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Sample records for human alcohol metabolism

  1. Low doses of alcohol substantially decrease glucose metabolism in the human brain.

    Science.gov (United States)

    Volkow, Nora D; Wang, Gene-Jack; Franceschi, Dinko; Fowler, Joanna S; Thanos, Panayotis Peter K; Maynard, Laurence; Gatley, S John; Wong, Christopher; Veech, Richard L; Kunos, George; Kai Li, Ting

    2006-01-01

    Moderate doses of alcohol decrease glucose metabolism in the human brain, which has been interpreted to reflect alcohol-induced decreases in brain activity. Here, we measure the effects of two relatively low doses of alcohol (0.25 g/kg and 0.5 g/kg, or 5 to 10 mM in total body H2O) on glucose metabolism in the human brain. Twenty healthy control subjects were tested using positron emission tomography (PET) and FDG after placebo and after acute oral administration of either 0.25 g/kg, or 0.5 g/kg of alcohol, administered over 40 min. Both doses of alcohol significantly decreased whole-brain glucose metabolism (10% and 23% respectively). The responses differed between doses; whereas the 0.25 g/kg dose predominantly reduced metabolism in cortical regions, the 0.5 g/kg dose reduced metabolism in cortical as well as subcortical regions (i.e. cerebellum, mesencephalon, basal ganglia and thalamus). These doses of alcohol did not significantly change the scores in cognitive performance, which contrasts with our previous results showing that a 13% reduction in brain metabolism by lorazepam was associated with significant impairment in performance on the same battery of cognitive tests. This seemingly paradoxical finding raises the possibility that the large brain metabolic decrements during alcohol intoxication could reflect a shift in the substrate for energy utilization, particularly in light of new evidence that blood-borne acetate, which is markedly increased during intoxication, is a substrate for energy production by the brain.

  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. Alcohol and radionuclide metabolism

    International Nuclear Information System (INIS)

    Mahlum, D.D.; Hess, J.O.

    1978-01-01

    The effect of ethanol administration on the deposition and retention of polymeric 239 Pu and 241 Am citrate was studied in the rat. Only in the case of polymeric Pu was there an effect of alcohol administration

  4. Detection of new human metabolic urinary markers in chronic alcoholism and their reversal by aqueous extract of Tinospora cordifolia stem.

    Science.gov (United States)

    Mittal, Ashwani; Dabur, Rajesh

    2015-05-01

    We have studied urine metabolic signature of chronic alcoholism (CA) before and after treatment with an Ayurvedic drug Tinospora cordifolia aqueous extract (TCE). Urinary metabolites of chronic alcoholics and apparently healthy subjects were profiled using HPLC-Q-TOF-MS. Discrimination models from the initial data sets were able to correctly assign the unknown samples to the CA, treated or healthy groups in validation sets with r(2) > 0.98. Metabolic signature in CA patients include changed tryptophan, fatty acids and pyrimidines metabolism. Several novel biomarkers of alcoholism were observed in urine for the first time which includes, 5-hydroxyindole, phenylacetic acid, picolinic acid, quinaldic acid, histidine, cystathionine, riboflavin, tetrahydrobiopterin and chenodeoxyglycocholic acid, in addition to previously reported biomarkers. Treatment of CA with TCE reverted the levels of most of the biomarkers except tetrahydrobiopterin levels. These results suggested that the measurement of these urine metabolites could be used as a non-invasive diagnostic method for the detection of CA. As TCE treatment significantly reversed the affected pathways without any side effect. Overall, the present data depicts that TCE may be used either alone or adjunct in reducing alcohol-induced disorders. © The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.

  5. Transgenic Mouse Models for Alcohol Metabolism, Toxicity and Cancer

    OpenAIRE

    Heit, Claire; Dong, Hongbin; Chen, Ying; Shah, Yatrik M.; Thompson, David C.; Vasiliou, Vasilis

    2015-01-01

    Alcohol abuse leads to tissue damage including a variety of cancers; however, the molecular mechanisms by which this damage occurs remains to be fully understood. The primary enzymes involved in ethanol metabolism include alcohol dehydrogenase (ADH), cytochrome P450 isoform 2E1, (CYP2E1), catalase (CAT), and aldehyde dehydrogenases (ALDH). Genetic polymorphisms in human genes encoding these enzymes are associated with increased risks of alcohol-related tissue damage, as well as differences in...

  6. The Adverse Effects of Alcohol on Vitamin A Metabolism

    Directory of Open Access Journals (Sweden)

    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.

  7. Transferrin metabolism in alcoholic liver disease

    International Nuclear Information System (INIS)

    Potter, B.J.; Chapman, R.W.; Nunes, R.M.; Sorrentino, D.; Sherlock, S.

    1985-01-01

    The metabolism of transferrin was studied using purified 125 I-labeled transferrin in 11 alcoholic patients; six with fatty liver and five with cirrhosis. Six healthy subjects whose alcohol intake was les than 40 gm daily were studied as a control group. There were no significant differences in the mean fractional catabolic rate and plasma volume in the alcoholic groups when compared with control subjects. A significantly decreased mean serum transferrin concentration was found in the alcoholic cirrhotic patients (1.8 +/- 0.3 gm per liter vs. 2.9 +/- 0.2; p less than 0.01), resulting from diminished total body synthesis (0.9 +/- 0.2 mg per kg per hr vs. 1.8 +/- 0.2; p less than 0.01). In contrast, in the patients with alcoholic fatty liver, the mean total body transferrin synthesis (2.4 +/- 0.3 mg per kg per hr) was significantly increased when compared with controls (p less than 0.05). For all the alcoholic patients, the serum transferrin correlated with transferrin synthesis (r = +0.70; p less than 0.01) but the serum iron did not. These results suggest that, in alcoholic cirrhosis, transferrin synthesis is decreased, probably reflecting diminished synthetic capacity by the liver. In contrast, in patients with alcoholic fatty liver, transferrin turnover is accelerated

  8. Human Body Exergy Metabolism

    OpenAIRE

    Mady, Carlos Eduardo Keutenedjian

    2013-01-01

    The exergy analysis of the human body is a tool that can provide indicators of health and life quality. To perform the exergy balance it is necessary to calculate the metabolism on an exergy basis, or metabolic exergy, although there is not yet consensus in its calculation procedure. Hence, the aim of this work is to provide a general method to evaluate this physical quantity for human body based on indirect calorimetry data. To calculate the metabolism on an exergy basis it is necessary to d...

  9. Engineering strategy of yeast metabolism for higher alcohol production

    Directory of Open Access Journals (Sweden)

    Shimizu Hiroshi

    2011-09-01

    Full Text Available Abstract Background While Saccharomyces cerevisiae is a promising host for cost-effective biorefinary processes due to its tolerance to various stresses during fermentation, the metabolically engineered S. cerevisiae strains exhibited rather limited production of higher alcohols than that of Escherichia coli. Since the structure of the central metabolism of S. cerevisiae is distinct from that of E. coli, there might be a problem in the structure of the central metabolism of S. cerevisiae. In this study, the potential production of higher alcohols by S. cerevisiae is compared to that of E. coli by employing metabolic simulation techniques. Based on the simulation results, novel metabolic engineering strategies for improving higher alcohol production by S. cerevisiae were investigated by in silico modifications of the metabolic models of S. cerevisiae. Results The metabolic simulations confirmed that the high production of butanols and propanols by the metabolically engineered E. coli strains is derived from the flexible behavior of their central metabolism. Reducing this flexibility by gene deletion is an effective strategy to restrict the metabolic states for producing target alcohols. In contrast, the lower yield using S. cerevisiae originates from the structurally limited flexibility of its central metabolism in which gene deletions severely reduced cell growth. Conclusions The metabolic simulation demonstrated that the poor productivity of S. cerevisiae was improved by the introduction of E. coli genes to compensate the structural difference. This suggested that gene supplementation is a promising strategy for the metabolic engineering of S. cerevisiae to produce higher alcohols which should be the next challenge for the synthetic bioengineering of S. cerevisiae for the efficient production of higher alcohols.

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

    Directory of Open Access Journals (Sweden)

    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

  11. 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...

  12. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    Human Drug Metabolism, An Introduction, Second Edition provides an accessible introduction to the subject and will be particularly invaluable to those who already have some understanding of the life sciences...

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

    Science.gov (United States)

    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).

  14. Mitigating health risks associated with alcoholic beverages through metabolic engineering.

    Science.gov (United States)

    Jayakody, Lahiru N; Lane, Stephan; Kim, Heejin; Jin, Yong-Su

    2016-02-01

    Epidemiological studies have established a positive relationship between the occurrence of cancer and consumption of alcoholic beverages. Metabolic engineering of brewing yeast to reduce potential carcinogenic compounds in alcoholic beverage is technically feasible as well as economically promising. This review presents the mechanisms of formation of potentially carcinogenic components in alcoholic beverages, such as formaldehyde, acetaldehyde, ethyl carbamate, acrylamide, and heavy metals, and introduces effective genetic perturbations to minimize the concentrations of these harmful components. As precise and effective genome editing tools for polyploid yeast are now available, we envision that yeast metabolic engineering might open up new research directions for improving brewing yeast in order to ensure product safety as well as to increase overall quality of alcoholic beverages. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. [Alcohol intake--a two-edged sword. Part 1: metabolism and pathogenic effects of alcohol].

    Science.gov (United States)

    Ströhle, Alexander; Wolters, Maike; Hahn, Andreas

    2012-08-01

    From the biomedical point of view alcohol is a Janus-faced dietary component with a dose-dependent effect varying from cardiovascular protection to cytotoxicity. Alcohol is absorbed in the upper gastrointestinal tract by passive diffusion, is quickly distributed throughout body water and is mostly eliminated through oxidation. The enzymatically-catalyzed oxidative degradation to acetaldehyde and further to acetate is primarily localized in the liver. In case of a low blood alcohol concentration (0.5 per thousand) are increasingly oxidized by the microsomal ethanoloxidizing system (MEOS). Alcohol consumption induces several metabolic reactions as well as acute effects on the central nervous system. Chronic alcohol consumption to some extent irreparably damages nearly every organ with the liver being particularly concerned. There are three stages of alcohol-induced liver disease (fatty liver, alcohol hepatitis, liver cirrhosis) and the liver damages mainly result from reaction products of alcohol degradation (acetaldehyde, NADH and reactive oxygen species). An especially dreaded clinical complication of the alcohol-induced liver disease is the hepatic encephalopathy. Its pathogenesis is a multifactorial and self-perpetuating process with the swelling of astrocytes being a crucial point. Swollen astrocytes induce several reactions such as oxidative/nitrosative stress, impaired signal transduction, protein modifications and a modified gene expression profile. The swelling of astrocytes and the change in neuronal activity are attributed to several neurotoxins, especially ammonia and aromatic amino acids. In alcohol addicted subjects multiple micronutrient deficiencies are common. The status of folic acid, thiamine, pyridoxine and zinc is especially critical.

  16. Sugar alcohols-induced oxidative metabolism in cotton callus culture

    African Journals Online (AJOL)

    Sugar alcohols (mannitol and sorbitol) may cause oxidative damage in plants if used in higher concentration. Our present experiment was undertaken to study physiological and metabolic responses in cotton (Gossypium hirsutum L.) callus against mannitol and sorbitol higher doses. Both markedly declined mean values of ...

  17. 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.

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

    Science.gov (United States)

    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; Pdrunk-driving abusers (P=.008), reported higher drink-units/d (P=.0126), and had larger MCV (P=.035). The rs698 ADH1C and rs671 ALDH2 polymorphisms were not associated with MCV. ADH1B*1/*1 polymorphism is significantly associated with being a drunk-driving abuser, higher alcohol 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. Copyright © 2012 Elsevier Inc. All rights reserved.

  19. Metabolic Engineering of Microorganisms for the Production of Higher Alcohols

    Science.gov (United States)

    Choi, Yong Jun; Lee, Joungmin; Jang, Yu-Sin

    2014-01-01

    ABSTRACT Due to the increasing concerns about limited fossil resources and environmental problems, there has been much interest in developing biofuels from renewable biomass. Ethanol is currently used as a major biofuel, as it can be easily produced by existing fermentation technology, but it is not the best biofuel due to its low energy density, high vapor pressure, hygroscopy, and incompatibility with current infrastructure. Higher alcohols, including 1-propanol, 1-butanol, isobutanol, 2-methyl-1-butanol, and 3-methyl-1-butanol, which possess fuel properties more similar to those of petroleum-based fuel, have attracted particular interest as alternatives to ethanol. Since microorganisms isolated from nature do not allow production of these alcohols at high enough efficiencies, metabolic engineering has been employed to enhance their production. Here, we review recent advances in metabolic engineering of microorganisms for the production of higher alcohols. PMID:25182323

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

    Science.gov (United States)

    Shayakhmetova, Ganna M; Bondarenko, Larysa B; Matvienko, Anatoliy V; Kovalenko, Valentina M

    2014-09-01

    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.

  1. [Intravenous ethyl alcohol in metabolic resuscitation].

    Science.gov (United States)

    Agolini, G; Lipartiti, T; Zaffiri, O; Musso, L; Belloni, G P

    1980-11-01

    Intravenously administered ethyl alcohol may be effective as analgesic and hypotensive peripheric vasoactive drug. In the Intensive Care Departments parenteral ethanol administration is infrequent because no "sure dosage" can be suggested in adults and children. Liver, kidney and C.N.S. diseases can worsen; foetopathy can follow. Drug-ethanol interaction may be particularly important for some patients admitted in Intensive Care Departments. Often the potential caloric support cannot be fully utilized ("empty" calories) and seldom hyperventilation, hyperlactacidemia and impaired protein synthesis can follow.

  2. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases.

    Science.gov (United States)

    Volkow, Nora D; Wang, Gene-Jack; Shokri Kojori, Ehsan; Fowler, Joanna S; Benveniste, Helene; Tomasi, Dardo

    2015-02-18

    During alcohol intoxication, the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis, we compared the effects of alcohol intoxication (0.75 g/kg alcohol vs placebo) on brain glucose metabolism during video stimulation (VS) versus when given with no stimulation (NS), in 25 heavy drinkers (HDs) and 23 healthy controls, each of whom underwent four PET-(18)FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p = 0.04); that alcohol (compared with placebo) decreased metabolism more in HD (20 ± 13%) than controls (9 ± 11%, p = 0.005) and in proportion to daily alcohol consumption (r = 0.36, p = 0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10 ± 12%) compared with NS in both groups (15 ± 13%, p = 0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e., acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in HDs, which might make them vulnerable to energy deficits during withdrawal. Copyright © 2015 the authors 0270-6474/15/353248-08$15.00/0.

  3. Alcohol decreases baseline brain glucose metabolism more in heavy drinkers than controls but has no effect on stimulation-induced metabolic increases

    International Nuclear Information System (INIS)

    Volkow, Nora D.; Fowler, Joanna S.; Wang, Gene-Jack; Kojori, Eshan Shokri; Benveniste, Helene; Tomasi, Dardo

    2015-01-01

    During alcohol intoxication the human brain increases metabolism of acetate and decreases metabolism of glucose as energy substrate. Here we hypothesized that chronic heavy drinking facilitates this energy substrate shift both for baseline and stimulation conditions. To test this hypothesis we compared the effects of alcohol intoxication (0.75g/kg alcohol versus placebo) on brain glucose metabolism during video-stimulation (VS) versus when given with no-stimulation (NS), in 25 heavy drinkers (HD) and 23 healthy controls each of whom underwent four PET- 18 FDG scans. We showed that resting whole-brain glucose metabolism (placebo-NS) was lower in HD than controls (13%, p=0.04); that alcohol (compared to placebo) decreased metabolism more in HD (20±13%) than controls (9±11%, p=0.005) and in proportion to daily alcohol consumption (r=0.36, p=0.01) but found that alcohol did not reduce the metabolic increases in visual cortex from VS in either group. Instead, VS reduced alcohol-induced decreases in whole-brain glucose metabolism (10±12%) compared to NS in both groups (15±13%, p=0.04), consistent with stimulation-related glucose metabolism enhancement. These findings corroborate our hypothesis that heavy alcohol consumption facilitates use of alternative energy substrates (i.e. acetate) for resting activity during intoxication, which might persist through early sobriety, but indicate that glucose is still favored as energy substrate during brain stimulation. Our findings are consistent with reduced reliance on glucose as the main energy substrate for resting brain metabolism during intoxication (presumably shifting to acetate or other ketones) and a priming of this shift in heavy drinkers, which might make them vulnerable to energy deficits during withdrawal

  4. [Carbohydrates metabolism disturbances when simulating prenatal alcohol intoxication].

    Science.gov (United States)

    Kurch, N M; Vysokogorskiĭ, V E

    2013-01-01

    The influence of prenatal alcohol intoxication on carbohydrate metabolism markers has been investigated at different terms of postnatal offspring development (15, 30 and 60 days). Plasma glucose decreased as compared with the same in control group was detected. In the liver homogenates an increase of phosphorylase activity and a decrease of glucose-6-phosphatase, aldolase and glucose-6-phosphate dehydrogenase activities were found. These changes were accompanied by the incease in the lactate/pyruvate index attributed to increased lactate content in the liver tissue. The obtained data indicate essential disturbances of carbohydrate metabolism markers in prenatal alcoholized offspring, which include stable hypoglycemia, suppression of glycolytic and pentosephosphate pathways of glucose metabolism and lactate accumulation in the liver.

  5. Glycogen metabolism in humans

    OpenAIRE

    Adeva-Andany, María M.; González-Lucán, Manuel; Donapetry-García, Cristóbal; Fernández-Fernández, Carlos; Ameneiros-Rodríguez, Eva

    2016-01-01

    In the human body, glycogen is a branched polymer of glucose stored mainly in the liver and the skeletal muscle that supplies glucose to the blood stream during fasting periods and to the muscle cells during muscle contraction. Glycogen has been identified in other tissues such as brain, heart, kidney, adipose tissue, and erythrocytes, but glycogen function in these tissues is mostly unknown. Glycogen synthesis requires a series of reactions that include glucose entrance into the cell through...

  6. 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, 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...

  7. Human metabolism of caesium

    International Nuclear Information System (INIS)

    Raeaef, C.L.; Falk, R.; Lauridsen, Bente; Rahola, T.; Soogard-Hansen, J.

    2006-04-01

    A study of the human biokinetics of caesium in two forms, i.) incorporated in foodstuff (137Cs in perch and mushrooms) and ii.) in ionic state ( 134 Cs in aqueous solution) has been carried out at the department of Radiation Physics in Malmoe, starting in 2001. The results of the pilot study were published in 2004, and a continuation of that study has now been carried out by means of NKS funding (NKS-B Cskinetik). The aim is to, i.) investigate whether Scandinavian populations exhibit shorter biological half-time of radiocaesium than other populations; ii.) extend the biokinetic study to additional human subjects from the other Nordic countries. Results from the continued study further indicate a near complete absorption of radiocaesium in the gastro-intestinal tract, be it in ion state or contained in food matrix. So far, the literature survey of Nordic studies on biokinetics of Cs suggests that the biological half time is somewhat shorter among Scandinavian males (84 days vs. ICRP-value of 110 days), although females do not exhibit any significant difference (64 days vs ICRP value of 65 days). (au)

  8. Human metabolism of caesium

    Energy Technology Data Exchange (ETDEWEB)

    Raeaef, C.L. [Lund Univ., Dept. of Radiation Physics in Malmoe (Sweden); Falk, R. [Swedish Radiation Protection Authority (Sweden); Lauridsen, Bente [Risoe National Lab. (Denmark); Rahola, T. [STUK - Radiation and Nuclear Safety Authority (Finland); Soogard-Hansen, J. [NRPA - Norwegian Radiation Protection Authority (Norway)

    2006-04-15

    A study of the human biokinetics of caesium in two forms, i.) incorporated in foodstuff (137Cs in perch and mushrooms) and ii.) in ionic state ({sup 134}Cs in aqueous solution) has been carried out at the department of Radiation Physics in Malmoe, starting in 2001. The results of the pilot study were published in 2004, and a continuation of that study has now been carried out by means of NKS funding (NKS-B Cskinetik). The aim is to, i.) investigate whether Scandinavian populations exhibit shorter biological half-time of radiocaesium than other populations; ii.) extend the biokinetic study to additional human subjects from the other Nordic countries. Results from the continued study further indicate a near complete absorption of radiocaesium in the gastro-intestinal tract, be it in ion state or contained in food matrix. So far, the literature survey of Nordic studies on biokinetics of Cs suggests that the biological half time is somewhat shorter among Scandinavian males (84 days vs. ICRP-value of 110 days), although females do not exhibit any significant difference (64 days vs ICRP value of 65 days). (au)

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

    Science.gov (United States)

    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. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  10. Carcinogenicity of acetaldehyde in alcoholic beverages: risk assessment outside ethanol metabolism.

    Science.gov (United States)

    Lachenmeier, Dirk W; Kanteres, Fotis; Rehm, Jürgen

    2009-04-01

    In addition to being produced in ethanol metabolism, acetaldehyde occurs naturally in alcoholic beverages. Limited epidemiological evidence points to acetaldehyde as an independent risk factor for cancer during alcohol consumption, in addition to the effects of ethanol. This study aims to estimate human exposure to acetaldehyde from alcoholic beverages and provide a quantitative risk assessment. The human dietary intake of acetaldehyde via alcoholic beverages was estimated based on World Health Organization (WHO) consumption data and literature on the acetaldehyde contents of different beverage groups (beer, wine, spirits and unrecorded alcohol). The risk assessment was conducted using the European Food Safety Authority's margin of exposure (MOE) approach with benchmark doses obtained from dose-response modelling of animal experiments. Life-time cancer risk was calculated using the T25 dose descriptor. The average exposure to acetaldehyde from alcoholic beverages was estimated at 0.112 mg/kg body weight/day. The MOE was calculated to be 498, and the life-time cancer risk at 7.6 in 10,000. Higher risk may exist for people exposed to high acetaldehyde contaminations, as we have found in certain unrecorded alcohol beverages in Guatemala and Russia, for which we have demonstrated possible exposure scenarios, with risks in the range of 1 in 1000. The life-time cancer risks for acetaldehyde from alcoholic beverages greatly exceed the usual limits for cancer risks from the environment set between 1 : 10,000 and 1 : 1,000,000. Alcohol consumption has thus been identified as a direct source of acetaldehyde exposure, which in conjunction with other sources (food flavourings, tobacco) results in a magnitude of risk requiring intervention. An initial public health measure could be to reduce the acetaldehyde content in alcoholic beverages as low as technologically possible, and to restrict its use as a food flavour additive.

  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. Regional cerebral glucose metabolism in patients with alcoholic Korsakoff's syndrome

    International Nuclear Information System (INIS)

    Kessler, R.M.; Parker, E.S.; Clark, C.M.; Martin, P.R.; George, D.T.; Weingartner, H.; Sokoloff, L.; Ebert, M.H.; Mishkin, M.

    1985-01-01

    Seven alcoholic male subjects diagnosed as having Korsakoff's syndrome and eight age-matched male normal volunteers were studied with /sup 18/F 2-fluoro-2-deoxy-D-glucose (2/sup 18/FDG). All subjects were examined at rest with eyes covered in a quiet, darkened room. Serial plasma samples were obtained following injection of 4 to 5 mCi of 2/sup 18/FDG. Tomographic slices spaced at 10mm axial increments were obtained (in-plane resolution = 1.75 cm, axial resolution = 1.78 cm). Four planes were selected from each subject, and a total of 46 regions of interest were sampled and glucose metabolic rates for each region calculated. The mean glucose metalbolic rate for the 46 regions in the Korsakoff subjects was significantly lower than that in the normal controls (5.17 +- .43 versus 6.6 +- 1.31). A Q-component analysis, which examined each subject's regional rates relative to his mean rate, revealed two distinct patterns in the Korsakoff group. Glucose metabolism was significantly reduced in 37 of the 46 regions sampled. Reduced cerebral glucose metabolism in a nondemented group of subjects has not previously been reported. The reduction in cortical metabolism may be the result of damage to sub-cortical projecting systems. The differing patterns of cerebral metabolism in Korsakoff's syndrome suggests subgroups with differing neuropathology. Regions implicated in memory function, medial temporal, thalamic and medial prefrontal were among the regions reduced in metabolism

  13. 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.

  14. 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.

  15. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ... metabolism and its impact on patient welfare. After underlining the relationship between efficacy, toxicity and drug concentration, the book then considers how metabolizing systems operate and how they impact upon drug concentration...

  16. [Alcohol].

    Science.gov (United States)

    Zima, T

    1996-07-14

    Alcohol is one of the most widely used addictive substances. It can be assumed that everybody encounters alcohol--ethanol in various forms and concentrations in the course of their lives. A global and social problem of our civilization is alcohol consumption which has a rising trend. Since 1989 the consumption of alcoholic beverages is rising and the mean annual consumption of concentrated ethanol per head is cea 10 litres. In ethanol abuse the organism is damaged not only by ethanol alone but in particular by substances formed during its metabolism. Its detailed knowledge is essential for the knowledge and investigations of the metabolic and toxic effect of ethanol on the organism. Ingested alcohol is in 90-98% eliminated from the organism by three known metabolic pathways: 1-alcohol dehydrogenase, 2-the microsomal ethanol oxidizing system and 3-catalase. Alcohol is a frequent important risk factor of serious "diseases of civilization" such as IHD, hypertension, osteoporosis, neoplastic diseases. Cirrhosis of the liver and chronic pancreatitis are the well known diseases associated with alcohol ingestion and also their most frequent cause. It is impossible to list all organs and diseases which develop as a result of alcohol consumption. It is important to realize that regular and "relatively" small amounts in the long run damage the organism and may be even fatal.

  17. Hepatic folate metabolism in the chronic alcoholic monkey

    International Nuclear Information System (INIS)

    Tamura, T.; Romero, J.J.; Watson, J.E.; Gong, E.J.; Halsted, C.H.

    1981-01-01

    To assess the role of altered hepatic folate metabolism in the pathogenesis of the folate deficiency of chronic alcoholism, the hepatic metabolism of a tracer dose of 3 H-PteGlu was compared in monkeys given 50% of energy as ethanol for 2 years and in control monkeys. Long-term ethanol feeding resulted in mild hepatic injury, with a significant decrease in hepatic folate levels. Chromatographic studies of liver biopsies obtained after the tracer dose indicated that the processes of reduction, methylation, and formylation of reduced folate and the synthesis of polyglutamyl folates were not affected by long-term ethanol feeding. Hepatic tritium levels were significantly decreased in the ethanol-fed group. These studies suggest that the decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decrease in hepatic folate levels observed after long-term ethanol ingestion is due to a decreased ability to retain folates in the liver, whereas reduction and further metabolism of folates is not affected

  18. Human drug metabolism: an introduction

    National Research Council Canada - National Science Library

    Coleman, Michael D

    2010-01-01

    ..., both under drug pressure and during inhibition. Factors affecting drug metabolism, such as genetic polymorphisms, age and diet are discussed and how metabolism can lead to toxicity is explained. The book concludes with the role of drug metabolism in the commercial development of therapeutic agents as well as the pharmacology of some illicit drugs.

  19. 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.

  20. Metabolic response of Candida albicans to phenylethyl alcohol under hyphae-inducing conditions.

    Science.gov (United States)

    Han, Ting-Li; Tumanov, Sergey; Cannon, Richard D; Villas-Boas, Silas G

    2013-01-01

    Phenylethyl alcohol was one of the first quorum sensing molecules (QSMs) identified in C. albicans. This extracellular signalling molecule inhibits the hyphal formation of C. albicans at high cell density. Little is known, however, about the underlying mechanisms by which this QSM regulates the morphological switches of C. albicans. Therefore, we have applied metabolomics and isotope labelling experiments to investigate the metabolic changes that occur in C. albicans in response to phenylethyl alcohol under defined hyphae-inducing conditions. Our results showed a global upregulation of central carbon metabolism when hyphal development was suppressed by phenylethyl alcohol. By comparing the metabolic changes in response to phenylethyl alcohol to our previous metabolomic studies, we were able to short-list 7 metabolic pathways from central carbon metabolism that appear to be associated with C. albicans morphogenesis. Furthermore, isotope-labelling data showed that phenylethyl alcohol is indeed taken up and catabolised by yeast cells. Isotope-labelled carbon atoms were found in the majority of amino acids as well as in lactate and glyoxylate. However, isotope-labelled carbon atoms from phenylethyl alcohol accumulated mainly in the pyridine ring of NAD(+)/NADH and NADP(-/)NADPH molecules, showing that these nucleotides were the main products of phenylethyl alcohol catabolism. Interestingly, two metabolic pathways where these nucleotides play an important role, nitrogen metabolism and nicotinate/nicotinamide metabolism, were also short-listed through our previous metabolomics works as metabolic pathways likely to be closely associated with C. albicans morphogenesis.

  1. 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.

  2. Effect of flomoxef on blood coagulation and alcohol metabolism.

    Science.gov (United States)

    Uchida, K; Matsubara, T

    1991-01-01

    The effect of flomoxef, a newly developed oxacephem antibiotic with an N-hydroxyethyltetrazolethiol (HTT) side chain, on blood coagulation and alcohol metabolism was compared with that of a series of cephalosporin antibiotics with N-methyltetrazolethiol (NMTT), thiadiazolethiol (TDT) or methylthiadiazolethiol (MTDT) side chains in position 3' of the cephalosporin nucleus known to cause hypoprothrombinemia and bleeding in patients who are malnourished, debilitated and/or of high age. A disulfiram-like effect caused by inhibition of aldehyde dehydrogenase was observed for NMTT-containing antibiotics. Studies were carried out on healthy volunteers and on rats. Eight-day treatment with 2 g flomoxef i.v. once or twice daily in five and six healthy male volunteers, respectively, did not cause any significant changes in prothrombin time (PT), coagulation factors II, VII, IX or X, in hepaplastin values or fibrinogen levels, activated partial thromboplastin time (APTT), platelet counts, bleeding time, or collagen- and ADP-induced platelet aggregation. Inhibition of vitamin K epoxide reductase was observed in rats treated with flomoxef, yet to a much lesser extent than observed for cephalosporins with NMTT, TDT or MTDT side chains. This defect was quickly normalized by vitamin K injection. There were no differences between oxacephem (1-O) and cephem (1-S) compounds with respect to effects on blood clotting and platelet aggregation. Flomoxef and its side chain HTT showed no influence on alcohol metbolism.

  3. 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

    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 alcohol

  4. Steroid metabolism by monkey and human spermatozoa

    International Nuclear Information System (INIS)

    Rajalakshmi, M.; Sehgal, A.; Pruthi, J.S.; Anand-Kumar, T.C.

    1983-01-01

    Freshly ejaculated spermatozoa from monkey and human were washed and incubated with tritium labelled androgens or estradiol to study the pattern of spermatozoa steroid metabolism. When equal concentrations of steroid substrates were used for incubation, monkey and human spermatozoa showed very similar pattern of steroid conversion. Spermatozoa from both species converted testosterone mainly to androstenedione, but reverse conversion of androstenedione to testosterone was negligible. Estradiol-17 beta was converted mainly to estrone. The close similarity between the spermatozoa of monkey and men in their steroid metabolic pattern indicates that the rhesus monkey could be an useful animal model to study the effect of drugs on the metabolic pattern of human spermatozoa

  5. Alcohol Metabolizing Gene Polymorphisms as Genetic Biomarkers of Alcoholic Liver Disease Susceptibility and Severity: A Northeast India Patient Based Study

    Directory of Open Access Journals (Sweden)

    Tarun K. Basumatary

    2017-07-01

    Full Text Available Background: Excessive alcohol consumption is associated with genetic predisposition to Alcoholic Liver Disease (ALD, but there is very limited data on both molecular and genetic aspects of ALD among the Northeast Indian (NEI population. Aim and Objectives: Screening the role of genetic alterations in alcohol metabolizing pathway genes in the pathogenesis of ALD which is prevalent in the ethnically NEI population. Material and Methods: Whole blood was collected from ALD patients (n=150 [alcoholic chronic liver disease (CLD, n=110 and alcoholic cirrhosis (Cirr/cirrhosis, n=40], Alcoholic Without Liver Disease (AWLD, n=93 and healthy controls (HC/controls, n=274 with informed consents along with Fibroscan based liver stiffness measurement (LSM score and clinical data. Alcohol Dehydrogenase 2 (ADH2 and Aldehyde Dehydrogenase 2 (ALDH2 genotyping was studied by Polymerase Chain Reaction with Confronting Two Pair Primers (PCR-CTPP; and Alcohol Dehydrogenase 3 (ADH3 by Polymerase Chain Reaction-Restriction Fragment Length Polymorphism (PCR-RFLP method. Results:ADH2*2 genotype was predominant and associated with increased risk of cirrhosis compared to healthy controls, AWLD and CLD cases; and CLD compared to AWLD cases. ADH3*1 genotype was associated with significantly increased risk of cirrhosis compared to healthy controls, AWLD and CLD cases (p<0.001. Variant ALDH2 genotype was rare and analysis of the joint effects of genotypes showed that higher variant genotype resulted increased risk of CLD and cirrhosis compared to AWLD, and cirrhosis compared to CLD; thereby confirming the association of the polymorphisms in key alcohol metabolizing genes in the predisposition to ALD susceptibility and severity. Presence of variant ADH2, ADH3 and ALDH2 genotypes correlated with higher LSM scores in ALD. Conclusion: Alterations in the alcohol metabolizing genes are critically associated with ALD susceptibility and severity.

  6. 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.

  7. 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

  8. The impact of alcohol om 241Am gastrointestinal absorption, distribution and metabolism kinetics in rats

    International Nuclear Information System (INIS)

    Zalikin, G.A.; Moskalev, Yu.I.; Nisimov, P.G.

    1986-01-01

    It is shown that alcohol may intensify gastrointestinal absorption of transuranium nuclides. Some intensification of 241 Am metabolism kinetics in rats and accelerated radionuclide excretion from skeleton are noticed that is due to toxic ethanol effect. Investigations in the above direction are thought to be interesting for development under conditions of chronic effect of different alcohol doses and transuranium nuclide incorporation

  9. 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.

  10. Aliphatic alcohols in spirits inhibit phagocytosis by human monocytes.

    Science.gov (United States)

    Pál, László; Árnyas, Ervin M; Bujdosó, Orsolya; Baranyi, Gergő; Rácz, Gábor; Ádány, Róza; McKee, Martin; Szűcs, Sándor

    2015-04-01

    A large volume of alcoholic beverages containing aliphatic alcohols is consumed worldwide. Previous studies have confirmed the presence of ethanol-induced immunosuppression in heavy drinkers, thereby increasing susceptibility to infectious diseases. However, the aliphatic alcohols contained in alcoholic beverages might also impair immune cell function, thereby contributing to a further decrease in microbicidal activity. Previous research has shown that aliphatic alcohols inhibit phagocytosis by granulocytes but their effect on human monocytes has not been studied. This is important as they play a crucial role in engulfment and killing of pathogenic microorganisms and a decrease in their phagocytic activity could lead to impaired antimicrobial defence in heavy drinkers. The aim of this study was to measure monocyte phagocytosis following their treatment with those aliphatic alcohols detected in alcoholic beverages. Monocytes were separated from human peripheral blood and phagocytosis of opsonized zymosan particles by monocytes treated with ethanol and aliphatic alcohols individually and in combination was determined. It was shown that these alcohols could suppress the phagocytic activity of monocytes in a concentration-dependent manner and when combined with ethanol, they caused a further decrease in phagocytosis. Due to their additive effects, it is possible that they may inhibit phagocytosis in a clinically meaningful way in alcoholics and episodic heavy drinkers thereby contribute to their increased susceptibility to infectious diseases. However, further research is needed to address this question.

  11. 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 ...... the body as hidden water loss increases after alcohol consumption by up to 25-26% over control values.......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...... and certain renal functions in rats during a period of 12 months. ANIMALS AND STUDY DESIGN: Male Wistar rats received either alcohol (15% v/v; group A, n = 65) or tap water (group C, n = 35) as drinking fluid. Urine and faeces were collected from 6 rats of each group during 7 days, at monthly intervals...

