol metabolism

    Directory of Open Access Journals (Sweden)

    Monakhova Yulia B

    2011-01-01

    Full Text Available Abstract Background An increasing body of evidence now implicates acetaldehyde as a major underlying factor for the carcinogenicity of alcoholic beverages and especially for oesophageal and oral cancer. Acetaldehyde associated with alcohol consumption is regarded as 'carcinogenic to humans' (IARC Group 1, with sufficient evidence available for the oesophagus, head and neck as sites of carcinogenicity. At present, research into the mechanistic aspects of acetaldehyde-related oral cancer has been focused on salivary acetaldehyde that is formed either from ethanol metabolism in the epithelia or from microbial oxidation of ethanol by the oral microflora. This study was conducted to evaluate the role of the acetaldehyde that is found as a component of alcoholic beverages as an additional factor in the aetiology of oral cancer. Methods Salivary acetaldehyde levels were determined in the context of sensory analysis of different alcoholic beverages (beer, cider, wine, sherry, vodka, calvados, grape marc spirit, tequila, cherry spirit, without swallowing, to exclude systemic ethanol metabolism. Results The rinsing of the mouth for 30 seconds with an alcoholic beverage is able to increase salivary acetaldehyde above levels previously judged to be carcinogenic in vitro, with levels up to 1000 μM in cases of beverages with extreme acetaldehyde content. In general, the highest salivary acetaldehyde concentration was found in all cases in the saliva 30 sec after using the beverages (average 353 μM. The average concentration then decreased at the 2-min (156 μM, 5-min (76 μM and 10-min (40 μM sampling points. The salivary acetaldehyde concentration depends primarily on the direct ingestion of acetaldehyde contained in the beverages at the 30-sec sampling, while the influence of the metabolic formation from ethanol becomes the major factor at the 2-min sampling point. Conclusions This study offers a plausible mechanism to explain the increased risk for oral

  17. Recovered Alcoholics and Career Development: Implications for Human Resource Development

    Science.gov (United States)

    Gedro, Julie; Mercer, Frances; Iodice, Jody D.

    2012-01-01

    This article presents three issues regarding alcoholism, recovery, and career development. First, alcoholism is a disease that creates health and wellness problems for those it afflicts. It also impacts individual and workplace productivity. Second, alcoholism has a persistent stigmatization. As a result, those alcoholics who are in recovery face…

  18. Recovered Alcoholics and Career Development: Implications for Human Resource Development

    Science.gov (United States)

    Gedro, Julie; Mercer, Frances; Iodice, Jody D.

    2012-01-01

    This article presents three issues regarding alcoholism, recovery, and career development. First, alcoholism is a disease that creates health and wellness problems for those it afflicts. It also impacts individual and workplace productivity. Second, alcoholism has a persistent stigmatization. As a result, those alcoholics who are in recovery face…

  19. Role of innate immune response in non alcoholic fatty liver disease: metabolic complications and therapeutic tools

    Directory of Open Access Journals (Sweden)

    Rosaria eMeli

    2014-04-01

    Full Text Available Non alcoholic fatty liver disease (NAFLD is currently the most common liver disease worldwide, both in adults and children. It is characterized by an aberrant lipid storage in hepatocytes, named hepatic steatosis. Simple steatosis remains a benign process in most affected patients, while some of them develop superimposed necroinflammatory activity with a nonspecific inflammatory infiltrate and a progression to non alcoholic steatohepatitis with or without fibrosis. Deep similarity and interconnections between innate immune cells and those of liver parenchyma have been highlighted and showed to play a key role in the development of chronic liver disease. The liver can be considered as an immune organ because it hosts non lymphoid cells, such as macrophage Kupffer cells, stellate and dendritic cells, and lymphoid cells. Many of these cells are components of the classic innate immune system, enabling the liver to play a major role in response to pathogens. Although the liver provides a tolerogenic environment , aberrant activation of innate immune signaling may trigger harmful inflammation, that contributes to tissue injury, fibrosis and carcinogenesis. Pathogen recognition receptors, such as toll-like receptors and nucleotide oligomerization domain-like receptors, are responsible for the recognition of immunogenic signals, and represent the major conduit for sensing hepatic and non-hepatic noxious stimuli. A pivotal role in liver inflammation is also played by cytokines, which can initiate or have a part in immune response, triggering hepatic intracellular signaling pathways. The sum of inflammatory signals and deranged substrate handling induce most of the metabolic alteration traits: insulin resistance, obesity, diabetes, hyperlipidemia and their compounded combined effects. In this review we discuss the relevant role of innate immune cell activation in relation to non alcoholic fatty liver disease, the metabolic complications associated to this

  20. Lifestyle Factors and Metabolic Syndrome among Workers: The Role of Interactions between Smoking and Alcohol to Nutrition and Exercise

    Directory of Open Access Journals (Sweden)

    Jui-Hua Huang

    2015-12-01

    Full Text Available This study aimed to investigate (1 relations of smoking and alcohol to metabolic syndrome (MetS and its components, with nutrition and exercise controlled; and (2 interactions between smoking/alcohol and nutrition/exercise on MetS. This cross-sectional study enrolled 4025 workers. Self-reported lifestyles, anthropometric values, blood pressure (BP, and biochemical determinations were obtained. Among males, smoking significantly increased the risk of low high-density lipoprotein cholesterol (HDL-C, high triglyceride, abdominal obesity (AO, and MetS. Additionally, smoking showed significant interaction effects with nutrition on high BP, AO, and MetS; after further analysis, nutrition did not decrease above-mentioned risks for smokers. However, there was no significant interaction of smoking with exercise on any metabolic parameter. Alcohol increased the risk of AO, but decreased low HDL-C. It also showed an interaction effect with exercise on AO; after further analysis, exercise decreased AO risk for drinkers. Among females, alcohol significantly decreased the risk of high fasting blood glucose, but did not show significant interaction with nutrition/exercise on any metabolic parameter. In conclusion, in males, smoking retained significant associations with MetS and its components, even considering benefits of nutrition; exercise kept predominance on lipid parameters regardless of smoking status. Alcohol showed inconsistencies on metabolic parameters for both genders.

  1. Lifestyle Factors and Metabolic Syndrome among Workers: The Role of Interactions between Smoking and Alcohol to Nutrition and Exercise.

    Science.gov (United States)

    Huang, Jui-Hua; Li, Ren-Hau; Huang, Shu-Ling; Sia, Hon-Ke; Chen, Yu-Ling; Tang, Feng-Cheng

    2015-12-16

    This study aimed to investigate (1) relations of smoking and alcohol to metabolic syndrome (MetS) and its components, with nutrition and exercise controlled; and (2) interactions between smoking/alcohol and nutrition/exercise on MetS. This cross-sectional study enrolled 4025 workers. Self-reported lifestyles, anthropometric values, blood pressure (BP), and biochemical determinations were obtained. Among males, smoking significantly increased the risk of low high-density lipoprotein cholesterol (HDL-C), high triglyceride, abdominal obesity (AO), and MetS. Additionally, smoking showed significant interaction effects with nutrition on high BP, AO, and MetS; after further analysis, nutrition did not decrease above-mentioned risks for smokers. However, there was no significant interaction of smoking with exercise on any metabolic parameter. Alcohol increased the risk of AO, but decreased low HDL-C. It also showed an interaction effect with exercise on AO; after further analysis, exercise decreased AO risk for drinkers. Among females, alcohol significantly decreased the risk of high fasting blood glucose, but did not show significant interaction with nutrition/exercise on any metabolic parameter. In conclusion, in males, smoking retained significant associations with MetS and its components, even considering benefits of nutrition; exercise kept predominance on lipid parameters regardless of smoking status. Alcohol showed inconsistencies on metabolic parameters for both genders.

  2. Alcohol

    NARCIS (Netherlands)

    Hendriks, H.F.; Tol, A. van

    2005-01-01

    Alcohol consumption affects overall mortality. Light to moderate alcohol consumption reduces the risk of coronary heart disease; epidemiological, physiological and genetic data show a causal relationship. Light to moderate drinking is also associated with a reduced risk of other vascular diseases an

  3. Metabolic syndrome, alcohol consumption and genetic factors are associated with serum uric acid concentration.

    Directory of Open Access Journals (Sweden)

    Blanka Stibůrková

    Full Text Available OBJECTIVE: Uric acid is the end product of purine metabolism in humans, and increased serum uric acid concentrations lead to gout. The objective of the current study was to identify factors that are independently associated with serum uric acid concentrations in a cohort of Czech control individuals. METHODS: The cohort consisted of 589 healthy subjects aged 18-65 years. We studied the associations between the serum uric acid concentration and the following: (i demographic, anthropometric and other variables previously reported to be associated with serum uric acid concentrations; (ii the presence of metabolic syndrome and the levels of metabolic syndrome components; and (iii selected genetic variants of the MTHFR (c.665C>T, c.1286A>C, SLC2A9 (c.844G>A, c.881G>A and ABCG2 genes (c.421C>A. A backward model selection procedure was used to build two multiple linear regression models; in the second model, the number of metabolic syndrome criteria that were met replaced the metabolic syndrome-related variables. RESULTS: The models had coefficients of determination of 0.59 and 0.53. The serum uric acid concentration strongly correlated with conventional determinants including male sex, and with metabolic syndrome-related variables. In the simplified second model, the serum uric acid concentration positively correlated with the number of metabolic syndrome criteria that were met, and this model retained the explanatory power of the first model. Moderate wine drinking did not increase serum uric acid concentrations, and the urate transporter ABCG2, unlike MTHFR, was a genetic determinant of serum uric acid concentrations. CONCLUSION: Metabolic syndrome, moderate wine drinking and the c.421C>A variant in the ABCG gene are independently associated with the serum uric acid concentration. Our model indicates that uric acid should be clinically monitored in persons with metabolic syndrome.

  4. The human startle reflex and alcohol cue reactivity: effects of early versus late abstinence.

    Science.gov (United States)

    Saladin, Michael E; Drobes, David J; Coffey, Scott F; Libet, Julian M

    2002-06-01

    This study investigated the human eyeblink startle reflex as a measure of alcohol cue reactivity. Alcohol-dependent participants early (n = 36) and late (n = 34) in abstinence received presentations of alcohol and water cues. Consistent with previous research, greater salivation and higher ratings of urge to drink occurred in response to the alcohol cues. Differential salivary and urge responding to alcohol versus water cues did not vary as a function of abstinence duration. Of special interest was the finding that startle response magnitudes were relatively elevated to alcohol cues, but only in individuals early in abstinence. Affective ratings of alcohol cues suggested that alcohol cues were perceived as aversive. Methodological and theoretical implications of the findings are discussed.

  5. Non-alcoholic fatty liver and metabolic syndrome in children: a vicious circle.

    Science.gov (United States)

    Alterio, Arianna; Alisi, Anna; Liccardo, Daniela; Nobili, Valerio

    2014-01-01

    During the last decade, paediatricians have observed a dramatic increase of non-alcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in children. Furthermore, several lines of evidence have reported that a large part of children with NAFLD presents one or more traits of MS making plausible that, in the coming years, these subjects may present a rapid course of disease towards more severe cirrhosis and cardiovascular disease. Genetic susceptibility and the pressure of intrauterine environment and lifestyle are all crucial to activate molecular machinery that leads to development of NAFLD and MS in childhood. In this scenario, central obesity and consequent adipose tissue inflammation are critical to promote both MS-associated metabolic dysfunctions and NAFLD-related hepatic damage. An excessive dietary intake may in fact cause a specific lipid partitioning and induce metabolic stressors, which in turn promote insulin resistance and the release of several circulating factors. These molecules, on the one hand, trigger steatosis and the inflammatory response that characterize liver damage in NAFLD, and on the other hand contribute to the onset of other features of MS. This review provides an overview of current genetic, pathogenetic and clinical evidence of the vicious circle created by NAFLD and MS in children.

  6. Polymorphism of ethanol-metabolism genes and alcoholism: correlation of allelic variations with the pharmacokinetic and pharmacodynamic consequences.

    Science.gov (United States)

    Chen, Yi-Chyan; Peng, Giia-Sheun; Wang, Ming-Fang; Tsao, Tien-Ping; Yin, Shih-Jiun

    2009-03-16

    Alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) are the principal enzymes responsible for metabolism of ethanol. Both ADH and ALDH exhibit genetic polymorphisms among racial populations. Functional variant alleles ADH1B*2 and ALDH2*2 have been consistently replicated to show protection against developing alcohol dependence. Multiple logistic regression analyses suggest that ADH1B*2 and ALDH2*2 may independently influence the risk for alcoholism. It has been well documented that homozygosity of ALDH2*2 almost fully protects against developing alcoholism and that the heterozygosity only affords a partial protection to varying degrees. Correlations of blood ethanol and acetaldehyde concentrations, cardiovascular hemodynamic responses, and subjective perceptions have been investigated in men with different combinatorial ADH1B and ALDH2 genotypes following challenge with ethanol for a period of 130 min. The pharmacokinetic and pharmacodynamic consequences indicate that acetaldehyde, rather than ethanol, is primarily responsible for the observed alcohol sensitivity reactions, suggesting that the full protection by ALDH2*2/*2 can be ascribed to the intense unpleasant physiological and psychological reactions caused by persistently elevated blood acetaldehyde after ingesting a small amount of alcohol and that the partial protection by ALDH2*1/*2 can be attributed to a faster elimination of acetaldehyde and the lower accumulation in circulation. ADH1B polymorphism does not significantly contribute to buildup of the blood acetaldehyde. Physiological tolerance or innate insensitivity to acetaldehyde may be crucial for development of alcohol dependence in alcoholics carrying ALDH2*2.

  7. Alcohol

    Science.gov (United States)

    ... changes that come from drinking alcohol can make people do stupid or embarrassing things, like throwing up or peeing on themselves. Drinking also gives people bad breath, and no one enjoys a hangover. ...

  8. Adipose Tissue, Metabolic Syndrome, and Non-Alcoholic Fatty Liver Disease – A Short Review

    Directory of Open Access Journals (Sweden)

    Panayiotis Kouis

    2014-05-01

    Full Text Available Non-alcoholic fatty liver disease (NAFLD is the most common chronic liver disease globally, and it is expected to rise even further as a result of the increase in obesity and related risk factors. This short review summarises current evidence on the role of adipose tissue and insulin resistance in NAFLD and the interrelationship between NAFLD and the metabolic syndrome (MetS, considering central adiposity is a major feature of both the MetS and NAFLD, and that NAFLD has been previously described as the hepatic manifestation of the MetS. In addition, genetic studies of NAFLD with relation to adiposity and insulin resistance are reviewed, and up-to-date diagnostic and therapeutic tools are also discussed.

  9. Genetic variation in alcohol metabolizing enzymes among Inuit and its relation to drinking patterns

    DEFF Research Database (Denmark)

    Bjerregaard, Peter; Mikkelsen, Stine Schou; Becker, Ulrik;

    2014-01-01

    BACKGROUND: Variation in genes involved in alcohol metabolism is associated with drinking patterns worldwide. We compared variation in these genes among the Inuit with published results from the general population of Denmark and, due to the Asian ancestry of the Inuit, with Han Chinese. We analyzed...... the association between gene variations and drinking patterns among the Inuit. METHODS: We genotyped 4162 Inuit participants from two population health surveys. Information on drinking patterns was available for 3560. Seven single nucleotide polymorphisms (SNPs) were examined: ADH1B arg48his, ADH1C ile350val, ADH...... A allele and an ALDH2 gene coding for an inactive enzyme was not present in Greenland. CONCLUSIONS: ADH1C and ALDH1B1 arg107leu SNPs play a role in the shaping of drinking patterns among the Inuit in Greenland. A low frequency of the ALDH1B1 arg107leu TT genotype compared with the general population...

  10. A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease.

    Directory of Open Access Journals (Sweden)

    Adeeba Ahmed

    Full Text Available CONTEXT: Non alcoholic fatty liver disease (NAFLD is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH and cirrhosis. The potential role of glucocorticoids (GC in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol (F from inactive cortisone (E (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR. OBJECTIVE AND METHODS: In vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone. RESULTS: In patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa. CONCLUSION: Patients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11

  11. Non-alcoholic fatty liver disease in obese children and the relationship between metabolic syndrome criteria.

    Science.gov (United States)

    Boyraz, Mehmet; Hatipoğlu, Nihal; Sarı, Erkan; Akçay, Arzu; Taşkın, Necati; Ulucan, Korkut; Akçay, Teoman

    2014-01-01

    To investigate metabolic syndrome (MetS) and MetS criteria, and to establish whether metabolic syndrome criteria were associated with non-alcoholic fatty liver disease (NAFLD) in obese children. A total of 451 pubertal obese children (8-18 years old) were enrolled in the study. Patients were divided into three groups according to the degree of steatosis. Antropometric and laboratory measurements of the participants were recorded. Of 451 obese children, 217 (48.1%) were diagnosed as having NAFLD and 96 (21.3%) as having MetS. The frequency of abdominal obesity, hypertension, impaired fasting glucose, hyperinsulinemia, dyslipidemia and type 2 diabetes mellitus (T2DM) were 61.8% (279), 25.7% (116), 4.4% (20), 54.3% (245), 41% (185) and 2.2% (10), respectively. The prevalence of NAFLD among patients with MetS [73% (70/96)], was significantly higher than the frequency of hypertension [55% (53/96)] and abnormalities of glucose metabolism [23% (22/96)], but almost equal to the frequency of dyslipidemia [78% (75/96)]. The prevalence of MetS criteria were higher in patients with NAFLD than those without NAFLD. Except impaired fasting glucose, blood pressure and T2DM significant difference was found between groups for all. It was observed that the number of MetS criteria increased in parallel with the severity of steatosis. NAFLD in obese children is strongly associated with multiple MetS criteria. In addition to NAFLD is not only a liver disease, but also early mediator that reflects metabolic disorder, and liver ultrasound can be a useful tool for MetS screening. Copyright © 2013 Asian Oceanian Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.

  12. Which metabolic syndrome criteria best predict non-alcoholic fatty liver disease in children?

    Science.gov (United States)

    Atabek, Mehmet Emre; Selver Eklioglu, Beray; Akyürek, Nesibe

    2014-12-01

    The aim of this study was to identify which metabolic syndrome criteria (WHO or IDF) better reflect the presence of non-alcoholic fatty liver disease (NAFLD) and to determine the prevalence of metabolic syndrome (MS) and NAFLD. Two hundred and seventeen obese children and adolescents, 8-15 years of age (body mass index >95 p), were included in the study. Anthropometric measurements, blood pressure measurements, an oral glucose tolerance test and lipid profile were measured. MS was diagnosed according to WHO and IDF criteria. NAFLD risk ratio was assessed according to the two MS criteria. The prevalence of MS according to the IDF criteria was 43.3 %, and according to WHO criteria it was 55.2 %. NAFLD prevalence in the metabolic syndrome group according to IDF criteria was 25.5 % and this was statistically significant (p = 0.007). The prevalence of NAFLD was 20.8 % in the group with MS according to WHO criteria and this was not a statistically significant difference (p = 0.15). NAFLD hazard ratios were 7.06 (95 % CI 1.29-5.50) in the MS group according to IDF criteria and 2.02 (95 % CI 0.81-3.53) in the group with metabolic syndrome according to WHO criteria. IDF criteria were found to have a higher odds ratio. The prevalence of MS depends on the diagnostic criteria used. IDF criteria give the best measure for the presence of NAFLD. NAFLD might be important as diagnostic criterion for MS.

  13. In vitro expression of Candida albicans alcohol dehydrogenase genes involved in acetaldehyde metabolism.

    Science.gov (United States)

    Bakri, M M; Rich, A M; Cannon, R D; Holmes, A R

    2015-02-01

    Alcohol consumption is a risk factor for oral cancer, possibly via its conversion to acetaldehyde, a known carcinogen. The oral commensal yeast Candida albicans may be one of the agents responsible for this conversion intra-orally. The alcohol dehydrogenase (Adh) family of enzymes are involved in acetaldehyde metabolism in yeast but, for C. albicans it is not known which family member is responsible for the conversion of ethanol to acetaldehyde. In this study we determined the expression of mRNAs from three C. albicans Adh genes (CaADH1, CaADH2 and CaCDH3) for cells grown in different culture media at different growth phases by Northern blot analysis and quantitative reverse transcription polymerase chain reaction. CaADH1 was constitutively expressed under all growth conditions but there was differential expression of CaADH2. CaADH3 expression was not detected. To investigate whether CaAdh1p or CaAdh2p can contribute to alcohol catabolism in C. albicans, each gene from the reference strain C. albicans SC5314 was expressed in Saccharomyces cerevisiae. Cell extracts from an CaAdh1p-expressing S. cerevisiae recombinant, but not an CaAdh2p-expressing recombinant, or an empty vector control strain, possessed ethanol-utilizing Adh activity above endogenous S. cerevisiae activity. Furthermore, expression of C. albicans Adh1p in a recombinant S. cerevisiae strain in which the endogenous ScADH2 gene (known to convert ethanol to acetaldehyde in this yeast) had been deleted, conferred an NAD-dependent ethanol-utilizing, and so acetaldehyde-producing, Adh activity. We conclude that CaAdh1p is the enzyme responsible for ethanol use under in vitro growth conditions, and may contribute to the intra-oral production of acetaldehyde. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  14. Beneifcial mechanisms of aerobic exercise on hepatic lipid metabolism in non-alcoholic fatty liver disease

    Institute of Scientific and Technical Information of China (English)

    Rui Guo; Emily C Liong; Kwok Fai So; Man-Lung Fung; George L Tipoe

    2015-01-01

    BACKGROUND:Non-alcoholic fatty liver disease (NAFLD) refers to any fatty liver disease that is not due to excessive use of alcohol. NAFLD probably results from abnormal hepatic lipid metabolism and insulin resistance. Aerobic exercise is shown to improve NAFLD. This review aimed to evaluate the molecular mechanisms involved in the beneifcial effects of aerobic exercise on NAFLD. DATA SOURCE:We searched articles in English on the role of aerobic exercise in NAFLD therapy in PubMed. RESULTS:The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include: (i) reducing in-trahepatic fat content by down-regulating sterol regulatory element-binding protein-1c and up-regulating peroxisome proliferator-activated receptorγ expression levels; (ii) decreas-ing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; (iii) ameliorating hepatic inlfammation via the inhibition of pro-inlfammatory media-tors such as tumor necrosis factor-alpha and interleukin-1 beta; (iv) attenuating mitochondrial dependent apoptosis by reducing cytochrome C released from the mitochondria to the cytosol; and (v) inducing hepato-protective autophagy. CONCLUSION:Aerobic exercise, via different mechanisms, signiifcantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

  15. Non-alcoholic fatty liver disease and obesity: biochemical, metabolic and clinical presentations.

    Science.gov (United States)

    Milić, Sandra; Lulić, Davorka; Štimac, Davor

    2014-07-28

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in the world. Presentation of the disease ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NAFLD is a hepatic manifestation of metabolic syndrome that includes central abdominal obesity along with other components. Up to 80% of patients with NAFLD are obese, defined as a body mass index (BMI) > 30 kg/m(2). However, the distribution of fat tissue plays a greater role in insulin resistance than the BMI. The large amount of visceral adipose tissue (VAT) in morbidly obese (BMI > 40 kg/m(2)) individuals contributes to a high prevalence of NAFLD. Free fatty acids derived from VAT tissue, as well as from dietary sources and de novo lipogenesis, are released to the portal venous system. Excess free fatty acids and chronic low-grade inflammation from VAT are considered to be two of the most important factors contributing to liver injury progression in NAFLD. In addition, secretion of adipokines from VAT as well as lipid accumulation in the liver further promotes inflammation through nuclear factor kappa B signaling pathways, which are also activated by free fatty acids, and contribute to insulin resistance. Most NAFLD patients are asymptomatic on clinical presentation, even though some may present with fatigue, dyspepsia, dull pain in the liver and hepatosplenomegaly. Treatment for NAFLD and NASH involves weight reduction through lifestyle modifications, anti-obesity medication and bariatric surgery. This article reviews the available information on the biochemical and metabolic phenotypes associated with obesity and fatty liver disease. The relative contribution of visceral and liver fat to insulin resistance is discussed, and recommendations for clinical evaluation of affected individuals is provided.

  16. The central role of the non alcoholic fatty liver disease in metabolic syndrome.

    Science.gov (United States)

    Hurjui, Daniela Maria; Niţă, Otilia; Graur, Lidia Iuliana; Mihalache, Laura; Popescu, Dana Stefana; Graur, Mariana

    2012-01-01

    Non-alcoholic fatty liver disease (NAFLD) covers a spectrum of liver disease from steatosis to non-alcoholic steatohepatitis (NASH) and cirrhosis. Most NAFLD patients are hyperinsulinaemic and more insulin resistant compared with nonsteatotic healthy subjects, and there is a near universal association between NAFLD and insulinresistance (IR) irrespective of obesity. The metabolic syndrome (MS) is highly prevalent in the general adult population (approximatively 22%) and it carries an increased cardiovascular morbidity and mortality. Pathophysiologic considerations, clinical associations, and laboratory investigations support that IR and hyperinsulinaemia have a central role in pathogenesis of both MS and NAFLD. The fatty liver is resistant to the action of insulin to suppress hepatic glucose production, which results in hyperglycaemia and, further, in hyperinsulinemia. The MS is associated with maldistribution of body fat, increased free fatty acids (FFAs) and IR, leading to type 2 diabetes, hypertension, dyslipidemia. Visceral fat is an important clinical marker of metabolic cardiovascular risk and a marker of IR in multiple tissues, independent of body mass index (BMI). NAFLD and atherosclerosis share common molecular mediators and NAFLD itself might play an early role in the development and progression of atherosclerosis. These data suggest that NAFLD should be considered part of a multi-organ system derangement in insulin sensitivity, and help explain why NAFLD is so closely linked with diabetes, MS and is an important risk factor for coronary heart disease. NAFLD may be the hepatic manifestation of the MS and raises the possibility that it may play an early role in the etiology of MS.

  17. [Metabolic parameters in patients with steatosis non alcoholic liver and controlled diabetes type 2 versus uncontrolled diabetes type 2].

    Science.gov (United States)

    Miranda Manrique, Gonzalo

    2016-01-01

    Non-alcoholic fatty liver (NASH) is widely distributed around the world and is more common in subjects with dyslipidemia, metabolic syndrome obese and DM2 (34-74%). However, the prevalence of cirrhosis by NASH in general population is unknown which is still subject of research.

  18. Alcohol induced alterations to the human fecal VOC metabolome.

    Directory of Open Access Journals (Sweden)

    Robin D Couch

    Full Text Available Studies have shown that excessive alcohol consumption impacts the intestinal microbiota composition, causing disruption of homeostasis (dysbiosis. However, this observed change is not indicative of the dysbiotic intestinal microbiota function that could result in the production of injurious and toxic products. Thus, knowledge of the effects of alcohol on the intestinal microbiota function and their metabolites is warranted, in order to better understand the role of the intestinal microbiota in alcohol associated organ failure. Here, we report the results of a differential metabolomic analysis comparing volatile organic compounds (VOC detected in the stool of alcoholics and non-alcoholic healthy controls. We performed the analysis with fecal samples collected after passage as well as with samples collected directly from the sigmoid lumen. Regardless of the approach to fecal collection, we found a stool VOC metabolomic signature in alcoholics that is different from healthy controls. The most notable metabolite alterations in the alcoholic samples include: (1 an elevation in the oxidative stress biomarker tetradecane; (2 a decrease in five fatty alcohols with anti-oxidant property; (3 a decrease in the short chain fatty acids propionate and isobutyrate, important in maintaining intestinal epithelial cell health and barrier integrity; (4 a decrease in alcohol consumption natural suppressant caryophyllene; (5 a decrease in natural product and hepatic steatosis attenuator camphene; and (6 decreased dimethyl disulfide and dimethyl trisulfide, microbial products of decomposition. Our results showed that intestinal microbiota function is altered in alcoholics which might promote alcohol associated pathologies.

  19. Hallucinogenic drugs attenuate the subjective response to alcohol in humans.

    Science.gov (United States)

    Barrett, Sean P; Archambault, Jennifer; Engelberg, Marla J; Pihl, Robert O

    2000-10-01

    This study investigated possible interactions between alcohol and hallucinogens in 22 lysergic acid diethylamide (LSD) and/or psilocybin users through retrospective structured interviews. Of those who had used LSD with alcohol, 86;7 per cent reported a complete blockade of subjective alcohol effects, while the remaining cases reported a diminished response. In addition, 60 per cent of respondents who had used alcohol and psilocybin together reported a partial antagonism of subjective alcohol effects.T-test analyses revealed that LSD's antagonism of alcohol effects were significantly greater than those associated with psilocybin. It is proposed that LSD's effect on alcohol intoxication may involve interactions with various serotonergic and/or dopaminergic receptor systems. Copyright 2000 John Wiley & Sons, Ltd.

  20. Puerarin improves metabolic function leading to hepatoprotective effects in chronic alcohol-induced liver injury in rats.

    Science.gov (United States)

    Chen, Xu; Li, Rong; Liang, Tao; Zhang, Kefeng; Gao, Ya; Xu, Lingyuan

    2013-07-15

    Puerarin (PR), an active component extracted from the kudzu root, has been widely used as an ethno-medicine to treat hepatopathy in China. Therefore, the aim of the present study was to investigate the hepatoprotective action of PR in chronic alcohol-induced liver injury in rats. Data showed that the serum levels of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) were elevated following PR administration. In addition, the levels of endogenous CYP2E1, CYP1A2, and CYP3A proteins in liver tissue were also gradually decreased following PR treatment. Histopathological examinations suggested that alcohol-induced hepatocellular lesions were mitigated by PR treatment. Collectively, these data indicate that PR contributes to cytoprotection against alcohol-induced liver lesions through improving metabolic function. Copyright © 2013 Elsevier GmbH. All rights reserved.

  1. Circadian Rhythms, Metabolism, and Chrononutrition in Rodents and Humans123

    Science.gov (United States)

    Johnston, Jonathan D; Scheer, Frank A; Turek, Fred W

    2016-01-01

    Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial responses. Recent work has elucidated the metabolic roles of circadian clocks in key metabolic tissues, including liver, pancreas, white adipose, and skeletal muscle. For example, tissue-specific clock disruption in a single peripheral organ can cause obesity or disruption of whole-organism glucose homeostasis. This review explains mechanistic insights gained from transgenic animal studies and how these data are being translated into the study of human genetics and physiology. The principles of chrononutrition have already been demonstrated to improve human weight loss and are likely to benefit the health of individuals with metabolic disease, as well as of the general population. PMID:26980824

  2. Relationship between Alcohol Consumption and Components of the Metabolic Syndrome in Adult Population from Maracaibo City, Venezuela

    Directory of Open Access Journals (Sweden)

    Valmore Bermúdez

    2015-01-01

    Full Text Available Introduction. Although the relationships between alcohol and disorders such as cancer and liver disease have been thoroughly researched, its effects on cardiometabolic health remain controversial. Therefore, the objective of this study was to assess the association between alcohol consumption, the Metabolic Syndrome (MS, and its components in our locality. Materials and Methods. Descriptive, cross-sectional study with randomized, multistaged sampling, which included 2,230 subjects of both genders. Two previously determined population-specific alcohol consumption pattern classifications were utilized in each gender: daily intake quartiles and conglomerates yielded by cluster analysis. MS was defined according to the 2009 consensus criteria. Association was evaluated through various multiple logistic regression models. Results. In univariate analysis (daily intake quartiles, only hypertriacylglyceridemia was associated with alcohol consumption in both genders. In multivariate analysis, daily alcohol intake ≤3.8 g/day was associated with lower risk of hypertriacylglyceridemia in females (OR = 0.29, CI 95%: 0.09–0.86; p=0.03. Among men, subjects consuming 28.41–47.33 g/day had significantly increased risk of MS, hyperglycemia, high blood pressure, hypertriacylglyceridemia, and elevated waist circumference. Conclusions. The relationship between drinking, MS, and its components is complex and not directly proportional. Categorization by daily alcohol intake quartiles appears to be the most efficient method for quantitative assessment of alcohol consumption in our region.

  3. Metabolic engineering of Escherichia coli for biotechnological production of high-value organic acids and alcohols

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Chao; Cao, Yujin; Zou, Huibin; Xian, Mo [Chinese Academy of Sciences, Qingdao (China). Key Lab. of Biofuels

    2011-02-15

    Confronted with the gradual and inescapable exhaustion of the earth's fossil energy resources, the bio-based process to produce platform chemicals from renewable carbohydrates is attracting growing interest. Escherichia coli has been chosen as a workhouse for the production of many valuable chemicals due to its clear genetic background, convenient to be genetically modified and good growth properties with low nutrient requirements. Rational strain development of E. coli achieved by metabolic engineering strategies has provided new processes for efficiently biotechnological production of various high-value chemical building blocks. Compared to previous reviews, this review focuses on recent advances in metabolic engineering of the industrial model bacteria E. coli that lead to efficient recombinant biocatalysts for the production of high-value organic acids like succinic acid, lactic acid, 3-hydroxypropanoic acid and glucaric acid as well as alcohols like 1,3-propanediol, xylitol, mannitol, and glycerol with the discussion of the future research in this area. Besides, this review also discusses several platform chemicals, including fumaric acid, aspartic acid, glutamic acid, sorbitol, itaconic acid, and 2,5-furan dicarboxylic acid, which have not been produced by E. coli until now. (orig.)

  4. Metabolic engineering of Escherichia coli for biotechnological production of high-value organic acids and alcohols.

    Science.gov (United States)

    Yu, Chao; Cao, Yujin; Zou, Huibin; Xian, Mo

    2011-02-01

    Confronted with the gradual and inescapable exhaustion of the earth's fossil energy resources, the bio-based process to produce platform chemicals from renewable carbohydrates is attracting growing interest. Escherichia coli has been chosen as a workhouse for the production of many valuable chemicals due to its clear genetic background, convenient to be genetically modified and good growth properties with low nutrient requirements. Rational strain development of E. coli achieved by metabolic engineering strategies has provided new processes for efficiently biotechnological production of various high-value chemical building blocks. Compared to previous reviews, this review focuses on recent advances in metabolic engineering of the industrial model bacteria E. coli that lead to efficient recombinant biocatalysts for the production of high-value organic acids like succinic acid, lactic acid, 3-hydroxypropanoic acid and glucaric acid as well as alcohols like 1,3-propanediol, xylitol, mannitol, and glycerol with the discussion of the future research in this area. Besides, this review also discusses several platform chemicals, including fumaric acid, aspartic acid, glutamic acid, sorbitol, itaconic acid, and 2,5-furan dicarboxylic acid, which have not been produced by E. coli until now.

  5. Metabolic heat production by human and animal populations in cities

    Science.gov (United States)

    Stewart, Iain D.; Kennedy, Chris A.

    2016-12-01

    Anthropogenic heating from building energy use, vehicle fuel consumption, and human metabolism is a key term in the urban energy budget equation. Heating from human metabolism, however, is often excluded from urban energy budgets because it is widely observed to be negligible. Few reports for low-latitude cities are available to support this observation, and no reports exist on the contribution of domestic animals to urban heat budgets. To provide a more comprehensive view of metabolic heating in cities, we quantified all terms of the anthropogenic heat budget at metropolitan scale for the world's 26 largest cities, using a top-down statistical approach. Results show that metabolic heat release from human populations in mid-latitude cities (e.g. London, Tokyo, New York) accounts for 4-8% of annual anthropogenic heating, compared to 10-45% in high-density tropical cities (e.g. Cairo, Dhaka, Kolkata). Heat release from animal populations amounts to human and animal metabolism combined is highest in Mumbai—the world's most densely populated megacity—at 6.5 W m-2, surpassing heat production by electricity use in buildings (5.8 W m-2) and fuel combustion in vehicles (3.9 W m-2). These findings, along with recent output from global climate models, suggest that in the world's largest and most crowded cities, heat emissions from human metabolism alone can force measurable change in mean annual temperature at regional scale.

  6. Alcohol use, antiretroviral therapy adherence, and preferences regarding an alcohol-focused adherence intervention in patients with human immunodeficiency virus

    Directory of Open Access Journals (Sweden)

    Kekwaletswe CT

    2014-03-01

    Full Text Available Connie T Kekwaletswe,1 Neo K Morojele1,21Alcohol and Drug Abuse Research Unit, Medical Research Council, Pretoria, 2School of Public Health, University of the Witwatersrand, Johannesburg, South AfricaBackground: The primary objectives of this study were to determine the association between alcohol and antiretroviral therapy (ART adherence and the perceived appropriateness and acceptability of elements of an adherence counseling program with a focus on alcohol-related ART nonadherence among a sample of ART recipients in human immunodeficiency virus (HIV clinics in Tshwane, South Africa.Methods: We conducted a cross-sectional study with purposive sampling. The sample comprised 304 male and female ART recipients at two President's Emergency Plan For AIDS Relief-supported HIV clinics. Using an interview schedule, we assessed patients' alcohol use (Alcohol Use Disorders Identification Test, other drug use, level of adherence to ART, and reasons for missing ART doses (AIDS Clinical Trials Group adherence instrument. Additionally, patients’ views were solicited on: the likely effectiveness of potential facilitators; the preferred quantity, duration, format, and setting of the sessions; the usefulness of having family members/friends attend sessions along with the patient; and potential skill sets to be imparted.Results: About half of the male drinkers’ and three quarters of the female drinkers’ Alcohol Use Disorders Identification Test scores were suggestive of hazardous or harmful drinking. Average self-reported ART adherence was 89.7%. There was a significant association between level of alcohol use and degree of ART adherence. Overall, participants perceived two clinic-based sessions, each of one hour’s duration, in a group format, and facilitated by a peer or adherence counselor, as most appropriate and acceptable. Participants also had a favorable attitude towards family and friends accompanying them to the sessions. They also favored an

  7. Carbohydrate Metabolism in Bifidobacteria: Human Symbiotic Bacteria

    Science.gov (United States)

    Bifidobacterium ssp. constitute up to 90% of microbial gut flora in the infant colon, but considerably less in adults. Carbohydrate metabolism in these bacteria is highly unusual. Data from four Bifidobacterium genomes indicates genes missing from glycolysis, gluconeogenesis, and the TCA cycle, in...

  8. Non-alcoholic fatty liver disease: An early mediator predicting metabolic syndrome in obese children?

    Science.gov (United States)

    Fu, Jun-Fen; Shi, Hong-Bo; Liu, Li-Rui; Jiang, Ping; Liang, Li; Wang, Chun-Lin; Liu, Xi-Yong

    2011-02-14

    To investigate if non-alcoholic fatty liver disease (NAFLD) is an early mediator for prediction of metabolic syndrome, and if liver B-ultrasound can be used for its diagnosis. We classified 861 obese children (6-16 years old) into three subgroups: group 0 (normal liver in ultrasound and normal transaminases); group 1 (fatty liver in ultrasound and normal transaminases); and group 2 (fatty liver in ultrasound and elevated transaminases). We measured the body mass index, waist and hip circumference, blood pressure, fasting blood glucose, insulin, homeostasis model assessment of insulin resistance (HOMA-IR), whole-body insulin sensitivity index (WBISI), lipid profile and transaminases in all the participants. The risk of developing metabolic syndrome (MS) was assessed according to the degree of liver fatty infiltration based on the B-ultrasound examination. Among the 861 obese children, 587 (68.18%) were classified as having NAFLD, and 221 (25.67%) as having MS. The prevalence of MS in NAFLD children (groups 1 and 2) was 37.64% (221/587), which was much higher than that in non-NAFLD group (group 0, 12.04%) (P liver fatty infiltration carried a high risk of hypertension [odds ratio (OR): 2.18, 95% confidence interval (95% CI): 1.27-3.75], dyslipidemia (OR: 7.99, 95% CI: 4.34-14.73), impaired fasting glucose (OR: 3.65, 95% CI: 1.04-12.85), and whole MS (OR: 3.77; 95% CI: 1.90-7.47, P fatty infiltration increased. NAFLD is not only a liver disease, but also an early mediator that reflects metabolic disorder, and liver B-ultrasound can be a useful tool for MS screening.

  9. Non-alcoholic fatty liver disease and metabolic syndrome in obese children.

    Science.gov (United States)

    Atabek, Mehmet Emre

    2011-10-21

    I read with great interest the article of Fu et al who investigated whether non-alcoholic fatty liver disease (NAFLD) is an early mediator for prediction of metabolic syndrome, and whether liver B-ultrasound could be used for its diagnosis, in a study involving 861 obese children (6-16 years old). In this study, it was reported that NAFLD is not only a liver disease, but also an early mediator that reflects metabolic disorder, and that liver B-ultrasound can be a useful tool for metabolic syndrome (MS) screening. The authors reported that NAFLD and MS were present in 68.18% and 25.67% of obese children, respectively. Moreover, they observed that the prevalence of MS in NAFLD children was 37.64%, which was much higher than that in the non-NAFLD group. Criteria analogous to those of the Adult Treatment Panel Ⅲ definition for MS were used for children in this study. The reported prevalence data on MS in the young has varied markedly, in large part because of disagreement among the variously proposed definitions of MS. Therefore, in my opinion, a study aiming to assess the association between MS components and NAFLD in obese children has to take into account a simple, easy-to-apply clinical definition proposed by the international diabetes federation for MS. Interpretation of the results of the Fu et al study are limited by another major caveat: that the diagnosis or exclusion of NAFLD was based on liver enzymes and ultrasound imaging, but was not confirmed by liver biopsy. Indeed, it is known that liver enzymes may be within the reference interval in up to 70% of patients with diagnosed NAFLD and that the full histopathological spectrum of NAFLD may be present in patients with normal liver enzymes, which therefore cannot be reliably used to exclude the presence of NAFLD.

  10. Non-alcoholic fatty liver disease and metabolic syndrome in obese children

    Institute of Scientific and Technical Information of China (English)

    Mehmet Emre Atabek

    2011-01-01

    I read with great interest the article of Fu et al who investigated whether non-alcoholic fatty liver disease (NAFLD) is an early mediator for prediction of metabolic syndrome, and whether liver B-ultrasound could be used for its diagnosis, in a study involving 861 obese children (6-16 years old). In this study, it was reported that NAFLD is not only a liver disease, but also an early mediator that reflects metabolic disorder, and that liver B-ultrasound can be a useful tool for metabolic syndrome (MS) screening.Theauthorsreportedthat The authorsreportedthat reported that NAFLD and MS were present in 68.18% and 25.67% of obese children, respectively. Moreover, they observed that the prevalence of MS in NAFLD children was 37.64%, which was much higher than that in the non-NAFLD group. Criteria analogous to those of the Adult Treatment Panel Ⅲ definition for MS were used for children in this study. The reported prevalence data on MS in the young has varied markedly, in large part because of disagreement among the variously proposed definitions of MS. Therefore, in my opinion, a study aiming to assess the association between MS components and NAFLD in obese children has to take into account a simple, easy-to-apply clinical definition proposed by the international diabetes federation for MS. Interpretation of the results of the Fu et al study are limited by another major caveat: that the diagnosis or exclusion of NAFLD was based on liver enzymes and ultrasound imaging, but was not confirmed by liver biopsy. Indeed, it is known that liver enzymes may be within the reference interval in up to 70% of patients with diagnosed NAFLD and that the full histopathological spectrum of NAFLD may be present in patients with normal liver enzymes, which therefore cannot be reliably used to exclude the presence of NAFLD.

  11. Metabolic danger signals, uric acid and ATP, mediate inflammatory cross-talk between hepatocytes and immune cells in alcoholic liver disease.

    Science.gov (United States)

    Petrasek, Jan; Iracheta-Vellve, Arvin; Saha, Banishree; Satishchandran, Abhishek; Kodys, Karen; Fitzgerald, Katherine A; Kurt-Jones, Evelyn A; Szabo, Gyongyi

    2015-08-01

    Inflammation defines the progression of ALD from reversible to advanced stages. Translocation of bacterial LPS to the liver from the gut is necessary for alcohol-induced liver inflammation. However, it is not known whether endogenous, metabolic danger signals are required for inflammation in ALD. Uric acid and ATP, 2 major proinflammatory danger signals, were evaluated in the serum of human volunteers exposed to a single dose of ethanol or in supernatants of primary human hepatocytes exposed to ethanol. In vitro studies were used to evaluate the role of uric acid and ATP in inflammatory cross-talk between hepatocytes and immune cells. The significance of signaling downstream of uric acid and ATP in the liver was evaluated in NLRP3-deficient mice fed a Lieber-DeCarli ethanol diet. Exposure of healthy human volunteers to a single dose of ethanol resulted in increased serum levels of uric acid and ATP. In vitro, we identified hepatocytes as a significant source of these endogenous inflammatory signals. Uric acid and ATP mediated a paracrine inflammatory cross-talk between damaged hepatocytes and immune cells and significantly increased the expression of LPS-inducible cytokines, IL-1β and TNF-α, by immune cells. Deficiency of NLRP3, a ligand-sensing component of the inflammasome recognizing uric acid and ATP, prevented the development of alcohol-induced liver inflammation in mice and significantly ameliorated liver damage and steatosis. Endogenous metabolic danger signals, uric acid, and ATP are involved in inflammatory cross-talk between hepatocytes and immune cells and play a crucial role in alcohol-induced liver inflammation.

  12. Metabolic Signatures of Exercise in Human Plasma

    Science.gov (United States)

    Lewis, Gregory D.; Farrell, Laurie; Wood, Malissa J.; Martinovic, Maryann; Arany, Zoltan; Rowe, Glenn C; Souza, Amanda; Cheng, Susan; McCabe, Elizabeth L.; Yang, Elaine; Shi, Xu; Deo, Rahul; Roth, Frederick P.; Asnani, Aarti; Rhee, Eugene P.; Systrom, David M.; Semigran, Marc J.; Vasan, Ramachandran S.; Carr, Steven A.; Wang, Thomas J.; Sabatine, Marc S.; Clish, Clary B.; Gerszten, Robert E.

    2010-01-01

    Exercise provides numerous salutary effects, but our understanding of how these occur is limited. To gain a clearer picture of exercise-induced metabolic responses, we have developed comprehensive plasma metabolite signatures by using mass spectrometry to measure over 200 metabolites before and after exercise. We identified plasma indicators of glycogenolysis (glucose-6-phosphate), tricarboxylic acid (TCA) cycle span 2 expansion (succinate, malate, and fumarate), and lipolysis (glycerol), as well as modulators of insulin sensitivity (niacinamide) and fatty acid oxidation (pantothenic acid). Metabolites that were highly correlated with fitness parameters were found in subjects undergoing acute exercise testing, marathon running, and in 302 subjects from a longitudinal cohort study. Exercise-induced increases in glycerol were strongly related to fitness levels in normal individuals and were attenuated in subjects with myocardial ischemia. A combination of metabolites that increased in plasma in response to exercise (glycerol, niacinamide, glucose-6-phosphate, pantothenate, and succinate) upregulated the expression of nur77, a transcriptional regulator of glucose utilization and lipid metabolism genes in skeletal muscle. Plasma metabolic profiles obtained during exercise provide signatures of exercise performance and cardiovascular disease susceptibility, in addition to highlighting molecular pathways that may modulate the salutary effects of exercise. PMID:20505214

  13. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    OpenAIRE

    2015-01-01

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in...

  14. The relationship of appetitive, reproductive and posterior pituitary hormones to alcoholism and craving in humans.

    Science.gov (United States)

    Kenna, George A; Swift, Robert M; Hillemacher, Thomas; Leggio, Lorenzo

    2012-09-01

    A significant challenge for understanding alcoholism lies in discovering why some, but not other individuals, become dependent on alcohol. Genetic, environmental, cultural, developmental, and neurobiological influences are recognized as essential factors underlying a person's risk for becoming alcohol dependent (AD); however, the neurobiological processes that trigger this vulnerability are still poorly understood. Hormones are important in the regulation of many functions and several hormones are strongly associated with alcohol use. While medical consequences are important, the primary focus of this review is on the underlying confluence of appetitive/feeding, reproductive and posterior pituitary hormones associated with distinct phases of alcoholism or assessed by alcohol craving in humans. While these hormones are of diverse origin, the involvement with alcoholism by these hormone systems is unmistakable, and demonstrates the complexity of interactions with alcohol and the difficulty of successfully pursuing effective treatments. Whether alcohol associated changes in the activity of certain hormones are the result of alcohol use or are the result of an underlying predisposition for alcoholism, or a combination of both, is currently of great scientific interest. The evidence we present in this review suggests that appetitive hormones may be markers as they appear involved in alcohol dependence and craving, that reproductive hormones provide an example of the consequences of drinking and are affected by alcohol, and that posterior pituitary hormones have potential for being targets for treatment. A better understanding of the nature of these associations may contribute to diagnosing and more comprehensively treating alcoholism. Pharmacotherapies that take advantage of our new understanding of hormones, their receptors, or their potential relationship to craving may shed light on the treatment of this disorder.

  15. The metabolic fingerprint of p,p'-DDE and HCB exposure in humans.

    Science.gov (United States)

    Salihovic, Samira; Ganna, Andrea; Fall, Tove; Broeckling, Corey D; Prenni, Jessica E; van Bavel, Bert; Lind, P Monica; Ingelsson, Erik; Lind, Lars

    2016-03-01

    Dichlorodiphenyldichloroethylene (p,p'-DDE) and hexachlorobenzene (HCB) are organochlorine pesticides with well-known endocrine disrupting properties. Exposure to p,p'-DDE and HCB concerns human populations worldwide and has been linked to metabolic disorders such as obesity and type 2 diabetes, but details about these associations in humans from the general population are largely unknown. We investigated the associations between p,p'-DDE and HCB exposure and global metabolomic profiles in serum samples from 1016 participants from the Swedish population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. HCB and p,p'-DDE levels were determined using gas chromatography coupled to high-resolution mass spectrometry (GC-HRMS). Metabolite levels were determined by using a non-targeted metabolomics approach with ultra-performance liquid chromatography coupled to time-of- flight mass spectrometry (UPLC-TOFMS). Association analyses were performed using multivariate linear regression. We found circulating levels of p,p-DDE and HCB to be significantly associated with circulating levels of 16 metabolites following adjustment for age, sex, education level, exercise habits, smoking, energy intake, and alcohol intake. The majority of the 16 metabolites belong to lipid metabolism pathways and include fatty acids, glycerophospholipids, sphingolipids, and glycerolipids. Overall, p,p'-DDE and HCB levels were found to be correlated to different metabolites, which suggests that different metabolic fingerprints may be related to circulating levels of these two pesticides. Our findings establish a link between human exposure to organochlorine pesticides and metabolites of key metabolic processes mainly related to human lipid metabolism. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. New paradigms for metabolic modeling of human cells

    DEFF Research Database (Denmark)

    Mardinoglu, Adil; Nielsen, Jens

    2015-01-01

    Abnormalities in cellular functions are associated with the progression of human diseases, often resulting in metabolic reprogramming. GEnome-scale metabolic Models (GEMs) have enabled studying global metabolic reprogramming in connection with disease development in a systematic manner. Here we......, challenges in integration of cell/tissue models for simulation of whole body functions as well as integration of GEMs with other biological networks for generating complete cell/tissue models are presented....... review recent work on reconstruction of GEMs for human cell/tissue types and cancer, and the use of GEMs for identification of metabolic changes occurring in response to disease development. We further discuss how GEMs can be used for the development of efficient therapeutic strategies. Finally...