  12. 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

  13. Human Metabolism and Interactions of Deployment-Related Chemicals

    National Research Council Canada - National Science Library

    Hodgson, Ernest

    2003-01-01

    This study examines the human-metabolism and metabolic interactions of a subset of deployment-related chemicals, including chlorpyrifos, DEET, permethrin, pyridostigmine bromide, and sulfur mustard metabolites...

  14. Enantiomeric metabolic interactions and stereoselective human methadone metabolism.

    Science.gov (United States)

    Totah, Rheem A; Allen, Kyle E; Sheffels, Pamela; Whittington, Dale; Kharasch, Evan D

    2007-04-01

    Methadone is administered as a racemate, although opioid activity resides in the R-enantiomer. Methadone disposition is stereoselective, with considerable unexplained variability in clearance and plasma R/S ratios. N-Demethylation of methadone in vitro is predominantly mediated by cytochrome P450 CYP3A4 and CYP2B6 and somewhat by CYP2C19. This investigation evaluated stereoselectivity, models, and kinetic parameters for methadone N-demethylation by recombinant CYP2B6, CYP3A4, and CYP2C19, and the potential for interactions between enantiomers during racemate metabolism. CYP2B6 metabolism was stereoselective. CYP2C19 was less active, and stereoselectivity was opposite that for CYP2B6. CYP3A4 was not stereoselective. With all three isoforms, enantiomer N-dealkylation rates in the racemate were lower than those of (R)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (R-methadone) or (S)-(6-dimethyamino-4,4-diphenyl-heptan-3-one) hydrochloride (S-methadone) alone, suggesting an enantiomeric interaction and mutual metabolic inhibition. For CYP2B6, the interaction between enantiomers was stereoselective, with S-methadone as a more potent inhibitor of R-methadone N-demethylation than R-of S-methadone. In contrast, enantiomer interactions were not stereoselective with CYP2C19 or CYP3A4. For all three cytochromes P450, methadone N-demethylation was best described by two-site enzyme models with competitive inhibition. There were minor model differences between cytochromes P450 to account for stereoselectivity of metabolism and enantiomeric interactions. Changes in plasma R/S methadone ratios observed after rifampin or troleandomycin pretreatment in humans in vivo were successfully predicted by CYP2B6- but not CYP3A4-catalyzed methadone N-demethylation. CYP2B6 is a predominant catalyst of stereoselective methadone metabolism in vitro. In vivo, CYP2B6 may be a major determinant of methadone metabolism and disposition, and CYP2B6 activity and stereoselective metabolic

  15. [Metabolic disturbances and ways of their pharmacological correction in acute poisoning with ethanol in patients with chronic alcoholism].

    Science.gov (United States)

    Livanov, G A; Lodyagin, A N; Lubsanova, S V; Kovalenko, A L; Batotsyrenov, B V; Sergeev, O A; Loladze, A T; Andrianov, A Yu

    2015-01-01

    To study an influence of chronic alcoholism on the clinical course and severity of metabolic disturbances in patients with acute poisoning with ethanol and to improve the treatment. Authors examined 93 patients stratified into three groups (acute poisoning with ethanol in patients with chronic alcoholism, without chronic alcoholism and those treated with reamberin). The presence of chronic alcoholism significantly augmented metabolic disturbances and influenced the disturbance of oxygen-transport function and free-radical processes in patients with acute intoxication with ethanol. Using of reamberin in the complex intensive therapy led to the decrease in metabolic disorders, which improved the clinical course of acute poisoning with ethanol in patients with chronic alcoholism.

  16. Lipid metabolism abnormalities in alcohol-treated rabbits: a morphometric and haematologic study comparing high and low alcohol doses.

    Science.gov (United States)

    Ikemura, Satoshi; Yamamoto, Takuaki; Motomura, Goro; Iwasaki, Kenyu; Yamaguchi, Ryosuke; Zhao, Garida; Iwamoto, Yukihide

    2011-08-01

    The pathogenesis of alcohol-induced osteonecrosis remains unclear. The purpose of the present study was to evaluate the morphological changes in bone marrow fat cells and the changes in the serum lipid levels in alcohol-treated rabbits. Fifteen rabbits were randomly assigned into three groups: Four rabbits intragastrically received low-dose alcohol (LDA) (15 ml/kg per day) containing 15% ethanol for 4 weeks, five rabbits received high-dose alcohol (HDA) (30 ml/kg per day) for 4 weeks and six rabbits received physiologic saline for 4 weeks as a control group. Six weeks after the initial alcohol administration, all rabbits were sacrificed. The mean size of the bone marrow fat cells in rabbits treated with HDA was significantly larger than that in the control group (P = 0.0001). Haematologically, the levels of triglycerides and free fatty acids in the rabbits treated with both low-dose and HDA were significantly higher than those in the control group (P = 0.001 for both comparisons). The results of this study are that there are lipid metabolism abnormalities, both morphologically and haematologically, after alcohol administration. Also these findings were more apparent in rabbits treated with HDA than those treated with LDA. © 2011 The Authors. International Journal of Experimental Pathology © 2011 International Journal of Experimental Pathology.

  17. Ethyl alcohol: high risk toxin for human healt socially accepted

    Directory of Open Access Journals (Sweden)

    Jairo Téllez Mosquera

    2006-01-01

    Full Text Available Alcohol is the most widely used drugs in World wide so it is in Colombia too. The United Nations Organization (UN report on substance abuse 2004, esteem that 2.6000 millions of persons used alcohol occasional, habitual, abuse or addictive way. In Colombia, RUMBOS, the presidential office for drugs addictions esteem that 89.7 % of the students in universities were habitual 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"

  18. Redesign of the Human Metabolic Simulator

    Science.gov (United States)

    Duffield, Bruce; Jeng, Frank; Lange, Kevin

    2004-01-01

    The National Aeronautics and Space Administration (NASA) is currently building a Human Metabolic Simulator (HMS) at the Johnson Space Center as part of the Advanced Life Support Air Revitalization Technology Evaluation Facility (ARTEF). The purpose of ARTEF is to evaluate Environmental Control and Life Support System Technologies for Advanced Missions. The HMS is needed to reproduce the primary metabolic effects of human respiration on an enclosed atmosphere when humans cannot be present and the impact of human presence on the system is required. A HMS was designed, built and successfully operated in 2000 but larger crew size requirements and the expense of upgrade of the current system necessitate redesign. This paper addresses the redesign. Several concepts were considered, ranging from chemical oxidation of a hydrocarbon like ethanol or ethyl acetate to carbon dioxide and water, oxidation of an iron-containing compound, or by using a fuel cell. For reasons of cost, simplicity, safety and other factors, the concept chosen includes: a molecular sieve packaged as an industrial oxygen concentrator to remove oxygen from the atmosphere, with direct carbon dioxide, water and heat injection. The water injection is done via heating water to steam with a heat exchanger and thermal effects are handled by directly adding heat to the air stream with a second heat exchanger. Both heat exchangers are supplied by a hot oil loop. The amount of oxygen removal, carbon dioxide addition, water addition and heat addition were calculated using metabolic profiles for respiration and heat, calculated using a series of empirical equations developed for International Space Station (ISS). Sketches of the Human Metabolic Simulator and the hot oil bath loop used to supply heat to the heat exchangers are included

  19. Energy Metabolism and Human Dosimetry of Tritium

    International Nuclear Information System (INIS)

    Galeriu, D.; Takeda, H.; Melintescu, A.; Trivedi, A.

    2005-01-01

    In the frame of current revision of human dosimetry of 14 C and tritium, undertaken by the International Commission of Radiological Protection, we propose a novel approach based on energy metabolism and a simple biokinetic model for the dynamics of dietary intake (organic 14 C, tritiated water and Organically Bound Tritium-OBT). The model predicts increased doses for HTO and OBT comparing to ICRP recommendations, supporting recent findings

  20. Metabolic engineering of Clostridium autoethanogenum for selective alcohol production.

    Science.gov (United States)

    Liew, Fungmin; Henstra, Anne M; Kӧpke, Michael; Winzer, Klaus; Simpson, Sean D; Minton, Nigel P

    2017-03-01

    Gas fermentation using acetogenic bacteria such as Clostridium autoethanogenum offers an attractive route for production of fuel ethanol from industrial waste gases. Acetate reduction to acetaldehyde and further to ethanol via an aldehyde: ferredoxin oxidoreductase (AOR) and alcohol dehydrogenase has been postulated alongside the classic pathway of ethanol formation via a bi-functional aldehyde/alcohol dehydrogenase (AdhE). Here we demonstrate that AOR is critical to ethanol formation in acetogens and inactivation of AdhE led to consistently enhanced autotrophic ethanol production (up to 180%). Using ClosTron and allelic exchange mutagenesis, which was demonstrated for the first time in an acetogen, we generated single mutants as well as double mutants for both aor and adhE isoforms to confirm the role of each gene. The aor1+2 double knockout strain lost the ability to convert exogenous acetate, propionate and butyrate into the corresponding alcohols, further highlighting the role of these enzymes in catalyzing the thermodynamically unfavourable reduction of carboxylic acids into alcohols. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  1. 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

  2. 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...

  3. 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.

  4. Alcohol metabolism in hangover sensitive versus hangover resistant social drinkers

    NARCIS (Netherlands)

    Mackus, Marlou; van Schrojenstein Lantman, Marith; van de Loo, A.J.A.E.; Kraneveld, A.D.; Garssen, J.; Verster, J.C.

    2018-01-01

    Background Previous research demonstrated that urinary ethanol concentrations were significantly lower in hangover resistant individuals compared to drinkers who reported having a hangover. This finding suggests that the rate of ethanol metabolism is faster in drinkers who do not experience an

  5. Multiparameter rodent chronic model for complex evaluation of alcoholism-mediated metabolic violations.

    Science.gov (United States)

    Shayakhmetova, Ganna M; Bondarenko, Larysa B; Kovalenko, Valentina M; Kharchenko, Olga I; Bohun, Larisa I; Omelchenko, Yuliya O

    2015-01-01

    Despite of the wide spectrum of alcoholism experimental models, the majority of them are very specialized on the short list of investigated parameters and could not provide reproduction of complex metabolic changes in the rats. The aim of the present study was to estimate whether rats selected by high alcohol preference, allowed free access to 15% alcohol for 150 days, develop simultaneous multilevel disturbances of cell macromolecules structure, metabolism and oxidative/nitrosative stress. Wistar albino male rats were divided into groups: I - rats selected by preferences to alcohol were used for chronic alcoholism modeling by replacing water with 15% ethanol (150 days), II - control. Contents of amino acids in serum, liver mRNA CYP2E1 and CYP3A2 expression, DNA fragmentation and lipid peroxidation levels, the reduced glutathione content, superoxide dismutase, catalase, iNOS and cNOS activities were evaluated. In serum of ethanol-treated rats contents of aspartic acid, serine, glycine, alanine and valine were decreased whereas contents of histidine, methionine and phenylalanine were increased. Liver CYP2E1, CYP3A2 mRNA expression, DNA fragmentation levels significantly elevated. Level of cNOS in ethanol-treated rat's hepatocytes was within the normal limits, whereas iNOS activity was raised 1.6 times. Liver pro- and anti-oxidant system alterations were shown. Rats' chronic 15% alcohol consumption (150 days) led solely to complex metabolomic changes at different levels, which simultaneously characterized cell macromolecules structure, metabolism, and oxidative/nitrosative stress. Rodent model of chronic alcoholism in the proposed modification could be an adequate and reasonably priced tool for further preclinical development and testing of pharmacotherapeutic agents.

  6. Variability in human metabolism of arsenic

    International Nuclear Information System (INIS)

    Loffredo, C.A.; Aposhian, H.V.; Cebrian, M.E.; Yamauchi, Hiroshi; Silbergeld, E.K.

    2003-01-01

    Estimating the nature and extent of human cancer risks due to arsenic (As) in drinking water is currently of great concern, since millions of persons worldwide are exposed to arsenic, primarily through natural enrichment of drinking water drawn from deep wells. Humans metabolize and eliminate As through oxidative methylation and subsequent urinary excretion. While there is debate as to the role of methylation in activation/detoxification, variations in arsenic metabolism may affect individual risks of toxicity and carcinogenesis. Using data from three populations, from Mexico, China, and Chile, we have analyzed the distribution in urine of total arsenic and arsenic species (inorganic arsenic (InAs), monomethyl arsenic (MMA), and dimethyl arsenic (DMA). Data were analyzed in terms of the concentration of each species and by evaluating MMA:DMA and (MMA+DMA):InAs ratios. In all persons most urinary As was present as DMA. Male:female differences were discernible in both high- and low-exposure groups from all three populations, but the gender differences varied by populations. The data also indicated bimodal distributions in the ratios of DMA to InAs and to MMA. While the gene or genes responsible for arsenic methylation are still unknown, the results of our studies among the ethnic groups in this study are consistent with the presence of functional genetic polymorphisms in arsenic methylation leading to measurable differences in toxicity. This analysis highlights the need for continuing research on the health effects of As in humans using molecular epidemiologic methods

  7. Relationship between hepatocellular carcinoma, metabolic syndrome and non-alcoholic fatty liver disease: which clinical arguments?

    Science.gov (United States)

    Rosmorduc, Olivier

    2013-05-01

    Obesity and the metabolic syndrome are growing epidemics associated with an increased risk for many types of cancer. In the liver, inflammatory and angiogenic changes due to insulin resistance and fatty liver disease are associated with an increased incidence of liver cancer. Regardless of underlying liver disease, cirrhosis remains the most important risk factor for hepatocellular carcinoma (HCC) although are cases of HCC arising without cirrhosis raise the possibility of a direct carcinogenesis secondary to Non-alcoholic Fatty Liver Disease (NAFLD). Moreover, metabolic syndrome and its different features may also increase the risk of HCC in the setting of chronic liver diseases of other causes such as viral hepatitis or alcohol abuse. Taking into account all these data, it is necessary to better determine the risk of developing HCC in patients with metabolic syndrome to improve the screening guidelines and develop prophylactic treatments in this setting. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

  8. 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

  9. Hyperthyroidism increases brown fat metabolism in humans.

    Science.gov (United States)

    Lahesmaa, Minna; Orava, Janne; Schalin-Jäntti, Camilla; Soinio, Minna; Hannukainen, Jarna C; Noponen, Tommi; Kirjavainen, Anna; Iida, Hidehiro; Kudomi, Nobuyuki; Enerbäck, Sven; Virtanen, Kirsi A; Nuutila, Pirjo

    2014-01-01

    Thyroid hormones are important regulators of brown adipose tissue (BAT) development and function. In rodents, BAT metabolism is up-regulated by thyroid hormones. The purpose of this article was to investigate the impact of hyperthyroidism on BAT metabolism in humans. This was a follow-up study using positron emission tomography imaging. Glucose uptake (GU) and perfusion of BAT, white adipose tissue, skeletal muscle, and thyroid gland were measured using [18F]2-fluoro-2-deoxy-D-glucose and [15O]H2O and positron emission tomography in 10 patients with overt hyperthyroidism and in 8 healthy participants. Five of the hyperthyroid patients were restudied after restoration of euthyroidism. Supraclavicular BAT was quantified with magnetic resonance imaging or computed tomography and energy expenditure (EE) with indirect calorimetry. Compared with healthy participants, hyperthyroid participants had 3-fold higher BAT GU (2.7±2.3 vs 0.9±0.1 μmol/100 g/min, P=.0013), 90% higher skeletal muscle GU (Phyperthyroidism, serum free T4 and free T3 were strongly associated with EE and lipid oxidation rates (Pmetabolism (PHyperthyroidism had no effect on BAT perfusion, whereas it stimulated skeletal muscle perfusion (P=.04). Thyroid gland GU did not differ between hyperthyroid and euthyroid study subjects. Hyperthyroidism increases GU in BAT independently of BAT perfusion. Hyperthyroid patients are characterized by increased skeletal muscle metabolism and lipid oxidation rates.

  10. 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

  11. Radioiodine 131I metabolism in human

    International Nuclear Information System (INIS)

    Mori, Toru

    1976-01-01

    Metabolic fate of orally administered 131 I in human was studied. Chronological observations of whole body radioactivity distribution and thyroid 131 I uptake curve revealed that 131 I metabolism was greatly affected by the amount of dietary iodine intake. Under the high iodine intake exceeding 1 mg per day, uptake curve showed biphasic descending type, that is, rapid accumulation during 3 to 6 hours and rapid fall up to 48 hours and gradual decrease afterwards. While, ascending type, monophasic and maximal at 24 hours, was found universary under low iodine intake less than 500 μg per day. Thyroid function should not be affected by the amount of iodine intake, and we analysed 131 I metabolism using a new four compartments which included intrathyroidal inorganic iodine pool. The results, especially hormone production rate, were found quite useful even under high iodine intake. Thyroidal organic iodine contents were calculated as approximately 2.5 mg and this value was much less than previously reported values from other countries. Administered radioiodine were mixed up with stable body iodine and reached equilibration by around 10 days. From seroimmunological, histological (microscopic and electron microscopic) studies, and irradiation studies to the cultured human thyroid cells, we concluded that this unexpected phenomenon was derived from chromosomal damage which induced gradual decrease in cell population because of inability to reproduce. Carcinogenic and genetic effects were not serious, and only three leukemic patients were reported in this country and 484 normal babies were born from 7,500 treated parents. Thus, therapeutic dose of 131 I was proved rather safe, and even when exposed to radioiodine, administration of perchlorate or thiocyanate, excessive iodine and TSH seemed effective to avoid radiation injuries. (auth.)

  12. 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.

  13. Exon microarray analysis of human dorsolateral prefrontal cortex in alcoholism.

    Science.gov (United States)

    Manzardo, Ann M; Gunewardena, Sumedha; Wang, Kun; Butler, Merlin G

    2014-06-01

    Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function, and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males. Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC; Brodmann area 9) of 7 adult alcoholic (6 males, 1 female, mean age 49 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using quantitative reverse transcription polymerase chain reaction, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA). Decreased mRNA expression was observed for genes involved in cellular adhesion (e.g., CTNNA3, ITGA2), transport (e.g., TF, ABCA8), nervous system development (e.g., LRP2, UGT8, GLDN), and signaling (e.g., RASGRP3, LGR5) with influence over lipid and myelin synthesis (e.g., ASPA, ENPP2, KLK6). IPA identified disturbances in network functions associated with neurological disease and development including cellular assembly and organization impacting on psychological disorders. Our data in alcoholism support a reduction in expression of dlPFC mRNA for genes involved with neuronal growth, differentiation, and signaling that targets white matter of the brain. Copyright © 2014 by the Research Society on Alcoholism.

  14. Dynamics of Metabolism and Decision Making During Alcohol Consumption: Modeling and Analysis.

    Science.gov (United States)

    Giraldo, Luis Felipe; Passino, Kevin M; Clapp, John D; Ruderman, Danielle

    2017-11-01

    Heavy alcohol consumption is considered an important public health issue in the United States as over 88 000 people die every year from alcohol-related causes. Research is being conducted to understand the etiology of alcohol consumption and to develop strategies to decrease high-risk consumption and its consequences, but there are still important gaps in determining the main factors that influence the consumption behaviors throughout the drinking event. There is a need for methodologies that allow us not only to identify such factors but also to have a comprehensive understanding of how they are connected and how they affect the dynamical evolution of a drinking event. In this paper, we use previous empirical findings from laboratory and field studies to build a mathematical model of the blood alcohol concentration dynamics in individuals that are in drinking events. We characterize these dynamics as the result of the interaction between a decision-making system and the metabolic process for alcohol. We provide a model of the metabolic process for arbitrary alcohol intake patterns and a characterization of the mechanisms that drive the decision-making process of a drinker during the drinking event. We use computational simulations and Lyapunov stability theory to analyze the effects of the parameters of the model on the blood alcohol concentration dynamics that are characterized. Also, we propose a methodology to inform the model using data collected in situ and to make estimations that provide additional information to the analysis. We show how this model allows us to analyze and predict previously observed behaviors, to design new approaches for the collection of data that improves the construction of the model, and help with the design of interventions.

  15. Prevalence of non alcoholic fatty liver disease in patients with metabolic syndrome

    International Nuclear Information System (INIS)

    Iftikhar, R.; Kamran, S.M.

    2015-01-01

    To determine frequency of Non Alcoholic fatty liver disease in patients with Metabolic Syndrome (MetS). Study Design: Cross sectional study. Place and Duration of Study: Department of medicine, CMH Okara, Jan 2013 to July 2013. Patients and Methods: We included 491 adult males, diagnosed with metabolic syndrome (MetS), presenting in outpatient department for routine review. MetS was diagnosed as per the International Diabetes Federation (IDF) proposed criteria of 2004. Detailed history and examination of each individual was done and data entered in pre designed performa. Brightness and posterior attenuation on ultrasound abdomen were considered indices for fatty liver disease in presence of elevated ALT, negative hepatitis serology and absence of alcohol intake. All the data was analyzed using SPSS version 16. p value of less than 0.05 was considered statistically significant. Results: Out of 491 participants with MetS, 222 (45.2%) had fatty liver disease. Mean BMI in patients with metabolic syndrome was 26.1 (± .89) and mean BMI in fatty liver patients was 27.3 (± 0.67). Out of total 5 components of Mets, patients with fatty liver disease had 3.24 (± 0.25) components, as compared to 2.1 (± 0.34) in whole of study group. Conclusion: A large number of patients with metabolic syndrome have fatty liver disease. Fatty liver disease is more frequent in patients who are overweight and those having multiple risk factors of metabolic syndrome. (author)

  16. Bone blood flow and metabolism in humans

    DEFF Research Database (Denmark)

    Heinonen, Ilkka; Kemppainen, Jukka; Kaskinoro, Kimmo

    2012-01-01

    Human bone blood flow and metabolism during physical exercise remains poorly characterised. In the present study we measured femoral bone blood flow and glucose uptake in young healthy subjects by positron emission tomography in three separate protocols. In six women, blood flow was measured...... in femoral bone at rest and during one leg intermittent isometric exercise with increasing exercise intensities. In nine men, blood flow in femur was determined at rest and during dynamic one leg exercise, and two other physiological perturbations: moderate systemic hypoxia (14 O(2) ) at rest and during...... exercise, and during intra-femoral infusion of high-dose adenosine. Bone glucose uptake was measured at rest and during dynamic one leg exercise in five men. The results indicate that isometric exercise increased femoral bone blood flow from rest (1.8 ± 0.6 ml/100g/min) to low intensity exercise (4.1 ± 1...

  17. 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.

  18. 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.

  19. Evidence that humans metabolize benzene via two pathways.

    NARCIS (Netherlands)

    Rappaport, S.M.; Kim, S.; Lan, Q.; Vermeulen, R.C.H.; Waidyanatha, S.; Zhang, L.; Li, G.; Yin, S.; Hayes, R.B.; Rothman, N.; Smith, M.T.

    2009-01-01

    BACKGROUND: Recent evidence has shown that humans metabolize benzene more efficiently at environmental air concentrations than at concentrations > 1 ppm. This led us to speculate that an unidentified metabolic pathway was mainly responsible for benzene metabolism at ambient levels. OBJECTIVE: We

  20. 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

  1. Red wine alcohol promotes quercetin absorption and directs its metabolism towards isorhamnetin and tamarixetin in rat intestine in vitro

    Science.gov (United States)

    Dragoni, Stefania; Gee, Jennifer; Bennett, Richard; Valoti, Massimo; Sgaragli, Giampietro

    2006-01-01

    Moderate consumption of red wine has been associated with beneficial effects on human health, and this has been attributed to the flavonoid content. Factors that influence the bioavailability of this group of polyphenolic compounds are therefore important. Using the rat cannulated everted jejunal sac technique, we have investigated the effect of alcohol on the intestinal absorption of quercetin and its 3-O-glucoside from red wine. Tissue preparations were incubated in whole or dealcoholised red wine, diluted 1 : 1 with Krebs buffer for 20 min at 37°C, after which the mucosa was removed and processed for HPLC analysis. Tissues exposed to red wine had significantly higher amounts of both quercetin (× 3; P<0.001) and quercetin-3-O-glucoside (× 1.5; P<0.01) associated with them, compared with sacs incubated in the dealcoholised equivalent. In addition, both tamarixetin (T) and isorhamnetin (I), in the mucosal tissue from sacs exposed to the whole wine, were significantly elevated approximately two fold (P<0.05; P<0.01, respectively). Similar results were obtained when sacs were incubated in Krebs buffer containing a mixture of pure quercetin and quercetin-3-O-glucoside with or without alcohol, and, although effects on the apparent absorption of Q and Q-3-G were not so marked, concentrations of the metabolites quercetin-3-O-glucuronide and I were significantly increased by the presence of alcohol (P<0.01 and P<0.001, respectively). It is therefore plausible that the moderate alcohol content of red wine contributes to its beneficial health effects in humans by both increasing the absorption of quercetin and quercetin-3-O-glucoside and by channelling their metabolism towards O-methylation to yield compounds (T and I), which have potential protective effects against cancer and cardiovascular diseases. PMID:16444288

  2. Association Between Alcohol Consumption and Metabolic Syndrome in a Community-Based Cohort of Korean Adults

    Science.gov (United States)

    Kim, Su Kang; Hong, Seung-Hee; Chung, Joo-Ho; Cho, Kyu Bong

    2017-01-01

    Background The relationship between alcohol consumption and metabolic syndrome (MetS) remains controversial. This study investigated the relationship between alcohol consumption and MetS components and prevalence. Material/Methods We analyzed 10 037 subjects (3076 MetS and 6961 non-MetS) in a community-based cohort. MetS was defined according to the ATP III Guidelines. Subjects were divided according to amount of alcohol consumption; non-drinker, very light (0.1–5.0 g/day), light (5.1–15.0 g/day), moderate (15.1–30.0 g/day), and heavy drinker (>30 g/day). Multiple logistic regression models were performed to estimate odds ratios (ORs) and confidence intervals (CIs). The analyses were performed in men and women separately. SPSS statistical software was used for analyses. Results The prevalence of MetS in both males and females was associated with alcohol drinking status (palcohol consumption (0.1–5.0 g/day) was significantly associated with lower prevalence of MetS in both genders compared to non-drinkers. Amount of alcohol consumption (>30.0 g/day) did not show a significant association with prevalence of MetS. However, alcohol consumption (>30.0 g/day) showed an association with glucose and HDL cholesterol among the components of MetS. Conclusions Our results indicate that alcohol drinking (0.1–5.0 g/day) contributed to decrease prevalence of MetS and components, including triglyceride and HDL cholesterol. PMID:28465500

  3. 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

  4. Human Health Assessment of Alcohol To Jet (ATJ) Synthetic Kerosenes

    Science.gov (United States)

    2016-07-30

    workplace . 15. SUBJECT TERMS Jet fuels, alternative fuels, synthetic kerosene, JP-8, biobased/bio-based, toxicity/toxicology, alcohol-to-jet, toxicity...ATJ fuels alone, or in a blend with petroleum-derived JP-8, is unlikely to increase human health risks in the military workplace . Therefore, the... pregnancy rate, gestation length, or number of pups per litter. The female-only exposure did result in decreased pup weights in the highest dose group

  5. [Effects of smoking and alcohol consumptionon reproductive and metabolic indicators in young men in western siberia].

    Science.gov (United States)

    Osadchuk, L V; Popova, A V; Erkovich, A A; Voroshilova, N A; Osadchuk, A V

    2017-09-01

    Smoking and alcohol consumption remain widespread throughout the world, including Russia. Recently, due to the increase in male infertility and subfertility, special attention has been paid to the effects of smoking and alcohol on the reproductive health of young men. The aim of this study was to assess the effects of smoking and moderate alcohol consumption on spermatogenesis, reproductive hormone levels and metabolic status in young men living in Western Siberia (Novosibirsk). One hundred thirty-three volunteers (mean age 21.1+/-0.3 years) were tested for the sperm concentration, the proportion of mobile and morphologically normal spermatozoa in the ejaculate, blood serum levels of follicle-stimulating and luteinizing hormones, prolactin, testosterone, estradiol, inhibin B, triglycerides, total cholesterol, high and low density lipoprotein cholesterol, glucose and uric acid. and conclusions The studied lifestyle factors were found to have no effects on spermatogenesis. Smoking more than 10 cigarettes per day and a moderate frequency of alcohol consumption (up to 1 time per week) was associated with higher blood serum testosterone levels and engaging in more frequent sexual contacts compared to non-smoking and non-drinking men. Drinking alcohol more than once a week and smoking more than 8 cigarettes per day was associated, along with the increase in testosterone levels and the frequency of sexual contacts, with lower levels of follicle-stimulating hormone and higher serum triglyceride levels. Thus, in young men, frequent drinking and smoking can alter the hormonal and metabolic balance, which, as the duration of the exposure and the strength of the factors increase, will increase the risk of reproductive disorders.

  6. Forensic relevance of glucuronidation in phase-II-metabolism of alcohols and drugs.

    Science.gov (United States)

    Kaeferstein, Herbert

    2009-04-01

    Forensic toxicology means detecting toxic or pharmacologically active substances in body fluids and organs and the evaluation and judgement of the respective results. In the legal judgement, not only the taken in active drugs, but also their metabolites are to be included. Regarding metabolism one distinguishes phase-I- and phase-II-metabolism. In the phase-I-metabolism, active substances are converted by oxidation, reduction or hydrolysis, but influencing the polarity of more lipophilic substances often not decisively. The pharmacological activity is often preserved or even increased. In phase-II-metabolism a highly hydrophilic substance--mostly glucuronic acid--is coupled to the active substances or the respective phase-I-metabolites. This reaction step decisively increases hydrophilicity of lipophilic substances, thus enhancing renal elimination and often also abolishing pharmacologically and/or toxicologically effects. Nevertheless the interaction of different drugs and alcohols in glucuronidation and the glucuronides of phase-II-metabolism still do not play a substantial role in the forensic-toxicological analysis and interpretation of results so far. However, in vitro investigations since 1999 in our lab show that such interactions are not unlikely. For valid interpretation of complex cases in the future it may become necessary not only to quantify drugs and the phase-I-metabolites but also the phase-II-metabolites and discuss possible interactions in the metabolism.

  7. Alcohol

    Science.gov (United States)

    ... because that's how many accidents occur. 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 ...

  8. 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 ...

  9. Alcohol

    International Nuclear Information System (INIS)

    Navarro Junior, L.

    1988-01-01

    The alcohol production as a secondary energy source, the participation of the alcohol in Brazilian national economic and social aspects are presented. Statistical data of alcohol demand compared with petroleum by-products and electricity are also included. (author)

  10. Towards metabolic mapping of the human retina.

    Science.gov (United States)

    Schweitzer, D; Schenke, S; Hammer, M; Schweitzer, F; Jentsch, S; Birckner, E; Becker, W; Bergmann, A

    2007-05-01

    Functional alterations are first signs of a starting pathological process. A device that measures parameter for the characterization of the metabolism at the human eye-ground would be a helpful tool for early diagnostics in stages when alterations are yet reversible. Measurements of blood flow and of oxygen saturation are necessary but not sufficient. The new technique of auto-fluorescence lifetime measurement (FLIM) opens in combination with selected excitation and emission ranges the possibility for metabolic mapping. FLIM not only adds an additional discrimination parameter to distinguish different fluorophores but also resolves different quenching states of the same fluorophore. Because of its high sensitivity and high temporal resolution, its capability to resolve multi-exponential decay functions, and its easy combination with laser scanner ophthalmoscopy, multi-dimensional time-correlated single photon counting was used for fundus imaging. An optimized set up for in vivo lifetime measurements at the human eye-ground will be explained. In this, the fundus fluorescence is excited at 446 or 468 nm and the time-resolved autofluorescence is detected in two spectral ranges between 510 and 560 nm as well as between 560 and 700 nm simultaneously. Exciting the fundus at 446 nm, several fluorescence maxima of lifetime t1 were detected between 100 and 220 ps in lifetime histograms of 40 degrees fundus images. In contrast, excitation at 468 nm results in a single maximum of lifetime t1 = 190 +/- 16 ps. Several fundus layers contribute to the fluorescence intensity in the short-wave emission range 510-560 nm. In contrast, the fluorescence intensity in the long-wave emission range between 560 and 700 nm is dominated by the fluorescence of lipofuscin in the retinal pigment epithelium. Comparing the lateral distribution of parameters of a tri-exponential model function in lifetime images of the fundus with the layered anatomical fundus structure, the shortest component (t1

  11. Red wine alcohol promotes quercetin absorption and directs its metabolism towards isorhamnetin and tamarixetin in rat intestine in vitro.

    Science.gov (United States)

    Dragoni, Stefania; Gee, Jennifer; Bennett, Richard; Valoti, Massimo; Sgaragli, Giampietro

    2006-04-01

    Moderate consumption of red wine has been associated with beneficial effects on human health, and this has been attributed to the flavonoid content. Factors that influence the bioavailability of this group of polyphenolic compounds are therefore important. Using the rat cannulated everted jejunal sac technique, we have investigated the effect of alcohol on the intestinal absorption of quercetin and its 3-O-glucoside from red wine. Tissue preparations were incubated in whole or dealcoholised red wine, diluted 1 : 1 with Krebs buffer for 20 min at 37 degrees C, after which the mucosa was removed and processed for HPLC analysis. Tissues exposed to red wine had significantly higher amounts of both quercetin (x 3; P wine, were significantly elevated approximately two fold (P moderate alcohol content of red wine contributes to its beneficial health effects in humans by both increasing the absorption of quercetin and quercetin-3-O-glucoside and by channelling their metabolism towards O-methylation to yield compounds (T and I), which have potential protective effects against cancer and cardiovascular diseases.

  12. 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...... a cohort study among 1250 postmenopausal breast cancer patients identified among 29 875 women in the Danish Diet, Cancer and Health Study. Participants completed questionnaires and anthropometric measurements were made at enrollment. Information on survival, socioeconomic position, and comorbidity...... 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...

  13. Peroxisomes, lipid metabolism, and human disease

    NARCIS (Netherlands)

    Wanders, R. J.

    2000-01-01

    In the past few years, much has been learned about the metabolic functions of peroxisomes. These studies have shown that peroxisomes play a major role in lipid metabolism, including fatty acid beta-oxidation, etherphospholipid biosynthesis, and phytanic acid alpha-oxidation. This article describes

  14. 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

    Aging is associated with oxidative stress-generated damage to DNA and this could be related to metabolic disturbances. This study investigated the association between levels of oxidatively damaged DNA in peripheral blood mononuclear cells (PBMCs) and metabolic risk factors in 1,019 subjects, aged...... 18-93 years. DNA damage was analyzed as strand breaks by the comet assay and levels of formamidopyrimidine (FPG-) and human 8-oxoguanine DNA glycosylase 1 (hOGG1)-sensitive sites There was an association between age and levels of FPG-sensitive sites for women, but not for men. The same tendency......, 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...

  15. Biochemical studies of effects of alcohol consumption on fat and carbohydrate metabolism in rats fed different levels of proteins

    International Nuclear Information System (INIS)

    Shalan, M.G.M.

    1996-01-01

    Alcohol, ethanol and ethyl alcohol are synonymously used during the present dissertation. Alcohol probably was among the first psychoactive substances to be used by man (Winger et al., 1992). Ethanol is mainly oxidized to acetaldehyde in the liver (Ugarte and Peresa, 1978) by alcohol dehydrogenase (ADH). Alcohol is associated with many metabolic disorders inside the body (Thayer and Rubin, 1979; Forsander and Poso, 1988; Poso and Hirsimaki, 1991; Bernal, et al., 1992). The nutritional factors which received little attention have an important role in alcoholic metabolizing alterations. Morphologically and biochemically, an increase in hepatic lipid was demonstrated when ethanol was given either as a supplement or as an iso caloric substitute for carbohydrate together with an otherwise nutritionally adequate diet. Low-protein diets have been shown to diminish hepatic alcohol dehydrogenase (ADH) levels in rats and to slow down the metabolism of ethanol considerably (Wilson et al., 1986). Hepatic steatosis was produced, even with a high-protein, vitamin-supplemented diet and was accompanied by major ultrastructural liver changes and by elevations of hepatic transaminases in blood (Lieber et al., 1963 and 1965 and Lane and Lieber, 1966). If dietary fat was reduced from 35 to 25% of total calories, hepatic triglyceride accumulation greatly decreased (Lieber and DeCarli, 970)

  16. Carboxylesterases in lipid metabolism: from mouse to human

    Directory of Open Access Journals (Sweden)

    Jihong Lian

    2017-07-01

    Full Text Available ABSTRACT Mammalian carboxylesterases hydrolyze a wide range of xenobiotic and endogenous compounds, including lipid esters. Physiological functions of carboxylesterases in lipid metabolism and energy homeostasis in vivo have been demonstrated by genetic manipulations and chemical inhibition in mice, and in vitro through (overexpression, knockdown of expression, and chemical inhibition in a variety of cells. Recent research advances have revealed the relevance of carboxylesterases to metabolic diseases such as obesity and fatty liver disease, suggesting these enzymes might be potential targets for treatment of metabolic disorders. In order to translate pre-clinical studies in cellular and mouse models to humans, differences and similarities of carboxylesterases between mice and human need to be elucidated. This review presents and discusses the research progress in structure and function of mouse and human carboxylesterases, and the role of these enzymes in lipid metabolism and metabolic disorders.

  17. Pharmacological interventions in human HDL metabolism

    NARCIS (Netherlands)

    Balder, Jan-Willem; Staels, Bart; Kuivenhoven, Jan A.

    2013-01-01

    PURPOSE OF REVIEW: This review focuses on the recent developments in the field of drugs that affect HDL metabolism. Additionally, some general (retrospective) thoughts on fighting cardiovascular disease through modulating circulating lipids are discussed. RECENT FINDINGS: Recently, the large

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

    Science.gov (United States)

    Ahmed, Adeeba; Rabbitt, Elizabeth; Brady, Theresa; Brown, Claire; Guest, Peter; Bujalska, Iwona J; Doig, Craig; Newsome, Philip N; Hubscher, Stefan; Elias, Elwyn; Adams, David H; Tomlinson, Jeremy W; Stewart, Paul M

    2012-01-01

    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). 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. 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. 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 11β-HSD1 activity and consequent cortisol regeneration may serve to

  19. 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 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.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.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.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 11β-HSD1 activity and consequent cortisol regeneration may

  20. Prevalence of metabolic risk factors in non-alcoholic fatty liver disease

    International Nuclear Information System (INIS)

    Ashraf, N.; Sarfraz, T.; Mumtaz, Z.; Rizwan, M.

    2017-01-01

    Objective: To determine the frequency of factors leading to metabolic syndrome among non-alcoholic fatty liver disease (NAFLD) patients at a tertiary care hospital. Study Design: Descriptive cross sectional study. Place and Duration of Study: Department of Medicine, Combined Military Hospital, Kharian. Study was carried out over a period of six months from Jan 2015 to Jun 2015. Material and Methods: A total of 110 patients were included in this study. Past history was taken to rule out alcohol intake, viral and drug induced etiology, to determine the presence of co-morbidities like obesity, type 2 diabetes mellitus, arterial hypertension and dyslipidemia. Physical examination was carried to determine the arterial blood pressure and to determine anthropometric data that is weight, height, body mass index (BMI) and abdominal obesity by measuring waist circumference. Results: Mean age of the patients was 49.95 +- 8.86 years. There were 72 male patients (65.5%) while 38 (34.5%) patients were female. Different metabolic factors were central obesity in 82 patients (74.5%), raised high density lipoprotein (HDL) in 19 patients (17.3%), raised cholesterol in 87 patients (79.1%), raised blood pressure in 65 patients (59.1%) and raised fasting plasma glucose in 82 patients (74.5%). Mean BMI was 26.31 kg/m2 +- 2.68, mean waist circumference was 109.82 cm +- 18.41, mean cholesterol was 237.50 +- 48.47mg/dl, mean systolic blood pressure was 148.88mmHg +- 22.10, mean diastolic blood pressure was 90.41mmHg +- 12.25 and mean fasting plasma glucose was 113.28mg/dl +- 22.80. Stratification with regard to age was carried out. Conclusion: A considerable number of patients with NAFLD had metabolic syndrome. There was a close correlation between NAFLD and metabolic syndrome. (author)

  1. Chronic free-choice drinking in crossed high alcohol preferring mice leads to sustained blood ethanol levels and metabolic tolerance without evidence of liver damage.

    Science.gov (United States)

    Matson, Liana; Liangpunsakul, Suthat; Crabb, David; Buckingham, Amy; Ross, Ruth Ann; Halcomb, Meredith; Grahame, Nicholas

    2013-02-01

    Crossed high alcohol preferring (cHAP) mice were selectively bred from a cross of the HAP1 × HAP2 replicate lines, and we demonstrate blood ethanol concentrations (BECs) during free-choice drinking that are reminiscent of those observed in alcohol-dependent humans. Therefore, this line may provide an unprecedented opportunity to learn about the consequences of excessive voluntary ethanol (EtOH) consumption, including metabolic tolerance and liver pathology. Cytochrome p450 2E1 (CYP2E1) induction plays a prominent role in driving both metabolic tolerance and EtOH-induced liver injury. In this report, we sought to characterize cHAP drinking by assessing whether pharmacologically relevant BEC levels are sustained throughout the active portion of the light-dark cycle. Given that cHAP intakes and BECs are similar to those observed in mice given an EtOH liquid diet, we assessed whether free-choice exposure results in metabolic tolerance, hepatic enzyme induction, and hepatic steatosis. In experiment 1, blood samples were taken across the dark portion of a 12:12 light-dark cycle to examine the pattern of EtOH accumulation in these mice. In experiments 1 and 2, mice were injected with EtOH following 3 to 4 weeks of access to water or 10% EtOH and water, and blood samples were taken to assess metabolic tolerance. In experiment 3, 24 mice had 4 weeks of access to 10% EtOH and water or water alone, followed by necropsy and hepatological assessment. In experiment 1, cHAP mice mean BEC values exceeded 80 mg/dl at all sampling points and approached 200 mg/dl during the middle of the dark cycle. In experiments 1 and 2, EtOH-exposed mice metabolized EtOH faster than EtOH-naïve mice, demonstrating metabolic tolerance (p alcohol dehydrogenase and aldehyde dehydrogenase. These results demonstrate that excessive intake by cHAP mice results in sustained BECs throughout the active period, leading to the development of metabolic tolerance and evidence of CYP2E1 induction

  2. Regional cerebral glucose metabolism in patients with alcoholic Korsakoff's syndrome

    Energy Technology Data Exchange (ETDEWEB)

    Kessler, R.M.; Parker, E.S.; Clark, C.M.; Martin, P.R.; George, D.T.; Weingartner, H.; Sokoloff, L.; Ebert, M.H.; Mishkin, M.

    1985-05-01

    Seven alcoholic male subjects diagnosed as having Korsakoff's syndrome and eight age-matched male normal volunteers were studied with /sup 18/F 2-fluoro-2-deoxy-D-glucose (2/sup 18/FDG). All subjects were examined at rest with eyes covered in a quiet, darkened room. Serial plasma samples were obtained following injection of 4 to 5 mCi of 2/sup 18/FDG. Tomographic slices spaced at 10mm axial increments were obtained (in-plane resolution = 1.75 cm, axial resolution = 1.78 cm). Four planes were selected from each subject, and a total of 46 regions of interest were sampled and glucose metabolic rates for each region calculated. The mean glucose metalbolic rate for the 46 regions in the Korsakoff subjects was significantly lower than that in the normal controls (5.17 +- .43 versus 6.6 +- 1.31). A Q-component analysis, which examined each subject's regional rates relative to his mean rate, revealed two distinct patterns in the Korsakoff group. Glucose metabolism was significantly reduced in 37 of the 46 regions sampled. Reduced cerebral glucose metabolism in a nondemented group of subjects has not previously been reported. The reduction in cortical metabolism may be the result of damage to sub-cortical projecting systems. The differing patterns of cerebral metabolism in Korsakoff's syndrome suggests subgroups with differing neuropathology. Regions implicated in memory function, medial temporal, thalamic and medial prefrontal were among the regions reduced in metabolism.

  3. 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

  4. Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD

    Directory of Open Access Journals (Sweden)

    Ali Saeed

    2017-12-01

    Full Text Available Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs and retinoid X receptors (RXRs.The liver plays a central role in vitamin A metabolism: (1 it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2 it produces retinol binding protein 4 (RBP4 that distributes vitamin A, as retinol, to peripheral tissues; and (3 it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs. In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH; it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M is the most prominent

  5. 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…

  6. 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.

  7. 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.

  8. 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 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.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.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.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.

  9. Different types of alcoholic beverages and incidence of metabolic syndrome and its components in a Mediterranean cohort.

    Science.gov (United States)

    Barrio-Lopez, Maria T; Bes-Rastrollo, Maira; Sayon-Orea, Carmen; Garcia-Lopez, Martin; Fernandez-Montero, Alejandro; Gea, Alfredo; Martinez-Gonzalez, Miguel A

    2013-10-01

    We prospectively assessed the association between alcohol consumption and the incidence of Metabolic Syndrome (MS) in a Mediterranean cohort. We included 8103 (mean age: 35.4 years) University graduates free of any MS criteria and followed-up during ≥6 years. Alcohol consumption was collected with a validated 136-item food frequency questionnaire. New-onset cases of MS were defined according to the updated harmonizing criteria. We observed 341 incident cases of MS. Consumers of ≥7 drinks/wk presented a significantly higher risk of developing MS (aOR: 1.80; 95% CI: 1.22-2.66; p Metabolism. All rights reserved.

  10. 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 <1% of anthropogenic heating in all cities. Heat flux density from 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.

  11. Tribbles-1: a novel regulator of hepatic lipid metabolism in humans.

    Science.gov (United States)

    Bauer, Robert C; Yenilmez, Batuhan O; Rader, Daniel J

    2015-10-01

    The protein tribbles-1, encoded by the gene TRIB1, is increasingly recognized as a major regulator of multiple cellular and physiological processes in humans. Recent human genetic studies, as well as molecular biological approaches, have implicated this intriguing protein in the aetiology of multiple human diseases, including myeloid leukaemia, Crohn's disease, non-alcoholic fatty liver disease (NAFLD), dyslipidaemia and coronary artery disease (CAD). Genome-wide association studies (GWAS) have repeatedly identified variants at the genomic TRIB1 locus as being significantly associated with multiple plasma lipid traits and cardiovascular disease (CVD) in humans. The involvement of TRIB1 in hepatic lipid metabolism has been validated through viral-mediated hepatic overexpression of the gene in mice; increasing levels of TRIB1 decreased plasma lipids in a dose-dependent manner. Additional studies have implicated TRIB1 in the regulation of hepatic lipogenesis and NAFLD. The exact mechanisms of TRIB1 regulation of both plasma lipids and hepatic lipogenesis remain undetermined, although multiple signalling pathways and transcription factors have been implicated in tribbles-1 function. Recent reports have been aimed at developing TRIB1-based lipid therapeutics. In summary, tribbles-1 is an important modulator of human energy metabolism and metabolic syndromes and worthy of future studies aimed at investigating its potential as a therapeutic target. © 2015 Authors; published by Portland Press Limited.

  12. Pregnane X Receptor-Humanized Mice Recapitulate Gender Differences in Ethanol Metabolism but Not Hepatotoxicity.

    Science.gov (United States)

    Spruiell, Krisstonia; Gyamfi, Afua A; Yeyeodu, Susan T; Richardson, Ricardo M; Gonzalez, Frank J; Gyamfi, Maxwell A

    2015-09-01

    Both human and rodent females are more susceptible to developing alcoholic liver disease following chronic ethanol (EtOH) ingestion. However, little is known about the relative effects of acute EtOH exposure on hepatotoxicity in female versus male mice. The nuclear receptor pregnane X receptor (PXR; NR1I2) is a broad-specificity sensor with species-specific responses to toxic agents. To examine the effects of the human PXR on acute EtOH toxicity, the responses of male and female PXR-humanized (hPXR) transgenic mice administered oral binge EtOH (4.5 g/kg) were analyzed. Basal differences were observed between hPXR males and females in which females expressed higher levels of two principal enzymes responsible for EtOH metabolism, alcohol dehydrogenase 1 and aldehyde dehydrogenase 2, and two key mediators of hepatocyte replication and repair, cyclin D1 and proliferating cell nuclear antigen. EtOH ingestion upregulated hepatic estrogen receptor α, cyclin D1, and CYP2E1 in both genders, but differentially altered lipid and EtOH metabolism. Consistent with higher basal levels of EtOH-metabolizing enzymes, blood EtOH was more rapidly cleared in hPXR females. These factors combined to provide greater protection against EtOH-induced liver injury in female hPXR mice, as revealed by markers for liver damage, lipid peroxidation, and endoplasmic reticulum stress. These results indicate that female hPXR mice are less susceptible to acute binge EtOH-induced hepatotoxicity than their male counterparts, due at least in part to the relative suppression of cellular stress and enhanced expression of enzymes involved in both EtOH metabolism and hepatocyte proliferation and repair in hPXR females. U.S. Government work not protected by U.S. copyright.

  13. 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......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...... before, during, and 2 h after cessation of the infusion. Glucose metabolism was unaffected by rhIL-6. In contrast, rhIL-6 increased systemic fatty acid oxidation approximately twofold after 60 min, and it remained elevated even 2 h after the infusion. The increase in oxidation was followed by an increase...

  14. 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......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...... before, during, and 2 h after cessation of the infusion. Glucose metabolism was unaffected by rhIL-6. In contrast, rhIL-6 increased systemic fatty acid oxidation approximately twofold after 60 min, and it remained elevated even 2 h after the infusion. The increase in oxidation was followed by an increase...

  15. New paradigms for metabolic modeling of human cells

    DEFF Research Database (Denmark)

    Mardinoglu, Adil; Nielsen, Jens

    2015-01-01

    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......, 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.......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...

  16. Metabolic engineering of Escherichia coli for limonene and perillyl alcohol production.

    Science.gov (United States)

    Alonso-Gutierrez, Jorge; Chan, Rossana; Batth, Tanveer S; Adams, Paul D; Keasling, Jay D; Petzold, Christopher J; Lee, Taek Soon

    2013-09-01

    Limonene is a valuable monoterpene used in the production of several commodity chemicals and medicinal compounds. Among them, perillyl alcohol (POH) is a promising anti-cancer agent that can be produced by hydroxylation of limonene. We engineered E. coli with a heterologous mevalonate pathway and limonene synthase for production of limonene followed by coupling with a cytochrome P450, which specifically hydroxylates limonene to produce POH. A strain containing all mevalonate pathway genes in a single plasmid produced limonene at titers over 400mg/L from glucose, substantially higher than has been achieved in the past. Incorporation of a cytochrome P450 to hydroxylate limonene yielded approximately 100mg/L of POH. Further metabolic engineering of the pathway and in situ product recovery using anion exchange resins would make this engineered E. coli a potential production platform for any valuable limonene derivative. © 2013 Elsevier Inc. All rights reserved.

  17. 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

  18. The effect of alcoholic beverages on iron and zinc metabolism in the rat.

    Science.gov (United States)

    Fairweather-Tait, S J; Southon, S; Piper, Z

    1988-09-01

    1. Male Wistar rats (approximately 200 g) were given distilled water and a semi-synthetic control diet for 6 d. On day 7, 37 kBq 65Zn were administered intramuscularly and the rats were given distilled water, beer, cider, red wine, whisky or ethanol as their only source of fluid. The wine, whisky and ethanol were diluted so that each of the beverages contained a similar ethanol concentration (approximately 30 g/l). Food and fluid intake, growth rate and whole-body 65Zn were measured regularly over 11 d, after which animals were killed and blood haemoglobin (Hb) concentration, liver iron stores and the Zn concentration in testes determined. 2. There were no differences in body-weight gain or food intake between groups but fluid intake for the beer group was considerably higher than that for the other groups. 3. There was a significant effect of the type of alcoholic beverage consumed on whole-body 65Zn retention. Rats given whisky had a smaller daily loss of 65Zn than those given water, beer or cider. The ethanol group also showed a lower rate of 65Zn loss compared with the water group. The observed changes in whole-body 65Zn retention could be explained by an adverse influence of ethanol on Zn absorption from the diet. 4. Blood Hb and testes Zn concentration were similar in all groups but the type of liquid consumed influenced liver Fe levels. The cider group had the lowest liver Fe values and the ethanol group the highest values. 5. It is apparent from the present study that ethanol and alcoholic beverages affect Zn and Fe metabolism, but that the effects of ethanol are moderated by other components of the alcoholic beverages.

  19. Comparative study of hop-containing products on human cytochrome p450-mediated metabolism.

    Science.gov (United States)

    Foster, Brian C; Kearns, Nikia; Arnason, John T; Saleem, Ammar; Ogrodowczyk, Carolina; Desjardins, Suzanne

    2009-06-10

    Thirty-five national and international brands of beer were examined for their potential to affect human cytochrome P450 (CYP)-mediated metabolism. They represented the two main categories of beer, ales and lagers, and included a number of specialty products including bitter (porter, stout), coffee, ice, wheat, Pilsner, and hemp seed. Aliquots were examined for nonvolatile soluble solids, effect on CYP metabolism and P-glycoprotein (Pgp) transport, and major alpha- and beta-hop acids. Wide variance was detected in contents of alcohol, nonvolatile suspended solids, and hop acids and in the potential to affect CYP-mediated metabolism and Pgp-mediated efflux transport. Many of the products affected CYP2C9-mediated metabolism, and only two (NRP 306 and 307) markedly affected CYP3A4; hence, some products have the capacity to affect drug safety. CYP3A4, CYP3A5, CYP3A7, and CYP19 (aromatase) inhibition to the log concentration of beta-acid content was significant with r(2) > 0.37, suggesting that these components can account for some of the variation in inhibition of CYP metabolism.

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

    Science.gov (United States)

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

    2015-04-01

    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 beneficial effects of aerobic exercise on NAFLD. We searched articles in English on the role of aerobic exercise in NAFLD therapy in PubMed. The mechanisms of chronic aerobic exercise in regulating the outcome of NAFLD include: (i) reducing intrahepatic fat content by down-regulating sterol regulatory element-binding protein-1c and up-regulating peroxisome proliferator-activated receptor gamma expression levels; (ii) decreasing hepatic oxidative stress through modulating the reactive oxygen species, and enhancing antioxidant enzymes such as catalase and glutathione peroxidase; (iii) ameliorating hepatic inflammation via the inhibition of pro-inflammatory mediators 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. Aerobic exercise, via different mechanisms, significantly decreases the fat content of the liver and improves the outcomes of patients with NAFLD.

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

    Directory of Open Access Journals (Sweden)

    Mkael Symmonds

    2010-06-01

    Full Text Available 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.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.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 this sensitivity in human risk-preference to current metabolic state has

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

    International Nuclear Information System (INIS)

    Welin, Martin; Nordlund, Paer

    2010-01-01

    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.

  3. Genetic alterations affecting cholesterol metabolism and human fertility.

    Science.gov (United States)

    DeAngelis, Anthony M; Roy-O'Reilly, Meaghan; Rodriguez, Annabelle

    2014-11-01

    Single nucleotide polymorphisms (SNPs) represent genetic variations among individuals in a population. In medicine, these small variations in the DNA sequence may significantly impact an individual's response to certain drugs or influence the risk of developing certain diseases. In the field of reproductive medicine, a significant amount of research has been devoted to identifying polymorphisms which may impact steroidogenesis and fertility. This review discusses current understanding of the effects of genetic variations in cholesterol metabolic pathways on human fertility that bridge novel linkages between cholesterol metabolism and reproductive health. For example, the role of the low-density lipoprotein receptor (LDLR) in cellular metabolism and human reproduction has been well studied, whereas there is now an emerging body of research on the role of the high-density lipoprotein (HDL) receptor scavenger receptor class B type I (SR-BI) in human lipid metabolism and female reproduction. Identifying and understanding how polymorphisms in the SCARB1 gene or other genes related to lipid metabolism impact human physiology is essential and will play a major role in the development of personalized medicine for improved diagnosis and treatment of infertility. © 2014 by the Society for the Study of Reproduction, Inc.

  4. 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.)

  5. 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%.

  6. Cranberry juice suppressed the diclofenac metabolism by human liver microsomes, but not in healthy human subjects

    Science.gov (United States)

    Ushijima, Kentarou; Tsuruoka, Shu-ichi; Tsuda, Hidetoshi; Hasegawa, Gohki; Obi, Yuri; Kaneda, Tae; Takahashi, Masaki; Maekawa, Tomohiro; Sasaki, Tomohiro; Koshimizu, Taka-aki; Fujimura, Akio

    2009-01-01

    AIM To investigate a potential interaction between cranberry juice and diclofenac, a substrate of CYP2C9. METHODS The inhibitory effect of cranberry juice on diclofenac metabolism was determined using human liver microsome assay. Subsequently, we performed a clinical trial in healthy human subjects to determine whether the repeated consumption of cranberry juice changed the diclofenac pharmacokinetics. RESULTS Cranberry juice significantly suppressed diclofenac metabolism by human liver microsomes. On the other hand, repeated consumption of cranberry juice did not influence the diclofenac pharmacokinetics in human subjects. CONCLUSIONS Cranberry juice inhibited diclofenac metabolism by human liver microsomes, but not in human subjects. Based on the present and previous findings, we think that although cranberry juice inhibits CYP2C9 activity in vitro, it does not change the pharmacokinetics of medications metabolized by CYP2C9 in clinical situations. PMID:19694738

  7. Metabolism of lipoproteins by human fetal hepatocytes

    International Nuclear Information System (INIS)

    Carr, B.R.

    1987-01-01

    The rate of clearance of lipoproteins from plasma appears to play a role in the development of atherogenesis. The liver may account for as much as two thirds of the removal of low-density lipoprotein and one third of the clearance of high-density lipoprotein in certain animal species and humans, mainly by receptor-mediated pathways. The purpose of the present investigation was to determine if human fetal hepatocytes maintained in vitro take up and degrade lipoproteins. We first determined that the maximal binding capacity of iodine 125-iodo-LDL was approximately 300 ng of low-density lipoprotein protein/mg of membrane protein and an apparent dissociation constant of approximately 60 micrograms low-density lipoprotein protein/ml in membranes prepared from human fetal liver. We found that the maximal uptake of [ 125 I]iodo-LDL and [ 125 I]iodo-HDL by fetal hepatocytes occurred after 12 hours of incubation. Low-density lipoprotein uptake preceded the appearance of degradation products by 4 hours, and thereafter the degradation of low-density lipoprotein increased linearly for at least 24 hours. In contrast, high-density lipoprotein was not degraded to any extent by fetal hepatocytes. [ 125 I]Iodo-LDL uptake and degradation were inhibited more than 75% by preincubation with low-density lipoprotein but not significantly by high-density lipoprotein, whereas [ 125 I]iodo-HDL uptake was inhibited 70% by preincubation with high-density lipoprotein but not by low-density lipoprotein. In summary, human fetal hepatocytes take up and degrade low-density lipoprotein by a receptor-mediated process similar to that described for human extrahepatic tissues

  8. 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 heating in all cities. Heat flux density from 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.

  9. Human Cytomegalovirus: Coordinating Cellular Stress, Signaling, and Metabolic Pathways.

    Science.gov (United States)

    Shenk, Thomas; Alwine, James C

    2014-11-01

    Viruses face a multitude of challenges when they infect a host cell. Cells have evolved innate defenses to protect against pathogens, and an infecting virus may induce a stress response that antagonizes viral replication. Further, the metabolic, oxidative, and cell cycle state may not be conducive to the viral infection. But viruses are fabulous manipulators, inducing host cells to use their own characteristic mechanisms and pathways to provide what the virus needs. This article centers on the manipulation of host cell metabolism by human cytomegalovirus (HCMV). We review the features of the metabolic program instituted by the virus, discuss the mechanisms underlying these dramatic metabolic changes, and consider how the altered program creates a synthetic milieu that favors efficient HCMV replication and spread.

  10. 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.

  11. 78 FR 37836 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2013-06-24

    ... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory... and Alcoholism Special Emphasis Panel; NIAAA Member Conflict Applications--Metabolism and Health...

  12. TXNIP regulates peripheral glucose metabolism in humans

    DEFF Research Database (Denmark)

    Parikh, Hemang; Carlsson, Emma; Chutkow, William A

    2007-01-01

    combined human insulin/glucose clamp physiological studies with genome-wide expression profiling to identify thioredoxin interacting protein (TXNIP) as a gene whose expression is powerfully suppressed by insulin yet stimulated by glucose. In healthy individuals, its expression was inversely correlated...... expression is consistently elevated in the muscle of prediabetics and diabetics, although in a panel of 4,450 Scandinavian individuals, we found no evidence for association between common genetic variation in the TXNIP gene and T2DM. CONCLUSIONS: TXNIP regulates both insulin-dependent and insulin......-independent pathways of glucose uptake in human skeletal muscle. Combined with recent studies that have implicated TXNIP in pancreatic beta-cell glucose toxicity, our data suggest that TXNIP might play a key role in defective glucose homeostasis preceding overt T2DM....

  13. Alcohol

    Science.gov (United States)

    ... created when grains, fruits, or vegetables are fermented . Fermentation is a process that uses yeast or bacteria to change the sugars in the food into alcohol. Fermentation is used to produce many necessary items — everything ...

  14. 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

    benzoxazinoids with abundant HBOA-Glc (219 nmol × μmol−1 of creatinine). The sulfate and glucuronide conjugates of 2-hydroxy-1,4-benzoxazin-3-one (HBOA) and 2,4-dihydroxy-1,4-benzoxazin-3-one (DIBOA) were detected in plasma and urine, indicating substantial phase II metabolism. Direct absorption of lactam......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...

  15. 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

  16. FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest

    DEFF Research Database (Denmark)

    Søberg, Susanna; Andersen, Emilie S; Dalgaard, Niels B

    2018-01-01

    . KLB encodes β-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active...... plasma FGF21 (FGF21 (1-181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain. METHODS: We recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1-181) measurement in plasma...... correlated fasting FGF21 (1-181) levels in 49 healthy, non-alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice. RESULTS: We show...

  17. Lipid metabolism in peroxisomes in relation to human disease

    NARCIS (Netherlands)

    Wanders, R. J.; Tager, J. M.

    1998-01-01

    Peroxisomes were long believed to play only a minor role in cellular metabolism but it is now clear that they catalyze a number of important functions. The importance of peroxisomes in humans is stressed by the existence of a group of genetic diseases in man in which one or more peroxisomal

  18. Human meniscal proteoglycan metabolism in long-term tissue culture

    NARCIS (Netherlands)

    Verbruggen, G.; Verdonk, R.; Veys, E. M.; van Daele, P.; de Smet, P.; van den Abbeele, K.; Claus, B.; Baeten, D.

    1996-01-01

    For the purpose of human meniscal allografting, menisci have been maintained viable in in vitro culture. The influence of long-term tissue culture on the extracellular matrix metabolism of the meniscus has been studied. Fetal calf serum (FCS) was used as a supplement for the growth factors necessary

  19. [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. To determine if there are significant differences between metabolic parameters of non-alcoholic fatty liver in controlled versus uncontrolled diabetes type 2 of recent diagnosis. retrospective case-control study, performed in the Hospital Guillermo Almenara Irigoyen, Lima, Peru from November 2014 to February 2015.This study included 231 patients: 147 patients (NASH with DM2 of recent diagnosis and poor control) and 84 patients (NASH with DM2 ofrecent diagnosis and adequate control). Levene test for evaluating homogeneity of variances intra groups and parametric test for independent samples. After applying Levene test of homogeneity and student test, significant metabolic parameters were the triglycerides, HbA1C level, metformin dose and gender. It is important in diabetic patients to diagnose NASH early for a tighter control, not only of glucose but other metabolic parameters mainly triglycerides which strongly supports existing concept of "multiple hits" which considers NASH affects glucose homeostasis, and it could be the starting point of new research to improve interventions for decreasing progression from to cirrhosis in diabetic patients and also to delay progression of diabetes mellitus in patients with non alcoholic steatohepatitis.

  20. 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.

  1. Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome.

    Science.gov (United States)

    Kargiotis, Konstantinos; Athyros, Vasilios G; Giouleme, Olga; Katsiki, Niki; Katsiki, Evangelia; Anagnostis, Panagiotis; Boutari, Chrysoula; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

    2015-07-07

    To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20(th), which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3(rd) treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6(th) treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3(rd) treatment month. No patient had MetS by the 9(th) treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should

  2. Effect of saccharin on metabolic cooperation between human fibroblasts

    International Nuclear Information System (INIS)

    Mosser, D.D.; Bols, N.C.

    1983-01-01

    Autoradiography was used to study the effect of saccharin on metabolic cooperation between human diploid fibroblasts. When the donors, HGPRT+ cells, and recipients, HGPRT- cells, were plated together in the presence of saccharin, all the interactions that developed in 4 and 24 h were positive for metabolic cooperation. When saccharin was added after donor cells and recipient cells had made contact, the proportion of interactions that were positive for metabolic cooperation was unchanged but the number of grains over primary recipients was reduced. However, in donor cells saccharin caused a reduction in [ 3 H]hypoxanthine incorporation into both acid-soluble and acid-insoluble fractions, although the relative distribution of radioactivity between these two fractions and between the phosphorylated and non-phosphorylated derivatives of [ 3 H]hypoxanthine was unchanged. Metabolic cooperation was studied under conditions in which the number of grains over the nuclei of both the primary recipient and the primary recipient's donor could be counted. The change in the number of grains over these two cell types in response to saccharin was compared and found to be the same. Thus in normal human fibroblasts saccharin does not appear to affect metabolic cooperation, which is a measure of cell-to-cell communication

  3. 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.

  4. Carbon Source-Dependent Inducible Metabolism of Veratryl Alcohol and Ferulic Acid in Pseudomonas putida CSV86

    Science.gov (United States)

    Mohan, Karishma

    2017-01-01

    ABSTRACT Pseudomonas putida CSV86 degrades lignin-derived metabolic intermediates, viz., veratryl alcohol, ferulic acid, vanillin, and vanillic acid, as the sole sources of carbon and energy. Strain CSV86 also degraded lignin sulfonate. Cell respiration, enzyme activity, biotransformation, and high-pressure liquid chromatography (HPLC) analyses suggest that veratryl alcohol and ferulic acid are metabolized to vanillic acid by two distinct carbon source-dependent inducible pathways. Vanillic acid was further metabolized to protocatechuic acid and entered the central carbon pathway via the β-ketoadipate route after ortho ring cleavage. Genes encoding putative enzymes involved in the degradation were found to be present at fer, ver, and van loci. The transcriptional analysis suggests a carbon source-dependent cotranscription of these loci, substantiating the metabolic studies. Biochemical and quantitative real-time (qRT)-PCR studies revealed the presence of two distinct O-demethylases, viz., VerAB and VanAB, involved in the oxidative demethylation of veratric acid and vanillic acid, respectively. This report describes the various steps involved in metabolizing lignin-derived aromatic compounds at the biochemical level and identifies the genes involved in degrading veratric acid and the arrangement of phenylpropanoid metabolic genes as three distinct inducible transcription units/operons. This study provides insight into the bacterial degradation of lignin-derived aromatics and the potential of P. putida CSV86 as a suitable candidate for producing valuable products. IMPORTANCE Pseudomonas putida CSV86 metabolizes lignin and its metabolic intermediates as a carbon source. Strain CSV86 displays a unique property of preferential utilization of aromatics, including for phenylpropanoids over glucose. This report unravels veratryl alcohol metabolism and genes encoding veratric acid O-demethylase, hitherto unknown in pseudomonads, thereby providing new insight into the

  5. Blockade of alcohol's amnestic activity in humans by an alpha5 subtype benzodiazepine receptor inverse agonist.

    Science.gov (United States)

    Nutt, David J; Besson, Marie; Wilson, Susan J; Dawson, Gerard R; Lingford-Hughes, Anne R

    2007-12-01

    Alcohol produces many subjective and objective effects in man including pleasure, sedation, anxiolysis, plus impaired eye movements and memory. In human volunteers we have used a newly available GABA-A/benzodiazepine receptor inverse agonist that is selective for the alpha5 subtype (a5IA) to evaluate the role of this subtype in mediating these effects of alcohol on the brain. After pre-treatment with a5IA, we found almost complete blockade of the marked impairment caused by alcohol (mean breath concentration 150mg/100ml) of word list learning and partial but non-significant reversal of subjective sedation without effects on other measures such as intoxication, liking, and slowing of eye movements. This action was not due to alterations in alcohol kinetics and so provides the first proof of concept that selectively decreasing GABA-A receptor function at a specific receptor subtype can offset some actions of alcohol in humans. It also supports growing evidence for a key role of the alpha5 subtype in memory. Inverse agonists at other GABA-A receptor subtypes may prove able to reverse other actions of alcohol, and so offer a new approach to understanding the actions of alcohol in the human brain and in the treatment of alcohol related disorders in humans.

  6. 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.

  7. Thinking After Drinking: Impaired Hippocampal Dependent Cognition in Human Alcoholics and Animal Models of Alcohol Dependence

    Directory of Open Access Journals (Sweden)

    Miranda Staples

    2016-09-01

    Full Text Available Alcohol use disorder currently affects approximately 18 million Americans, with at least half of these individuals having significant cognitive impairments subsequent to their chronic alcohol use. This is most widely apparent as frontal cortex dependent cognitive dysfunction, where executive function and decision making are severely compromised, as well as hippocampus dependent cognitive dysfunction, where contextual and temporal reasoning are negatively impacted. This review discusses the relevant clinical literature to support the theory that cognitive recovery in tasks dependent on the prefrontal cortex and hippocampus is temporally different across extended periods of abstinence from alcohol. Additional studies from preclinical models are discussed to support clinical findings. Finally, the unique cellular composition of the hippocampus and cognitive impairment dependent on the hippocampus is highlighted in the context of alcohol dependence.

  8. Clinical and metabolic effects associated with weight changes and obeticholic acid in non-alcoholic steatohepatitis.

    Science.gov (United States)

    Hameed, B; Terrault, N A; Gill, R M; Loomba, R; Chalasani, N; Hoofnagle, J H; Van Natta, M L

    2018-03-01

    In a 72-week, randomised controlled trial of obeticholic acid (OCA) in non-alcoholic steatohepatitis (NASH), OCA was superior to placebo in improving serum ALT levels and liver histology. OCA therapy also reduced weight. Because weight loss by itself can improve histology, to perform a post hoc analysis of the effects of weight loss and OCA treatment in improving clinical and metabolic features of NASH. The analysis was limited to the 200 patients with baseline and end-of-treatment liver biopsies. Weight loss was defined as a relative decline from baseline of 2% or more at treatment end. Weight loss occurred in 44% (45/102) of OCA and 32% (31/98) of placebo-treated patients (P = 0.08). The NAFLD Activity score (NAS) improved more in those with than without weight loss in both the OCA- (-2.4 vs -1.2, POCA- (-43 vs -34 U/L, P = 0.12) and placebo-treated patients (-29 vs -10 U/L, P = 0.02). However, among those who lost weight, OCA was associated with opposite effects from placebo on changes in alkaline phosphatase (+21 vs -12 U/L, POCA leads to weight loss in up to 44% of patients with NASH, and OCA therapy and weight loss have additive benefits on serum aminotransferases and histology. However, favourable effects of weight loss on alkaline phosphatase, lipids and blood glucose seen in placebo-treated patients were absent or reversed on OCA treatment. These findings stress the importance of assessing concomitant metabolic effects of new therapies of NASH. Clinical trial number: NCT01265498. © 2018 John Wiley & Sons Ltd.

  9. 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.

  10. 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...

  11. Non-alcoholic Fatty Liver Disease and Metabolic Syndrome in Hypopituitary Patients

    Science.gov (United States)

    Nyenwe, Ebenezer A; Williamson-Baddorf, Sarah; Waters, Bradford; Wan, Jim Y; Solomon, Solomon S.