  17. Non-alcoholic fatty liver disease: An early mediator predicting metabolic syndrome in obese children?

    Institute of Scientific and Technical Information of China (English)

    Jun-Fen Fu; Hong-Bo Shi; Li-Rui Liu; Ping Jiang; Li Liang; Chun-Lin Wang; Xi-Yong Liu

    2011-01-01

    AIM: To investigate if non-alcoholic fatty liver disease (NAFLD) is an early mediator for prediction of metabolic syndrome, and if liver B-ultrasound can be used for its diagnosis.METHODS: We classified 861 obese children (6-16 years old) into three subgroups: group 0 (normal liver in ultrasound and normal transaminases); group 1 (fatty liver in ultrasound and normal transaminases); and group 2 (fatty liver in ultrasound and elevated transaminases).We measured the body mass index, waist and hip circumference,blood pressure, fasting blood glucose, insulin,homeostasis model assessment of insulin resistance (HOMA-IR), whole-body insulin sensitivity index (WBISI),lipid profile and transaminases in all the participants.The risk of developing metabolic syndrome (MS) was assessed according to the degree of liver fatty infiltration based on the B-ultrasound examination.RESULTS: Among the 861 obese children, 587 (68.18%)were classified as having NAFLD, and 221 (25.67%)as having MS. The prevalence of MS in NAFLD children (groups 1 and 2) was 37.64% (221/587), which was much higher than that in non-NAFLD group (group 0,12.04%) (P < 0.01). There were significantly higher incidences concerning every component of MS in group 2 compared with group 0 (P < 0.05). The incidence of NAFLD in MS patients was 84.61% (187/221), which was significantly higher than that of hypertension (57.46%,127/221) and glucose metabolic anomalies (22.62%,50/221), and almost equal to the prevalence of dyslipidemia (89.14%, 197/221). Based on the B-ultrasound scales, the presence of moderate and severe liver fatty infiltration carried a high risk of hypertension [odds ratio (OR): 2.18, 95% confidence interval (95% CI):1.27-3.75], dyslipidemia (OR: 7.99, 95% CI: 4.34-14.73),impaired fasting glucose (OR: 3.65, 95% CI: 1.04-12.85),and whole MS (OR: 3.77; 95% CI: 1.90-7.47, P < 0.01).The state of insulin resistance (calculated by HOMA-IR and WBISI) deteriorated as the degree of fatty infiltration increased

  18. CardioNet: A human metabolic network suited for the study of cardiomyocyte metabolism

    Directory of Open Access Journals (Sweden)

    Karlstädt Anja

    2012-08-01

    Full Text Available Abstract Background Availability of oxygen and nutrients in the coronary circulation is a crucial determinant of cardiac performance. Nutrient composition of coronary blood may significantly vary in specific physiological and pathological conditions, for example, administration of special diets, long-term starvation, physical exercise or diabetes. Quantitative analysis of cardiac metabolism from a systems biology perspective may help to a better understanding of the relationship between nutrient supply and efficiency of metabolic processes required for an adequate cardiac output. Results Here we present CardioNet, the first large-scale reconstruction of the metabolic network of the human cardiomyocyte comprising 1793 metabolic reactions, including 560 transport processes in six compartments. We use flux-balance analysis to demonstrate the capability of the network to accomplish a set of 368 metabolic functions required for maintaining the structural and functional integrity of the cell. Taking the maintenance of ATP, biosynthesis of ceramide, cardiolipin and further important phospholipids as examples, we analyse how a changed supply of glucose, lactate, fatty acids and ketone bodies may influence the efficiency of these essential processes. Conclusions CardioNet is a functionally validated metabolic network of the human cardiomyocyte that enables theorectical studies of cellular metabolic processes crucial for the accomplishment of an adequate cardiac output.

  19. Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

    NARCIS (Netherlands)

    Gibbs, S.; Sandt, J.J.M. van de; Merk, H.F.; Lockley, D.J.; Pendlington, R.U.; Pease, C.K.

    2007-01-01

    In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental

  20. Xenobiotic metabolism in human skin and 3D human skin reconstructs: A review

    NARCIS (Netherlands)

    Gibbs, S.; Sandt, J.J.M. van de; Merk, H.F.; Lockley, D.J.; Pendlington, R.U.; Pease, C.K.

    2007-01-01

    In this review, we discuss and compare studies of xenobiotic metabolism in both human skin and 3D human skin reconstructs. In comparison to the liver, the skin is a less studied organ in terms of characterising metabolic capability. While the skin forms the major protective barrier to environmental

  1. Diet-microbiota interactions as moderators of human metabolism.

    Science.gov (United States)

    Sonnenburg, Justin L; Bäckhed, Fredrik

    2016-07-06

    It is widely accepted that obesity and associated metabolic diseases, including type 2 diabetes, are intimately linked to diet. However, the gut microbiota has also become a focus for research at the intersection of diet and metabolic health. Mechanisms that link the gut microbiota with obesity are coming to light through a powerful combination of translation-focused animal models and studies in humans. A body of knowledge is accumulating that points to the gut microbiota as a mediator of dietary impact on the host metabolic status. Efforts are focusing on the establishment of causal relationships in people and the prospect of therapeutic interventions such as personalized nutrition.

  2. Metabolic fate of extracted glucose in normal human myocardium.

    OpenAIRE

    Wisneski, J A; Gertz, E W; Neese, R A; Gruenke, L D; D. L. Morris; Craig, J. C.

    1985-01-01

    Glucose is an important substrate for myocardial metabolism. This study was designed to determine the effect of circulating metabolic substrates on myocardial glucose extraction and to determine the metabolic fate of glucose in normal human myocardium. Coronary sinus and arterial catheters were placed in 23 healthy male volunteers. [6-14C]Glucose was infused as a tracer in 10 subjects. [6-14C]Glucose and [U-13C]lactate were simultaneously infused in the other 13 subjects. Simultaneous blood s...

  3. Bioactive compounds derived from the yeast metabolism of aromatic amino acids during alcoholic fermentation.

    Science.gov (United States)

    Mas, Albert; Guillamon, Jose Manuel; Torija, Maria Jesus; Beltran, Gemma; Cerezo, Ana B; Troncoso, Ana M; Garcia-Parrilla, M Carmen

    2014-01-01

    Metabolites resulting from nitrogen metabolism in yeast are currently found in some fermented beverages such as wine and beer. Their study has recently attracted the attention of researchers. Some metabolites derived from aromatic amino acids are bioactive compounds that can behave as hormones or even mimic their role in humans and may also act as regulators in yeast. Although the metabolic pathways for their formation are well known, the physiological significance is still far from being understood. The understanding of this relevance will be a key element in managing the production of these compounds under controlled conditions, to offer fermented food with specific enrichment in these compounds or even to use the yeast as nutritional complements.

  4. Bioactive Compounds Derived from the Yeast Metabolism of Aromatic Amino Acids during Alcoholic Fermentation

    Science.gov (United States)

    Guillamon, Jose Manuel; Torija, Maria Jesus; Beltran, Gemma; Troncoso, Ana M.; Garcia-Parrilla, M. Carmen

    2014-01-01

    Metabolites resulting from nitrogen metabolism in yeast are currently found in some fermented beverages such as wine and beer. Their study has recently attracted the attention of researchers. Some metabolites derived from aromatic amino acids are bioactive compounds that can behave as hormones or even mimic their role in humans and may also act as regulators in yeast. Although the metabolic pathways for their formation are well known, the physiological significance is still far from being understood. The understanding of this relevance will be a key element in managing the production of these compounds under controlled conditions, to offer fermented food with specific enrichment in these compounds or even to use the yeast as nutritional complements. PMID:24895623

  5. Bioactive Compounds Derived from the Yeast Metabolism of Aromatic Amino Acids during Alcoholic Fermentation

    Directory of Open Access Journals (Sweden)

    Albert Mas

    2014-01-01

    Full Text Available Metabolites resulting from nitrogen metabolism in yeast are currently found in some fermented beverages such as wine and beer. Their study has recently attracted the attention of researchers. Some metabolites derived from aromatic amino acids are bioactive compounds that can behave as hormones or even mimic their role in humans and may also act as regulators in yeast. Although the metabolic pathways for their formation are well known, the physiological significance is still far from being understood. The understanding of this relevance will be a key element in managing the production of these compounds under controlled conditions, to offer fermented food with specific enrichment in these compounds or even to use the yeast as nutritional complements.

  6. Effects of prenatal alcohol exposure on social behavior in humans and other species.

    Science.gov (United States)

    Kelly, S J; Day, N; Streissguth, A P

    2000-01-01

    Alcohol exposure during development causes central nervous system alterations in both humans and animals. Although the most common behavioral manifestation of these alterations is a reduction in cognitive abilities, it is becoming increasingly apparent that deficits in social behavior may be very prevalent sequelae of developmental alcohol exposure. In infancy and early childhood, deficits in attachment behavior and state regulation are seen in both alcohol-exposed people and animals, suggesting that these changes are largely the result of the alcohol exposure rather than maternal behavior. In the periadolescent period, people exposed to alcohol during development show a variety of difficulties in the social domain as measured by checklists filled out by either a parent or teacher. Rats exposed to alcohol during development show changes in play and parenting behaviors. In adulthood, prenatal alcohol exposure is related to high rates of trouble with the law, inappropriate sexual behavior, depression, suicide, and failure to care for children. These high rates all suggest that there may be fundamental problems in the social domain. In other animals, perinatal alcohol exposure alters aggression, active social interactions, social communication and recognition, maternal behavior, and sexual behavior in adults. In conclusion, research suggests that people exposed to alcohol during development may exhibit striking changes in social behavior; the animal research suggests that these changes may be largely the result of the alcohol insult and not the environment.

  7. Metabolic state alters economic decision making under risk in humans.

    Directory of Open Access Journals (Sweden)

    Mkael Symmonds

    Full Text Available BACKGROUND: Animals' attitudes to risk are profoundly influenced by metabolic state (hunger and baseline energy stores. Specifically, animals often express a preference for risky (more variable food sources when below a metabolic reference point (hungry, and safe (less variable food sources when sated. Circulating hormones report the status of energy reserves and acute nutrient intake to widespread targets in the central nervous system that regulate feeding behaviour, including brain regions strongly implicated in risk and reward based decision-making in humans. Despite this, physiological influences per se have not been considered previously to influence economic decisions in humans. We hypothesised that baseline metabolic reserves and alterations in metabolic state would systematically modulate decision-making and financial risk-taking in humans. METHODOLOGY/PRINCIPAL FINDINGS: We used a controlled feeding manipulation and assayed decision-making preferences across different metabolic states following a meal. To elicit risk-preference, we presented a sequence of 200 paired lotteries, subjects' task being to select their preferred option from each pair. We also measured prandial suppression of circulating acyl-ghrelin (a centrally-acting orexigenic hormone signalling acute nutrient intake, and circulating leptin levels (providing an assay of energy reserves. We show both immediate and delayed effects on risky decision-making following a meal, and that these changes correlate with an individual's baseline leptin and changes in acyl-ghrelin levels respectively. CONCLUSIONS/SIGNIFICANCE: We show that human risk preferences are exquisitely sensitive to current metabolic state, in a direction consistent with ecological models of feeding behaviour but not predicted by normative economic theory. These substantive effects of state changes on economic decisions perhaps reflect shared evolutionarily conserved neurobiological mechanisms. We suggest that

  8. Analyzing the regulation of metabolic pathways in human breast cancer

    Directory of Open Access Journals (Sweden)

    Schramm Gunnar

    2010-09-01

    Full Text Available Abstract Background Tumor therapy mainly attacks the metabolism to interfere the tumor's anabolism and signaling of proliferative second messengers. However, the metabolic demands of different cancers are very heterogeneous and depend on their origin of tissue, age, gender and other clinical parameters. We investigated tumor specific regulation in the metabolism of breast cancer. Methods For this, we mapped gene expression data from microarrays onto the corresponding enzymes and their metabolic reaction network. We used Haar Wavelet transforms on optimally arranged grid representations of metabolic pathways as a pattern recognition method to detect orchestrated regulation of neighboring enzymes in the network. Significant combined expression patterns were used to select metabolic pathways showing shifted regulation of the aggressive tumors. Results Besides up-regulation for energy production and nucleotide anabolism, we found an interesting cellular switch in the interplay of biosynthesis of steroids and bile acids. The biosynthesis of steroids was up-regulated for estrogen synthesis which is needed for proliferative signaling in breast cancer. In turn, the decomposition of steroid precursors was blocked by down-regulation of the bile acid pathway. Conclusion We applied an intelligent pattern recognition method for analyzing the regulation of metabolism and elucidated substantial regulation of human breast cancer at the interplay of cholesterol biosynthesis and bile acid metabolism pointing to specific breast cancer treatment.

  9. Understanding specificity in metabolic pathways--structural biology of human nucleotide metabolism.

    Science.gov (United States)

    Welin, Martin; Nordlund, Pär

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  10. Understanding specificity in metabolic pathways-Structural biology of human nucleotide metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Welin, Martin [Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm (Sweden); Nordlund, Paer, E-mail: Par.Nordlund@ki.se [Structural Genomics Consortium, Karolinska Institutet, 17177 Stockholm (Sweden); Division of Biophysics, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm (Sweden)

    2010-05-21

    Interactions are the foundation of life at the molecular level. In the plethora of activities in the cell, the evolution of enzyme specificity requires the balancing of appropriate substrate affinity with a negative selection, in order to minimize interactions with other potential substrates in the cell. To understand the structural basis for enzyme specificity, the comparison of structural and biochemical data between enzymes within pathways using similar substrates and effectors is valuable. Nucleotide metabolism is one of the largest metabolic pathways in the human cell and is of outstanding therapeutic importance since it activates and catabolises nucleoside based anti-proliferative drugs and serves as a direct target for anti-proliferative drugs. In recent years the structural coverage of the enzymes involved in human nucleotide metabolism has been dramatically improved and is approaching completion. An important factor has been the contribution from the Structural Genomics Consortium (SGC) at Karolinska Institutet, which recently has solved 33 novel structures of enzymes and enzyme domains in human nucleotide metabolism pathways and homologs thereof. In this review we will discuss some of the principles for substrate specificity of enzymes in human nucleotide metabolism illustrated by a selected set of enzyme families where a detailed understanding of the structural determinants for specificity is now emerging.

  11. Absorption and metabolic fate of bioactive dietary benzoxazinoids in humans

    DEFF Research Database (Denmark)

    Adhikari, Khem B; Laursen, Bente B; Gregersen, Per L;

    2013-01-01

    Scope Benzoxazinoids, which are natural compounds recently identified in mature whole grain cereals and bakery products, have been suggested to have a range of pharmacological properties and health-protecting effects. There are no published reports concerned with the absorption and metabolism...... of bioactive benzoxazinoids in humans. Methods and results The absorption, metabolism, and excretion of ten different dietary benzoxazinoids were examined by LC-MS/MS by analyzing plasma and urine from 20 healthy human volunteers after daily intake of 143 μmol of total benzoxazinoids from rye bread and rye...... glycosides, the reduction of hydroxamic acid glycosides, glucuronidation, and sulfation were the main mechanisms of the absorption and metabolism of benzoxazinoids. Conclusion These results indicate that following ingestion in healthy humans, a range of unmetabolized bioactive dietary benzoxazinoids...

  12. Non-alcoholic and alcoholic Fatty Liver Disease - two Diseases of Affluence associated with the Metabolic Syndrome and Type 2 Diabetes: the FIN-D2D Survey

    Directory of Open Access Journals (Sweden)

    Saltevo Juha

    2010-05-01

    Full Text Available Abstract Background Non-alcoholic fatty liver disease (NAFLD is known to be associated with the metabolic syndrome (MetS and abnormal glucose tolerance. Whether alcoholic fatty liver disease (AFLD is associated with similar metabolic abnormalities has not been examined in a population-based study. We aimed at assessing the prevalences of NAFLD and AFLD, and to examine to what extent these conditions are associated with MetS and abnormal glucose tolerance. Methods The cohort included 2766 Finnish subjects (45-74 years from the population-based FIN-D2D survey. Features of insulin resistance, components of the MetS, glucose tolerance status by oral glucose tolerance test, serum liver enzyme concentrations, and daily alcohol consumption were assessed. Results Subjects with NAFLD and AFLD were equally obese and had similar fasting and insulin concentrations. The prevalences of NAFLD and AFLD were 21% (95% CI: 19%-22% and 7% (95% CI: 6%-8%. The MetS was slightly more prevalent in AFLD (73% than in NAFLD (70%, p = 0.028, and type 2 diabetes was similarly prevalent in NAFLD and AFLD (24-25%. The MetS and type 2 diabetes were more prevalent in subjects with NAFLD or AFLD compared to subjects with normal LFTs (53% and 14%, p Discussion and conclusion In Finnish middle-aged population, the prevalence of NAFLD is 3-fold higher than that of AFLD. The prevalences of MetS and type 2 diabetes are, however, significantly increased in both NAFLD and AFLD compared to subjects with normal LFTs. Subjects with AFLD are thus similarly metabolically unhealthy as subjects with NAFLD.

  13. Comparison of metabolism of sesamin and episesamin by drug-metabolizing enzymes in human liver.

    Science.gov (United States)

    Yasuda, Kaori; Ikushiro, Shinichi; Wakayama, Shuto; Itoh, Toshimasa; Yamamoto, Keiko; Kamakura, Masaki; Munetsuna, Eiji; Ohta, Miho; Sakaki, Toshiyuki

    2012-10-01

    Sesamin and episesamin are two epimeric lignans that are found in refined sesame oil. Commercially available sesamin supplements contain both sesamin and episesamin at an approximate 1:1 ratio. Our previous study clarified the sequential metabolism of sesamin by cytochrome P450 (P450) and UDP-glucuronosyltransferase in human liver. In addition, we revealed that sesamin caused a mechanism-based inhibition (MBI) of CYP2C9, the P450 enzyme responsible for sesamin monocatecholization. In the present study, we compared the metabolism and the MBI of episesamin with those of sesamin. Episesamin was first metabolized to the two epimers of monocatechol, S- and R-monocatechols in human liver microsomes. The P450 enzymes responsible for S- and R-monocatechol formation were CYP2C9 and CYP1A2, respectively. The contribution of CYP2C9 was much larger than that of CYP1A2 in sesamin metabolism, whereas the contribution of CYP2C9 was almost equal to that of CYP1A2 in episesamin metabolism. Docking of episesamin to the active site of CYP1A2 explained the stereoselectivity in CYP1A2-dependent episesamin monocatecholization. Similar to sesamin, the episesamin S- and R-monocatechols were further metabolized to dicatechol, glucuronide, and methylate metabolites in human liver; however, the contribution of each reaction was significantly different between sesamin and episesamin. The liver microsomes from CYP2C19 ultra-rapid metabolizers showed a significant amount of episesamin dicatechol. In this study, we have revealed significantly different metabolism by P450, UDP-glucuronosyltransferase, and catechol-O-methyltransferase for sesamin and episesamin, resulting in different biological effects.

  14. Metabolic heat production by human and animal populations in cities

    Science.gov (United States)

    Stewart, Iain D.; Kennedy, Chris A.

    2017-07-01

    Anthropogenic heating from building energy use, vehicle fuel consumption, and human metabolism is a key term in the urban energy budget equation. Heating from human metabolism, however, is often excluded from urban energy budgets because it is widely observed to be negligible. Few reports for low-latitude cities are available to support this observation, and no reports exist on the contribution of domestic animals to urban heat budgets. To provide a more comprehensive view of metabolic heating in cities, we quantified all terms of the anthropogenic heat budget at metropolitan scale for the world's 26 largest cities, using a top-down statistical approach. Results show that metabolic heat release from human populations in mid-latitude cities (e.g. London, Tokyo, New York) accounts for 4-8% of annual anthropogenic heating, compared to 10-45% in high-density tropical cities (e.g. Cairo, Dhaka, Kolkata). Heat release from animal populations amounts to world's most densely populated megacity—at 6.5 W m-2, surpassing heat production by electricity use in buildings (5.8 W m-2) and fuel combustion in vehicles (3.9 W m-2). These findings, along with recent output from global climate models, suggest that in the world's largest and most crowded cities, heat emissions from human metabolism alone can force measurable change in mean annual temperature at regional scale.

  15. Integrative strategies to identify candidate genes in rodent models of human alcoholism.

    Science.gov (United States)

    Treadwell, Julie A

    2006-01-01

    The search for genes underlying alcohol-related behaviours in rodent models of human alcoholism has been ongoing for many years with only limited success. Recently, new strategies that integrate several of the traditional approaches have provided new insights into the molecular mechanisms underlying ethanol's actions in the brain. We have used alcohol-preferring C57BL/6J (B6) and alcohol-avoiding DBA/2J (D2) genetic strains of mice in an integrative strategy combining high-throughput gene expression screening, genetic segregation analysis, and mapping to previously published quantitative trait loci to uncover candidate genes for the ethanol-preference phenotype. In our study, 2 genes, retinaldehyde binding protein 1 (Rlbp1) and syntaxin 12 (Stx12), were found to be strong candidates for ethanol preference. Such experimental approaches have the power and the potential to greatly speed up the laborious process of identifying candidate genes for the animal models of human alcoholism.

  16. Morphine metabolism in human skin microsomes.

    Science.gov (United States)

    Heilmann, S; Küchler, S; Schäfer-Korting, M

    2012-01-01

    For patients with severe skin wounds, topically applied morphine is an option to induce efficient analgesia due to the presence of opioid receptors in the skin. However, for topical administration it is important to know whether the substance is biotransformed in the skin as this can eventually reduce the concentration of the active agent considerably. We use skin microsomes to elucidate the impact of skin metabolism on the activity of topically applied morphine. We are able to demonstrate that morphine is only glucuronidated in traces, indicating that the biotransformation in the skin can be neglected when morphine is applied topically. Hence, there is no need to take biotransformation into account when setting up the treatment regimen.

  17. Dynamic proteomic analysis reveals a switch between central carbon metabolism and alcoholic fermentation in rice filling grains.

    Science.gov (United States)

    Xu, Sheng Bao; Li, Tang; Deng, Zhu Yun; Chong, Kang; Xue, Yongbiao; Wang, Tai

    2008-10-01

    Accumulation of reserve materials in filling grains involves the coordination of different metabolic and cellular processes, and understanding the molecular mechanisms underlying the interconnections remains a major challenge for proteomics. Rice (Oryza sativa) is an excellent model for studying grain filling because of its importance as a staple food and the available genome sequence database. Our observations showed that embryo differentiation and endosperm cellularization in developing rice seeds were completed approximately 6 d after flowering (DAF); thereafter, the immature seeds mainly underwent cell enlargement and reached the size of mature seeds at 12 DAF. Grain filling began at 6 DAF and lasted until 20 DAF. Dynamic proteomic analyses revealed 396 protein spots differentially expressed throughout eight sequential developmental stages from 6 to 20 DAF and determined 345 identities. These proteins were involved in different cellular and metabolic processes with a prominently functional skew toward metabolism (45%) and protein synthesis/destination (20%). Expression analyses of protein groups associated with different functional categories/subcategories showed that substantially up-regulated proteins were involved in starch synthesis and alcoholic fermentation, whereas the down-regulated proteins in the process were involved in central carbon metabolism and most of the other functional categories/subcategories such as cell growth/division, protein synthesis, proteolysis, and signal transduction. The coordinated changes were consistent with the transition from cell growth and differentiation to starch synthesis and clearly indicated that a switch from central carbon metabolism to alcoholic fermentation may be important for starch synthesis and accumulation in the developmental process.

  18. Non-alcoholic fatty liver disease and cardiovascular risk: metabolic aspects and novel treatments.

    Science.gov (United States)

    Scorletti, E; Calder, P C; Byrne, C D

    2011-12-01

    Non-alcoholic fatty liver disease (NAFLD) is usually a silent disease that occurs in a very high proportion of people with features of the metabolic syndrome, including overweight, insulin resistance and type 2 diabetes. Because obesity and type 2 diabetes are now extremely common in Westernised societies, it is likely that the prevalence of NAFLD increases markedly in the future. Although previously it was thought that NAFLD was harmless, it is now recognised that NAFLD can be a progressive liver condition that increases risk of cirrhosis, end-stage liver disease and hepatocellular carcinoma. Additionally, liver fat accumulation causes insulin resistance and increases risk of type 2 diabetes. Increasing evidence now shows NAFLD is a risk factor for cardiovascular disease (CVD). The purpose of this review is to briefly discuss the pathogenesis of NAFLD, to describe the relationship between NAFLD and CVD and the mechanisms linking both conditions and to discuss some of the treatment options (including lifestyle, nutrition and drugs) that may influence both NAFLD and risk of CVD.

  19. In silico prediction of xenobiotic metabolism in humans

    Energy Technology Data Exchange (ETDEWEB)

    Mu, Fangping [Los Alamos National Laboratory

    2009-01-01

    Xenobiotic metabolism in humans is catalyzed by a few enzymes with broad substrate specificities, which provide the overall broad chemical specificity for nearly all xenobiotics that humans encounter. Xenobiotic metabolism are classified into functional group biotransformations. Based on bona fide reactions and negative examples for each reaction class, support vector machine (SVM) classifiers are built. The input to SVM is a set of atomic and molecular features to define the electrostatic, steric, energetic, geometrical and topological environment of the atoms in the reaction center under the molecule. Results show that the overall sensitivity and specificity of classifiers is around 87%.

  20. Gene expression signatures affected by alcohol-induced DNA methylomic deregulation in human embryonic stem cells

    OpenAIRE

    Khalid, Omar; Kim, Jeffrey J.; Kim, Hyun-Sung; Hoang, Michael; Tu, Thanh G.; Elie, Omid; Lee, Connie; Vu, Catherine; Horvath, Steve; Spigelman, Igor; Kim, Yong

    2014-01-01

    Stem cells, especially human embryonic stem cells (hESCs), are useful models to study molecular mechanisms of human disorders that originate during gestation. Alcohol (ethanol, EtOH) consumption during pregnancy causes a variety of prenatal and postnatal disorders collectively referred to as fetal alcohol spectrum disorders (FASDs). To better understand the molecular events leading to FASDs, we performed a genome-wide analysis of EtOH's effects on the maintenance and differentiation of hESCs ...

  1. multicopper oxidases important for human iron metabolism

    Directory of Open Access Journals (Sweden)

    Diana Wierzbicka

    2014-01-01

    Full Text Available Multi-copper oxidases are a group of proteins which demonstrate enzymatic activity and are capable of oxidizing their substrates with the concomitant reduction of dioxygen to two water molecules. For some multi-copper oxidases there has been demonstrated ferroxidase activity which is related to their specific structure characterized by the presence of copper centres and iron-binding sites. Three multi-copper oxidases have been included in this group: ceruloplasmin, hephaestin and zyklopen. Multi copper oxidases which are expressed in different tissues are capable of oxidizing a wide spectrum of substrates. Multi-copper oxidases are capable of oxidizing a wide spectrum of substrates. Ceruloplasmin exhibits antioxidant activity as well as being involved in many other biological processes. The observations of phenotypic effects of absence or low expression of multi-copper ferroxidase-coding genes suggest that the main role of these proteins is taking part in iron metabolism. The main role of ceruloplasmin in iron turnover is oxidizing Fe2+ into Fe3+, a process which is essential for iron binding to transferrin (the main iron-transporting protein, as well as to ferritin (the main iron-storage protein. The function of hephaestin as ferroxidase is essential for iron binding to apotransferrin in the lamina propria of the intestinal mucosa, a process that is important for further transport of iron to the liver by the portal vein. Available data indicate that zyklopen is responsible for the placental iron transport. The presence of three multi-copper oxidases with ferroxidase activity emphasizes the significance of oxidation for iron metabolism. The distribution of multi-copper ferroxidases in many tissues ensures the proper iron turnover in the body as well as preventing toxic effects related to the presence of Fe2+ ions. These ions contribute to generation of free radicals, including the highly reactive hydroxyl radical, through the Fenton and Haber

  2. Interaction of Disulfiram with Antiretroviral Medications: Efavirenz Increases While Atazanavir Decreases Disulfiram Effect on Enzymes of Alcohol Metabolism

    Science.gov (United States)

    McCance-Katz, Elinore F; Gruber, Valerie A; Beatty, George; Lum, Paula; Ma, Qing; DiFrancesco, Robin; Hochreiter, Jill; Wallace, Paul K; Faiman, Morris D; Morse, Gene D

    2013-01-01

    Background and Objectives Alcohol abuse complicates treatment of HIV disease and is linked to poor outcomes. Alcohol pharmacotherapies, including disulfiram (DIS), are infrequently utilized in co-occurring HIV and alcohol use disorders possibly related to concerns about drug interactions between antiretroviral (ARV) medications and DIS. Method This pharmacokinetics study (n=40) examined the effect of DIS on efavirenz (EFV), ritonavir (RTV), or atazanavir (ATV) and the effect of these ARV medications on DIS metabolism and aldehyde dehydrogenase (ALDH) activity which mediates the DIS-alcohol reaction. Results EFV administration was associated with decreased S-Methyl-N-N-diethylthiocarbamate (DIS carbamate), a metabolite of DIS (p=0.001) and a precursor to the metabolite responsible for ALDH inhibition, S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO). EFV was associated with increased DIS inhibition of ALDH activity relative to DIS alone administration possibly as a result of EFV-associated induction of CYP 3A4 which metabolizes the carbamate to DETC-MeSO (which inhibits ALDH). Conversely, ATV co-administration reduced the effect of DIS on ALDH activity possibly as a result of ATV inhibition of CYP 3A4. DIS administration had no significant effect on any ARV studied. Discussion/Conclusions ATV may render DIS ineffective in treatment of alcoholism. Future Directions DIS is infrequently utilized in HIV-infected individuals due to concerns about adverse interactions and side effects. Findings from this study indicate that, with ongoing clinical monitoring, DIS should be reconsidered given its potential efficacy for alcohol and potentially, cocaine use disorders, that may occur in this population. PMID:24118434

  3. Human liver epigenetic alterations in non-alcoholic steatohepatitis are related to insulin action.

    Science.gov (United States)

    de Mello, Vanessa D; Matte, Ashok; Perfilyev, Alexander; Männistö, Ville; Rönn, Tina; Nilsson, Emma; Käkelä, Pirjo; Ling, Charlotte; Pihlajamäki, Jussi

    2017-04-03

    Both genetic and lifestyle factors contribute to the risk of non-alcoholic steatohepatitis (NASH). Additionally, epigenetic modifications may also play a key role in the pathogenesis of NASH. We therefore investigated liver DNA methylation, as a marker for epigenetic alterations, in individuals with simple steatosis and NASH, and further tested if these alterations were associated with clinical phenotypes. Liver biopsies obtained from 95 obese individuals (age: 49.5 ± 7.7 years, BMI: 43 ± 5.7 kg/m(2), type 2 diabetes [T2D]: 35) as a wedge biopsy during a Roux-en-Y gastric bypass operation were investigated. Thirty-four individuals had a normal liver phenotype, 35 had simple steatosis, and 26 had NASH. Genome-wide DNA methylation pattern was analyzed using the Infinium HumanMethylation450 BeadChip. mRNA expression was analyzed from 42 individuals using the HumanHT-12 Expression BeadChip. We identified 1,292 CpG sites representing 677 unique genes differentially methylated in liver of individuals with NASH (q liver. These epigenetic alterations in NASH are linked with insulin metabolism.

  4. Obesity in children and adolescents: the relation between metabolic syndrome and non-alcoholic fatty-liver disease

    OpenAIRE

    DUARTE, Maria Amélia Soares de Melo; Silva,Giselia Alves Pontes da

    2010-01-01

    This article aims to review clinical and diagnostic aspects of non-alcoholic fatty liver disease associated with obesity and its relation to metabolic syndrome in children and adolescents. An on-line search was carried out of original articles in the Medical Literature Analysis and Retrieval System Online (MEDLINE), Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) and Scientific Eletronic Library Online (SciELO) databases, using the following key words: "hepatic steatosis...

  5. Redox Balance in Lactobacillus reuteri DSM20016: Roles of Iron-Dependent Alcohol Dehydrogenases in Glucose/ Glycerol Metabolism.

    Science.gov (United States)

    Chen, Lu; Bromberger, Paul David; Nieuwenhuiys, Gavin; Hatti-Kaul, Rajni

    2016-01-01

    Lactobacillus reuteri, a heterofermentative bacterium, metabolizes glycerol via a Pdu (propanediol-utilization) pathway involving dehydration to 3-hydroxypropionaldehyde (3-HPA) followed by reduction to 1,3-propandiol (1,3-PDO) with concomitant generation of an oxidized cofactor, NAD+ that is utilized to maintain cofactor balance required for glucose metabolism and even for oxidation of 3-HPA by a Pdu oxidative branch to 3-hydroxypropionic acid (3-HP). The Pdu pathway is operative inside Pdu microcompartment that encapsulates different enzymes and cofactors involved in metabolizing glycerol or 1,2-propanediol, and protects the cells from the toxic effect of the aldehyde intermediate. Since L. reuteri excretes high amounts of 3-HPA outside the microcompartment, the organism is likely to have alternative alcohol dehydrogenase(s) in the cytoplasm for transformation of the aldehyde. In this study, diversity of alcohol dehydrogenases in Lactobacillus species was investigated with a focus on L. reuteri. Nine ADH enzymes were found in L. reuteri DSM20016, out of which 3 (PduQ, ADH6 and ADH7) belong to the group of iron-dependent enzymes that are known to transform aldehydes/ketones to alcohols. L. reuteri mutants were generated in which the three ADHs were deleted individually. The lagging growth phenotype of these deletion mutants revealed that limited NAD+/NADH recycling could be restricting their growth in the absence of ADHs. Notably, it was demonstrated that PduQ is more active in generating NAD+ during glycerol metabolism within the microcompartment by resting cells, while ADH7 functions to balance NAD+/NADH by converting 3-HPA to 1,3-PDO outside the microcompartment in the growing cells. Moreover, evaluation of ADH6 deletion mutant showed strong decrease in ethanol level, supporting the role of this bifuctional alcohol/aldehyde dehydrogenase in ethanol production. To the best of our knowledge, this is the first report revealing both internal and external recycling

  6. The Food and Beverage Occurrence of Furfuryl Alcohol and Myrcene—Two Emerging Potential Human Carcinogens?

    Directory of Open Access Journals (Sweden)

    Alex O. Okaru

    2017-03-01

    Full Text Available For decades, compounds present in foods and beverages have been implicated in the etiology of human cancers. The World Health Organization (WHO International Agency for Research on Cancer (IARC continues to classify such agents regarding their potential carcinogenicity in humans based on new evidence from animal and human studies. Furfuryl alcohol and β-myrcene are potential human carcinogens due to be evaluated. The major source of furfuryl alcohol in foods is thermal processing and ageing of alcoholic beverages, while β-myrcene occurs naturally as a constituent of the essential oils of plants such as hops, lemongrass, and derived products. This study aimed to summarize the occurrence of furfuryl alcohol and β-myrcene in foods and beverages using literature review data. Additionally, results of furfuryl alcohol occurrence from our own nuclear magnetic resonance (NMR analysis are included. The highest content of furfuryl alcohol was found in coffee beans (>100 mg/kg and in some fish products (about 10 mg/kg, while among beverages, wines contained between 1 and 10 mg/L, with 8 mg/L in pineapple juice. The content of β-myrcene was highest in hops. In conclusion, the data about the occurrence of the two agents is currently judged as insufficient for exposure and risk assessment. The results of this study point out the food and beverage groups that may be considered for future monitoring of furfuryl alcohol and β-myrcene.

  7. Enantioselective Metabolism of Flufiprole in Rat and Human Liver Microsomes.

    Science.gov (United States)

    Lin, Chunmian; Miao, Yelong; Qian, Mingrong; Wang, Qiang; Zhang, Hu

    2016-03-23

    The enantioselective metabolism of flufiprole in rat and human liver microsomes in vitro was investigated in this study. The separation and determination were performed using a liquid chromatography system equipped with a triple-quadrupole mass spectrometer and a Lux Cellulose-2 chiral column. The enantioselective metabolism of rac-flufiprole was dramatically different in rat and human liver microsomes in the presence of the β-nicotinamide adenine dinucleotide phosphate regenerating system. The half-lives (t1/2) of flufiprole in rat and human liver microsomes were 7.22 and 21.00 min, respectively, for R-(+)-flufiprole, whereas the values were 11.75 and 17.75 min, respectively, for S-(-)-flufiprole. In addition, the Vmax of R-(+)-flufiprole was about 3-fold that of S-(-)-flufiprole in rat liver microsomes, whereas its value in the case of S-(-)-flufiprole was about 2-fold that of R-(+)-flufiprole in human liver microsomes. The CLint of rac-flufiprole also showed opposite enantioselectivy in rat and human liver microsomes. The different compositions and contents of metabolizing enzyme in the two liver microsomes might be the reasons for the difference in the metabolic behavior of the two enantiomers.

  8. Gastrointestinal metabolization of human milk oligosaccharides

    NARCIS (Netherlands)

    Albrecht, S.A.; Heuvel, van den E.G.H.M.; Gruppen, H.; Schols, H.A.

    2013-01-01

    Breast feeding has a great impact on the growth of infants both physically and psychologically. Human breast milk is beneficial to infant health because it contains the necessary macro- and micro-nutrients for tissue accretion, repair and behavioural developments. The production of milk is a complex

  9. APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons

    Directory of Open Access Journals (Sweden)

    Steven Moore

    2015-05-01

    Full Text Available Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD. To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, all of which increase the release of pathogenic Aβ peptides. We identified marked increases in intracellular tau in genetic forms of AD that either mutated APP or increased its dosage, suggesting that APP metabolism is coupled to changes in tau proteostasis. Manipulating APP metabolism by β-secretase and γ-secretase inhibition, as well as γ-secretase modulation, results in specific increases and decreases in tau protein levels. These data demonstrate that APP metabolism regulates tau proteostasis and suggest that the relationship between APP processing and tau is not mediated solely through extracellular Aβ signaling to neurons.

  10. Hepatic metabolism of toluene after gastrointestinal uptake in humans

    DEFF Research Database (Denmark)

    Bælum, Jesper; Mølhave, Lars; Honoré Hansen, S

    1993-01-01

    The metabolism of toluene and the influence of small doses of ethanol were measured in eight male volunteers after gastrointestinal uptake, the toluene concentration in alveolar air and the urinary excretion of hippuric acid and ortho-cresol being used as the measures of metabolism. During toluene...... exposure to 2 mg.min-1 for 3 h the alveolar toluene concentration was 0.07 (range 0-0.11) mg.m-3; exposure to 6 mg.min-1 for 30 min increased the alveolar concentration to 0.9 (range 0.03-2.6) mg.m-3. Ingestion of 0.08, 0.16, and 0.32 g of ethanol per kilogram of body weight during toluene exposure of 2 mg...... doses of ethanol inhibit toluene metabolism, and the procedure is sensitive enough to measure metabolic interactions between solvents and other xenobiotics in humans....

  11. Metabolism as a tool for understanding human brain evolution: lipid energy metabolism as an example.

    Science.gov (United States)

    Wang, Shu Pei; Yang, Hao; Wu, Jiang Wei; Gauthier, Nicolas; Fukao, Toshiyuki; Mitchell, Grant A

    2014-12-01

    Genes and the environment both influence the metabolic processes that determine fitness. To illustrate the importance of metabolism for human brain evolution and health, we use the example of lipid energy metabolism, i.e. the use of fat (lipid) to produce energy and the advantages that this metabolic pathway provides for the brain during environmental energy shortage. We briefly describe some features of metabolism in ancestral organisms, which provided a molecular toolkit for later development. In modern humans, lipid energy metabolism is a regulated multi-organ pathway that links triglycerides in fat tissue to the mitochondria of many tissues including the brain. Three important control points are each suppressed by insulin. (1) Lipid reserves in adipose tissue are released by lipolysis during fasting and stress, producing fatty acids (FAs) which circulate in the blood and are taken up by cells. (2) FA oxidation. Mitochondrial entry is controlled by carnitine palmitoyl transferase 1 (CPT1). Inside the mitochondria, FAs undergo beta oxidation and energy production in the Krebs cycle and respiratory chain. (3) In liver mitochondria, the 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) pathway produces ketone bodies for the brain and other organs. Unlike most tissues, the brain does not capture and metabolize circulating FAs for energy production. However, the brain can use ketone bodies for energy. We discuss two examples of genetic metabolic traits that may be advantageous under most conditions but deleterious in others. (1) A CPT1A variant prevalent in Inuit people may allow increased FA oxidation under nonfasting conditions but also predispose to hypoglycemic episodes. (2) The thrifty genotype theory, which holds that energy expenditure is efficient so as to maximize energy stores, predicts that these adaptations may enhance survival in periods of famine but predispose to obesity in modern dietary environments. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Response of Differentiated Human Airway Epithelia to Alcohol Exposure and Klebsiella pneumoniae Challenge

    Directory of Open Access Journals (Sweden)

    Sammeta V. Raju

    2013-07-01

    Full Text Available Alcohol abuse has been associated with increased susceptibility to pulmonary infection. It is not fully defined how alcohol contributes to the host defense compromise. Here primary human airway epithelial cells were cultured at an air-liquid interface to form a differentiated and polarized epithelium. This unique culture model allowed us to closely mimic lung infection in the context of alcohol abuse by basolateral alcohol exposure and apical live bacterial challenge. Application of clinically relevant concentrations of alcohol for 24 h did not significantly alter epithelial integrity or barrier function. When apically challenged with viable Klebsiella pneumoniae, the cultured epithelia had an enhanced tightness which was unaffected by alcohol. Further, alcohol enhanced apical bacterial growth, but not bacterial binding to the cells. The cultured epithelium in the absence of any treatment or stimulation had a base-level IL-6 and IL-8 secretion. Apical bacterial challenge significantly elevated the basolateral secretion of inflammatory cytokines including IL-2, IL-4, IL-6, IL-8, IFN-γ, GM-CSF, and TNF-α. However, alcohol suppressed the observed cytokine burst in response to infection. Addition of adenosine receptor agonists negated the suppression of IL-6 and TNF-α. Thus, acute alcohol alters the epithelial cytokine response to infection, which can be partially mitigated by adenosine receptor agonists.

  13. Neuroadaptations in human chronic alcoholics: dysregulation of the NF-kappaB system.

    Directory of Open Access Journals (Sweden)

    Anna Okvist

    Full Text Available BACKGROUND: Alcohol dependence and associated cognitive impairments apparently result from neuroadaptations to chronic alcohol consumption involving changes in expression of multiple genes. Here we investigated whether transcription factors of Nuclear Factor-kappaB (NF-kappaB family, controlling neuronal plasticity and neurodegeneration, are involved in these adaptations in human chronic alcoholics. METHODS AND FINDINGS: Analysis of DNA-binding of NF-kappaB (p65/p50 heterodimer and the p50 homodimer as well as NF-kappaB proteins and mRNAs was performed in postmortem human brain samples from 15 chronic alcoholics and 15 control subjects. The prefrontal cortex involved in alcohol dependence and cognition was analyzed and the motor cortex was studied for comparison. The p50 homodimer was identified as dominant kappaB binding factor in analyzed tissues. NF-kappaB and p50 homodimer DNA-binding was downregulated, levels of p65 (RELA mRNA were attenuated, and the stoichiometry of p65/p50 proteins and respective mRNAs was altered in the prefrontal cortex of alcoholics. Comparison of a number of p50 homodimer/NF-kappaB target DNA sites, kappaB elements in 479 genes, down- or upregulated in alcoholics demonstrated that genes with kappaB elements were generally upregulated in alcoholics. No significant differences between alcoholics and controls were observed in the motor cortex. CONCLUSIONS: We suggest that cycles of alcohol intoxication/withdrawal, which may initially activate NF-kappaB, when repeated over years downregulate RELA expression and NF-kappaB and p50 homodimer DNA-binding. Downregulation of the dominant p50 homodimer, a potent inhibitor of gene transcription apparently resulted in derepression of kappaB regulated genes. Alterations in expression of p50 homodimer/NF-kappaB regulated genes may contribute to neuroplastic adaptation underlying alcoholism.

  14. Metabolic costs and evolutionary implications of human brain development.

    Science.gov (United States)

    Kuzawa, Christopher W; Chugani, Harry T; Grossman, Lawrence I; Lipovich, Leonard; Muzik, Otto; Hof, Patrick R; Wildman, Derek E; Sherwood, Chet C; Leonard, William R; Lange, Nicholas

    2014-09-09

    The high energetic costs of human brain development have been hypothesized to explain distinctive human traits, including exceptionally slow and protracted preadult growth. Although widely assumed to constrain life-history evolution, the metabolic requirements of the growing human brain are unknown. We combined previously collected PET and MRI data to calculate the human brain's glucose use from birth to adulthood, which we compare with body growth rate. We evaluate the strength of brain-body metabolic trade-offs using the ratios of brain glucose uptake to the body's resting metabolic rate (RMR) and daily energy requirements (DER) expressed in glucose-gram equivalents (glucosermr% and glucoseder%). We find that glucosermr% and glucoseder% do not peak at birth (52.5% and 59.8% of RMR, or 35.4% and 38.7% of DER, for males and females, respectively), when relative brain size is largest, but rather in childhood (66.3% and 65.0% of RMR and 43.3% and 43.8% of DER). Body-weight growth (dw/dt) and both glucosermr% and glucoseder% are strongly, inversely related: soon after birth, increases in brain glucose demand are accompanied by proportionate decreases in dw/dt. Ages of peak brain glucose demand and lowest dw/dt co-occur and subsequent developmental declines in brain metabolism are matched by proportionate increases in dw/dt until puberty. The finding that human brain glucose demands peak during childhood, and evidence that brain metabolism and body growth rate covary inversely across development, support the hypothesis that the high costs of human brain development require compensatory slowing of body growth rate.

  15. Correlation between blood adenosine metabolism and sleep in humans.

    Science.gov (United States)

    Díaz-Muñoz, M; Hernández-Muñoz, R; Suárez, J; Vidrio, S; Yááñez, L; Aguilar-Roblero, R; Rosenthal, L; Villalobos, L; Fernández-Cancino, F; Drucker-Colín, R; Chagoya De Sanchez, V

    1999-01-01

    Blood adenosine metabolism, including metabolites and metabolizing enzymes, was studied during the sleep period in human volunteers. Searching for significant correlations among biochemical parameters found: adenosine with state 1 of slow-wave sleep (SWS); activity of 5'-nucleotidase with state 2 of SWS; inosine and AMP with state 3-4 of SWS; and activity of 5'-nucleotidase and lactate with REM sleep. The correlations were detected in all of the subjects that presented normal hypnograms, but not in those who had fragmented sleep the night of the experiment. The data demonstrate that it is possible to obtain information of complex brain operations such as sleep by measuring biochemical parameters in blood. The results strengthen the notion of a role played by adenosine, its metabolites and metabolizing enzymes, during each of the stages that constitute the sleep process in humans.

  16. Assessing the human gut microbiota in metabolic diseases.

    Science.gov (United States)

    Karlsson, Fredrik; Tremaroli, Valentina; Nielsen, Jens; Bäckhed, Fredrik

    2013-10-01

    Recent findings have demonstrated that the gut microbiome complements our human genome with at least 100-fold more genes. In contrast to our Homo sapiens-derived genes, the microbiome is much more plastic, and its composition changes with age and diet, among other factors. An altered gut microbiota has been associated with several diseases, including obesity and diabetes, but the mechanisms involved remain elusive. Here we discuss factors that affect the gut microbiome, how the gut microbiome may contribute to metabolic diseases, and how to study the gut microbiome. Next-generation sequencing and development of software packages have led to the development of large-scale sequencing efforts to catalog the human microbiome. Furthermore, the use of genetically engineered gnotobiotic mouse models may increase our understanding of mechanisms by which the gut microbiome modulates host metabolism. A combination of classical microbiology, sequencing, and animal experiments may provide further insights into how the gut microbiota affect host metabolism and physiology.

  17. IL-6 selectively stimulates fat metabolism in human skeletal muscle

    DEFF Research Database (Denmark)

    Wolsk, Emil; Mygind, Helene; Grøndahl, Thomas S

    2010-01-01

    Interleukin (IL)-6 is chronically elevated in type 2 diabetes but also during exercise. However, the exact metabolic role, and hence the physiological significance, has not been elucidated. The objective of this study was to investigate the in vivo effect of recombinant human (rh) IL-6 on human fat...... and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ~40 and ~1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed...... in systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged with rhIL-6 compared with saline infusion. Conversely, rhIL-6 infusion caused an increase in skeletal muscle unidirectional fatty acid and glycerol release, indicative of an increase in lipolysis. The increased lipolysis...

  18. Hepatic scavenger receptor BI is associated with type 2 diabetes but unrelated to human and murine non-alcoholic fatty liver disease.

    Science.gov (United States)

    Rein-Fischboeck, Lisa; Krautbauer, Sabrina; Eisinger, Kristina; Pohl, Rebekka; Meier, Elisabeth M; Weiss, Thomas S; Buechler, Christa

    2015-11-13

    Scavenger receptor, class B type I (SR-BI) is a physiologically relevant regulator of high density lipoprotein (HDL) metabolism. Low HDL is a common feature of patients with non-alcoholic fatty liver disease (NAFLD). Here, hepatic SR-BI expression was analyzed in human and murine NAFLD. In primary human hepatocytes NAFLD relevant factors like inflammatory cytokines, lipopolysaccharide and TGF-β did not affect SR-BI protein. Similarly, oleate and palmitate had no effect. The adipokines chemerin, adiponectin, leptin and omentin did not regulate SR-BI expression. Accordingly, hepatic SR-BI was not changed in human and murine fatty liver and non-alcoholic steatohepatits. SR-BI was higher in type 2 diabetes patients but not in those with hypercholesterolemia. The current study indicates a minor if any role of SR-BI in human and murine NAFLD.

  19. Metabolism and pharmacokinetics of indacaterol in humans.

    Science.gov (United States)

    Kagan, Mark; Dain, Jeremy; Peng, Lana; Reynolds, Christine

    2012-09-01

    The metabolism, pharmacokinetics, and excretion of [(14)C]indacaterol were investigated in healthy male subjects. Although indacaterol is administered to patients via inhalation, the dose in this study was administered orally. This was done to avoid the complications and concerns associated with the administration of a radiolabeled compound via the inhalation route. The submilligram doses administered in this study made metabolite identification and structural elucidation by mass spectrometry especially challenging. In serum, the mean t(max), C(max), and AUC(0-last) values were 1.75 h, 0.47 ng/ml, and 1.81 ng · h/ml for indacaterol and 2.5 h, 1.4 ngEq/ml, and 27.2 ngEq · h/ml for total radioactivity. Unmodified indacaterol was the most abundant drug-related compound in the serum, contributing 30% to the total radioactivity in the AUC(0-24h) pools, whereas monohydroxylated indacaterol (P26.9), the glucuronide conjugate of P26.9 (P19), and the 8-O-glucuronide conjugate of indacaterol (P37) were the most abundant metabolites, with each contributing 4 to 13%. In addition, the N-glucuronide (2-amino) conjugate (P37.7) and two metabolites (P38.2 and P39) that resulted from the cleavage about the aminoethanol group linking the hydroxyquinolinone and diethylindane moieties had a combined contribution of 12.5%. For all four subjects in the study, ≥90% of the radioactivity dose was recovered in the excreta (85% in feces and 10% in urine, mean values). In feces, unmodified indacaterol and metabolite P26.9 were the most abundant drug-related compounds (54 and 17% of the dose, respectively). In urine, unmodified indacaterol accounted for ∼0.3% of the dose, with no single metabolite accounting for >1.3%.

  20. Richness of human gut microbiome correlates with metabolic markers

    DEFF Research Database (Denmark)

    Le Chatelier, Emmanuelle; Nielsen, Trine; Qin, Junjie

    2013-01-01

    We are facing a global metabolic health crisis provoked by an obesity epidemic. Here we report the human gut microbial composition in a population sample of 123 non-obese and 169 obese Danish individuals. We find two groups of individuals that differ by the number of gut microbial genes and thus...

  1. Aflatoxin B1 transfer and metabolism in human placenta.

    Science.gov (United States)

    Partanen, Heidi A; El-Nezami, Hani S; Leppänen, Jukka M; Myllynen, Päivi K; Woodhouse, Heather J; Vähäkangas, Kirsi H

    2010-01-01

    Aflatoxin B1 (AFB1), a common dietary contaminant, is a major risk factor of hepatocellular carcinoma (HCC). Early onset of HCC in some countries in Africa and South-East Asia indicates the importance of early life exposure. Placenta is the primary route for various compounds, both nutrients and toxins, from the mother to the fetal circulation. Furthermore, placenta contains enzymes for xenobiotic metabolism. AFB1, AFB1-metabolites, and AFB1-albumin adducts have been detected in cord blood of babies after maternal exposure during pregnancy. However, the role that the placenta plays in the transfer and metabolism of AFB1 is not clear. In this study, placental transfer and metabolism of AFB1 were investigated in human placental perfusions and in in vitro studies. Eight human placentas were perfused with 0.5 or 5microM AFB1 for 2-4 h. In vitro incubations with placental microsomal and cytosolic proteins from eight additional placentas were also conducted. Our results from placental perfusions provide the first direct evidence of the actual transfer of AFB1 and its metabolism to aflatoxicol (AFL) by human placenta. In vitro incubations with placental cytosolic fraction confirmed the capacity of human placenta to form AFL. AFL was the only metabolite detected in both perfusions and in vitro incubations. Since AFL is less mutagenic, but putatively as carcinogenic as AFB1, the formation of AFL may not protect the fetus from the toxicity of AFB1.

  2. Diet-microbiota interactions as moderators of human metabolism

    DEFF Research Database (Denmark)

    Sonnenburg, Justin L; Bäckhed, Gert Fredrik

    2016-01-01

    are coming to light through a powerful combination of translation-focused animal models and studies in humans. A body of knowledge is accumulating that points to the gut microbiota as a mediator of dietary impact on the host metabolic status. Efforts are focusing on the establishment of causal relationships...

  3. Subjective Response to Alcohol and Associated Craving in Heavy Drinkers vs. Alcohol Dependents: An Examination of Koob's Allostatic Model in Humans*

    OpenAIRE

    Bujarski, S; Ray, LA

    2014-01-01

    Background: Koob's allostatic model of addiction emphasizes the transition from positive reinforcement to negative reinforcement as dependence develops. This study seeks to extend this well-established neurobiological model to humans by examining subjective response to alcohol (SR) as a biobehavioral marker of alcohol reinforcement. Specifically, this study examines (a) differential SR in heavy drinkers (HDs) vs. alcohol dependent individuals (ADs) and (b) whether HDs and ADs differ in terms ...

  4. Alcohol and drug use in the workplace : managing the human factor

    Energy Technology Data Exchange (ETDEWEB)

    McKibbon, D. [Kelly Luttmer and Associates Ltd., Edmonton, AB (Canada)

    1999-07-01

    The importance of implementing comprehensive drug and alcohol policies in the workplace was discussed with particular emphasis on the procedures which are needed to ensure that employers meet due diligence requirements regarding alcoholism and drug abuse. A study of workplace substance abuse issues in Alberta revealed that 80 per cent of the Alberta workforce uses alcohol, 27 per cent use cold medication, and 6.5 per cent use illicit drugs. The impact of drug and alcohol use in the workplace was also reviewed. Under the Canadian human rights legislation an employer cannot terminate an employee for having a medical illness including alcoholism or drug addiction. The issue of drug testing and when to drug screen was also discussed. It was suggested that addressing substance abuse in the workplace through policy procedures and practices can reduce costs related to lost productivity, absenteeism, workers` compensation claims, staff turnover, health benefit premiums and legal liabilities. 3 refs.

  5. Human health risk assessment of long chain alcohols (LCOH)

    DEFF Research Database (Denmark)

    Veenstra, Gauke; Sanderson, Hans; Webb, Catherine;

    2009-01-01

    Representative chemicals from the long chain alcohols category have been extensively tested to define their toxicological hazard properties. These chemicals show low acute and repeat dose toxicity with high-dose effects (if any) related to minimal liver toxicity. These chemicals do not show...... evidence of activity in genetic toxicity tests or to the reproductive system or the developing organism. These chemicals also are not sensitizers. Irritation is dependant on chain length; generally, alcohols in the range C6-C11 are considered as irritant, intermediate chain lengths (C12-C16) alcohols...... are considered to be mild irritants and chain lengths of C18 and above are considered non-irritants. These chemicals are broadly used across the consumer products industry with highest per person consumer exposures resulting from use in personal care products. Margins of exposure adequate for the protection...

  6. Aerobic and anaerobic metabolism in oxygen minimum layer fishes: the role of alcohol dehydrogenase.

    Science.gov (United States)

    Torres, Joseph J; Grigsby, Michelle D; Clarke, M Elizabeth

    2012-06-01

    Zones of minimum oxygen form at intermediate depth in all the world's oceans as a result of global circulation patterns that keep the water at oceanic mid-depths out of contact with the atmosphere for hundreds of years. In areas where primary production is very high, the microbial oxidation of sinking organic matter results in very low oxygen concentrations at mid-depths. Such is the case with the Arabian Sea, with O(2) concentrations reaching zero at 200 m and remaining very low (fishes (primarily lanternfishes: Mytophidae) inhabiting the Arabian Sea and California borderland perform a daily vertical migration into the low-oxygen layer, spending daylight hours in the oxygen minimum zone and migrating upward into normoxic waters at night. To find out how fishes were able to survive their daily sojourns into the minimum zone, we tested the activity of four enzymes, one (lactate dehydrogenase, LDH) that served as a proxy for anaerobic glycolysis with a conventional lactate endpoint, a second (citrate synthase, CS) that is indicative of aerobic metabolism, a third (malate dehydrogenase) that functions in the Krebs' cycle and as a bridge linking mitochondrion and cytosol, and a fourth (alcohol dehydrogenase, ADH) that catalyzes the final reaction in a pathway where pyruvate is reduced to ethanol. Ethanol is a metabolic product easily excreted by fish, preventing lactate accumulation. The ADH pathway is rarely very active in vertebrate muscle; activity has previously been seen only in goldfish and other cyprinids capable of prolonged anaerobiosis. Activity of the enzyme suite in Arabian Sea and California fishes was compared with that of ecological analogs in the same family and with the same lifestyle but living in systems with much higher oxygen concentrations: the Gulf of Mexico and the Southern Ocean. ADH activities in the Arabian Sea fishes were similar to those of goldfish, far higher than those of confamilials from the less severe minimum in the Gulf of Mexico

  7. Inhibition of fatty acid metabolism reduces human myeloma cells proliferation.

    Directory of Open Access Journals (Sweden)

    José Manuel Tirado-Vélez

    Full Text Available Multiple myeloma is a haematological malignancy characterized by the clonal proliferation of plasma cells. It has been proposed that targeting cancer cell metabolism would provide a new selective anticancer therapeutic strategy. In this work, we tested the hypothesis that inhibition of β-oxidation and de novo fatty acid synthesis would reduce cell proliferation in human myeloma cells. We evaluated the effect of etomoxir and orlistat on fatty acid metabolism, glucose metabolism, cell cycle distribution, proliferation, cell death and expression of G1/S phase regulatory proteins in myeloma cells. Etomoxir and orlistat inhibited β-oxidation and de novo fatty acid synthesis respectively in myeloma cells, without altering significantly glucose metabolism. These effects were associated with reduced cell viability and cell cycle arrest in G0/G1. Specifically, etomoxir and orlistat reduced by 40-70% myeloma cells proliferation. The combination of etomoxir and orlistat resulted in an additive inhibitory effect on cell proliferation. Orlistat induced apoptosis and sensitized RPMI-8226 cells to apoptosis induction by bortezomib, whereas apoptosis was not altered by etomoxir. Finally, the inhibitory effect of both drugs on cell proliferation was associated with reduced p21 protein levels and phosphorylation levels of retinoblastoma protein. In conclusion, inhibition of fatty acid metabolism represents a potential therapeutic approach to treat human multiple myeloma.

  8. Application of chimeric mice with humanized liver for study of human-specific drug metabolism.

    Science.gov (United States)

    Bateman, Thomas J; Reddy, Vijay G B; Kakuni, Masakazu; Morikawa, Yoshio; Kumar, Sanjeev

    2014-06-01

    Human-specific or disproportionately abundant human metabolites of drug candidates that are not adequately formed and qualified in preclinical safety assessment species pose an important drug development challenge. Furthermore, the overall metabolic profile of drug candidates in humans is an important determinant of their drug-drug interaction susceptibility. These risks can be effectively assessed and/or mitigated if human metabolic profile of the drug candidate could reliably be determined in early development. However, currently available in vitro human models (e.g., liver microsomes, hepatocytes) are often inadequate in this regard. Furthermore, the conduct of definitive radiolabeled human ADME studies is an expensive and time-consuming endeavor that is more suited for later in development when the risk of failure has been reduced. We evaluated a recently developed chimeric mouse model with humanized liver on uPA/SCID background for its ability to predict human disposition of four model drugs (lamotrigine, diclofenac, MRK-A, and propafenone) that are known to exhibit human-specific metabolism. The results from these studies demonstrate that chimeric mice were able to reproduce the human-specific metabolite profile for lamotrigine, diclofenac, and MRK-A. In the case of propafenone, however, the human-specific metabolism was not detected as a predominant pathway, and the metabolite profiles in native and humanized mice were similar; this was attributed to the presence of residual highly active propafenone-metabolizing mouse enzymes in chimeric mice. Overall, the data indicate that the chimeric mice with humanized liver have the potential to be a useful tool for the prediction of human-specific metabolism of xenobiotics and warrant further investigation.

  9. Alcohol, Athletic Performance and Recovery

    Directory of Open Access Journals (Sweden)

    David Cameron-Smith

    2010-07-01

    Full Text Available Alcohol consumption within elite sport has been continually reported both anecdotally within the media and quantitatively in the literature. The detrimental effects of alcohol on human physiology have been well documented, adversely influencing neural function, metabolism, cardiovascular physiology, thermoregulation and skeletal muscle myopathy. Remarkably, the downstream effects of alcohol consumption on exercise performance and recovery, has received less attention and as such is not well understood. The focus of this review is to identify the acute effects of alcohol on exercise performance and give a brief insight into explanatory factors.

  10. Review article: coffee consumption, the metabolic syndrome and non-alcoholic fatty liver disease.

    Science.gov (United States)

    Yesil, A; Yilmaz, Y

    2013-11-01

    Coffee consumption may modulate the risk of the metabolic syndrome (MetS) and non-alcoholic fatty liver disease (NAFLD). To review the experimental, epidemiological and clinical studies investigating the association between coffee consumption and the risk of MetS and NAFLD. A literature search was conducted with the aim of finding original experimental, epidemiological and clinical articles on the association between coffee consumption, MetS and NAFLD. The following databases were used: PubMed, Embase, Scopus and Science Direct. We included articles written in English and published up to July 2013. Three experimental animal studies investigated the effects of coffee in the MetS, whereas five examined whether experimental coffee intake may modulate the risk of fatty liver infiltration. All of the animal studies showed a protective effect of coffee towards the development of MetS and NAFLD. Moreover, we identified eleven epidemiological and clinical studies that met the inclusion criteria. Of them, six were carried out on the risk of the MetS and five on the risk of NAFLD. Four of the six studies reported an inverse association between coffee consumption and the risk of MetS. The two studies showing negative results were from the same study cohort consisting of young persons with a low prevalence of the MetS. All of the epidemiological and clinical studies on NAFLD reported a protective effect of coffee intake. Coffee intake can reduce the risk of NAFLD. Whether this effect may be mediated by certain components of the MetS deserves further investigation. © 2013 John Wiley & Sons Ltd.

  11. Human leucocyte antigens in patients with alcoholic liver cirrhosis

    DEFF Research Database (Denmark)

    Gluud, C; Aldershvile, J; Dietrichson, O;

    1980-01-01

    No significant differences in the frequencies of HLA-B8, -B40, and other HLA-A, -B, and -C phenotypes were found among patients with histologically verified alcoholic cirrhosis compared with normal controls when the p values were multiplied by the number of comparisons. This was found both...... in the present study of 45 patients and in the combined data of this and three other similar studies. However, these findings do not rule out that alcoholic cirrhosis might be associated with HLA factors (for example. HLA-D/DR antigens) controlling immune responses....

  12. Relevance of the Human Genome Project to inherited metabolic disease.

    Science.gov (United States)

    Burn, J

    1994-01-01

    The Human Genome Project is an international effort to identify the complete structure of the human genome. HUGO, the Human Genome Organization, facilitates international cooperation and exchange of information while the Genome Data Base will act as the on-line information retrieval and storage system for the huge amount of information being accumulated. The clinical register MIM (Mendelian Inheritance in Man) established by Victor McKusick is now an on-line resource that will allow biochemists working with inborn errors of metabolism to access the rapidly expanding body of knowledge. Biochemical and molecular genetics are complementary and should draw together to find solutions to the academic and clinical problems posed by inborn errors of metabolism.

  13. In Vitro Drug Metabolism by Human Carboxylesterase 1

    DEFF Research Database (Denmark)

    Thomsen, Ragnar; Rasmussen, Henrik B; Linnet, Kristian

    2014-01-01

    Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed...... a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine...... calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug...

  14. Effect of specific amino acids on hepatic lipid metabolism in fructose-induced non-alcoholic fatty liver disease.

    Science.gov (United States)

    Jegatheesan, Prasanthi; Beutheu, Stéphanie; Ventura, Gabrielle; Sarfati, Gilles; Nubret, Esther; Kapel, Nathalie; Waligora-Dupriet, Anne-Judith; Bergheim, Ina; Cynober, Luc; De-Bandt, Jean-Pascal

    2016-02-01

    Fructose diets have been shown to induce insulin resistance and to alter liver metabolism and gut barrier function, ultimately leading to non-alcoholic fatty liver disease. Citrulline, Glutamine and Arginine may improve insulin sensitivity and have beneficial effects on gut trophicity. Our aim was to evaluate their effects on liver and gut functions in a rat model of fructose-induced non-alcoholic fatty liver disease. Male Sprague-Dawley rats (n = 58) received a 4-week fructose (60%) diet or standard chow with or without Citrulline (0.15 g/d) or an isomolar amount of Arginine or Glutamine. All diets were made isonitrogenous by addition of non-essential amino acids. At week 4, nutritional and metabolic status (plasma glucose, insulin, cholesterol, triglycerides and amino acids, net intestinal absorption) was determined; steatosis (hepatic triglycerides content, histological examination) and hepatic function (plasma aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin) were assessed; and gut barrier integrity (myeloperoxidase activity, portal endotoxemia, tight junction protein expression and localization) and intestinal and hepatic inflammation were evaluated. We also assessed diets effects on caecal microbiota. In these experimental isonitrogenous fructose diet conditions, fructose led to steatosis with dyslipidemia but without altering glucose homeostasis, liver function or gut permeability. Fructose significantly decreased Bifidobacterium and Lactobacillus and tended to increase endotoxemia. Arginine and Glutamine supplements were ineffective but Citrulline supplementation prevented hypertriglyceridemia and attenuated liver fat accumulation. While nitrogen supply alone can attenuate fructose-induced non-alcoholic fatty liver disease, Citrulline appears to act directly on hepatic lipid metabolism by partially preventing hypertriglyceridemia and steatosis. Copyright © 2015 Elsevier Ltd and European Society for Clinical Nutrition

  15. Effects of brain evolution on human nutrition and metabolism.

    Science.gov (United States)

    Leonard, William R; Snodgrass, J Josh; Robertson, Marcia L

    2007-01-01

    The evolution of large human brain size has had important implications for the nutritional biology of our species. Large brains are energetically expensive, and humans expend a larger proportion of their energy budget on brain metabolism than other primates. The high costs of large human brains are supported, in part, by our energy- and nutrient-rich diets. Among primates, relative brain size is positively correlated with dietary quality, and humans fall at the positive end of this relationship. Consistent with an adaptation to a high-quality diet, humans have relatively small gastrointestinal tracts. In addition, humans are relatively "undermuscled" and "over fat" compared with other primates, features that help to offset the high energy demands of our brains. Paleontological evidence indicates that rapid brain evolution occurred with the emergence of Homo erectus 1.8 million years ago and was associated with important changes in diet, body size, and foraging behavior.

  16. Alleviation of alcoholic liver injury by betaine involves an enhancement of antioxidant defense via regulation of sulfur amino acid metabolism.

    Science.gov (United States)

    Jung, Young Suk; Kim, Sun Ju; Kwon, Do Young; Ahn, Chul Won; Kim, Young Soon; Choi, Dal Woong; Kim, Young Chul

    2013-12-01

    Previous studies suggested that the hepatoprotective activity of betaine is associated with its effects on sulfur amino acid metabolism. We examined the mechanism by which betaine prevents the progression of alcoholic liver injury and its therapeutic potential. Rats received a liquid ethanol diet for 6 wk. Ethanol consumption elevated serum triglyceride and TNFα levels, alanine aminotransferase and aspartate aminotransferase activities, and lipid accumulation in liver. The oxyradical scavenging capacity of liver was reduced, and expression of CD14, TNFα, COX-2, and iNOS mRNAs was induced markedly. These ethanol-induced changes were all inhibited effectively by betaine supplementation. Hepatic S-adenosylmethionine, cysteine, and glutathione levels, reduced in the ethanol-fed rats, were increased by betaine supplementation. Methionine adenosyltransferase and cystathionine γ-lyase were induced, but cysteine dioxygenase was down-regulated, which appeared to account for the increment in cysteine availability for glutathione synthesis in the rats supplemented with betaine. Betaine supplementation for the final 2 wk of ethanol intake resulted in a similar degree of hepatoprotection, revealing its potential therapeutic value in alcoholic liver. It is concluded that the protective effects of betaine against alcoholic liver injury may be attributed to the fortification of antioxidant defense via improvement of impaired sulfur amino acid metabolism.

  17. Alcohol liver disease and metabolic syndrome%酒精性肝病与代谢综合征

    Institute of Scientific and Technical Information of China (English)

    张鸿; 袁乐媛; 王炳元

    2013-01-01

    长期持续大量饮酒不仅直接导致终末期肝硬化或肝癌的发生,还可以影响肝脏的代谢而出现代谢综合征(MS).众多研究表明,酗酒可增加MS的危险性,后者可发展为肝性糖尿病、高血压和冠心病,并增加这些疾病的死亡率.研究表明,相对于没有或者偶尔饮酒,适度饮酒的人群高血压和2型糖尿病的患病率较低.事实并非如此,饮酒与MS各组分之间存在着保护、有害或J型的复杂机制.因此,本文回顾了饮酒与MS组分的关系,并讨论了酒精合理的潜在的生物学机制,以期引起临床和研究的注意.%Long-term excessive alcohol consumption can not only cause end-stage liver cirrhosis and liver carcinoma directly,but also affect the metabolism of the liver,leading to metabolic syndrome.Growing evidence indicates that,compared with moderate drinkers,the heavy drinkers have a higher risk of metabolic syndrome,which is closely associated with hepatic diabetes,hypertension and cardiovascular diseases.Studies have shown that,moderate alcohol consumption has a lower incidence of hypertension and type Ⅱ diabetes than none or occasional drinking.In fact,the relationship between alcohol consumption and components of metabolic syndrome is more complex than we used to know,such as protective,detrimental and J-shaped association.This article makes an overview about the relationship between alcohol consumption and metabolic syndrome,and discusses the plausible underlying biological mechanisms in the hope of getting more attention from clinicians and investigators.

  18. The human urinary exosome as a potential metabolic effector cargo.

    Science.gov (United States)

    Bruschi, Maurizio; Ravera, Silvia; Santucci, Laura; Candiano, Giovanni; Bartolucci, Martina; Calzia, Daniela; Lavarello, Chiara; Inglese, Elvira; Petretto, Andrea; Ghiggeri, Gianmarco; Panfoli, Isabella

    2015-08-01

    Exosomes are nanovesicles, derived from the endocytic pathway, released by most cell types and found in many body fluids, including urine. A variety of exosomal functions have been reported, including transfer of RNA, cell communication, control of apoptosis and protein lifespan. Exosomes from mesenchymal stem cells can rescue bioenergetics of injured cells. Here the urinary exosome proteome, non-urinary exosome proteome and urinome are compared. A consistent number of identified proteins cluster to metabolic functions. Cytoscape software analysis based on biological processes gene ontology database shows that metabolic pathways such as aerobic glycolysis and oxidative phosphorylation have a high probability (p ≤ 0.05) of being expressed and therefore functional. A metabolic function appears to be associated with human urinary exosomes, whose relevance experimental studies can assess.

  19. Diagnosis and management of non-alcoholic fatty liver disease and related metabolic disorders: consensus statement from the Study Group of Liver and Metabolism, Chinese Society of Endocrinology.

    Science.gov (United States)

    Gao, Xin; Fan, Jian-Gao

    2013-12-01

    Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries, affecting 20%-33% of the general population. Large population-based surveys in China indicate a prevalence of approximately 15%-30%. Worldwide, including in China, the prevalence of NAFLD has increased rapidly in parallel with regional trends of obesity, type 2 diabetes and metabolic syndrome. In addition, NAFLD has contributed significantly to increased overall, as well as cardiovascular and liver-related, mortality in the general population. In view of rapid advances in research into NAFLD in recent years, this consensus statement provides a brief update on the progress in the field and suggests preferred approaches for the comprehensive management of NAFLD and its related metabolic diseases.

  20. Metabolic interaction between toluene, trichloroethylene and n-hexane in humans

    DEFF Research Database (Denmark)

    Bælum, Jesper; Mølhave, Lars; Hansen, S H

    1998-01-01

    This human experimental study describes the mutual metabolic interaction between toluene, trichloroethylene, and n-hexane.......This human experimental study describes the mutual metabolic interaction between toluene, trichloroethylene, and n-hexane....

  1. SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans.

    Science.gov (United States)

    Mathies, Laura D; Blackwell, GinaMari G; Austin, Makeda K; Edwards, Alexis C; Riley, Brien P; Davies, Andrew G; Bettinger, Jill C

    2015-03-10

    Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.

  2. Regulation of Metabolic Signaling in Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Albers, Peter Hjorth

    sensitivity in type I muscle fibers possibly reflects a superior effect of insulin on metabolic signaling compared to type II muscle fibers. This was investigated in the present thesis by examining muscle biopsies from lean and obese healthy subjects as well as patients with type 2 diabetes. From these muscle...... enzymes. Skeletal muscle consists of thousands of muscle fibers. These fibers can roughly be classified into type I and type II muscle fibers. The overall aim of this PhD thesis was to investigate the effect of insulin and exercise on human muscle fiber type specific metabolic signaling. The importance...... of human type I muscle fibers is illustrated by the finding of a positive correlation between the relative distribution of type I fibers in the muscle and whole-body insulin sensitivity. This suggests, that type I muscle fibers are more insulin sensitive than type II muscle fibers. Improved insulin...

  3. APP metabolism regulates tau proteostasis in human cerebral cortex neurons

    OpenAIRE

    Steven Moore; Evans, Lewis D.B.; Therese Andersson; Erik Portelius; James Smith; Tatyana B. Dias; Nathalie Saurat; Amelia McGlade; Peter Kirwan; Kaj Blennow; John Hardy; Henrik Zetterberg; Frederick J. Livesey

    2015-01-01

    This is the final version. It was first published by Elsevier at http://www.sciencedirect.com/science/article/pii/S2211124715003599. Accumulation of Aβ peptide fragments of the APP protein and neurofibrillary tangles of the microtubule-associated protein tau are the cellular hallmarks of Alzheimer’s disease (AD). To investigate the relationship between APP metabolism and tau protein levels and phosphorylation, we studied human-stem-cell-derived forebrain neurons with genetic forms of AD, a...

  4. Metabolic thrift and the genetic basis of human obesity

    OpenAIRE

    O’Rourke, Robert W.

    2014-01-01

    Evolution has molded metabolic thrift within humans, a genetic heritage that, when thrust into our modern “obesogenic” environment, creates the current obesity crisis. Modern genetic analysis has identified genetic and epigenetic contributors to obesity, an understanding of which will guide the development of environmental, pharmacologic, and genetic therapeutic interventions. “The voyage was so long, food and water ran out. One hundred of the paddlers died; forty men remained. The voyager...

  5. [Metabolism of mitomycin C by human liver microsomes in vitro].

    Science.gov (United States)

    Hao, Fu-rong; Yan, Min-fen; Hu, Zhuo-han; Jin, Yi-zun

    2007-02-01

    To provide the profiles of metabolism of mitomycin C (MMC) by human liver microsomes in vitro, MMC was incubated with human liver microsomes, then the supernatant component was isolated and detected by HPLC. Types of metabolic enzymes were estimated by the effect of NADPH or dicumarol (DIC) on metabolism of MMC. Standard, reaction, background control (microsomes was inactivated), negative control (no NADPH), and inhibitor group (adding DIC) were assigned, the results were analyzed by Graphpad Prism 4. 0 software. Reaction group compared with background control and negative control groups, 3 NADPH-dependent absorption peaks were additionally isolated by HPLC after MMC were incubated with human liver microsomes. Their retention times were 10. 0, 14. 0, 14. 8 min ( named as Ml, M2, M3) , respectively. Their formation was kept as Sigmoidal dose-response and their Km were 0. 52 (95% CI, 0. 40 - 0.67) mmol x L(-1), 0. 81 (95% CI, 0. 59 - 1. 10) mmol x L(-1), 0. 54 (95% CI, 0. 41 -0. 71) mmol x L(-1) , respectively. The data indicated that the three absorption peaks isolated by HPLC were metabolites of MMC. DIC can inhibit formation of M2, it' s dose-effect fitted to Sigmoidal curve and it' s IC50 was 59. 68 (95% CI, 40. 66 - 87. 61) micromol x L(-1) , which indicated DT-diaphorase could take part in the formation of M2. MMC can be metabolized by human liver microsomes in vitro, and at least three metabolites of MMC could be isolated by HPLC in the experiment, further study showed DT-diaphorase participated in the formation of M2.

  6. Oxidation of methanol, ethylene glycol, and isopropanol with human alcohol dehydrogenases and the inhibition by ethanol and 4-methylpyrazole.

    Science.gov (United States)

    Lee, Shou-Lun; Shih, Hsuan-Ting; Chi, Yu-Chou; Li, Yeung-Pin; Yin, Shih-Jiun

    2011-05-30

    Human alcohol dehydrogenases (ADHs) include multiple isozymes with broad substrate specificity and ethnic distinct allozymes. ADH catalyzes the rate-limiting step in metabolism of various primary and secondary aliphatic alcohols. The oxidation of common toxic alcohols, that is, methanol, ethylene glycol, and isopropanol by the human ADHs remains poorly understood. Kinetic studies were performed in 0.1M sodium phosphate buffer, at pH 7.5 and 25°C, containing 0.5 mM NAD(+) and varied concentrations of substrate. K(M) values for ethanol with recombinant human class I ADH1A, ADH1B1, ADH1B2, ADH1B3, ADH1C1, and ADH1C2, and class II ADH2 and class IV ADH4 were determined to be in the range of 0.12-57 mM, for methanol to be 2.0-3500 mM, for ethylene glycol to be 4.3-2600mM, and for isopropanol to be 0.73-3400 mM. ADH1B3 appeared to be inactive toward ethylene glycol, and ADH2 and ADH4, inactive with methanol. The variations for V(max) for the toxic alcohols were much less than that of the K(M) across the ADH family. 4-Methylpyrazole (4MP) was a competitive inhibitor with respect to ethanol for ADH1A, ADH1B1, ADH1B2, ADH1C1 and ADH1C2, and a noncompetitive inhibitor for ADH1B3, ADH2 and ADH4, with the slope inhibition constants (K(is)) for the whole family being 0.062-960 μM and the intercept inhibition constants (K(ii)), 33-3000 μM. Computer simulation studies using inhibition equations in the presence of alternate substrate ethanol and of dead-end inhibitor 4MP with the determined corresponding kinetic parameters for ADH family, indicate that the oxidation of the toxic alcohols up to 50mM are largely inhibited by 20 mM ethanol or by 50 μM 4MP with some exceptions. The above findings provide an enzymological basis for clinical treatment of methanol and ethylene glycol poisoning by 4MP or ethanol with pharmacogenetic perspectives. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  7. Aspartate aminotransferase – key enzyme in the human systemic metabolism

    Directory of Open Access Journals (Sweden)

    Dagmara Otto-Ślusarczyk

    2016-03-01

    Full Text Available Aspartate aminotransferase is an organ - nonspecific enzyme located in many tissues of the human body where it catalyzes reversible reaction of transamination. There are two aspartate aminotransferase isoforms - cytoplasmic (AST1 and mitochondrial (AST2, that usually occur together and interact with each other metabolically. Both isoforms are homodimers containing highly conservative regions responsible for catalytic properties of enzyme. The common feature of all aspartate aminotransfeses is Lys – 259 residue covalent binding with prosthetic group - pyridoxal phosphate. The differences in the primary structure of AST isoforms determine their physico-chemical, kinetic and immunological properties. Because of the low concentration of L-aspartate (L-Asp in the blood, AST is the only enzyme, which supply of this amino acid as a substrate for many metabolic processes, such as urea cycle or purine and pyrimidine nucleotides in the liver, synthesis of L-arginine in the kidney and purine nucleotide cycle in the brain and the skeletal muscle. AST is also involved in D-aspartate production that regulates the metabolic activity at the auto-, para- and endocrine level. Aspartate aminotransferase is a part of the malate-aspartate shuttle in the myocardium, is involved in gluconeogenesis in the liver and kidney, glyceroneogenesis in the adipose tissue, and synthesis of neurotransmitters and neuro-glial pathway in the brain. Recently, the significant role of AST in glutaminolysis - normal metabolic pathway in tumor cells, was demonstrated. The article is devoted the role of AST, known primarily as a diagnostic liver enzyme, in metabolism of various human tissues and organs.

  8. Mutational analysis of primary alcohol metabolism in the methylotrophic actinomycete Amycolatopsis methanolica

    NARCIS (Netherlands)

    Hektor, Harm J.; Dijkhuizen, Lubbert

    1996-01-01

    Mutants of the methylotrophic actinomycete Amycolatopsis methanolica unable to grow on methanol as carbon source were isolated and characterized. Mutants specifically affected in methanol utilization were deficient in formaldehyde assimilation. Mutants blocked in the first step of primary alcohol ox

  9. The impact of metabolic disease associated with metabolic syndrome on human pregnancy.

    Science.gov (United States)

    Malek, Antoine

    2014-01-01

    Metabolic diseases induced by metabolic syndrome (MS) have been increased during the past two decades. During healthy pregnancy maternal organs and placenta are challenged to adapt to the increasingly physiological changes. In addition to the increasingly proatherogenic MS, pregnant woman develops a high cardiac output, hypercoagulability, increased inflammatory activity and insulin resistance with dyslipidemia. The MS describes a cluster of metabolic changes associated with an impact on the physiology of many organs. While the metabolic syndrome is directly responsible for the development of atherosclerotic cardiovascular disease, additional impact on human pregnancy like preterm delivery with low-birth-weight infants as well as the development of diseases such as diabetes, preeclampsia and hypertension. Recent evidence suggests that MS is originated in fetal life in association with maternal nutrition during pregnancy and fetal programming which apparently increases the susceptibility for MS in children and later life. This review will describe the MS in association with the origin of the emerging diseases during pregnancy such as diabetes, preeclampsia and others. The influence of perinatal environment and maternal diet and smoking on MS as well as the genetic biomarkers of MS will be described.

  10. Identification of individuals with non-alcoholic fatty liver disease by the diagnostic criteria for the metabolic syndrome

    Institute of Scientific and Technical Information of China (English)

    Masahide Hamaguchi; Noriyuki Takeda; Takao Kojima; Akihiro Ohbora; Takahiro Kato; Hiroshi Sarui; Michiaki Fukui

    2012-01-01

    AIM:To clarify the efficiency of the criterion of metabolic syndrome to detecting non-alcoholic fatty liver disease (NAFLD).METHODS:Authors performed a cross-sectional study involving participants of a medical health checkup program including abdominal ultrasonography.This study involved 11 714 apparently healthy Japanese men and women,18 to 83 years of age.NAFLD was defined by abdominal ultrasonography without an alcohol intake of more than 20 g/d,known liver disease,or current use of medication.The revised criteria of the National Cholesterol Education Program Adult Treatment Panel Ⅲ were used to characterize the metabolic syndrome.RESULTS:NAFLD was detected in 32.2% (95% CI:31.0%-33.5%) of men (n =1874 of 5811) and in 8.7%(95% CI:8.0%-9.5%) of women (n =514 of 5903).Among obese people,the prevalence of NAFLD was as high as 67.3% (95% CI:64.8%-69.7%) in men and 45.8% (95% CI:41.7%-50.0%) in women.Although NAFLD was thought of as being the liver phenotype of metabolic syndrome,the prevalence of the metabolic syndrome among subjects with NAFLD was low both in men and women.66.8% of men and 70.4% of women with NAFLD were not diagnosed with the metabolic syndrome.48.2% of men with NAFLD and 49.8% of women with NAFLD weren't overweight [body mass index (BMI) ≥ 25 kg/m2].In the same way,68.6% of men with NAFLD and 37.9% of women with NAFLD weren't satisfied with abdominal classification (≥ 90cm for men and ≥ 80 cm for women).Next,authors defined it as positive at screening for NAFLD when participants satisfied at least one criterion of metabolic syndrome.The sensitivity of the definition "at least 1 criterion" was as good as 84.8% in men and 86.6% in women.Separating subjects by BMI,the sensitivity was higher in obese men and women than in non-obese men and women (92.3% vs 76.8% in men,96.1% vs 77.0% in women,respectively).CONCLUSION:Authors could determine NAFLD effectively in epidemiological study by

  11. Human and laboratory rodent low response to alcohol: is better consilience possible?

    Science.gov (United States)

    Crabbe, John C; Bell, Richard L; Ehlers, Cindy L

    2010-04-01

    If people are brought into the laboratory and given alcohol, there are pronounced differences among individuals in many responses to the drug. Some participants in alcohol challenge protocols show a cluster of 'low level of responses to alcohol' determined by observing post-drinking-related changes in subjective, motor and physiological effects at a given dose level. Those individuals characterized as having low level of response (LR) to alcohol have been shown to be at increased risk for a lifetime diagnosis of alcohol dependence (AD), and this relationship between low LR and AD appears to be in part genetic. LR to alcohol is an area where achieving greater consilience between the human and the rodent phenotypes would seem to be highly likely. However, despite extensive data from both human and rodent studies, few attempts have been made to evaluate the human and animal data systematically in order to understand which aspects of LR appear to be most directly comparable across species and thus the most promising for further study. We review four general aspects of LR that could be compared between humans and laboratory animals: (1) behavioral measures of subjective intoxication; (2) body sway; (3) endocrine responses; and (4) stimulant, autonomic and electrophysiological responses. None of these aspects of LR provide completely face-valid direct comparisons across species. Nevertheless, one of the most replicated findings in humans is the low subjective response, but, as it may reflect either aversively valenced and/or positively valenced responses to alcohol as usually assessed, it is unclear which rodent responses are analogous. Stimulated heart rate appears to be consistent in animal and human studies, although at-risk subjects appear to be more rather than less sensitive to alcohol using this measure. The hormone and electrophysiological data offer strong possibilities of understanding the neurobiological mechanisms, but the rodent data in particular are rather

  12. Pyruvate decarboxylase and alcohol dehydrogenase overexpression in Escherichia coli resulted in high ethanol production and rewired metabolic enzyme networks.

    Science.gov (United States)

    Yang, Mingfeng; Li, Xuefeng; Bu, Chunya; Wang, Hui; Shi, Guanglu; Yang, Xiushan; Hu, Yong; Wang, Xiaoqin

    2014-11-01

    Pyruvate decarboxylase and alcohol dehydrogenase are efficient enzymes for ethanol production in Zymomonas mobilis. These two enzymes were over-expressed in Escherichia coli, a promising candidate for industrial ethanol production, resulting in high ethanol production in the engineered E. coli. To investigate the intracellular changes to the enzyme overexpression for homoethanol production, 2-DE and LC-MS/MS were performed. More than 1,000 protein spots were reproducibly detected in the gel by image analysis. Compared to the wild-type, 99 protein spots showed significant changes in abundance in the recombinant E. coli, in which 46 were down-regulated and 53 were up-regulated. Most proteins related to tricarboxylic acid cycle, glycerol metabolism and other energy metabolism were up-regulated, whereas proteins involved in glycolysis and glyoxylate pathway were down-regulated, indicating the rewired metabolism in the engineered E. coli. As glycolysis is the main pathway for ethanol production, and it was inhibited significantly in engineered E. coli, further efforts should be directed at minimizing the repression of glycolysis to optimize metabolism network for higher yields of ethanol production.

  13. Effect of rosuvastatin on non-alcoholic steatohepatitis in patients with metabolic syndrome and hypercholesterolaemia: a preliminary report.

    Science.gov (United States)

    Kargiotis, Konstantinos; Katsiki, Niki; Athyros, Vasilios G; Giouleme, Olga; Patsiaoura, Kalliopi; Katsiki, Evangelia; Mikhailidis, Dimitri P; Karagiannis, Asterios

    2014-05-01

    There is no widely accepted treatment for non-alcoholic fatty liver disease (NAFLD) or its advanced form, non-alcoholic steatohepatitis (NASH). We administered rosuvastatin (10 mg/day) for 1 year in patients with metabolic syndrome (MetS), NASH on liver biopsy and dyslipidaemia (but without diabetes or arterial hypertension). Patients also received lifestyle advice. We report preliminary results for 6 patients. The second biopsy (at the end of the study) showed complete resolution of NASH in 5 patients, while the 6(th), which had no improvement, developed arterial hypertension and substantial rise in triglyceride levels during the study. We suspect alcohol abuse despite advice to abstain. Serum alanine transaminase (ALT) and aspartate transaminase (AST) activities were reduced by 76 and 61%, respectively (p < 0.001 for both), during treatment, while γ-glutamyl transpeptidase (γ-GT), and alkaline phosphatase (AP) showed smaller non significant reductions. Fasting plasma glucose and glycated haemoglobin (HbA1c) were significantly reduced (p<0.05). Lipid values were totally normalised and liver ultrasonography showed a complete resolution of NASH in 5 patients. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should be attributed to treatment with rosuvastatin. A substantial limitation of the study is the small number of patients. These preliminary findings suggest that rosuvastatin could ameliorate NASH within a year of treatment in MetS patients with dyslipidaemia.

  14. Metabolism

    Science.gov (United States)

    ... Surgery? Choosing the Right Sport for You Shyness Metabolism KidsHealth > For Teens > Metabolism Print A A A ... food through a process called metabolism. What Is Metabolism? Metabolism (pronounced: meh-TAB-uh-lih-zem) is ...

  15. Human Metabolic Enzymes Deficiency: A Genetic Mutation Based Approach

    Science.gov (United States)

    Chaturvedi, Swati; Singh, Ashok K.; Maity, Siddhartha; Sarkar, Srimanta

    2016-01-01

    One of the extreme challenges in biology is to ameliorate the understanding of the mechanisms which emphasize metabolic enzyme deficiency (MED) and how these pretend to have influence on human health. However, it has been manifested that MED could be either inherited as inborn error of metabolism (IEM) or acquired, which carries a high risk of interrupted biochemical reactions. Enzyme deficiency results in accumulation of toxic compounds that may disrupt normal organ functions and cause failure in producing crucial biological compounds and other intermediates. The MED related disorders cover widespread clinical presentations and can involve almost any organ system. To sum up the causal factors of almost all the MED-associated disorders, we decided to embark on a less traveled but nonetheless relevant direction, by focusing our attention on associated gene family products, regulation of their expression, genetic mutation, and mutation types. In addition, the review also outlines the clinical presentations as well as diagnostic and therapeutic approaches. PMID:27051561

  16. Using skin to assess iron accumulation in human metabolic disorders

    Energy Technology Data Exchange (ETDEWEB)

    Guinote, I. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal); Fleming, R. [Imunohaemotherapy Department, Hospital de St. Maria, Lisbon (Portugal); Silva, R. [Dermatology Department, Hospital de St. Maria, Lisbon (Portugal); Filipe, P. [Dermatology Department, Hospital de St. Maria, Lisbon (Portugal); Silva, J.N. [Dermatology Department, Hospital de St. Maria, Lisbon (Portugal); Verissimo, A. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal); Napoleao, P. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal); Centro de Fisica Nuclear, Universidade de Lisbon (Portugal); Alves, L.C. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal); Centro de Fisica Nuclear, Universidade de Lisbon (Portugal); Pinheiro, T. [Laboratorio de Feixes de Ioes, Instituto Tecnologico e Nuclear, E.N. 10, 2685-953 Sacavem (Portugal) and Centro de Fisica Nuclear, Universidade de Lisbon (Portugal)]. E-mail: murmur@itn.pt

    2006-08-15

    The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p < 0.004), serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

  17. Using skin to assess iron accumulation in human metabolic disorders

    Science.gov (United States)

    Guinote, I.; Fleming, R.; Silva, R.; Filipe, P.; Silva, J. N.; Veríssimo, A.; Napoleão, P.; Alves, L. C.; Pinheiro, T.

    2006-08-01

    The distribution of Fe in skin was assessed to monitor body Fe status in human hereditary hemochromatosis. The paper reports on data from nine patients with hemochromatosis that were studied along the therapeutic programme. Systemic evaluation of Fe metabolism was carried out by measuring with PIXE technique the Fe concentration in plasma and blood cells, and by determining with biochemical methods the indicators of Fe transport in serum (ferritin and transferrin). The Fe distribution and concentration in skin was assessed by nuclear microscopy and Fe deposits in liver estimated through nuclear magnetic resonance. Elevated Fe concentrations in skin were related to increased plasma Fe (p serum ferritin content (p < 0.01) and Fe deposits in liver (p < 0.004). The relationship of Fe deposits in organs and metabolism markers may help to better understand Fe pools mobilisation and to establish the quality of skin as a marker for the disease progression and therapy efficacy.

  18. Thyroid hormone metabolism and the developing human lung.

    Science.gov (United States)

    Hume, R; Richard, K; Kaptein, E; Stanley, E L; Visser, T J; Coughtrie, M W

    2001-05-01

    Thyroid hormones are involved in the regulation of fetal lung development, and maturation is accelerated in animal models by antepartum exposure to raised concentrations of the receptor-active thyroid hormone triiodothyronine and glucocorticoids. It is essential that the nature of the regulation of the spatial and temporal metabolism of iodothyronines in the human fetus and infant is known before effective therapies can be developed to modify human lung maturation. Thyroid hormone bioavailability to the human fetus is regulated in part by enzymatic deiodination and reversible sulfation of iodothyronines, with contributions from other factors such as fetomaternal and fetoamniotic hormone transfers, fetal thyroid gland production, and the activities of plasma membrane transporters mediating uptake of iodothyronines from plasma into tissues. Copyright 2001 S. Karger AG, Basel.

  19. Physicochemical characterization of the human nail: solvent effects on the permeation of homologous alcohols.

    Science.gov (United States)

    Walters, K A; Flynn, G L; Marvel, J R

    1985-11-01

    To assess how vehicles might influence permeation through human nail, the diffusion of homologous alcohols (methanol to decanol) administered as neat liquids through finger nail plate has been studied using in-vitro diffusion cell methods and compared with permeation data for the same compounds in aqueous media. Permeation rates of the homologous alcohols through lipid depleted nail plate have also been assessed and the influences of dimethylsulphoxide (DMSO) and isopropyl alcohol on permeation rates of methanol and hexanol have been examined. With the exception of methanol, permeability coefficients are uniformly about five-fold smaller when the alcohols are undiluted than when they are applied in water. Overall parallelism in the permeability profiles under these separate circumstances of application is an indication that the external concentrations of the alcohols themselves are a determinant of their permeation velocities through the nail plate matrix. The even separation of the profiles suggests a facilitating role of water within the nail matrix. Chloroform/methanol delipidization of the nail led to increased penetration rates of water, methanol, ethanol and butanol. On the other hand, it caused a six-fold decrease in the permeation rate of decanol. Application of methanol and hexanol in DMSO somewhat retards their rates of permeation. Isopropyl alcohol also slows the permeation rate of hexanol but has little influence on that of methanol. Thus it appears that solvents which tend to promote diffusion through the skin horny layer have little promise as accelerants of nail plate permeability.

  20. Human folate metabolism using 14C-accelerator mass spectrometry

    Energy Technology Data Exchange (ETDEWEB)

    Clifford, A. J. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Arjomand, A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Duecker, S. R. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Johnson, H. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Schneider, P. D. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Zulim, R. A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Bucholz, B. A. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States); Vogel, J. S. [Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States)

    1999-03-25

    Folate is a water soluble vitamin required for optimal health, growth and development. It occurs naturally in various states of oxidation of the pteridine ring and with varying lengths to its glutamate chain. Folates function as one-carbon donors through methyl transferase catalyzed reactions. Low-folate diets, especially by those with suboptimal methyltransferase activity, are associated with increased risk of neural tube birth defects in children, hyperhomocysteinemic heart disease, and cancer in adults. Rapidly dividing (neoplastic) cells have a high folate need for DNA synthesis. Chemical analogs of folate (antifolates) that interfere with folate metabolism are used as therapeutic agents in cancer treatment. Although much is known about folate chemistry, metabolism of this vitamin in vivo in humans is not well understood. Since folate levels in blood and tissues are very low and methods to measure them are inadequate, the few previous studies that have examined folate metabolism used large doses of radiolabeled folic acid in patients with Hodgkin's disease and cancer (Butterworth et al. 1969, Krumdieck et al. 1978). A subsequent protocol using deuterated folic acid was also insufficiently sensitive to trace a physiologic folate dose (Stites et al. 1997). Accelerator mass spectrometry (AMS) is an emerging bioanalytical tool that overcomes the limitations of traditional mass spectrometry and of decay counting of long lived radioisotopes (Vogel et al. 1995). AMS can detect attomolar concentrations of 14 C in milligram-sized samples enabling in vivo radiotracer studies in healthy humans. We used AMS to study the metabolism of a physiologic 80 nmol oral dose of 14 C-folic acid (1/6 US RDA) by measuring the 14 C-folate levels in serial plasma, urine and feces samples taken over a 150-day period after dosing a healthy adult volunteer.

  1. PREVALENCE OF NON-ALCOHOLIC FATTY LIVER DISEASE IN WOMEN WITH POLYCYSTIC OVARY SYNDROME AND ITS CORRELATION WITH METABOLIC SYNDROME

    Directory of Open Access Journals (Sweden)

    Mariana Drechmer ROMANOWSKI

    2015-06-01

    Full Text Available Background The polycystic ovary syndrome (PCOS is one of the most common endocrine disorders in women at childbearing age. Metabolic syndrome is present from 28% to 46% of patients with PCOS. Non-alcoholic fatty liver disease (NAFLD is considered the hepatic expression of metabolic syndrome. There are few published studies that correlate PCOS and NAFLD. Objective To determine the prevalence of NAFLD and metabolic syndrome in patients with PCOS, and to verify if there is a correlation between NAFLD and metabolic syndrome in this population. Methods Study developed at Gynecology Department of Clinical Hospital of Federal University of Parana (UFPR. The sessions were conducted from April 2008 to January 2009. One hundred and thirty-one patients joined the analysis; 101 were diagnosed with PCOS and 30 formed the control group. We subdivided the PCOS patients into two subgroups: PCOS+NAFLD and PCOS. All the patients were submitted to hepatic sonography. For hepatoestheatosis screening, hepatic ecotexture was compared do spleen’s. For diagnosis of metabolic syndrome, we adopted the National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATP III criteria, as well as the criteria proposed by International Diabetes Federation. Statistical analysis were performed with t of student and U of Mann-Whitney test for means and chi square for proportions. Results At PCOS group, NAFLD was present in 23.8% of the population. At control group, it represented 3.3%, with statistical significance (P=0.01. Metabolic syndrome, by NCEP/ATP III criteria, was diagnosed in 32.7% of the women with PCOS and in 26.6% of the women at control group (no statistical difference, P=0.5. At PCOS+DHGNA subgroup, age, weight, BMI, abdominal circumference and glucose tolerance test results were higher when compared to PCOS group (P<0.01. Metabolic syndrome by NCEP/ATPIII criteria was present in 75% and by International Diabetes Federation criteria in 95.8% of women with

  2. Alcohol-Induced Molecular Dysregulation in Human Embryonic Stem Cell-Derived Neural Precursor Cells

    Science.gov (United States)

    Kim, Yi Young; Roubal, Ivan; Lee, Youn Soo; Kim, Jin Seok; Hoang, Michael; Mathiyakom, Nathan; Kim, Yong

    2016-01-01

    Adverse effect of alcohol on neural function has been well documented. Especially, the teratogenic effect of alcohol on neurodevelopment during embryogenesis has been demonstrated in various models, which could be a pathologic basis for fetal alcohol spectrum disorders (FASDs). While the developmental defects from alcohol abuse during gestation have been described, the specific mechanisms by which alcohol mediates these injuries have yet to be determined. Recent studies have shown that alcohol has significant effect on molecular and cellular regulatory mechanisms in embryonic stem cell (ESC) differentiation including genes involved in neural development. To test our hypothesis that alcohol induces molecular alterations during neural differentiation we have derived neural precursor cells from pluripotent human ESCs in the presence or absence of ethanol treatment. Genome-wide transcriptomic profiling identified molecular alterations induced by ethanol exposure during neural differentiation of hESCs into neural rosettes and neural precursor cell populations. The Database for Annotation, Visualization and Integrated Discovery (DAVID) functional analysis on significantly altered genes showed potential ethanol’s effect on JAK-STAT signaling pathway, neuroactive ligand-receptor interaction, Toll-like receptor (TLR) signaling pathway, cytokine-cytokine receptor interaction and regulation of autophagy. We have further quantitatively verified ethanol-induced alterations of selected candidate genes. Among verified genes we further examined the expression of P2RX3, which is associated with nociception, a peripheral pain response. We found ethanol significantly reduced the level of P2RX3 in undifferentiated hESCs, but induced the level of P2RX3 mRNA and protein in hESC-derived NPCs. Our result suggests ethanol-induced dysregulation of P2RX3 along with alterations in molecules involved in neural activity such as neuroactive ligand-receptor interaction may be a molecular event

  3. Three-dimensional perfused human in vitro model of non-alcoholic fatty liver disease

    Science.gov (United States)

    Kostrzewski, Tomasz; Cornforth, Terri; Snow, Sophie A; Ouro-Gnao, Larissa; Rowe, Cliff; Large, Emma M; Hughes, David J

    2017-01-01

    AIM To develop a human in vitro model of non-alcoholic fatty liver disease (NAFLD), utilising primary hepatocytes cultured in a three-dimensional (3D) perfused platform. METHODS Fat and lean culture media were developed to directly investigate the effects of fat loading on primary hepatocytes cultured in a 3D perfused culture system. Oil Red O staining was used to measure fat loading in the hepatocytes and the consumption of free fatty acids (FFA) from culture medium was monitored. Hepatic functions, gene expression profiles and adipokine release were compared for cells cultured in fat and lean conditions. To determine if fat loading in the system could be modulated hepatocytes were treated with known anti-steatotic compounds. RESULTS Hepatocytes cultured in fat medium were found to accumulate three times more fat than lean cells and fat uptake was continuous over a 14-d culture. Fat loading of hepatocytes did not cause any hepatotoxicity and significantly increased albumin production. Numerous adipokines were expressed by fatty cells and genes associated with NAFLD and liver disease were upregulated including: Insulin-like growth factor-binding protein 1, fatty acid-binding protein 3 and CYP7A1. The metabolic activity of hepatocytes cultured in fatty conditions was found to be impaired and the activities of CYP3A4 and CYP2C9 were significantly reduced, similar to observations made in NAFLD patients. The utility of the model for drug screening was demonstrated by measuring the effects of known anti-steatotic compounds. Hepatocytes, cultured under fatty conditions and treated with metformin, had a reduced cellular fat content compared to untreated controls and consumed less FFA from cell culture medium. CONCLUSION The 3D in vitro NAFLD model recapitulates many features of clinical NAFLD and is an ideal tool for analysing the efficacy of anti-steatotic compounds. PMID:28127194

  4. Craving for alcohol and drugs in animals and humans: biology and behavior.

    Science.gov (United States)

    Miller, N S; Goldsmith, R J

    2001-01-01

    Research studies indicate that sites and pathways for appetitive drive states, that are located in the limbic system, appear to be responsible for normal and pathological craving for alcohol and other addicting drugs. Pathological craving for alcohol and drugs in humans has been substantiated by animal studies, which have identified neurosubstrates and neurotransmitters associated with behavioral models of addiction. Repetitive administration of alcohol and drugs appears to affect hedonic homeostasis of the appetitive drives leading to the hedonic alleostasis where negative reinforcement exceeds positive returns despite continued drug use. Neuroimaging studies have concentrated on areas in the brain related to reward or reinforcement of alcohol/drug use, but the technique can be employed to find support for a neurosubstrate to distinguish normal craving or "liking" from pathological craving or "wanting" a drug. Identifying the neurobasis of "wanting" a drug long after not "liking it" is central to understanding pathological craving and loss of control over drug use in addiction in humans. Neuroimaging is currently the only method to directly visualize sites for craving in the brain in humans. Neuroimaging techniques will provide methods, which are not possible in animals, for studying addictive disease in humans.

  5. Ethanol metabolism, oxidative stress, and endoplasmic reticulum stress responses in the lungs of hepatic alcohol dehydrogenase deficient deer mice after chronic ethanol feeding.

    Science.gov (United States)

    Kaphalia, Lata; Boroumand, Nahal; Hyunsu, Ju; Kaphalia, Bhupendra S; Calhoun, William J

    2014-06-01

    Consumption and over-consumption of alcoholic beverages are well-recognized contributors to a variety of pulmonary disorders, even in the absence of intoxication. The mechanisms by which alcohol (ethanol) may produce disease include oxidative stress and prolonged endoplasmic reticulum (ER) stress. Many aspects of these processes remain incompletely understood due to a lack of a suitable animal model. Chronic alcohol over-consumption reduces hepatic alcohol dehydrogenase (ADH), the principal canonical metabolic pathway of ethanol oxidation. We therefore modeled this situation using hepatic ADH-deficient deer mice fed 3.5% ethanol daily for 3 months. Blood ethanol concentration was 180 mg% in ethanol fed mice, compared to alcoholic lung disease. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Intestinal and hepatic metabolism of glutamine and citrulline in humans.