    2009-01-01

    Background Increased incidence of cardiovascular mortality and non-alcoholic fatty liver disease (NAFLD) has been reported in hypopituitarism; but previous studies did not correct for obesity in these patients. Therefore it remained unclear if endocrine deficiency in hypopituitarism is associated with metabolic consequences independent of obesity. This study was designed to determine the burden of cardiovascular disease and NAFLD in hypopituitarism. Methods We performed a retrospective case-control analysis of hypopituitary patients at Veterans Affair Medical center, Memphis; from January 1997- June 2007. After matching for age, gender, obesity and race, relevant data were abstracted from the subjects' records to determine the presence of hypopituitarism, cardiovascular risk factors and fatty liver disease. Cases and controls were characterized by descriptive statistics, and compared using Chi-square and Student's t- tests. Results Hypopituitary patients exhibited higher prevalence of hypertension- 88% vs 78% (P0.3). Hypopituitary patients had higher elevations in serum aminotransferase levels and hyperbilirubinemia-24% vs 11% (Phypopituitarism. Although hypopituitary patients had higher prevalence of cardiovascular risk factors than controls, they were not disproportionately affected by cardiovascular disease. PMID:19745609

  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. Dietary Omega-3 Fatty Acid Deficiency and High Fructose Intake in the Development of Metabolic Syndrome, Brain Metabolic Abnormalities, and Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Artemis P. Simopoulos

    2013-07-01

    Full Text Available Western diets are characterized by both dietary omega-3 fatty acid deficiency and increased fructose intake. The latter found in high amounts in added sugars such as sucrose and high fructose corn syrup (HFCS. Both a low intake of omega-3 fatty acids or a high fructose intake contribute to metabolic syndrome, liver steatosis or non-alcoholic fatty liver disease (NAFLD, promote brain insulin resistance, and increase the vulnerability to cognitive dysfunction. Insulin resistance is the core perturbation of metabolic syndrome. Multiple cognitive domains are affected by metabolic syndrome in adults and in obese adolescents, with volume losses in the hippocampus and frontal lobe, affecting executive function. Fish oil supplementation maintains proper insulin signaling in the brain, ameliorates NAFLD and decreases the risk to metabolic syndrome suggesting that adequate levels of omega-3 fatty acids in the diet can cope with the metabolic challenges imposed by high fructose intake in Western diets which is of major public health importance. This review presents the current status of the mechanisms involved in the development of the metabolic syndrome, brain insulin resistance, and NAFLD a most promising area of research in Nutrition for the prevention of these conditions, chronic diseases, and improvement of Public Health.

  14. Respiratory compensation to a primary metabolic alkalosis in humans.

    Science.gov (United States)

    Feldman, Mark; Alvarez, Naiara M; Trevino, Michael; Weinstein, Gary L

    2012-11-01

    There is limited and disparate information about the extent of the respiratory compensation (hypoventilation) that occurs in response to a primary metabolic alkalosis in humans. Our aim was to examine the influence of the plasma bicarbonate concentration, the plasma base excess, and the arterial pH on the arterial carbon dioxide tension in 52 adult patients with primary metabolic alkalosis, mostly due to diuretic use or vomiting. Linear regression analysis was used to correlate degrees of alkalosis with arterial carbon dioxide tensions. In this alkalotic cohort, whose arterial plasma bicarbonate averaged 31.6 mEq/l, plasma base excess averaged 7.8 mEq/l, and pH averaged 7.48, both plasma bicarbonate and base excess correlated closely with arterial carbon dioxide tensions (r = 0.97 and 0.96, respectively; p respiratory compensation (hypoventilation) to primary metabolic alkalosis than has been reported in prior smaller studies.

  15. Alcohol

    Science.gov (United States)

    ... to do. Wondering if adding a glass of wine or beer might help lower your blood glucose if it is high? The effects of alcohol can be unpredictable and it is not recommended as a treatment for high blood glucose. The risks likely outweigh any benefit that may be seen in blood glucose alone. ...

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

    Science.gov (United States)

    Kekwaletswe, Connie T; Morojele, Neo K

    2014-01-01

    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. 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. 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 alcohol-focused adherence counseling program that employs motivational interviewing and cognitive behavioral therapy-type approaches. The association between alcohol use and ART nonadherence points to a need for alcohol-focused ART adherence

  17. Nonalcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Childhood: Endocrine-Metabolic “Mal-Programming”

    Science.gov (United States)

    Manti, Sara; Romano, Claudio; Chirico, Valeria; Filippelli, Martina; Cuppari, Caterina; Loddo, Italia; Salpietro, Carmelo; Arrigo, Teresa

    2014-01-01

    Context: Nonalcoholic Fatty Liver Disease (NAFLD) is the major chronic liver disease in the pediatric population. NAFLD includes a broad spectrum of abnormalities (inflammation, fibrosis and cirrhosis), ranging from accumulation of fat (also known as steatosis) towards non-alcoholic steatohepatitis (NASH). The development of NAFLD in children is significantly increased. Evidence Acquisition: A literature search of electronic databases was undertaken for the major studies published from 1998 to today. The databases searched were: PubMed, EMBASE, Orphanet, Midline and Cochrane Library. We used the key words: "non-alcoholic fatty liver disease, children, non-alcoholic steatohepatitis and fatty liver". Results: NAFLD/NASH is probably promoted by “multiple parallel hits”: environmental and genetic factors, systemic immunological disorders (oxidative stress, persistent-low grade of inflammation) as well as obesity and metabolic alterations (insulin resistance and metabolic syndrome). However its exact cause still underdiagnosed and unknown. Conclusions: Pediatric NAFLD/NASH is emerging problem. Longitudinal follow-up studies, unfortunately still insufficient, are needed to better understand the natural history and outcome of NAFLD in children. This review focuses on the current knowledge regarding the epidemiology, pathogenesis, environmental, genetic and metabolic factors of disease. The review also highlights the importance of studying the underlying mechanisms of pediatric NAFLD and the need for complete and personalized approach in the management of NAFLD/NASH. PMID:24829591

  18. A review of metabolic potential of human gut microbiome in human nutrition.

    Science.gov (United States)

    Yadav, Monika; Verma, Manoj Kumar; Chauhan, Nar Singh

    2018-03-01

    The human gut contains a plethora of microbes, providing a platform for metabolic interaction between the host and microbiota. Metabolites produced by the gut microbiota act as a link between gut microbiota and its host. These metabolites act as messengers having the capacity to alter the gut microbiota. Recent advances in the characterization of the gut microbiota and its symbiotic relationship with the host have provided a platform to decode metabolic interactions. The human gut microbiota, a crucial component for dietary metabolism, is shaped by the genetic, epigenetic and dietary factors. The metabolic potential of gut microbiota explains its significance in host health and diseases. The knowledge of interactions between microbiota and host metabolism, as well as modification of microbial ecology, is really beneficial to have effective therapeutic treatments for many diet-related diseases in near future. This review cumulates the information to map the role of human gut microbiota in dietary component metabolism, the role of gut microbes derived metabolites in human health and host-microbe metabolic interactions in health and diseases.

  19. Interconnectivity of human cellular metabolism and disease prevalence

    International Nuclear Information System (INIS)

    Lee, Deok-Sun

    2010-01-01

    Fluctuations of metabolic reaction fluxes may cause abnormal concentrations of toxic or essential metabolites, possibly leading to metabolic diseases. The mutual binding of enzymatic proteins and ones involving common metabolites enforces distinct coupled reactions, by which local perturbations may spread through the cellular network. Such network effects at the molecular interaction level in human cellular metabolism can reappear in the patterns of disease occurrence. Here we construct the enzyme-reaction network and the metabolite-reaction network, capturing the flux coupling of metabolic reactions caused by the interacting enzymes and the shared metabolites, respectively. Diseases potentially caused by the failure of individual metabolic reactions can be identified by using the known disease–gene association, which allows us to derive the probability of an inactivated reaction causing diseases from the disease records at the population level. We find that the greater the number of proteins that catalyze a reaction, the higher the mean prevalence of its associated diseases. Moreover, the number of connected reactions and the mean size of the avalanches in the networks constructed are also shown to be positively correlated with the disease prevalence. These findings illuminate the impact of the cellular network topology on disease development, suggesting that the global organization of the molecular interaction network should be understood to assist in disease diagnosis, treatment, and drug discovery

  20. Interconnectivity of human cellular metabolism and disease prevalence

    Science.gov (United States)

    Lee, Deok-Sun

    2010-12-01

    Fluctuations of metabolic reaction fluxes may cause abnormal concentrations of toxic or essential metabolites, possibly leading to metabolic diseases. The mutual binding of enzymatic proteins and ones involving common metabolites enforces distinct coupled reactions, by which local perturbations may spread through the cellular network. Such network effects at the molecular interaction level in human cellular metabolism can reappear in the patterns of disease occurrence. Here we construct the enzyme-reaction network and the metabolite-reaction network, capturing the flux coupling of metabolic reactions caused by the interacting enzymes and the shared metabolites, respectively. Diseases potentially caused by the failure of individual metabolic reactions can be identified by using the known disease-gene association, which allows us to derive the probability of an inactivated reaction causing diseases from the disease records at the population level. We find that the greater the number of proteins that catalyze a reaction, the higher the mean prevalence of its associated diseases. Moreover, the number of connected reactions and the mean size of the avalanches in the networks constructed are also shown to be positively correlated with the disease prevalence. These findings illuminate the impact of the cellular network topology on disease development, suggesting that the global organization of the molecular interaction network should be understood to assist in disease diagnosis, treatment, and drug discovery.

  1. 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....

  2. Effect of Garden Cress Seeds Powder and Its Alcoholic Extract on the Metabolic Activity of CYP2D6 and CYP3A4

    Directory of Open Access Journals (Sweden)

    Fahad I. Al-Jenoobi

    2014-01-01

    Full Text Available The powder and alcoholic extract of dried seeds of garden cress were investigated for their effect on metabolic activity of CYP2D6 and CYP3A4 enzymes. In vitro and clinical studies were conducted on human liver microsomes and healthy human subjects, respectively. Dextromethorphan was used as a common marker for measuring metabolic activity of CYP2D6 and CYP3A4 enzymes. In in vitro studies, microsomes were incubated with NADPH in presence and absence of different concentrations of seeds extract. Clinical investigations were performed in two phases. In phase I, six healthy female volunteers were administered a single dose of dextromethorphan and in phase II volunteers were treated with seeds powder for seven days and dextromethorphan was administered with last dose. The O-demethylated and N-demethylated metabolites of dextromethorphan were measured as dextrorphan (DOR and 3-methoxymorphinan (3-MM, respectively. Observations suggested that garden cress inhibits the formation of DOR and 3-MM metabolites. This inhibition of metabolite level was attributed to the inhibition of CYP2D6 and CYP3A4 activity. Garden cress decreases the level of DOR and 3-MM in urine and significantly increases the urinary metabolic ratio of DEX/DOR and DEX/3-MM. The findings suggested that garden cress seeds powder and ethanolic extract have the potential to interact with CYP2D6 and CYP3A4 substrates.

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

    Science.gov (United States)

    Okaru, Alex O; Lachenmeier, Dirk W

    2017-03-11

    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.

  4. 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.

  5. Non-alcoholic fatty liver disease and metabolic syndrome in Brazilian middle-aged and older adults

    Directory of Open Access Journals (Sweden)

    Mauro Karnikowski

    Full Text Available CONTEXT AND OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD is a complex clinicopathological entity characterized by diffuse or focal fat accumulation in the hepatic parenchyma of patients who deny abusive alcohol consumption. This study aimed to assess idiopathic NAFLD in community-dwelling, middle-aged and older adults living in the Brazilian Federal District. Associations between NAFLD and components of metabolic syndrome and the whole syndrome were investigated. DESIGN AND SETTINGS: This was a cross-sectional study on 139 subjects aged 55 years or older. METHODS: NAFLD was diagnosed by means of clinical procedures, to exclude subjects with signs of liver disorders, abusive alcohol consumption and influence from hepatotoxic drugs. Phenotypes were graded based on ultrasound examination. Metabolic syndrome was defined using the NCEP ATP III criteria. Laboratory tests were performed to assist clinical examinations and define the syndrome. RESULTS NAFLD was present in 35.2% of the subjects. Taken together, the two most intense phenotypes correlated with increased serum fasting glucose, triglyceride and VLDL cholesterol levels. Metabolic syndrome was diagnosed in 25.9% of the sample. In addition to associating NAFLD with specific traits of metabolic syndrome, non-parametric analysis confirmed the existence of a relationship (p < 0.05 between the steatotic manifestation and the syndromic condition. CONCLUSION: Compared with the literature, this study reveals greater frequency of idiopathic NAFLD among Brazilian middle-aged and older adults than is described elsewhere. The findings also suggest that impaired glycemic metabolism coupled with increased fat delivery and/or sustained endogenous biosynthesis is the most likely physiopathogenic mechanisms underlying the onset of NAFLD in this population.

  6. Effect of alcohol on skin permeation and metabolism of an ester-type prodrug in Yucatan micropig skin.

    Science.gov (United States)

    Fujii, Makiko; Ohara, Rieko; Matsumi, Azusa; Ohura, Kayoko; Koizumi, Naoya; Imai, Teruko; Watanabe, Yoshiteru

    2017-11-15

    We studied the effect that three alcohols, ethanol (EA), propanol (PA), and isopropanol (IPA), have on the skin permeation of p-hydroxy benzoic acid methyl ester (HBM), a model ester-type prodrug. HBM was applied to Yucatan micropig skin in a saturated phosphate buffered solution with or without 10% alcohol, and HBM and related materials in receptor fluid and skin were determined with HPLC. In the absence of alcohol, p-hydroxy benzoic acid (HBA), a metabolite of HBM, permeated the skin the most. The three alcohols enhanced the penetration of HBM at almost the same extent. The addition of 10% EA or PA to the HBM solution led to trans-esterification into the ethyl ester or propyl ester of HBA, and these esters permeated skin as well as HBA and HBM did. In contrast, the addition of 10% IPA promoted very little trans-esterification. Both hydrolysis and trans-esterification in the skin S9 fraction were inhibited by BNPP, an inhibitor of carboxylesterase (CES). Western blot and native PAGE showed the abundant expression of CES in micropig skin. Both hydrolysis and trans-esterification was simultaneously catalyzed by CES during skin permeation. Our data indicate that the alcohol used in dermal drug preparations should be selected not only for its ability to enhance the solubility and permeation of the drug, but also for the effect on metabolism of the drug in the skin. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Differences in the subjective and motivational properties of alcohol across alcohol use severity: application of a novel translational human laboratory paradigm.

    Science.gov (United States)

    Bujarski, Spencer; Jentsch, J David; Roche, Daniel J O; Ramchandani, Vijay A; Miotto, Karen; Ray, Lara A

    2018-05-08

    The Allostatic Model proposes that Alcohol Use Disorder (AUD) is associated with a transition in the motivational structure of alcohol drinking: from positive reinforcement in early-stage drinking to negative reinforcement in late-stage dependence. However, direct empirical support for this preclinical model from human experiments is limited. This study tests predictions derived from the Allostatic Model in humans. Specifically, this study tested whether alcohol use severity (1) independently predicts subjective responses to alcohol (SR; comprised of stimulation/hedonia, negative affect, sedation and craving domains), and alcohol self-administration and 2) moderates associations between domains of SR and alcohol self-administration. Heavy drinking participants ranging in severity of alcohol use and problems (N = 67) completed an intravenous alcohol administration paradigm combining an alcohol challenge (target BrAC = 60 mg%), with progressive ratio self-administration. Alcohol use severity was associated with greater baseline negative affect, sedation, and craving but did not predict changes in any SR domain during the alcohol challenge. Alcohol use severity also predicted greater self-administration. Craving during the alcohol challenge strongly predicted self-administration and sedation predicted lower self-administration. Neither stimulation, nor negative affect predicted self-administration. This study represents a novel approach to translating preclinical neuroscientific theories to the human laboratory. As expected, craving predicted self-administration and sedation was protective. Contrary to the predictions of the Allostatic Model, however, these results were inconsistent with a transition from positively to negatively reinforced alcohol consumption in severe AUD. Future studies that assess negative reinforcement in the context of an acute stressor are warranted.

  8. 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.

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

    DEFF Research Database (Denmark)

    Boushel, Robert Christopher

    2003-01-01

    that combined blockade of NOS and PGI2, and NOS and cytochrome P450, both attenuate exercise-induced hyperemia in humans. Combined vasodilator blockade studies offer the potential to uncover important interactions and compensatory vasodilator responses. The signaling pathways that link metabolic events evoked...... to exert control of muscle vasodilation. Adenosine, nitric oxide (NO), prostacyclin (PGI2), and endothelial-derived hyperpolarization factor (EDHF) are possible mediators of muscle vasodilation during exercise. In humans, adenosine has been shown to contribute to functional hyperemia as blood flow...... by muscle contraction to vasodilatory signals in the local vascular bed remains an important area of study....

  10. Reconstruction of genome-scale human metabolic models using omics data

    DEFF Research Database (Denmark)

    Ryu, Jae Yong; Kim, Hyun Uk; Lee, Sang Yup

    2015-01-01

    used to describe metabolic phenotypes of healthy and diseased human tissues and cells, and to predict therapeutic targets. Here we review recent trends in genome-scale human metabolic modeling, including various generic and tissue/cell type-specific human metabolic models developed to date, and methods......, databases and platforms used to construct them. For generic human metabolic models, we pay attention to Recon 2 and HMR 2.0 with emphasis on data sources used to construct them. Draft and high-quality tissue/cell type-specific human metabolic models have been generated using these generic human metabolic...... refined through gap filling, reaction directionality assignment and the subcellular localization of metabolic reactions. We review relevant tools for this model refinement procedure as well. Finally, we suggest the direction of further studies on reconstructing an improved human metabolic model....

  11. Systems biology of human metabolism - Defining the epithelial to mesenchymal transition and the activity of human gluconokinase

    OpenAIRE

    Rohatgi, Neha

    2016-01-01

    Studying human metabolism is crucial for the understanding of diseases and improvement of therapy as metabolic alterations are central to a number of human diseases. A variety of experimental disciplines, such as biochemistry, biophysics and systems biology are involved in the elucidation of metabolic pathways. The work presented in this thesis is divided into three main studies, which expand the knowledge of human metabolism using systems biology and biochemical techniques....

  12. Clinical and Metabolic Characterization of Lean Caucasian Subjects With Non-alcoholic Fatty Liver.

    Science.gov (United States)

    Feldman, Alexandra; Eder, Sebastian K; Felder, Thomas K; Kedenko, Lyudmyla; Paulweber, Bernhard; Stadlmayr, Andreas; Huber-Schönauer, Ursula; Niederseer, David; Stickel, Felix; Auer, Simon; Haschke-Becher, Elisabeth; Patsch, Wolfgang; Datz, Christian; Aigner, Elmar

    2017-01-01

    Non-alcoholic fatty liver disease (NAFLD) is closely linked to obesity; however, 5-8% of lean subjects also have evidence of NAFLD. We aimed to investigate clinical, genetic, metabolic and lifestyle characteristics in lean Caucasian subjects with NAFLD. Data from 187 subjects allocated to one of the three groups according to body mass index (BMI) and hepatic steatosis on ultrasound were obtained: lean healthy (BMI≤25 kg/m 2 , no steatosis, N=71), lean NAFLD (BMI≤25 kg/m 2 , steatosis, N=55), obese NAFLD (BMI≥30 kg/m 2 , steatosis; N=61). All subjects received a detailed clinical and laboratory examination including oral glucose tolerance test. The serum metabolome was assessed using the Metabolomics AbsoluteIDQ p180 kit (BIOCRATES Life Sciences). Genotyping for single-nucleotide polymorphisms (SNPs) associated with NAFLD was performed. Lean NAFLD subjects had fasting insulin concentrations similar to lean healthy subjects but had markedly impaired glucose tolerance. Lean NAFLD subjects had a higher rate of the mutant PNPLA3 CG/GG variant compared to lean controls (P=0.007). Serum adiponectin concentrations were decreased in both NAFLD groups compared to controls (Pphosphatidylcholines (PCaa C36:3; false discovery rate (FDR)-corrected P-value<0.001) as well as lysine, tyrosine, and valine (FDR<0.001). Lean subjects with evidence of NAFLD have clinically relevant impaired glucose tolerance, low adiponectin concentrations and a distinct metabolite profile with an increased rate of PNPLA3 risk allele carriage.

  13. 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.

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

    Science.gov (United States)

    Bjerregaard, Peter; Mikkelsen, Stine Schou; Becker, Ulrik; Hansen, Torben; Tolstrup, Janne S

    2014-11-01

    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. 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, ADH1C arg272gln, ALDH2 glu504lys, ALDH2 5'-UTR A-357G, ALDH1B1 ala86val and ALDH1B1 arg107leu. The allele distribution differed significantly between Inuit and the general population of Denmark. A protective effect on heavy drinking was found for the TT genotype of the ALDH1B1 arg107leu SNP (OR=0.59; 95% CI 0.37-0.92), present in 3% of pure Inuit and 37% of Danes. The ADH1C GG genotype was associated with heavy drinking and a positive CAGE test (OR 1.34; 95% CI 1.05-1.72). It was present in 27% of Inuit and 18% of Danes. The Asian genotype pattern with a high frequency of the ADH1B A allele and an ALDH2 gene coding for an inactive enzyme was not present in Greenland. 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 in Denmark deserves further study. This genotype was protective of heavy drinking among the Inuit. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  15. Constitutional and functional genetics of human alcohol-related hepatocellular carcinoma.

    Science.gov (United States)

    Nahon, Pierre; Nault, Jean-Charles

    2017-11-01

    Exploration of the constitutional genetics of hepatocellular carcinoma (HCC) has identified numerous variants associated with a higher risk of liver cancer in alcoholic cirrhotic patients. Although Genome-Wide Association studies have not been carried out in the field of alcohol-related HCC, common single nucleotide polymorphisms conferring a small increase in the risk of liver cancer risk have been identified and shown to modulate ethanol metabolism, inflammation, oxidative stress, iron or lipid metabolism. Specific patterns of gene mutations including CTNNB1, TERT, ARID1A and SMARCA2 exist in alcohol-related HCC. Moreover, a specific mutational process observed at the nucleotide level by next generation sequencing has revealed cooperation between alcohol and tobacco in the development of HCC. Combining this genetic information with epidemiological and clinical data that might define specific HCC risk classes and refine surveillance strategies needs to be assessed in large prospective cohorts of patients with alcoholic cirrhosis. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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

    DEFF Research Database (Denmark)

    Veenstra, Gauke; Sanderson, Hans; Webb, Catherine

    2009-01-01

    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...

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

    Science.gov (United States)

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

    2015-05-05

    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. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

  18. 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

  19. 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.

  20. 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

    2013-01-01

    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, type2 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. PMID:23560695

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

    Czech Academy of Sciences Publication Activity Database

    Tabakoff, B.; Saba, L.; Printz, M.; Flodman, P.; Hodgkinson, C.; Goldman, D.; Koob, G.; Richardson, H.N.; Kechris, K.; Bell, R.L.; Hübner, N.; Heinig, M.; Pravenec, Michal; Mangion, J.; Legault, L.; Dongier, M.; Conigrave, K.M.; Whitfield, J.B.; Saunders, J.; Grant, B.; Hoffman, P.L.

    2009-01-01

    Roč. 7, - (2009), s. 70-70 ISSN 1741-7007 R&D Projects: GA MŠk(CZ) 1M0520 Grant - others:Howard Hughes Medical Institute(US) 55005624 Institutional research plan: CEZ:AV0Z50110509 Keywords : alcohol consumption * rat * gene expression profiles Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.636, year: 2009

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

    Directory of Open Access Journals (Sweden)

    Swati Chaturvedi

    2016-01-01

    Full Text Available 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.

  3. The human NAD metabolome: Functions, metabolism and compartmentalization

    Science.gov (United States)

    Nikiforov, Andrey; Kulikova, Veronika; Ziegler, Mathias

    2015-01-01

    Abstract The metabolism of NAD has emerged as a key regulator of cellular and organismal homeostasis. Being a major component of both bioenergetic and signaling pathways, the molecule is ideally suited to regulate metabolism and major cellular events. In humans, NAD is synthesized from vitamin B3 precursors, most prominently from nicotinamide, which is the degradation product of all NAD-dependent signaling reactions. The scope of NAD-mediated regulatory processes is wide including enzyme regulation, control of gene expression and health span, DNA repair, cell cycle regulation and calcium signaling. In these processes, nicotinamide is cleaved from NAD+ and the remaining ADP-ribosyl moiety used to modify proteins (deacetylation by sirtuins or ADP-ribosylation) or to generate calcium-mobilizing agents such as cyclic ADP-ribose. This review will also emphasize the role of the intermediates in the NAD metabolome, their intra- and extra-cellular conversions and potential contributions to subcellular compartmentalization of NAD pools. PMID:25837229

  4. Hepatitis C, human immunodeficiency virus and metabolic syndrome: interactions.

    Science.gov (United States)

    Kotler, Donald P

    2009-03-01

    Significant concerns have been raised about the metabolic effects of antiretroviral medication, including the classic triad of dyslipidaemia, insulin resistance (IR) and characteristic alterations in fat distribution (lipoatrophy and lipohypertrophy). Co-infection with hepatitis C appears to exacerbate IR, reduce serum lipids and induce prothrombotic changes in the treated human immunodeficiency virus patient. The effects of co-infection are complex. While combination antiretroviral therapy has been shown to be associated with an increased risk of cardiovascular events through promotion of dyslipidaemia, IR and fat redistribution, co-infection exacerbates IR while reducing serum lipids. Co-infection also promotes a prothrombotic state characterized by endothelial dysfunction and platelet activation, which may enhance risk for cardiovascular disease. Consideration must be given to selection of appropriate treatment regimens and timing of therapy in co-infected patients to minimize metabolic derangements and, ultimately, reduce cardiovascular risk.

  5. An Overview of Novel Dietary Supplements and Food Ingredients in Patients with Metabolic Syndrome and Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Priscila Silva Figueiredo

    2018-04-01

    Full Text Available Metabolic syndrome (MetS is characterized by interconnected factors related to metabolic disturbances, and is directly related to the occurrence of some diseases such as cardiovascular diseases and type 2 diabetes. MetS is described as one or both of insulin resistance and visceral adiposity, considered the initial causes of abnormalities that include hyperglycemia, elevated blood pressure, dyslipidemia, elevated inflammatory markers, and prothrombotic state, as well as polycystic ovarian syndrome in women. Other than in MetS, visceral adiposity and the pro-inflammatory state are also key in the development of non-alcoholic fatty liver disease (NAFLD, which is the most prevalent chronic liver disease in modern society. Both MetS and NAFLD are related to diet and lifestyle, and their treatment may be influenced by dietary pattern changes and the use of certain dietary supplements. This study aimed to review the role of food ingredients and supplements in the management of MetS and NAFLD specifically in human clinical trials. Moreover, bioactive compounds and polyunsaturated fatty acids (PUFAs may be used as strategies for preventing the onset of and treatment of metabolic disorders, such as MetS and NAFLD, improving the inflammatory state and other comorbidities, such as obesity, dyslipidemias, and cardiovascular diseases (CVD.

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

    International Nuclear Information System (INIS)

    Arjomand, A; Bucholz, B A; Clifford, A J; Duecker, S R; Johnson, H; Schneider, P D; Zulim, R A.

    1999-01-01

    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 Hodgkins 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

  7. 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.

  8. Starmerella bombicola influences the metabolism of Saccharomyces cerevisiae at pyruvate decarboxylase and alcohol dehydrogenase level during mixed wine fermentation

    Science.gov (United States)

    2012-01-01

    Background The use of a multistarter fermentation process with Saccharomyces cerevisiae and non-Saccharomyces wine yeasts has been proposed to simulate natural must fermentation and to confer greater complexity and specificity to wine. In this context, the combined use of S. cerevisiae and immobilized Starmerella bombicola cells (formerly Candida stellata) was assayed to enhance glycerol concentration, reduce ethanol content and to improve the analytical composition of wine. In order to investigate yeast metabolic interaction during controlled mixed fermentation and to evaluate the influence of S. bombicola on S. cerevisiae, the gene expression and enzymatic activity of two key enzymes of the alcoholic fermentation pathway such as pyruvate decarboxylase (Pdc1) and alcohol dehydrogenase (Adh1) were studied. Results The presence of S. bombicola immobilized cells in a mixed fermentation trial confirmed an increase in fermentation rate, a combined consumption of glucose and fructose, an increase in glycerol and a reduction in the production of ethanol as well as a modification in the fermentation of by products. The alcoholic fermentation of S. cerevisiae was also influenced by S. bombicola immobilized cells. Indeed, Pdc1 activity in mixed fermentation was lower than that exhibited in pure culture while Adh1 activity showed an opposite behavior. The expression of both PDC1 and ADH1 genes was highly induced at the initial phase of fermentation. The expression level of PDC1 at the end of fermentation was much higher in pure culture while ADH1 level was similar in both pure and mixed fermentations. Conclusion In mixed fermentation, S. bombicola immobilized cells greatly affected the fermentation behavior of S. cerevisiae and the analytical composition of wine. The influence of S. bombicola on S. cerevisiae was not limited to a simple additive contribution. Indeed, its presence caused metabolic modifications during S. cerevisiae fermentation causing variation in the gene

  9. Starmerella bombicola influences the metabolism of Saccharomyces cerevisiae at pyruvate decarboxylase and alcohol dehydrogenase level during mixed wine fermentation

    Directory of Open Access Journals (Sweden)

    Milanovic Vesna

    2012-02-01

    Full Text Available Abstract Background The use of a multistarter fermentation process with Saccharomyces cerevisiae and non-Saccharomyces wine yeasts has been proposed to simulate natural must fermentation and to confer greater complexity and specificity to wine. In this context, the combined use of S. cerevisiae and immobilized Starmerella bombicola cells (formerly Candida stellata was assayed to enhance glycerol concentration, reduce ethanol content and to improve the analytical composition of wine. In order to investigate yeast metabolic interaction during controlled mixed fermentation and to evaluate the influence of S. bombicola on S. cerevisiae, the gene expression and enzymatic activity of two key enzymes of the alcoholic fermentation pathway such as pyruvate decarboxylase (Pdc1 and alcohol dehydrogenase (Adh1 were studied. Results The presence of S. bombicola immobilized cells in a mixed fermentation trial confirmed an increase in fermentation rate, a combined consumption of glucose and fructose, an increase in glycerol and a reduction in the production of ethanol as well as a modification in the fermentation of by products. The alcoholic fermentation of S. cerevisiae was also influenced by S. bombicola immobilized cells. Indeed, Pdc1 activity in mixed fermentation was lower than that exhibited in pure culture while Adh1 activity showed an opposite behavior. The expression of both PDC1 and ADH1 genes was highly induced at the initial phase of fermentation. The expression level of PDC1 at the end of fermentation was much higher in pure culture while ADH1 level was similar in both pure and mixed fermentations. Conclusion In mixed fermentation, S. bombicola immobilized cells greatly affected the fermentation behavior of S. cerevisiae and the analytical composition of wine. The influence of S. bombicola on S. cerevisiae was not limited to a simple additive contribution. Indeed, its presence caused metabolic modifications during S. cerevisiae fermentation

  10. Metabolism of gentiopicroside (gentiopicrin) by human intestinal bacteria.

    Science.gov (United States)

    el-Sedawy, A I; Hattori, M; Kobashi, K; Namba, T

    1989-09-01

    As a part of our studies on the metabolism of crude drug components by intestinal bacteria, gentiopicroside (a secoiridoid glucoside isolated from Gentiana lutea), was anaerobically incubated with various defined strains of human intestinal bacteria. Many species had ability to transform it to a series of metabolites. Among them, Veillonella parvula ss parvula produced five metabolites, which were identified as erythrocentaurin, gentiopicral, 5-hydroxymethylisochroman-1-one,5-hydroxymethylisochromen-1- one and trans-5,6-dihydro-5-hydroxymethyl-6-methyl-1H,3H-pyrano[3,4-c]pyra n-1-one.

  11. 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 ...... and obese participants. Our classifications based on variation in the gut microbiome identify subsets of individuals in the general white adult population who may be at increased risk of progressing to adiposity-associated co-morbidities....

  12. Alcohol, Methamphetamine, and Marijuana Exposure Have Distinct Effects on the Human Placenta.

    Science.gov (United States)

    Carter, R Colin; Wainwright, Helen; Molteno, Christopher D; Georgieff, Michael K; Dodge, Neil C; Warton, Fleur; Meintjes, Ernesta M; Jacobson, Joseph L; Jacobson, Sandra W

    2016-04-01

    Animal studies have demonstrated adverse effects of prenatal alcohol exposure on placental development, but few studies have examined these effects in humans. Little is known about effects of prenatal exposure to methamphetamine, marijuana, and cigarette smoking on placental development. Placentas were collected from 103 Cape Coloured (mixed ancestry) pregnant women recruited at their first antenatal clinic visit in Cape Town, South Africa. Sixty-six heavy drinkers and 37 nondrinkers were interviewed about their alcohol, cigarette smoking, and drug use at 3 antenatal visits. A senior pathologist, blinded to exposure status, performed comprehensive pathology examinations on each placenta using a standardized protocol. In multivariable regression models, effects of prenatal exposure were examined on placental size, structure, and presence of infections and meconium. Drinkers reported a binge pattern of heavy drinking, averaging 8.0 drinks/occasion across pregnancy on 1.4 d/wk. 79.6% smoked cigarettes; 22.3% used marijuana; and 17.5% used methamphetamine. Alcohol exposure was related to decreased placental weight and a smaller placenta-to-birthweight ratio. By contrast, methamphetamine was associated with larger placental weight and a larger placenta-to-birthweight ratio. Marijuana was also associated with larger placental weight. Alcohol exposure was associated with increased risk of placental hemorrhage. Prenatal alcohol, drug, and cigarette use were not associated with chorioamnionitis, villitis, deciduitis, or maternal vascular underperfusion. Alcohol and cigarette smoking were associated with a decreased risk of intrauterine passing of meconium, a sign of acute fetal stress and/or hypoxia; methamphetamine, with an increased risk. This is the first human study to show that alcohol, methamphetamine, and marijuana were associated with distinct patterns of pathology, suggesting different mechanisms mediating their effects on placental development. Given the growing

  13. The effects of chronic alcoholism on cell proliferation in the human brain.

    Science.gov (United States)

    Sutherland, G T; Sheahan, P J; Matthews, J; Dennis, C V P; Sheedy, D S; McCrossin, T; Curtis, M A; Kril, J J

    2013-09-01

    Neurogenesis continues in the human subventricular zone and to a lesser extent in the hippocampal subgranular zone throughout life. Subventricular zone-derived neuroblasts migrate to the olfactory bulb where survivors become integrated as interneurons and are postulated to contribute to odor discrimination. Adult neurogenesis is dysregulated in many neurological, neurovascular and neurodegenerative diseases. Alcohol abuse can result in a neurodegenerative condition called alcohol-related brain damage. Alcohol-related brain damage manifests clinically as cognitive dysfunction and the loss of smell sensation (hyposmia) and pathologically as generalized white matter atrophy and focal neuronal loss. The exact mechanism linking chronic alcohol intoxication with alcohol-related brain damage remains largely unknown but rodent models suggest that decreased neurogenesis is an important component. We investigated this idea by comparing proliferative events in the subventricular zone and olfactory bulb of a well-characterized cohort of 15 chronic alcoholics and 16 age-matched controls. In contrast to the findings in animal models there was no difference in the number of proliferative cell nuclear antigen-positive cells in the subventricular zone of alcoholics (mean±SD=28.7±20.0) and controls (27.6±18.9, p=1.0). There were also no differences in either the total (p=0.89) or proliferative cells (p=0.98) in the granular cell layer of the olfactory bulb. Our findings show that chronic alcohol consumption does not affect cell proliferation in the human SVZ or olfactory bulb. In fact only microglial proliferation could be demonstrated in the latter. Therefore neurogenic deficits are unlikely to contribute to hyposmia in chronic alcoholics. Copyright © 2013 Elsevier Inc. All rights reserved.