    Science.gov (United States)

    van de Poll, Marcel C G; Ligthart-Melis, Gerdien C; Boelens, Petra G; Deutz, Nicolaas E P; van Leeuwen, Paul A M; Dejong, Cornelis H C

    2007-06-01

    Glutamine plays an important role in nitrogen homeostasis and intestinal substrate supply. It has been suggested that glutamine is a precursor for arginine through an intestinal-renal pathway involving inter-organ transport of citrulline. The importance of intestinal glutamine metabolism for endogenous arginine synthesis in humans, however, has remained unaddressed. The aim of this study was to investigate the intestinal conversion of glutamine to citrulline and the effect of the liver on splanchnic citrulline metabolism in humans. Eight patients undergoing upper gastrointestinal surgery received a primed continuous intravenous infusion of [2-(15)N]glutamine and [ureido-(13)C-(2)H(2)]citrulline. Arterial, portal venous and hepatic venous blood were sampled and portal and hepatic blood flows were measured. Organ specific amino acid uptake (disposal), production and net balance, as well as whole body rates of plasma appearance were calculated according to established methods. The intestines consumed glutamine at a rate that was dependent on glutamine supply. Approximately 13% of glutamine taken up by the intestines was converted to citrulline. Quantitatively glutamine was the only important precursor for intestinal citrulline release. Both glutamine and citrulline were consumed and produced by the liver, but net hepatic flux of both amino acids was not significantly different from zero. Plasma glutamine was the precursor of 80% of plasma citrulline and plasma citrulline in turn was the precursor of 10% of plasma arginine. In conclusion, glutamine is an important precursor for the synthesis of arginine after intestinal conversion to citrulline in humans.

  7. Prevalence of biopsy-proven non-alcoholic fatty liver disease in severely obese subjects without metabolic syndrome.

    Science.gov (United States)

    Qureshi, K; Abrams, G A

    2016-04-01

    Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD). NAFLD encompasses simple fatty liver (FL) and non-alcoholic steatohepatitis (NASH) in its spectrum. NASH can progress to liver cirrhosis and is associated with liver cancer. Not all obese subjects have insulin resistance (IR) or develop metabolic syndrome (MS). This study evaluates the prevalence of NAFLD in severely obese subjects without MS. We retrospectively reviewed 445 charts from our database of severely obese subjects with clinical suspicion of NAFLD and who were selected for laparoscopic Roux-en-Y gastric bypass surgery. One hundred five subjects who did not have MS, as defined by the International Diabetes Foundation, based on comprehensive pre-operative metabolic evaluation were included. Liver biopsy specimens were evaluated for NAFLD. 24% of morbidly obese (mean body mass index [BMI] 48 kg m(-2) ) adult subjects (mean age 38 years) who underwent bariatric surgery did not have MS. NAFLD was identified in 77 (73%) on liver biopsy, out of which 59 (56%) were labelled as FL and 18 (17%) had histological diagnosis of NASH. Age, gender, race and BMI were the same among all groups. Among NAFLD subjects, 22% did not have any additional metabolic component of MS, while 36% had low high-density lipoprotein, 27% had hypertension, 8% had high triglycerides and 6% had hyperglycaemia. IR calculated by HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) and diagnosis of hyperglycaemia was statistically higher in NASH group compared to those who did not have NASH. NAFLD is highly prevalent in morbidly obese individuals who undergo bariatric surgery despite the absence of MS. Diagnosis of hyperglycaemia in such subjects suggests the presence of IR and may have underlying NASH, which is a progressive form of NAFLD.

  8. Nrf2-mediated antioxidant response by ethanolic extract of Sida cordifolia provides protection against alcohol-induced oxidative stress in liver by upregulation of glutathione metabolism.

    Science.gov (United States)

    Rejitha, S; Prathibha, P; Indira, M

    2015-03-01

    Objective The study aimed to evaluate the antioxidant property of ethanolic extract of Sida cordifolia (SAE) on alcohol-induced oxidative stress and to elucidate its mechanism of action. Methods Male albino rats of the Sprague-Dawley strain were grouped into four: (1) control, (2) alcohol (4 g/kg body weight), (3) SAE (50 mg/100 g body weight), and (4) alcohol (4 g/kg body weight) + SAE (50 mg/100 g body weight). Alcohol and SAE were given orally each day by gastric intubation. The duration of treatment was 90 days. Results The activities of toxicity markers in liver and serum increased significantly in alcohol-treated rats and to a lesser extent in the group administered SAE + alcohol. The activity of alcohol dehydrogenase and the reactive oxygen species level were increased significantly in alcohol-treated rats but attenuated in the SAE co-administered group. Oxidative stress was increased in alcohol-treated rats as evidenced by the lowered activities of antioxidant enzymes, decreased level of reduced glutathione (GSH), increased lipid peroxidation products, and decreased expression of γ-glutamyl cysteine synthase in liver. The co-administration of SAE with alcohol almost reversed these changes. The activity of glutathione-S-transferase and translocation of Nrf2 from cytosol to nucleus in the liver was increased in both the alcohol and alcohol + SAE groups, but the maximum changes were observed in the latter group. Discussion The SAE most likely elicits its antioxidant potential by reducing oxidative stress, enhancing the translocation of Nrf2 to nucleus and thereby regulating glutathione metabolism, leading to enhanced GSH content.

  9. Human Metabolism and Interactions of Deployment-Related Chemicals

    Science.gov (United States)

    2008-08-01

    consisted of the pGL3- CYP3A4, pCDG1-SXR, and pRL-TK plasmids in the amounts of 360, 90, and 10 ng, respectively, along with 540 ng sonicated salmon sperm...oxidative stress in rat brain and liver is prevented by vitamin E or allopurinol. Toxicol. Lett. 2001; 118: 139-146. 34. Li, P., Nijhawan, D...acids, eicosanoids, fat- soluble vitamins /1/. Among fifty-seven CYP isoforms known in humans, fifteen are involved in the metabolism of

  10. Fetal alcohol syndrome, chemo-biology and OMICS: ethanol effects on vitamin metabolism during neurodevelopment as measured by systems biology analysis.

    Science.gov (United States)

    Feltes, Bruno César; de Faria Poloni, Joice; Nunes, Itamar José Guimarães; Bonatto, Diego

    2014-06-01

    Fetal alcohol syndrome (FAS) is a prenatal disease characterized by fetal morphological and neurological abnormalities originating from exposure to alcohol. Although FAS is a well-described pathology, the molecular mechanisms underlying its progression are virtually unknown. Moreover, alcohol abuse can affect vitamin metabolism and absorption, although how alcohol impairs such biochemical pathways remains to be elucidated. We employed a variety of systems chemo-biology tools to understand the interplay between ethanol metabolism and vitamins during mouse neurodevelopment. For this purpose, we designed interactomes and employed transcriptomic data analysis approaches to study the neural tissue of Mus musculus exposed to ethanol prenatally and postnatally, simulating conditions that could lead to FAS development at different life stages. Our results showed that FAS can promote early changes in neurotransmitter release and glutamate equilibrium, as well as an abnormal calcium influx that can lead to neuroinflammation and impaired neurodifferentiation, both extensively connected with vitamin action and metabolism. Genes related to retinoic acid, niacin, vitamin D, and folate metabolism were underexpressed during neurodevelopment and appear to contribute to neuroinflammation progression and impaired synapsis. Our results also indicate that genes coding for tubulin, tubulin-associated proteins, synapse plasticity proteins, and proteins related to neurodifferentiation are extensively affected by ethanol exposure. Finally, we developed a molecular model of how ethanol can affect vitamin metabolism and impair neurodevelopment.

  11. Correlation of HIFs/PPAR signaling pathway activation degree and lipid metabolism in liver tissue of alcoholic fatty liver rat model

    Institute of Scientific and Technical Information of China (English)

    Li-Ying Guo; Ya-Min Li; Qing-Chun Li

    2015-01-01

    Objective:To study the correlation of HIFs/PPAR signaling pathway activation degree and lipid metabolism in liver tissue of alcoholic fatty liver rat model.Methods:Adult SD rats were selected and alcoholic fatty liver rat models were established by alcohol administration and high-fat diet feeding. Liver tissue was collected and contents of HIF-1α, PPARγ and lipid metabolism-related enzymes were detected; serum was collected and contents of lipid metabolism indexes and liver cell damage indexes were detected.Results:(1) one week, two weeks, three weeks and four weeks after models were established, HIF-1αα in livers of the model group showed an increasing trend and PPARγ showed a decreasing trend; HIF-1α content was higher than that of the control group and PPARγ content was lower than that of the control group; (2) contents of apoCII, apoCIII,α-GST and GLDH in serum as well as levels of FAT, FABP1, FAS, ACC and ACAT-2 in liver tissue of the model group all significantly increased, and were positively correlated with HIF-1α and negatively correlated with PPARγ.Conclusion:Transcription factor HIF-1α content abnormally increases and PPARγ content abnormally decreases in liver tissue of alcoholic fatty liver rat models; it results in abnormal lipid metabolism and liver cell damage through increasing the expression of lipid metabolism-related enzymes in the liver.

  12. Non-alcoholic fatty liver disease and the metabolic syndrome: An update

    Institute of Scientific and Technical Information of China (English)

    R Scott Rector; John P Thyfault; Yongzhong Wei; Jamal A Ibdah

    2008-01-01

    Sedentary lifestyle and poor dietary choices are leading to a weight gain epidemic in westernized countries,subsequently increasing the risk for developing the metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). NAFLD is estimated to affect approximate 30% of the general US population and is considered the hepatic manifestation of the metabolic syndrome.Recent findings linking the components of the metabolic syndrome with NAFLD and the progression to nonalcoholic steatohepatitis (NASH) will be reviewed;in particular, the role of visceral adipose tissue, insulin resistance, and adipocytokines in the exacerbation of these conditions. While no therapy has been proven effective for treating NAFLD/NASH, common recommendations will be discussed.

  13. Additive Effect of Non-Alcoholic Fatty Liver Disease on Metabolic Syndrome-Related Endothelial Dysfunction in Hypertensive Patients

    Directory of Open Access Journals (Sweden)

    Maria Perticone

    2016-03-01

    Full Text Available Metabolic syndrome (MS is characterized by an increased risk of incident diabetes and cardiovascular (CV events, identifying insulin resistance (IR and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD is bidirectionally linked with MS as a consequence of metabolic and inflammatory abnormalities. We addressed the question if the evolution in NAFLD might worsen endothelium-dependent vasodilating response in MS hypertensives. We recruited 272 Caucasian newly-diagnosed never-treated hypertensive outpatients divided into three groups according to the presence/absence of MS alone or in combination with NAFLD. MS and NAFLD were defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII and non-invasive fatty liver index, respectively. We determined IR by using the homeostasis model assessment (HOMA index. Vascular function, as forearm blood flow (FBF, was determined through strain-gauge plethysmography after intra-arterial infusion of acetylcholine (ACh and sodium nitroprusside. MS+NAFLD+ group showed worse metabolic, inflammatory and vascular profiles compared with MS−NAFLD− and MS+NAFLD−. HOMA resulted in being the strongest predictor of FBF both in the MS+NAFLD− and in the MS+NAFLD+ groups, accounting for 20.5% and 33.2% of its variation, respectively. In conclusion, we demonstrated that MS+NAFLD+ hypertensives show a worse endothelium-dependent vasodilation compared with MS+NAFLD−, allowing for consideration of NAFLD as an early marker of endothelial dysfunction in hypertensives.

  14. Additive Effect of Non-Alcoholic Fatty Liver Disease on Metabolic Syndrome-Related Endothelial Dysfunction in Hypertensive Patients.

    Science.gov (United States)

    Perticone, Maria; Cimellaro, Antonio; Maio, Raffaele; Caroleo, Benedetto; Sciacqua, Angela; Sesti, Giorgio; Perticone, Francesco

    2016-03-26

    Metabolic syndrome (MS) is characterized by an increased risk of incident diabetes and cardiovascular (CV) events, identifying insulin resistance (IR) and endothelial dysfunction as key elements. Moreover, non-alcoholic fatty liver disease (NAFLD) is bidirectionally linked with MS as a consequence of metabolic and inflammatory abnormalities. We addressed the question if the evolution in NAFLD might worsen endothelium-dependent vasodilating response in MS hypertensives. We recruited 272 Caucasian newly-diagnosed never-treated hypertensive outpatients divided into three groups according to the presence/absence of MS alone or in combination with NAFLD. MS and NAFLD were defined according to the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) and non-invasive fatty liver index, respectively. We determined IR by using the homeostasis model assessment (HOMA) index. Vascular function, as forearm blood flow (FBF), was determined through strain-gauge plethysmography after intra-arterial infusion of acetylcholine (ACh) and sodium nitroprusside. MS+NAFLD+ group showed worse metabolic, inflammatory and vascular profiles compared with MS-NAFLD- and MS+NAFLD-. HOMA resulted in being the strongest predictor of FBF both in the MS+NAFLD- and in the MS+NAFLD+ groups, accounting for 20.5% and 33.2% of its variation, respectively. In conclusion, we demonstrated that MS+NAFLD+ hypertensives show a worse endothelium-dependent vasodilation compared with MS+NAFLD-, allowing for consideration of NAFLD as an early marker of endothelial dysfunction in hypertensives.

  15. Invertebrate models of alcoholism.

    Science.gov (United States)

    Scholz, Henrike; Mustard, Julie A

    2013-01-01

    For invertebrates to become useful models for understanding the genetic and physiological mechanisms of alcoholism related behaviors and the predisposition towards alcoholism, several general requirements must be fulfilled. The animal should encounter ethanol in its natural habitat, so that the central nervous system of the organism will have evolved mechanisms for responding to ethanol exposure. How the brain adapts to ethanol exposure depends on its access to ethanol, which can be regulated metabolically and/or by physical barriers. Therefore, a model organism should have metabolic enzymes for ethanol degradation similar to those found in humans. The neurons and supporting glial cells of the model organism that regulate behaviors affected by ethanol should share the molecular and physiological pathways found in humans, so that results can be compared. Finally, the use of invertebrate models should offer advantages over traditional model systems and should offer new insights into alcoholism-related behaviors. In this review we will summarize behavioral similarities and identified genes and mechanisms underlying ethanol-induced behaviors in invertebrates. This review mainly focuses on the use of the nematode Caenorhabditis elegans, the honey bee Apis mellifera and the fruit fly Drosophila melanogaster as model systems. We will discuss insights gained from those studies in conjunction with their vertebrate model counterparts and the implications for future research into alcoholism and alcohol-induced behaviors.

  16. Discovery of Infection Associated Metabolic Markers in Human African Trypanosomiasis.

    Science.gov (United States)

    Lamour, Sabrina D; Gomez-Romero, Maria; Vorkas, Panagiotis A; Alibu, Vincent P; Saric, Jasmina; Holmes, Elaine; Sternberg, Jeremy M

    2015-01-01

    Human African trypanosomiasis (HAT) remains a major neglected tropical disease in Sub-Saharan Africa. As clinical symptoms are usually non-specific, new diagnostic and prognostic markers are urgently needed to enhance the number of identified cases and optimise treatment. This is particularly important for disease caused by Trypanosoma brucei rhodesiense, where indirect immunodiagnostic approaches have to date been unsuccessful. We have conducted global metabolic profiling of plasma from T.b.rhodesiense HAT patients and endemic controls, using 1H nuclear magnetic resonance (NMR) spectroscopy and ultra-performance liquid chromatography, coupled with mass spectrometry (UPLC-MS) and identified differences in the lipid, amino acid and metabolite profiles. Altogether 16 significantly disease discriminatory metabolite markers were found using NMR, and a further 37 lipid markers via UPLC-MS. These included significantly higher levels of phenylalanine, formate, creatinine, N-acetylated glycoprotein and triglycerides in patients relative to controls. HAT patients also displayed lower concentrations of histidine, sphingomyelins, lysophosphatidylcholines, and several polyunsaturated phosphatidylcholines. While the disease metabolite profile was partially consistent with previous data published in experimental rodent infection, we also found unique lipid and amino acid profile markers highlighting subtle but important differences between the host response to trypanosome infections between animal models and natural human infections. Our results demonstrate the potential of metabolic profiling in the identification of novel diagnostic biomarkers and the elucidation of pathogenetic mechanisms in this disease.

  17. Alcohol and drug abuse in the workplace - managing the human factor

    Energy Technology Data Exchange (ETDEWEB)

    McKibbon, D.; Glass, H. [Kelly Luttmer and Associates Ltd., (Canada)

    1998-09-01

    The impact of drugs and alcohol in the workplace was reviewed. The policies and procedures which are required to ensure that employers meet due diligence requirements were discussed. Under the Canadian human rights legislation an employer cannot terminate an employee for having a medical illness including alcoholism or drug addiction. The implementation of a comprehensive drug and alcohol policy was said to be important to demonstrate to employees that the organization is ready to take a proactive and supportive role in addressing this health concern. The issue of drug testing and when to drug screen was also discussed. It was suggested that addressing substance abuse in the workplace through policies, procedures and practices can reduce costs related to lost productivity, absenteeism, workers` compensation claims, staff turnover, health benefit premiums and legal liabilities.

  18. Heavy alcohol consumption and neuropathological lesions: a post-mortem human study.

    Science.gov (United States)

    Aho, Leena; Karkola, Kari; Juusela, Jari; Alafuzoff, Irina

    2009-09-01

    Epidemiological studies have indicated that excessive alcohol consumption leads to cognitive impairment, but the specific pathological mechanism involved remains unknown. The present study evaluated the association between heavy alcohol intake and the neuropathological hallmark lesions of the three most common neurodegenerative disorders, i.e., Alzheimer's disease (AD), dementia with Lewy bodies (DLB), and vascular cognitive impairment (VCI), in post-mortem human brains. The study cohort was sampled from the subjects who underwent a medicolegal autopsy during a 6-month period in 1999 and it included 54 heavy alcohol consumers and 54 age- and gender-matched control subjects. Immunohistochemical methodology was used to visualize the aggregation of beta-amyloid, hyperphosphorylated tau, and alpha-synuclein and the extent of infarcts. In the present study, no statistically significant influence was observed for alcohol consumption on the extent of neuropathological lesions encountered in the three most common degenerative disorders. Our results indicate that alcohol-related dementia differs from VCI, AD, and DLB; i.e., it has a different etiology and pathogenesis.

  19. Effect of a synbiotic food consumption on human gut metabolic profiles evaluated by (1)H Nuclear Magnetic Resonance spectroscopy.

    Science.gov (United States)

    Ndagijimana, Maurice; Laghi, Luca; Vitali, Beatrice; Placucci, Giuseppe; Brigidi, Patrizia; Guerzoni, M Elisabetta

    2009-08-31

    The capacity of human lactobacilli and bifidobacteria to produce metabolites under conditions that may prevail in the human intestine has been studied "in vitro". However, the effect of systematic probiotic consumption on human metabolic phenotype has not been investigated in faeces. This paper shows the potential for the use of (1)H Nuclear Magnetic Resonance ((1)H NMR) spectroscopy for studying the changes of the metabolic profiles of human faecal slurries. Faeces of 16 subjects, characterized by different natural levels of lactobacilli and bifidobacteria were recovered before and after 1 month of supplementation with a synbiotic food based on Lactobacillus acidophilus, Bifidobacterium longum and fructooligosaccharides, and analyzed by (1)H NMR. Multivariate statistical approach has been applied to the data obtained and particularly Canonical Discriminant Analysis of Principal Coordinates (CAP). More than 150 molecules belonging to short chain fatty acids, organic acids, esters, alcohols and amino acids were detected and quantified in the samples considered. The number and the extent of these molecules in faecal slurries were strongly affected by the synbiotic food consumption and gave rise to characteristic metabolic signature. In particular, the short chain fatty acid concentrations significantly increased while the amino acids contents decreased. The comparison of the data indicated that the intake of the synbiotic food alters the host metabolism in a measure dependent on the initial level of lactobacilli and bifidobacteria detected in the faecal specimens. The analysis of (1)H NMR profiles with CAP allowed a separation of faecal samples of the subjects on the basis of the synbiotic food intake. The multivariate statistical approach used demonstrated the potential of NMR metabolic profiles to provide biomarkers of the gut-microbial activity related to dietary supplementation of probiotics.

  20. The effect of different alcoholic beverages on blood alcohol levels, plasma insulin and plasma glucose in humans.

    Science.gov (United States)

    Nogueira, L C; Couri, S; Trugo, N F; Lollo, P C B

    2014-09-01

    In the present work we studied the effects of four alcoholic beverages on blood alcohol levels, plasma insulin concentrations and plasma glucose concentrations in men and women. The volunteers were healthy non-smokers and they were divided according to sex into two groups of ten individuals. The alcoholic beverages used in the study were beer, red wine, whisky and "cachaça". In men, ingestion of the distilled drinks promoted a spike in blood alcohol levels more quickly than ingestion of the fermented drinks. In women, beer promoted the lowest blood alcohol levels over the 6h of the experiment. Whisky promoted highest blood alcohol levels in both sexes. The ingestion of wine promoted a significant difference in relation to the blood alcohol concentration (BAC) as a function of gender. The ingestion of cachaça by women produced BAC levels significantly smaller than those obtained for wine.

  1. A versatile UHPLC–MSMS method for simultaneous quantification of various alcohol intake related compounds in human urine and blood

    DEFF Research Database (Denmark)

    Monosik, Rastislav; Dragsted, Lars Ove

    2016-01-01

    Alcohol intake has been associated with preventive as well as negative effects on health. However, the intake estimates are often based on subjective reporting and therefore biased and the types of beverages consumed are often inaccurately reported. Accurate and specific quantification of alcohol...... related compounds in biological samples may help to understand dietary exposure and metabolic kinetics. The aim of this study was to develop a simple, rapid and versatile UHPLC–MSMS method able of quantifying various alcohol derived compounds or potential effect markers. The method was thoroughly...

  2. Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.

    Science.gov (United States)

    Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron; Hardesty, Josiah E; Song, Ming; Clair, Heather B; Clark, Barbara J; States, J Christopher; Arteel, Gavin E; Cave, Matthew C

    2016-02-01

    Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis.

  3. [Thiamine metabolism disorders in the rat brain in experimental alcoholism and a possibility of their correction by vitamin E].

    Science.gov (United States)

    Parkhomenko, Iu M; Pilipchuk, S Iu; Sidorova, A A; Stepanenko, S P; Chekhovskaia, L I; Donchenko, G V

    2008-01-01

    The influence of the chronic consumption of alcohol on biochemical reactions of thiamine metabolism in the rat brain is investigated. It is shown that the content of thiamine diphosphate (ThDP) in the brain tissue does not change at these conditions, though there is an essential decrease in the thiamine-kinase activity. The ability of the isolated nerve terminals (synaptosomes) to absorb labelled thiamine also decreases under this condition. The specified disturbances are probably the reason for deceleration of exchange of free (uncombined with proteins) thiamine and its phosphates in nervous cells, that results in the observed reduction in activity of pyruvate dehydrogenase complex (PDC) due to inactivation by phosphorylation. Thiamine-binding and thiaminetriphosphatase activities of thiamine-binding protein (ThBP) in the structure of synaptic plasma membranes (SPM), isolated from the rat brain in various experimental groups, have been investigated. The increase, with respect to control, in the both enzymes activity in SPM, isolated from the brain of rats with chronic alcoholism has been shown. Kinetic researches testify to an increase of affinity of SPM (ThBP) for thiamine and thiaminetriphosphate in these conditions. When vitamin E was given to animals with a model of chronic alcoholism the normalization of PDC activity in nervous cells was observed, that can testify to the transient character of these changes. Inability of vitamin E to normalize biological activities of ThBP in PMS, that has been analyzed, can testify to more deep disturbances in the structure of SPM or thiamine binding protein in their structure.

  4. Metabolic pathway of non-alcoholic fatty liver disease: Network properties and robustness

    Directory of Open Access Journals (Sweden)

    WenJun Zhang

    2017-03-01

    Full Text Available Nonalcoholic fatty liver disease (NAFLD is a systematic and complex disease involving various cytokines/metabolites. In present article, we use methodology of network biology to analyze network properties of NAFLD metabolic pathway. It is found that the metabolic pathway of NAFLD is not a typical complex network with power-law degree distribution, p(x=x^(-4.4275, x>=5. There is only one connected component in the metabolic pathway. The calculated cut cytokines/metabolites of the metabolic pathway are SREBP-1c, ChREBP, ObR, AMPK, IRE1alpha, ROS, PERK, elF2alpha, ATF4, CHOP, Bim, CASP8, Bid, CxII, Lipogenic enzymes, XBP1, and FFAs. The most important cytokine/metabolite for possible network robustness is FFAs, seconded by TNF-alpha. It is concluded that FFAs is the most important cytokine/metabolite in the metabolic pathway, seconded by ROS. FFAs, LEP, ACDC, CYP2E1, and Glucose are the only cytokines/metabolites that affect others without influences from other cytokines/metabolites. Finally, the IDs matrix for identifying possible sub-networks/modules is given. However, jointly combining the results of connectedness analysis and sub-networks/modules identification, we hold that there are not significant sub-networks/modules in the pathway.

  5. Metabolism of methyl tert-butyl ether and other gasoline ethers by human liver microsomes and heterologously expressed human cytochromes P450: identification of CYP2A6 as a major catalyst.

    Science.gov (United States)

    Hong, J Y; Wang, Y Y; Bondoc, F Y; Lee, M; Yang, C S; Hu, W Y; Pan, J

    1999-10-01

    To reduce the production of carbon monoxide and other pollutants in motor vehicle exhaust, methyl tert-butyl ether (MTBE), ethyl tert-butyl ether (ETBE), and tert-amyl methyl ether (TAME) are added to gasoline as oxygenates for more complete combustion. Previously, we demonstrated that human liver is active in metabolizing MTBE to tert-butyl alcohol (TBA) and that cytochrome P450 (CYP) enzymes play a critical role in the metabolism of MTBE. The present study demonstrates that human liver is also active in the oxidative metabolism of ETBE and TAME. A large interindividual variation in metabolizing these gasoline ethers was observed in 15 human liver microsomal samples. The microsomal activities in metabolizing MTBE, ETBE, and TAME were highly correlated among each other (r, 0.91-0. 96), suggesting that these ethers are metabolized by the same enzyme(s). Correlation analysis of the ether-metabolizing activities with individual CYP enzyme activities in the liver microsomes showed that the highest degree of correlation was with human CYP2A6 (r, 0. 90-0.95), which is constitutively expressed in human livers and known to be polymorphic. CYP2A6 displayed the highest turnover number in metabolizing gasoline ethers among a battery of human CYP enzymes expressed in human B-lymphoblastoid cells. Kinetic studies on MTBE metabolism with three human liver microsomes exhibited apparent Km values that ranged from 28 to 89 microM and the V(max) values from 215 to 783 pmol/min/mg, with similar catalytic efficiency values (7.7 to 8.8 microl/min/mg protein). Metabolism of MTBE, ETBE, and TAME by human liver microsomes was inhibited by coumarin, a known substrate of human CYP2A6, in a concentration-dependent manner. Monoclonal antibody against human CYP2A6 caused a significant inhibition (75% to 95%) of the metabolism of MTBE, ETBE, and TAME in human liver microsomes. Taken together, these results clearly indicate that in human liver, CYP2A6 is the major enzyme responsible for the

  6. Obesity-related metabolic dysfunction in dogs: a comparison with human metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Tvarijonaviciute Asta

    2012-08-01

    Full Text Available Abstract Background Recently, metabolic syndrome (MS has gained attention in human metabolic medicine given its associations with development of type 2 diabetes mellitus and cardiovascular disease. Canine obesity is associated with the development of insulin resistance, dyslipidaemia, and mild hypertension, but the authors are not aware of any existing studies examining the existence or prevalence of MS in obese dogs. Thirty-five obese dogs were assessed before and after weight loss (median percentage loss 29%, range 10-44%. The diagnostic criteria of the International Diabetes Federation were modified in order to define canine obesity-related metabolic dysfunction (ORMD, which included a measure of adiposity (using a 9-point body condition score [BCS], systolic blood pressure, fasting plasma cholesterol, plasma triglyceride, and fasting plasma glucose. By way of comparison, total body fat mass was measured by dual-energy X-ray absorptiometry, whilst total adiponectin, fasting insulin, and high-sensitivity C-reactive protein (hsCRP were measured using validated assays. Results Systolic blood pressure (P = 0.008, cholesterol (P = 0.003, triglyceride (P = 0.018, and fasting insulin (P P = 0.001. However, hsCRP did not change with weight loss. Prior to weight loss, 7 dogs were defined as having ORMD, and there was no difference in total fat mass between these dogs and those who did not meet the criteria for ORMD. However, plasma adiponectin concentration was less (P = 0.031, and plasma insulin concentration was greater (P = 0.030 in ORMD dogs. Conclusions In this study, approximately 20% of obese dogs suffer from ORMD, and this is characterized by hypoadiponectinaemia and hyperinsulinaemia. These studies can form the basis of further investigations to determine path genetic mechanisms and the health significance for dogs, in terms of disease associations and outcomes of weight loss.

  7. Study of effective atomic numbers and electron densities, kerma of alcohols, phantom and human organs, and tissues substitutes

    Directory of Open Access Journals (Sweden)

    Singh Vishwanath P.

    2013-01-01

    Full Text Available Effective atomic numbers (ZPIeff and electron densities of eighteen alcohols such as wood alcohol, CH3OH; grain alcohol, C2H5OH; rubbing alcohol, C3H7OH; butanol, C4H9OH; amyl alcohol, C5H11OH; cetyl alcohol, C16H33OH; ethylene glycol, C2H4(OH2; glycerin, C3H5(OH3; PVA, C2H4O; erythritol, C4H6(OH4; xylitol, C5H7(OH5; sorbitol, C6H8(OH6; volemitol, C7H9(OH7; allyl alcohol, C3H5OH; geraniol, C10H17OH; propargyl alcohol, C3H3OH; inositol, C6H6(OH6, and menthol, C10H19OH have been calculated in the photon energy region of 1 keV-100 GeV. The estimated values have been compared with experimental values wherever possible. The comparison of ZPIeff of the alcohols with water phantom and PMMA phantom indicate that the ethylene glycol, glycerin, and PVA are substitute for PMMA phantom and PVA is substitute of water phantom. ZPIeff of alcohols have also been compared with human organs and tissues. Ethylene glycol, glycerin and PVA, allyl alcohol, and wood alcohols are found tissue substitutes for most of human organs. Kerma which is the product of the energy fluence and mass energy-absorption coefficient, have been calculated in the energy region from 1 keV to 20 MeV for the alcohols. The results show the kerma is more or less independent of energy above 100 keV.

  8. Beneficial effects of non-alcoholic grape-derived products on human health: A literature review

    Directory of Open Access Journals (Sweden)

    Di Lorenzo Chiara

    2015-01-01

    Full Text Available Vine is widely cultivated due to the economic value of wine and other grape derivatives. The grape berry is character- ized by the presence of a wide variety of flavonoids, which have been investigated for their health promoting properties. Several epidemiological studies have shown that a moderate consumption of wine is associated with a J-shaped effect on some risk fac- tors for chronic diseases. On the other hand, the wine market has shown a decreasing trend due to the frequent abuse of alcoholic beverages also by young people, as denounced by WHO. Accordingly, the scientific research in the field of non-alcoholic grape products has been further stimulated. The aim of this paper was a preliminary collection of data on human studies supporting the beneficial properties of unfermented grape products. The most convincing positive effects, observed in humans, consisted in the reduction of risk factors for cardiovascular diseases, such as hypertension and oxidative stress. Other human trials have been published in the area of: immune system, diabetes, cognitive functions, oral health, and cancer. Generally speaking, the findings listed in this review support the use of non-alcoholic grape derivatives, as a source of beneficial compounds for the human diet, even though further studies are necessary.

  9. Short-term effect of recombinant human growth hormone in patients with alcoholic cirrhosis

    DEFF Research Database (Denmark)

    Møller, S; Becker, U; Grønbaek, M;

    1994-01-01

    As growth hormone possesses anabolic properties that are active on protein metabolism, and thus of potential benefit to patients with chronic liver disease, we determined the metabolic effects of recombinant human growth hormone on insulin-like growth factor-I (IGF-I) its specific binding proteins...... an increase in very low levels of insulin-like growth factor-I, even in patients with cirrhosis with advanced disease, but the clinical benefits remain to be demonstrated....

  10. Age and metabolic risk factors associated with oxidatively damaged DNA in human peripheral blood mononuclear cells

    DEFF Research Database (Denmark)

    Løhr, Mille; Jensen, Annie; Eriksen, Louise;

    2015-01-01

    , cholesterol and glycosylated hemoglobin (HbA1c). In the group of men, there were significant positive associations between alcohol intake, HbA1c and FPG-sensitive sites in multivariate analysis. The levels of metabolic risk factors were positively associated with age, yet only few subjects fulfilled all...

  11. Triglycerides, fatty acids, sterols, mono- and disaccharides and sugar alcohols in human milk and current types of infant formula milk

    NARCIS (Netherlands)

    Huisman, M; vanBeusekom, CM; Nijeboer, HJ; Muskiet, FAJ; Boersma, ER

    Objective: To investigate differences in the fatty acid composition, sterols, minor carbohydrates and sugar alcohols between human and formula milk. Design: We analyzed the concentrations of triglycerides, sterols, di- and monosaccharides and sugar alcohols, as well as the fatty acid composition of

  12. Triglycerides, fatty acids, sterols, mono- and disaccharides and sugar alcohols in human milk and current types of infant formula milk

    NARCIS (Netherlands)

    Huisman, M; vanBeusekom, CM; Nijeboer, HJ; Muskiet, FAJ; Boersma, ER

    1996-01-01

    Objective: To investigate differences in the fatty acid composition, sterols, minor carbohydrates and sugar alcohols between human and formula milk. Design: We analyzed the concentrations of triglycerides, sterols, di- and monosaccharides and sugar alcohols, as well as the fatty acid composition of

  13. Fatty acid metabolism studies of human epidermal cell cultures.

    Science.gov (United States)

    Marcelo, C L; Dunham, W R

    1993-12-01

    Adult human epidermal keratinocytes grow rapidly in medium that is essential fatty acid (EFA)-deficient. In this medium they exhibit decreased amounts of the fatty acids, 18:2, 20:3, 20:4, and contain increased amounts of monounsaturated fatty acids. [14C]- and [3H]acetate and radiolabeled fatty acids, 16:0, 18:2, and 20:4 were used to study the fatty acid metabolism of these cells. Label from acetate appeared in 14- to 20-carbon fatty acids, both saturated and monounsaturated. No label was seen in the essential fatty acid 18:2, 18:3, and 20:4. Radiolabel from [9, 10-3H]palmitic acid (16:0) was detected in 16:0, 16:1, 18:0, and 18:1. [14C]linoleic acid (18:2) was converted to 18:3, 20:2, 20:3, and 20:4, demonstrating delta 6 and delta 5 desaturase activity in keratinocytes. Label from acetate, 16:0, or 18:2 was found mostly in the cellular phospholipids while only one third of the label from [14C]arachidonic was found in the phospholipids. [14C]acetate and [14C]18:2 time course data were used to construct a model of the metabolism of these reactants, using coupled, first-order differential equations. The data show that EFA-deficient keratinocytes metabolize fatty acids using pathways previously found in liver; they suggest the positioning of 18:2 desaturase and 18:3 elongase near the plasma membrane; they indicate that for the synthesis of nonessential fatty acids the formation of 18:0 from 16:0 is the rate-determining step; and they show that the conversion of 18:2 to 20:3 is rapid. These experiments demonstrate a method to study lipid enzyme kinetics in living cells.

  14. Metabolic Effects of the Very-Low-Carbohydrate Diets: Misunderstood "Villains" of Human Metabolism

    Directory of Open Access Journals (Sweden)

    Manninen Anssi H

    2004-12-01

    Full Text Available Abstract During very low carbohydrate intake, the regulated and controlled production of ketone bodies causes a harmless physiological state known as dietary ketosis. Ketone bodies flow from the liver to extra-hepatic tissues (e.g., brain for use as a fuel; this spares glucose metabolism via a mechanism similar to the sparing of glucose by oxidation of fatty acids as an alternative fuel. In comparison with glucose, the ketone bodies are actually a very good respiratory fuel. Indeed, there is no clear requirement for dietary carbohydrates for human adults. Interestingly, the effects of ketone body metabolism suggest that mild ketosis may offer therapeutic potential in a variety of different common and rare disease states. Also, the recent landmark study showed that a very-low-carbohydrate diet resulted in a significant reduction in fat mass and a concomitant increase in lean body mass in normal-weight men. Contrary to popular belief, insulin is not needed for glucose uptake and utilization in man. Finally, both muscle fat and carbohydrate burn in an amino acid flame.

  15. Autonomous exoskeleton reduces metabolic cost of human walking.

    Science.gov (United States)

    Mooney, Luke M; Rouse, Elliott J; Herr, Hugh M

    2014-11-03

    Passive exoskeletons that assist with human locomotion are often lightweight and compact, but are unable to provide net mechanical power to the exoskeletal wearer. In contrast, powered exoskeletons often provide biologically appropriate levels of mechanical power, but the size and mass of their actuator/power source designs often lead to heavy and unwieldy devices. In this study, we extend the design and evaluation of a lightweight and powerful autonomous exoskeleton evaluated for loaded walking in (J Neuroeng Rehab 11:80, 2014) to the case of unloaded walking conditions. The metabolic energy consumption of seven study participants (85 ± 12 kg body mass) was measured while walking on a level treadmill at 1.4 m/s. Testing conditions included not wearing the exoskeleton and wearing the exoskeleton, in both powered and unpowered modes. When averaged across the gait cycle, the autonomous exoskeleton applied a mean positive mechanical power of 26 ± 1 W (13 W per ankle) with 2.12 kg of added exoskeletal foot-shank mass (1.06 kg per leg). Use of the leg exoskeleton significantly reduced the metabolic cost of walking by 35 ± 13 W, which was an improvement of 10 ± 3% (p = 0.023) relative to the control condition of not wearing the exoskeleton. The results of this study highlight the advantages of developing lightweight and powerful exoskeletons that can comfortably assist the body during walking.

  16. Glucose metabolism in cultured trophoblasts from human placenta

    Energy Technology Data Exchange (ETDEWEB)

    Moe, A.J.; Farmer, D.R.; Nelson, D.M.; Smith, C.H. (Washington Univ., St. Louis, MO (United States))

    1990-02-26

    The development of appropriate placental trophoblast isolation and culture techniques enables the study of pathways of glucose utilization by this important cell layer in vitro. Trophoblasts from normal term placentas were isolated and cultured 24 hours and 72 hours in uncoated polystyrene culture tubes or tubes previously coated with a fibrin matrix. Trophoblasts cultured on fibrin are morphologically distinct from those cultured on plastic or other matrices and generally resemble in vivo syncytium. Cells were incubated up to 3 hours with {sup 14}C-labeled glucose and reactions were stopped by addition of perchloric acid. {sup 14}CO{sub 2} production by trophoblasts increased linearly with time however the largest accumulation of label was in organic acids. Trophoblasts cultured in absence of fibrin utilized more glucose and accumulated more {sup 14}C in metabolic products compared to cells cultured on fibrin. Glucose oxidation to CO{sub 2} by the phosphogluconate (PG) pathway was estimated from specific yields of {sup 14}CO{sub 2} from (1-{sup 14}C)-D-glucose and (6-{sup 14}C)-D-glucose. Approximately 6% of glucose oxidation was by the PG pathway when cells were cultured on fibrin compared to approximately 1% by cells cultured in the absence of fibrin. The presence of a fibrin growth matrix appears to modulate the metabolism of glucose by trophoblast from human placenta in vitro.

  17. Targeting NAD+ metabolism in the human malaria parasite Plasmodium falciparum.

    Directory of Open Access Journals (Sweden)

    Jessica K O'Hara

    Full Text Available Nicotinamide adenine dinucleotide (NAD+ is an essential metabolite utilized as a redox cofactor and enzyme substrate in numerous cellular processes. Elevated NAD+ levels have been observed in red blood cells infected with the malaria parasite Plasmodium falciparum, but little is known regarding how the parasite generates NAD+. Here, we employed a mass spectrometry-based metabolomic approach to confirm that P. falciparum lacks the ability to synthesize NAD+ de novo and is reliant on the uptake of exogenous niacin. We characterized several enzymes in the NAD+ pathway and demonstrate cytoplasmic localization for all except the parasite nicotinamidase, which concentrates in the nucleus. One of these enzymes, the P. falciparum nicotinate mononucleotide adenylyltransferase (PfNMNAT, is essential for NAD+ metabolism and is highly diverged from the human homolog, but genetically similar to bacterial NMNATs. Our results demonstrate the enzymatic activity of PfNMNAT in vitro and demonstrate its ability to genetically complement the closely related Escherichia coli NMNAT. Due to the similarity of PfNMNAT to the bacterial enzyme, we tested a panel of previously identified bacterial NMNAT inhibitors and synthesized and screened twenty new derivatives, which demonstrate a range of potency against live parasite culture. These results highlight the importance of the parasite NAD+ metabolic pathway and provide both novel therapeutic targets and promising lead antimalarial compounds.

  18. Silibinin regulates lipid metabolism and differentiation in functional human adipocytes

    Directory of Open Access Journals (Sweden)

    Ignazio eBarbagallo

    2016-01-01

    Full Text Available Silibinin, a natural plant flavonoid, is the main active constituent found in milk thistle (Silybum marianum. It is known to have hepatoprotective, anti-neoplastic effect and suppresses lipid accumulation in adipocytes. Objective of this study was to investigate the effect of silibinin on adipogenic differentiation and thermogenic capacity of human adipose tissue derived mesenchymal stem cells. Silibinin (10 μM treatment, either at the beginning or at the end of adipogenic differentiation, resulted in an increase of SIRT-1, PPARα, Pgc-1α and UCPs gene expression. Moreover, silibinin administration resulted in a decrease of PPARγ, FABP4, FAS and MEST/PEG1 gene expression during the differentiation, confirming that this compound is able to reduce fatty acid accumulation and adipocyte size. Our data showed that silibinin regulated adipocyte lipid metabolism, inducing thermogenesis and promoting a brown remodelling in adipocyte. Taken together, our findings suggest that silibinin increases UCPs expression by stimulation of SIRT1, PPARα and Pgc-1α, improved metabolic parameters, decreased lipid mass leading to the formation of functional adipocytes.

  19. Electromagnetic respiratory effort harvester: human testing and metabolic cost analysis.

    Science.gov (United States)

    Shahhaidar, E; Padasdao, B; Romine, R; Stickley, C; Lubecke, O Boric

    2015-03-01

    Remote health monitoring is increasingly recognized as a valuable tool in chronic disease management. Continuous respiratory monitoring could be a powerful tool in managing chronic diseases, however it is infrequently performed because of obtrusiveness and inconvenience of the existing methods. The movements of the chest wall and abdominal area during normal breathing can be monitored and harvested to enable self-powered wearable biosensors for continuous remote monitoring. This paper presents human testing results of a light-weight (30 g), wearable respiratory effort energy harvesting sensor. The harvester output voltage, power, and its metabolic burden, are measured on twenty subjects in two resting and exercise conditions each lasting 5 min. The system includes two off-the-shelf miniature electromagnetic generators harvesting and sensing thoracic and abdominal movements. Modules can be placed in series to increase the output voltage for rectification purposes. Electromagnetic respiratory effort harvester/sensor system can produce up to 1.4 V, 6.44 mW, and harvests 30.4 mJ during a 5-min exercise stage. A statistical paired t-test analysis of the calculated EE confirmed there is no significant change ( P > 0.05 ) in the metabolic rate of subjects wearing the electromagnetic harvester and biosensor.

  20. Gene Coexpression Analysis Reveals Complex Metabolism of the Monoterpene Alcohol Linalool in Arabidopsis FlowersW

    NARCIS (Netherlands)

    Ginglinger, J.F.; Boachon, B.; Hofer, R.; Paetz, C.; Kollner, T.G.; Miesch, L.; Lugan, R.; Baltenweck, R.; Mutterer, J.; Ullman, P.; Verstappen, F.W.A.; Bouwmeester, H.J.

    2013-01-01

    The cytochrome P450 family encompasses the largest family of enzymes in plant metabolism, and the functions of many of its members in Arabidopsis thaliana are still unknown. Gene coexpression analysis pointed to two P450s that were coexpressed with two monoterpene synthases in flowers and were thus

  1. Gene Coexpression Analysis Reveals Complex Metabolism of the Monoterpene Alcohol Linalool in Arabidopsis FlowersW

    NARCIS (Netherlands)

    Ginglinger, J.F.; Boachon, B.; Hofer, R.; Paetz, C.; Kollner, T.G.; Miesch, L.; Lugan, R.; Baltenweck, R.; Mutterer, J.; Ullman, P.; Verstappen, F.W.A.; Bouwmeester, H.J.

    2013-01-01

    The cytochrome P450 family encompasses the largest family of enzymes in plant metabolism, and the functions of many of its members in Arabidopsis thaliana are still unknown. Gene coexpression analysis pointed to two P450s that were coexpressed with two monoterpene synthases in flowers and were thus

  2. Expression in Escherichia coli of active human alcohol dehydrogenase lacking N-terminal acetylation.

    Science.gov (United States)

    Höög, J O; Weis, M; Zeppezauer, M; Jörnvall, H; von Bahr-Lindström, H

    1987-12-01

    Human alcohol dehydrogenase (ADH, beta beta isozyme of class I) was expressed in Escherichia coli, purified to homogeneity, and characterized regarding N-terminal processing. The expression system was obtained by ligation of a cDNA fragment corresponding to the beta-subunit of human liver alcohol dehydrogenase into the vector pKK 223-3 containing the tac promoter. The enzyme, detected by Western-blot analysis and ethanol oxidizing activity, constituted up to 3% of the total amount of protein. Recombinant ADH was separated from E. coli ADH by ion-exchange chromatography and the isolated enzyme was essentially pure as judged by SDS-polyacrylamide gel electrophoresis and sequence analysis. The N-terminal sequence was identical to that of the authentic beta-subunit except that the N-terminus was non-acetylated, indicating a correct removal of the initiator methionine, but lack of further processing.

  3. Pediatric non alcoholic fatty liver disease: old and new concepts on development, progression, metabolic insight and potential treatment targets.

    Science.gov (United States)

    Giorgio, Valentina; Prono, Federica; Graziano, Francesca; Nobili, Valerio

    2013-03-25

    Nonalcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease in children. NAFLD has emerged to be extremely prevalent, and predicted by obesity and male gender. It is defined by hepatic fat infiltration >5% hepatocytes, in the absence of other causes of liver pathology. It includes a spectrum of disease ranging from intrahepatic fat accumulation (steatosis) to various degrees of necrotic inflammation and fibrosis (non-alcoholic steatohepatatis [NASH]). NAFLD is associated, in children as in adults, with severe metabolic impairments, determining an increased risk of developing the metabolic syndrome. It can evolve to cirrhosis and hepatocellular carcinoma, with the consequent need for liver transplantation. Both genetic and environmental factors seem to be involved in the development and progression of the disease, but its physiopathology is not yet entirely clear. In view of this mounting epidemic phenomenon involving the youth, the study of NAFLD should be a priority for all health care systems. This review provides an overview of current and new clinical-histological concepts of pediatric NAFLD, going through possible implications into patho-physiolocical and therapeutic perspectives.

  4. Social use of alcohol among adolescent offenders: a fundamental approach toward human needs

    Directory of Open Access Journals (Sweden)

    Gustavo D?Andrea

    2014-02-01

    Full Text Available This study examined some basic health care approaches toward human needs, with a particular focus on nursing. We aimed to incorporate these approaches into the discussion of the mental health of adolescent offenders who consume alcohol. We discuss specific needs of the delinquent group, critique policies that prioritize coercion of adolescent offenders, and the role that nurses could play in the sphere of juvenile delinquency.

  5. [Social use of alcohol among adolescent offenders: a fundamental approach toward human needs].

    Science.gov (United States)

    D'Andrea, Gustavo; Ventura, Carla Aparecida Arena; da Costa, Moacyr Lobo

    2014-02-01

    This study examined some basic health care approaches toward human needs, with a particular focus on nursing. We aimed to incorporate these approaches into the discussion of the mental health of adolescent offenders who consume alcohol. We discuss specific needs of the delinquent group, critique policies that prioritize coercion of adolescent offenders, and the role that nurses could play in the sphere of juvenile delinquency.

  6. Quantitative determination of caffeine and alcohol in energy drinks and the potential to produce positive transdermal alcohol concentrations in human subjects.

    Science.gov (United States)

    Ayala, Jessica; Simons, Kelsie; Kerrigan, Sarah

    2009-01-01

    The purpose of this study was to determine whether non-alcoholic energy drinks could result in positive "alcohol alerts" based on transdermal alcohol concentration (TAC) using a commercially available electrochemical monitoring device. Eleven energy drinks were quantitatively assayed for both ethanol and caffeine. Ethanol concentrations for all of the non-alcoholic energy drinks ranged in concentration from 0.03 to 0.230% (w/v) and caffeine content per 8-oz serving ranged from 65 to 126 mg. A total of 15 human subjects participated in the study. Subjects consumed between 6 and 8 energy drinks over an 8-h period. The SCRAM II monitoring device was used to determine TACs every 30 min before, during, and after the study. None of the subjects produced TAC readings that resulted in positive "alcohol alerts". TAC measurements for all subjects before, during and after the energy drink study period (16 h total) were energy drink that greatly exceeds what would be considered typical. Based on these results, it appears that energy drink consumption is an unlikely explanation for elevated TACs that might be identified as potential drinking episodes or "alcohol alerts" using this device.

  7. Expression of energy metabolism related genes in the gastric tissue of obese individuals with non-alcoholic fatty liver disease.

    Science.gov (United States)

    Mehta, Rohini; Birerdinc, Aybike; Wang, Lei; Younoszai, Zahra; Moazzez, Amir; Elariny, Hazem; Goodman, Zachary; Chandhoke, Vikas; Baranova, Ancha; Younossi, Zobair M

    2014-04-09

    Stomach is an integral part of the energy balance regulating circuit. Studies exploring the effects of cross-system changes in the energy homeostasis in stomach tissue are scarce. The proximity of the stomach to liver--the most common secondary target affected by obesity--suggests that these two organs are exposed to each other's local secretion. Therefore, we aimed at expression profiling of energy metabolism associated genes in the gastric tissue of obese non-alcoholic fatty liver disease (NAFLD) patients. A total of 24 patients with histologically-proven NAFLD were included. In the gastric tissue, gene expression profiling of 84 energy metabolism associated genes was carried out. The accumulation of the fat in the liver parenchyma is accompanied by downregulation of genes encoding for carboxypeptidase E (CPE) and Interleukin 1B (IL1B) in the gastric mucosa of same patient. In patients with high grade hepatic steatosis, Interleukin 1 beta encoding gene with anorexigenic function, IL1B was downregulated. The levels expression of 21 genes, including ADRA2B, CNR1 and LEP were significantly altered in the gastric tissue of NAFLD patients with hepatic inflammation. There were also indications of an increase in the opioid signaling within gastric mucosa that may results in a shift to proinflammatory environment within this organ and contribute to systemic inflammation and the pathogenic processes in hepatic parenchyma. We have shown differential expression of energy metabolism associated genes in the gastric tissue of obese NAFLD patients. Importantly, these gene expression profiles are associated with changes in the hepatic parenchyma as reflected in increased scores for hepatic steatosis, inflammation, fibrosis and NASH. This study suggests the complex interplay of multiple organs in the pathogenesis of obesity-related complications such as NAFLD and provides further evidence supporting an important role for gastric tissue in promoting obesity-related complications.

  8. Non-alcoholic fatty liver disease is associated with cardiovascular risk factors of metabolic syndrome.

    Science.gov (United States)

    Hurjui, Daniela Maria; Niţă, Otilia; Graur, Lidia Iuliana; Mihalache, Laura; Popescu, Dana Stefana; Huţanaşu, I C; Ungureanu, Didona; Graur, Mariana

    2012-01-01

    To evaluate the prevalence of steatosis and to assess its correlations with the classical cardiovascular (CV) risk factors, components of metabolic syndrome (MS) in a rural population. A sample of 254 subjects was enrolled in the study. Collected data included: age, gender, complete medical history, anthropometric and blood pressure (BP) measurements. The biological evaluation included metabolic and hepatic parameters. Ultrasound evaluation of steatosis relied on the criteria of the National Health and Nutrition Examination Survey (NHANES) III. Two thirds of the study population were obese or overweight (64.96%); 32.66% had systolic BP and 27.16% diastolic BP levels higher than normal. 38% of the subjects had abnormal fasting blood glucose levels, 14.56% having glycated hemoglobin (HbA1c) values corresponding to pre-diabetes, and 9.84% to overt diabetes; 8% had low HDL-cholesterol and 14.96% high triglycerides (Tg) levels. MS was present in 50.8% of individuals. Only 10.8% of all subjects did not have an ultrasound appearance of steatosis; 28.8% had moderate and 32% severe steatosis. There were statistically significant differences in subjects with steatosis vs. subjects without steatosis with regard to body mass index (BMI), WC, presence of MS, and BP and Tg levels, but not to ALAT, ASAT and GGT values. The important prevalence of obesity, fasting hyperglycamia, steatosis and MS shows a particularly metabolic fragile population; early diagnosis and interventional strategies are mandatory.

  9. 75 FR 57473 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2010-09-21

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Special Emphasis... Officer, National Institute on Alcohol Abuse and Alcoholism, Office of Extramural Activities,...

  10. 78 FR 42530 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2013-07-16

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Initial Review..., Ph.D., Scientific Review Officer, National Institute on Alcohol Abuse & Alcoholism,...

  11. 76 FR 78014 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2011-12-15

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Initial Review...., Scientific Review Administrator, National Institutes on Alcohol Abuse & Alcoholism, National Institutes...

  12. 75 FR 10808 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2010-03-09

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Special Emphasis... Officer, National Institute on Alcohol Abuse & Alcoholism, National Institutes of Health, 5635...

  13. 78 FR 42529 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2013-07-16

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Initial Review....D., Scientific Review Administrator, National Institutes on Alcohol Abuse & Alcoholism,...

  14. 75 FR 24961 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meetings

    Science.gov (United States)

    2010-05-06

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Special Emphasis... Extramural Activities, National Institutes of Health, National Institute on Alcohol Abuse & Alcoholism,...

  15. 76 FR 26308 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2011-05-06

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Initial Review..., Scientific Review Administrator, National Institutes On Alcohol Abuse & Alcoholism National, Institutes...

  16. 75 FR 63494 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2010-10-15

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Special Emphasis..., Extramural Project Review Branch, EPRB, National Institute on Alcohol Abuse and Alcoholism,...

  17. 77 FR 22794 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2012-04-17

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Initial Review..., Ph.D., Scientific Review Administrator, National Institutes on Alcohol Abuse & Alcoholism...

  18. Alcoholism and Alcohol Abuse

    Science.gov (United States)

    ... their drinking causes distress and harm. It includes alcoholism and alcohol abuse. Alcoholism, or alcohol dependence, is a disease that causes ... groups. NIH: National Institute on Alcohol Abuse and Alcoholism

  19. Ethanol metabolism by alcohol dehydrogenase or cytochrome P450 2E1 differentially impairs hepatic protein trafficking and growth hormone signaling.

    Science.gov (United States)

    Doody, Erin E; Groebner, Jennifer L; Walker, Jetta R; Frizol, Brittnee M; Tuma, Dean J; Fernandez, David J; Tuma, Pamela L

    2017-09-01

    The liver metabolizes alcohol using alcohol dehydrogenase (ADH) and cytochrome P450 2E1 (CYP2E1). Both enzymes metabolize ethanol into acetaldehyde, but CYP2E1 activity also results in the production of reactive oxygen species (ROS) that promote oxidative stress. We have previously shown that microtubules are hyperacetylated in ethanol-treated polarized, hepatic WIF-B cells and livers from ethanol fed rats. We have also shown that enhanced protein acetylation correlates with impaired clathrin-mediated endocytosis, constitutive secretion and nuclear translocation and that the defects are likely mediated by acetaldehyde. However, the roles of CYP2E1-generated metabolites and ROS in microtubule acetylation and these alcohol-induced impairments have not been examined. To determine if CYP2E1-mediated alcohol metabolism is required for enhanced acetylation and the trafficking defects, we co-incubated cells with ethanol and diallyl sulfide (a CYP2E1 inhibitor) or N-acetyl cysteine (an anti-oxidant). Both agents failed to prevent microtubule hyperacetylation in ethanol-treated cells and also failed to prevent impaired secretion or clathrin-mediated endocytosis. Somewhat surprisingly, both NAS and DAC prevented impaired STAT5B nuclear translocation. Further examination of microtubule-independent steps of the pathway revealed that Jak2/STAT5B activation by growth hormone (GH) was prevented by DAS and NAC. These results were confirmed in ethanol-exposed HepG2 cells expressing only ADH or CYP2E1. Using quantitative RT-PCR, we further determined that ethanol exposure led to blunted GH-mediated gene expression. In conclusion, we determined that alcohol-induced microtubule acetylation and associated defects in microtubule-dependent trafficking are mediated by ADH metabolism whereas impaired microtubule-independent Jak2/STAT5B activation is mediated by CYP2E1 activity. Copyright © 2017, American Journal of Physiology-Gastrointestinal and Liver Physiology.

  20. Seven weeks of Western diet in apolipoprotein-E-deficient mice induce metabolic syndrome and non-alcoholic steatohepatitis with liver fibrosis.

    Science.gov (United States)

    Schierwagen, Robert; Maybüchen, Lara; Zimmer, Sebastian; Hittatiya, Kanishka; Bäck, Christer; Klein, Sabine; Uschner, Frank E; Reul, Winfried; Boor, Peter; Nickenig, Georg; Strassburg, Christian P; Trautwein, Christian; Plat, Jogchum; Lütjohann, Dieter; Sauerbruch, Tilman; Tacke, Frank; Trebicka, Jonel

    2015-08-11

    Non-alcoholic steatohepatitis (NASH) is characterised by hepatic steatosis, inflammation and fibrosis, which might progress to cirrhosis. Human NASH is associated with metabolic syndrome (MS). Currently, rodent NASH models either lack significant fibrosis or MS. ApoE(-/-) mice are a MS model used in cardiovascular research. The aim of this work was to establish and characterise a novel mouse NASH model with significant fibrosis and MS. ApoE(-/-) and wild-type mice (wt) were fed either a western-diet (WD), methionine-choline-deficient-diet (MCD) or normal chow. Liver histology, RT-PCR, hepatic hydroxyproline content, triglycerides and cholesterol levels, and fasting glucose levels assessed hepatic steatosis, inflammation and fibrosis. Further, portal pressure was measured invasively, and kidney pathology was assessed by histology. ApoE(-/-) mice receiving WD showed abnormal glucose tolerance, hepatomegaly, weight gain and full spectrum of NASH including hepatic steatosis, fibrosis and inflammation, with no sign of renal damage. MCD-animals showed less severe liver fibrosis, but detectable renal pathological changes, besides weight loss and unchanged glucose tolerance. This study describes a murine NASH model with distinct hepatic steatosis, inflammation and fibrosis, without renal pathology. ApoE(-/-) mice receiving WD represent a novel and fast model with all characteristic features of NASH and MS well suitable for NASH research.

  1. Genome-scale modeling of human metabolism - a systems biology approach.

    Science.gov (United States)

    Mardinoglu, Adil; Gatto, Francesco; Nielsen, Jens

    2013-09-01

    Altered metabolism is linked to the appearance of various human diseases and a better understanding of disease-associated metabolic changes may lead to the identification of novel prognostic biomarkers and the development of new therapies. Genome-scale metabolic models (GEMs) have been employed for studying human metabolism in a systematic manner, as well as for understanding complex human diseases. In the past decade, such metabolic models - one of the fundamental aspects of systems biology - have started contributing to the understanding of the mechanistic relationship between genotype and phenotype. In this review, we focus on the construction of the Human Metabolic Reaction database, the generation of healthy cell type- and cancer-specific GEMs using different procedures, and the potential applications of these developments in the study of human metabolism and in the identification of metabolic changes associated with various disorders. We further examine how in silico genome-scale reconstructions can be employed to simulate metabolic flux distributions and how high-throughput omics data can be analyzed in a context-dependent fashion. Insights yielded from this mechanistic modeling approach can be used for identifying new therapeutic agents and drug targets as well as for the discovery of novel biomarkers. Finally, recent advancements in genome-scale modeling and the future challenge of developing a model of whole-body metabolism are presented. The emergent contribution of GEMs to personalized and translational medicine is also discussed. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Metabolic syndrome in human immunodeficiency virus positive patients

    Directory of Open Access Journals (Sweden)

    Sarita Bajaj

    2013-01-01

    Full Text Available Aims and Objectives : To assess the prevalence of metabolic syndrome (MetS in human immunodeficiency virus (HIV positive patients. Prevalence of MetS was compared in patients who were not on highly active antiretroviral therapy (HAART to patients who were on HAART. Materials and Methods: Seventy HIV positive cases were studied. Pregnant and lactating women, patients on drugs other than HAART known to cause metabolic abnormalities and those having diabetes or hypertension were excluded. Cases were evaluated for MetS by using National Cholesterol Education Program Adult Treatment Panel-III. Results: 47 cases were on HAART and 23 cases were not on HAART. Fasting Blood Glucose ≥100 mg/dl was present in 28.6% cases, out of whom 27.7% were on HAART and 30.4% were not on HAART (P = 0.8089. 12.9% cases had BP ≥130/≥85 mm Hg, out of whom 14.9% were on HAART and 8.7% were not on HAART (P = 0.4666. 42.9% cases had TG ≥150 mg/dl, out of whom 44.7% were on HAART and 39.1% were not on HAART (P = 0.6894. HDL cholesterol was low (males <40 mg/dl, females <50 mg/dl in 50% cases, out of whom 55.3% were on HAART and 39.1% were not on HAART (P = 0.2035. Conclusions: Prevalence of MetS was 20%. Majority of patients had only one component of MetS (32.9%. Low HDL was present in 50%, followed by raised triglycerides in 42.9%. Waist circumference was not increased in any of the patients. There was no statistically significant difference between those on HAART and those not on HAART in distribution of risk factors and individual components of MetS.

  3. Glucose Metabolism of Human Prostate Cancer Mouse Xenografts

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    Hossein Jadvar

    2005-04-01

    Full Text Available We hypothesized that the glucose metabolism of prostate cancer is modulated by androgen. We performed in vivo biodistribution and imaging studies of [F-18] fluorodeoxyglucose (FDG accumulation in androgen-sensitive (CWR-22 and androgen-independent (PC-3 human prostate cancer xenografts implanted in castrated and noncastrated male athymic mice. The growth pattern of the CWR-22 tumor was best approximated by an exponential function (tumor size in mm3 = 14.913 e0.108 × days, R2 = .96, n = 5. The growth pattern of the PC-3 tumor was best approximated by a quadratic function (tumor size in mm3 = 0.3511 × days2 + 49.418 × day −753.33, R2 = .96, n = 3. The FDG accumulation in the CWR-22 tumor implanted in the castrated mice was significantly lower, by an average of 55%, in comparison to that implanted in the noncastrated host (1.27 vs. 2.83, respectively, p < .05. The 3-week maximal standardized uptake value (SUVmax was 0.99 ± 0.43 (mean ± SD for CWR-22 and 1.21 ± 0.32 for PC-3, respectively. The 5-week SUVmax was 1.22 ± 0.08 for CWR-22 and 1.35 ± 0.17 for PC-3, respectively. The background muscle SUVmax was 0.53 ± 0.11. Glucose metabolism was higher in the PC-3 tumor than in the CWR-22 tumor at both the 3-week (by 18% and the 5-week (by 9.6% micro-PET imaging sessions. Our results support the notions that FDG PET may be useful in the imaging evaluation of response to androgen ablation therapy and in the early prediction of hormone refractoriness in men with metastatic prostate cancer.

  4. In vitro metabolism of genistein and tangeretin by human and murine cytochrome p450s

    DEFF Research Database (Denmark)

    Breinholt, Vibeke; Rasmussen, Salka; Brøsen, Kim

    2003-01-01

    Recombinant cytochrome P450 (CYP) 1A2, 3A4, 2C9 or 2D6 enzymes obtained from Escherichia coli and human liver microsomes samples were used to investigate the ability of human CYP enzymes to metabolize the two dietary flavonoids, genistein and tangeretin. Analysis of the metabolic profile from...

  5. Retinal Remodeling And Metabolic Alterations in Human AMD

    Directory of Open Access Journals (Sweden)

    Bryan William Jones

    2016-04-01

    Full Text Available Age-related macular degeneration (AMD is a progressive retinal degeneration resulting in central visual field loss, ultimately causing debilitating blindness. AMD affects 18% of Americans from 65 to 74, 30% older than 74 years of age and is the leading cause of severe vision loss and blindness in Western populations. While many genetic and environmental risk factors are known for AMD, we currently know less about the mechanisms mediating disease progression.The pathways and mechanisms through which genetic and non-genetic risk factors modulate development of AMD pathogenesis remain largely unexplored. Moreover, current treatment for AMD is palliative and limited to wet/exudative forms. Retina is a complex, heterocellular tissue and most retinal cell classes are impacted or altered in AMD. Defining disease and stage-specific cytoarchitectural and metabolic responses in AMD is critical for highlighting targets for intervention. The goal of this paper is to illustrate cell types impacted in AMD and demonstrate the implications of those changes, likely beginning in the retinal pigment epithelium (RPE, for remodeling of the the neural retina.Tracking heterocellular responses in disease progression is best achieved with computational molecular phenotyping (CMP, a tool that enables acquisition of a small molecule fingerprint for every cell in the retina. CMP uncovered critical cellular and molecular pathologies (remodeling and reprogramming in progressive retinal degenerations such as retinitis pigmentosa (RP. We now applied these approaches to normal human and AMD tissues mapping progression of cellular and molecular changes in AMD retinas, including late-stage forms of the disease.Major findings: 1 Evidence of metabolic instability in RPE in dry-AMD.2 Photoreceptors show clear indications of stress prior to cell death.3 Cone opsin processing by the RPE in AMD retinas may be differentially compromised vs. rod opsin.4 Müller cells in AMD exhibit

  6. METABOLISM OF 3 PHARMACOLOGICALLY ACTIVE-DRUGS IN ISOLATED HUMAN AND RAT HEPATOCYTES - ANALYSIS OF INTERSPECIES VARIABILITY AND COMPARISON WITH METABOLISM IN-VIVO

    NARCIS (Netherlands)

    SANDKER, GW; VOS, RME; DELBRESSINE, LPC; SLOOFF, MJH; MEIJER, DKF; GROOTHUIS, GMM

    1994-01-01

    1. The metabolism of the three drugs (Org GB 94, Org 3770 and Org OD 14) was studied in isolated human and rat hepatocytes. The metabolic profiles in rat and human hepatocytes were compared with the available in vivo data in both species. 2. All three drugs were metabolized extensively under the con

  7. The association of alcohol and alcohol metabolizing gene variants with diabetes and coronary heart disease risk factors in a white population

    DEFF Research Database (Denmark)

    Husemoen, Lise Lotte N; Jørgensen, Torben; Borch-Johnsen, Knut

    2010-01-01

    Epidemiological studies have shown a J- or U-shaped relation between alcohol and type 2 diabetes and coronary heart disease (CHD). The underlying mechanisms are not clear. The aim was to examine the association between alcohol intake and diabetes and intermediate CHD risk factors in relation...

  8. Smoking and alcoholism target genes associated with plasticity and glutamate transmission in the human ventral tegmental area.

    Science.gov (United States)

    Flatscher-Bader, T; Zuvela, N; Landis, N; Wilce, P A

    2008-01-01

    Drugs of abuse including nicotine and alcohol elicit their effect by stimulating the mesocorticolimbic dopaminergic system. There is a high incidence of nicotine dependence in alcoholics. To date only limited data is available on the molecular mechanism underlying the action of alcohol and nicotine in the human brain. This study utilized gene expression screening to identify genes sensitive to chronic alcohol abuse within the ventral tegmental area (VTA) of the human brain. Alcohol-responsive genes encoded proteins primarily involved in structural plasticity and neurotransmitter transport and release. In particular, genes involved with brain-derived neurotrophic factor signalling and glutamatergic transmission were found to be affected. The possibility that glutamate transport was a target of chronic alcohol and/or tobacco abuse was further investigated in an extended case set by measurement of mRNA and protein expression. Expression levels of vesicular glutamate transporters SLC17A6 and SLC17A7 were robustly induced by smoking, an effect that was reduced by alcohol co-exposure. Glutamatergic transmission is vital for the control of the VTA and may also be critical to the weighting of novelty and importance of a stimulus, an essential output of this brain region. We conclude that enduring plasticity within the VTA may be a major molecular mechanism for the maintenance of smoking addiction and that alcohol, nicotine and co-abuse have distinct impacts on glutamatergic transmission with important implications for the control of this core mesolimbic structure.

  9. In vitro studies on the oxidative metabolism of 20(s)-ginsenoside Rh2 in human, monkey, dog, rat, and mouse liver microsomes, and human liver s9.

    Science.gov (United States)

    Li, Liang; Chen, Xiaoyan; Zhou, Jialan; Zhong, Dafang

    2012-10-01

    20(S)-Ginsenoside Rh2 (Rh2)-containing products are widely used in Asia, Europe, and North America. However, extremely limited metabolism information greatly impedes the complete understanding of its clinical safety and effectiveness. The present study aims to systematically investigate the oxidative metabolism of Rh2 using a complementary set of in vitro models. Twenty-five oxidative metabolites were found using liquid chromatography-electrospray ionization ion-trap mass spectrometry. Six metabolites and a metabolic intermediate were synthesized. The metabolites were structurally identified as 26-hydroxy Rh2 (M1-1), (20S,24S)-epoxydammarane-12,25-diol-3-β-d-glucopyranoside (M1-3), (20S,24R)-epoxydammarane-12,25-diol-3-β-d-glucopyranoside (M1-5), 26,27-dihydroxy Rh2 (M3-6), (20S,24S)-epoxydammarane-12,25,26-triol-3-β-d-glucopyranoside (M3-10), (20S,24R)-epoxydammarane-12,25,26-triol-3-β-d-glucopyranoside (M3-11), and 26-aldehyde Rh2 on the basis of detailed mass spectrometry and nuclear magnetic resonance data analysis. Double-bond epoxidation followed by rearrangement and vinyl-methyl group hydroxylation represent the initial metabolic pathways generating monooxygenated metabolites M1-1 to M1-5. Further sequential metabolites (M2-M5) from the dehydrogenation and/or oxygenation of M1 were also detected. CYP3A4 was the predominant enzyme involved in the oxidative metabolism of Rh2, whereas alcohol dehydrogenase and aldehyde dehydrogenase mainly catalyzed the metabolic conversion of alcohol to the corresponding carboxylic acid. No significant differences were observed in the phase I metabolite profiles of Rh2 among the five species tested. Reactive epoxide metabolite formation in both humans and animals was evident. However, GSH conjugate M6 was detected only in cynomolgus monkey liver microsomal incubations. In conclusion, Rh2 is a good substrate for CYP3A4 and could undergo extensive oxidative metabolism under the catalysis of CYP3A4.

  10. Reference Cap of Poly Vinyl Alcohol for Quantitative Elastography of the Human Uterine Cervix

    DEFF Research Database (Denmark)

    Leonhard, Anne Katrine; Sandager, Puk; Rasmussen, Christina Kjærgaard

    CONTROL ID: 2522419 ABSTRACT FINAL ID: EP22.04 TITLE: Reference Cap of Poly Vinyl Alcohol for Quantitative Elastography of the Human Uterine Cervix AUTHORS (FIRST NAME, LAST NAME): Anne Katrine Leonhard1, Puk Sandager1, Christina K. Rasmussen1, Hee Lene1, Niels Uldbjerg1 INSTITUTIONS (ALL): 1....... Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus N, Denmark. ABSTRACT BODY: Objectives: To develop a reference cap for the ultrasound probe that allows for quantitative elastography of the cervical uterine tissue with preservation of a good ultrasonic image. Further to perform...... inter-intra observer evaluations. Methods: Two types of reference caps were developed. Cap 1 made of Poly Vinyl Alcohol [PVA] with the Young’s modulus [E] of 0.09 N/mm2. Cap 2 made of silicone and oil with the Young’s modulus of 0.4 N/mm2. Elastography was conducted with the caps applied to a 2D...

  11. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome.

    Science.gov (United States)

    Dietrich, Peter; Hellerbrand, Claus

    2014-08-01

    Nonalcoholic fatty liver disease (NAFLD) is now recognized as the most common cause of chronic liver disease worldwide. Its prevalence has increased to more than 30% of adults in developed countries and its incidence is still rising. The majority of patients with NAFLD have simple steatosis but in up to one third of patients, NAFLD progresses to its more severe form nonalcoholic steatohepatitis (NASH). NASH is characterized by liver inflammation and injury thereby determining the risk to develop liver fibrosis and cancer. NAFLD is considered the hepatic manifestation of the metabolic syndrome. However, the liver is not only a passive target but affects the pathogenesis of the metabolic syndrome and its complications. Conversely, pathophysiological changes in other organs such as in the adipose tissue, the intestinal barrier or the immune system have been identified as triggers and promoters of NAFLD progression. This article details the pathogenesis of NAFLD along with the current state of its diagnosis and treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  12. Alteration of liver parameters in non-alcoholic fatty liver disease in patients with metabolic síndrome

    Directory of Open Access Journals (Sweden)

    Alicia Sahuquillo Martínez

    2016-06-01

    Full Text Available The interest of non-alcoholic fatty liver disease (NAFLD is growing due to several reasons: high prevalence of the disease in the Western World, its capability to progress towards more aggressive histological forms and its association with diseases that increase cardiovascular risk. Objective: To analyze the alteration of liver parameters in NAFLD in patients with metabolic syndrome. Methods: A transverse, descriptive study of 100 patients with two or more cardiovascular risk factors was conducted. All patients signed informed consent. Patients selected were among those attending our Medical Office of Primary Attention and who had very little or no alcoholic consumption. A complete battery of analysis was performed including total abdominal ultrasound. Steatosis was evaluated and, if determined positive, patients were stratified in three degrees. The following determinations were collected: sex, personal and familial history of diabetes, arterial hypertension, dyslipidemia, age, weight, BMI, present pharmacological treatment, analytical parameters, blood pressure and abdominal perimeter. Results: 100 patients were included in the study, 56 (56% women and 44 (44% men, with an average age of 61,84 + 9,5 years 23% of all patients did not have NAFLD; 29% had mild NAFLD, 29% had moderate NAFLD and 19% had severe NAFLD. 82% of men presented NAFLD. 29% of women did not nave NAFLD. 22% were overweight and 38% were obese. Blood pressure was altered in 22% of men and 18% of women. 60% had altered fasting blood glucose. 36% had hypertriglyceridemia, 41% hypercholesterolemia with 65% high LDL cholesterol and 16% of low HDL cholesterol. 83% of patients had two or more criteria of metabolic syndrome. Average transaminases were: ALT 24.98 u/i; AST 32.19 u/i; GGT 55,65 u/i; ALT/AST ratio: 0.77. Lactate dehydrogenase 255.30 u/L. Alkaline phosphatase 82.80 u/L and bilirubin 0.78 mg/dL Conclusions: We did not find correlation between liver steatosis and alteration

  13. Impact of maternal metabolic abnormalities in pregnancy on human milk and subsequent infant metabolic development: methodology and design

    Directory of Open Access Journals (Sweden)

    Hamilton Jill K

    2010-10-01

    Full Text Available Abstract Background Childhood obesity is on the rise and is a major risk factor for type 2 diabetes later in life. Recent evidence indicates that abnormalities that increase risk for diabetes may be initiated early in infancy. Since the offspring of women with diabetes have an increased long-term risk for obesity and type 2 diabetes, the impact of maternal metabolic abnormalities on early nutrition and infant metabolic trajectories is of considerable interest. Human breast milk, the preferred food during infancy, contains not only nutrients but also an array of bioactive substances including metabolic hormones. Nonetheless, only a few studies have reported concentrations of metabolic hormones in human milk specifically from women with metabolic abnormalities. We aim to investigate the impact of maternal metabolic abnormalities in pregnancy on human milk hormones and subsequently on infant development over the first year of life. The objective of this report is to present the methodology and design of this study. Methods/Design The current investigation is a prospective study conducted within ongoing cohort studies of women and their offspring. Pregnant women attending outpatient obstetrics clinics in Toronto, Canada were recruited. Between April 2009 and July 2010, a total of 216 pregnant women underwent a baseline oral glucose tolerance test and provided medical and lifestyle history. Follow-up visits and telephone interviews are conducted and expected to be completed in October 2011. Upon delivery, infant birth anthropometry measurements and human breast milk samples are collected. At 3 and 12 months postpartum, mothers and infants are invited for follow-up assessments. Interim telephone interviews are conducted during the first year of offspring life to characterize infant feeding and supplementation behaviors. Discussion An improved understanding of the link between maternal metabolic abnormalities in pregnancy and early infant nutrition may

  14. Combined transcriptome analysis of fetal human and mouse cerebral cortex exposed to alcohol.

    Science.gov (United States)

    Hashimoto-Torii, Kazue; Kawasawa, Yuka Imamura; Kuhn, Alexandre; Rakic, Pasko

    2011-03-08

    Fetal exposure to environmental insults increases the susceptibility to late-onset neuropsychiatric disorders. Alcohol is listed as one of such prenatal environmental risk factors and known to exert devastating teratogenetic effects on the developing brain, leading to complex neurological and psychiatric symptoms observed in fetal alcohol spectrum disorder (FASD). Here, we performed a coordinated transcriptome analysis of human and mouse fetal cerebral cortices exposed to ethanol in vitro and in vivo, respectively. Up- and down-regulated genes conserved in the human and mouse models and the biological annotation of their expression profiles included many genes/terms related to neural development, such as cell proliferation, neuronal migration and differentiation, providing a reliable connection between the two species. Our data indicate that use of the combined rodent and human model systems provides an effective strategy to reveal and analyze gene expression changes inflicted by various physical and chemical environmental exposures during prenatal development. It also can potentially provide insight into the pathogenesis of environmentally caused brain disorders in humans.

  15. Amphiregulin activates human hepatic stellate cells and is upregulated in non alcoholic steatohepatitis

    Science.gov (United States)

    McKee, Chad; Sigala, Barbara; Soeda, Junpei; Mouralidarane, Angelina; Morgan, Maelle; Mazzoccoli, Gianluigi; Rappa, Francesca; Cappello, Francesco; Cabibi, Daniela; Pazienza, Valerio; Selden, Claire; Roskams, Tania; Vinciguerra, Manlio; Oben, Jude A.

    2015-01-01

    Amphiregulin (AR) involvement in liver fibrogenesis and hepatic stellate cells (HSC) regulation is under study. Non-alcoholic fatty liver disease (NAFLD) and its more severe form non-alcoholic steatohepatitis (NASH) may progress to cirrhosis and hepatocellular cancer (HCC). Our aim was to investigate ex vivo the effect of AR on human primary HSC (hHSC) and verify in vivo the relevance of AR in NAFLD fibrogenesis. hHSC isolated from healthy liver segments were analyzed for expression of AR and its activator, TNF-α converting enzyme (TACE). AR induction of hHSC proliferation and matrix production was estimated in the presence of antagonists. AR involvement in fibrogenesis was also assessed in a mouse model of NASH and in humans with NASH. hHSC time dependently expressed AR and TACE. AR increased hHSC proliferation through several mitogenic signaling pathways such as EGFR, PI3K and p38. AR also induced marked upregulation of hHSC fibrogenic markers and reduced hHSC death. AR expression was enhanced in the HSC of a murine model of NASH and of severe human NASH. In conclusion, AR induces hHSC fibrogenic activity via multiple mitogenic signaling pathways, and is upregulated in murine and human NASH, suggesting that AR antagonists may be clinically useful anti-fibrotics in NAFLD. PMID:25744849

  16. Metabolic syndrome--psycho neuropathogenesis and human brain evolution.

    Science.gov (United States)

    Perumal, Madhusoothanan Bhagavathi

    2011-01-01

    Metabolic syndrome (MS) is a major risk factor for coronary artery disease. Heightened hypothalamo-pituitary-adrenal axis activity is associated with pathogenesis of MS. Life style, food habits and physical activity also play critical role in the pathogenesis of MS. However, the precise neurophysiology behind chronic stress leading on to such effects is unknown. Review of recent animal and human studies have shown the subtle differences in morphological changes associated with chronic stress between medial prefrontal cortex and amygdaloid complex. The loss of dendritic spines in pyramidal neurons of medial prefrontal cortex, dendritic hypertrophy in basolateral amygdala and dendritic loss in central nucleus of amygdala causes increased basal output from amygdaloid complex to HPA axis and other targets whose networks are evolutionarily well conserved. The increased HPA axis activity, elevated blood pressure and appetite for high calorie diet leads to MS. The evolution of isocortex in primates and associated regression in size of limbic structures predisposed to increased synaptic noise in amygdaloid complex which in turn cause heighetened output from amygdala during chronic stress. Copyright © 2010 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  17. L-carnitine--metabolic functions and meaning in humans life.

    Science.gov (United States)

    Pekala, Jolanta; Patkowska-Sokoła, Bozena; Bodkowski, Robert; Jamroz, Dorota; Nowakowski, Piotr; Lochyński, Stanisław; Librowski, Tadeusz

    2011-09-01

    L-Carnitine is an endogenous molecule involved in fatty acid metabolism, biosynthesized within the human body using amino acids: L-lysine and L-methionine, as substrates. L-Carnitine can also be found in many foods, but red meats, such as beef and lamb, are the best choices for adding carnitine into the diet. Good carnitine sources also include fish, poultry and milk. Essentially, L-carnitine transports the chains of fatty acids into the mitochondrial matrix, thus allowing the cells to break down fat and get energy from the stored fat reserves. Recent studies have started to shed light on the beneficial effects of L-carnitine when used in various clinical therapies. Because L-carnitine and its esters help reduce oxidative stress, they have been proposed as a treatment for many conditions, i.e. heart failure, angina and weight loss. For other conditions, such as fatigue or improving exercise performance, L-carnitine appears safe but does not seem to have a significant effect. The presented review of the literature suggests that continued studies are required before L-carnitine administration could be recommended as a routine procedure in the noted disorders. Further research is warranted in order to evaluate the biochemical, pharmacological, and physiological determinants of the response to carnitine supplementation, as well as to determine the potential benefits of carnitine supplements in selected categories of individuals who do not have fatty acid oxidation defects.

  18. Ammonia metabolism during intense dynamic exercise and recovery in humans

    DEFF Research Database (Denmark)

    Graham, T; Bangsbo, Jens; Gollnick, PD

    1990-01-01

     declined immediately on cessation of exercise. Recovery was complete in approximately 20 min. Arterial [NH3] increased less rapidly and reached itsmaximum 2-3 min into recovery. These data demonstrate that NH3 clearance is more sensitive to the cessation of exercise than is NH3 release from skeletal muscle. Muscle [NH......This study examined the dynamics for ammonia (NH3) metabolism in human skeletal muscle during and after intense one-legged exercise. Subjects (n = 8) performed dynamic leg extensor exercise to exhaustion (3.2 min). MuscleNH3 release increased rapidly to a maximum of 314 +/- 42 mumol/min and......3] increased three to fourfold during exercise and represented 74 +/- 8% of the total net NH3 formation. Thus the change in muscle [NH3] alone underestimates the NH3 production. There was no evidence that the muscle-to-venous blood NH3 ratio shifts in accordance with the H+ data. Thus other factors...

  19. Short-term effect of recombinant human growth hormone in patients with alcoholic cirrhosis

    DEFF Research Database (Denmark)

    Møller, S; Becker, U; Grønbaek, M;

    1994-01-01

    As growth hormone possesses anabolic properties that are active on protein metabolism, and thus of potential benefit to patients with chronic liver disease, we determined the metabolic effects of recombinant human growth hormone on insulin-like growth factor-I (IGF-I) its specific binding proteins......, and liver function. Twenty consecutive patients with cirrhosis were randomized to recombinant human growth hormone (Norditropin, 4 I.U. twice daily) subcutaneously for 6 weeks (n = 10) or conventional medical treatment (n = 10). The serum concentrations of insulin-like growth factor-I in the recombinant...... human growth hormone group increased after 3 (p growth factor-I during the treatment period was expressed as area under the curve (AUC). The AUCIGF-I was significantly larger...

  20. Biochemical characterization of human gluconokinase and the proposed metabolic impact of gluconic Acid as determined by constraint based metabolic network analysis

    DEFF Research Database (Denmark)

    Rohatgi, Neha; Nielsen, Tine Kragh; Bjørn, Sara Petersen

    2014-01-01

    and strict specificity towards gluconate out of 122 substrates tested. In order to evaluate the metabolic impact of gluconate in humans we modeled gluconate metabolism using steady state metabolic network analysis. The results indicate that significant metabolic flux changes in anabolic pathways linked......The metabolism of gluconate is well characterized in prokaryotes where it is known to be degraded following phosphorylation by gluconokinase. Less is known of gluconate metabolism in humans. Human gluconokinase activity was recently identified proposing questions about the metabolic role...... to the hexose monophosphate shunt (HMS) are induced through a small increase in gluconate concentration. We argue that the enzyme takes part in a context specific carbon flux route into the HMS that, in humans, remains incompletely explored. Apart from the biochemical description of human gluconokinase...

  1. Integrated analysis of transcript-level regulation of metabolism reveals disease-relevant nodes of the human metabolic network.

    Science.gov (United States)

    Galhardo, Mafalda; Sinkkonen, Lasse; Berninger, Philipp; Lin, Jake; Sauter, Thomas; Heinäniemi, Merja

    2014-02-01

    Metabolic diseases and comorbidities represent an ever-growing epidemic where multiple cell types impact tissue homeostasis. Here, the link between the metabolic and gene regulatory networks was studied through experimental and computational analysis. Integrating gene regulation data with a human metabolic network prompted the establishment of an open-sourced web portal, IDARE (Integrated Data Nodes of Regulation), for visualizing various gene-related data in context of metabolic pathways. Motivated by increasing availability of deep sequencing studies, we obtained ChIP-seq data from widely studied human umbilical vein endothelial cells. Interestingly, we found that association of metabolic genes with multiple transcription factors (TFs) enriched disease-associated genes. To demonstrate further extensions enabled by examining these networks together, constraint-based modeling was applied to data from human preadipocyte differentiation. In parallel, data on gene expression, genome-wide ChIP-seq profiles for peroxisome proliferator-activated receptor (PPAR) γ, CCAAT/enhancer binding protein (CEBP) α, liver X receptor (LXR) and H3K4me3 and microRNA target identification for miR-27a, miR-29a and miR-222 were collected. Disease-relevant key nodes, including mitochondrial glycerol-3-phosphate acyltransferase (GPAM), were exposed from metabolic pathways predicted to change activity by focusing on association with multiple regulators. In both cell types, our analysis reveals the convergence of microRNAs and TFs within the branched chain amino acid (BCAA) metabolic pathway, possibly providing an explanation for its downregulation in obese and diabetic conditions.

  2. Disruption of lactate dehydrogenase and alcohol dehydrogenase for increased hydrogen production and its effect on metabolic flux in Enterobacter aerogenes.

    Science.gov (United States)

    Zhao, Hongxin; Lu, Yuan; Wang, Liyan; Zhang, Chong; Yang, Cheng; Xing, Xinhui

    2015-10-01

    Hydrogen production by Enterobacter aerogenes from glucose was enhanced by deleting the targeted ldhA and adh genes responsible for two NADH-consuming pathways which consume most NADH generated from glycolysis. Compared with the wild-type, the hydrogen yield of IAM1183-ΔldhA increased 1.5 fold. Metabolic flux analysis showed both IAM1183-ΔldhA and IAM1183-Δadh exhibited significant changes in flux, including enhanced flux towards the hydrogen generation. The lactate production of IAM1183-ΔldhA significantly decreased by 91.42%, while the alcohol yield of IAM1183-Δadh decreased to 30%. The mutant IAM1183-ΔldhA with better hydrogen-producing performance was selected for further investigation in a 5-L fermentor. The hydrogen production of IAM1183-ΔldhA was 2.3 times higher than the wild-type. Further results from the fermentation process showed that the pH decreased to 5.39 levels, then gradually increased to 5.96, indicating that some acidic metabolites might be degraded or uptaken by cells.

  3. The association of metabolic syndrome, insulin resistance and non-alcoholic fatty liver disease in overweight/obese children

    Directory of Open Access Journals (Sweden)

    Nehal M El-Koofy

    2012-01-01

    Full Text Available Background/Aim: To study the prevalence of metabolic syndrome (MS, insulin resistance (IR and non-alcoholic fatty liver disease (NAFLD in overweight/obese children with clinical hepatomegaly and/or raised alanine aminotransferase (ALT. Patients and Methods: Thirty-three overweight and obese children, aged 2-13 years, presenting with hepatomegaly and/or raised ALT, were studied for the prevalence of MS, IR and NAFLD. Laboratory analysis included fasting blood glucose, serum insulin, serum triglycerides (TG, total cholesterol, high-density lipoprotein cholesterol (HDL-c, low-density lipoprotein cholesterol (LDL-c and liver biochemical profile, in addition to liver ultrasound and liver biopsy. Results: Twenty patients (60.6% were labeled with MS. IR was present in 16 (48.4%. Fifteen (44% patients had biopsy-proven NAFLD. Patients with MS were more likely to have NAFLD by biopsy (P=0.001. Children with NAFLD had significantly higher body mass index, waist circumference, ALT, total cholesterol, LDL-c, TG, fasting insulin, and lower HDL-c compared to patients with normal liver histology (P< 0.05 and fitted more with the criteria of MS (80% vs. 44%. IR was significantly more common among NAFLD patients (73% vs. 28%. Conclusion: There is a close association between obesity, MS, IR and NAFLD. Obese children with clinical or biochemical hepatic abnormalities are prone to suffer from MS, IR and NAFLD.

  4. The Association of Metabolic Syndrome, Insulin Resistance and Non-alcoholic Fatty Liver Disease in Overweight/Obese Children

    Science.gov (United States)

    El-Koofy, Nehal M.; Anwar, Ghada M.; El-Raziky, Mona S.; El-Hennawy, Ahmad M.; El-Mougy, Fatma M.; El-Karaksy, Hanaa M.; Hassanin, Fetouh M.; Helmy, Heba M.

    2012-01-01

    Background/Aim: To study the prevalence of metabolic syndrome (MS), insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) in overweight/obese children with clinical hepatomegaly and/or raised alanine aminotransferase (ALT). Patients and Methods: Thirty-three overweight and obese children, aged 2-13 years, presenting with hepatomegaly and/or raised ALT, were studied for the prevalence of MS, IR and NAFLD. Laboratory analysis included fasting blood glucose, serum insulin, serum triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and liver biochemical profile, in addition to liver ultrasound and liver biopsy. Results: Twenty patients (60.6%) were labeled with MS. IR was present in 16 (48.4%). Fifteen (44%) patients had biopsy-proven NAFLD. Patients with MS were more likely to have NAFLD by biopsy (P=0.001). Children with NAFLD had significantly higher body mass index, waist circumference, ALT, total cholesterol, LDL-c, TG, fasting insulin, and lower HDL-c compared to patients with normal liver histology (P< 0.05) and fitted more with the criteria of MS (80% vs. 44%). IR was significantly more common among NAFLD patients (73% vs. 28%). Conclusion: There is a close association between obesity, MS, IR and NAFLD. Obese children with clinical or biochemical hepatic abnormalities are prone to suffer from MS, IR and NAFLD. PMID:22249092

  5. The association of metabolic syndrome, insulin resistance and non-alcoholic fatty liver disease in overweight/obese children.

    Science.gov (United States)

    El-Koofy, Nehal M; Anwar, Ghada M; El-Raziky, Mona S; El-Hennawy, Ahmad M; El-Mougy, Fatma M; El-Karaksy, Hanaa M; Hassanin, Fetouh M; Helmy, Heba M

    2012-01-01

    To study the prevalence of metabolic syndrome (MS), insulin resistance (IR) and non-alcoholic fatty liver disease (NAFLD) in overweight/obese children with clinical hepatomegaly and/or raised alanine aminotransferase (ALT). Thirty-three overweight and obese children, aged 2-13 years, presenting with hepatomegaly and/or raised ALT, were studied for the prevalence of MS, IR and NAFLD. Laboratory analysis included fasting blood glucose, serum insulin, serum triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and liver biochemical profile, in addition to liver ultrasound and liver biopsy. Twenty patients (60.6%) were labeled with MS. IR was present in 16 (48.4%). Fifteen (44%) patients had biopsy-proven NAFLD. Patients with MS were more likely to have NAFLD by biopsy (P=0.001). Children with NAFLD had significantly higher body mass index, waist circumference, ALT, total cholesterol, LDL-c, TG, fasting insulin, and lower HDL-c compared to patients with normal liver histology (Pobesity, MS, IR and NAFLD. Obese children with clinical or biochemical hepatic abnormalities are prone to suffer from MS, IR and NAFLD.

  6. Can human rights standards help protect children and youth from the detrimental impact of alcohol beverage marketing and promotional activities?

    Science.gov (United States)

    Chapman, Audrey R

    2017-01-01

    The alcohol industry in the Latin American and Caribbean (LAC) region promotes demand for alcohol products actively through a number of channels, including advertising and sponsorship of sports and other events. This paper evaluates whether human rights instruments that Latin American countries have ratified can be used to limit children's exposure to alcohol advertising and promotion. A review was conducted of the text of, and interpretative documents related to, a series of international and regional human rights instruments ratified by most countries in the LAC region that enumerate the right to health. The Convention on the Rights of the Child has the most relevant provisions to protect children and youth from alcohol promotion and advertising. Related interpretive documents by the United Nations Committee on the Rights of the Child affirm that corporations hold duties to respect and protect children's right to health. Human rights norms and law can be used to regulate or eliminate alcohol beverage marketing and promotional activities in the Latin American region. The paper recommends developing a human rights based Framework Convention on Alcohol Control to provide guidance. © 2016 Society for the Study of Addiction.

  7. Metabolism

    Science.gov (United States)

    ... Are More Common in People With Type 1 Diabetes Metabolic Syndrome Your Child's Weight Healthy Eating Endocrine System Blood Test: Basic Metabolic Panel (BMP) Activity: Endocrine System Growth Disorders Diabetes Center Thyroid Disorders Your Endocrine System Movie: Endocrine ...

  8. The Role of Lipid and Lipoprotein Metabolism in Non‐Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Francesco Massimo Perla

    2017-06-01

    Full Text Available Due to the epidemic of obesity across the world, nonalcoholic fatty liver disease (NAFLD has become one of the most prevalent chronic liver disorders in children and adolescents. NAFLD comprises a spectrum of fat-associated liver conditions that can result in end-stage liver disease and the need for liver transplantation. Simple steatosis, or fatty liver, occurs early in NAFLD and may progress to nonalcoholic steatohepatitis, fibrosis and cirrhosis with increased risk of hepatocellular carcinoma. The mechanism of the liver injury in NAFLD is currently thought to be a “multiple-hit process” where the first “hit” is an increase in liver fat, followed by multiple additional factors that trigger the inflammatory activity. At the onset of disease, NAFLD is characterized by hepatic triglyceride accumulation and insulin resistance. Liver fat accumulation is associated with increased lipotoxicity from high levels of free fatty acids, free cholesterol and other lipid metabolites. As a consequence, mitochondrial dysfunction with oxidative stress and production of reactive oxygen species and endoplasmic reticulum stress-associated mechanisms, are activated. The present review focuses on the relationship between intra-cellular lipid accumulation and insulin resistance, as well as on lipid and lipoprotein metabolism in NAFLD.

  9. The prevalence of non-alcoholic fatty liver disease and metabolic syndrome in obese children.

    Science.gov (United States)

    Gupta, Rishi; Bhangoo, Amrit; Matthews, Nicole A V; Anhalt, Henry; Matta, Yesu; Lamichhane, Basant; Malik, Shahid; Narwal, Shivinder; Wetzler, Graciela; Ten, Svetlana

    2011-01-01

    In the context of present epidemic of childhood obesity, we aimed to find the prevalence of nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome (MS) in a cohort of obese children. Retrospective chart analysis of 700 obese children was done for their anthropometric and biochemical investigations. Some 15.4% (9.8% girls, 22% boys) subjects had NAFLD (ALT > 40 IU/L) after excluding other identifiable causes of liver dysfunction. Age, weight, TG, fasting serum insulin and HOMA-IR levels were higher in children with NAFLD. Twenty-eight percent children had MS. Children with NAFLD had an odds ratio of 2.65 for having MS (boys 4.6, girls 1.7). The prevalence of MS increased with age 5-9 years (21%), 10-16 years (30%), 17-20 years (35%). Given high prevalence of NAFLD and MS in obese children, childhood obesity should be seriously considered as a disease and not just a cosmetic issue.

  10. Effects of Probiotics and Synbiotics on Obesity, Insulin Resistance Syndrome, Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease: A Review of Human Clinical Trials.

    Science.gov (United States)

    Sáez-Lara, Maria Jose; Robles-Sanchez, Candido; Ruiz-Ojeda, Francisco Javier; Plaza-Diaz, Julio; Gil, Angel

    2016-06-13

    The use of probiotics and synbiotics in the prevention and treatment of different disorders has dramatically increased over the last decade. Both probiotics and synbiotics are well known ingredients of functional foods and nutraceuticals and may provide beneficial health effects because they can influence the intestinal microbial ecology and immunity. The present study reviews the effects of probiotics and synbiotics on obesity, insulin resistance syndrome (IRS), type 2 diabetes (T2D) and non-alcoholic fatty liver disease (NAFLD) in human randomized clinical trials. Select probiotics and synbiotics provided beneficial effects in patients with obesity, mainly affecting the body mass index and fat mass. Some probiotics had beneficial effects on IRS, decreasing the cell adhesion molecule-1 levels, and the synbiotics decreased the insulin resistance and plasma lipid levels. Moreover, select probiotics improved the carbohydrate metabolism, fasting blood glucose, insulin sensitivity and antioxidant status and also reduced metabolic stress in subjects with T2D. Some probiotics and synbiotics improved the liver and metabolic parameters in patients with NAFLD. The oral intake of probiotics and synbiotics as co-adjuvants for the prevention and treatment of obesity, IRS, T2D and NAFLD is partially supported by the data shown in the present review. However, further studies are required to understand the precise mechanism of how probiotics and synbiotics affect these metabolic disorders.

  11. Effects of Probiotics and Synbiotics on Obesity, Insulin Resistance Syndrome, Type 2 Diabetes and Non-Alcoholic Fatty Liver Disease: A Review of Human Clinical Trials

    Directory of Open Access Journals (Sweden)

    Maria Jose Sáez-Lara

    2016-06-01

    Full Text Available The use of probiotics and synbiotics in the prevention and treatment of different disorders has dramatically increased over the last decade. Both probiotics and synbiotics are well known ingredients of functional foods and nutraceuticals and may provide beneficial health effects because they can influence the intestinal microbial ecology and immunity. The present study reviews the effects of probiotics and synbiotics on obesity, insulin resistance syndrome (IRS, type 2 diabetes (T2D and non-alcoholic fatty liver disease (NAFLD in human randomized clinical trials. Select probiotics and synbiotics provided beneficial effects in patients with obesity, mainly affecting the body mass index and fat mass. Some probiotics had beneficial effects on IRS, decreasing the cell adhesion molecule-1 levels, and the synbiotics decreased the insulin resistance and plasma lipid levels. Moreover, select probiotics improved the carbohydrate metabolism, fasting blood glucose, insulin sensitivity and antioxidant status and also reduced metabolic stress in subjects with T2D. Some probiotics and synbiotics improved the liver and metabolic parameters in patients with NAFLD. The oral intake of probiotics and synbiotics as co-adjuvants for the prevention and treatment of obesity, IRS, T2D and NAFLD is partially supported by the data shown in the present review. However, further studies are required to understand the precise mechanism of how probiotics and synbiotics affect these metabolic disorders.

  12. Metabolism

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008255 Serum adiponectin level declines in the elderly with metabolic syndrome.WU Xiaoyan(吴晓琰),et al.Dept Geriatr,Huashan Hosp,Fudan UnivShanghai200040.Chin J Geriatr2008;27(3):164-167.Objective To investigate the correlation between ser-um adiponectin level and metabolic syndrome in the elderly·Methods Sixty-one subjects with metabolic syndrome and140age matched subjects without metabolic

  13. Fat-specific Protein 27/CIDEC Promotes Development of Alcoholic Steatohepatitis in Mice and Humans

    Science.gov (United States)

    Xu, Ming-Jiang; Cai, Yan; Wang, Hua; Altamirano, José; Chang, Binxia; Bertola, Adeline; Odena, Gemma; Lu, Jim; Tanaka, Naoki; Matsusue, Kimihiko; Matsubara, Tsutomu; Mukhopadhyay, Partha; Kimura, Shioko; Pacher, Pal; Gonzalez, Frank J; Bataller, Ramon; Gao, Bin

    2015-01-01

    Background & Aims Alcoholic steatohepatitis (ASH) is the progressive form of alcoholic liver disease and may lead to cirrhosis and hepatocellular carcinoma. We studied mouse models and human tissues to identify molecules associated with ASH progression, and focused on mouse fat-specific protein 27 (FSP-27)/human cell death-inducing DFF45-like effector C (CIDEC) protein, which is expressed in white adipose tissues and promotes formation of fat droplets. Methods C57BL/6N mice or mice with hepatocyte-specific disruption of Fsp27 (Fsp27Hep−/− mice) were fed the Lieber-Decarli ethanol liquid diet (5% ethanol) for 10 days to 12 weeks, followed by 1 or multiple binges of ethanol (5 or 6 g/kg) during the chronic feeding. Some mice were given an inhibitor of the peroxisome proliferator-activated receptor-γ (PPARG) (GW9662). Adenoviral vectors were used to express transgenes or small hairpin (sh) RNAs in cultured hepatocytes and in mice. Liver tissue samples were collected from ethanol-fed mice or from 31 patients with alcoholic hepatitis (AH) with biopsy-proved ASH and analyzed by histologic, immunohistochemical, transcriptome, immunoblot, and real-time PCR analyses. Results Chronic-plus-binge ethanol feeding of mice, which mimics the drinking pattern of patients with AH, produced severe ASH and mild fibrosis. Microarray analyses revealed similar alterations in expression of many hepatic genes in ethanol-fed mice and humans with ASH, including upregulation of mouse Fsp27 (also called Cidec) and human CIDEC. Fsp27Hep−/− mice and mice given injections of adenovirus-Fsp27shRNA had markedly reduced ASH following chronic-plus-binge ethanol feeding. Inhibition of PPARG and cyclic AMP-responsive element binding protein H (CREBH) prevented the increases in Fsp27α and FSP27β mRNAs, respectively, and reduced liver injury in this chronic-plus-binge ethanol feeding model. Overexpression of FSP27 and ethanol exposure had synergistic effects in inducing production of

  14. The role of gut microbiota in human metabolism

    NARCIS (Netherlands)

    Vrieze, A.

    2013-01-01

    This thesis supports the hypothesis that gut microbiota can be viewed as an ‘exteriorised organ’ that contributes to energy metabolism and the modulation of our immune system. Following Koch’s postulates, it has now been shown that gut microbiota are associated with metabolic disease and that these

  15. Cerebrovascular response to acute metabolic acidosis in humans.

    NARCIS (Netherlands)

    Ven, M.T.P. van de; Colier, W.N.J.M.; Kersten, B.T.P.; Oeseburg, B.; Folgering, H.T.M.

    2003-01-01

    OBJECTIVES: Evaluation of the cerebrovascular response (delta CBV/delta PaCO2) during baseline metabolic conditions and acute metabolic acidosis. METHODS: 15 healthy subjects, 5 m, 10 f, 56 +/- 10 yrs were investigated. For acidification, NH4Cl was given orally. CBV was measured using Near Infrared

  16. The role of gut microbiota in human metabolism

    NARCIS (Netherlands)

    Vrieze, A.

    2013-01-01

    This thesis supports the hypothesis that gut microbiota can be viewed as an ‘exteriorised organ’ that contributes to energy metabolism and the modulation of our immune system. Following Koch’s postulates, it has now been shown that gut microbiota are associated with metabolic disease and that these

  17. Metabolic control of muscle blood flow during exercise in humans

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher

    2003-01-01

    During muscle contraction, several mechanisms regulate blood flow to ensure a close coupling between muscle oxygen delivery and metabolic demand. No single factor has been identified to constitute the primary metabolic regulator, yet there are signal transduction pathways between skeletal muscle...

  18. Circadian rhythms, metabolism, and chrononutrition in rodents and humans

    Science.gov (United States)

    Chrononutrition is an emerging discipline that builds on the intimate relation between endogenous circadian (24-h) rhythms and metabolism. Circadian regulation of metabolic function can be observed from the level of intracellular biochemistry to whole-organism physiology and even postprandial respon...