  14. Preliminary observation of dynamic changes in alcohol concentration in the human brain with proton magnetic resonance spectroscopy on a 3T MR instrument

    International Nuclear Information System (INIS)

    Kubo, Hitoshi; Harada, Masafumi; Sakama, Minoru; Otsuka, Hideki; Matsuda, Tsuyoshi

    2013-01-01

    Our purposes were to establish suitable conditions for proton magnetic resonance spectroscopy (MRS) to measure dynamic changes in alcohol concentration in the human brain, to evaluate these changes, and to compare the findings with data from analysis of breath vapor and blood samples. We evaluated 4 healthy volunteers (mean age 26.5 years; 3 males, one female) with no neurological findings. All studies were performed with 3-tesla clinical equipment using an 8-channel head coil. We applied our modified single-voxel point-resolved spectroscopy (PRESS) sequence. Continuous measurements of MRS, breath vapor, and blood samples were conducted before and after the subjects drank alcohol with a light meal. The obtained spectra were quantified by LCModel Ver. 6.1, and the accuracy of the MRS measurements was estimated using the estimated standard deviation expressed in percentage (% standard deviation (SD)) as a criterion. Alcohol peaks after drinking were clearly detected at 1.2 ppm for all durations of measurement. Good correlations between breath vapor or blood sample and MRS were found by sub-minute MRS measurement. The continuous measurement showed time-dependent changes in alcohol in the brain and various patterns that differed among subjects. The clinical 3 T equipment enables direct evaluation of sub-minute changes in alcohol metabolism in the human brain. (author)

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

    Science.gov (United States)

    Tvarijonaviciute, Asta; Ceron, Jose J; Holden, Shelley L; Cuthbertson, Daniel J; Biourge, Vincent; Morris, Penelope J; German, Alexander J

    2012-08-28

    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. Systolic blood pressure (P = 0.008), cholesterol (P = 0.003), triglyceride (P = 0.018), and fasting insulin (P disease associations and outcomes of weight loss.

  16. The effect of phorbols on metabolic cooperation between human fibroblasts

    International Nuclear Information System (INIS)

    Mosser, D.D.; Bols, N.C.

    1982-01-01

    Autoradiography has been used to study the effect of 12-O-tetradecanoylphorbol-13-acetate (TPA), 4-O-methyl TPA, and phorbol on metabolic cooperation between human diploid fibroblasts. When the donors, hypoxanthine-guanine phosphoribosyl transferase+ (HGPRT+) cells, and recipients, HGPRT- cells, were plated together in the presence of [ 3 H]hypoxanthine and either 4-O-methyl TPA or phorbol, nearly all interactions that developed in 4 h were positive for metabolic cooperation whereas when high concentrations of TPA were used, the number of positive interactions was significantly less than the control. If the phorbol analogs were added after the donors and recipients had made contact, the number of positive interactions was the same as the control in all cases. However, although primary recipients in the cultures that had been treated with phorbol had the same number of grains as those in the control, primary recipients in cultures that had been treated with TPA or high concentrations of 4-O-methyl TPA had significantly fewer grains than those in the control. TPA treatment for 4 h had no effect on total [ 3 H]hypoxanthine incorporation or incorporation into acid-soluble and acid-insoluble fractions. Thus, the effect of TPA on metabolic cooperation is interpreted as a reduction in the transfer of [ 3 H]nucleotides and is an indication of an interference with intercellular communication

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

    Directory of Open Access Journals (Sweden)

    Lu Chen

    Full Text Available 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

  18. Computer modelling of HT gas metabolism in humans

    International Nuclear Information System (INIS)

    Peterman, B.F.

    1982-01-01

    A mathematical model was developed to simulate the metabolism of HT gas in humans. The rate constants of the model were estimated by fitting the calculated curves to the experimental data by Pinson and Langham in 1957. The calculations suggest that the oxidation of HT gas (which probably occurs as a result of the enzymatic action of hydrogenase present in bacteria of human gut) occurs at a relatively low rate with a half-time of 10-12 hours. The inclusion of the dose due to the production of the HT oxidation product (HTO) in the soft tissues lowers the value of derived air concentration by about 50%. Furthermore the relationship between the concentration of HTO in urine and the dose to the lung from HT in the air in lungs is linear after short HT exposures, and hence HTO concentrations in urine can be used to estimate the upper limits on the lung dose from HT exposures. (author)

  19. Metabolism of dimethylnitrosamine and 1,2-dimethylhydrazine in cultured human bronchi

    DEFF Research Database (Denmark)

    Harris, Curtis C.; Autrup, Herman; Stoner, Gary D.

    1977-01-01

    The metabolic activation of several chemical classes of procarcinogens is being studied in cultured human bronchi. Previous studies have shown that carcinogenic polynuclear aromatic hydrocarbons are metabolically activated by the bronchial epithelium. In the study reported here, dimethylnitrosami...

  20. Enhanced motivation to alcohol in transgenic mice expressing human α-synuclein.

    Science.gov (United States)

    Rotermund, Carola; Reolon, Gustavo K; Leixner, Sarah; Boden, Cindy; Bilbao, Ainhoa; Kahle, Philipp J

    2017-11-01

    α-Synuclein (αSYN) is the neuropathological hallmark protein of Parkinson's disease (PD) and related neurodegenerative disorders. Moreover, the gene encoding αSYN (SNCA) is a major genetic contributor to PD. Interestingly, independent genome-wide association studies also identified SNCA as the most important candidate gene for alcoholism. Furthermore, single-nucleotide-polymorphisms have been associated with alcohol-craving behavior and alcohol-craving patients showed augmented αSYN expression in blood. To investigate the effect of αSYN on the addictive properties of chronic alcohol use, we examined consumption, motivation, and seeking responses induced by environmental stimuli and relapse behavior in transgenic mice expressing the human mutant [A30P]αSYN throughout the brain. The primary reinforcing effects of alcohol under operant self-administration conditions were increased, while consumption and the alcohol deprivation effect were not altered in the transgenic mice. The same mice were subjected to immunohistochemical measurements of immediate-early gene inductions in brain regions involved in addiction-related behaviors. Acute ethanol injection enhanced immunostaining for the phosphorylated form of cAMP response element binding protein in both amygdala and nucleus accumbens of αSYN transgenic mice, while in wild-type mice no effect was visible. However, at the same time, levels of cFos remain unchanged in both genotypes. These results provide experimental confirmation of SNCA as a candidate gene for alcoholism in addition to its known link to PD. © 2017 International Society for Neurochemistry.

  1. Norepinephrine metabolism in humans. Kinetic analysis and model

    International Nuclear Information System (INIS)

    Linares, O.A.; Jacquez, J.A.; Zech, L.A.; Smith, M.J.; Sanfield, J.A.; Morrow, L.A.; Rosen, S.G.; Halter, J.B.

    1987-01-01

    The present study was undertaken to quantify more precisely and to begin to address the problem of heterogeneity of the kinetics of distribution and metabolism of norepinephrine (NE) in humans, by using compartmental analysis. Steady-state NE specific activity in arterialized plasma during [ 3 H]NE infusion and postinfusion plasma disappearance of [ 3 H]NE were measured in eight healthy subjects in the supine and upright positions. Two exponentials were clearly identified in the plasma [ 3 H]NE disappearance curves of each subject studied in the supine (r = 0.94-1.00, all P less than 0.01) and upright (r = 0.90-0.98, all P less than 0.01) positions. A two-compartment model was the minimal model necessary to simultaneously describe the kinetics of NE in the supine and upright positions. The NE input rate into the extravascular compartment 2, estimated with the minimal model, increased with upright posture (1.87 +/- 0.08 vs. 3.25 +/- 0.2 micrograms/min per m2, P less than 0.001). Upright posture was associated with a fall in the volume of distribution of NE in compartment 1 (7.5 +/- 0.6 vs. 4.7 +/- 0.3 liters, P less than 0.001), and as a result of that, there was a fall in the metabolic clearance rate of NE from compartment 1 (1.80 +/- 0.11 vs. 1.21 +/- 0.08 liters/min per m2, P less than 0.001). We conclude that a two-compartment model is the minimal model that can accurately describe the kinetics of distribution and metabolism of NE in humans

  2. Strain-Specific Virolysis Patterns of Human Noroviruses in Response to Alcohols.

    Science.gov (United States)

    Park, Geun Woo; Collins, Nikail; Barclay, Leslie; Hu, Liya; Prasad, B V Venkataram; Lopman, Benjamin A; Vinjé, Jan

    2016-01-01

    Alcohol-based hand sanitizers are widely used to disinfect hands to prevent the spread of pathogens including noroviruses. Alcohols inactivate norovirus by destruction of the viral capsid, resulting in the leakage of viral RNA (virolysis). Since conflicting results have been reported on the susceptibility of human noroviruses against alcohols, we exposed a panel of 30 human norovirus strains (14 GI and 16 GII strains) to different concentrations (50%, 70%, 90%) of ethanol and isopropanol and tested the viral RNA titer by RT-qPCR. Viral RNA titers of 10 (71.4%), 14 (100%), 3 (21.4%) and 7 (50%) of the 14 GI strains were reduced by > 1 log10 RNA copies/ml after exposure to 70% and 90% ethanol, and 70% and 90% isopropanol, respectively. RNA titers of 6 of the 7 non-GII 4 strains remained unaffected after alcohol exposure. Compared to GII strains, GI strains were more susceptible to ethanol than to isopropanol. At 90%, both alcohols reduced RNA titers of 8 of the 9 GII.4 strains by ≥ 1 log10 RNA copies/ml. After exposure to 70% ethanol, RNA titers of GII.4 Den Haag and Sydney strains decreased by ≥ 1.9 log10, whereas RNA reductions for GII.4 New Orleans strains were alcohol susceptibility patterns between different norovirus genotypes vary widely and that virolysis data for a single strain or genotype are not representative for all noroviruses.

  3. 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...

  4. Clinical features of male patients with alcoholic liver cirrhosis or hepatitis B cirrhosis complicated by abnormal glucose metabolism

    Directory of Open Access Journals (Sweden)

    CHEN Qidan

    2016-02-01

    Full Text Available ObjectiveTo investigate the clinical features of male patients with alcoholic liver cirrhosis (ALC or hepatitis B cirrhosis (HBC complicated by abnormal glucose metabolism. MethodsA total of 287 patients with liver cirrhosis who were admitted to Guangzhou Panyu Central Hospital from January 2008 to September 2013 were selected. Among these patients, 74 had ALC and were all male, including 54 with abnormal glucose metabolism; the other 213 had HBC, including 97 with abnormal glucose metabolism (69 male patients and 28 female patients. A controlled study was performed for the clinical data of ALC and HBC patients with abnormal glucose metabolism, to investigate the association of patients′ clinical manifestations with the indices for laboratory examination, insulin resistance index, incidence rate of abnormal glucose metabolism, and Child-Pugh class. The t-test was applied for comparison of continuous data between groups, the chi-square test was applied for comparison of categorical data between groups, and the Spearman rank correlation was applied for correlation analysis. ResultsCompared with HBC patients, ALC patients had significantly higher incidence rates of abnormal glucose metabolism (730% vs 32.4%, hepatogenous diabetes (35.1% vs 14.6%, fasting hypoglycemia (27.0% vs 10.3%, and impaired glucose tolerance (31.1% vs 14.1% (χ2=4.371, 3.274, 4.784, and 1.633, all P<0.05. The Spearman correlation analysis showed that in ALC and HBC patients, the incidence rate of abnormal glucose metabolism was positively correlated with Child-Pugh class (rs=0.41, P<005. Compared with the HBC patients with abnormal glucose metabolism, the ALC patients with abnormal glucose metabolism had a significantly higher incidence rate of Child-Pugh class A (χ2=7.520, P=0.001, and a significantly lower incidence rate of Child-Pugh class C (χ2=6.542, P=0.003. There were significant differences in the incidence rates of dim complexion, telangiectasia of the

  5. Study of cerebral metabolism of glucose in normal human brain correlated with age

    International Nuclear Information System (INIS)

    Si, M.

    2007-01-01

    Full text: The objective was to determine whether cerebral metabolism in various regions of the brain differs with advancing age by using 18F-FDG PET instrument and SPM software. Materials and Methods We reviewed clinical information of 295 healthy normal samples who were examined by a whole body GE Discovery LS PET-CT instrument in our center from Aug. 2004 to Dec. 2005.They (with the age ranging from 21 to 88; mean age+/-SD: 49.77+/-13.51) were selected with: (i)absence of clear focal brain lesions (epilepsy.cerebrovascular diseases etc);(ii) absence of metabolic diseases, such as hyperthyroidism, hypothyroidism and diabetes;(iii) absence of psychiatric disorders and abuse of drugs and alcohol. They were sub grouped into six groups with the interval of 10 years old starting from 21, and the gender, educational background and serum glucose were matched. All subgroups were compared to the control group of 31-40 years old (84 samples; mean age+/-SD: 37.15+/-2.63). All samples were injected with 18F-FDG (5.55MBq/kg), 45-60 minutes later, their brains were scanned for 10min. Pixel-by-pixel t-statistic analysis was applied to all brain images using the Statistical parametric mapping (SPM2) .The hypometabolic areas (p < 0. 01 or p<0.001, uncorrected) were identified in the Stereotaxic coordinate human brain atlas and three-dimensional localized by MNI Space utility (MSU) software. Results:Relative hypometabolic brain areas detected are mainly in the cortical structures such as bilateral prefrontal cortex, superior temporal gyrus(BA22), parietal cortex (inferior parietal lobule and precuneus(BA40, insula(BA13)), parahippocampal gyrus and amygdala (p<0.01).It is especially apparent in the prefrontal cortex (BA9)and sensory-motor cortex(BA5, 7) (p<0.001), while basal ganglia and cerebellum remained metabolically unchanged with advancing age. Conclusions Regional cerebral metabolism of glucose shows a descent tendency with aging, especially in the prefrontal cortex (BA9)and

  6. Metabolism of aspartame by human and pig intestinal microvillar peptidases.

    Science.gov (United States)

    Hooper, N M; Hesp, R J; Tieku, S

    1994-01-01

    The artificial sweetener aspartame (N-L-alpha-aspartyl-L-phenyl-alanine-1-methyl ester; Nutrasweet), its decomposition product alpha Asp-Phe and the related peptide alpha Asp-PheNH2 were rapidly hydrolysed by microvillar membranes prepared from human duodenum, jejunum and ileum, and from pig duodenum and kidney. The metabolism of aspartame by the human and pig intestinal microvillar membrane preparations was inhibited significantly (> 78%) by amastatin or 1,10-phenanthroline, and partially (> 38%) by actinonin or bestatin, and was activated 2.9-4.5-fold by CaCl2. The inhibition by amastatin and 1,10-phenanthroline, and the activation by CaCl2 are characteristic of the cell-surface ectoenzyme aminopeptidase A (EC 3.4.11.7) and a purified preparation of this enzyme hydrolysed aspartame with a Km of 0.25 mM and a Vmax of 126 mumol/min per mg. A purified preparation of aminopeptidase W (EC 3.4.11.16) also hydrolysed aspartame but with a Km of 4.96 mM and a Vmax of 110 mumol/min per mg. However, rentiapril, an inhibitor of aminopeptidase W, caused only slight inhibition (maximally 19%) of the hydrolysis of aspartame by the microvillar membrane preparations. Similar patterns of inhibition and kinetic parameters were observed for alpha Asp-Phe and alpha Asp-PheNH2. Two other decomposition products of aspartame, beta Asp-PheMe and cyclo-Asp-Phe, were essentially resistant to hydrolysis by both the human and pig intestinal microvillar membrane preparations and the purified preparations of aminopeptidases A and W. Although the relatively selective inhibitor of aminopeptidase N (EC 3.4.11.2), actinonin, partially inhibited the metabolism of aspartame, alpha Asp-Phe and alpha Asp-PheNH2 by the human and pig intestinal microvillar membrane preparations, these peptides were not hydrolysed by a purified preparation of aminopeptidase N. Membrane dipeptidase (EC 3.4.13.19) only hydrolysed the unblocked dipeptide, alpha Asp-Phe, but the selective inhibitor of this enzyme, cilastatin

  7. Alcohol enhances oxysterol-induced apoptosis in human endothelial cells by a calcium-dependent mechanism.

    Science.gov (United States)

    Spyridopoulos, I; Wischhusen, J; Rabenstein, B; Mayer, P; Axel, D I; Fröhlich, K U; Karsch, K R

    2001-03-01

    Controversy exists about the net effect of alcohol on atherogenesis. A protective effect is assumed, especially from the tannins and phenolic compounds in red wine, owing to their inhibition of low density lipoprotein (LDL) oxidation. However, increased atherogenesis occurs in subjects with moderate to heavy drinking habits. The purpose of this study was to investigate the influence of alcohol in combination with oxysterols on the endothelium. Cultured human arterial endothelial cells (HAECs) served as an in vitro model to test the cellular effects of various oxysterols. Oxysterols (7beta-hydroxycholesterol, 7-ketocholesterol, and cholesterol-5,6-epoxides), which are assumed to be the most toxic constituents of oxidized LDL, induced apoptosis in HAECs through calcium mobilization followed by activation of caspase-3. Ethanol, methanol, isopropanol, tert-butanol, and red wine all potentiated oxysterol-induced cell death up to 5-fold, paralleled by further induction of caspase-3. The alcohol effect occurred in a dose-dependent manner and reached a plateau at 0.05% concentration. Alcohol itself did not affect endothelial cell viability, nor did other solvents such as dimethyl sulfoxide mimic the alcohol effect. So far as the physiologically occurring oxysterols are concerned, this effect was apparent only for oxysterols oxidized at the steran ring. The possibility of alcohol facilitating the uptake of oxysterols into the cell was not supported by the data from an uptake study with radiolabeled compounds. Finally, alcohol in combination with oxysterols did cause a dramatic increase in cytosolic calcium influx. Blockage of calcium influx by the calcium channel blocker aurintricarboxylic acid or the calcium chelator ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid abrogated the alcohol-mediated enhancement of oxysterol toxicity. We describe for the first time a mechanistic concept explaining possible adverse effects of alcohol in conjunction with

  8. Neuroimmune Pathways in Alcohol Consumption: Evidence from Behavioral and Genetic Studies in Rodents and Humans

    Science.gov (United States)

    Robinson, Gizelle; Most, Dana; Ferguson, Laura B.; Mayfield, Jody; Harris, R. Adron; Blednov, Yuri A.

    2014-01-01

    Immune or brain proinflammatory signaling has been linked to some of the behavioral effects of alcohol. Immune signaling appears to regulate voluntary ethanol intake in rodent models, and ethanol intake activates the immune system in multiple models. This bidirectional link raises the possibility that consumption increases immune signaling, which in turn further increases consumption in a feed-forward cycle. Data from animal and human studies provide overlapping support for the involvement of immune-related genes and proteins in alcohol action, and combining animal and human data is a promising approach to systematically evaluate and nominate relevant pathways. Based on rodent models, neuroimmune pathways may represent unexplored, nontraditional targets for medication development to reduce alcohol consumption and prevent relapse. Peroxisome proliferator-activated receptor agonists are one class of anti-inflammatory medications that demonstrate antiaddictive properties for alcohol and other drugs of abuse. Expression of immune-related genes is altered in animals and humans following chronic alcohol exposure, and the regulatory influences of specific mRNAs, microRNAs, and activated cell types are areas of intense study. Ultimately, the use of multiple datasets combined with behavioral validation will be needed to link specific neuroimmune pathways to addiction vulnerability. PMID:25175860

  9. Metabolism of 123I-FP-CIT in humans

    International Nuclear Information System (INIS)

    Tanaka, Akihiro; Okano, Kyoko; Tamagami, Hiroshi

    1999-01-01

    The metabolism of N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl)nortropane ( 123 I) ( 123 I-FP-CIT) in healthy humans was studied. Plasma and urine samples, obtained after i.v. administration of 123 I-FP-CIT, were analyzed using the two-dimensional thin-layer chromatography technique. Eleven radiochemical components were detected in both plasma and urine, and four of them were the parent 123 I-FP-CIT and its metabolites, N-(3-fluoropropyl)-2β-carboxy-3β-(4-iodophenyl)nortropane ( 123 I) ( 123 I-acid), 2β-carboxy-3β-(4-iodophenyl)nortropane ( 123 I) ( 123 I-nor-acid) and 2β-carbomethoxy-3β-(4-iodophenyl)nortropane ( 123 I) ( 123 I-nor-CIT). These four identified radiochemical components occupied about 80% or more in ratio of the radiochemical components in the plasma and urine. In the metabolites of 123 I-FP-CIT, the high polar metabolites- 123 I-acid and 123 I-nor-acid-were found to be the major components, while lipophilic 123 I-nor-CIT was a minor component. Free iodide ( 123 I - ) was not found in the plasma or urine. Thus, the main metabolic reactions which 123 I-FP-CIT undergoes in humans seem to be hydrolysis of the ester bond and N-dealkylation. In vivo deiodination of 123 I-FP-CIT was found to be minimum. Current results suggest that the metabolites of 123 I-FP-CIT hardly influence evaluation of the dopamine transporter in the human brain. (author)

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

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    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

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

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    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.

  12. Bacterial metabolism of human polymorphonuclear leukocyte-derived arachidonic acid.

    Science.gov (United States)

    Sorrell, T C; Muller, M; Sztelma, K

    1992-05-01

    Evidence for transcellular bacterial metabolism of phagocyte-derived arachidonic acid was sought by exposing human blood polymorphonuclear leukocytes, prelabelled with [3H]arachidonic acid, to opsonized, stationary-phase Pseudomonas aeruginosa (bacteria-to-phagocyte ratio of 50:1) for 90 min at 37 degrees C. Control leukocytes were stimulated with the calcium ionophore A23187 (5 microM) for 5 min. Radiochromatograms of arachidonic acid metabolites, extracted from A23187-stimulated cultures and then separated by reverse-phase high-performance liquid chromatography, revealed leukotriene B4, its omega-oxidation products, and 5-hydroxy-eicosatetraenoic acid. In contrast, two major metabolite peaks, distinct from known polymorphonuclear leukocyte arachidonic acid products by high-performance liquid chromatography or by thin-layer chromatography, were identified in cultures of P. aeruginosa with [3H]arachidonic acid-labelled polymorphonuclear leukocytes. Respective chromatographic characteristics of these novel products were identical to those of two major metabolite peaks produced by incubation of stationary-phase P. aeruginosa with [3H]arachidonic acid. Production of the metabolites was dependent upon pseudomonal viability. UV spectral data were consistent with a conjugated diene structure. Metabolism of arachidonic acid by P. aeruginosa was not influenced by the presence of catalase, superoxide dismutase, nordihydroguaiaretic acid, ethanol, dimethyl sulfoxide, or ferrous ions but was inhibited by carbon monoxide, ketoconazole, and 1,2-epoxy-3,3,3-trichloropropane. Our data suggest that pseudomonal metabolism of polymorphonuclear leukocyte-derived arachidonic acid occurs during phagocytosis, probably by enzymatic epoxidation and hydroxylation via an oxygenase. By this means, potential proinflammatory effects of arachidonic acid or its metabolites may be modulated by P. aeruginosa at sites of infection in vivo.

  13. Accumulation of Citrulline by Microbial Arginine Metabolism during Alcoholic Fermentation of Soy Sauce.

    Science.gov (United States)

    Fang, Fang; Zhang, Jiran; Zhou, Jingwen; Zhou, Zhaohui; Li, Tieqiao; Lu, Liling; Zeng, Weizhu; Du, Guocheng; Chen, Jian

    2018-03-07

    Citrulline, the major precursor of ethyl carbamate in soy sauce, is an intermediate catabolite of arginine produced by bacteria present in soy sauce moromi mash. Pediococcus acidilactici is responsible for the formation of citrulline during the lactic acid fermentation process of soy sauce. However, citrulline accumulation during the alcoholic fermentation process and the corresponding bacteria involved have not been identified. Salt-tolerant, arginine-utilizing bacteria were isolated from moromi mash during the alcoholic fermentation process. Under normal cultivation conditions, arginine utilization by these strains did not contribute to citrulline accumulation. However, the conversion of arginine to citrulline by these bacteria increased when cultivated during the alcoholic fermentation process. Additionally, the ethanol-enhanced solubility of free fatty acids in moromi mash stimulated the accumulation of citrulline. Staphylococcus exhibited the highest capability in the conversion of arginine to citrulline.

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

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    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. Age-dependent metabolic model of radionuclides in Human body

    International Nuclear Information System (INIS)

    Ye Changqing

    1986-01-01

    Age-dependent metabolic model of radionuclides in human body was introduced briefly. These data are necessary in setting up the secondary dose limit of internal exposure of the general public. For the gastro-intestinal tract model, it was shown that the dose of various sections of GI tract caused by unsoluble radioactive materials were influenced by the mass of section and mean residence time, both of which are age-dependent, but the absorption fraction f 1 through gastro-intestinal tract should be corrected only for the infant less than 1 year of age. For the lung model, it was indicated that the fraction of deposition or clearance of particles in the different compartments of lung were related to age. The doses of tracheobronchial and pulmonary compartment of adult for 222 Rn or 220 Rn with their decay products were one third of that of 6-years old child who received the maximum dose in comparison with other ages. The age-dependent metabolic models in organ and/or body of Tritium, Iodine-131, Caesium-137, radioactive Strontium, Radium and Plutonium were reported. A generalized approach for estimating the effect of age on deposition fractions and retention half-time were presented. Calculated results indicated that younger ages were characterized by increased deposition fraction and decreased half-time for retention. Representative examples were provided for 21 elements of current interest in health physics

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

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    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.

  17. 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.

  18. Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes.

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    Helen P McWilliams-Koeppen

    Full Text Available Light chain (AL amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(PH-dependent oxidoreductase, without causing significant cell death. The presence of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. These data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.

  19. Glucose metabolism in cultured trophoblasts from human placenta

    International Nuclear Information System (INIS)

    Moe, A.J.; Farmer, D.R.; Nelson, D.M.; Smith, C.H.

    1990-01-01

    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 14 C-labeled glucose and reactions were stopped by addition of perchloric acid. 14 CO 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 14 C in metabolic products compared to cells cultured on fibrin. Glucose oxidation to CO 2 by the phosphogluconate (PG) pathway was estimated from specific yields of 14 CO 2 from [1- 14 C]-D-glucose and [6- 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

  20. Human macrophage hemoglobin-iron metabolism in vitro

    International Nuclear Information System (INIS)

    Custer, G.; Balcerzak, S.; Rinehart, J.

    1982-01-01

    An entirely in vitro technique was employed to characterize hemoglobin-iron metabolism by human macrophages obtained by culture of blood monocytes and pulmonary alveolar macrophages. Macrophages phagocytized about three times as many erythrocytes as monocytes and six times as many erythrocytes as pulmonary alveolar macrophages. The rate of subsequent release of 59 Fe to the extracellular transferrin pool was two- to fourfold greater for macrophages as compared to the other two cell types. The kinetics of 59 Fe-transferrin release were characterized by a relatively rapid early phase (hours 1-4) followed by a slow phase (hours 4-72) for all three cell types. Intracellular movement of iron was characterized by a rapid shift from hemoglobin to ferritin that was complete with the onset of the slow phase of extracellular release. A transient increase in 59 Fe associated with an intracellular protein eluting with transferrin was also observed within 1 hour after phagocytosis. The process of hemoglobin-iron release to extracellular transferrin was inhibited at 4 degrees C but was unaffected by inhibitory of protein synthesis, glycolysis, microtubule function, and microfilament function. These data emphasize the rapidity of macrophage hemoglobin iron metabolism, provide a model for characterization of this process in vitro, and in general confirm data obtained utilizing in vivo animal models

  1. RAS signalling in energy metabolism and rare human diseases.

    Science.gov (United States)

    Dard, L; Bellance, N; Lacombe, D; Rossignol, R

    2018-05-08

    The RAS pathway is a highly conserved cascade of protein-protein interactions and phosphorylation that is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Recent findings indicate that the RAS pathway plays a role in the regulation of energy metabolism via the control of mitochondrial form and function but little is known on the participation of this effect in RAS-related rare human genetic diseases. Germline mutations that hyperactivate the RAS pathway have been discovered and linked to human developmental disorders that are known as RASopathies. Individuals with RASopathies, which are estimated to affect approximately 1/1000 human birth, share many overlapping characteristics, including cardiac malformations, short stature, neurocognitive impairment, craniofacial dysmorphy, cutaneous, musculoskeletal, and ocular abnormalities, hypotonia and a predisposition to developing cancer. Since the identification of the first RASopathy, type 1 neurofibromatosis (NF1), which is caused by the inactivation of neurofibromin 1, several other syndromes have been associated with mutations in the core components of the RAS-MAPK pathway. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), which was formerly called LEOPARD syndrome, Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). Here, we review current knowledge about the bioenergetics of the RASopathies and discuss the molecular control of energy homeostasis and mitochondrial physiology by the RAS pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

  2. Independent and supra-additive effects of alcohol consumption, cigarette smoking, and metabolic syndrome on the elevation of serum liver enzyme levels.

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    Eun Young Park

    Full Text Available We investigated the independent and combined effects of alcohol consumption, cigarette smoking and metabolic syndrome on abnormal liver function, i.e., the elevation of serum liver enzyme levels. Participants of a Korean population-based prospective cohort aged ≥30 years without liver disease, diabetes, or cardiovascular diseases were included. Information on alcohol consumption, smoking status, and metabolic syndrome, defined as per the criteria of the Adult Treatment Panel III, were applied to evaluate their impact on serum levels of aspartate aminotransferase (AST, alanine aminotransferase (ALT, and gamma-glutamyl transferase (GGT. Alcohol consumption, cigarette smoking and metabolic syndrome were the significant individual factors that elevated serum liver enzyme levels. Supra-additive effects of metabolic syndrome and either alcohol consumption or cigarette smoking were also identified. The combination of heavy drinking (≥24 g/day and metabolic syndrome conferred an effect that was higher than the sum of the two individual effects (Synergic Index (SI: AST, 2.37 [1.20-4.67]; GGT, 1.91 [1.17-3.13]. Only GGT level (odds ratio 6.04 [3.68-9.94], SI 2.33 [1.24-4.41] was significantly elevated when the effect of moderate drinking (20 pack years, 1.80 for ≥24 g/day and ≤20 pack years, 2.03 for ≥24 g/day and >20 pack years, while only the combined effect of drinking ≥24 g/day and smoking >20 pack years elevated the AST level (SI 4.55 [3.12-6.61]. The combined effect of cigarette smoking and metabolic syndrome was not supra-additive. To prevent fatty liver disease and other related diseases, a multifactorial prevention strategy that includes limited alcohol consumption, smoking cessation and rectification of adverse metabolic profiles is required.

  3. Aliphatic alcohol contaminants of illegally produced spirits inhibit phagocytosis by human granulocytes.

    Science.gov (United States)

    Pál, László; Árnyas, Ervin M; Tóth, Béla; Ádám, Balázs; Rácz, Gábor; Ádány, Róza; McKee, Martin; Szűcs, Sándor

    2013-04-01

    Unregulated production of spirits in many countries leads to products containing appreciable levels of aliphatic alcohols (AAs) and is the main source of human exposure to these substances worldwide. Previous studies have confirmed that alcohol abuse can lead to ethanol-induced immunosuppression and thereby increased susceptibility to infectious diseases. Granulocytes, as professional phagocytic cells, play a crucial role in engulfment and killing of pathogenic microorganisms. Thus, a decrease in their phagocytic activity has been invoked as a factor in the impaired antimicrobial defense observed in alcoholics. However, AAs consumed as contaminants of illicit spirits may also influence phagocytosis, thereby contributing to a further decrease in microbicidal activity but, so far, this has not been studied. Therefore, the aim of this study was to measure granulocyte phagocytosis following treatment of granulocytes with those higher alcohols found in illegal spirits. Granulocytes were isolated from human peripheral blood. Then phagocytosis of opsonized zymosan particles by granulocytes treated with AAs individually and in combination was determined. These alcohols inhibited phagocytosis in a concentration-dependent manner and at lower concentrations when combined than when tested individually. Due to their synergistic effects, it is possible that, in combination with ethanol, they may inhibit phagocytosis in a clinically meaningful way in episodic heavy drinkers.

  4. 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.

  5. On the Metabolism of Exogenous Ketones in Humans

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    Brianna J. Stubbs

    2017-10-01

    Full Text Available Background and aims: Currently there is considerable interest in ketone metabolism owing to recently reported benefits of ketosis for human health. Traditionally, ketosis has been achieved by following a high-fat, low-carbohydrate “ketogenic” diet, but adherence to such diets can be difficult. An alternative way to increase blood D-β-hydroxybutyrate (D-βHB concentrations is ketone drinks, but the metabolic effects of exogenous ketones are relatively unknown. Here, healthy human volunteers took part in three randomized metabolic studies of drinks containing a ketone ester (KE; (R-3-hydroxybutyl (R-3-hydroxybutyrate, or ketone salts (KS; sodium plus potassium βHB.Methods and Results: In the first study, 15 participants consumed KE or KS drinks that delivered ~12 or ~24 g of βHB. Both drinks elevated blood D-βHB concentrations (D-βHB Cmax: KE 2.8 mM, KS 1.0 mM, P < 0.001, which returned to baseline within 3–4 h. KS drinks were found to contain 50% of the L-βHB isoform, which remained elevated in blood for over 8 h, but was not detectable after 24 h. Urinary excretion of both D-βHB and L-βHB was <1.5% of the total βHB ingested and was in proportion to the blood AUC. D-βHB, but not L-βHB, was slowly converted to breath acetone. The KE drink decreased blood pH by 0.10 and the KS drink increased urinary pH from 5.7 to 8.5. In the second study, the effect of a meal before a KE drink on blood D-βHB concentrations was determined in 16 participants. Food lowered blood D-βHB Cmax by 33% (Fed 2.2 mM, Fasted 3.3 mM, P < 0.001, but did not alter acetoacetate or breath acetone concentrations. All ketone drinks lowered blood glucose, free fatty acid and triglyceride concentrations, and had similar effects on blood electrolytes, which remained normal. In the final study, participants were given KE over 9 h as three drinks (n = 12 or a continuous nasogastric infusion (n = 4 to maintain blood D-βHB concentrations greater than 1 mM. Both drinks

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

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    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.

  7. 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.

  8. GABAA receptor B subunit expression in the superior frontal cortex of human alcoholics

    International Nuclear Information System (INIS)

    Buckley, S.T.; Dodd, P.R.

    2001-01-01

    Full text: Changes in GABA A receptor pharmacology can be ascribed to alterations in expression of specific GABA A receptor subunits. Ethanol is known to be a potent agonist of the GABA A receptor. Chronic abuse of alcohol in humans results in damage of selective brain regions such as the superior frontal cortex (SFC), leading to neuronal cell loss. Studies in our laboratory 1 and elsewhere 2 have shown differences in expression of a number of GABA A receptor subunits in chronic human alcoholism. This suggests that alterations in GABA A receptor composition may be involved in the pathogenesis of alcoholic brain damage. We analysed the expression of the β 1 ,β 2 and β 3 isoforms of the GABA A receptor by a competitive reverse transcription polymerase chain reaction (RT-PCR) technique, which utilised an internal standard (IS) for quantitation. 35 S-dATP was incorporated to enable visualisation of the PCR products. Human brain tissue was obtained at autopsy and stored in 0.32 M sucrose at -80 deg C. Total RNA was extracted from pathologically susceptible and spared regions, SFC and motor cortex respectively,of 22 control and 22 alcoholic patients. 1 μg of total RNA from each sample was co-amplified with 0.5 pg of IS and a ratio determined. A standard consisting of known amounts of β 1 cRNA titrated against 0.5 pg of IS enabled a standard curve to be generated for quantitation of each unknown sample. The samples were subjected to polyacrylamide gel electrophoresis and the dried gel exposed to a phosphorimager screen. Data analysis was performed using the ImageQuant program. Initial results indicate that there is a reduction in expression of all the β transcripts in alcoholics when compared with controls, which supports the hypothesis that the GABA A receptor is altered by alcohol abuse. Supported by NHMRC. Copyright (2001) Australian Neuroscience Society

  9. Porphyrin metabolisms in human skin commensal Propionibacterium acnes bacteria: potential application to monitor human radiation risk.

    Science.gov (United States)

    Shu, M; Kuo, S; Wang, Y; Jiang, Y; Liu, Y-T; Gallo, R L; Huang, C-M

    2013-01-01

    Propionibacterium acnes (P. acnes), a Gram-positive anaerobic bacterium, is a commensal organism in human skin. Like human cells, the bacteria produce porphyrins, which exhibit fluorescence properties and make bacteria visible with a Wood's lamp. In this review, we compare the porphyrin biosynthesis in humans and P. acnes. Also, since P. acnes living on the surface of skin receive the same radiation exposure as humans, we envision that the changes in porphyrin profiles (the absorption spectra and/or metabolism) of P. acnes by radiation may mirror the response of human cells to radiation. The porphyrin profiles of P. acnes may be a more accurate reflection of radiation risk to the patient than other biodosimeters/biomarkers such as gene up-/down-regulation, which may be non-specific due to patient related factors such as autoimmune diseases. Lastly, we discuss the challenges and possible solutions for using the P. acnes response to predict the radiation risk.