  19. Reconstruction of genome-scale metabolic models for 126 human tissues using mCADRE.

    Science.gov (United States)

    Wang, Yuliang; Eddy, James A; Price, Nathan D

    2012-12-13

    Human tissues perform diverse metabolic functions. Mapping out these tissue-specific functions in genome-scale models will advance our understanding of the metabolic basis of various physiological and pathological processes. The global knowledgebase of metabolic functions categorized for the human genome (Human Recon 1) coupled with abundant high-throughput data now makes possible the reconstruction of tissue-specific metabolic models. However, the number of available tissue-specific models remains incomplete compared with the large diversity of human tissues. We developed a method called metabolic Context-specificity Assessed by Deterministic Reaction Evaluation (mCADRE). mCADRE is able to infer a tissue-specific network based on gene expression data and metabolic network topology, along with evaluation of functional capabilities during model building. mCADRE produces models with similar or better functionality and achieves dramatic computational speed up over existing methods. Using our method, we reconstructed draft genome-scale metabolic models for 126 human tissue and cell types. Among these, there are models for 26 tumor tissues along with their normal counterparts, and 30 different brain tissues. We performed pathway-level analyses of this large collection of tissue-specific models and identified the eicosanoid metabolic pathway, especially reactions catalyzing the production of leukotrienes from arachidnoic acid, as potential drug targets that selectively affect tumor tissues. This large collection of 126 genome-scale draft metabolic models provides a useful resource for studying the metabolic basis for a variety of human diseases across many tissues. The functionality of the resulting models and the fast computational speed of the mCADRE algorithm make it a useful tool to build and update tissue-specific metabolic models.

  20. Morphological and glucose metabolism abnormalities in alcoholic Korsakoff's syndrome: group comparisons and individual analyses.

    Directory of Open Access Journals (Sweden)

    Anne-Lise Pitel

    Full Text Available BACKGROUND: Gray matter volume studies have been limited to few brain regions of interest, and white matter and glucose metabolism have received limited research attention in Korsakoff's syndrome (KS. Because of the lack of brain biomarkers, KS was found to be underdiagnosed in postmortem studies. METHODOLOGY/PRINCIPAL FINDINGS: Nine consecutively selected patients with KS and 22 matched controls underwent both structural magnetic resonance imaging and (18F-fluorodeoxyglucose positron emission tomography examinations. Using a whole-brain analysis, the between-group comparisons of gray matter and white matter density and relative glucose uptake between patients with KS and controls showed the involvement of both the frontocerebellar and the Papez circuits, including morphological abnormalities in their nodes and connection tracts and probably resulting hypometabolism. The direct comparison of the regional distribution and degree of gray matter hypodensity and hypometabolism within the KS group indicated very consistent gray matter distribution of both abnormalities, with a single area of significant difference in the middle cingulate cortex showing greater hypometabolism than hypodensity. Finally, the analysis of the variability in the individual patterns of brain abnormalities within our sample of KS patients revealed that the middle cingulate cortex was the only brain region showing significant GM hypodensity and hypometabolism in each of our 9 KS patients. CONCLUSIONS/SIGNIFICANCE: These results indicate widespread brain abnormalities in KS including both gray and white matter damage mainly involving two brain networks, namely, the fronto-cerebellar circuit and the Papez circuit. Furthermore, our findings suggest that the middle cingulate cortex may play a key role in the pathophysiology of KS and could be considered as a potential in vivo brain biomarker.

  1. Endocannabinoid metabolism in human glioblastomas and meningiomas compared to human non-tumour brain tissue

    DEFF Research Database (Denmark)

    Petersen, G.; Moesgaard, B.; Hansen, Harald S.

    2005-01-01

    The endogenous levels of the two cannabinoid receptor ligands 2-arachidonoyl glycerol and anandamide, and their respective congeners, monoacyl glycerols and N-acylethanolamines, as well as the phospholipid precursors of N-acylethanolamines, were measured by gas chromatography-mass spectrometry in...... in glioblastoma (WHO grade IV) tissue and meningioma (WHO grade I) tissue and compared with human non-tumour brain tissue. Furthermore, the metabolic turnover of N-acylethanolamines was compared by measurements of the enzymatic activity of N-acyltransferase, N...

  2. [Metabolism, Distribution and Excretion of Recombinant Human Thrombopoietin in Mice

    Science.gov (United States)

    Liu, Xiu-Wen; Tang, Zhong-Ming; Song, Hai-Feng; Dou, Gui-Fang

    2001-12-01

    The metabolism, distribution and excretion profiles of recombinant human thrombopoietin (rhTPO) in mice were studied by means of (125)I-labeled rhTPO ((125)I-rhTPO) combined with size exclusive high performance liquid chromatography (SHPLC) or trichloroacetic acid (TCA) precipitation analysis. (125)I-rhTPO was prepared by iodogen method. Purification was performed on Sephacryl S-200 HR gel. Radioactive-purity of (125)I-rhTPO identified by SHPLC was (96.9 +/- 1.5)% (n = 3). The proliferation effect of TPO dependent cell line (TD-3) and the increase of peripheral platelet counts in mouse by (125)I-rhTPO demonstrated that (125)I-labeled protein maintained the biological activities of TPO both in vitro and in vivo. SHPLC analysis of serum and urine samples taken after sc 1 micro g/mouse (345 kBq/mouse) of (125)I-rhTPO revealed that there were two lower molecular weight (125)I-degradation metabolites ((125)I-MI and (125)I-MII) other than parent molecule. (125)I-MI was mainly found in urine, and (125)I-MII was detected both in serum and in urine. The maximal concentration of (125)I-rhTPO was reached at 2 hours after injection. The terminal half-life was 10.8 hours, which was much longer than those of other peptides. TCA precipitable radioactivity in tissue showed that the radioactivity in bone marrow was rather high. The highest level was found in urinary system. Levels in adrenals, lymph nodes, and fat were near to that in serum. Lowest was found in brain. The main excretion route was urinary system and (98 +/- 5.6)% of (125)I-rhTPO was excreted within 72 hours after dosing.

  3. Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats.

    Science.gov (United States)

    Alwahsh, Salamah Mohammad; Xu, Min; Schultze, Frank Christian; Wilting, Jörg; Mihm, Sabine; Raddatz, Dirk; Ramadori, Giuliano

    2014-01-01

    Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control), liquid Lieber-DeCarli (LDC) diet, LDC +30%J of ethanol (L-Et) or fructose (L-Fr), and LDC combined with 30%J ethanol and 30%J fructose (L-EF). Body weight (BW) and liver weight (LW) were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week), whereas fructose-fed animals had higher LW than controls (Pfructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group). The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions) compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on dyslipidemia and insulin resistance-accompanied liver damage.

  4. Combination of alcohol and fructose exacerbates metabolic imbalance in terms of hepatic damage, dyslipidemia, and insulin resistance in rats.

    Directory of Open Access Journals (Sweden)

    Salamah Mohammad Alwahsh

    Full Text Available Although both alcohol and fructose are particularly steatogenic, their long-term effect in the development of a metabolic syndrome has not been studied in vivo. Consumption of fructose generally leads to obesity, whereas ethanol can induce liver damage in the absence of overweight. Here, Sprague-Dawley rats were fed ad libitum for 28 days on five diets: chow (control, liquid Lieber-DeCarli (LDC diet, LDC +30%J of ethanol (L-Et or fructose (L-Fr, and LDC combined with 30%J ethanol and 30%J fructose (L-EF. Body weight (BW and liver weight (LW were measured. Blood and liver samples were harvested and subjected to biochemical tests, histopathological examinations, and RT-PCR. Alcohol-containing diets substantially reduced the food intake and BW (≤3rd week, whereas fructose-fed animals had higher LW than controls (P<0.05. Additionally, leukocytes, plasma AST and leptin levels were the highest in the fructose-administered rats. Compared to the chow and LDC diets, the L-EF diet significantly elevated blood glucose, insulin, and total-cholesterol levels (also vs. the L-Et group. The albumin and Quick-test levels were the lowest, whereas ALT activity was the highest in the L-EF group. Moreover, the L-EF diet aggravated plasma triglyceride and reduced HDL-cholesterol levels more than 2.7-fold compared to the sum of the effects of the L-Et and L-Fr diets. The decreased hepatic insulin clearance in the L-EF group vs. control and LDC groups was reflected by a significantly decreased C-peptide:insulin ratio. All diets except the control caused hepatosteatosis, as evidenced by Nile red and H&E staining. Hepatic transcription of insulin receptor substrate-1/2 was mainly suppressed by the L-Fr and L-EF diets. The L-EF diet did not enhance the mitochondrial β-oxidation of fatty acids (Cpt1α and Ppar-α expressions compared to the L-Et or L-Fr diet. Together, our data provide evidence for the coaction of ethanol and fructose with a high-fat-diet on

  5. Metabolic activity, experiment M171. [space flight effects on human metabolism

    Science.gov (United States)

    Michel, E. L.; Rummel, J. A.

    1973-01-01

    The Skylab metabolic activity experiment determines if man's metabolic effectiveness in doing mechanical work is progressively altered by a simulated Skylab environment, including environmental factors such as slightly increased pCO2. This test identified several hardware/procedural anomalies. The most important of these were: (1) the metabolic analyzer measured carbon dioxide production and expired water too high; (2) the ergometer load module failed under continuous high workload conditions; (3) a higher than desirable number of erroneous blood pressure measurements were recorded; (4) vital capacity measurements were unreliable; and (5) anticipated crew personal exercise needs to be more structured.

  6. Is the Mouse a Good Model of Human PPARγ-Related Metabolic Diseases?

    Science.gov (United States)

    Pap, Attila; Cuaranta-Monroy, Ixchelt; Peloquin, Matthew; Nagy, Laszlo

    2016-01-01

    With the increasing number of patients affected with metabolic diseases such as type 2 diabetes, obesity, atherosclerosis and insulin resistance, academic researchers and pharmaceutical companies are eager to better understand metabolic syndrome and develop new drugs for its treatment. Many studies have focused on the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ), which plays a crucial role in adipogenesis and lipid metabolism. These studies have been able to connect this transcription factor to several human metabolic diseases. Due to obvious limitations concerning experimentation in humans, animal models—mainly mouse models—have been generated to investigate the role of PPARγ in different tissues. This review focuses on the metabolic features of human and mouse PPARγ-related diseases and the utility of the mouse as a model. PMID:27483259

  7. Metabolic acceleration and the evolution of human brain size and life history.

    Science.gov (United States)

    Pontzer, Herman; Brown, Mary H; Raichlen, David A; Dunsworth, Holly; Hare, Brian; Walker, Kara; Luke, Amy; Dugas, Lara R; Durazo-Arvizu, Ramon; Schoeller, Dale; Plange-Rhule, Jacob; Bovet, Pascal; Forrester, Terrence E; Lambert, Estelle V; Thompson, Melissa Emery; Shumaker, Robert W; Ross, Stephen R

    2016-05-19

    Humans are distinguished from the other living apes in having larger brains and an unusual life history that combines high reproductive output with slow childhood growth and exceptional longevity. This suite of derived traits suggests major changes in energy expenditure and allocation in the human lineage, but direct measures of human and ape metabolism are needed to compare evolved energy strategies among hominoids. Here we used doubly labelled water measurements of total energy expenditure (TEE; kcal day(-1)) in humans, chimpanzees, bonobos, gorillas and orangutans to test the hypothesis that the human lineage has experienced an acceleration in metabolic rate, providing energy for larger brains and faster reproduction without sacrificing maintenance and longevity. In multivariate regressions including body size and physical activity, human TEE exceeded that of chimpanzees and bonobos, gorillas and orangutans by approximately 400, 635 and 820 kcal day(-1), respectively, readily accommodating the cost of humans' greater brain size and reproductive output. Much of the increase in TEE is attributable to humans' greater basal metabolic rate (kcal day(-1)), indicating increased organ metabolic activity. Humans also had the greatest body fat percentage. An increased metabolic rate, along with changes in energy allocation, was crucial in the evolution of human brain size and life history.

  8. Effects of alcohol abstinence on glucose metabolism in Japanese men with elevated fasting glucose: A pilot study

    Science.gov (United States)

    Funayama, Takashi; Tamura, Yoshifumi; Takeno, Kageumi; Kawaguchi, Minako; Kakehi, Saori; Watanabe, Takahiro; Furukawa, Yasuhiko; Kaga, Hideyoshi; Yamamoto, Risako; Kanazawa, Akio; Fujitani, Yoshio; Kawamori, Ryuzo; Watada, Hirotaka

    2017-01-01

    It has been demonstrated that moderate alcohol consumption provides protection against the development of type 2 diabetes. However, several other reports suggested that moderate alcohol intake may increase the risk of type 2 diabetes in non-obese Japanese. The aim of present study was to investigate the effect of 1-week alcohol abstinence on hepatic insulin sensitivity and fasting plasma glucose (FPG) in non-obese Japanese men. We recruited 8 non-obese Japanese men with mildly elevated FPG and drinking habits alcohol (mean frequency; 5.6 ± 2.5 times/week, mean alcohol consumption; 32.1 ± 20.0 g/day). Before and after the 1-week alcohol abstinence, we used the 2-step hyperinsulinemic-euglycemic clamp to measure endogenous glucose production (EGP) and insulin sensitivity (IS) in muscle and liver. One-week alcohol abstinence significantly reduced both FPG by 7% (from 105.5 ± 11.7 to 98.2 ± 7.8 mg/dl, P alcohol abstinence significantly improved hepatic-IS, but not muscle-IS. In conclusion, one week alcohol abstinence improved hepatic IS and FPG in non-obese Japanese men with mildly elevated FPG and drinking habits alcohol. PMID:28067302

  9. ALCOHOL ETÍLICO: Un tóxico de alto riesgo para la salud humana socialmente aceptado Ethyl alcohol: high risk toxin for human healt socially accepted

    Directory of Open Access Journals (Sweden)

    Jairo Téllez Mosquera

    2006-03-01

    consumer of alcohol. Alcohol is the first psicoactivas substances use for people than after use illegal substances. When ethyl alcohol is used in permanent and frequent way produced acute and chronic adverses effect on the health. The long run alcohol abusers has adverse effect in the nutricions, neurological, hepatic and teratogenic. The neurological, gastrointestinal, endocrine and acid-base equilibrium area affected in acute ways principally. The social aspects in quite important too alcohol has been related to interfamiliar violence, traffic accidents and violence in general. The high incidence in use and consumption, its toxic effect over human health, its negative social effect and the fact that it´s a legal and social accept substance made alcohol and real public health problem. Its necessary to say "be careful with alcohol in general".

  10. Substrate availability and transcriptional regulation of metabolic genes in human skeletal muscle during recovery from exercise

    DEFF Research Database (Denmark)

    Pilegaard, Henriette; Osada, Takuya; Andersen, Lisbeth Tingsted

    2005-01-01

    In skeletal muscle of humans, transcription of several metabolic genes is transiently induced during recovery from exercise when no food is consumed. To determine the potential influence of substrate availability on the transcriptional regulation of metabolic genes during recovery from exercise, ...

  11. Patterns of amino acid metabolism by proliferating human mesenchymal stem cells

    NARCIS (Netherlands)

    Higuera, G.A.; Schop, D.; Spitters, T.W.; Dijkhuizen, R.; Bracke, M.; Bruijn, J.D.; Martens, D.E.; Karperien, M.; Boxtel, van A.J.B.; Blitterswijk, van C.A.

    2012-01-01

    The nutritional requirements of stem cells have not been determined; in particular, the amino acid metabolism of stem cells is largely unknown. In this study, we investigated the amino acid metabolism of human mesenchymal stem cells (hMSCs), with focus on two questions: Which amino acids are consume

  12. Aspergillus niger metabolism of citrus furanocoumarin inhibitors of human cytochrome P450 3A4

    Science.gov (United States)

    Fungi metabolize polycyclic aromatic hydrocarbons by a number of detoxification processes, including the formation of sulfated and glycosidated conjugates. A class of aromatic compounds important to the citrus industry is the furanocoumarins in grapefruit, and their metabolism in humans is critical...

  13. Equine metabolic myopathies with emphasis on the diagnostic approach - Comparison with human myopathies - A review

    NARCIS (Netherlands)

    Westermann, C. M.; Dorland, L.; Wijnberg, I. D.; van der Kolk, J. H.

    2007-01-01

    This review gives an overview of the presently known human and equine metabolic myopathies with emphasis on the diagnostic approach. Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system, which results in inefficient muscle performance. Myopath

  14. Equine metabolic myopathies with emphasis on the diagnostic approach - Comparison with human myopathies - A review

    NARCIS (Netherlands)

    Westermann, C. M.; Dorland, L.; Wijnberg, I. D.; van der Kolk, J. H.

    2007-01-01

    This review gives an overview of the presently known human and equine metabolic myopathies with emphasis on the diagnostic approach. Metabolic myopathies are muscle disorders caused by a biochemical defect of the skeletal muscle energy system, which results in inefficient muscle performance. Myopath

  15. Metabolic effects of overnight continuous infusion of unacylated ghrelin in humans

    NARCIS (Netherlands)

    A. Benso; Y. St-Pierre (Yves); F. Prodam (Flavia); E. Gramaglia (Elena); R. Granata (Riccarda); A-J. van der Lely (Aart-Jan); E. Ghigo (Ezio); F. Broglio (Fabio)

    2012-01-01

    textabstractObjective: To clarify the metabolic effects of an overnight i.v. infusion of unacylated ghrelin (UAG) in humans. UAG exerts relevant metabolic actions, likely mediated by a still unknown ghrelin receptor subtype, including effects on β-cell viability and function, insulin secretion and s

  16. Inhibition of fipronil and nonane metabolism in human liver microsomes and human cytochrome P450 isoforms by chlorpyrifos.

    Science.gov (United States)

    Joo, Hyun; Choi, Kyoungju; Rose, Randy L; Hodgson, Ernest

    2007-01-01

    Previous studies have established that chlorpyrifos (CPS), fipronil, and nonane can all be metabolized by human liver microsomes (HLM) and a number of cytochrome P450 (CYP) isoforms. However, metabolic interactions between these three substrates have not been described. In this study the effect of either coincubation or preincubation of CPS with HLM or CYP isoforms with either fipronil or nonane as substrate was investigated. In both co- and preincubation experiments, CPS significantly inhibited the metabolism of fipronil or nonane by HLM although CPS inhibited the metabolism of fipronil more effectively than that of nonane. CPS significantly inhibited the metabolism of fipronil by CYP3A4 as well as the metabolism of nonane by CYP2B6. In both cases, preincubation with CPS caused greater inhibition than coincubation, suggesting that the inhibition is mechanism based.

  17. miR-21 regulates triglyceride and cholesterol metabolism in non-alcoholic fatty liver disease by targeting HMGCR.

    Science.gov (United States)

    Sun, Chuanzheng; Huang, Feizhou; Liu, Xunyang; Xiao, Xuefei; Yang, Mingshi; Hu, Gui; Liu, Huaizheng; Liao, Liangkan

    2015-03-01

    Non-alcoholic fatty liver disease (NAFLD) has emerged as a public health issue with a prevalence of 15-30% in Western populations and 6-25% in Asian populations. Certain studies have revealed the alteration of microRNA (miRNA or miR) profiles in NAFLD and it has been suggested that miR-21 is associated with NAFLD. In the present study, we measured the serum levels of miR-21 in patients with NAFLD and also performed in vitro experiments using a cellular model of NAFLD to further investigate the effects of miR-21 on triglyceride and cholesterol metabolism. Furthermore, a novel target through which miR-21 exerts its effects on NAFLD was identified. The results revealed that the serum levels of miR-21 were lower in patients with NAFLD compared with the healthy controls. In addition, 3-hydroxy-3-methylglutaryl-co-enzyme A reductase (HMGCR) expression was increased in the serum of patients with NAFLD both at the mRNA and protein level. To mimic the NAFLD condition in vitro, HepG2 cells were treated with palmitic acid (PA) and oleic acid (OA). Consistent with the results obtained in the in vivo experiments, the expression levels of miR-21 were decreased and those of HMGCR were increased in the in vitro model of NAFLD. Luciferase reporter assay revealed that HMGCR was a direct target of miR-21 and that miR-21 exerted an effect on both HMGCR transcript degradation and protein translation. Furthermore, the results from the in vitro experiments revealed that miR-21 decreased the levels of triglycerides (TG), free cholesterol (FC) and total cholesterol (TC) in the PA/OA-treated HepG2 cells and that this effect was attenuated by HMGCR overexpression. Taken together, to the best of our knowledge, the present study is the first to report that miR-21 regulates triglyceride and cholesterol metabolism in an in vitro model of NAFLD, and that this effect is achieved by the inhibition of HMGCR expression. We speculate that miR-21 may be a useful biomarker for the diagnosis and

  18. Reconstruction of Pathways Associated with Amino Acid Metabolism in Human Mitochondria

    Institute of Scientific and Technical Information of China (English)

    Purnima Guda; Chittibabu Guda; Shankar Subramaniam

    2007-01-01

    We have used a bioinformatics approach for the identification and reconstruction of metabolic pathways associated with amino acid metabolism in human mitochon- dria. Human mitochondrial proteins determined by experimental and computa- tional methods have been superposed on the reference pathways from the KEGG database to identify mitochondrial pathways. Enzymes at the entry and exit points for each reconstructed pathway were identified, and mitochondrial solute carrier proteins were determined where applicable. Intermediate enzymes in the mito- chondrial pathways were identified based on the annotations available from public databases, evidence in current literature, or our MITOPRED program, which pre- dicts the mitochondrial localization of proteins. Through integration of the data derived from experimental, bibliographical, and computational sources, we recon- structed the amino acid metabolic pathways in human mitochondria, which could help better understand the mitochondrial metabolism and its role in human health.

  19. Metabolically Derived Human Ventilation Rates: A Revised Approach Based Upon Oxygen Consumption Rates (Final Report, 2009)

    Science.gov (United States)

    EPA announced the availability of the final report, Metabolically Derived Human Ventilation Rates: A Revised Approach Based Upon Oxygen Consumption Rates. This report provides a revised approach for calculating an individual's ventilation rate directly from their oxygen c...

  20. The potential role of inhibitor of differentiation-3 in human adipose tissue remodeling and metabolic health

    DEFF Research Database (Denmark)

    Svendstrup, Mathilde; Vestergaard, Henrik

    2014-01-01

    in the tissue. Regulation of angiogenesis in SAT and VAT in response to diet is therefore crucial for the metabolic outcome in obesity. Knowledge about the underlying genetic mechanisms determining metabolic health in obesity is very limited. We aimed to review the literature of the inhibitor of differentiation......-3 (ID3) gene in relation to adipose tissue and angiogenesis in humans in order to determine whether ID3 could be involved in the regulation of adipose tissue expansion and metabolic health in human obesity. We find evidence that ID3 is involved in regulatory mechanisms in adipose tissue...... literature suggest ID3 to play a potential role in the underlying regulatory mechanisms of metabolic health in human obesity. The literature is still sparse and further studies focusing on human ID3 in relation to the nature of obesity are warranted....

  1. Computational Modeling of Human Metabolism and Its Application to Systems Biomedicine.

    Science.gov (United States)

    Aurich, Maike K; Thiele, Ines

    2016-01-01

    Modern high-throughput techniques offer immense opportunities to investigate whole-systems behavior, such as those underlying human diseases. However, the complexity of the data presents challenges in interpretation, and new avenues are needed to address the complexity of both diseases and data. Constraint-based modeling is one formalism applied in systems biology. It relies on a genome-scale reconstruction that captures extensive biochemical knowledge regarding an organism. The human genome-scale metabolic reconstruction is increasingly used to understand normal cellular and disease states because metabolism is an important factor in many human diseases. The application of human genome-scale reconstruction ranges from mere querying of the model as a knowledge base to studies that take advantage of the model's topology and, most notably, to functional predictions based on cell- and condition-specific metabolic models built based on omics data.An increasing number and diversity of biomedical questions are being addressed using constraint-based modeling and metabolic models. One of the most successful biomedical applications to date is cancer metabolism, but constraint-based modeling also holds great potential for inborn errors of metabolism or obesity. In addition, it offers great prospects for individualized approaches to diagnostics and the design of disease prevention and intervention strategies. Metabolic models support this endeavor by providing easy access to complex high-throughput datasets. Personalized metabolic models have been introduced. Finally, constraint-based modeling can be used to model whole-body metabolism, which will enable the elucidation of metabolic interactions between organs and disturbances of these interactions as either causes or consequence of metabolic diseases. This chapter introduces constraint-based modeling and describes some of its contributions to systems biomedicine.

  2. Metabolism of puerarin and daidzin by human intestinal bacteria and their relation to in vitro cytotoxicity.

    Science.gov (United States)

    Kim, D H; Yu, K U; Bae, E A; Han, M J

    1998-06-01

    When puerarin or daidzin were incubated for 24 h with human intestinal bacteria, two metabolites, daidzein and calycosin, were produced from them, respectively. The metabolic time course of puerarin was as follows: at an early time, puerarin was converted to daidzin, and then calycosin. The metabolic time course of daidzin by human intestinal bacteria was also similar to that of puerarin. The in vitro cytotoxicities of these metabolites, calycosin and daidzein, were superior to those of puerarin and daidzein.

  3. Leg exoskeleton reduces the metabolic cost of human hopping.

    Science.gov (United States)

    Grabowski, Alena M; Herr, Hugh M

    2009-09-01

    During bouncing gaits such as hopping and running, leg muscles generate force to enable elastic energy storage and return primarily from tendons and, thus, demand metabolic energy. In an effort to reduce metabolic demand, we designed two elastic leg exoskeletons that act in parallel with the wearer's legs; one exoskeleton consisted of a multiple leaf (MLE) and the other of a single leaf (SLE) set of fiberglass springs. We hypothesized that hoppers, hopping on both legs, would adjust their leg stiffness while wearing an exoskeleton so that the combination of the hopper and exoskeleton would behave as a linear spring-mass system with the same total stiffness as during normal hopping. We also hypothesized that decreased leg force generation while wearing an exoskeleton would reduce the metabolic power required for hopping. Nine subjects hopped in place at 2.0, 2.2, 2.4, and 2.6 Hz with and without an exoskeleton while we measured ground reaction forces, exoskeletal compression, and metabolic rates. While wearing an exoskeleton, hoppers adjusted their leg stiffness to maintain linear spring-mass mechanics and a total stiffness similar to normal hopping. Without accounting for the added weight of each exoskeleton, wearing the MLE reduced net metabolic power by an average of 6% and wearing the SLE reduced net metabolic power by an average of 24% compared with hopping normally at frequencies between 2.0 and 2.6 Hz. Thus, when hoppers used external parallel springs, they likely decreased the mechanical work performed by the legs and substantially reduced metabolic demand compared with hopping without wearing an exoskeleton.

  4. The implications of relationships between human diseases and metabolic subpathways.

    Directory of Open Access Journals (Sweden)

    Xia Li

    Full Text Available One of the challenging problems in the etiology of diseases is to explore the relationships between initiation and progression of diseases and abnormalities in local regions of metabolic pathways. To gain insight into such relationships, we applied the "k-clique" subpathway identification method to all disease-related gene sets. For each disease, the disease risk regions of metabolic pathways were then identified and considered as subpathways associated with the disease. We finally built a disease-metabolic subpathway network (DMSPN. Through analyses based on network biology, we found that a few subpathways, such as that of cytochrome P450, were highly connected with many diseases, and most belonged to fundamental metabolisms, suggesting that abnormalities of fundamental metabolic processes tend to cause more types of diseases. According to the categories of diseases and subpathways, we tested the clustering phenomenon of diseases and metabolic subpathways in the DMSPN. The results showed that both disease nodes and subpathway nodes displayed slight clustering phenomenon. We also tested correlations between network topology and genes within disease-related metabolic subpathways, and found that within a disease-related subpathway in the DMSPN, the ratio of disease genes and the ratio of tissue-specific genes significantly increased as the number of diseases caused by the subpathway increased. Surprisingly, the ratio of essential genes significantly decreased and the ratio of housekeeping genes remained relatively unchanged. Furthermore, the coexpression levels between disease genes and other types of genes were calculated for each subpathway in the DMSPN. The results indicated that those genes intensely influenced by disease genes, including essential genes and tissue-specific genes, might be significantly associated with the disease diversity of subpathways, suggesting that different kinds of genes within a disease-related subpathway may play

  5. Report: Human biochemical genetics: an insight into inborn errors of metabolism

    Institute of Scientific and Technical Information of China (English)

    YU Chunli; SCOTT C. Ronald

    2006-01-01

    Inborn errors of metabolism (IEM) include a broad spectrum of defects of various gene products that affect intermediary metabolism in the body. Studying the molecular and biochemical mechanisms of those inherited disorder, systematically summarizing the disease phenotype and natural history, providing diagnostic rationale and methodology and treatment strategy comprise the context of human biochemical genetics. This session focused on: (1) manifestations of representative metabolic disorders; (2) the emergent technology and application of newborn screening of metabolic disorders using tandem mass spectrometry; (3) principles of managing IEM; (4) the concept of carrier testing aiming prevention. Early detection of patients with IEM allows early intervention and more options for treatment.

  6. A global evolutionary and metabolic analysis of human obesity gene risk variants.

    Science.gov (United States)

    Castillo, Joseph J; Hazlett, Zachary S; Orlando, Robert A; Garver, William S

    2017-09-05

    It is generally accepted that the selection of gene variants during human evolution optimized energy metabolism that now interacts with our obesogenic environment to increase the prevalence of obesity. The purpose of this study was to perform a global evolutionary and metabolic analysis of human obesity gene risk variants (110 human obesity genes with 127 nearest gene risk variants) identified using genome-wide association studies (GWAS) to enhance our knowledge of early and late genotypes. As a result of determining the mean frequency of these obesity gene risk variants in 13 available populations from around the world our results provide evidence for the early selection of ancestral risk variants (defined as selection before migration from Africa) and late selection of derived risk variants (defined as selection after migration from Africa). Our results also provide novel information for association of these obesity genes or encoded proteins with diverse metabolic pathways and other human diseases. The overall results indicate a significant differential evolutionary pattern for the selection of obesity gene ancestral and derived risk variants proposed to optimize energy metabolism in varying global environments and complex association with metabolic pathways and other human diseases. These results are consistent with obesity genes that encode proteins possessing a fundamental role in maintaining energy metabolism and survival during the course of human evolution. Copyright © 2017. Published by Elsevier B.V.

  7. Metabolite profiling identifies pathways associated with metabolic risk in humans.

    Science.gov (United States)

    Cheng, Susan; Rhee, Eugene P; Larson, Martin G; Lewis, Gregory D; McCabe, Elizabeth L; Shen, Dongxiao; Palma, Melinda J; Roberts, Lee D; Dejam, Andre; Souza, Amanda L; Deik, Amy A; Magnusson, Martin; Fox, Caroline S; O'Donnell, Christopher J; Vasan, Ramachandran S; Melander, Olle; Clish, Clary B; Gerszten, Robert E; Wang, Thomas J

    2012-05-08

    Although metabolic risk factors are known to cluster in individuals who are prone to developing diabetes mellitus and cardiovascular disease, the underlying biological mechanisms remain poorly understood. To identify pathways associated with cardiometabolic risk, we used liquid chromatography/mass spectrometry to determine the plasma concentrations of 45 distinct metabolites and to examine their relation to cardiometabolic risk in the Framingham Heart Study (FHS; n=1015) and the Malmö Diet and Cancer Study (MDC; n=746). We then interrogated significant findings in experimental models of cardiovascular and metabolic disease. We observed that metabolic risk factors (obesity, insulin resistance, high blood pressure, and dyslipidemia) were associated with multiple metabolites, including branched-chain amino acids, other hydrophobic amino acids, tryptophan breakdown products, and nucleotide metabolites. We observed strong associations of insulin resistance traits with glutamine (standardized regression coefficients, -0.04 to -0.22 per 1-SD change in log-glutamine; Prisk of incident diabetes mellitus in FHS (odds ratio, 0.79; adjusted P=0.03) but not in MDC. In experimental models, administration of glutamine in mice led to both increased glucose tolerance (P=0.01) and decreased blood pressure (Pprofiling identified circulating metabolites not previously associated with metabolic traits. Experimentally interrogating one of these pathways demonstrated that excess glutamine relative to glutamate, resulting from exogenous administration, is associated with reduced metabolic risk in mice.

  8. Treatment of human muscle cells with popular dietary supplements increase mitochondrial function and metabolic rate

    Directory of Open Access Journals (Sweden)

    Vaughan Roger A

    2012-11-01

    Full Text Available Abstract Background Obesity is a common pathology with increasing incidence, and is associated with increased mortality and healthcare costs. Several treatment options for obesity are currently available ranging from behavioral modifications to pharmaceutical agents. Many popular dietary supplements claim to enhance weight loss by acting as metabolic stimulators, however direct tests of their effect on metabolism have not been performed. Purpose This work identified the effects popular dietary supplements on metabolic rate and mitochondrial biosynthesis in human skeletal muscle cells. Methods Human rhabdomyosarcoma cells were treated with popular dietary supplements at varied doses for 24 hours. Peroxisome proliferator-activated receptor coactivator 1 alpha (PGC-1α, an important stimulator of mitochondrial biosynthesis, was quantified using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR. Mitochondrial content was measured using flow cytometry confirmed with confocal microscopy. Glycolytic metabolism was quantified by measuring extracellular acidification rate (ECAR and oxidative metabolism was quantified by measuring oxygen consumption rate (OCR. Total relative metabolism was quantified using WST-1 end point assay. Results Treatment of human rhabdomyosarcoma cells with dietary supplements OxyElite Pro (OEP or Cellucore HD (CHD induced PGC-1α leading to significantly increased mitochondrial content. Glycolytic and oxidative capacities were also significantly increased following treatment with OEP or CHD. Conclusion This is the first work to identify metabolic adaptations in muscle cells following treatment with popular dietary supplements including enhanced mitochondrial biosynthesis, and glycolytic, oxidative and total metabolism.

  9. Metabolomic analysis of human cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis diseases.

    Science.gov (United States)

    Safaei, Akram; Arefi Oskouie, Afsaneh; Mohebbi, Seyed Reza; Rezaei-Tavirani, Mostafa; Mahboubi, Mohammad; Peyvandi, Maryam; Okhovatian, Farshad; Zamanian-Azodi, Mona

    2016-01-01

    Metabolome analysis is used to evaluate the characteristics and interactions of low molecular weight metabolites under a specific set of conditions. In cirrhosis, hepatocellular carcinoma, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatotic hepatitis (NASH) the liver does not function thoroughly due to long-term damage. Unfortunately the early detection of cirrhosis, HCC, NAFLD and NASH is a clinical problem and determining a sensitive, specific and predictive novel method based on biomarker discovery is an important task. On the other hand, metabolomics has been reported as a new and powerful technology in biomarker discovery and dynamic field that cause global comprehension of system biology. In this review, it has been collected a heterogeneous set of metabolomics published studies to discovery of biomarkers in researches to introduce diagnostic biomarkers for early detection and the choice of patient-specific therapies.

  10. Laser light induced modulations in metabolic activities in human brain cancer

    Science.gov (United States)

    Tata, Darrell B.; Waynant, Ronald W.

    2008-03-01

    The role of low visible or near infra-red laser intensity in suppressing metabolic activity of malignant human brain cancer (glioblastoma) cells was investigated through the application of either a continuous wave 633nm HeNe or a pulsed picosecond 1,552nm wavelength laser. Human glioblastomas were exposed in their growth culture medium with serum for several energy doses. For both types of laser exposures the glioblastomas exhibited a maximal decline in the metabolic activity relative to their respective sham control counterparts at 10 J/cm2. The cellular metabolic activities for various treatment doses were measured through the colorimetric MTS metabolic assay after the laser exposure. Interestingly, addition of (the enzyme) catalase in the growth medium prior to the laser exposure was found to diminish the laser induced metabolic suppression for all fluence treatment conditions, thus suggesting a functional role of H IIO II in the metabolic suppression. Taken together, our findings reveal that visible or near infra-red low level light exposures could potentially be a viable tool in reducing the metabolic activity of cancers; evidence at hand implicates a role of light induced H IIO II in bringing about in part, suppression in the metabolic activity. Due to the cellular "biphasic" response to the laser exposure, further research needs to be undertaken to determine exposure parameters which would optimize metabolic and cellular growth suppression in-vivo.

  11. In vitro Metabolism of Strychnine by Human Cytochrome P450 and Its Interaction with Glycyrrhetic Acid

    Institute of Scientific and Technical Information of China (English)

    LIU Li; XIAO Juan; PENG Zhi-hong; WU Wen-hua; DU Peng; CHEN Yong

    2012-01-01

    Objective To investigate the metabolism of strychnine (STN) and the metabolic interaction between STN and glycyrthetic acid (GA) in vitro.Methods Human liver microsomes (HLM) and human recombinant cytochrome P450 (CYP) isoforms were employed to study the metabolism of STN and the metabolic interaction of STN with GA in vitro.Results In HLM,the Km,Vmax,and clearance of STN were 88.50 μmol/L,0.88 nmol/(mg·min),and 9.93 mL/(mg·min),respectively.STN was metabolized mainly by CYP3A4.However,STN noncompetitively inhibited CYP3A4-catalyzed testosterone 6β-hydroxylation with IC50 value of 5.9 μtmol/L and Ki value of 5.5μmol/L.Moreover,GA competitively inhibited STN metabolism with IC5o value of 10.6 μmol/L and Ki value of 17.7 μmol/L.Conclusion Although STN is mainly metabolized by CYP3A4 in vitro,STN has noncompetitive inhibition on CYP3A4-catalyzed testosterone 6β-hydroxylation.Moreover,GA could competitively inhibit STN metabolism.The present work is helpful to elucidate the metabolic interaction between STN and GA.

  12. Metabolomics and systems pharmacology: why and how to model the human metabolic network for drug discovery☆

    Science.gov (United States)

    Kell, Douglas B.; Goodacre, Royston

    2014-01-01

    Metabolism represents the ‘sharp end’ of systems biology, because changes in metabolite concentrations are necessarily amplified relative to changes in the transcriptome, proteome and enzyme activities, which can be modulated by drugs. To understand such behaviour, we therefore need (and increasingly have) reliable consensus (community) models of the human metabolic network that include the important transporters. Small molecule ‘drug’ transporters are in fact metabolite transporters, because drugs bear structural similarities to metabolites known from the network reconstructions and from measurements of the metabolome. Recon2 represents the present state-of-the-art human metabolic network reconstruction; it can predict inter alia: (i) the effects of inborn errors of metabolism; (ii) which metabolites are exometabolites, and (iii) how metabolism varies between tissues and cellular compartments. However, even these qualitative network models are not yet complete. As our understanding improves so do we recognise more clearly the need for a systems (poly)pharmacology. PMID:23892182

  13. Metabolomics analysis of Cistus monspeliensis leaf extract on energy metabolism activation in human intestinal cells.

    Science.gov (United States)

    Shimoda, Yoichi; Han, Junkyu; Kawada, Kiyokazu; Smaoui, Abderrazak; Isoda, Hiroko

    2012-01-01

    Energy metabolism is a very important process to improve and maintain health from the point of view of physiology. It is well known that the intracellular ATP production is contributed to energy metabolism in cells. Cistus monspeliensis is widely used as tea, spices, and medical herb; however, it has not been focusing on the activation of energy metabolism. In this study, C. monspeliensis was investigated as the food resources by activation of energy metabolism in human intestinal epithelial cells. C. monspeliensis extract showed high antioxidant ability. In addition, the promotion of metabolites of glycolysis and TCA cycle was induced by C. monspeliensis treatment. These results suggest that C. monspeliensis extract has an ability to enhance the energy metabolism in human intestinal cells.

  14. Metabolomics Analysis of Cistus monspeliensis Leaf Extract on Energy Metabolism Activation in Human Intestinal Cells

    Directory of Open Access Journals (Sweden)

    Yoichi Shimoda

    2012-01-01

    Full Text Available Energy metabolism is a very important process to improve and maintain health from the point of view of physiology. It is well known that the intracellular ATP production is contributed to energy metabolism in cells. Cistus monspeliensis is widely used as tea, spices, and medical herb; however, it has not been focusing on the activation of energy metabolism. In this study, C. monspeliensis was investigated as the food resources by activation of energy metabolism in human intestinal epithelial cells. C. monspeliensis extract showed high antioxidant ability. In addition, the promotion of metabolites of glycolysis and TCA cycle was induced by C. monspeliensis treatment. These results suggest that C. monspeliensis extract has an ability to enhance the energy metabolism in human intestinal cells.

  15. Human myotubes from myoblast cultures undergoing senescence exhibit defects in glucose and lipid metabolism

    DEFF Research Database (Denmark)

    Nehlin, Jan O; Just, Marlene; Rustan, Arild C

    2011-01-01

    that the observed metabolic defects accompany the induction of a senescent state. The main function of SCs is regeneration and skeletal muscle-build up. Thus, the metabolic defects observed during aging of SC-derived myotubes could have a role in sarcopenia, the gradual age-related loss of muscle mass and strength.......Adult stem cells are known to have a finite replication potential. Muscle biopsy-derived human satellite cells (SCs) were grown at different passages and differentiated to human myotubes in culture to analyze the functional state of various carbohydrate and lipid metabolic pathways...

  16. Alcohol and liver

    Institute of Scientific and Technical Information of China (English)

    Natalia Osna

    2009-01-01

    @@ Liver is a primary site of ethanol metabolism, which makes this organ susceptible to alcohol-induced damage.Alcoholic liver disease (ALD) has many manifestations and complicated pathogenesis. In this Topic Highlight, we included the key reviews that characterize new findings about the mechanisms of ALD development and might be of strong interest for clinicians and researchers involved in liver alcohol studies.

  17. 78 FR 65347 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2013-10-31

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Special Emphasis... Abuse and Alcoholism, 5635 Fishers Lane (Teleconference), Rockville, MD 20855. Contact Person:...

  18. 78 FR 21615 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2013-04-11

    ... HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice... personal privacy. Name of Committee: National Institute on Alcohol Abuse and Alcoholism Initial ] Review... Foster, Ph.D., Scientific Review Administrator, National Institutes on Alcohol Abuse &...

  19. Cerebral blood flow and oxidative metabolism during human endotoxemia

    DEFF Research Database (Denmark)

    Møller, Kirsten; Strauss, Gitte Irene; Qvist, Jesper;

    2002-01-01

    The proinflammatory cytokine, tumor necrosis factor-alpha (TNF-alpha), has been suggested to mediate septic encephalopathy through an effect on cerebral blood flow (CBF) and metabolism. The effect of an intravenous bolus of endotoxin on global CBF, metabolism, and net flux of cytokines...... and catecholamines was investigated in eight healthy young volunteers. Cerebral blood flow was measured by the Kety-Schmidt technique at baseline (during normocapnia and voluntary hyperventilation for calculation of subject-specific cerebrovascular CO reactivity), and 90 minutes after an intravenous bolus...

  20. Reconstruction and analysis of human liver-specific metabolic network based on CNHLPP data.

    Science.gov (United States)

    Zhao, Jing; Geng, Chao; Tao, Lin; Zhang, Duanfeng; Jiang, Ying; Tang, Kailin; Zhu, Ruixin; Yu, Hong; Zhang, Weidong; He, Fuchu; Li, Yixue; Cao, Zhiwei

    2010-04-05

    Liver is the largest internal organ in the body that takes central roles in metabolic homeostasis, detoxification of various substances, as well as in the synthesis and storage of nutrients. To fulfill these complex tasks, thousands of biochemical reactions are going on in liver to cope with a wide range of foods and environmental variations, which are densely interconnected into an intricate metabolic network. Here, the first human liver-specific metabolic network was reconstructed according to proteomics data from Chinese Human Liver Proteome Project (CNHLPP), and then investigated in the context of the genome-scale metabolic network of Homo sapiens. Topological analysis shows that this organ-specific metabolic network exhibits similar features as organism-specific networks, such as power-law degree distribution, small-world property, and bow-tie structure. Furthermore, the structure of liver network exhibits a modular organization where the modules are formed around precursors from primary metabolism or hub metabolites from derivative metabolism, respectively. Most of the modules are dominated by one major category of metabolisms, while enzymes within same modules have a tendency of being expressed concertedly at protein level. Network decomposition and comparison suggest that the liver network overlays a predominant area in the global metabolic network of H. sapiens genome; meanwhile the human network may develop extra modules to gain more specialized functionality out of liver. The results of this study would permit a high-level interpretation of the metabolite information flow in human liver and provide a basis for modeling the physiological and pathological metabolic states of liver.

  1. Dietary sodium, potassium, and alcohol: key players in the pathophysiology, prevention, and treatment of human hypertension.

    Science.gov (United States)

    Koliaki, Chrysi; Katsilambros, Nicholas

    2013-06-01

    Western industrialized societies are currently experiencing an epidemic expansion of hypertension (HTN), which extends alarmingly even to children and adolescents. HTN constitutes an independent risk factor for cardiorenal disease and represents an extremely common comorbidity of diabetes and obesity. Numerous randomized clinical trials and meta-analyses have provided robust scientific evidence that reduced dietary salt intake, increased dietary potassium intake, moderation of alcohol consumption, optimal weight maintenance, and the adoption of "heart-friendly" dietary patterns such as the Dietary Approaches to Stop Hypertension or the Mediterranean diet can effectively lower blood pressure. Interestingly, the susceptibility of blood pressure to nutritional interventions is greatly variable among individuals, depending on age, race, genetic background, and comorbidities. The purpose of this review is to provide a comprehensive overview of currently available scientific evidence in the constantly evolving field of diet and HTN, placing particular emphasis on the key role of dietary sodium, dietary potassium, and alcohol intake in the pathophysiology, prevention, and treatment of human hypertension. © 2013 International Life Sciences Institute.

  2. Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage.

    Science.gov (United States)

    Neuman, Manuela G; French, Samuel W; Zakhari, Samir; Malnick, Stephen; Seitz, Helmut K; Cohen, Lawrence B; Salaspuro, Mikko; Voinea-Griffin, Andreea; Barasch, Andrei; Kirpich, Irina A; Thomes, Paul G; Schrum, Laura W; Donohue, Terrence M; Kharbanda, Kusum K; Cruz, Marcus; Opris, Mihai

    2017-02-01

    This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed

  3. Genome-scale metabolic model of Pichia pastoris with native and humanized glycosylation of recombinant proteins

    DEFF Research Database (Denmark)

    Irani, Zahra Azimzadeh; Kerkhoven, Eduard J.; Shojaosadati, Seyed Abbas;

    2016-01-01

    Pichia pastoris is used for commercial production of human therapeutic proteins, and genome-scale models of P. pastoris metabolism have been generated in the past to study the metabolism and associated protein production by this yeast. A major challenge with clinical usage of recombinant proteins...... produced by P. pastoris is the difference in N-glycosylation of proteins produced by humans and this yeast. However, through metabolic engineering, a P. pastoris strain capable of producing humanized N-glycosylated proteins was constructed. The current genome-scale models of P. pastoris do not address...... native nor humanized N-glycosylation, and we therefore developed ihGlycopastoris, an extension to the iLC915 model with both native and humanized N-glycosylation for recombinant protein production, but also an estimation of N-glycosylation of P. pastoris native proteins. This new model gives a better...

  4. The human hepatocyte cell lines IHH and HepaRG : models to study glucose, lipid and lipoprotein metabolism

    NARCIS (Netherlands)

    Samanez, Carolina Huaman; Caron, Sandrine; Briand, Olivier; Dehondt, Helene; Duplan, Isabelle; Kuipers, Folkert; Hennuyer, Nathalie; Clavey, Veronique; Staels, Bart

    2012-01-01

    Metabolic diseases reach epidemic proportions. A better knowledge of the associated alterations in the metabolic pathways in the liver is necessary. These studies need in vitro human cell models. Several human hepatoma models are used, but the response of many metabolic pathways to physiological sti

  5. The human hepatocyte cell lines IHH and HepaRG : models to study glucose, lipid and lipoprotein metabolism

    NARCIS (Netherlands)

    Samanez, Carolina Huaman; Caron, Sandrine; Briand, Olivier; Dehondt, Helene; Duplan, Isabelle; Kuipers, Folkert; Hennuyer, Nathalie; Clavey, Veronique; Staels, Bart

    Metabolic diseases reach epidemic proportions. A better knowledge of the associated alterations in the metabolic pathways in the liver is necessary. These studies need in vitro human cell models. Several human hepatoma models are used, but the response of many metabolic pathways to physiological

  6. CYP3A4 mediated in vitro metabolism of vinflunine in human liver microsomes

    Institute of Scientific and Technical Information of China (English)

    Xiao-ping ZHAO; Jiao ZHONG; Xiao-quan LIU; Guang-ji WANG

    2007-01-01

    Aim: To study the metabolism of vinflunine and the effects of selective cyto-chrome P-450 (CYP450) inhibitors on the metabolism of vinflunine in human liver microsomes. Methods: Individual selective CYP450 inhibitors were used to inves-tigate their effects on the metabolism of vinflunine and the principal CYP450 isoform involved in the formation of metabolites M1 and M2 in human liver microsomes.Results: Vinflunine was rapidly metabolized to 2 metabolites: M1 and M2 in human liver microsomes. M1 and M2 were tentatively presumed to be the N-oxide metabo-lite or hydroxylated metabolite and epoxide metabolite of vinflunine, respectively. Ketoconazole uncompetitively inhibited the formation of M1, and competitively inhibited the formation of M2, while α-naphthoflavone, sulfaphenazole, diethyl dithiocarbamate, tranylcypromine and quinidine had little or no inhibitory effect on the formation of M1 and M2. Conclusion: Vinflunine is rapidly metabolized in human liver microsomes, and CYP3A4 is the major human CYP450 involved in the metabolism of vinflunine.

  7. Alcohol- and water-based extracts obtained from Rhodiola rosea affect differently the number and metabolic activity of circulating granulocytes in Balb/c mice.

    Science.gov (United States)

    Zdanowski, Robert; Lewicki, Sławomir; Skopińska-Różewska, Ewa; Buchwald, Waldemar; Mrozikiewicz, Przemysław Michał; Stankiewicz, Wanda

    2014-01-01

    Rhodiola rosea (RR) rhizomes with roots extracts are traditional natural drugs originated from Asia and now commonly used as adaptogens and antidepressants. The aim of this work was to study the in vivo effect of aqueous (RRW) and 50% hydro-alcoholic (RRA) extracts on the number and metabolic activity of blood granulocytes in mice. Mice were fed for 7 days RR extract in daily doses 0.05, 0.1, 0.2 or 0.4 mg. The metabolic activity of blood granulocytes was determined by measuring of their luminol-dependent chemiluminescent activity in scintillation counter, after zymosan stimulation. Number of blood granulocytes was diminished and their chemiluminescence was enhanced in all groups of mice fed R.rosea hydro-alcoholic extract. Aqueous extract (RRW) was ineffective in all doses applied. This study revealed difference in the number and metabolic activity of granulocytes mice fed RRA or RRW extracts. Immune characteristics of some individual compounds from RRA and RRW extracts, selected by HPLC analysis, should be carried out in the next experiments.

  8. Non-alcoholic fatty liver disease and the metabolic syndrome: Effects of weight loss and a review of popular diets. Are low carbohydrate diets the answer?

    Institute of Scientific and Technical Information of China (English)

    Harjot K Gill; George Y Wu

    2006-01-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of fat-induced liver injury, ranging from relatively benign steatosis to cirrhosis and liver failure.The presence of obesity and insulin resistance is strongly associated with non-alcoholic fatty liver and confers on it a greater risk of histologically advanced disease. There is a growing concern in the medical profession as the prevalence of this disease continues to rise in parallel with the rise in obesity and the metabolic syndrome.Treatment options are limited and dietary weight loss is often advised. Low fat diets are difficult to adhere to and recent studies have shown the potential of low carbohydrate diets for weight loss and improving insulin resistance. Thus far, no study has evaluated the effect of low carbohydrate diets on NAFLD. Future studies will be required to address this question and others with regards to the nutritional adequacy and long-term side effects of these diets.

  9. Mechanistic modeling of aberrant energy metabolism in human disease

    Directory of Open Access Journals (Sweden)

    Vineet eSangar

    2012-10-01

    Full Text Available Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell.

  10. Characterization of energy and neurotransmitter metabolism in cortical glutamatergic neurons derived from human induced pluripotent stem cells: A novel approach to study metabolism in human neurons.

    Science.gov (United States)

    Aldana, Blanca I; Zhang, Yu; Lihme, Maria Fog; Bak, Lasse K; Nielsen, Jørgen E; Holst, Bjørn; Hyttel, Poul; Freude, Kristine K; Waagepetersen, Helle S

    2017-02-24

    Alterations in the cellular metabolic machinery of the brain are associated with neurodegenerative disorders such as Alzheimer's disease. Novel human cellular disease models are essential in order to study underlying disease mechanisms. In the present study, we characterized major metabolic pathways in neurons derived from human induced pluripotent stem cells (hiPSC). With this aim, cultures of hiPSC-derived neurons were incubated with [U-(13)C]glucose, [U-(13)C]glutamate or [U-(13)C]glutamine. Isotopic labeling in metabolites was determined using gas chromatography coupled to mass spectrometry, and cellular amino acid content was quantified by high-performance liquid chromatography. Additionally, we evaluated mitochondrial function using real-time assessment of oxygen consumption via the Seahorse XF(e)96 Analyzer. Moreover, in order to validate the hiPSC-derived neurons as a model system, a metabolic profiling was performed in parallel in primary neuronal cultures of mouse cerebral cortex and cerebellum. These serve as well-established models of GABAergic and glutamatergic neurons, respectively. The hiPSC-derived neurons were previously characterized as being forebrain-specific cortical glutamatergic neurons. However, a comparable preparation of predominantly mouse cortical glutamatergic neurons is not available. We found a higher glycolytic capacity in hiPSC-derived neurons compared to mouse neurons and a substantial oxidative metabolism through the mitochondrial tricarboxylic acid (TCA) cycle. This finding is supported by the extracellular acidification and oxygen consumption rates measured in the cultured human neurons. [U-(13)C]Glutamate and [U-(13)C]glutamine were found to be efficient energy substrates for the neuronal cultures originating from both mice and humans. Interestingly, isotopic labeling in metabolites from [U-(13)C]glutamate was higher than that from [U-(13)C]glutamine. Although the metabolic profile of hiPSC-derived neurons in vitro was

  11. Effects of chronic alcohol consumption on neuronal function in the non-human primate BNST

    Science.gov (United States)

    Alterations in hypothalamic–pituitary–adrenal axis function contribute to many of the adverse behavioral effects of chronic voluntary alcohol drinking, including alcohol dependence and mood disorders; limbic brain structures such as the bed nucleus of the stria termin...

  12. Metabolism

    Science.gov (United States)

    ... a particular food provides to the body. A chocolate bar has more calories than an apple, so ... acid phenylalanine, needed for normal growth and protein production). Inborn errors of metabolism can sometimes lead to ...

  13. Reconstruction and Analysis of Human Kidney-Specific Metabolic Network Based on Omics Data

    Directory of Open Access Journals (Sweden)

    Ai-Di Zhang

    2013-01-01

    Full Text Available With the advent of the high-throughput data production, recent studies of tissue-specific metabolic networks have largely advanced our understanding of the metabolic basis of various physiological and pathological processes. However, for kidney, which plays an essential role in the body, the available kidney-specific model remains incomplete. This paper reports the reconstruction and characterization of the human kidney metabolic network based on transcriptome and proteome data. In silico simulations revealed that house-keeping genes were more essential than kidney-specific genes in maintaining kidney metabolism. Importantly, a total of 267 potential metabolic biomarkers for kidney-related diseases were successfully explored using this model. Furthermore, we found that the discrepancies in metabolic processes of different tissues are directly corresponding to tissue's functions. Finally, the phenotypes of the differentially expressed genes in diabetic kidney disease were characterized, suggesting that these genes may affect disease development through altering kidney metabolism. Thus, the human kidney-specific model constructed in this study may provide valuable information for the metabolism of kidney and offer excellent insights into complex kidney diseases.

  14. The metabolic cost of human running: is swinging the arms worth it?

    Science.gov (United States)

    Arellano, Christopher J; Kram, Rodger

    2014-07-15

    Although the mechanical function is quite clear, there is no consensus regarding the metabolic benefit of arm swing during human running. We compared the metabolic cost of running using normal arm swing with the metabolic cost of running while restricting the arms in three different ways: (1) holding the hands with the arms behind the back in a relaxed position (BACK), (2) holding the arms across the chest (CHEST) and (3) holding the hands on top of the head (HEAD). We hypothesized that running without arm swing would demand a greater metabolic cost than running with arm swing. Indeed, when compared with running using normal arm swing, we found that net metabolic power demand was 3, 9 and 13% greater for the BACK, CHEST and HEAD conditions, respectively (all Prunning without arm swing, subjects significantly increased the peak-to-peak amplitudes of both shoulder and pelvis rotation about the vertical axis, most likely a compensatory strategy to counterbalance the rotational angular momentum of the swinging legs. In conclusion, our findings support our general hypothesis that swinging the arms reduces the metabolic cost of human running. Our findings also demonstrate that arm swing minimizes torso rotation. We infer that actively swinging the arms provides both metabolic and biomechanical benefits during human running.

  15. The Relationship of Appetitive, Reproductive and Posterior Pituitary Hormones to Alcoholism and Craving in Humans

    OpenAIRE

    2012-01-01

    A significant challenge for understanding alcoholism lies in discovering why some, but not other individuals, become dependent on alcohol. Genetic, environmental, cultural, developmental, and neurobiological influences are recognized as essential factors underlying a person's risk for becoming alcohol dependent (AD); however, the neurobiological processes that trigger this vulnerability are still poorly understood. Hormones are important in the regulation of many functions and several hormone...

  16. Metabolic signatures of cultured human adipocytes from metabolically healthy versus unhealthy obese individuals.

    Directory of Open Access Journals (Sweden)

    Anja Böhm

    Full Text Available Among obese subjects, metabolically healthy and unhealthy obesity (MHO/MUHO can be differentiated: the latter is characterized by whole-body insulin resistance, hepatic steatosis, and subclinical inflammation. Aim of this study was, to identify adipocyte-specific metabolic signatures and functional biomarkers for MHO versus MUHO.10 insulin-resistant (IR vs. 10 insulin-sensitive (IS non-diabetic morbidly obese (BMI >40 kg/m2 Caucasians were matched for gender, age, BMI, and percentage of body fat. From subcutaneous fat biopsies, primary preadipocytes were isolated and differentiated to adipocytes in vitro. About 280 metabolites were investigated by a targeted metabolomic approach intracellularly, extracellularly, and in plasma.Among others, aspartate was reduced intracellularly to one third (p = 0.0039 in IR adipocytes, pointing to a relative depletion of citric acid cycle metabolites or reduced aspartate uptake in MUHO. Other amino acids, already known to correlate with diabetes and/or obesity, were identified to differ between MUHO's and MHO's adipocytes, namely glutamine, histidine, and spermidine. Most species of phosphatidylcholines (PCs were lower in MUHO's extracellular milieu, though simultaneously elevated intracellularly, e.g., PC aa C32∶3, pointing to increased PC synthesis and/or reduced PC release. Furthermore, altered arachidonic acid (AA metabolism was found: 15(S-HETE (15-hydroxy-eicosatetraenoic acid; 0 vs. 120pM; p = 0.0014, AA (1.5-fold; p = 0.0055 and docosahexaenoic acid (DHA, C22∶6; 2-fold; p = 0.0033 were higher in MUHO. This emphasizes a direct contribution of adipocytes to local adipose tissue inflammation. Elevated DHA, as an inhibitor of prostaglandin synthesis, might be a hint for counter-regulatory mechanisms in MUHO.We identified adipocyte-inherent metabolic alterations discriminating between MHO and MUHO.

  17. A single dose of alcohol does not meaningfully alter circadian phase advances and phase delays to light in humans.

    Science.gov (United States)

    Burgess, Helen J; Rizvydeen, Muneer; Fogg, Louis F; Keshavarzian, Ali

    2016-04-15

    Central circadian timing influences mental and physical health. Research in nocturnal rodents has demonstrated that when alcohol is consumed, it reaches the central hypothalamic circadian pacemaker (suprachiasmatic nuclei) and can directly alter circadian phase shifts to light. In two separate studies, we examined, for the first time, the effects of a single dose of alcohol on circadian phase advances and phase delays to light in humans. Two 23-day within-subjects placebo-controlled counterbalanced design studies were conducted. Both studies consisted of 6 days of fixed baseline sleep to stabilize circadian timing, a 2-day laboratory session, a 6-day break, and a repeat of 6 days of fixed sleep and a 2-day laboratory session. In the phase advance study (n= 10 light drinkers, 24-45 yr), the laboratory sessions consisted of a baseline dim light phase assessment, sleep episode, alcohol (0.6 g/kg) or placebo, 2-h morning bright light pulse, and final phase assessment. In the phase-delay study (n= 14 light drinkers, 22-44 yr), the laboratory sessions consisted of a baseline phase assessment, alcohol (0.8 g/kg) or placebo, 2-h late night bright light pulse, sleep episode, and final phase assessment. In both studies, alcohol either increased or decreased the observed phase shifts to light (interaction P≥ 0.46), but the effect of alcohol vs. placebo on phase shifts to light was always on average smaller than 30 min. Thus, no meaningful effects of a single dose of alcohol vs. placebo on circadian phase shifts to light in humans were observed.

  18. Functional Metabolic Map of Faecalibacterium prausnitzii, a Beneficial Human Gut Microbe

    NARCIS (Netherlands)

    Heinken, Almut; Khan, M. Tanweer; Paglia, Giuseppe; Rodionov, Dmitry A.; Harmsen, Hermie J. M.; Thiele, Ines

    2014-01-01

    The human gut microbiota plays a central role in human well-being and disease. In this study, we present an integrated, iterative approach of computational modeling, in vitro experiments, metabolomics, and genomic analysis to accelerate the identification of metabolic capabilities for poorly charact

  19. The glucagon-like peptide-1 receptor as a potential treatment target in alcohol use disorder: evidence from human genetic association studies and a mouse model of alcohol dependence.

    Science.gov (United States)

    Suchankova, P; Yan, J; Schwandt, M L; Stangl, B L; Caparelli, E C; Momenan, R; Jerlhag, E; Engel, J A; Hodgkinson, C A; Egli, M; Lopez, M F; Becker, H C; Goldman, D; Heilig, M; Ramchandani, V A; Leggio, L

    2015-06-16

    The hormone glucagon-like peptide-1 (GLP-1) regulates appetite and food intake. GLP-1 receptor (GLP-1R) activation also attenuates the reinforcing properties of alcohol in rodents. The present translational study is based on four human genetic association studies and one preclinical study providing data that support the hypothesis that GLP-1R may have a role in the pathophysiology of alcohol use disorder (AUD). Case-control analysis (N = 908) was performed on a sample of individuals enrolled in the National Institute on Alcohol Abuse and Alcoholism (NIAAA) intramural research program. The Study of Addiction: Genetics and Environment (SAGE) sample (N = 3803) was used for confirmation purposes. Post hoc analyses were carried out on data from a human laboratory study of intravenous alcohol self-administration (IV-ASA; N = 81) in social drinkers and from a functional magnetic resonance imaging study in alcohol-dependent individuals (N = 22) subjected to a Monetary Incentive Delay task. In the preclinical study, a GLP-1R agonist was evaluated in a mouse model of alcohol dependence to demonstrate the role of GLP-1R for alcohol consumption. The previously reported functional allele 168Ser (rs6923761) was nominally associated with AUD (P = 0.004) in the NIAAA sample, which was partially replicated in males of the SAGE sample (P = 0.033). The 168 Ser/Ser genotype was further associated with increased alcohol administration and breath alcohol measures in the IV-ASA experiment and with higher BOLD response in the right globus pallidus when receiving notification of outcome for high monetary reward. Finally, GLP-1R agonism significantly reduced alcohol consumption in a mouse model of alcohol dependence. These convergent findings suggest that the GLP-1R may be an attractive target for personalized pharmacotherapy treatment of AUD.

  20. IL-6 selectively stimulates fat metabolism in human skeletal muscle

    DEFF Research Database (Denmark)

    Wolsk, Emil; Mygind, Helene; Grøndahl, Thomas S

    2010-01-01

    and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ∼40 and ∼1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed...... in systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged with rhIL-6 compared with saline infusion. Conversely, rhIL-6 infusion caused an increase in skeletal muscle unidirectional fatty acid and glycerol release, indicative of an increase in lipolysis. The increased lipolysis...... in muscle could account for the systemic changes. Skeletal muscle signaling increased after 1 h of rhIL-6 infusion, indicated by a fourfold increase in the phosphorylated signal transducer and activator of transcription (STAT) 3-to-STAT3 ratio, whereas no changes in phosphorylated AMP-activated protein...

  1. IL-6 selectively stimulates fat metabolism in human skeletal muscle

    DEFF Research Database (Denmark)

    Wolsk, Emil; Mygind, Helene; Grøndahl, Thomas S

    2010-01-01

    and glucose metabolism and signaling of both adipose tissue and skeletal muscle. Eight healthy postabsorptive males were infused with either rhIL-6 or saline for 4 h, eliciting IL-6 levels of ~40 and ~1 pg/ml, respectively. Systemic, skeletal muscle, and adipose tissue fat and glucose metabolism was assessed...... in systemic lipolysis. Adipose tissue lipolysis and fatty acid kinetics were unchanged with rhIL-6 compared with saline infusion. Conversely, rhIL-6 infusion caused an increase in skeletal muscle unidirectional fatty acid and glycerol release, indicative of an increase in lipolysis. The increased lipolysis...... in muscle could account for the systemic changes. Skeletal muscle signaling increased after 1 h of rhIL-6 infusion, indicated by a fourfold increase in the phosphorylated signal transducer and activator of transcription (STAT) 3-to-STAT3 ratio, whereas no changes in phosphorylated AMP-activated protein...

  2. Acute alcohol-induced liver injury

    Directory of Open Access Journals (Sweden)

    Gavin Edward Arteel

    2012-06-01

    Full Text Available Alcohol consumption is customary in most cultures and alcohol abuse is common worldwide. For example, more than 50% of Americans consume alcohol, with an estimated 23.1% of Americans participating in heavy and/or binge drinking at least once a month. A safe and effective therapy for alcoholic liver disease (ALD in humans is still elusive, despite significant advances in our understanding of how the disease is initiated and progresses. It is now clear that acute alcohol binges not only can be acutely toxic to the liver, but also can contribute to the chronicity of ALD. Potential mechanisms by which acute alcohol causes damage include steatosis, dysregulated immunity and inflammation and altered gut permeability. Recent interest in modeling acute alcohol exposure has yielded new insights into potential mechanisms of acute injury, that also may well be relevant for chronic ALD. Recent work by this group on the role of PAI-1 and fibrin metabolism in mediating acute alcohol-induced liver damage serve as an example of possible new targets that may be useful for alcohol abuse, be it acute or chronic.

  3. Temporal variations of adenosine metabolism in human blood.

    Science.gov (United States)

    Chagoya de Sánchez, V; Hernández-Muñoz, R; Suárez, J; Vidrio, S; Yáñez, L; Aguilar-Roblero, R; Oksenberg, A; Vega-González, A; Villalobos, L; Rosenthal, L; Fernández-Cancino, F; Drucker-Colín, R; Díaz-Muñoz, M

    1996-08-01

    Eight diurnally active (06:00-23:00 h) subjects were adapted for 2 days to the room conditions where the experiments were performed. Blood sampling for adenosine metabolites and metabolizing enzymes was done hourly during the activity span and every 30 min during sleep. The results showed that adenosine and its catabolites (inosine, hypoxanthine, and uric acid), adenosine synthesizing (S-adenosylhomocysteine hydrolase and 5'-nucleotidase), degrading (adenosine deaminase) and nucleotide-forming (adenosine kinase) enzymes as well as adenine nucleotides (AMP, ADP, and ATP) undergo statistically significant fluctuations (ANOVA) during the 24 h. However, energy charge was invariable. Glucose and lactate chronograms were determined as metabolic indicators. The same data analyzed by the chi-square periodogram and Fourier series indicated ultradian oscillatory periods for all the metabolites and enzymatic activities determined, and 24-h oscillatory components for inosine, hypoxanthine, adenine nucleotides, glucose, and the activities of SAH-hydrolase, 5'-nucleotidase, and adenosine kinase. The single cosinor method showed significant oscillatory components exclusively for lactate. As a whole, these results suggest that adenosine metabolism may play a role as a biological oscillator coordinating and/or modulating the energy homeostasis and physiological status of erythrocytes in vivo and could be an important factor in the distribution of purine rings for the rest of the organism.

  4. Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

    Energy Technology Data Exchange (ETDEWEB)

    Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de [Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany); Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de [Department for Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany); Weiskirchen, Ralf, E-mail: rweiskirchen@ukaachen.de [Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany); Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig (Germany)

    2014-08-15

    Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.

  5. Dynamic simulation and finite element analysis of the human mandible injury protected by polyvinyl alcohol sponge

    Energy Technology Data Exchange (ETDEWEB)

    Karimi, Alireza; Navidbakhsh, Mahdi, E-mail: mnavid@iust.ac.ir; Razaghi, Reza

    2014-09-01

    There have been intensive efforts to find a suitable kinetic energy absorbing material for helmet and bulletproof vest design. Polyvinyl alcohol (PVA) sponge is currently in extensive use as scaffolding material for tissue engineering applications. PVA can also be employed instead of commonly use kinetic energy absorbing materials to increase the kinetic energy absorption capacity of current helmet and bulletproof vest materials owing to its excellent mechanical properties. In this study, a combined hexahedral finite element (FE) model is established to determine the potential protection ability of PVA sponge in controlling the level of injury for gunshot wounds to the human mandible. Digital computed tomography data for the human mandible are used to establish a three-dimensional FE model of the human mandible. The mechanism by which a gunshot injures the protected mandible by PVA sponge is dynamically simulated using the LS-DYNA code under two different shot angles. The stress distributions in different parts of the mandible and sponge after injury are also simulated. The modeling results regardless of shot angle reveal that the substantial amount of kinetic energy of the steel ball (67%) is absorbed by the PVA sponge and, consequently, injury severity of the mandible is significantly decreased. The highest energy loss (170 J) is observed for the impact at entry angle of 70°. The results suggest the application of the PVA sponge as an alternative reinforcement material in helmet and bulletproof vest design to absorb most of the impact energy and reduce the transmitted load. - Highlights: • The ability of PVA sponge to control the injury to the human mandible is computed. • A hexahedral FE model for gunshot wounds to the human mandible is established. • The kinetic energy and injury severity of the mandible is minimized by the sponge. • The highest energy loss (170 J) is observed for the impact at entry angle of 70°. • PVA suggests as an alternative

  6. Alcohol and aldehyde dehydrogenases: structures of the human liver enzymes, functional properties and evolutionary aspects.

    Science.gov (United States)

    Jörnvall, H; Hempel, J; von Bahr-Lindström, H; Höög, J O; Vallee, B L

    1987-01-01

    All three types of subunit of class I human alcohol dehydrogenase have been analyzed both at the protein and cDNA levels, and the structures of alpha, beta 1, beta 2, gamma 1, and gamma 2 subunits are known. The same applies to class II pi subunits. Extensive protein data are also available for class III chi subunits. In the class I human isozymes, amino acid exchanges occur at 35 positions in total, with 21-28 replacements between any pair of the alpha/beta/gamma chains. These values, compared with those from species differences between the corresponding human and horse enzymes, suggest that isozyme developments in the class I enzyme resulted from separate gene duplications after the divergence of the human and equine evolutionary lines. All subunits exhibit some unique properties, with slightly closer similarity between the human gamma and horse enzyme subunits and somewhat greater deviations towards the human alpha subunit. Differences are large also in segments close to the active site zinc ligands and other functionally important positions. Species differences are distributed roughly equally between the two types of domain in the subunit, whereas isozyme differences are considerably more common in the catalytic than in the coenzyme-binding domain. These facts illustrate a functional divergence among the isozymes but otherwise similar changes during evolution. Polymorphic forms of beta and gamma subunits are characterized by single replacements at one and two positions, respectively, explaining known deviating properties. Class II and class III subunits are considerably more divergent. Their homology with class I isozymes exhibits only 60-65% positional identity. Hence, they reflect further steps towards the development of new enzymes, with variations well above the horse/human species levels, in contrast to the class I forms. Again, functionally important residues are affected, and patterns resembling those previously established for the divergently related

  7. Association of polymorphisms in nicotinic acetylcholine receptor alpha 4 subunit gene (CHRNA4), mu-opioid receptor gene (OPRM1), and ethanol-metabolizing enzyme genes with alcoholism in Korean patients.

    Science.gov (United States)

    Kim, Soon Ae; Kim, Jong-Woo; Song, Ji-Young; Park, Sunny; Lee, Hee Jae; Chung, Joo-Ho

    2004-01-01

    Findings obtained from several studies indicate that ethanol enhances the activity of alpha4beta2 neuronal nicotinic acetylcholine receptor and support the possibility that a polymorphism of the nicotinic acetylcholine receptor alpha4 subunit gene (CHRNA4) modulates enhancement of nicotinic receptor function by ethanol. To identify the association between the CfoI polymorphism of the CHRNA4 and alcoholism, we examined distribution of genotypes and allele frequencies in Korean patients diagnosed with alcoholism (n = 127) and Korean control subjects without alcoholism (n = 185) with polymerase chain reaction-restriction fragment length polymorphism methods. We were able to detect the association between the CfoI polymorphism of the CHRNA4 and alcoholism in Korean patients (genotype P = .023; allele frequency P = .047). The genotypes and allele frequencies of known polymorphisms in other alcoholism candidate genes, such as alcohol metabolism-related genes [alcohol dehydrogenase 2 (ADH2), aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 3 (ADH3), and cytochrome P450 2E1 (CYP2E1)] and mu-opioid receptor gene (OPRM1), were studied. The polymorphisms of ADH2, ALDH2, and CYP2E1 were significantly different in Korean patients with alcoholism and Korean control subjects without alcoholism, but ADH3 and OPRM1 did not differ between the two groups.

  8. Evolutionary Medicine: The Ongoing Evolution of Human Physiology and Metabolism.

    Science.gov (United States)

    Rühli, Frank; van Schaik, Katherine; Henneberg, Maciej

    2016-11-01

    The field of evolutionary medicine uses evolutionary principles to understand changes in human anatomy and physiology that have occurred over time in response to environmental changes. Through this evolutionary-based approach, we can understand disease as a consequence of anatomical and physiological "trade-offs" that develop to facilitate survival and reproduction. We demonstrate how diachronic study of human anatomy and physiology is fundamental for an increased understanding of human health and disease.

  9. The Molecular Circadian Clock and Alcohol-Induced Liver Injury.

    Science.gov (United States)

    Udoh, Uduak S; Valcin, Jennifer A; Gamble, Karen L; Bailey, Shannon M

    2015-10-14

    Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  10. The Molecular Circadian Clock and Alcohol-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Uduak S. Udoh

    2015-10-01

    Full Text Available Emerging evidence from both experimental animal studies and clinical human investigations demonstrates strong connections among circadian processes, alcohol use, and alcohol-induced tissue injury. Components of the circadian clock have been shown to influence the pathophysiological effects of alcohol. Conversely, alcohol may alter the expression of circadian clock genes and the rhythmic behavioral and metabolic processes they regulate. Therefore, we propose that alcohol-mediated disruption in circadian rhythms likely underpins many adverse health effects of alcohol that cut across multiple organ systems. In this review, we provide an overview of the circadian clock mechanism and showcase results from new studies in the alcohol field implicating the circadian clock as a key target of alcohol action and toxicity in the liver. We discuss various molecular events through which alcohol may work to negatively impact circadian clock-mediated processes in the liver, and contribute to tissue pathology. Illuminating the mechanistic connections between the circadian clock and alcohol will be critical to the development of new preventative and pharmacological treatments for alcohol use disorders and alcohol-mediated organ diseases.

  11. Role of Innate Immune Response in Non-Alcoholic Fatty Liver Disease: Metabolic Complications and Therapeutic Tools

    OpenAIRE

    Rosaria eMeli; Giuseppina eMattace Raso; Antonio eCalignano

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is currently the most common liver disease worldwide, both in adults and children. It is characterized by an aberrant lipid storage in hepatocytes, named hepatic steatosis. Simple steatosis remains a benign process in most affected patients, while some of them develop superimposed necroinflammatory activity with a non-specific inflammatory infiltrate and a progression to non-alcoholic steatohepatitis with or without fibrosis. Deep similarity and inter...

  12. NEUROBIOLOGICAL BASES OF ALCOHOL ADDICTION.

    Science.gov (United States)

    Matošić, Ana; Marušić, Srđan; Vidrih, Branka; Kovak-Mufić, Ana; Cicin-Šain, Lipa

    2016-03-01

    characteristic of alcoholism type 2 is seeking for excitement (Novelty Seeking, NS), unchanged dopamine transmission and decreased serotonin transmission. These neurochemical differences among alcoholism subtypes represent the basis for a different therapy approach. Intake of alcohol changes different gene expression in the human brain. The inheritance model of alcoholism is not fully explained, however, it is considered that the disease is connected to a larger gene number included in neurotransmission, cell mechanisms and general metabolic function, with a simultaneous influence of the environment. The contribution of genetic factors is stronger in certain types of alcoholism and thus we have been confronted in the last years of alcoholism research with studies researching the connections of some alcoholism subtypes with the polymorphism phenomenon in the genes coding the synaptic proteins included in the alcoholism etiology. The primary role of monoamine oxidase (MAO) in the brain is catalysis of deamination of the oxidative neurotransmitter amines, i.e. serotonin, adrenaline, noradrenaline and dopamine. Thus, this enzyme is the key factor for maintaining cytoplasmic concentration of various neurotransmitters and for regulation of the neurotransmitting synaptic activity. Taken this MAO function into consideration, MAO is the enzyme included in the etiology and pathogenesis of various neuropsychiatric and neurological disorders. The finding of the decreased platelet MAO activity in various psychiatric disorders has brought us to the assumption that this enzyme may be a constitutional/genetic indicator (trait marker) or an indicator of disease condition (state marker) in biologic psychiatry. There are only a few studies of alcohol addiction researching the connections of the MAO coding gene polymorphism and alcoholism; however, these studies are primarily related to the variable number of tandem repeats (VTNR) polymorphism in the regulatory gene region for MAO-A, considered to

  13. Energy metabolism in human pluripotent stem cells and their differentiated counterparts.

    Directory of Open Access Journals (Sweden)

    Sandra Varum

    Full Text Available Human pluripotent stem cells have the ability to generate all cell types present in the adult organism, therefore harboring great potential for the in vitro study of differentiation and for the development of cell-based therapies. Nonetheless their use may prove challenging as incomplete differentiation of these cells might lead to tumoregenicity. Interestingly, many cancer types have been reported to display metabolic modifications with features that might be similar to stem cells. Understanding the metabolic properties of human pluripotent stem cells when compared to their differentiated counterparts can thus be of crucial importance. Furthermore recent data has stressed distinct features of different human pluripotent cells lines, namely when comparing embryo-derived human embryonic stem cells (hESCs and induced pluripotent stem cells (IPSCs reprogrammed from somatic cells.We compared the energy metabolism of hESCs, IPSCs, and their somatic counterparts. Focusing on mitochondria, we tracked organelle localization and morphology. Furthermore we performed gene expression analysis of several pathways related to the glucose metabolism, including glycolysis, the pentose phosphate pathway and the tricarboxylic acid (TCA cycle. In addition we determined oxygen consumption rates (OCR using a metabolic extracellular flux analyzer, as well as total intracellular ATP levels by high performance liquid chromatography (HPLC. Finally we explored the expression of key proteins involved in the regulation of glucose metabolism.Our results demonstrate that, although the metabolic signature of IPSCs is not identical to that of hESCs, nonetheless they cluster with hESCs rather than with their somatic counterparts. ATP levels, lactate production and OCR revealed that human pluripotent cells rely mostly on glycolysis to meet their energy demands. Furthermore, our work points to some of the strategies which human pluripotent stem cells may use to maintain high

  14. The effects of detergent, sodium tripoly-phosphate and ethoxyled oleyl-cetyl alcohol on metabolic parameters of the fungus Trichothecium roseum link

    Directory of Open Access Journals (Sweden)

    Stojanović Jelica

    2011-01-01

    Full Text Available The degradation of detergents that are dispersed in water and soil partially depends on the metabolic activities of fungi. Among the fungi that have this ability, Deuteromycetes are particularly noted for their biochemical characteristics. Taking this into account, it was of interest to analyze the influence of detergent and its main compounds, ethoxyled oleylcetyl alcohol (AOC and sodium tripoly-phosphate (TTP, on the metabolism of the fungus Trichothecium roseum. Our results revealed that both detergent and AOC had an inhibitory effect on the bioproduction of free organic acids, while TTP stimulated their production. Also, detergent inhibited the bioproduction of basic amino acids, with the exception of alanine. In addition, detergent applied at 1% concentration inhibited the bioproduction of proteins and the total biomass of the fungus, while AOC and TTP inhibited the production of proteins, but stimulatedl the production of Trichothecium.

  15. [Non-alcoholic fatty liver disease (NAFLD) in patients with metabolic syndrome and type 2 diabetes mellitus. Pathomechanism, new diagnostic markers].

    Science.gov (United States)

    Kieć-Wilk, Beata; Klupa, Tomasz; Dembińska-Kieć, Aldona

    2010-01-01

    Non-alcoholic fatty liver disease (NAFLD) is a complex of a wide spectrum of liver pathology--from steatosis alone, to cirrhosis and liver cancer. The pathogenic concept of NAFLD covers overnutrition with fatty acids, underactivity. Insulin resistance is believed to play the main role in this process. NAFLD is mostly related to visceral adiposity, metabolic syndrome and type 2 diabetes melitus. The presented work is a review of in vitro and in vivo modern studies, as well as clinical observations on molecular mechanisms leading to development and progress of NAFLD. Up till today their is no treatment od NAFLD, and this pathology is not benign--it may lead to patients' death in 10 years. The clinical approach to NAFLD is prevention of it's development. The manuscript is a review of new biochemical markers allowing for early detection of metabolic disorders leading to NAFLD development, thus to sufficient prevention of this pathology in patients.

  16. Alcohol: A Nutrient with Multiple Salutary Effects

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    Henry J. Pownall

    2015-03-01

    Full Text Available Numerous studies have shown that cardiovascular disease is lower among alcohol consumers than among nonconsumers. Many of the metabolic effects of alcohol are mediated by its terminal metabolite, acetate, which has reported insulinemic properties. There have been few rational metabolic targets that underly its cardioprotective effects until it was reported that acetate, the terminal product of alcohol metabolism, is the ligand for G-protein coupled receptor 43 (GPCR43, which is highly expressed in adipose tissue. Here, we recast much of some of the major lipid and lipoprotein effects of alcohol in the context of this newly discovered G-protein and develop a mechanistic model connecting the interaction of acetate with adipose tissue-GPCR43 with these effects. According to our model, ingestions of acetate could replace alcohol as a means of improving plasma lipid risk factors, improving glucose disposal, and reducing cardiovascular disease. Future studies should include biochemical, cell, animal, and human tests of acetate on energy metabolism.

  17. A reduced cerebral metabolic ratio in exercise reflects metabolism and not accumulation of lactate within the human brain

    DEFF Research Database (Denmark)

    Dalsgaard, Mads K; Quistorff, Bjørn; Danielsen, Else R

    2003-01-01

    During maximal exercise lactate taken up by the human brain contributes to reduce the cerebral metabolic ratio, O(2)/(glucose + 1/2 lactate), but it is not known whether the lactate is metabolized or if it accumulates in a distribution volume. In one experiment the cerebral arterio...... young subjects. In a second experiment magnetic resonance spectroscopy ((1)H-MRS) was performed after exhaustive exercise to assess lactate levels in the brain (n = 5). Exercise increased the AV(O2) from 3.2 +/- 0.1 at rest to 3.5 +/- 0.2 mM (mean +/-s.e.m.; P ...-venous differences (AV) for O(2), glucose (glc) and lactate (lac) were evaluated in nine healthy subjects at rest and during and after exercise to exhaustion. The cerebrospinal fluid (CSF) was drained through a lumbar puncture immediately after exercise, while control values were obtained from six other healthy...

  18. IMPACT OF ALCOHOL ON HUMAN VITAL SEMINAL PARAMETER WHICH INFLUENCE FERTILITY

    Directory of Open Access Journals (Sweden)

    Abhishek

    2015-07-01

    Full Text Available Alcohol has wide impact (affect on male reproductive function like impotence, loss of sexual interest, gynecomastia and on male infertility. Alcohol can adversely affect the leydig cells which secretes the male hormone testosterone, Several studied have been conducted to evaluate the effect of alcohol in men and results shows reduced testosterone levels in the blood. Alcohol has dual effect on the hypothalamic pituitary – gonadal axis and blocking the release of LH - releasing hormone. 110 subjects were inc luded in the present study amongst whom 25 were non - alcoholic, 53 with low alcoholic and 32 with high alcoholic intake. Our study shows that ethanol exhibits alteration in their spermatozoa concentration, abnormal motility and morphology.

  19. Exploring causal associations of alcohol with cardiovascular and metabolic risk factors in a Chinese population using Mendelian randomization analysis.

    Science.gov (United States)

    Taylor, Amy E; Lu, Feng; Carslake, David; Hu, Zhibin; Qian, Yun; Liu, Sijun; Chen, Jiaping; Shen, Hongbing; Smith, George Davey

    2015-09-14

    Observational studies suggest that moderate alcohol consumption may be protective for cardiovascular disease, but results may be biased by confounding and reverse causality. Mendelian randomization, which uses genetic variants as proxies for exposures, can minimise these biases and therefore strengthen causal inference. Using a genetic variant in the ALDH2 gene associated with alcohol consumption, rs671, we performed a Mendelian randomization analysis in 1,712 diabetes cases and 2,076 controls from Nantong, China. Analyses were performed using linear and logistic regression, stratified by sex and diabetes status. The A allele of rs671 was strongly associated with reduced odds of being an alcohol drinker in all groups, but prevalence of alcohol consumption amongst females was very low. The A allele was associated with reduced systolic and diastolic blood pressure and decreased total and HDL cholesterol in males. The A allele was also associated with decreased triglyceride levels, but only robustly in diabetic males. There was no strong evidence for associations between rs671 and any outcomes in females. Our results suggest that associations of alcohol consumption with blood pressure and HDL-cholesterol are causal. Alcohol also appeared to have adverse effects on triglyceride levels, although this may be restricted to diabetics.

  20. First-pass metabolism of ethanol in human beings: effect of intravenous infusion of fructose

    DEFF Research Database (Denmark)

    Parlesak, Alexandr; Billinger, MH; Schäfer, C.

    2004-01-01

    Intravenous infusion of fructose has been shown to enhance reduced form of nicotinamide adenine dinucleotide reoxidation and, thereby, to enhance the metabolism of ethanol. In the current study, the effect of fructose infusion on first-pass metabolism of ethanol was studied in human volunteers....... A significantly higher first-pass metabolism of ethanol was obtained after administration of fructose in comparison with findings for control experiments with an equimolar dose of glucose. Because fructose is metabolized predominantly in the liver and can be presumed to have virtually no effects in the stomach......, results of the current study support the assumption that only a negligible part of first-pass metabolism of ethanol occurs in the stomach....

  1. Experimental study on trace chemical contaminant generation rates of human metabolism in spacecraft crew module

    Science.gov (United States)

    Lihua, Guo; Xinxing, He; Guoxin, Xu; Xin, Qi

    2012-12-01

    Trace chemical contaminants generated by human metabolism is a major source of contamination in spacecraft crew module. In this research, types and generation rates of pollutants from human metabolism were determined in the Chinese diets. Expired air, skin gas, and sweat of 20 subjects were analyzed at different exercise states in a simulated module. The exercise states were designed according to the basic activities in the orbit of astronauts. Qualitative and quantitative analyses of contaminants generated by human metabolic were performed with gas chromatography/mass spectrometry, gas chromatography and UV spectrophotometer. Sixteen chemical compounds from metabolic sources were found. With the increase in physical load, the concentrations of chemical compounds from human skin and expired air correspondingly increased. The species and the offgassing rates of pollutants from human metabolism are different among the Chinese, Americans and the Russians due to differences in ethnicity and dietary customs. This research provides data to aid in the design, development and operation of China's long duration space mission.

  2. Tag single nucleotide polymorphisms of alcohol-metabolizing enzymes modify the risk of upper aerodigestive tract cancers: HapMap database analysis.

    Science.gov (United States)

    Chung, C-S; Lee, Y-C; Liou, J-M; Wang, C-P; Ko, J-Y; Lee, J-M; Wu, M-S; Wang, H-P

    2014-07-01

    Although alcohol is associated with higher upper aerodigestive tract (UADT) cancer risk, only a small fraction of alcoholics develop cancers. There is a lack of evidence proving the association of tag single nucleotide polymorphisms of alcohol-metabolizing enzymes with cancer risk. The aim of this study was to determine the association of these genetic polymorphisms with UADT cancer risk in a Chinese population. It was a hospital-based case-control candidate gene study. The databases of the International HapMap Project were searched for haplotype tag single nucleotide polymorphisms of the genes alcohol dehydrogenase (ADH)1B, ADH1C, and aldehyde dehydrogenase (ALDH)2. The genotyping was performed by the Sequenom MassARRAY system. Totally, 120 head and neck squamous cell carcinoma, 138 esophageal squamous cell carcinoma patients, and 276 age- and gender-matched subjects were enrolled between June 2008 and June 2010.Minor alleles of ADH1B (rs1229984) and ALDH2(rs671) were not only associated with the risk of UADT cancers (odds ratio [OR] [95% confidence interval, CI]: 3.53 [2.14-5.80] and 2.59 [1.79-3.75], respectively) but also potentiated the carcinogenic effects of alcohol (OR [95% CI]: 53.44 [25.21-113.29] and 70.08 [33.65-145.95], respectively). Similar effects were observed for head/neck and esophageal cancer subgroups. Multivariate logistic regression analysis identified four significant risk factors, including habitual use of cigarettes, alcohol, betel quid, and lower body mass index (P < 0.001). The haplotypes GAGC (OR 1.61, 95% CI 1.08-2.40, P = 0.018) and CCAATG (OR 1.69, 95% CI 1.24-2.30, P < 0.001) on chromosomes 4 and 12, respectively, were associated with higher cancer risk. These findings suggested that risk allele or haplotype carriers who consume alcohol and other carcinogens should be advised to undergo endoscopy screening. The information can be used to determine the degree of susceptibility of each subject and can be combined with other

  3. Spaceflight and protein metabolism, with special reference to humans

    Science.gov (United States)

    Stein, T. P.; Gaprindashvili, T.

    1994-01-01

    Human space missions have shown that human spaceflight is associated with a loss of body protein. Specific changes include a loss of lean body mass, decreased muscle mass in the calves, decreased muscle strength, and changes in plasma proteins and amino acids. The major muscle loss is believed to be associated with the antigravity (postural) muscle. The most significant loss of protein appears to occur during the first month of flight. The etiology is believed to be multifactorial with contributions from disuse atrophy, undernutrition, and a stress type of response. This article reviews the results of American and Russian space missions to investigate this problem in humans, monkeys, and rats. The relationship of the flight results with ground-based models including bedrest for humans and hindlimb unweighting for rats is also discussed. The results suggest that humans adapt to spaceflight much better than either monkeys or rats.

  4. Plasticity in mitochondrial cristae density allows metabolic capacity modulation in human skeletal muscle

    DEFF Research Database (Denmark)

    Nielsen, Joachim; Gejl, Kasper D; Hey-Mogensen, Martin;

    2016-01-01

    that this mechanism allows evasion of the trade-off between cell occupancy by mitochondria and other cellular constituents and improved metabolic capacity and fuel catabolism during prolonged elevated energy requirements. This article is protected by copyright. All rights reserved.......-body level, muscle mitochondrial cristae density is a better predictor of maximal oxygen uptake rate than muscle mitochondrial volume. Our findings establish elevating mitochondrial cristae density as a regulatory mechanism for increasing metabolic power in human skeletal muscle. We propose...

  5. Inhibition of Sphingolipid Metabolism Enhances Resveratrol Chemotherapy in Human Gastric Cancer Cells

    OpenAIRE

    Shin, Kyong-Oh; Park, Nam-Young; Seo, Cho-Hee; Hong, Seon-Pyo; Oh, Ki-Wan; Hong, Jin-Tae; Han, Sang-Kil; Lee, Yong-Moon

    2012-01-01

    Resveratrol, a chemopreventive agent, is rapidly metabolized in the intestine and liver via glucuronidation. Thus, the pharmacokinetics of resveratrol limits its efficacy. To improve efficacy, the activity of resveratrol was investigated in the context of sphingolipid metabolism in human gastric cancer cells. Diverse sphingolipid metabolites, including dihydroceramides (DHCer), were tested for their ability to induce resveratrol cytotoxicity. Exposure to resveratrol (100 μM) for 24 hr induced...

  6. Inhibition of Sphingolipid Metabolism Enhances Resveratrol Chemotherapy in Human Gastric Cancer Cells

    OpenAIRE

    Shin, Kyong-Oh; Park, Nam-Young; Seo, Cho-hee; Hong, Seon-Pyo; Oh, Ki-Wan; Hong, Jin-Tae; Han, Sang-Kil; Lee, Yong-Moon

    2012-01-01

    Resveratrol, a chemopreventive agent, is rapidly metabolized in the intestine and liver via glucuronidation. Thus, the pharmacokinetics of resveratrol limits its efficacy. To improve efficacy, the activity of resveratrol was investigated in the context of sphingolipid metabolism in human gastric cancer cells. Diverse sphingolipid metabolites, including dihydroceramides (DHCer), were tested for their ability to induce resveratrol cytotoxicity. Exposure to resveratrol (100 μM) for 24 hr induced...

  7. Metabolism of fatty acids and lipid hydroperoxides in human body monitoring with Fourier transform Infrared Spectroscopy

    Directory of Open Access Journals (Sweden)

    Zhang Qin-Zeng

    2009-07-01

    Full Text Available Abstract Background The metabolism of dietary fatty acids in human has been measured so far using human blood cells and stable-isotope labeled fatty acids, however, no direct data was available for human peripheral tissues and other major organs. To realize the role of dietary fatty acids in human health and diseases, it would be eager to develop convenient and suitable method to monitor fatty acid metabolism in human. Results We have developed the measurement system in situ for human lip surface lipids using the Fourier transform infrared spectroscopy (FTIR – attenuated total reflection (ATR detection system with special adaptor to monitor metabolic changes of lipids in human body. As human lip surface lipids may not be much affected by skin sebum constituents and may be affected directly by the lipid constituents of diet, we could detect changes of FTIR-ATR spectra, especially at 3005~3015 cm-1, of lip surface polyunsaturated fatty acids in a duration time-dependent manner after intake of the docosahexaenoic acid (DHA-containing triglyceride diet. The ingested DHA appeared on the lip surface and was detected by FTIR-ATR directly and non-invasively. It was found that the metabolic rates of DHA for male volunteer subjects with age 60s were much lower than those with age 20s. Lipid hydroperoxides were found in lip lipids which were extracted from the lip surface using a mixture of ethanol/ethylpropionate/iso-octane solvents, and were the highest in the content just before noon. The changes of lipid hydroperoxides were detected also in situ with FTIR-ATR at 968 cm-1. Conclusion The measurements of lip surface lipids with FTIR-ATR technique may advance the investigation of human lipid metabolism in situ non-invasively.

  8. Sequential metabolism of sesamin by cytochrome P450 and UDP-glucuronosyltransferase in human liver.

    Science.gov (United States)

    Yasuda, Kaori; Ikushiro, Shinichi; Kamakura, Masaki; Munetsuna, Eiji; Ohta, Miho; Sakaki, Toshiyuki

    2011-09-01

    Our previous study revealed that CYP2C9 played a central role in sesamin monocatecholization. In this study, we focused on the metabolism of sesamin monocatechol that was further converted into the dicatechol form by cytochrome P450 (P450) or the glucuronide by UDP-glucuronosyltransferase (UGT). Catecholization of sesamin monocatechol enhances its antioxidant activity, whereas glucuronidation strongly reduces its antioxidant activity. In human liver microsomes, the glucuronidation activity was much higher than the catecholization activity toward sesamin monocatechol. In contrast, in rat liver microsomes, catecholization is predominant over glucuronidation. In addition, rat liver produced two isomers of the glucuronide, whereas human liver produced only one glucuronide. These results suggest a significant species-based difference in the metabolism of sesamin between humans and rats. Kinetic studies using recombinant human UGT isoforms identified UGT2B7 as the most important UGT isoform for glucuronidation of sesamin monocatechol. In addition, a good correlation was observed between the glucuronidation activity and UGT2B7-specific activity in in vitro studies using 10 individual human liver microsomes. These results strongly suggest that UGT2B7 plays an important role in glucuronidation of sesamin monocatechol. Interindividual difference among the 10 human liver microsomes is approximately 2-fold. These results, together with our previous results on the metabolism of sesamin by human P450, suggest a small interindividual difference in sesamin metabolism. We observed the methylation activity toward sesamin monocatechol by catechol O-methyl transferase (COMT) in human liver cytosol. On the basis of these results, we concluded that CYP2C9, UGT2B7, and COMT played essential roles in the metabolism of sesamin in the human liver.

  9. Mathematical modeling of the human energy metabolism based on the Selfish Brain Theory.

    Science.gov (United States)

    Chung, Matthias; Göbel, Britta

    2012-01-01

    Deregulations in the human energy metabolism may cause diseases such as obesity and type 2 diabetes mellitus. The origins of these pathologies are fairly unknown. The key role of the brain is the regulation of the complex whole body energy metabolism. The Selfish Brain Theory identifies the priority of brain energy supply in the competition for available energy resources within the organism. Here, we review mathematical models of the human energy metabolism supporting central aspects of the Selfish Brain Theory. First, we present a dynamical system modeling the whole body energy metabolism. This model takes into account the two central control mechanisms of the brain, i.e., allocation and appetite. Moreover, we present mathematical models of regulatory subsystems. We examine a neuronal model which specifies potential elements of the brain to sense and regulate cerebral energy content. We investigate a model of the HPA system regulating the allocation of energy within the organism. Finally, we present a robust modeling approach of appetite regulation. All models account for a systemic understanding of the human energy metabolism and thus do shed light onto defects causing metabolic diseases.

  10. The Impacts of Obesity and Metabolic Abnormality on Carotid Intima-Media Thickness and Non-Alcoholic Fatty Liver Disease in Children from an Inland Chinese City.

    Science.gov (United States)

    Wang, Xiao-Yue; Zhang, Xiang-Hua; Yao, Chao Hua; Zhu, Hong-Hui; Zhang, Liang

    2014-03-20

    The Chinese inland, where low child obesity and overweight rates were reported in earlier studies, has recently experienced rapid economy changes. This may impact children's health. In the present study, we investigated the obesity rate, metabolic health status, and their impacts on carotid intima-media thickness (IMT) and non-alcoholic fatty liver disease (NAFLD) among children from Yueyang, an inland city of China. We found that the obesity rate was about 5% for both 7- and 11-year olds. Overweightness rates were 9.5% and 11.5% for the 7- and 11-year olds, respectively. Clinical and laboratory examinations revealed significant differences among different weight groups in the 11-year old volunteers, which were absent in the 7-year olds. Further statistical analysis showed that: age, BMI, blood pressure, triglyceride level, and metabolic abnormality were positively correlated to carotid IMT; triglyceride level, obesity, male, and the number of metabolic abnormalities were independent risk factors for NAFLD in these children. Our study suggests that: childhood overweightness and obesity are now epidemic in Yueyang, which have contributed to increased carotid IMT and may also increased NAFLD incidents; and serum triglyceride level is a critical factor in the development of childhood NAFLD. Thus, childhood metabolic health warrants further vigorous research in the inland of China.

  11. The Impacts of Obesity and Metabolic Abnormality on Carotid Intima-Media Thickness and Non-Alcoholic Fatty Liver Disease in Children from an Inland Chinese City

    Directory of Open Access Journals (Sweden)

    Xiao-Yue Wang

    2014-03-01

    Full Text Available The Chinese inland, where low child obesity and overweight rates were reported in earlier studies, has recently experienced rapid economy changes. This may impact children’s health. In the present study, we investigated the obesity rate, metabolic health status, and their impacts on carotid intima-media thickness (IMT and non-alcoholic fatty liver disease (NAFLD among children from Yueyang, an inland city of China. We found that the obesity rate was about 5% for both 7- and 11-year olds. Overweightness rates were 9.5% and 11.5% for the 7- and 11-year olds, respectively. Clinical and laboratory examinations revealed significant differences among different weight groups in the 11-year old volunteers, which were absent in the 7-year olds. Further statistical analysis showed that: age, BMI, blood pressure, triglyceride level, and metabolic abnormality were positively correlated to carotid IMT; triglyceride level, obesity, male, and the number of metabolic abnormalities were independent risk factors for NAFLD in these children. Our study suggests that: childhood overweightness and obesity are now epidemic in Yueyang, which have contributed to increased carotid IMT and may also increased NAFLD incidents; and serum triglyceride level is a critical factor in the development of childhood NAFLD. Thus, childhood metabolic health warrants further vigorous research in the inland of China.

  12. Comparison between a pediatric health promotion center and a pediatric obesity clinic in detecting metabolic syndrome and non-alcoholic fatty liver disease in children.

    Science.gov (United States)

    Yang, Hye Ran; Yi, Dae Yong; Choi, Hyoung Soo

    2014-12-01

    This study was done to evaluate the efficacy of health check-ups in children in detecting metabolic syndrome and non-alcoholic fatty liver disease (NAFLD) by comparing the pediatric health promotion center with the pediatric obesity clinic. Children who visited a pediatric health promotion center (n=218) or a pediatric obesity clinic (n=178) were included. Anthropometric data, blood pressure, laboratory tests, and abdominal ultrasonography were evaluated. Two different criteria were applied to diagnose metabolic syndrome. The prevalence of metabolic syndrome in the 2 units was 3.2%-3.7% in a pediatric health promotion center and 23%-33.2% in a pediatric obesity clinic. Significant differences were observed in the prevalence of each component of metabolic syndrome between the 2 units including abdominal adiposity, blood pressure, serum triglycerides, and fasting blood glucose (Pobesity clinic targeting obese children than that among patients visiting the health promotion center offering routine check-ups. An obesity-oriented approach is required to prevent obesity-related health problems in children.

  13. Determination of two mebeverine metabolites, mebeverine alcohol and desmethylmebeverine alcohol, in human plasma by a dual stable isotope-based gas chromatographic-mass spectrometric method.

    Science.gov (United States)

    Tulich, L J; Randall, J L; Kelm, G R; Wehmeyer, K R

    1996-07-12

    A dual stable isotope-based GC-MS method was developed for the simultaneous determination of two metabolites of mebeverine, mebeverine alcohol and desmethylmebeverine alcohol, in human plasma. Plasma samples were treated with beta-glucuronidase to cleave the glucuronide conjugates of both compounds prior to analysis. The treated plasma was prepared for analysis by solid-phase extraction using octadecylsilane cartridges. The isolated metabolites were derivatized and analyzed by GC-MS using selected-ion monitoring. Plots of peak-area ratio were linear with metabolite concentration from 2 to 200 ng/ml and the limit of detection for both metabolites was 0.5 ng/ml. The GC-MS methodology was applied to the analysis of plasma from human subjects following peroral administration of mebeverine. Pharmacokinetic parameters for both metabolites were determined and suggest that relative systemic mebeverine exposure may potentially be assessed using metabolite kinetics, if the latter subsequently are demonstrated to be linear with mebeverine dose.

  14. Alcohol and cannabinoids differentially affect HIV infection and function of human monocyte-derived dendritic cells (MDDC

    Directory of Open Access Journals (Sweden)

    Marisela eAgudelo

    2015-12-01

    Full Text Available During human immunodeficiency virus (HIV infection, alcohol has been known to induce inflammation while cannabinoids have been shown to have an anti-inflammatory role. For instance cannabinoids have been shown to reduce susceptibility to HIV-1 infection and attenuate HIV replication in macrophages. Recently, we demonstrated that alcohol induces cannabinoid receptors and regulates cytokine production by monocyte-derived dendritic cells (MDDC. However, the ability of alcohol and cannabinoids to alter MDDC function during HIV infection has not been clearly elucidated yet. In order to study the potential impact of alcohol and cannabinoids on differentiated MDDC infected with HIV, monocytes were cultured for 7 days with GM-CSF and IL-4, differentiated MDDC were infected with HIV-1Ba-L and treated with EtOH (0.1 and 0.2%, THC (5 and 10 uM, or JWH-015 (5 and 10 uM for 4-7 days. HIV infection of MDDC was confirmed by p24 and Long Terminal Repeats (LTR estimation. MDDC endocytosis assay and cytokine array profiles were measured to investigate the effects of HIV and substances of abuse on MDDC function. Our results show the HIV+EtOH treated MDDC had the highest levels of p24 production and expression when compared with the HIV positive controls and the cannabinoid treated cells. Although both cannabinoids, THC and JWH-015 had lower levels of p24 production and expression, the HIV+JWH-015 treated MDDC had the lowest levels of p24 when compared to the HIV+THC treated cells. In addition, MDDC endocytic function and cytokine production were also differentially altered after alcohol and cannabinoid treatments. Our results show a differential effect of alcohol and cannabinoids, which may provide insights into the divergent inflammatory role of alcohol and cannabinoids to modulate MDDC function in the context of HIV infection.

  15. Metabolic gene profile in early human fetal heart development

    National Research Council Canada - National Science Library

    Iruretagoyena, J I; Davis, W; Bird, C; Olsen, J; Radue, R; Teo Broman, A; Kendziorski, C; Splinter BonDurant, S; Golos, T; Bird, I; Shah, D

    2014-01-01

    .... In order to describe normal cardiac development during late first and early second trimester in human fetuses this study used microarray and pathways analysis and created a corresponding 'normal' database...