  10. Metabolism of tributyltin and triphenyltin by rat, hamster and human hepatic microsomes

    Energy Technology Data Exchange (ETDEWEB)

    Ohhira, Shuji; Watanabe, Masatomo; Matsui, Hisao [Department of Hygiene, Dokkyo University School of Medicine, Mibu-machi, 321-0293, Tochigi (Japan)

    2003-03-01

    Tributyltin and triphenyltin are metabolized by cytochrome P-450 system enzymes, and their metabolic fate may contribute to the toxicity of the chemicals. In the current study, the in vitro metabolism of tributyltin and triphenyltin by rat, hamster and human hepatic microsomes was investigated to elucidate the metabolic competence for these compounds in humans. The metabolic reaction using microsome-NADPH system that is usually conducted was not applicable to in vitro metabolism of organotins, especially triphenyltin. We therefore examined the effects of dithiothreitol (DTT), one of the antioxidants for sulfhydryl groups, to determine the in vitro metabolism of tributyltin and triphenyltin. As a result, the treatment with 0.1 mM DTT in vitro increased the activity of the microsomal monooxygenase system for metabolism of tributyltin as well as triphenyltin; the total yield of tributyltin and triphenyltin metabolites as tin increased, respectively, by approximately 1.8 and 8.9 times for rat, 2.1 and 1.2 times for hamster, and 1.6 and 1.5 times for human. It is suggested that the organotins directly inactivate cytochrome P-450 because of the interaction with critical sulfhydryl groups of the hemoprotein. We confirmed the utility of this in vitro metabolic system using DTT in the hepatic microsomes of phenobarbital (PB)-pretreated and untreated hamsters. Thus, the in vitro metabolic system described here was applied to a comparative study of the metabolism of organotins in rats, hamsters and humans. Tributyltin was metabolized more readily than triphenyltin in all the species. In humans, the in vitro metabolic pattern resembled that of hamsters, which were susceptible to in vivo triphenyltin toxicity because of incompetent metabolism. It is possible that the hamster is a qualitatively and quantitatively suitable animal model for exploring the influence of tributyltin and triphenyltin in humans. (orig.)

  11. Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network

    OpenAIRE

    Mart?n-Jim?nez, Cynthia A.; Salazar-Barreto, Diego; Barreto, George E.; Gonz?lez, Janneth

    2017-01-01

    Astrocytes are the most abundant cells of the central nervous system; they have a predominant role in maintaining brain metabolism. In this sense, abnormal metabolic states have been found in different neuropathological diseases. Determination of metabolic states of astrocytes is difficult to model using current experimental approaches given the high number of reactions and metabolites present. Thus, genome-scale metabolic networks derived from transcriptomic data can be used as a framework t...

  12. 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.

  13. Metabolism of dietary fatty alcohol, fatty acid, and wax ester in carp

    International Nuclear Information System (INIS)

    Mankura, Mitsumasa; Kayama, Mitsu; Iijima, Noriaki.

    1987-01-01

    Lipids in various tissues of the carp, Cyprinus carpio were analyzed. The fates of force-fed [1- 14 C]palmitic acids, [1- 14 C]cetyl alcohol, and oleyl[1- 14 C]linoleate, were compared with those given in vitro experiments. Major lipid classes in all except adipose tissue were found to be polar lipids (phospholipids) and triacylglycerols. The major fatty acids in nearly all the tissues were 16 : 0, 18 : 1, 18 : 2, and 22 : 6. Although the radioactivity incorporation into wax esters from [1- 14 C]palmitic acid and [1- 14 C]cetyl alcohol for various tissue homogenates was quite high, in vivo incorporation of these labelled compounds into wax esters was very low and radioactivity was distributed mainly in the lipids of muscle, skin, hepatopancreas, intestine, and gill. Almost all the radioactivity in various tissues was present in phospatidylcholine and triacylglycerols. Most of the oleyl[1- 14 C]linoleate was easily hydrolyzed by various tissue homogenates. Force-fed oleyl[1- 14 C]linoleate was hydrolyzed in the intestine and then transported to other tissues, such as muscle, kin, gill, and hepatopancreas. Moreover, released radioactivity from oleyl[1- 14 C]linoleate was present in mainly phosphatidylcholine and triacylglycerols. Radioactivity was also detected in wax esters in plasma. Certain amounts for fatty acids released from [1- 14 C]triolein in the hepatopancreas homogenates were incorporated into wax esters; this was stimulated by the addition of oleyl alcohol. The present results indicate extensive hydrolysis of wax ester to possibly occur in the intestine and certain portions of the fatty alcohol moiety to be resterfied. The portions may be oxidized to fatty acids and which subsequently behave as dietary fatty acids. (author) 50 ref

  14. 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. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

  15. 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.

  16. Glucose Metabolism of Human Prostate Cancer Mouse Xenografts

    Directory of Open Access Journals (Sweden)

    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.

  17. Brain lactate metabolism in humans with subarachnoid hemorrhage.

    Science.gov (United States)

    Oddo, Mauro; Levine, Joshua M; Frangos, Suzanne; Maloney-Wilensky, Eileen; Carrera, Emmanuel; Daniel, Roy T; Levivier, Marc; Magistretti, Pierre J; LeRoux, Peter D

    2012-05-01

    Lactate is central for the regulation of brain metabolism and is an alternative substrate to glucose after injury. Brain lactate metabolism in patients with subarachnoid hemorrhage has not been fully elucidated. Thirty-one subarachnoid hemorrhage patients monitored with cerebral microdialysis (CMD) and brain oxygen (PbtO(2)) were studied. Samples with elevated CMD lactate (>4 mmol/L) were matched to PbtO(2) and CMD pyruvate and categorized as hypoxic (PbtO(2) 119 μmol/L) versus nonhyperglycolytic. Median per patient samples with elevated CMD lactate was 54% (interquartile range, 11%-80%). Lactate elevations were more often attributable to cerebral hyperglycolysis (78%; interquartile range, 5%-98%) than brain hypoxia (11%; interquartile range, 4%-75%). Mortality was associated with increased percentage of samples with elevated lactate and brain hypoxia (28% [interquartile range 9%-95%] in nonsurvivors versus 9% [interquartile range 3%-17%] in survivors; P=0.02) and lower percentage of elevated lactate and cerebral hyperglycolysis (13% [interquartile range, 1%-87%] versus 88% [interquartile range, 27%-99%]; P=0.07). Cerebral hyperglycolytic lactate production predicted good 6-month outcome (odds ratio for modified Rankin Scale score, 0-3 1.49; CI, 1.08-2.05; P=0.016), whereas increased lactate with brain hypoxia was associated with a reduced likelihood of good outcome (OR, 0.78; CI, 0.59-1.03; P=0.08). Brain lactate is frequently elevated in subarachnoid hemorrhage patients, predominantly because of hyperglycolysis rather than hypoxia. A pattern of increased cerebral hyperglycolytic lactate was associated with good long-term recovery. Our data suggest that lactate may be used as an aerobic substrate by the injured human brain.

  18. Comparison of the effect of fatty alcohols on the permeation of melatonin between porcine and human skin.

    Science.gov (United States)

    Andega, S; Kanikkannan, N; Singh, M

    2001-11-09

    Melatonin (MT) is a hormone secreted by the pineal gland that plays an important role in the regulation of the circadian sleep-wake cycle. It would be advantageous to administer MT using a transdermal delivery system for the treatment of sleep disorders such as delayed sleep syndrome, jet lag in travelers, cosmonauts and shift workers. The porcine skin has been found to have similar morphological and functional characteristics as human skin. The elastic fibres in the dermis, enzyme pattern of the epidermis, epidermal tissue turnover time, keratinous proteins and thickness of epidermis of porcine skin are similar to human skin. However, the fat deposition and vascularisation of the cutaneous glands of porcine skin are different from human skin. In addition, porcine skin has been found to have a close permeability character to human skin. However, the comparative effect of chemical penetration enhancers on the permeation of drugs between porcine and human skin has not been reported. The purpose of this study was to compare the effect of fatty alcohols on the permeability of porcine and human skin using MT as a model compound. The effect of saturated fatty alcohols (octanol, nonanol, decanol, undecanol, lauryl alcohol, tridecanol, myristyl alcohol) and unsaturated fatty alcohols (oleyl alcohol, linoleyl alcohol, linolenyl alcohol) at 5% concentration was tested across dermatomed porcine and human skin. Our studies showed a parabolic relationship between the carbon chain length of saturated fatty alcohols and permeation enhancement of MT with both porcine and human skin. Maximum permeation of MT was observed when fatty alcohol carbon chain length was 10. In general, as the level of unsaturation increased from one to two double bonds, there was an increase in the permeation of MT both in porcine and human skin. However, a decrease in the permeation was observed with three double bonds. Regression analysis using the steady state flux data showed a significant positive

  19. Family history of alcoholism and the human brain response to oral sucrose.

    Science.gov (United States)

    Eiler, William J A; Dzemidzic, Mario; Soeurt, Christina M; Carron, Claire R; Oberlin, Brandon G; Considine, Robert V; Harezlak, Jaroslaw; Kareken, David A

    2018-01-01

    A heightened hedonic response to sweet tastes has been associated with increased alcohol preference and alcohol consumption in both humans and animals. The principal goal of this study was to examine blood oxygenation level dependent (BOLD) activation to high- and low-concentration sweet solutions in subjects who are either positive (FHP) or negative (FHN) for a family history of alcoholism. Seventy-four non-treatment seeking, community-recruited, healthy volunteers (22.8 ± 1.6 SD years; 43% men) rated a range of sucrose concentrations in a taste test and underwent functional magnetic resonance imaging (fMRI) during oral delivery of water, 0.83 M, and 0.10 M sucrose. Sucrose compared to water produced robust activation in primary gustatory cortex, ventral insula, amygdala, and ventral striatum. FHP subjects displayed greater bilateral amygdala activation than FHN subjects in the low sucrose concentration (0.10 M). In secondary analyses, the right amygdala response to the 0.10 M sucrose was greatest in FHP women. When accounting for group differences in drinks per week, the family history groups remained significantly different in their right amygdala response to 0.10 M sucrose. Our findings suggest that the brain response to oral sucrose differs with a family history of alcoholism, and that this response to a mildly reinforcing primary reward might be an endophenotypic marker of alcoholism risk.

  20. Family history of alcoholism and the human brain response to oral sucrose

    Directory of Open Access Journals (Sweden)

    William J.A. Eiler, II

    2018-01-01

    Full Text Available A heightened hedonic response to sweet tastes has been associated with increased alcohol preference and alcohol consumption in both humans and animals. The principal goal of this study was to examine blood oxygenation level dependent (BOLD activation to high- and low-concentration sweet solutions in subjects who are either positive (FHP or negative (FHN for a family history of alcoholism. Seventy-four non-treatment seeking, community-recruited, healthy volunteers (22.8 ± 1.6 SD years; 43% men rated a range of sucrose concentrations in a taste test and underwent functional magnetic resonance imaging (fMRI during oral delivery of water, 0.83 M, and 0.10 M sucrose. Sucrose compared to water produced robust activation in primary gustatory cortex, ventral insula, amygdala, and ventral striatum. FHP subjects displayed greater bilateral amygdala activation than FHN subjects in the low sucrose concentration (0.10 M. In secondary analyses, the right amygdala response to the 0.10 M sucrose was greatest in FHP women. When accounting for group differences in drinks per week, the family history groups remained significantly different in their right amygdala response to 0.10 M sucrose. Our findings suggest that the brain response to oral sucrose differs with a family history of alcoholism, and that this response to a mildly reinforcing primary reward might be an endophenotypic marker of alcoholism risk.

  1. Chimeric mice with humanized liver: Application in drug metabolism and pharmacokinetics studies for drug discovery.

    Science.gov (United States)

    Naritomi, Yoichi; Sanoh, Seigo; Ohta, Shigeru

    2018-02-01

    Predicting human drug metabolism and pharmacokinetics (PK) is key to drug discovery. In particular, it is important to predict human PK, metabolite profiles and drug-drug interactions (DDIs). Various methods have been used for such predictions, including in vitro metabolic studies using human biological samples, such as hepatic microsomes and hepatocytes, and in vivo studies using experimental animals. However, prediction studies using these methods are often inconclusive due to discrepancies between in vitro and in vivo results, and interspecies differences in drug metabolism. Further, the prediction methods have changed from qualitative to quantitative to solve these issues. Chimeric mice with humanized liver have been developed, in which mouse liver cells are mostly replaced with human hepatocytes. Since human drug metabolizing enzymes are expressed in the liver of these mice, they are regarded as suitable models for mimicking the drug metabolism and PK observed in humans; therefore, these mice are useful for predicting human drug metabolism and PK. In this review, we discuss the current state, issues, and future directions of predicting human drug metabolism and PK using chimeric mice with humanized liver in drug discovery. Copyright © 2017 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

  2. Chimeric mice transplanted with human hepatocytes as a model for prediction of human drug metabolism and pharmacokinetics.

    Science.gov (United States)

    Sanoh, Seigo; Ohta, Shigeru

    2014-03-01

    Preclinical studies in animal models are used routinely during drug development, but species differences of pharmacokinetics (PK) between animals and humans have to be taken into account in interpreting the results. Human hepatocytes are also widely used to examine metabolic activities mediated by cytochrome P450 (P450) and other enzymes, but such in vitro metabolic studies also have limitations. Recently, chimeric mice with humanized liver (h-chimeric mice), generated by transplantation of human donor hepatocytes, have been developed as a model for the prediction of metabolism and PK in humans, using both in vitro and in vivo approaches. The expression of human-specific metabolic enzymes and metabolic activities was confirmed in humanized liver of h-chimeric mice with high replacement ratios, and several reports indicate that the profiles of P450 and non-P450 metabolism in these mice adequately reflect those in humans. Further, the combined use of h-chimeric mice and r-chimeric mice, in which endogenous hepatocytes are replaced with rat hepatocytes, is a promising approach for evaluation of species differences in drug metabolism. Recent work has shown that data obtained in h-chimeric mice enable the semi-quantitative prediction of not only metabolites, but also PK parameters, such as hepatic clearance, of drug candidates in humans, although some limitations remain because of differences in the metabolic activities, hepatic blood flow and liver structure between humans and mice. In addition, fresh h-hepatocytes can be isolated reproducibly from h-chimeric mice for metabolic studies. Copyright © 2013 John Wiley & Sons, Ltd.

  3. 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 study consumed a quantity of non-alcoholic 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.

  4. 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

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

    Science.gov (United States)

    Ley, Sylvia H; O'Connor, Deborah L; Retnakaran, Ravi; Hamilton, Jill K; Sermer, Mathew; Zinman, Bernard; Hanley, Anthony J

    2010-10-06

    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. 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. An improved understanding of the link between maternal metabolic abnormalities in pregnancy and early infant nutrition may assist in the development of optimal prevention and intervention

  6. MECHANISMS IN ENDOCRINOLOGY: The sexually dimorphic role of androgens in human metabolic disease.

    Science.gov (United States)

    Schiffer, Lina; Kempegowda, Punith; Arlt, Wiebke; O'Reilly, Michael W

    2017-09-01

    Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance. © 2017 The authors.

  7. 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

  8. Epstein–Barr Virus-Induced Metabolic Rearrangements in Human B-Cell Lymphomas

    Directory of Open Access Journals (Sweden)

    Pier P. Piccaluga

    2018-06-01

    Full Text Available Tumor metabolism has been the object of several studies in the past, leading to the pivotal observation of a consistent shift toward aerobic glycolysis (so-called Warburg effect. More recently, several additional investigations proved that tumor metabolism is profoundly affected during tumorigenesis, including glucose, lipid and amino-acid metabolism. It is noticeable that metabolic reprogramming can represent a suitable therapeutic target in many cancer types. Epstein–Barr virus (EBV was the first virus linked with cancer in humans when Burkitt lymphoma (BL was described. Besides other well-known effects, it was recently demonstrated that EBV can induce significant modification in cell metabolism, which may lead or contribute to neoplastic transformation of human cells. Similarly, virus-induced tumorigenesis is characterized by relevant metabolic abnormalities directly induced by the oncoviruses. In this article, the authors critically review the most recent literature concerning EBV-induced metabolism alterations in lymphomas.

  9. 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.

  10. A human dietary arachidonic acid supplementation study conducted in a metabolic research unit: rationale and design.

    Science.gov (United States)

    Nelson, G J; Kelley, D S; Emken, E A; Phinney, S D; Kyle, D; Ferretti, A

    1997-04-01

    While there are many reports of studies that fed arachidonic acid (AA) to animals, there are very few reports of AA feeding to humans under controlled conditions. This 130-d study was conceived as a controlled, symmetrical crossover design with healthy, adult male volunteers. They lived in the metabolic research unit (MRU) of the Western Human Nutrition Research (WHNRC) for the entire study. All food was prepared by the WHNRC kitchen. The basal (low-AA) diet consisted of natural foods (30 en% fat, 15 en% protein, and 55 en% carbohydrate), containing 210 mg/d of AA, and met the recommended daily allowance for all nutrients. The high-AA (intervention) diet was similar except that 1.5 g/d of AA in the form of a triglyceride containing 50% AA replaced an equal amount of high-oleic safflower oil in the basal diet. The subjects (ages 20 to 39) were within -10 to +20% of ideal body weight, nonsmoking, and not allowed alcohol in the MRU. Their exercise level was constant, and their body weights were maintained within 2% of entry level. Subjects were initially fed the low-AA diet for 15 d. On day 16, half of the subjects (group A) wee placed on the high-AA diet, and the other group (B) remained on the low-AA diets. On day 65, the two groups switched diets. On day 115, group B returned to the low-AA diet. This design, assuming no carryover effect, allowed us to merge the data from the two groups, with the data comparison days being 65 (low-AA) and 115 (high-AA) for group B and 130 (low-AA) and 65 (high-AA) for group A. The main indices studied were the fatty acid composition of the plasma, red blood cells, platelets, and adipose tissue; in vitro platelet aggregation, bleeding times, clotting factors; immune response as measured by delayed hypersensitivity skin tests, cellular proliferation of peripheral blood mononuclear cells in response to various mitogens and antigens, natural killer cell activity, and response to measles/mumps/rubella and influenza vaccines; the

  11. R-Limonene metabolism in humans and metabolite kinetics after oral administration.

    Science.gov (United States)

    Schmidt, Lukas; Göen, Thomas

    2017-03-01

    We studied the R-limonene (LMN) metabolism and elimination kinetics in a human in vivo study. Four volunteers were orally exposed to a single LMN dose of 100-130 µg kg -1 bw. In each case, one pre-exposure and subsequently all 24 h post-exposure urine samples were collected. From two subjects, blood samples were drawn up to 5 h after exposure. The parent compound was analysed in blood using headspace GC-MS. The metabolites cis- and trans-carveol (cCAR), perillyl alcohol (POH), perillic acid (PA), limonene-1,2-diol (LMN-1,2-OH), and limonene-8,9-diol (LMN-8,9-OH) were quantified in both blood and urine using GC-PCI-MS/MS. Moreover, GC-PCI-MS full-scan experiments were applied for identification of unknown metabolites in urine. In both matrices, metabolites reached maximum concentrations 1-2 h post-exposure followed by rapid elimination with half-lives of 0.7-2.5 h. In relation to the other metabolites, LMN-1,2-OH was eliminated slowest. Nonetheless, overall renal metabolite elimination was completed within the 24-h observation period. The metabolite amounts excreted via urine corresponded to 0.2 % (cCAR), 0.2 % (tCAR), <0.1 % (POH), 2.0 % (PA), 4.3 % (LMN-1,2-OH), and 32 % (LMN-8,9-OH) of the orally administered dose. GC-PCI-MS full-scan analyses revealed dihydroperillic acid (DHPA) as an additional LMN metabolite. DHPA was estimated to account for 5 % of the orally administered dose. The study revealed that human LMN metabolism proceeds fast and is characterised by oxidation mainly of the exo-cyclic double bond but also of the endo-cyclic double bond and of the methyl side chain. The study results may support the prediction of the metabolism of other terpenes or comparable chemical structures.

  12. Synthesis of specifically deuterium-labelled pregnanolone and pregnanediol sulphates for metabolic studies in humans.

    Science.gov (United States)

    Baillie, T A; Sjövall, J; Herz, J E

    1975-10-01

    A synthesis is reported of 3beta-hydroxy-5alpha-pregnan-20-one sulphate and the disulphate and 3-monosulphate of 5alpha-pregnane-3beta,20alpha-diol, labelled specifically with deuterium in high isotopic purity for metabolic studies in humans. Base-catalyzed equilibration of 3beta-hydroxy-5alpha-25R-spirostan-12-one (hemcogenin, II) with deuterium oxide, followed by removal of the 12-keto group and degradation of the sapogenin side-chain afforded 3beta-hydroxy-5alpha-[11,11-2H2]pregn-16-en-20-one (VII). Further deuterium atoms were introduced at the 3alpha and 20beta positions by reductions with sodium borodeuteride and lithium aluminum deuteride, respectively. These reactions led to 3beta-hydroxy-5alpha-[3alpha,11,11-2H3]pregnan-20-one (X; isotopic purity 87.2%) and 5alpha-[3alpha,11,11,20beta-2H4]pregnane-3beta,20alpha-diol (XIV; isotopic purity 83.9%). The 3-sulphate of the pregnanolone and the 3,20-disulphate of the pregnanediol were prepared directly form the free alcohols, while the 3-monosulphate of the pregnanediol was obtained via 5alpha-[3alpha,11,11,20beta-2H4]pregnane-3beta,20alpha-diol 20-acetate (XVII).

  13. Proline and hydroxyproline metabolism: implications for animal and human nutrition

    Science.gov (United States)

    Bazer, Fuller W.; Burghardt, Robert C.; Johnson, Gregory A.; Kim, Sung Woo; Knabe, Darrell A.; Li, Peng; Li, Xilong; McKnight, Jason R.; Satterfield, M. Carey; Spencer, Thomas E.

    2013-01-01

    Proline plays important roles in protein synthesis and structure, metabolism (particularly the synthesis of arginine, polyamines, and glutamate via pyrroline-5-carboxylate), and nutrition, as well as wound healing, antioxidative reactions, and immune responses. On a pergram basis, proline plus hydroxyproline are most abundant in collagen and milk proteins, and requirements of proline for whole-body protein synthesis are the greatest among all amino acids. Therefore, physiological needs for proline are particularly high during the life cycle. While most mammals (including humans and pigs) can synthesize proline from arginine and glutamine/glutamate, rates of endogenous synthesis are inadequate for neonates, birds, and fish. Thus, work with young pigs (a widely used animal model for studying infant nutrition) has shown that supplementing 0.0, 0.35, 0.7, 1.05, 1.4, and 2.1% proline to a proline-free chemically defined diet containing 0.48% arginine and 2% glutamate dose dependently improved daily growth rate and feed efficiency while reducing concentrations of urea in plasma. Additionally, maximal growth performance of chickens depended on at least 0.8% proline in the diet. Likewise, dietary supplementation with 0.07, 0.14, and 0.28% hydroxyproline (a metabolite of proline) to a plant protein-based diet enhanced weight gains of salmon. Based on its regulatory roles in cellular biochemistry, proline can be considered as a functional amino acid for mammalian, avian, and aquatic species. Further research is warranted to develop effective strategies of dietary supplementation with proline or hydroxyproline to benefit health, growth, and development of animals and humans. PMID:20697752

  14. A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease

    Directory of Open Access Journals (Sweden)

    Martina Goffredo

    2017-06-01

    Full Text Available Dysregulation of several metabolite pathways, including branched-chain amino acids (BCAAs, are associated with Non-Alcoholic Fatty Liver Disease (NAFLD and insulin resistance in adults, while studies in youth reported conflicting results. We explored whether, independently of obesity and insulin resistance, obese adolescents with NAFLD display a metabolomic signature consistent with disturbances in amino acid and lipid metabolism. A total of 180 plasma metabolites were measured by a targeted metabolomic approach in 78 obese adolescents with (n = 30 or without (n = 48 NAFLD assessed by magnetic resonance imaging (MRI. All subjects underwent an oral glucose tolerance test and subsets of patients underwent a two-step hyperinsulinemic-euglycemic clamp and/or a second MRI after a 2.2 ± 0.8-year follow-up. Adolescents with NAFLD had higher plasma levels of valine (p = 0.02, isoleucine (p = 0.03, tryptophan (p = 0.02, and lysine (p = 0.02 after adjustment for confounding factors. Circulating BCAAs were negatively correlated with peripheral and hepatic insulin sensitivity. Furthermore, higher baseline valine levels predicted an increase in hepatic fat content (HFF at follow-up (p = 0.01. These results indicate that a dysregulation of BCAA metabolism characterizes obese adolescents with NAFLD independently of obesity and insulin resistance and predict an increase in hepatic fat content over time.

  15. Coenzyme Q Metabolism Is Disturbed in High Fat Diet-Induced Non Alcoholic Fatty Liver Disease in Rats

    Directory of Open Access Journals (Sweden)

    Kathleen M Botham

    2012-02-01

    Full Text Available Oxidative stress is believed to be a major contributory factor in the development of non alcoholic fatty liver disease (NAFLD, the most common liver disorder worldwide. In this study, the effects of high fat diet-induced NAFLD on Coenzyme Q (CoQ metabolism and plasma oxidative stress markers in rats were investigated. Rats were fed a standard low fat diet (control or a high fat diet (57% metabolizable energy as fat for 18 weeks. The concentrations of total (reduced + oxidized CoQ9 were increased by > 2 fold in the plasma of animals fed the high fat diet, while those of total CoQ10 were unchanged. Reduced CoQ levels were raised, but oxidized CoQ levels were not, thus the proportion in the reduced form was increased by about 75%. A higher percentage of plasma CoQ9 as compared to CoQ10 was in the reduced form in both control and high fat fed rats. Plasma protein thiol (SH levels were decreased in the high fat-fed rats as compared to the control group, but concentrations of lipid hydroperoxides and low density lipoprotein (LDL conjugated dienes were unchanged. These results indicate that high fat diet-induced NAFLD in rats is associated with altered CoQ metabolism and increased protein, but not lipid, oxidative stress.

  16. 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

  17. Human Metabolism and Interactions of Deployment-Related Chemicals

    Science.gov (United States)

    2008-08-01

    stimulated by CPO (Fig. 6). Coincidently, α- naphthoflavone inhibited CYP1A2 metabolism of flavonoids /23/ and stimulated CYP3A4 metabolism of...by flavonoids of benzo[a]pyrene hydroxylation by cytochrome P-450 isozymes from rabbit liver microsomes, J. Biol. Chem. 1981; 256: 10897-10901. 17...P450-mediated metabolism of dietary flavonoids , Food Chem. Toxicol. 2002; 40: 609-616. 24. Cameron MD, Wen B, Allen KE, Roberts AG, Schuman JT

  18. The role of heme oxygenase-1 in drug metabolizing dysfunction in the alcoholic fatty liver exposed to ischemic injury

    Energy Technology Data Exchange (ETDEWEB)

    Park, Sang Won [Department of Pharmacology, Institute of Health Sciences, Gyeongsang National University School of Medicine, Jinju 52727 (Korea, Republic of); Kang, Jung-Woo [School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419 (Korea, Republic of); Lee, Sun-Mee, E-mail: sunmee@skku.edu [School of Pharmacy, Sungkyunkwan University, Suwon, Gyeonggi-do 16419 (Korea, Republic of)

    2016-02-01

    This study was designed to investigate the role of heme oxygenase-1 (HO-1) in hepatic drug metabolizing dysfunction after ischemia/reperfusion (IR) in alcoholic fatty liver (AFL). Rats were fed a Lieber–DeCarli diet for five weeks to allow for development of AFL and were then subjected to 90 min of hepatic ischemia and 5 h of reperfusion. Rats were pretreated with hemin (HO-1 inducer) or ZnPP (HO-1 inhibitor) for 16 h and 3 h before hepatic ischemia. After hepatic IR, ethanol diet (ED)-fed rats had higher serum aminotransferase activities and more severe hepatic necrosis compared to the control diet (CD)-fed rats. These changes were attenuated by hemin and exacerbated by ZnPP. The activity and gene expression of HO-1 and its transcription factor (Nrf2) level increased significantly after 5 h of reperfusion in CD-fed rats but not in ED-fed rats. After reperfusion, cytochrome P450 (CYP) 1A1, 1A2, and 2B1 activities were reduced to levels lower than those observed in sham group, whereas CYP2E1 activity increased. The decrease in CYP2B1 activity and the increase in CYP2E1 activity were augmented after hepatic IR in ED-fed animals. These changes were significantly attenuated by hemin but aggravated by ZnPP. Finally, CHOP expression and PERK phosphorylation, microsomal lipid peroxidation, and levels of proinflammatory mediators increased in ED-fed rats compared to CD-fed rats after reperfusion. These increases were attenuated by hemin. Our results suggest that AFL exacerbates hepatic drug metabolizing dysfunction during hepatic IR via endoplasmic reticulum stress and lipid peroxidation and this is associated with impaired HO-1 induction. - Highlights: • Endogenous HO-1 is generated in insufficient quantities in steatotic ischemic injury. • Impaired HO-1 induction leads to excessive ER stress response and lipid peroxidation. • Alcoholic steatosis exacerbates IR-induced hepatic drug-metabolizing dysfunction. • HO-1 induction is required for appropriate medication

  19. Mitochondrial gene polymorphisms alter hepatic cellular energy metabolism and aggravate diet-induced non-alcoholic steatohepatitis

    Directory of Open Access Journals (Sweden)

    Torsten Schröder

    2016-04-01

    Full Text Available Objective: Non-alcoholic fatty liver disease (NAFLD is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH. However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. Methods: To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mtFVB/N mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T of the mitochondrial ATP synthase protein 8 (mt-ATP8. Results: At baseline conditions, C57BL/6J-mtFVB/N mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS. Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mtFVB/N mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. Conclusions: We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial

  20. Human Metabolism and Interactions of Deployment-Related Chemicals

    National Research Council Canada - National Science Library

    Hodgson, Ernest; Brimfield, Alan A; Goldstein, Joyce E; Rose, Randy L; Wallace, Andrew D

    2008-01-01

    .... The metabolism of chlorpyrifos, DEET, permethrin, pyridostigmine bromide, sulfur mustard, naphthalene and nonane as well as a number of their metabolites and related chemicals was investigated...

  1. 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.

  2. Effect of alcohol on insulin secretion and viability of human pancreatic islets

    Directory of Open Access Journals (Sweden)

    Nikolić Dragan

    2017-01-01

    Full Text Available Introduction/Objective. There are controversial data in the literature on the topic of effects of alcohol on insulin secretion, apoptosis, and necrosis of the endocrine and exocrine pancreas. The goal of this research was to determine how alcohol affects the insulin secretion and viability of human adult pancreatic islets in vitro during a seven-day incubation. Methods. Human pancreatic tissue was digested with Collagenase XI, using a non-automated method. Cultures were incubated in Roswell Park Memorial Institute (RPMI medium containing alcohol (10 μl of alcohol in 100 ml of medium. Insulin stimulation index (SI and viability of the islets were determined on the first, third, and seventh day of cultivation. Results. Analysis of the viability of the islets showed that there wasn’t significant difference between the control and the test group. In the test group, viability of the cultures declined with the time of incubation. SI of the test group was higher compared to the control group, by 50% and 25% on the first and third day of cultivation, respectively. On the seventh day, insulin secretion was reduced by 25%. The difference was not statistically significant (p > 0.05. In the test group, significant decline in insulin secretion was found on the third and seventh day of incubation (p ≤ 0.05. Conclusion. Alcohol can increase or decrease insulin secretion of islets cultures, which may result in an inadequate response of pancreatic β-cells to blood glucose, leading to insulin resistance, and increased risk of developing type 2 diabetes. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 41002

  3. Alcohol consumption decreases the protection efficiency of the antioxidant network and increases the risk of sunburn in human skin.

    Science.gov (United States)

    Darvin, M E; Sterry, W; Lademann, J; Patzelt, A

    2013-01-01

    In recent years, epidemiological data has demonstrated that alcohol consumption is a risk factor for sunburn, melanoma and nonmelanoma skin cancer. We hypothesized that if the concentration of the antioxidants in the skin has already decreased due to alcohol consumption, then an adequate neutralization of the free radicals induced by ultraviolet light cannot be performed. Based on this hypothesis, we determined the carotenoid concentration in the skin and the minimal erythema dose (MED) of 6 male human volunteers before and after consumption of alcohol or alcohol and orange juice combined. The results showed a significant decrease in the carotenoid concentration in the skin and the MED after alcohol consumption, but no significant decrease after a combined intake of alcohol and orange juice. Copyright © 2012 S. Karger AG, Basel.

  4. 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

  5. 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...

  6. 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...

  7. Diet-microbiota interactions as moderators of human metabolism

    DEFF Research Database (Denmark)

    Sonnenburg, Justin L; Bäckhed, Gert Fredrik

    2016-01-01

    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...

  8. 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 ...

  9. Comparative study of hops-containing products on human cytochrome P450-mediated metabolism.

    Science.gov (United States)

    Foster, Brian C; Arnason, John T; Saleem, Ammar; Tam, Teresa W; Liu, Rui; Mao, Jingqin; Desjardins, Suzanne

    2011-05-11

    The potential for 15 different ales (6), ciders (2 apple and 1 pear), and porters (6) and 2 non-alcoholic products to affect cytochrome P450 (CYP)-mediated biotransformation and P-glycoprotein-mediated efflux of rhodamine was examined. As in our previous study, a wide range of recovered nonvolatile suspended solids dry weights were noted. Aliquots were also found to have varying effects on biotransformation and efflux. Distinct differences in product ability to affect the safety and efficacy of therapeutic products confirmed our initial findings that some porters (stouts) have a potential to affect the safety and efficacy of health products metabolized by CYP2D6 and CYP3A4 isozymes. Most products, except 2 of the ciders and the 2 non-alcoholic products, also have the potential to affect the safety of CYP2C9 metabolized medications and supplements. Further studies are required to determine the clinical significance of these findings.

  10. Dynamics of human whole body amino acid metabolism

    International Nuclear Information System (INIS)

    Young, V.R.

    1981-01-01

    The mechanism of regulation of the nitrogen metabolism in humans under various nutritional and physiological states was examined using stable isotopes. In the simultaneous continuous infusion of 1- [ 13 ] - leucine and α- [ 15 N]- lysine, their fluxed decreased when individuals received lower protein intake. The rates of oxidation and incorporation into body proteins of leucine changed in parallel with the protein intake. Such effects of diet on whole body leucine kinetics were modified by the energy state and dietary energy level. The nitrogen balance was also improved by an excess level of dietary energy. When the intake of dietary protein was lowered below the maintenance level, the whole body flux and de novo synthesis of glycine were lowered, but alanine synthesis was clearly increased. The intravenous infusion of glucose at 4 mg/kg.min, which causes increase in excess blood sugar and plasma insulin, increased the alanine flux, but had no effect on the glycine flux. The rate of albumin synthesis, determined by giving 15 N-glycine orally every 3 hr, decreased with the lowered intake of dietary protein in young men, but not in elderly men. This explains why the serum albumin synthesis increases with the increase in the intake of dietary protein in young men, but not in elderly men. The rate of whole body protein synthesis in young men receiving the L-amino acid diets providing with the required intake of specific amino acid was much lower than that in the men receiving the diets providing with generous intake of specific amino acid. Thus the control mechanism to maintain the homeostasis of body nitrogen and amino acids is related in some unknown way to the nutritional requirement of the hosts. (Kaihara, S.)

  11. Innovative methods to study human intestinal drug metabolism in vitro : Precision-cut slices compared with Ussing chamber preparations

    NARCIS (Netherlands)

    van de Kerkhof, Esther G.; Ungell, Anna-Lena B.; Sjoberg, Asa K.; de Jager, Marina H.; Hilgendorf, Constanze; de Graaf, Inge A. M.; Groothuis, Geny M. M.