  16. METABOLISM

    Institute of Scientific and Technical Information of China (English)

    1999-01-01

    Objective: To determine the allele frequencies of genetic variants 373 Ala→Pro and 451 Arg→Gln of cholesteryl ester transfer protein (CETP) and to explore their potential impacts on serum lipid metabolism. Methods: The genotypes in CETP codon 373 and 451 in 91 German healthy students and 409 an-

  17. Short-term fasting alters cytochrome P450-mediated drug metabolism in humans.

    Science.gov (United States)

    Lammers, Laureen A; Achterbergh, Roos; de Vries, Emmely M; van Nierop, F Samuel; Klümpen, Heinz-Josef; Soeters, Maarten R; Boelen, Anita; Romijn, Johannes A; Mathôt, Ron A A

    2015-06-01

    Experimental studies indicate that short-term fasting alters drug metabolism. However, the effects of short-term fasting on drug metabolism in humans need further investigation. Therefore, the aim of this study was to evaluate the effects of short-term fasting (36 h) on P450-mediated drug metabolism. In a randomized crossover study design, nine healthy subjects ingested a cocktail consisting of five P450-specific probe drugs [caffeine (CYP1A2), S-warfarin (CYP2C9), omeprazole (CYP2C19), metoprolol (CYP2D6), and midazolam (CYP3A4)] on two occasions (control study after an overnight fast and after 36 h of fasting). Blood samples were drawn for pharmacokinetic analysis using nonlinear mixed effects modeling. In addition, we studied in Wistar rats the effects of short-term fasting on hepatic mRNA expression of P450 isoforms corresponding with the five studied P450 enzymes in humans. In the healthy subjects, short-term fasting increased oral caffeine clearance by 20% (P = 0.03) and decreased oral S-warfarin clearance by 25% (P fasting increased mRNA expression of the orthologs of human CYP1A2, CYP2C19, CYP2D6, and CYP3A4 (P fasting alters cytochrome P450-mediated drug metabolism in a nonuniform pattern. Therefore, short-term fasting is another factor affecting cytochrome P450-mediated drug metabolism in humans.

  18. [Methionine metabolism regulates maintenance and differentiation of human ES/iPS cells].

    Science.gov (United States)

    Shiraki, Nobuaki; Kume, Shoen

    2015-05-01

    Embryonic stem (ES) and induced pluripotent stem (iPS) cells are pluripotent and can give rise to all cell types. ES/iPS cells have a unique transcriptional circuit that sustains the pluripotent state. These cells also possess a characteristically high rate of proliferation as well as an abbreviated G1 phase. These unique molecular properties distinguish ES and iPS cells from somatic cells. Mouse ES/iPS cells are in a high-flux metabolic state, with a high dependence on threonine catabolism. However, little is known about amino acid metabolism in human ES/iPS cells. Recently, we reported that human ES/iPS cells require high amounts of methionine (Met) and express high levels of Met metabolism enzymes (Shriaki N, et al: Cell Metabolism, 2014). Met deprivation results in a rapid decrease in intracellular S-adenosyl-methionine (SAM), triggering the activation of p53 signaling, reducing pluripotent marker gene NANOG expression, and poising human ES/iPS cells for differentiation, follow by potentiated differentiation into all three germ layers. However, when exposed to prolonged Met deprivation, the cells went to apoptosis. In this review, we explain the importance of SAM in Met metabolism and its relationship with pluripotency, cell survival, and differentiation of human ES/iPS cells.

  19. Effect of fatty acids on human bone marrow mesenchymal stem cell energy metabolism and survival.

    Science.gov (United States)

    Fillmore, Natasha; Huqi, Alda; Jaswal, Jagdip S; Mori, Jun; Paulin, Roxane; Haromy, Alois; Onay-Besikci, Arzu; Ionescu, Lavinia; Thébaud, Bernard; Michelakis, Evangelos; Lopaschuk, Gary D

    2015-01-01

    Successful stem cell therapy requires the optimal proliferation, engraftment, and differentiation of stem cells into the desired cell lineage of tissues. However, stem cell therapy clinical trials to date have had limited success, suggesting that a better understanding of stem cell biology is needed. This includes a better understanding of stem cell energy metabolism because of the importance of energy metabolism in stem cell proliferation and differentiation. We report here the first direct evidence that human bone marrow mesenchymal stem cell (BMMSC) energy metabolism is highly glycolytic with low rates of mitochondrial oxidative metabolism. The contribution of glycolysis to ATP production is greater than 97% in undifferentiated BMMSCs, while glucose and fatty acid oxidation combined only contribute 3% of ATP production. We also assessed the effect of physiological levels of fatty acids on human BMMSC survival and energy metabolism. We found that the saturated fatty acid palmitate induces BMMSC apoptosis and decreases proliferation, an effect prevented by the unsaturated fatty acid oleate. Interestingly, chronic exposure of human BMMSCs to physiological levels of palmitate (for 24 hr) reduces palmitate oxidation rates. This decrease in palmitate oxidation is prevented by chronic exposure of the BMMSCs to oleate. These results suggest that reducing saturated fatty acid oxidation can decrease human BMMSC proliferation and cause cell death. These results also suggest that saturated fatty acids may be involved in the long-term impairment of BMMSC survival in vivo.

  20. Chemical Carcinogen-Induced Changes in tRNA Metabolism in Human Cells.

    Science.gov (United States)

    1981-11-01

    the resolution and quantitation of modified ucleosides in the urine of cancer patients would not be particularly useful for the cell culture studies...Comparison of nucleic acid catabolism by normal human fibroblasts and fibroblasts transformed with methylazoxymethyl alcohol ( MAMA ),an activated...catabolite in long-term, pulse-chase experiments. However, the kinetics of catabolism differed, in that only the MAMA -transformed cells had generated

  1. Critical assessment of human metabolic pathway databases: a stepping stone for future integration

    Science.gov (United States)

    2011-01-01

    Background Multiple pathway databases are available that describe the human metabolic network and have proven their usefulness in many applications, ranging from the analysis and interpretation of high-throughput data to their use as a reference repository. However, so far the various human metabolic networks described by these databases have not been systematically compared and contrasted, nor has the extent to which they differ been quantified. For a researcher using these databases for particular analyses of human metabolism, it is crucial to know the extent of the differences in content and their underlying causes. Moreover, the outcomes of such a comparison are important for ongoing integration efforts. Results We compared the genes, EC numbers and reactions of five frequently used human metabolic pathway databases. The overlap is surprisingly low, especially on reaction level, where the databases agree on 3% of the 6968 reactions they have combined. Even for the well-established tricarboxylic acid cycle the databases agree on only 5 out of the 30 reactions in total. We identified the main causes for the lack of overlap. Importantly, the databases are partly complementary. Other explanations include the number of steps a conversion is described in and the number of possible alternative substrates listed. Missing metabolite identifiers and ambiguous names for metabolites also affect the comparison. Conclusions Our results show that each of the five networks compared provides us with a valuable piece of the puzzle of the complete reconstruction of the human metabolic network. To enable integration of the networks, next to a need for standardizing the metabolite names and identifiers, the conceptual differences between the databases should be resolved. Considerable manual intervention is required to reach the ultimate goal of a unified and biologically accurate model for studying the systems biology of human metabolism. Our comparison provides a stepping stone

  2. Critical assessment of human metabolic pathway databases: a stepping stone for future integration

    Directory of Open Access Journals (Sweden)

    Stobbe Miranda D

    2011-10-01

    Full Text Available Abstract Background Multiple pathway databases are available that describe the human metabolic network and have proven their usefulness in many applications, ranging from the analysis and interpretation of high-throughput data to their use as a reference repository. However, so far the various human metabolic networks described by these databases have not been systematically compared and contrasted, nor has the extent to which they differ been quantified. For a researcher using these databases for particular analyses of human metabolism, it is crucial to know the extent of the differences in content and their underlying causes. Moreover, the outcomes of such a comparison are important for ongoing integration efforts. Results We compared the genes, EC numbers and reactions of five frequently used human metabolic pathway databases. The overlap is surprisingly low, especially on reaction level, where the databases agree on 3% of the 6968 reactions they have combined. Even for the well-established tricarboxylic acid cycle the databases agree on only 5 out of the 30 reactions in total. We identified the main causes for the lack of overlap. Importantly, the databases are partly complementary. Other explanations include the number of steps a conversion is described in and the number of possible alternative substrates listed. Missing metabolite identifiers and ambiguous names for metabolites also affect the comparison. Conclusions Our results show that each of the five networks compared provides us with a valuable piece of the puzzle of the complete reconstruction of the human metabolic network. To enable integration of the networks, next to a need for standardizing the metabolite names and identifiers, the conceptual differences between the databases should be resolved. Considerable manual intervention is required to reach the ultimate goal of a unified and biologically accurate model for studying the systems biology of human metabolism. Our comparison

  3. Vitamin D receptor and vitamin D metabolizing enzymes are expressed in the human male reproductive tract

    DEFF Research Database (Denmark)

    Blomberg Jensen, Martin; Nielsen, John E; Jørgensen, Anne

    2010-01-01

    , since it is not solely dependent on VDR expression, but also on cellular uptake of circulating VD and presence and activity of VD metabolizing enzymes. Expression of VD metabolizing enzymes has not previously been investigated in human testis and male reproductive tract. Therefore, we performed......The vitamin D receptor (VDR) is expressed in human testis, and vitamin D (VD) has been suggested to affect survival and function of mature spermatozoa. Indeed, VDR knockout mice and VD deficient rats show decreased sperm counts and low fertility. However, the cellular response to VD is complex...

  4. Metabolism of 7-benzyloxy-4-trifluoromethyl-coumarin by human hepatic cytochrome P450 isoforms.

    Science.gov (United States)

    Renwick, A B; Surry, D; Price, R J; Lake, B G; Evans, D C

    2000-10-01

    1. The metabolism of 7-benzyloxy-4-trifluoromethylcoumarin (BFC) to 7-hydroxy-4-trifluoromethylcoumarin (HFC) was studied in human liver microsomal preparations and in cDNA-expressed human cytochrome P450 (CYP) isoforms. 2. Kinetic analysis of the NADPH-dependent metabolism of BFC to HFC in four preparations of pooled human liver microsomes revealed mean (+/- SEM) Km and Vmax of 8.3 +/- 1.3 microM and 454 +/- 98 pmol/min/mg protein respectively. 3. The metabolism of BFC to HFC was determined in a characterized bank of 24 individual human liver microsomal preparations employing BFC substrate concentrations of 20 and 50 microM (i.e. about two and six times Km respectively). With 20 microM BFC the highest correlations were observed between BFC metabolism and markers of CYP1A2 (r2 = 0.784-0.797) and then with CYP3A (r2 = 0.434-0.547) isoforms, whereas with 50 microM BFC the highest correlations were observed between BFC metabolism and markers of CYP3A (r2 = 0.679-0.837) and then with CYP1A2 (r2 = 0.421-0.427) isoforms. At both BFC substrate concentrations, lower correlations were observed between BFC metabolism and enzymatic markers for CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP4A9/11. 4. Using human beta-lymphoblastoid cell microsomes containing cDNA-expressed CYP isoforms, 20 microM BFC was metabolized by CYP1A2 and CYP3A4, with lower rates of metabolism being observed with CYP2C9 and CYP2C19. Kinetic studies with the CYP1A2 and CYP3A4 preparations demonstrated a lower Km with the CYP1A2 preparation, but a higher Vmax with the CYP3A4 preparation. 5. The metabolism of 20 microM BFC in human liver microsomes was inhibited to 37-48% of control by 5-100 microM of the mechanism-based CYP1A2 inhibitor furafylline and to 64-69% of control by 5-100 microM of the mechanism-based CYP3A4 inhibitor troleandomycin. While some inhibition of BFC metabolism was observed in the presence of 100 and 200 microM diethyldithiocarbamate, the addition of 2-50 micro

  5. Metabolism of (/sup 3/H)benzo(a)pyrene by cultured human bronchus and cultured human pulmonary alveolar macrophages

    DEFF Research Database (Denmark)

    1978-01-01

    The metabolism of (/sup 3/H)benzo(a)pyrene by cultured human bronchial epithelium and pulmonary alveolar macrophages was studied. Explants of bronchus were prepared and pulmonary alveolar macrophages were isolated from peripheral lung by trypsinization and by differential adhesion to plastic tissue...

  6. The role of active brown adipose tissue in human metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Ozguven, Salih; Turoglu, H.T. [S.B. Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi, Department of Nuclear Medicine, Istanbul (Turkey); Ones, Tunc [S.B. Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi, Department of Nuclear Medicine, Istanbul (Turkey); Kozyatagi/Kadikoy, Istanbul (Turkey); Yilmaz, Yusuf; Imeryuz, Nese [S.B. Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi, Department of Internal Medicine, Division of Gastroenterology, Istanbul (Turkey)

    2016-02-15

    The presence of activated brown adipose tissue (ABAT) has been associated with a reduced risk of obesity in adults. We aimed to investigate whether the presence of ABAT in patients undergoing {sup 18}F-FDG PET/CT examinations was related to blood lipid profiles, liver function, and the prevalence of non-alcoholic fatty liver disease (NAFLD). We retrospectively and prospectively analysed the {sup 18}F-FDG PET/CT scans from 5,907 consecutive patients who were referred to the Nuclear Medicine Department of the Marmara University School of Medicine from outpatient oncology clinics between July 2008 and June 2014 for a variety of diagnostic reasons. Attenuation coefficients for the liver and spleen were determined for at least five different areas. Blood samples were obtained before PET/CT to assess the blood lipid profiles and liver function. A total of 25 of the 5,907 screened individuals fulfilling the inclusion criteria for the study demonstrated brown fat tissue uptake [ABAT(+) subjects]. After adjustment for potential confounders, 75 individuals without evidence of ABAT on PET [ABAT(-) subjects] were enrolled for comparison purposes. The ABAT(+) group had lower total cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, and aspartate transaminase levels (p < 0.01), whereas we found no significant differences in the serum triglyceride and high-density lipoprotein cholesterol levels between the two groups. The prevalence of NAFLD was significantly lower in ABAT(+) than in ABAT(-) subjects (p < 0.01). Our study showed that the presence of ABAT in adults had a positive effect on their blood lipid profiles and liver function and was associated with reduced prevalence of NAFLD. Thus, our data suggest that activating brown adipose tissue may be a potential target for preventing and treating dyslipidaemia and NAFLD. (orig.)

  7. Mice with chimeric livers are an improved model for human lipoprotein metabolism.

    Directory of Open Access Journals (Sweden)

    Ewa C S Ellis

    Full Text Available OBJECTIVE: Rodents are poor model for human hyperlipidemias because total cholesterol and low density lipoprotein levels are very low on a normal diet. Lipoprotein metabolism is primarily regulated by hepatocytes and we therefore assessed whether chimeric mice extensively repopulated with human cells can model human lipid and bile acid metabolism. DESIGN: FRG [ F ah(-/- R ag2(-/-Il2r g (-/-] mice were repopulated with primary human hepatocytes. Serum lipoprotein lipid composition and distribution (VLDL, LDL, and HDL was analyzed by size exclusion chromatography. Bile was analyzed by LC-MS or by GC-MS. RNA expression levels were measured by quantitative RT-PCR. RESULTS: Chimeric mice displayed increased LDL and VLDL fractions and a lower HDL fraction compared to wild type, thus significantly shifting the ratio of LDL/HDL towards a human profile. Bile acid analysis revealed a human-like pattern with high amounts of cholic acid and deoxycholic acid (DCA. Control mice had only taurine-conjugated bile acids as expcted, but highly repopulated mice had glycine-conjugated cholic acid as found in human bile. RNA levels of human genes involved in bile acid synthesis including CYP7A1, and CYP27A1 were significantly upregulated as compared to human control liver. However, administration of recombinant hFGF19 restored human CYP7A1 levels to normal. CONCLUSION: Humanized-liver mice showed a typical human lipoprotein profile with LDL as the predominant lipoprotein fraction even on a normal diet. The bile acid profile confirmed presence of an intact enterohepatic circulation. Although bile acid synthesis was deregulated in this model, this could be fully normalized by FGF19 administration. Taken together these data indicate that chimeric FRG-mice are a useful new model for human lipoprotein and bile-acid metabolism.

  8. Metabolism of bromopride in mouse, rat, rabbit, dog, monkey, and human hepatocytes.

    Science.gov (United States)

    Dunne, Christine E; Bushee, Jennifer L; Argikar, Upendra A

    2013-01-01

    Bromopride (BRP) has been utilized clinically for treatment of nausea, vomiting and gastro-intestinal motility disorders. The pharmacokinetics of BRP have been characterized in dogs and humans; however, the metabolic profile of BRP has not been well studied. The present study was aimed at better understanding BRP metabolism across species. We investigated biotransformation of BRP in mouse, rat, rabbit, dog, monkey, and human hepatocytes with the help of LC-MS(n) and accurate mass measurement. Mice, rats, dogs, and monkeys are relevant in drug discovery and development as pre-clinical species to be compared with humans, whereas rabbits were efficacy models for BRP. Overall, twenty metabolites of BRP were identified across hepatocytes from the six species. Monkeys offered the most coverage for humans, in terms of number of metabolites identified. Interestingly, M14, an N-sulfate metabolite of BRP, was identified as a human-specific metabolite. BRP metabolism had only been reported in dog plasma and urine, historically. Our investigation is the first documentation of in vitro metabolism of BRP in the six species reported here. Metabolites M1, M2, M4-M10, M12, M13, and M15-M20 have not been previously reported. In summary, this report documents seventeen metabolites of BRP for the first time, thus providing a deeper insight into the biotransformation of BRP.

  9. IMP metabolism in human skeletal muscle after exhaustive exercise

    DEFF Research Database (Denmark)

    Tullson, P. C.; Bangsbo, Jens; Hellsten, Ylva

    1995-01-01

    This study addressed whether AMP deaminase (AMPD)myosin binding occurs with deamination during intense exercise in humans and the extent of purine loss from muscle during the initial minutes of recovery. Male subjects performed cycle exercise (265 +/- 2 W for 4.39 +/- 0.04 min) to stimulate muscle...

  10. Aldehyde sources, metabolism, molecular toxicity mechanisms, and possible effects on human health.

    Science.gov (United States)

    O'Brien, Peter J; Siraki, Arno G; Shangari, Nandita

    2005-08-01

    Aldehydes are organic compounds that are widespread in nature. They can be formed endogenously by lipid peroxidation (LPO), carbohydrate or metabolism ascorbate autoxidation, amine oxidases, cytochrome P-450s, or myeloperoxidase-catalyzed metabolic activation. This review compares the reactivity of many aldehydes towards biomolecules particularly macromolecules. Furthermore, it includes not only aldehydes of environmental or occupational concerns but also dietary aldehydes and aldehydes formed endogenously by intermediary metabolism. Drugs that are aldehydes or form reactive aldehyde metabolites that cause side-effect toxicity are also included. The effects of these aldehydes on biological function, their contribution to human diseases, and the role of nucleic acid and protein carbonylation/oxidation in mutagenicity and cytotoxicity mechanisms, respectively, as well as carbonyl signal transduction and gene expression, are reviewed. Aldehyde metabolic activation and detoxication by metabolizing enzymes are also reviewed, as well as the toxicological and anticancer therapeutic effects of metabolizing enzyme inhibitors. The human health risks from clinical and animal research studies are reviewed, including aldehydes as haptens in allergenic hypersensitivity diseases, respiratory allergies, and idiosyncratic drug toxicity; the potential carcinogenic risks of the carbonyl body burden; and the toxic effects of aldehydes in liver disease, embryo toxicity/teratogenicity, diabetes/hypertension, sclerosing peritonitis, cerebral ischemia/neurodegenerative diseases, and other aging-associated diseases.

  11. Metabolism of [U-13C]glucose in Human Brain Tumors In Vivo

    Science.gov (United States)

    Maher, Elizabeth A.; Marin-Valencia, Isaac; Bachoo, Robert M.; Mashimo, Tomoyuki; Raisanen, Jack; Hatanpaa, Kimmo J.; Jindal, Ashish; Jeffrey, F. Mark; Choi, Changho; Madden, Christopher; Mathews, Dana; Pascual, Juan M.; Mickey, Bruce E.; Malloy, Craig R.; DeBerardinis, Ralph J.

    2012-01-01

    Glioblastomas (GBMs) and brain metastases demonstrate avid uptake of 18fluoro-2-deoxyglucose (FDG) by positron emission tomography (PET) and display perturbations of intracellular metabolite pools by 1H magnetic resonance spectroscopy (MRS). These observations suggest that metabolic reprogramming contributes to brain tumor growth in vivo. The Warburg effect, excess metabolism of glucose to lactate in the presence of oxygen, is a hallmark of cancer cells in culture. FDG-positive tumors are assumed to metabolize glucose in a similar manner, with high rates of lactate formation compared to mitochondrial glucose oxidation, but few studies have specifically examined the metabolic fates of glucose in vivo. In particular, the capacity of human brain malignancies to oxidize glucose in the tricarboxylic acid cycle is unknown. Here we studied the metabolism of human brain tumors in situ. [U-13C]glucose was infused during surgical resection, and tumor samples were subsequently subjected to 13C NMR spectroscopy. Analysis of tumor metabolites revealed lactate production, as expected. We also determined that pyruvate dehydrogenase, turnover of the TCA cycle, anaplerosis and de novo glutamine and glycine synthesis contributed significantly to the ultimate disposition of glucose carbon. Surprisingly, less than 50% of the acetyl-CoA pool was derived from blood-borne glucose, suggesting that additional substrates contribute to tumor bioenergetics. This study illustrates a convenient approach that capitalizes on the high information content of 13C NMR spectroscopy and enables the analysis of intermediary metabolism in diverse malignancies growing in their native microenvironment. PMID:22419606

  12. Identification of CYP3A7 for Glyburide Metabolism in Human Fetal Livers

    Science.gov (United States)

    Shuster, Diana L.; Risler, Linda J.; Prasad, Bhagwat; Calamia, Justina C.; Voellinger, Jenna L.; Kelly, Edward J.; Unadkat, Jashvant D.; Hebert, Mary F.; Shen, Danny D.; Thummel, Kenneth E.; Mao, Qingcheng

    2014-01-01

    Glyburide is commonly prescribed for the treatment of gestational diabetes mellitus; however, fetal exposure to glyburide is not well understood and may have short- and long-term consequences for the health of the child. Glyburide can cross the placenta; fetal concentrations at term are nearly comparable to maternal levels. Whether or not glyburide is metabolized in the fetus and by what mechanisms has yet to be determined. In this study, we determined the kinetic parameters for glyburide depletion by CYP3A isoenzymes; characterized glyburide metabolism by human fetal liver tissues collected during the first or early second trimester of pregnancy; and identified the major enzyme responsible for glyburide metabolism in human fetal livers. CYP3A4 had the highest metabolic capacity towards glyburide, followed by CYP3A7 and CYP3A5 (Clint,u = 37.1, 13.0, and 8.7 ml/min/nmol P450, respectively). M5 was the predominant metabolite generated by CYP3A7 and human fetal liver microsomes (HFLMs) with approximately 96% relative abundance. M5 was also the dominant metabolite generated by CYP3A4, CYP3A5, and adult liver microsomes; however, M1-M4 were also present, with up to 15% relative abundance. CYP3A7 protein levels in HFLMs were highly correlated with glyburide Clint, 16α-OH DHEA formation, and 4′-OH midazolam formation. Likewise, glyburide Clint was highly correlated with 16α-OH DHEA formation. Fetal demographics as well as CYP3A5 and CYP3A7 genotype did not alter CYP3A7 protein levels or glyburide Clint. These results indicate that human fetal livers metabolize glyburide predominantly to M5 and that CYP3A7 is the major enzyme responsible for glyburide metabolism in human fetal livers. PMID:25450675

  13. Why Eating Breakfast Is Important for Optimising Human Metabolism?

    Directory of Open Access Journals (Sweden)

    HR Farshchi

    2005-10-01

    Full Text Available Breakfast consumption appears to have declined in the last decades and eating breakfast, especially cereal, is associated with a lower risk of obesity. Serum cholesterol concentration is reported to be lower in adults eating breakfast (EB and higher among those not. No study, to our knowledge, has investigated the effect of skipping breakfast (SB on various aspect of energy metabolism. Thus, this study evaluated the effect of EB or SB on adult energy, carbohydrate and lipid metabolism. 10 healthy women (BMI: 23.2, SD: 1.4 were recruited after giving informed consent. Each subject participated in a randomised crossover trial which encompassed two 14-day intervention periods; EB in one of them and SB in the other with a 2-wk wash out period between. In EB, subjects were asked to consume a pack of whole grain cereal (Kellogg’s, UK, 45 g with 200 ml semi-skimmed milk between 07:00-08:00 and eat a chocolate bar (Nestle, 48g. at 10.30-11.00. Then, they consumed 4 further meals of similar content to usual in the rest of the day at predetermined times every day for 2 wk. In SB, subjects consumed the chocolate at 10.30-11.00, and then had the cereal and semi-skimmed milk at 12.00-12.30. Then, they consumed 4 further meals of similar content to usual as for EB. Subjects consumed their normal diet for a 2-wk washout period between the two intervention periods. Subjects recorded their food intake on 3 days during each intervention, and came to the laboratory after an overnight fast at the start and end of each intervention period and their weight and anthropometric variables were measured. Blood samples were taken for glucose, lipids and insulin before and for 3 hr after a test meal (milk shake containing 30 kJ/kg, 50% CHO. Resting metabolic rate (RMR was measured by indirect calorimetry before and after the test meal. Repeated-measures ANOVA, and paired t.test were used for the statistical comparisons. SB was associated with higher fasting total (3.4±0

  14. Genetic research: who is at risk for alcoholism.

    Science.gov (United States)

    Foroud, Tatiana; Edenberg, Howard J; Crabbe, John C

    2010-01-01

    The National Institute on Alcohol Abuse and Alcoholism (NIAAA) was founded 40 years ago to help elucidate the biological underpinnings of alcohol dependence, including the potential contribution of genetic factors. Twin, adoption, and family studies conclusively demonstrated that genetic factors account for 50 to 60 percent of the variance in risk for developing alcoholism. Case-control studies and linkage analyses have helped identify DNA variants that contribute to increased risk, and the NIAAA-sponsored Collaborative Studies on Genetics of Alcoholism (COGA) has the expressed goal of identifying contributing genes using state-of-the-art genetic technologies. These efforts have ascertained several genes that may contribute to an increased risk of alcoholism, including certain variants encoding alcohol-metabolizing enzymes and neurotransmitter receptors. Genome-wide association studies allowing the analysis of millions of genetic markers located throughout the genome will enable discovery of further candidate genes. In addition to these human studies, genetic animal models of alcohol's effects and alcohol use have greatly advanced our understanding of the genetic basis of alcoholism, resulting in the identification of quantitative trait loci and allowing for targeted manipulation of candidate genes. Novel research approaches-for example, into epigenetic mechanisms of gene regulation-also are under way and undoubtedly will further clarify the genetic basis of alcoholism.

  15. A novel untargeted metabolomics correlation-based network analysis incorporating human metabolic reconstructions.

    Science.gov (United States)

    Kotze, Helen L; Armitage, Emily G; Sharkey, Kieran J; Allwood, James W; Dunn, Warwick B; Williams, Kaye J; Goodacre, Royston

    2013-10-23

    Metabolomics has become increasingly popular in the study of disease phenotypes and molecular pathophysiology. One branch of metabolomics that encompasses the high-throughput screening of cellular metabolism is metabolic profiling. In the present study, the metabolic profiles of different tumour cells from colorectal carcinoma and breast adenocarcinoma were exposed to hypoxic and normoxic conditions and these have been compared to reveal the potential metabolic effects of hypoxia on the biochemistry of the tumour cells; this may contribute to their survival in oxygen compromised environments. In an attempt to analyse the complex interactions between metabolites beyond routine univariate and multivariate data analysis methods, correlation analysis has been integrated with a human metabolic reconstruction to reveal connections between pathways that are associated with normoxic or hypoxic oxygen environments. Correlation analysis has revealed statistically significant connections between metabolites, where differences in correlations between cells exposed to different oxygen levels have been highlighted as markers of hypoxic metabolism in cancer. Network mapping onto reconstructed human metabolic models is a novel addition to correlation analysis. Correlated metabolites have been mapped onto the Edinburgh human metabolic network (EHMN) with the aim of interlinking metabolites found to be regulated in a similar fashion in response to oxygen. This revealed novel pathways within the metabolic network that may be key to tumour cell survival at low oxygen. Results show that the metabolic responses to lowering oxygen availability can be conserved or specific to a particular cell line. Network-based correlation analysis identified conserved metabolites including malate, pyruvate, 2-oxoglutarate, glutamate and fructose-6-phosphate. In this way, this method has revealed metabolites not previously linked, or less well recognised, with respect to hypoxia before. Lactate

  16. Systems biology from micro-organisms to human metabolic diseases: the role of detailed kinetic models.

    Science.gov (United States)

    Bakker, Barbara M; van Eunen, Karen; Jeneson, Jeroen A L; van Riel, Natal A W; Bruggeman, Frank J; Teusink, Bas

    2010-10-01

    Human metabolic diseases are typically network diseases. This holds not only for multifactorial diseases, such as metabolic syndrome or Type 2 diabetes, but even when a single gene defect is the primary cause, where the adaptive response of the entire network determines the severity of disease. The latter may differ between individuals carrying the same mutation. Understanding the adaptive responses of human metabolism naturally requires a systems biology approach. Modelling of metabolic pathways in micro-organisms and some mammalian tissues has yielded many insights, qualitative as well as quantitative, into their control and regulation. Yet, even for a well-known pathway such as glycolysis, precise predictions of metabolite dynamics from experimentally determined enzyme kinetics have been only moderately successful. In the present review, we compare kinetic models of glycolysis in three cell types (African trypanosomes, yeast and skeletal muscle), evaluate their predictive power and identify limitations in our understanding. Although each of these models has its own merits and shortcomings, they also share common features. For example, in each case independently measured enzyme kinetic parameters were used as input. Based on these 'lessons from glycolysis', we will discuss how to make best use of kinetic computer models to advance our understanding of human metabolic diseases.

  17. NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome.

    Science.gov (United States)

    Chaldakov, G N; Fiore, M; Stankulov, I S; Hristova, M; Antonelli, A; Manni, L; Ghenev, P I; Angelucci, F; Aloe, L

    2001-10-01

    While multiple growth factor, cytokines, and immune cells are identified in atherosclerotic lesions, as well as an essential nonneuronal function of neurotrophins implicated in cardiovascular tissue development and in lipid and glucose metabolism, the role of the neurotrophins NGF and BDNF and also the adipokine leptin in human coronary atherosclerosis and related disorders, such as metabolic syndrome, remains unclear. Here we report that (i) both the amount and the immunoreactivity of NGF was reduced and the expression of p75NGF receptor and the number of mast cell increased in human atherosclerotic coronary arteries (n = 12) compared with control specimens (n = 9) obtained from autopsy cases, and (ii) NGF and BDNF plasma levels were reduced in patients with metabolic syndrome (n = 23) compared with control subjects (n = 10). Also, in metabolic syndrome patients, a positive correlation between the plasma leptin levels and the number of adipose tissue mast cells was found, suggesting that leptin may be a novel adipoimmune mediator. Altogether, the results provide the first correlative evidence for the potential involvement of NGF, BDNF, leptin, and mast cells in human coronary atherosclerosis and metabolic syndrome, implying neuroimmune and adipoimmune pathways in the pathobiology of these cardiovascular disorders.

  18. Colonic transit time is related to bacterial metabolism and mucosal turnover in the human gut

    DEFF Research Database (Denmark)

    Roager, Henrik Munch; Hansen, Lea Benedicte Skov; Bahl, Martin Iain

    transit time and the gut microbial composition and metabolism, we assessed the colonic transit time of 98 subjects using radiopaque markers, and profiled their gut microbiota by16S rRNA gene sequencing and their urine metabolome by ultra performance liquid chromatography mass spectrometry. Based......Little is known about how colonic transit time relates to human colonic metabolism, and its importance for host health, although stool consistency, a proxy for colonic transit time, has recently been negatively associated with gut microbial richness. To address the relationships between colonic...... on correlation analyses, we show that colonic transit time is associated with overall gut microbial composition, diversity and metabolism. A relatively prolonged colonic transit time associates with high microbial species richness and a shift in colonic metabolism from carbohydrate fermentation to protein...

  19. Characterization of the Usage of the Serine Metabolic Network in Human Cancer

    Directory of Open Access Journals (Sweden)

    Mahya Mehrmohamadi

    2014-11-01

    Full Text Available The serine, glycine, one-carbon (SGOC metabolic network is implicated in cancer pathogenesis, but its general functions are unknown. We carried out a computational reconstruction of the SGOC network and then characterized its expression across thousands of cancer tissues. Pathways including methylation and redox metabolism exhibited heterogeneous expression indicating a strong context dependency of their usage in tumors. From an analysis of coexpression, simultaneous up- or downregulation of nucleotide synthesis, NADPH, and glutathione synthesis was found to be a common occurrence in all cancers. Finally, we developed a method to trace the metabolic fate of serine using stable isotopes, high-resolution mass spectrometry, and a mathematical model. Although the expression of single genes didn’t appear indicative of flux, the collective expression of several genes in a given pathway allowed for successful flux prediction. Altogether, these findings identify expansive and heterogeneous functions for the SGOC metabolic network in human cancer.

  20. Establishment of steady-state metabolism of ethanol in perfused rat liver: the quantitative analysis using kinetic mechanism-based rate equations of alcohol dehydrogenase.

    Science.gov (United States)

    Yao, Chung-Tay; Lai, Ching-Long; Hsieh, Hsiu-Shan; Chi, Chin-Wen; Yin, Shih-Jiun

    2010-09-01

    Alcohol dehydrogenase (ADH) catalyzes oxidation of ingested ethanol to acetaldehyde, the first step in hepatic metabolism. The purpose of this study was to establish an ex vivo rat liver perfusion system under defined and verified steady states with respect to the metabolites and the metabolic rates, and to quantitatively correlate the observed rates with simulations based on the kinetic mechanism-based rate equations of rat liver ADH. Class I ADH1 was isolated from male Sprague-Dawley rats and characterized by steady-state kinetics in the Krebs-Ringer perfusion buffer with supplements. Nonrecirculating liver perfusion with constant input of ethanol at near physiological hepatic blood flow rate was performed in situ. Ethanol and the related metabolites acetaldehyde, acetate, lactate, and pyruvate in perfusates were determined. Results of the initial velocity, product, and dead-end inhibition studies showed that rat ADH1 conformed to the Theorell-Chance Ordered Bi Bi mechanism. Steady-state metabolism of ethanol in the perfused liver maintained up to 3h as evidenced by the steady-state levels of ethanol and metabolites in the effluent, and the steady-state ethanol disappearance rates and acetate production rates. The changes of the metabolic rates were qualitatively and in general quantitatively correlated to the results from simulations with the kinetic rate equations of ADH1 under a wide range of ethanol, in the presence of competitive inhibitor 4-methylpyrazole and of uncompetitive inhibitor isobutyramide. Preliminary flux control analysis estimated that apparent C(ADH)(J) in the perfused liver may approximate 0.7 at constant infusion with 1-2 mM ethanol, suggesting that ADH plays a major but not the exclusive role in governing hepatic ethanol metabolism. The reported steady-state rat liver perfusion system may potentially be applicable to other drug or drug-ethanol interaction studies.

  1. Evaluation of renographic and metabolic parameters in human kidney transplantation

    Energy Technology Data Exchange (ETDEWEB)

    Gonzalez, A. [Barcelone, Univ. (Spain). Lab. of Biophysics and Bioengineering; Vigues, F.; Franco, E. [Hospital of Bellvitge, Bellvitge (Spain). Service of Urology; Puchal, R. [Hospital of Bellvitge, Bellvitge (Spain). Service of Nuclear Medicine; Bartrons, R.; Ambrosio, S. [Barcelona, Univ. (Spain). Faculty of Odontology, Laboratory of Biochemistry

    1997-03-01

    Background: the aim of this work is to demonstrate that the value of the mean transit time (MTT) obtained from the {sup 99m}Tc-MAG3 renogram deconvolution is related to the levels of adenine nucleotides determined in cortical biopsies from transplanted kidneys. Methods: the functional state was estimated by means of the MTT and the initial height (HO) of the renal retention function obtained from the {sup 99m}Tc-MAG3 renogram deconvolution and by the measure of adenine nucleotides obtained from biopsies. We studied 30 kidney graft recipients, 25 normal functioning grafts (NFG) and 5 with acute tubular necrosis (ATN). Results: the MTT is significantly longer for ATN (p<0.001). The initial uptake values (HO) are significantly lower for ATN (p<0.001). The sum of adenine nucleotides (SAN) is significantly greater for NFG than for ATN (p<0.001). The values of the MTT seem to reflect the energy state of the cells in transplanted kidney. Conclusion: the analysis of MTT may be indicative of the functional metabolic recovery and thus it may be predictive of the renal graft function at least in the same extent than the biochemical analysis of a cortical renal biopsy immediately after blood reperfusion of the tissue.

  2. Therapeutic Targets of Triglyceride Metabolism as Informed by Human Genetics.

    Science.gov (United States)

    Bauer, Robert C; Khetarpal, Sumeet A; Hand, Nicholas J; Rader, Daniel J

    2016-04-01

    Human genetics has contributed to the development of multiple drugs to treat hyperlipidemia and coronary artery disease (CAD), most recently including antibodies targeting PCSK9 to reduce LDL cholesterol. Despite these successes, a large burden of CAD remains. Genetic and epidemiological studies have suggested that circulating triglyceride (TG)-rich lipoproteins (TRLs) are a causal risk factor for CAD, presenting an opportunity for novel therapeutic strategies. We discuss recent unbiased human genetics testing, including genome-wide association studies (GWAS) and whole-genome or -exome sequencing, that have identified the lipoprotein lipase (LPL) and hepatic lipogenesis pathways as important mechanisms in the regulation of circulating TRLs. Further strengthening the causal relationship between TRLs and CAD, findings such as these may provide novel targets for much-needed potential therapeutic interventions. Copyright © 2016. Published by Elsevier Ltd.

  3. Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

    DEFF Research Database (Denmark)

    Pant, Sameer Dinkar; Karlskov-Mortensen, Peter; Jacobsen, Mette Juul

    2015-01-01

    in different populations. Several important genes previously associated to obesity in human studies, along with novel genes were identified. Altogether, this study provides novel insight that may further the current understanding of the molecular mechanisms underlying human obesity.......The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological...... features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits...

  4. Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population

    Directory of Open Access Journals (Sweden)

    Ellis James K

    2012-06-01

    Full Text Available Abstract Background The 'exposome' represents the accumulation of all environmental exposures across a lifetime. Top-down strategies are required to assess something this comprehensive, and could transform our understanding of how environmental factors affect human health. Metabolic profiling (metabonomics/metabolomics defines an individual's metabolic phenotype, which is influenced by genotype, diet, lifestyle, health and xenobiotic exposure, and could also reveal intermediate biomarkers for disease risk that reflect adaptive response to exposure. We investigated changes in metabolism in volunteers living near a point source of environmental pollution: a closed zinc smelter with associated elevated levels of environmental cadmium. Methods High-resolution 1H NMR spectroscopy (metabonomics was used to acquire urinary metabolic profiles from 178 human volunteers. The spectral data were subjected to multivariate and univariate analysis to identify metabolites that were correlated with lifestyle or biological factors. Urinary levels of 8-oxo-deoxyguanosine were also measured, using mass spectrometry, as a marker of systemic oxidative stress. Results Six urinary metabolites, either associated with mitochondrial metabolism (citrate, 3-hydroxyisovalerate, 4-deoxy-erythronic acid or one-carbon metabolism (dimethylglycine, creatinine, creatine, were associated with cadmium exposure. In particular, citrate levels retained a significant correlation to urinary cadmium and smoking status after controlling for age and sex. Oxidative stress (as determined by urinary 8-oxo-deoxyguanosine levels was elevated in individuals with high cadmium exposure, supporting the hypothesis that heavy metal accumulation was causing mitochondrial dysfunction. Conclusions This study shows evidence that an NMR-based metabolic profiling study in an uncontrolled human population is capable of identifying intermediate biomarkers of response to toxicants at true environmental

  5. Metabolism of Kaempferia parviflora polymethoxyflavones by human intestinal bacterium Bautia sp. MRG-PMF1.

    Science.gov (United States)

    Kim, Mihyang; Kim, Nayoung; Han, Jaehong

    2014-12-24

    Poylmethoxyflavones (PMFs) are major bioactive flavonoids, which exhibit various biological activities, such as anticancer effects. The biotransformation of PMFs and characterization of a PMF-metabolizing human intestinal bacterium were studied herein for the first time. Hydrolysis of aryl methyl ether functional groups by human fecal samples was observed from the bioconversion of various PMFs. Activity-guided screening for PMF-metabolizing intestinal bacteria under anaerobic conditions resulted in the isolation of a strict anaerobic bacterium, which was identified as Blautia sp. MRG-PMF1. The isolated MRG-PMF1 was able to metabolize various PMFs to the corresponding demethylated flavones. The microbial conversion of bioactive 5,7-dimethoxyflavone (5,7-DMF) and 5,7,4'-trimethoxyflavone (5,7,4'-TMF) was studied in detail. 5,7-DMF and 5,7,4'-TMF were completely metabolized to 5,7-dihydroxyflavone (chrysin) and 5,7,4'-trihydroxyflavone (apigenin), respectively. From a kinetics study, the methoxy group on the flavone C-7 position was found to be preferentially hydrolyzed. 5-Methoxychrysin, the intermediate of 5,7-DMF metabolism by Blautia sp. MRG-PMF1, was isolated and characterized by nuclear magnetic resonance spectroscopy. Apigenin was produced from the sequential demethylation of 5,7,4'-TMF, via 5,4'-dimethoxy-7-hydroxyflavone and 7,4'-dihydroxy-5-methoxyflavone (thevetiaflavone). Not only demethylation activity but also deglycosylation activity was exhibited by Blautia sp. MRG-PMF1, and various flavonoids, including isoflavones, flavones, and flavanones, were found to be metabolized to the corresponding aglycones. The unprecedented PMF demethylation activity of Blautia sp. MRG-PMF1 will expand our understanding of flavonoid metabolism in the human intestine and lead to novel bioactive compounds.

  6. Physical activity is associated with retained muscle metabolism in human myotubes challenged with palmitate

    DEFF Research Database (Denmark)

    Green, C J; Bunprajun, T; Pedersen, B K

    2013-01-01

      The aim of this study was to investigate whether physical activity is associated with preserved muscle metabolism in human myotubes challenged with saturated fatty acids. Human muscle satellite cells were isolated from sedentary or active individuals and differentiated into myocytes in culture...... and correlated positively to JNK phosphorylation. In conclusion, muscle satellite cells retain metabolic differences associated with physical activity. Physical activity partially protects myocytes from fatty acid-induced insulin resistance and inactivity is associated with dysregulation of metabolism...... in satellite cells challenged with palmitate. Although the benefits of physical activity on whole body physiology have been well investigated, this paper presents novel findings that both diet and exercise impact satellite cells directly. Given the fact that satellite cells are important for muscle maintenance...

  7. Comparative analyses of QTLs influencing obesity and metabolic phenotypes in pigs and humans

    DEFF Research Database (Denmark)

    Pant, Sameer Dinkar; Karlskov-Mortensen, Peter; Jacobsen, Mette Juul;

    2015-01-01

    The pig is a well-known animal model used to investigate genetic and mechanistic aspects of human disease biology. They are particularly useful in the context of obesity and metabolic diseases because other widely used models (e.g. mice) do not completely recapitulate key pathophysiological...... features associated with these diseases in humans. Therefore, we established a F2 pig resource population (n = 564) designed to elucidate the genetics underlying obesity and metabolic phenotypes. Segregation of obesity traits was ensured by using breeds highly divergent with respect to obesity traits...... in the parental generation. Several obesity and metabolic phenotypes were recorded (n = 35) from birth to slaughter (242 ± 48 days), including body composition determined at about two months of age (63 ± 10 days) via dual-energy x-ray absorptiometry (DXA) scanning. All pigs were genotyped using Illumina Porcine...

  8. Metabolic pathways and activity-dependent modulation of glutamate concentration in the human brain.

    Science.gov (United States)

    Mangia, Silvia; Giove, Federico; Dinuzzo, Mauro

    2012-11-01

    Glutamate is one of the most versatile molecules present in the human brain, involved in protein synthesis, energy production, ammonia detoxification, and transport of reducing equivalents. Aside from these critical metabolic roles, glutamate plays a major part in brain function, being not only the most abundant excitatory neurotransmitter, but also the precursor for γ-aminobutyric acid, the predominant inhibitory neurotransmitter. Regulation of glutamate levels is pivotal for normal brain function, as abnormal extracellular concentration of glutamate can lead to impaired neurotransmission, neurodegeneration and even neuronal death. Understanding how the neuron-astrocyte functional and metabolic interactions modulate glutamate concentration during different activation status and under physiological and pathological conditions is a challenging task, and can only be tentatively estimated from current literature. In this paper, we focus on describing the various metabolic pathways which potentially affect glutamate concentration in the brain, and emphasize which ones are likely to produce the variations in glutamate concentration observed during enhanced neuronal activity in human studies.

  9. Cutaneous in vivo metabolism of topical lidocaine formulation in human skin

    DEFF Research Database (Denmark)

    Rolsted, K; Benfeldt, E; Kissmeyer, A-M

    2009-01-01

    , the enzymes involved are also expressed in the skin. Hence, the aim of the current study was to investigate the extent of the cutaneous in vivo metabolism of topically applied lidocaine in human volunteers. A dose of 5 mg/cm(2) of Xylocaine(R) (5% lidocaine) ointment was applied onto the buttock skin...... of the volunteers. After 2 h, residual formulation was removed, and two 4-mm punch biopsies were taken from each volunteer. The quantity of lidocaine extracted from the skin samples (epidermis + dermis) was 109 +/- 43 ng/mm(2) skin. One metabolite (monoethylglycine xylidide, MEGX) was detected in skin from 7......Little is known about the metabolising capacity of the human skin in relation to topically applied drugs and formulations. We chose lidocaine as a model compound since the metabolic pathways are well known from studies concerning hepatic metabolism following systemic drug administration. However...

  10. Identification of CYP isozymes involved in benzbromarone metabolism in human liver microsomes.

    Science.gov (United States)

    Kobayashi, Kaoru; Kajiwara, Eri; Ishikawa, Masayuki; Oka, Hidenobu; Chiba, Kan

    2012-11-01

    Benzbromarone (BBR) is metabolized to 1'-hydroxy BBR and 6-hydroxy BBR in the liver. 6-Hydroxy BBR is further metabolized to 5,6-dihydroxy BBR. The aim of this study was to identify the CYP isozymes involved in the metabolism of BBR to 1'-hydroxy BBR and 6-hydroxy BBR and in the metabolism of 6-hydroxy BBR to 5,6-dihydroxy BBR in human liver microsomes. Among 11 recombinant P450 isozymes examined, CYP3A4 showed the highest formation rate of 1'-hydroxy BBR. The formation rate of 1'-hydroxy BBR significantly correlated with testosterone 6β-hydroxylation activity in a panel of 12 human liver microsomes. The formation of 1'-hydroxy BBR was completely inhibited by ketoconazole in pooled human liver microsomes. On the other hand, the highest formation rate of 6-hydroxy BBR was found in recombinant CYP2C9. The highest correlation was observed between the formation rate of 6-hydroxy BBR and diclofenac 4'-hydroxylation activity in 12 human liver microsomes. The formation of 6-hydroxy BBR was inhibited by tienilic acid in pooled human liver microsomes. The formation of 5,6-dihydroxy BBR from 6-hydroxy BBR was catalysed by recombinant CYP2C9 and CYP1A2. The formation rate of 5,6-dihydroxy BBR was significantly correlated with diclofenac 4'-hydroxylation activity and phenacetin O-deethylation activity in 12 human liver microsomes. The formation of 5,6-dihydroxy BBR was inhibited with either tienilic acid or α-naphthoflavone in human liver microsomes. These results suggest that (i) the formation of 1'-hydroxy BBR and 6-hydroxy BBR is mainly catalysed by CYP3A4 and CYP2C9, respectively, and (ii) the formation of 5,6-dihydroxy BBR is catalysed by CYP2C9 and CYP1A2 in human liver microsomes.

  11. Nutrient dynamics and metabolism in Mediterranean streams affected by nutrient inputs from human activities

    OpenAIRE

    2006-01-01

    A full understanding of nutrient cycling in lotic ecosystems is crucial given the increasing influence of human activities on the eutrophication of streams and rivers. However, existing knowledge about nutrient cycling in human-altered streams (i.e., receiving point and diffuse sources) is still limited. The general objective of this dissertation was to examine point source effects on stream functional attributes, such as nutrient retention, denitrification and metabolism rates. We also quant...

  12. Metabolism of small RNAs in cultured human cells.

    Science.gov (United States)

    Choudhury, K; Choudhury, I; Eliceiri, G L

    1989-02-01

    There are gaps in what is known about the metabolism of some mammalian small RNA species. Our present observations can be summarized as follows. The level of radiolabeled mature U1 RNA doubled between 2 and 24 hr of label chase, while that of all other small RNA species tested did not change. These results are compatible with the possibility that the nucleotide precursor pool for U1 RNA transcription may be partly segregated, or that there may be a second pathway of U1 RNA formation. Precursors of nucleolar U3 RNA were detected whose electrophoretic mobilities are equivalent to those of transcripts approximately 14 and approximately 8 nucleotides longer than the mature species, and which are apparently cytoplasmic. The ladder of U2 RNA precursors showed a gap, suggesting that some of the cleavages during U2 RNA processing are endonucleolytic. We detected an apparent U5 RNA precursor whose electrophoretic mobility is equivalent to that of a species approximately 1 nucleotide longer than mature U5 RNA. There was a predominant band in the middle of the ladder of U4 RNA precursors (apparently approximately 3 nucleotides longer than mature U4 RNA) which suggests that U4 RNA maturation may pause briefly at that intermediate. There are apparently two additional species of mature hY3 RNA, which are less abundant and are about 1 and 2 bases longer than the major hY3 RNA species. An apparent hY3 RNA precursor was detected, which may be approximately 2-3 nucleotides longer than the main mature hY3 RNA species.

  13. The metabolic effects of olanzapine and topiramate in rats and humans

    NARCIS (Netherlands)

    Evers, S.S.; van Dijk, G.; van Vliet, A.; Scheurink, A.J.W.

    2011-01-01

    In humans the anti-psychotic Olanzapine (OLZ) has negative side effects on metabolism: it causes weight gain and increases the risk of developing type 2 Diabetes. The anti-convulsant Topiramate (TPM) has the opposite effects: it reduces body weight and improves insulin sensitivity. Because of this,

  14. Effects of fenofibrate on hyperlipidemia and postprandial triglyceride metabolism in human apolipoprotein C1 transgenic mice

    NARCIS (Netherlands)

    Jong, M.C.; Dahlmans, V.E.H.; Princen, H.M.G.; Hofker, M.H.; Havekes, L.M.

    1998-01-01

    To study the in vivo role of apolipoprotein (apo) C1 in lipoprotein metabolism, we have generated transgenic mice expressing the human apo C1 gene. Apo C1 is a small 6.6 kDa protein that is primarily synthesized by the liver and is present on chylomicrons, very low density lipoproteins (VLDL) and hi

  15. ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

    Directory of Open Access Journals (Sweden)

    Lakshini Weerasekera

    2017-01-01

    Full Text Available Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D. We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19 correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF-α levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF-α levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D.

  16. METABOLISM OF MYCLOBUTANIL AND TRIADIMEFON BY HUMAN AND RAT CYTOCHROME P450 ENZYMES AND LIVER MICROSOMES.

    Science.gov (United States)

    Metabolism of two triazole-containing antifungal azoles was studied using expressed human and rat cytochrome P450s (CYP) and liver microsomes. Substrate depletion methods were used due to the complex array of metabolites produced from myclobutanil and triadimefon. Myclobutanil wa...

  17. Simulating the physiology of athletes during endurance sports events: Modelling human energy conversion and metabolism

    NARCIS (Netherlands)

    Beek, J.H.G.M. van; Supandi, F.; Gavai, A.K.; Graaf, A.A. de; Binsl, T.W.; Hettling, H.

    2011-01-01

    The human physiological system is stressed to its limits during endurance sports competition events.We describe a whole body computational model for energy conversion during bicycle racing. About 23 per cent of the metabolic energy is used for muscle work, the rest is converted to heat. We

  18. Effects of fenofibrate on hyperlipidemia and postprandial triglyceride metabolism in human apolipoprotein C1 transgenic mice

    NARCIS (