    2006-01-01

    Predictive in vitro methods to investigate drug metabolism in the human intestine using intact tissue are of high importance. Therefore, we studied the metabolic activity of human small intestinal and colon slices and compared it with the metabolic activity of the same human intestinal segments

  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. Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular CarcinomaSummary

    Directory of Open Access Journals (Sweden)

    Zeribe Chike Nwosu

    2017-09-01

    Full Text Available Background & Aims: Cancer cells rely on metabolic alterations to enhance proliferation and survival. Metabolic gene alterations that repeatedly occur in liver cancer are largely unknown. We aimed to identify metabolic genes that are consistently deregulated, and are of potential clinical significance in human hepatocellular carcinoma (HCC. Methods: We studied the expression of 2,761 metabolic genes in 8 microarray datasets comprising 521 human HCC tissues. Genes exclusively up-regulated or down-regulated in 6 or more datasets were defined as consistently deregulated. The consistent genes that correlated with tumor progression markers (ECM2 and MMP9 (Pearson correlation P < .05 were used for Kaplan-Meier overall survival analysis in a patient cohort. We further compared proteomic expression of metabolic genes in 19 tumors vs adjacent normal liver tissues. Results: We identified 634 consistent metabolic genes, ∼60% of which are not yet described in HCC. The down-regulated genes (n = 350 are mostly involved in physiologic hepatocyte metabolic functions (eg, xenobiotic, fatty acid, and amino acid metabolism. In contrast, among consistently up-regulated metabolic genes (n = 284 are those involved in glycolysis, pentose phosphate pathway, nucleotide biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, proton transport, membrane lipid, and glycan metabolism. Several metabolic genes (n = 434 correlated with progression markers, and of these, 201 predicted overall survival outcome in the patient cohort analyzed. Over 90% of the metabolic targets significantly altered at the protein level were similarly up- or down-regulated as in genomic profile. Conclusions: We provide the first exposition of the consistently altered metabolic genes in HCC and show that these genes are potentially relevant targets for onward studies in preclinical and clinical contexts. Keywords: Liver Cancer, HCC, Tumor Metabolism

  14. Methods of measuring metabolism during surgery in humans: focus on the liver-brain relationship.

    Science.gov (United States)

    Battezzati, Alberto; Bertoli, Simona

    2004-09-01

    The purpose of this work is to review recent advances in setting methods and models for measuring metabolism during surgery in humans. Surgery, especially solid organ transplantation, may offer unique experimental models in which it is ethically acceptable to gain information on difficult problems of amino acid and protein metabolism. Two areas are reviewed: the metabolic study of the anhepatic phase during liver transplantation and brain microdialysis during cerebral surgery. The first model offers an innovative approach to understand the relative role of liver and extrahepatic organs in gluconeogenesis, and to evaluate whether other organs can perform functions believed to be exclusively or almost exclusively performed by the liver. The second model offers an insight to intracerebral metabolism that is closely bound to that of the liver. The recent advances in metabolic research during surgery provide knowledge immediately useful for perioperative patient management and for a better control of surgical stress. The studies during the anhepatic phase of liver transplantation have showed that gluconeogenesis and glutamine metabolism are very active processes outside the liver. One of the critical organs for extrahepatic glutamine metabolism is the brain. Microdialysis studies helped to prove that in humans there is an intense trafficking of glutamine, glutamate and alanine among neurons and astrocytes. This delicate network is influenced by systemic amino acid metabolism. The metabolic dialogue between the liver and the brain is beginning to be understood in this light in order to explain the metabolic events of brain damage during liver failure.

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

    OpenAIRE

    Mkael Symmonds; Julian J Emmanuel; Megan E Drew; Rachel L Batterham; Raymond J Dolan

    2010-01-01

    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 regio...

  16. Brain Lactate Metabolism in Humans With Subarachnoid Hemorrhage

    OpenAIRE

    Oddo M; Levine JM; Frangos S; Maloney-Wilensky E; Carrera E; Daniel RT; Levivier M; Magistretti PJ; LeRoux PD

    2012-01-01

    Abstract BACKGROUND AND PURPOSE: Lactate is central for the regulation of brain metabolism and is an alternative substrate to glucose after injury. Brain lactate metabolism in patients with subarachnoid hemorrhage has not been fully elucidated. METHODS: Thirty one subarachnoid hemorrhage patients monitored with cerebral microdialysis (CMD) and brain oxygen (PbtO(2)) were studied. Samples with elevated CMD lactate (>4 mmol/L) were matched to PbtO(2) and CMD pyruvate and categorized as hypoxi...

  17. Recon3D enables a three-dimensional view of gene variation in human metabolism

    DEFF Research Database (Denmark)

    Brunk, Elizabeth; Sahoo, Swagatika; Zielinski, Daniel C.

    2018-01-01

    Genome-scale network reconstructions have helped uncover the molecular basis of metabolism. Here we present Recon3D, a computational resource that includes three-dimensional (3D) metabolite and protein structure data and enables integrated analyses of metabolic functions in humans. We use Recon3D...

  18. Short-term fasting alters cytochrome P450-mediated drug metabolism in humans

    NARCIS (Netherlands)

    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.

    2015-01-01

    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

  19. Metabolism of acyclic and cyclic N-nitroamines by cultured human colon

    DEFF Research Database (Denmark)

    Autrup, Herman; Harris, Curtis C.; Trump, Benjamin F.

    1978-01-01

    Cultured human colon mucosa was found to metabolize both acyclic and cyclic N-nitrosamines as measured by 14C-CO2 formation and reaction of the activated moieties with cellular macromolecules. Dimethylnitrosamine and N-nitrosopyrrolidine were metabolized by explants from all patients studied. A p...

  20. Deregulation of fatty acid metabolism and cannabinoid receptors in liver of morbidly obese women with non-alcoholic fatty liver disease

    OpenAIRE

    Berlanga Bustos, Alba

    2015-01-01

    Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH), with the latter being more frequently progressive. Due to lipid accumulation in the human liver seems to be a crucial mechanism in the NAFLD pathogenesis, an improved understanding of the underlying mechanisms leading to the initial hepatic lipid accumulation could be of great interest for controlling the progression of NAFLD. It has also been repor...

  1. Alcohol and the calcium-dependent potassium transport of human erythrocytes

    International Nuclear Information System (INIS)

    Harris, R.A.; Caldwell, K.K.

    1985-01-01

    In vitro exposure of human red blood cells to ethanol (100 and 400 mM) was found to increase the initial rate of calcium-dependent potassium efflux through the red cell membrane. This effect of ethanol was apparently not due to an elevation of the intracellular free calcium but rather to a direct action of the drug on the transport process as, (1) intracellular calcium concentrations were tightly buffered with EGTA, (2) ethanol did not alter the efflux of 45 Ca from the cells, and (3) dantrolene, which has been proposed to counteract the effect of ethanol on intracellular calcium levels in the erythrocyte, did not inhibit the stimulatory action of ethanol. The efflux of potassium from erythrocytes obtained from chronic alcoholics was not different from that of erythrocytes from non-alcoholic individuals. The relationship of these findings to neuronal potassium transport is discussed

  2. Functional analysis of lipid metabolism genes in wine yeasts during alcoholic fermentation at low temperature.

    Science.gov (United States)

    López-Malo, María; García-Ríos, Estéfani; Chiva, Rosana; Guillamon, José M

    2014-10-29

    Wine produced by low-temperature fermentation is mostly considered to have improved sensory qualities. However few commercial wine strains available on the market are well-adapted to ferment at low temperature (10 - 15°C). The lipid metabolism of Saccharomyces cerevisiae plays a central role in low temperature adaptation. One strategy to modify lipid composition is to alter transcriptional activity by deleting or overexpressing the key genes of lipid metabolism. In a previous study, we identified the genes of the phospholipid, sterol and sphingolipid pathways, which impacted on growth capacity at low temperature. In the present study, we aimed to determine the influence of these genes on fermentation performance and growth during low-temperature wine fermentations. We analyzed the phenotype during fermentation at the low and optimal temperature of the lipid mutant and overexpressing strains in the background of a derivative commercial wine strain. The increase in the gene dosage of some of these lipid genes, e.g., PSD1 , LCB3, DPL1 and OLE1, improved fermentation activity during low-temperature fermentations, thus confirming their positive role during wine yeast adaptation to cold. Genes whose overexpression improved fermentation activity at 12°C were overexpressed by chromosomal integration into commercial wine yeast QA23. Fermentations in synthetic and natural grape must were carried out by this new set of overexpressing strains. The strains overexpressing OLE1 and DPL1 were able to finish fermentation before commercial wine yeast QA23. Only the OLE1 gene overexpression produced a specific aroma profile in the wines produced with natural grape must.

  3. Functional analysis of lipid metabolism genes in wine yeasts during alcoholic fermentation at low temperature

    Directory of Open Access Journals (Sweden)

    María López-Malo

    2014-10-01

    Full Text Available Wine produced by low-temperature fermentation is mostly considered to have improved sensory qualities. However few commercial wine strains available on the market are well-adapted to ferment at low temperature (10 – 15°C. The lipid metabolism of Saccharomyces cerevisiae plays a central role in low temperature adaptation. One strategy to modify lipid composition is to alter transcriptional activity by deleting or overexpressing the key genes of lipid metabolism. In a previous study, we identified the genes of the phospholipid, sterol and sphingolipid pathways, which impacted on growth capacity at low temperature. In the present study, we aimed to determine the influence of these genes on fermentation performance and growth during low-temperature wine fermentations. We analyzed the phenotype during fermentation at the low and optimal temperature of the lipid mutant and overexpressing strains in the background of a derivative commercial wine strain. The increase in the gene dosage of some of these lipid genes, e.g., PSD1, LCB3, DPL1 and OLE1, improved fermentation activity during low-temperature fermentations, thus confirming their positive role during wine yeast adaptation to cold. Genes whose overexpression improved fermentation activity at 12°C were overexpressed by chromosomal integration into commercial wine yeast QA23. Fermentations in synthetic and natural grape must were carried out by this new set of overexpressing strains. The strains overexpressing OLE1 and DPL1 were able to finish fermentation before commercial wine yeast QA23. Only the OLE1 gene overexpression produced a specific aroma profile in the wines produced with natural grape must.

  4. 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...... patients as well as in controls, whereas no change in insulin-like growth factor binding protein-1 concentrations was found. No significant changes were seen in the area under the curve for biochemical liver function tests. We conclude that administration of recombinant human growth hormone induces...

  5. 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.

  6. Metabolic clearance and production rates of human growth hormone

    Science.gov (United States)

    Taylor, Andrew L.; Finster, Joseph L.; Mintz, Daniel H.

    1969-01-01

    The metabolic clearance rate (MCR) of human growth hormone (HGH) was determined by the constant infusion to equilibrium technique utilizing HGH-125I. 22 control subjects had a MCR of 229 ±52 ml/min (mean ±SD). No difference was evident between sexes, or between various age groups. Patients with acromegaly demonstrated normal MCR's. Moreover, acute elevations of plasma growth hormone concentrations in normal subjects did not alter the MCR of HGH. The MCR was relatively constant from day to day and within the day when subjects were evaluated in the supine position. In contrast, the assumption of the upright position was associated with a mean 24% decrease in the MCR. These results were contrasted with the MCR of HGH observed in a small number of patients with altered thyroid function or diabetes mellitus. In six patients with hypothyroidism the MCR (131 ±36 ml/min) was significantly decreased (P < 0.001); whereas the MCR in eight patients with hyperthyroidism (240 ±57 ml/min) did not differ from control subjects. The MCR in eight patients with insulin-independent diabetes mellitus (IID) (185 ±41 ml/min) and in eight patients with insulin-dependent diabetes mellitus (IDD) (136 ±31 ml/min) were significantly different from control subjects (P = < 0.05 and P = < 0.001, respectively). These data were interpreted to indicate that the plasma HGH-removing mechanism(s) is not saturated at physiologic plasma HGH levels, that plasma HGH levels alone may not permit distinction between variations in pituitary release of the hormone and its rate of clearance from the plasma, and that the estimation of the MCR of HGH may help clarify the mechanism of abnormal plasma HGH responses to various stimuli. Production rates of HGH (PR) in control subjects (347 ±173 mμg/min) were contrasted with hyperthyroid patients (529 ±242 mμg/min, P < 0.05), hypothyroid patients (160 ±69 mμg/min, P < 0.02), IID (245 ±100 mμg/min, NS), and IDD (363 ±153 mμg/min, NS). Considerable

  7. Identification of the Consistently Altered Metabolic Targets in Human Hepatocellular Carcinoma.

    Science.gov (United States)

    Nwosu, Zeribe Chike; Megger, Dominik Andre; Hammad, Seddik; Sitek, Barbara; Roessler, Stephanie; Ebert, Matthias Philip; Meyer, Christoph; Dooley, Steven

    2017-09-01

    Cancer cells rely on metabolic alterations to enhance proliferation and survival. Metabolic gene alterations that repeatedly occur in liver cancer are largely unknown. We aimed to identify metabolic genes that are consistently deregulated, and are of potential clinical significance in human hepatocellular carcinoma (HCC). We studied the expression of 2,761 metabolic genes in 8 microarray datasets comprising 521 human HCC tissues. Genes exclusively up-regulated or down-regulated in 6 or more datasets were defined as consistently deregulated. The consistent genes that correlated with tumor progression markers ( ECM2 and MMP9) (Pearson correlation P < .05) were used for Kaplan-Meier overall survival analysis in a patient cohort. We further compared proteomic expression of metabolic genes in 19 tumors vs adjacent normal liver tissues. We identified 634 consistent metabolic genes, ∼60% of which are not yet described in HCC. The down-regulated genes (n = 350) are mostly involved in physiologic hepatocyte metabolic functions (eg, xenobiotic, fatty acid, and amino acid metabolism). In contrast, among consistently up-regulated metabolic genes (n = 284) are those involved in glycolysis, pentose phosphate pathway, nucleotide biosynthesis, tricarboxylic acid cycle, oxidative phosphorylation, proton transport, membrane lipid, and glycan metabolism. Several metabolic genes (n = 434) correlated with progression markers, and of these, 201 predicted overall survival outcome in the patient cohort analyzed. Over 90% of the metabolic targets significantly altered at the protein level were similarly up- or down-regulated as in genomic profile. We provide the first exposition of the consistently altered metabolic genes in HCC and show that these genes are potentially relevant targets for onward studies in preclinical and clinical contexts.

  8. Evaluation of Human Adipose Tissue Stromal Heterogeneity in Metabolic Disease Using Single Cell RNA-Seq

    Science.gov (United States)

    2017-09-01

    AWARD NUMBER: W81XWH-15-1-0251 TITLE: “Evaluation of Human Adipose Tissue Stromal Heterogeneity in Metabolic Disease Using Single Cell RNA...Heterogeneity in Metabolic Disease Using Single- Cell RNA-Seq 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER Linus Tzu-Yen...ABSTRACT We have developed a robust protocol to generate single cell transcriptional profiles from subcutaneous adipose tissue samples of both human

  9. Metabolic mapping of the brain's response to visual stimulation: studies in humans

    International Nuclear Information System (INIS)

    Phelps, M.E.; Kuhl, D.E.; Mazziotta, J.C.

    1981-01-01

    These studies demonstrated increasing glucose metabolic rates in the human primary (PVC) and associative (AVC) visual cortex as the complexity of visual scenes increased. The metabolic response of the AVC increased more rapidly with scene complexity than that of the PVC, indicating the greater involvement of the higher order AVC for complex visual interpretations. Increases in local metabolic activity by as much as a factor of 2 above that of control subjects with eyes closed indicate the wide range and metabolic reserve of the visual cortex

  10. 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...

  11. 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

    2017-12-01

    The liver metabolizes alcohol using alcohol dehydrogenase (ADH) and cytochrome P 450 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 coincubated cells with ethanol and diallyl sulfide (DAS; a CYP2E1 inhibitor) or N -acetyl cysteine (NAC; an antioxidant). 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 DAS and NAC prevented impaired STAT5B nuclear translocation. Further examination of microtubule-independent steps of the pathway revealed that Jak2/STAT5B activation by growth hormone 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 growth hormone-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. NEW & NOTEWORTHY Impaired growth hormone-mediated signaling is observed in ethanol

  12. Neural correlates of the severity of cocaine, heroin, alcohol, MDMA and cannabis use in polysubstance abusers: a resting-PET brain metabolism study.

    Directory of Open Access Journals (Sweden)

    Laura Moreno-López

    Full Text Available INTRODUCTION: Functional imaging studies of addiction following protracted abstinence have not been systematically conducted to look at the associations between severity of use of different drugs and brain dysfunction. Findings from such studies may be relevant to implement specific interventions for treatment. The aim of this study was to examine the association between resting-state regional brain metabolism (measured with 18F-fluorodeoxyglucose Positron Emission Tomography (FDG-PET and the severity of use of cocaine, heroin, alcohol, MDMA and cannabis in a sample of polysubstance users with prolonged abstinence from all drugs used. METHODS: Our sample consisted of 49 polysubstance users enrolled in residential treatment. We conducted correlation analyses between estimates of use of cocaine, heroin, alcohol, MDMA and cannabis and brain metabolism (BM (using Statistical Parametric Mapping voxel-based (VB whole-brain analyses. In all correlation analyses conducted for each of the drugs we controlled for the co-abuse of the other drugs used. RESULTS: The analysis showed significant negative correlations between severity of heroin, alcohol, MDMA and cannabis use and BM in the dorsolateral prefrontal cortex (DLPFC and temporal cortex. Alcohol use was further associated with lower metabolism in frontal premotor cortex and putamen, and stimulants use with parietal cortex. CONCLUSIONS: Duration of use of different drugs negatively correlated with overlapping regions in the DLPFC, whereas severity of cocaine, heroin and alcohol use selectively impact parietal, temporal, and frontal-premotor/basal ganglia regions respectively. The knowledge of these associations could be useful in the clinical practice since different brain alterations have been associated with different patterns of execution that may affect the rehabilitation of these patients.

  13. Comparison of cerebral metabolism of glucose in normal human and cancer patients

    International Nuclear Information System (INIS)

    Si, M.

    2007-01-01

    Full text: Objective: To determine whether the cerebral metabolism in various regions of the normal human brain differs from those of cancer patients in aging by using 18F-FDG PET instrument and SPM software. Materials and Methods We reviewed clinical information of 295 healthy normal samples so called 'normal group' (ranging 21 to 88; mean age+/-SD: 50+/-14) and 290 cancer patients called 'cancer group' (ranging 21 to 85; mean age+/-SD: 54+/-14) who were examined by a whole body GE Discovery LS PET-CT instrument in our center from Aug. 2004 to Dec. 2005.They were selected with: (i) absence of clear focal brain lesions (epilepsy, cerebrovascular diseases etc.); (ii) absence of metabolic diseases, such as hyperthyroidism, hypothyroidism and diabetes; (iii) absence of psychiatric disorders and abuse of drugs and alcohol;( iiii) cancer patients were diagnosed definitely of variable cancers except brain cancer or brain metastasis. Both groups were sub grouped into six with the interval of 10 years old starting from 21, and the gender, educational background and serum glucose are matched. All 12 subgroups were compared to the subgroup of normal 31-40 years old called 'control subgroup' (84 samples; mean age+/-SD: 37.15+/- 2.63). All samples were injected with 18F-FDG (5.55MBq/kg), 45-60 minutes later; their brains were scanned for 10 minutes. Pixel-by-pixel t-statistic analysis was applied to all brain images using the Statistical parametric mapping (SPM2). The hypometabolic areas (p < 0. 01 or p<0.001, uncorrected) were identified in the Stereotaxic coordinate human brain atlas and three dimensional localized by MNI Space utility (MSU) software. Results:1.With increasing of age interval, similar hypometabolic brain areas are detected in both 'normal group' and 'cancer group', they are mainly in the cortical structures such as bilateral prefrontal cortex (BA9), superior temporal gyrus (BA22), parietal cortex (inferior parietal lobule and precuneus(BA40), insula (BA13

  14. 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-venous differe......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......-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.......0 to 0.9 +/- 0.1 mM (P ratio from 6.0 +/- 0.3 to 2.8 +/- 0.2 (P

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. Sex differences of human cortical blood flow and energy metabolism

    DEFF Research Database (Denmark)

    Aanerud, Joel; Borghammer, Per; Rodell, Anders

    2017-01-01

    cerebral blood flow and cerebral metabolic rate of oxygen as functions of age in healthy volunteers of both sexes. Cerebral metabolic rate of oxygen did not change with age for either sex and there were no differences of mean values of cerebral metabolic rate of oxygen between men and women in cerebral...... cortex. Women had significant decreases of cerebral blood flow as function of age in frontal and parietal lobes. Young women had significantly higher cerebral blood flow than men in frontal and temporal lobes, but these differences had disappeared at age 65. The absent sex difference of cerebral energy...... turnover suggests that the known differences of synaptic density between the sexes are counteracted by opposite differences of individual synaptic activity....

  20. Monkey alcohol tissue research resource: banking tissues for alcohol research.

    Science.gov (United States)

    Daunais, James B; Davenport, April T; Helms, Christa M; Gonzales, Steven W; Hemby, Scott E; Friedman, David P; Farro, Jonathan P; Baker, Erich J; Grant, Kathleen A

    2014-07-01

    An estimated 18 million adults in the United States meet the clinical criteria for diagnosis of alcohol abuse or alcoholism, a disorder ranked as the third leading cause of preventable death. In addition to brain pathology, heavy alcohol consumption is comorbid with damage to major organs including heart, lungs, liver, pancreas, and kidneys. Much of what is known about risk for and consequences of heavy consumption derive from rodent or retrospective human studies. The neurobiological effects of chronic intake in rodent studies may not easily translate to humans due to key differences in brain structure and organization between species, including a lack of higher-order cognitive functions, and differences in underlying prefrontal cortical neural structures that characterize the primate brain. Further, rodents do not voluntarily consume large quantities of ethanol (EtOH) and they metabolize it more rapidly than primates. The basis of the Monkey Alcohol Tissue Research Resource (MATRR) is that nonhuman primates, specifically monkeys, show a range of drinking excessive amounts of alcohol (>3.0 g/kg or a 12 drink equivalent per day) over long periods of time (12 to 30 months) with concomitant pathological changes in endocrine, hepatic, and central nervous system (CNS) processes. The patterns and range of alcohol intake that monkeys voluntarily consume parallel what is observed in humans with alcohol use disorders and the longitudinal experimental design spans stages of drinking from the EtOH-naïve state to early exposure through chronic abuse. Age- and sex-matched control animals self-administer an isocaloric solution under identical operant procedures. The MATRR is a unique postmortem tissue bank that provides CNS and peripheral tissues, and associated bioinformatics from monkeys that self-administer EtOH using a standardized experimental paradigm to the broader alcohol research community. This resource provides a translational platform from which we can better

  1. Metabolism

    Science.gov (United States)

    ... lin), which signals cells to increase their anabolic activities. Metabolism is a complicated chemical process, so it's not ... how those enzymes or hormones work. When the metabolism of body chemicals is ... Hyperthyroidism (pronounced: hi-per-THIGH-roy-dih-zum). Hyperthyroidism ...

  2. Detection of driver metabolites in the human liver metabolic network using structural controllability analysis

    Science.gov (United States)

    2014-01-01

    Background Abnormal states in human liver metabolism are major causes of human liver diseases ranging from hepatitis to hepatic tumor. The accumulation in relevant data makes it feasible to derive a large-scale human liver metabolic network (HLMN) and to discover important biological principles or drug-targets based on network analysis. Some studies have shown that interesting biological phenomenon and drug-targets could be discovered by applying structural controllability analysis (which is a newly prevailed concept in networks) to biological networks. The exploration on the connections between structural controllability theory and the HLMN could be used to uncover valuable information on the human liver metabolism from a fresh perspective. Results We applied structural controllability analysis to the HLMN and detected driver metabolites. The driver metabolites tend to have strong ability to influence the states of other metabolites and weak susceptibility to be influenced by the states of others. In addition, the metabolites were classified into three classes: critical, high-frequency and low-frequency driver metabolites. Among the identified 36 critical driver metabolites, 27 metabolites were found to be essential; the high-frequency driver metabolites tend to participate in different metabolic pathways, which are important in regulating the whole metabolic systems. Moreover, we explored some other possible connections between the structural controllability theory and the HLMN, and find that transport reactions and the environment play important roles in the human liver metabolism. Conclusion There are interesting connections between the structural controllability theory and the human liver metabolism: driver metabolites have essential biological functions; the crucial role of extracellular metabolites and transport reactions in controlling the HLMN highlights the importance of the environment in the health of human liver metabolism. PMID:24885538

  3. 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.

  4. 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.

  5. Alcohol consumption and prevalence of human papillomavirus (HPV) infection among US men in the HPV in Men (HIM) study.

    Science.gov (United States)

    Schabath, Matthew B; Thompson, Zachary J; Egan, Kathleen M; Torres, B Nelson; Nguyen, Anthony; Papenfuss, Mary R; Abrahamsen, Martha E; Giuliano, Anna R

    2015-02-01

    Moderate alcohol consumption can impair host defence against viral infections. The objective of this cross-sectional analysis was to assess the association between alcohol intake and prevalent human papillomavirus (HPV) infection among US men enrolled in the HPV in Men (HIM) study using quantitative alcohol intake measured from a Food Frequency Questionnaire. The HIM study is a prospective, multinational study of the natural history of HPV infection. For this report, we restricted our analyses to men from the US cohort (N = 1313). Samples from the corona of glans penis, penile shaft and scrotum were combined for HPV DNA testing. Self-reported alcohol intake was quantified by grams of alcohol intake per day. Multivariable prevalence ratios (mPRs) were used to assess the association between alcohol intake and HPV infections. Prevalent infections were significantly higher among men in the highest quartile of alcohol intake and multivariable models revealed that the highest quartile of alcohol intake was associated with significantly increased risks for any (mPR = 1.13; 95% CI 1.00 to 1.27) HPV types and oncogenic (mPR = 1.35; 95% CI 1.08 to 1.68) HPV types. The fourth quartile of alcohol intake was associated with elevated risks for prevalent HPV infection across all strata of number of sexual partners and among never-smokers and current smokers, but not among former smokers. These results demonstrate that high intake of alcohol is associated with an increased risk for prevalent HPV infections among men. The biological role that alcohol plays in genital HPV infection remains understudied and limited epidemiological data exist, especially among men. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  6. 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.

  7. Quantifying interictal metabolic activity in human temporal lobe epilepsy

    International Nuclear Information System (INIS)

    Henry, T.R.; Mazziotta, J.C.; Engel, J. Jr.; Christenson, P.D.; Zhang, J.X.; Phelps, M.E.; Kuhl, D.E.

    1990-01-01

    The majority of patients with complex partial seizures of unilateral temporal lobe origin have interictal temporal hypometabolism on [18F]fluorodeoxyglucose positron emission tomography (FDG PET) studies. Often, this hypometabolism extends to ipsilateral extratemporal sites. The use of accurately quantified metabolic data has been limited by the absence of an equally reliable method of anatomical analysis of PET images. We developed a standardized method for visual placement of anatomically configured regions of interest on FDG PET studies, which is particularly adapted to the widespread, asymmetric, and often severe interictal metabolic alterations of temporal lobe epilepsy. This method was applied by a single investigator, who was blind to the identity of subjects, to 10 normal control and 25 interictal temporal lobe epilepsy studies. All subjects had normal brain anatomical volumes on structural neuroimaging studies. The results demonstrate ipsilateral thalamic and temporal lobe involvement in the interictal hypometabolism of unilateral temporal lobe epilepsy. Ipsilateral frontal, parietal, and basal ganglial metabolism is also reduced, although not as markedly as is temporal and thalamic metabolism

  8. 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...

  9. Sex differences of human cortical blood flow and energy metabolism.

    Science.gov (United States)

    Aanerud, Joel; Borghammer, Per; Rodell, Anders; Jónsdottir, Kristjana Y; Gjedde, Albert

    2017-07-01

    Brain energy metabolism is held to reflect energy demanding processes in neuropil related to the density and activity of synapses. There is recent evidence that men have higher density of synapses in temporal cortex than women. One consequence of these differences would be different rates of cortical energy turnover and blood flow in men and women. To test the hypotheses that rates of oxygen consumption (CMRO 2 ) and cerebral blood flow are higher in men than in women in regions of cerebral cortex, and that the differences persist with aging, we used positron emission tomography to determine cerebral blood flow and cerebral metabolic rate of oxygen as functions of age in healthy volunteers of both sexes. Cerebral metabolic rate of oxygen did not change with age for either sex and there were no differences of mean values of cerebral metabolic rate of oxygen between men and women in cerebral cortex. Women had significant decreases of cerebral blood flow as function of age in frontal and parietal lobes. Young women had significantly higher cerebral blood flow than men in frontal and temporal lobes, but these differences had disappeared at age 65. The absent sex difference of cerebral energy turnover suggests that the known differences of synaptic density between the sexes are counteracted by opposite differences of individual synaptic activity.

  10. 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

  11. 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

    2017-06-01

    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

  12. 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.

  13. 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. © 2014. Published by The Company of Biologists Ltd.

  14. 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.

  15. Proline and hydroxyproline metabolism: implications for animal and human nutrition

    OpenAIRE

    Wu, Guoyao; Bazer, Fuller W.; Burghardt, Robert C.; Johnson, Gregory A.; Kim, Sung Woo; Knabe, Darrell A.; Li, Peng; Li, Xilong; McKnight, Jason R.; Satterfield, M. Carey; Spencer, Thomas E.

    2010-01-01

    Proline plays important roles in protein synthesis and structure, metabolism (particularly the synthesis of arginine, polyamines, and glutamate via pyrroline-5-carboxylate), and nutrition, as well as wound healing, antioxidative reactions, and immune responses. On a pergram basis, proline plus hydroxyproline are most abundant in collagen and milk proteins, and requirements of proline for whole-body protein synthesis are the greatest among all amino acids. Therefore, physiological needs for pr...

  16. Gas-chromatographic resolution of enantiomeric secondary alcohols. Stereoselective reductive metabolism of ketones in rabbit-liver cytosol.

    Science.gov (United States)

    Gal, J; DeVito, D; Harper, T W

    1981-01-01

    Chiral secondary alcohols were treated with (S)-(-)-1-phenylethyl isocyanate. For each racemic alcohol, the resulting diastereomeric urethane derivatives were resolved on flexible fused-silica capillary GLC columns with retention times of 15 min or less. Derivatization of individual enantiomers showed that the urethane derivatives of (R)-(-)-2-octanol, (R)-(+)-1-phenylethyl alcohol, and (S)-(+)-2,2,2-trifluoro-1-phenylethanol are eluted before the corresponding diastereomers. The procedure is simple and rapid, and is suitable for the determination of the enantiomeric composition of chiral alcohols extracted from biological media. A series of aliphatic alcohols, aryl alkyl carbinols, and arylalkyl alkyl carbinols were resolved with the procedure, and the degree of resolution varied from good to excellent. Eight achiral ketones were incubated, individually, with rabbit-liver 90,000 g supernatant fractions, and the enantiomeric composition of the alcohol metabolites was determined with the GLC procedure. The reductions proceeded with high stereoselectivity to give alcohol products of 90% or greater enantiomeric purity. The reduction of 2-octanone and acetophenone gave predominant alcohols of (S)-configuration, in agreement with the Baumann-Prelog rule. The configuration of the predominant alcohols arising in the reduction of the remainder of the ketones could not be firmly established, but the evidence suggests that they are also of the (S)-configuration. Fluorine or methyl substitution in the ortho position of acetophenone produced an increase in the stereoselectivity, and the alcohol produced from ortho-methylacetophenone was enantiomerically greater than 99% pure.

  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. Probiotic modulation of symbiotic gut microbial-host metabolic interactions in a humanized microbiome mouse model

    NARCIS (Netherlands)

    Martin, F.P.J.; Wang, Y.; Sprenger, N.; Yap, K.S.; Rezzi, S.; Ramadan, Z.; Peré-Trepat, E.; Rochat, F.; Cherbut, C.; Bladeren, van P.J.; Fay, L.B.; Kochhar, S.; LindOn, J.C.; Holmes, E.; Nicholson, J.K.

    2008-01-01

    The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse

  19. Alcohol Inhibits Odontogenic Differentiation of Human Dental Pulp Cells by Activating mTOR Signaling

    Directory of Open Access Journals (Sweden)

    Wei Qin

    2017-01-01

    Full Text Available Long-term heavy alcohol consumption could result in a range of health, social, and behavioral problems. People who abuse alcohol are at high risks of seriously having osteopenia, periodontal disease, and compromised oral health. However, the role of ethanol (EtOH in the biological functions of human dental pulp cells (DPCs is unknown. Whether EtOH affects the odontoblastic differentiation of DPCs through the mechanistic target of rapamycin (mTOR remains unexplored. The objective of this study was to investigate the effects of EtOH on DPC differentiation and mineralization. DPCs were isolated and purified from human dental pulps. The proliferation and odontoblastic differentiation of DPCs treated with EtOH were subsequently investigated. Different doses of EtOH were shown to be cytocompatible with DPCs. EtOH significantly activated the mTOR pathway in a dose-dependent manner. In addition, EtOH downregulated the alkaline phosphatase activity, attenuated the mineralized nodule formation, and suppressed the expression of odontoblastic markers including ALP, DSPP, DMP-1, Runx2, and OCN. Moreover, the pretreatment with rapamycin, a specific mTOR inhibitor, markedly reversed the EtOH-induced odontoblastic differentiation and cell mineralization. Our findings show for the first time that EtOH can suppress DPC differentiation and mineralization in a mTOR-dependent manner, indicating that EtOH may be involved in negatively regulating the dental pulp repair.

  20. Alcohol Inhibits Odontogenic Differentiation of Human Dental Pulp Cells by Activating mTOR Signaling.

    Science.gov (United States)

    Qin, Wei; Huang, Qi-Ting; Weir, Michael D; Song, Zhi; Fouad, Ashraf F; Lin, Zheng-Mei; Zhao, Liang; Xu, Hockin H K

    2017-01-01

    Long-term heavy alcohol consumption could result in a range of health, social, and behavioral problems. People who abuse alcohol are at high risks of seriously having osteopenia, periodontal disease, and compromised oral health. However, the role of ethanol (EtOH) in the biological functions of human dental pulp cells (DPCs) is unknown. Whether EtOH affects the odontoblastic differentiation of DPCs through the mechanistic target of rapamycin (mTOR) remains unexplored. The objective of this study was to investigate the effects of EtOH on DPC differentiation and mineralization. DPCs were isolated and purified from human dental pulps. The proliferation and odontoblastic differentiation of DPCs treated with EtOH were subsequently investigated. Different doses of EtOH were shown to be cytocompatible with DPCs. EtOH significantly activated the mTOR pathway in a dose-dependent manner. In addition, EtOH downregulated the alkaline phosphatase activity, attenuated the mineralized nodule formation, and suppressed the expression of odontoblastic markers including ALP, DSPP, DMP-1, Runx2, and OCN. Moreover, the pretreatment with rapamycin, a specific mTOR inhibitor, markedly reversed the EtOH-induced odontoblastic differentiation and cell mineralization. Our findings show for the first time that EtOH can suppress DPC differentiation and mineralization in a mTOR-dependent manner, indicating that EtOH may be involved in negatively regulating the dental pulp repair.

  1. Pro-inflammatory and atherogenic circulating factors in non-alcoholic fatty liver disease associated to metabolic syndrome.

    Science.gov (United States)

    Lucero, Diego; Zago, Valeria; López, Graciela I; Graffigna, Mabel; Fainboim, Hugo; Miksztowicz, Verónica; Meroño, Tomás; Belli, Susana; Levalle, Oscar; Wikinski, Regina; Brites, Fernando; Berg, Gabriela; Schreier, Laura

    2011-01-14

    It is not elucidated if liver fat deposits associated to metabolic syndrome (MS) aggravate the atherogenic state. We evaluated, in MS patients, if the presence of non-alcoholic hepatic steatosis (HS) determines differences in inflammatory markers and VLDL characteristics. Seventy-five patients with MS were divided into 2 groups depending on the presence or absence of HS, assessed by ultrasound. Lipid profile, free fatty acids (FFA), VLDL composition, adiponectin, tumor necrosis factor-alpha (TNF-α), high sensitivity C-reactive protein (hs-CRP), and soluble adhesion molecules (sVCAM-1 and sICAM-1) were measured. HS patients presented increased triglycerides levels, HOMA-IR and FFA. Patients with HS showed a reduction in adiponectin (p = 0.04) and increase in hs-CRP (p = 0.02), independently of insulin-resistance (IR). FFA correlated positively with TNF-α (p = 0.04) and inversely with adiponectin (p = 0.01). hs-CRP correlated with all inflammatory markers, independently of IR: TNF-α (r = 0.34, p = 0.02), sVCAM-1 (r = 0.29 p = 0.03), sICAM-1 (r = 0.56, p = 0.01), adiponectin (r = -0.34, p = 0.04). HS patients presented higher VLDL mass and number of particles. Adiponectin correlated with VLDL cholesterol content (r = -0.47, p = 0.04), independently of IR. VLDL, once secreted, would suffer from changes, becoming more atherogenic. Simple HS would play an important role increasing cardiovascular risk, independently of IR. hs-CRP may represent a useful biomarker of this condition. Copyright © 2010 Elsevier B.V. All rights reserved.

  2. Acute effect of intravenously applied alcohol in the human striatal and extrastriatal D2 /D3 dopamine system.

    Science.gov (United States)

    Pfeifer, Philippe; Tüscher, Oliver; Buchholz, Hans Georg; Gründer, Gerhard; Vernaleken, Ingo; Paulzen, Michael; Zimmermann, Ulrich S; Maus, Stephan; Lieb, Klaus; Eggermann, Thomas; Fehr, Christoph; Schreckenberger, Mathias

    2017-09-01

    Investigations on the acute effects of alcohol in the human mesolimbic dopamine D 2 /D 3 receptor system have yielded conflicting results. With respect to the effects of alcohol on extrastriatal D 2 /D 3 dopamine receptors no investigations have been reported yet. Therefore we applied PET imaging using the postsynaptic dopamine D 2 /D 3 receptor ligand [ 18 F]fallypride addressing the question, whether intravenously applied alcohol stimulates the extrastriatal and striatal dopamine system. We measured subjective effects of alcohol and made correlation analyses with the striatal and extrastriatal D 2 /D 3 binding potential. Twenty-four healthy male μ-opioid receptor (OPRM1)118G allele carriers underwent a standardized intravenous and placebo alcohol administration. The subjective effects of alcohol were measured with a visual analogue scale. For the evaluation of the dopamine response we calculated the binding potential (BP ND ) by using the simplified reference tissue model (SRTM). In addition, we calculated distribution volumes (target and reference regions) in 10 subjects for which metabolite corrected arterial samples were available. In the alcohol condition no significant dopamine response in terms of a reduction of BP ND was observed in striatal and extrastriatal brain regions. We found a positive correlation for 'liking' alcohol and the BP ND in extrastriatal brain regions (Inferior frontal cortex (IFC) (r = 0.533, p = 0.007), orbitofrontal cortex (OFC) (r = 0.416, p = 0.043) and prefrontal cortex (PFC) (r = 0.625, p = 0.001)). The acute alcohol effects on the D 2 /D 3 dopamine receptor binding potential of the striatal and extrastriatal system in our experiment were insignificant. A positive correlation of the subjective effect of 'liking' alcohol with cortical D 2 /D 3 receptors may hint at an addiction relevant trait. © 2016 Society for the Study of Addiction.

  3. Expression and Regulation of Drug Transporters and Metabolizing Enzymes in the Human Gastrointestinal Tract.

    Science.gov (United States)

    Drozdzik, M; Oswald, S

    2016-01-01

    Orally administered drugs must pass through the intestinal wall and then through the liver before reaching systemic circulation. During this process drugs are subjected to different processes that may determine the therapeutic value. The intestinal barrier with active drug metabolizing enzymes and drug transporters in enterocytes plays an important role in the determination of drug bioavailability. Accumulating information demonstrates variable distribution of drug metabolizing enzymes and transporters along the human gastrointestinal tract (GI), that creates specific barrier characteristics in different segments of the GI. In this review, expression of drug metabolizing enzymes and transporters in the healthy and diseased human GI as well as their regulatory aspects: genetic, miRNA, DNA methylation are outlined. The knowledge of unique interplay between drug metabolizing enzymes and transporters in specific segments of the GI tract allows more precise definition of drug release sites within the GI in order to assure more complete bioavailability and prediction of drug interactions.

  4. 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 ... the liver, brain, and other organs. Drinking during pregnancy can harm your baby. Alcohol also increases the ...

  5. Ablation of Steroid Receptor Coactivator-3 resembles the human CACT metabolic myopathy

    OpenAIRE

    York, Brian; Reineke, Erin L.; Sagen, Jørn V.; Nikolai, Bryan C.; Zhou, Suoling; Louet, Jean-Francois; Chopra, Atul R.; Chen, Xian; Reed, Graham; Noebels, Jeffrey; Adesina, Adekunle M.; Yu, Hui; Wong, Lee-Jun C.; Tsimelzon, Anna; Hilsenbeck, Susan

    2012-01-01

    Oxidation of lipid substrates is essential for survival in fasting and other catabolic conditions, sparing glucose for the brain and other glucose-dependent tissues. Here we show Steroid Receptor Coactivator-3 (SRC-3) plays a central role in long chain fatty acid metabolism by directly regulating carnitine/acyl-carnitine translocase (CACT) gene expression. Genetic deficiency of CACT in humans is accompanied by a constellation of metabolic and toxicity phenotypes including hypoketonemia, hypog...

  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 ?M) for 24 hr induced...

  7. Metabolic profiling detects early effects of environmental and lifestyle exposure to cadmium in a human population

    OpenAIRE

    Ellis, James K; Athersuch, Toby J; Thomas, Laura DK; Teichert, Friederike; Pérez-Trujillo, Miriam; Svendsen, Claus; Spurgeon, David J; Singh, Rajinder; Järup, Lars; Bundy, Jacob G; Keun, Hector C

    2012-01-01

    Background: The ‘exposome’ represents the accumulation of all environmental exposures across a lifetime. Topdown 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...

  8. Identifying anti-growth factors for human cancer cell lines through genome-scale metabolic modeling

    DEFF Research Database (Denmark)

    Ghaffari, Pouyan; Mardinoglu, Adil; Asplund, Anna

    2015-01-01

    Human cancer cell lines are used as important model systems to study molecular mechanisms associated with tumor growth, hereunder how genomic and biological heterogeneity found in primary tumors affect cellular phenotypes. We reconstructed Genome scale metabolic models (GEMs) for eleven cell lines...... based on RNA-Seq data and validated the functionality of these models with data from metabolite profiling. We used cell line-specific GEMs to analyze the differences in the metabolism of cancer cell lines, and to explore the heterogeneous expression of the metabolic subsystems. Furthermore, we predicted...... for inhibition of cell growth may provide leads for the development of efficient cancer treatment strategies....

  9. 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. ©2016 Int. Union Physiol. Sci./Am. Physiol. Soc.

  10. Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine

    Science.gov (United States)

    Kirkwood, L. C.; Nation, R. L.; Somogyi, A. A.

    1997-01-01

    Aims Using human liver microsomes from donors of the CYP2D6 poor and extensive metabolizer genotypes, the role of individual cytochromes P-450 in the oxidative metabolism of dihydrocodeine was investigated. Methods The kinetics of formation of N- and O-demethylated metabolites, nordihydrocodeine and dihydromorphine, were determined using microsomes from six extensive and one poor metabolizer and the effects of chemical inhibitors selective for individual P-450 enzymes of the 1A, 2A, 2C, 2D, 2E and 3A families and of LKM1 (anti-CYP2D6) antibodies were studied. Results Nordihydrocodeine was the major metabolite in both poor and extensive metabolizers. Kinetic constants for N-demethylation derived from the single enzyme Michaelis-Menten model did not differ between the two groups. Troleandomycin and erythromycin selectively inhibited N-demethylation in both extensive and poor metabolizers. The CYP3A inducer, α-naphthoflavone, increased N-demethylation rates. The kinetics of formation of dihydromorphine in both groups were best described by a single enzyme Michaelis-Menten model although inhibition studies in extensive metabolizers suggested involvement of two enzymes with similar Km values. The kinetic constants for O-demethylation were significantly different in extensive and poor metabolizers. The extensive metabolizers had a mean intrinsic clearance to dihydromorphine more than ten times greater than the poor metabolizer. The CYP2D6 chemical inhibitors, quinidine and quinine, and LKM1 antibodies inhibited O-demethylation in extensive metabolizers; no effect was observed in microsomes from a poor metabolizer. Conclusions CYP2D6 is the major enzyme mediating O-demethylation of dihydrocodeine to dihydromorphine. In contrast, nordihydrocodeine formation is predominantly catalysed by CYP3A. PMID:9431830

  11. Changes in cerebral [18F]-FDG uptake induced by acute alcohol administration in a rat model of alcoholism.

    Science.gov (United States)

    Gispert, Juan D; Figueiras, Francisca P; Vengeliene, Valentina; Herance, José R; Rojas, Santiago; Spanagel, Rainer

    2017-06-01

    Several [ 18 F]-FDG positron emission tomography (PET) studies in alcoholics have consistently reported decreases in overall brain glucose metabolism at rest and following acute alcohol administration. However, changes in cerebral glucose utilization associated with the transition to addiction are not well understood and require longitudinal translational imaging studies in animal models of alcoholism. Here, we studied brain glucose uptake in alcohol drinking rats in order to provide convergent evidence to what has previously been reported in human studies. Brain glucose metabolism was measured by [ 18 F]-FDG microPET imaging in different male Wistar rat groups: short-term drinking (three months), long-term drinking (twelve months) and alcohol-naïve. Global and regional cerebral glucose uptake was measured at rest and following acute alcohol administration. We showed that alcohol significantly reduced the whole-brain glucose metabolism. This effect was most pronounced in the parietal cortex and cerebellum. Alcohol-induced decreases in brain [ 18 F]-FDG uptake was most apparent in alcohol-naïve rats, less intense in short-term drinkers and absent in long-term drinkers. The latter finding indicates the occurrence of tolerance to the intoxicating effects of alcohol in long-term drinking individuals. In contrast, some regions, like the ventral striatum and entorhinal cortex, showed enhanced metabolic activity, an effect that did not undergo tolerance during long-term alcohol consumption. Our findings are comparable to those described in human studies using the same methodology. We conclude that [ 18 F]-FDG PET studies in rat models of alcoholism provide good translation and can be used for future longitudinal studies investigating alterations in brain function during different stages of the addiction cycle. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. Kinetics of adenylate metabolism in human and rat myocardium

    OpenAIRE

    Tavenier, M.; Skladanowski, A.C.; Abreu, R.A. de; Jong, J.W. de

    1995-01-01

    textabstractPathways producing and converting adenosine have hardly been investigated in human heart, contrasting work in other species. We compared the kinetics of enzymes associated with purine degradation and salvage in human and rat heart cytoplasm assaying for adenosine deaminase, nucleoside phosphorylase, xanthine oxidoreductase, AMP deaminase, AMP- and IMP-specific 5′-nucleotidases, adenosine kinase and hypoxanthine guanine phosphoribosyltransferase (HGPRT). Xanthine oxidoreductase was...

  13. 76 FR 17140 - National Institute on Alcohol Abuse and Alcoholism; Notice of Closed Meeting

    Science.gov (United States)

    2011-03-28

    ... Alcohol Abuse and Alcoholism; Notice of Closed Meeting Pursuant to section 10(d) of the Federal Advisory... Alcohol Abuse and Alcoholism Special Emphasis Panel; RFA-AA-11-02 Alcohol Induced Metabolic and Hepatic...: Philippe Marmillot, PhD, Scientific Review Officer, National Institute on Alcohol Abuse and Alcoholism...

  14. Metabolic activity and mRNA levels of human cardiac CYP450s involved in drug metabolism.

    Directory of Open Access Journals (Sweden)

    Veronique Michaud

    2010-12-01

    Full Text Available Tissue-specific expression of CYP450s can regulate the intracellular concentration of drugs and explain inter-subject variability in drug action. The overall objective of our study was to determine in a large cohort of samples, mRNA levels and CYP450 activity expressed in the human heart.CYP450 mRNA levels were determined by RTPCR in left ventricular samples (n = 68 of explanted hearts from patients with end-stage heart failure. Samples were obtained from ischemic and non-ischemic hearts. In some instances (n = 7, samples were available from both the left and right ventricles. A technique for the preparation of microsomes from human heart tissue was developed and CYP450-dependent activity was determined using verapamil enantiomers as probe-drug substrates.Our results show that CYP2J2 mRNA was the most abundant isoform in all human heart left ventricular samples tested. Other CYP450 mRNAs of importance were CYP4A11, CYP2E1, CYP1A1 and CYP2C8 mRNAs while CYP2B6 and CYP2C9 mRNAs were present at low levels in only some of the hearts analyzed. CYP450 mRNAs did not differ between ischemic and non-ischemic hearts and appeared to be present at similar levels in the left and right ventricles. Incubation of verapamil with heart microsomes led to the formation of nine CYP450-dependent metabolites: a major finding was the observation that stereoselectivity was reversed compared to human liver microsomes, in which the R-enantiomer is metabolized to a greater extent.This study determined cardiac mRNA levels of various CYP450 isozymes involved in drug metabolism and demonstrated the prevalent expression of CYP2J2 mRNA. It revealed that cardiomyocytes can efficiently metabolize drugs and that cardiac CYP450s are highly relevant with regard to clearance of drugs in the heart. Our results support the claim that drug metabolism in the vicinity of a drug effector site can modulate drug effects.

  15. Aliphatic alcohols of illegally produced spirits can act synergistically on superoxide-anion production by human granulocytes.

    Science.gov (United States)

    Arnyas, Ervin M; Pál, László; Kovács, Csilla; Adány, Róza; McKee, Martin; Szűcs, Sándor

    2012-10-01

    Aliphatic alcohols present in illegally produced spirits in a large number of low and middle income countries have been implicated in the etiology of chronic liver disease and cirrhosis. Previous studies have confirmed that chronic alcoholism can lead to increased susceptibility to infectious diseases. Reduced superoxide-anion (O(2)·(-)) production by granulocytes could provide a mechanism by which antimicrobial defense is impaired in alcoholics. In vitro experiments have also demonstrated that ethanol can inhibit granulocyte O(2)·(-) generation. Aliphatic alcohols consumed as contaminants of illicit spirits may also influence O(2)·(-) production thereby contributing to a decrease in microbicidal activity. The aim of this study was to investigate this possibility. It measured the O(2)·(-) production by human granulocytes following treatment of the cells with aliphatic alcohol contaminants found in illicit spirits. Granulocytes were isolated from human buffy coats with centrifugal elutriation and then treated with individual aliphatic alcohols and their mixture. The O(2)·(-) production was stimulated with phorbol-12-13-dibutyrate and N-formyl-methionyl-leucyl-phenylalanine (FMLP) and measured by superoxide dismutase inhibitable reduction of ferricytochrome c. Aliphatic alcohols of illegally produced spirits inhibited the FMLP-induced O(2)·(-) production in a concentration dependent manner. They suppressed O(2)·(-) generation at 2.5-40 times lower concentrations when combined than when tested individually. Aliphatic alcohols found in illegally produced spirits can inhibit FMLP-induced O(2)·(-) production by granulocytes in a concentration-dependent manner. Due to their synergistic effects, it is possible that, in combination with ethanol, they may inhibit O(2)·(-) formation in heavy episodic drinkers.

  16. Study I: effects of 0.06% and 0.10% blood alcohol concentration on human postural control.

    Science.gov (United States)

    Modig, F; Patel, M; Magnusson, M; Fransson, P A

    2012-03-01

    Alcohol intoxication causes many accidental falls presented at emergency departments, with the injury severity often related to level of blood alcohol concentration (BAC). One way to evaluate the decline in postural control and the fall risk is to assess standing stability when challenged. The study objective was to comprehensively investigate alcohol-related impairments on postural control and adaptive motor learning at specific BAC levels. Effects of alcohol intoxication at 0.06% and 0.10% BAC were examined with posturography when unperturbed or perturbed by calf vibration. Twenty-five participants (mean age 25.1 years) were investigated standing with either eyes open or closed. Our results revealed several significant findings: (1) stability declined much faster from alcohol intoxication between 0.06% and 0.10% BAC (60-140%) compared with between 0.0% and 0.06% BAC (30%); (2) sustained exposure to repeated balance perturbations augmented the alcohol-related destabilization; (3) there were stronger effects of alcohol intoxication on stability in lateral direction than in anteroposterior direction; and (4) there was a gradual degradation of postural control particularly in lateral direction when the balance perturbations were repeated at 0.06% and 0.10% BAC, indicating adaptation deficits when intoxicated. To summarize, alcohol has profound deteriorating effects on human postural control, which are dose dependent, time dependent and direction specific. The maximal effects of alcohol intoxication on physiological performance might not be evident initially, but may be revealed first when under sustained sensory-motor challenges. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Profile of Class I Histone Deacetylases (HDAC) by Human Dendritic Cells after Alcohol Consumption and In Vitro Alcohol Treatment and Their Implication in Oxidative Stress: Role of HDAC Inhibitors Trichostatin A and Mocetinostat.

    Science.gov (United States)

    Agudelo, Marisela; Figueroa, Gloria; Parira, Tiyash; Yndart, Adriana; Muñoz, Karla; Atluri, Venkata; Samikkannu, Thangavel; Nair, Madhavan P

    2016-01-01

    Epigenetic mechanisms have been shown to play a role in alcohol use disorders (AUDs) and may prove to be valuable therapeutic targets. However, the involvement of histone deacetylases (HDACs) on alcohol-induced oxidative stress of human primary monocyte-derived dendritic cells (MDDCs) has not been elucidated. In the current study, we took a novel approach combining ex vivo, in vitro and in silico analyses to elucidate the mechanisms of alcohol-induced oxidative stress and role of HDACs in the periphery. ex vivo and in vitro analyses of alcohol-modulation of class I HDACs and activity by MDDCs from self-reported alcohol users and non-alcohol users was performed. Additionally, MDDCs treated with alcohol were assessed using qRT-PCR, western blot, and fluorometric assay. The functional effects of alcohol-induce oxidative stress were measured in vitro using PCR array and in silico using gene expression network analysis. Our findings show, for the first time, that MDDCs from self-reported alcohol users have higher levels of class I HDACs compare to controls and alcohol treatment in vitro differentially modulates HDACs expression. Further, HDAC inhibitors (HDACi) blocked alcohol-induction of class I HDACs and modulated alcohol-induced oxidative stress related genes expressed by MDDCs. In silico analysis revealed new target genes and pathways on the mode of action of alcohol and HDACi. Findings elucidating the ability of alcohol to modulate class I HDACs may be useful for the treatment of alcohol-induced oxidative damage and may delineate new potential immune-modulatory mechanisms.

  18. The human gut microbiota: metabolism and perspective in obesity.

    Science.gov (United States)

    Gomes, Aline Corado; Hoffmann, Christian; Mota, João Felipe

    2018-04-18

    The gut microbiota has been recognized as an important factor in the development of metabolic diseases such as obesity and is considered an endocrine organ involved in the maintenance of energy homeostasis and host immunity. Dysbiosis can change the functioning of the intestinal barrier and the gut-associated lymphoid tissues (GALT) by allowing the passage of structural components of bacteria, such as lipopolysaccharides (LPS), which activate inflammatory pathways that may contribute to the development of insulin resistance. Furthermore, intestinal dysbiosis can alter the production of gastrointestinal peptides related to satiety, resulting in an increased food intake. In obese people, this dysbiosis seems be related to increases of the phylum Firmicutes, the genus Clostridium, and the species Eubacterium rectale, Clostridium coccoides, Lactobacillus reuteri, Akkermansia muciniphila, Clostridium histolyticum, and Staphylococcus aureus.

  19. 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

  20. Partitioning the Metabolic Cost of Human Running: A Task-by-Task Approach

    Science.gov (United States)

    Arellano, Christopher J.; Kram, Rodger

    2014-01-01

    Compared with other species, humans can be very tractable and thus an ideal “model system” for investigating the metabolic cost of locomotion. Here, we review the biomechanical basis for the metabolic cost of running. Running has been historically modeled as a simple spring-mass system whereby the leg acts as a linear spring, storing, and returning elastic potential energy during stance. However, if running can be modeled as a simple spring-mass system with the underlying assumption of perfect elastic energy storage and return, why does running incur a metabolic cost at all? In 1980, Taylor et al. proposed the “cost of generating force” hypothesis, which was based on the idea that elastic structures allow the muscles to transform metabolic energy into force, and not necessarily mechanical work. In 1990, Kram and Taylor then provided a more explicit and quantitative explanation by demonstrating that the rate of metabolic energy consumption is proportional to body weight and inversely proportional to the time of foot-ground contact for a variety of animals ranging in size and running speed. With a focus on humans, Kram and his colleagues then adopted a task-by-task approach and initially found that the metabolic cost of running could be “individually” partitioned into body weight support (74%), propulsion (37%), and leg-swing (20%). Summing all these biomechanical tasks leads to a paradoxical overestimation of 131%. To further elucidate the possible interactions between these tasks, later studies quantified the reductions in metabolic cost in response to synergistic combinations of body weight support, aiding horizontal forces, and leg-swing-assist forces. This synergistic approach revealed that the interactive nature of body weight support and forward propulsion comprises ∼80% of the net metabolic cost of running. The task of leg-swing at most comprises ∼7% of the net metabolic cost of running and is independent of body weight support and forward

  1. 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...

  2. Ketogenic Diet Suppresses Alcohol Withdrawal Syndrome in Rats.

    Science.gov (United States)

    Dencker, Ditte; Molander, Anna; Thomsen, Morgane; Schlumberger, Chantal; Wortwein, Gitta; Weikop, Pia; Benveniste, Helene; Volkow, Nora D; Fink-Jensen, Anders

    2018-02-01

    Alcohol use disorder is underdiagnosed and undertreated, and up to 50% of alcohol-abstinent patients diagnosed with alcohol dependence relapse within the first year of treatment. Current treatments for the maintenance of alcohol abstinence in patients with alcohol use disorder have limited efficacy, and there is an urgent need for novel treatment strategies. Decreased cerebral glucose metabolism and increased brain uptake of acetate were recently reported in heavy drinkers, relative to controls. Given the switch of metabolic fuel from glucose to acetate in the alcohol-dependent brain, we investigated the potential therapeutic benefit of a ketogenic diet in managing alcohol withdrawal symptoms during detoxification. Male Sprague Dawley rats fed either ketogenic or regular diet were administered ethanol or water orally, twice daily for 6 days while the diet conditions were maintained. Abstinence symptoms were rated 6, 24, 48, and 72 hours after the last alcohol administration. Maintenance on a ketogenic diet caused a significant decrease in the alcohol withdrawal symptoms' "rigidity" and "irritability." Our preclinical pilot study suggests that a ketogenic diet may be a novel approach for treating alcohol withdrawal symptoms in humans. Copyright © 2017 by the Research Society on Alcoholism.

  3. Host homeostatic responses to alcohol-induced cellular stress in animal models of alcoholic liver disease.

    Science.gov (United States)

    Wang, He Joe; Murray, Gary J; Jung, Mary Katherine

    2015-01-01

    Humans develop various clinical phenotypes of severe alcoholic liver disease, including alcoholic hepatitis and cirrhosis, generally after decades of heavy drinking. In such individuals, following each episode of drinking, their livers experience heightened intracellular and extracellular stresses that are closely associated with alcohol consumption and alcohol metabolism. This article focuses on the latest advances made in animal models on evolutionarily conserved homeostatic mechanisms for coping with and resolving these stress conditions. The mechanisms discussed include the stress-activated protein kinase JNK, energy regulator AMPK, autophagy and the inflammatory response. Over time, the host may respond variably to stress with protective mechanisms that are critical in determining an individual's vulnerability to developing severe alcoholic liver disease. A systematic review of these mechanisms and their temporal changes in animal models provides the basis for general conclusions, and raises questions for future studies. The relevance of these data to human conditions is also discussed.

  4. 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.)

  5. Mice with chimeric livers are an improved model for human lipoprotein metabolism.

    Science.gov (United States)

    Ellis, Ewa C S; Naugler, Willscott Edward; Nauglers, Scott; Parini, Paolo; Mörk, Lisa-Mari; Jorns, Carl; Zemack, Helen; Sandblom, Anita Lövgren; Björkhem, Ingemar; Ericzon, Bo-Göran; Wilson, Elizabeth M; Strom, Stephen C; Grompe, Markus

    2013-01-01

    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. 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. 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. 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.

  6. Multi-Copper Oxidases and Human Iron Metabolism

    Science.gov (United States)

    Vashchenko, Ganna; MacGillivray, Ross T. A.

    2013-01-01

    Multi-copper oxidases (MCOs) are a small group of enzymes that oxidize their substrate with the concomitant reduction of dioxygen to two water molecules. Generally, multi-copper oxidases are promiscuous with regards to their reducing substrates and are capable of performing various functions in different species. To date, three multi-copper oxidases have been detected in humans—ceruloplasmin, hephaestin and zyklopen. Each of these enzymes has a high specificity towards iron with the resulting ferroxidase activity being associated with ferroportin, the only known iron exporter protein in humans. Ferroportin exports iron as Fe2+, but transferrin, the major iron transporter protein of blood, can bind only Fe3+ effectively. Iron oxidation in enterocytes is mediated mainly by hephaestin thus allowing dietary iron to enter the bloodstream. Zyklopen is involved in iron efflux from placental trophoblasts during iron transfer from mother to fetus. Release of iron from the liver relies on ferroportin and the ferroxidase activity of ceruloplasmin which is found in blood in a soluble form. Ceruloplasmin, hephaestin and zyklopen show distinctive expression patterns and have unique mechanisms for regulating their expression. These features of human multi-copper ferroxidases can serve as a basis for the precise control of iron efflux in different tissues. In this manuscript, we review the biochemical and biological properties of the three human MCOs and discuss their potential roles in human iron homeostasis. PMID:23807651

  7. Tryptophan Biochemistry: Structural, Nutritional, Metabolic, and Medical Aspects in Humans.

    Science.gov (United States)

    Palego, Lionella; Betti, Laura; Rossi, Alessandra; Giannaccini, Gino

    2016-01-01

    L-Tryptophan is the unique protein amino acid (AA) bearing an indole ring: its biotransformation in living organisms contributes either to keeping this chemical group in cells and tissues or to breaking it, by generating in both cases a variety of bioactive molecules. Investigations on the biology of Trp highlight the pleiotropic effects of its small derivatives on homeostasis processes. In addition to protein turn-over, in humans the pathways of Trp indole derivatives cover the synthesis of the neurotransmitter/hormone serotonin (5-HT), the pineal gland melatonin (MLT), and the trace amine tryptamine. The breakdown of the Trp indole ring defines instead the "kynurenine shunt" which produces cell-response adapters as L-kynurenine, kynurenic and quinolinic acids, or the coenzyme nicotinamide adenine dinucleotide (NAD(+)). This review aims therefore at tracing a "map" of the main molecular effectors in human tryptophan (Trp) research, starting from the chemistry of this AA, dealing then with its biosphere distribution and nutritional value for humans, also focusing on some proteins responsible for its tissue-dependent uptake and biotransformation. We will thus underscore the role of Trp biochemistry in the pathogenesis of human complex diseases/syndromes primarily involving the gut, neuroimmunoendocrine/stress responses, and the CNS, supporting the use of -Omics approaches in this field.

  8. 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...

  9. Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans.

    Science.gov (United States)

    Kullmann, Stephanie; Heni, Martin; Hallschmid, Manfred; Fritsche, Andreas; Preissl, Hubert; Häring, Hans-Ulrich

    2016-10-01

    Ever since the brain was identified as an insulin-sensitive organ, evidence has rapidly accumulated that insulin action in the brain produces multiple behavioral and metabolic effects, influencing eating behavior, peripheral metabolism, and cognition. Disturbances in brain insulin action can be observed in obesity and type 2 diabetes (T2D), as well as in aging and dementia. Decreases in insulin sensitivity of central nervous pathways, i.e., brain insulin resistance, may therefore constitute a joint pathological feature of metabolic and cognitive dysfunctions. Modern neuroimaging methods have provided new means of probing brain insulin action, revealing the influence of insulin on both global and regional brain function. In this review, we highlight recent findings on brain insulin action in humans and its impact on metabolism and cognition. Furthermore, we elaborate on the most prominent factors associated with brain insulin resistance, i.e., obesity, T2D, genes, maternal metabolism, normal aging, inflammation, and dementia, and on their roles regarding causes and consequences of brain insulin resistance. We also describe the beneficial effects of enhanced brain insulin signaling on human eating behavior and cognition and discuss potential applications in the treatment of metabolic and cognitive disorders. Copyright © 2016 the American Physiological Society.

  10. Cunninghamella Biotransformation--Similarities to Human Drug Metabolism and Its Relevance for the Drug Discovery Process.

    Science.gov (United States)

    Piska, Kamil; Żelaszczyk, Dorota; Jamrozik, Marek; Kubowicz-Kwaśny, Paulina; Pękala, Elżbieta

    2016-01-01

    Studies of drug metabolism are one of the most significant issues in the process of drug development, its introduction to the market and also in treatment. Even the most promising molecule may show undesirable metabolic properties that would disqualify it as a potential drug. Therefore, such studies are conducted in the early phases of drug discovery and development process. Cunninghamella is a filamentous fungus known for its catalytic properties, which mimics mammalian drug metabolism. It has been proven that C. elegans carries at least one gene coding for a CYP enzyme closely related to the CYP51 family. The transformation profile of xenobiotics in Cunninghamella spp. spans a number of reactions catalyzed by different mammalian CYP isoforms. This paper presents detailed data on similar biotransformation drug products in humans and Cunninghamella spp. and covers the most important aspects of preparative biosynthesis of metabolites, since this model allows to obtain metabolites in sufficient quantities to conduct the further detailed investigations, as quantification, structure analysis and pharmacological activity and toxicity testing. The metabolic activity of three mostly used Cunninghamella species in obtaining hydroxylated, dealkylated and oxidated metabolites of different drugs confirmed its convergence with human biotransformation. Though it cannot replace the standard methods, it can provide support in the field of biotransformation and identifying metabolic soft spots of new chemicals and in predicting possible metabolic pathways. Another aspect is the biosynthesis of metabolites. In this respect, techniques using Cunninghamella spp. seem to be competitive to the chemical methods currently used.

  11. Probiotic modulation of symbiotic gut microbial–host metabolic interactions in a humanized microbiome mouse model

    Science.gov (United States)

    Martin, Francois-Pierre J; Wang, Yulan; Sprenger, Norbert; Yap, Ivan K S; Lundstedt, Torbjörn; Lek, Per; Rezzi, Serge; Ramadan, Ziad; van Bladeren, Peter; Fay, Laurent B; Kochhar, Sunil; Lindon, John C; Holmes, Elaine; Nicholson, Jeremy K

    2008-01-01

    The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics. PMID:18197175

  12. Three human alcohol dehydrogenase subunits: cDNA structure and molecular and evolutionary divergence

    International Nuclear Information System (INIS)

    Ikuta, T.; Szeto, S.; Yoshida, A.

    1986-01-01

    Class I human alcohol dehydrogenase (ADH; alcohol:NAD + oxidoreductase, EC 1.1.1.1) consists of several homo- and heterodimers of α, β, and γ subunits that are governed by the ADH1, ADH2, and ADH3 loci. The authors previously cloned a full length of cDNA for the β subunit, and the complete sequence of 374 amino acid residues was established. cDNAs for the α and γ subunits were cloned and characterized. A human liver cDNA library, constructed in phage λgt11, was screened by using a synthetic oligonucleotide probe that was matched to the γ but not to the β sequence. Clone pUCADHγ21 and clone pUCADHα15L differed from β cDNA with respect to restriction sites and hybridization with the nucleotide probe. Clone pUCADHγ21 contained an insertion of 1.5 kilobase pairs (kbp) and encodes 374 amino acid residues compatible with the reported amino acid sequence of the γ subunit. Clone pUCADHα15L contained an insertion of 2.4 kbp and included nucleotide sequences that encode 374 amino acid residues for another subunit, the γ subunit. In addition, this clone contained the sequences that encode the COOH-terminal part of the β subunit at its extended 5' region. The amino acid sequences and coding regions of the cDNAs of the three subunits are very similar. A high degree of resemblance is observed also in their 3' noncoding regions. However, distinctive differences exist in the vicinity of the Zn-binding cysteine residue at position 46. Based on the cDNA sequences and the deduced amino acid sequences of the three subunits, their structural and evolutionary relationships are discussed

  13. Heterologous transporter expression for improved fatty alcohol secretion in yeast

    DEFF Research Database (Denmark)

    Hu, Yating; Zhu, Zhiwei; Nielsen, Jens

    2017-01-01

    The yeast Saccharomyces cerevisiae is an attractive host for industrial scale production of biofuels including fatty alcohols due to its robustness and tolerance towards harsh fermentation conditions. Many metabolic engineering strategies have been applied to generate high fatty alcohol production...... transporters tested, human FATP1 was shown to mediate fatty alcohol export in a high fatty alcohol production yeast strain. An approximately five-fold increase of fatty alcohol secretion was achieved. The results indicate that the overall cell fitness benefited from fatty alcohol secretion and that the acyl......-CoA synthase activity of FATP1 contributed to increased cell growth as well. This is the first study that enabled an increased cell fitness for fatty alcohol production by heterologous transporter expression in yeast, and this investigation indicates a new potential function of FATP1, which has been known...

  14. 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

  15. Application of a hierarchical enzyme classification method reveals the role of gut microbiome in human metabolism.

    Science.gov (United States)

    Mohammed, Akram; Guda, Chittibabu

    2015-01-01

    Enzymes are known as the molecular machines that drive the metabolism of an organism; hence identification of the full enzyme complement of an organism is essential to build the metabolic blueprint of that species as well as to understand the interplay of multiple species in an ecosystem. Experimental characterization of the enzymatic reactions of all enzymes in a genome is a tedious and expensive task. The problem is more pronounced in the metagenomic samples where even the species are not adequately cultured or characterized. Enzymes encoded by the gut microbiota play an essential role in the host metabolism; thus, warranting the need to accurately identify and annotate the full enzyme complements of species in the genomic and metagenomic projects. To fulfill this need, we develop and apply a method called ECemble, an ensemble approach to identify enzymes and enzyme classes and study the human gut metabolic pathways. ECemble method uses an ensemble of machine-learning methods to accurately model and predict enzymes from protein sequences and also identifies the enzyme classes and subclasses at the finest resolution. A tenfold cross-validation result shows accuracy between 97 and 99% at different levels in the hierarchy of enzyme classification, which is superior to comparable methods. We applied ECemble to predict the entire complements of enzymes from ten sequenced proteomes including the human proteome. We also applied this method to predict enzymes encoded by the human gut microbiome from gut metagenomic samples, and to study the role played by the microbe-derived enzymes in the human metabolism. After mapping the known and predicted enzymes to canonical human pathways, we identified 48 pathways that have at least one bacteria-encoded enzyme, which demonstrates the complementary role of gut microbiome in human gut metabolism. These pathways are primarily involved in metabolizing dietary nutrients such as carbohydrates, amino acids, lipids, cofactors and

  16. Application of a hierarchical enzyme classification method reveals the role of gut microbiome in human metabolism

    Science.gov (United States)

    2015-01-01

    Background Enzymes are known as the molecular machines that drive the metabolism of an organism; hence identification of the full enzyme complement of an organism is essential to build the metabolic blueprint of that species as well as to understand the interplay of multiple species in an ecosystem. Experimental characterization of the enzymatic reactions of all enzymes in a genome is a tedious and expensive task. The problem is more pronounced in the metagenomic samples where even the species are not adequately cultured or characterized. Enzymes encoded by the gut microbiota play an essential role in the host metabolism; thus, warranting the need to accurately identify and annotate the full enzyme complements of species in the genomic and metagenomic projects. To fulfill this need, we develop and apply a method called ECemble, an ensemble approach to identify enzymes and enzyme classes and study the human gut metabolic pathways. Results ECemble method uses an ensemble of machine-learning methods to accurately model and predict enzymes from protein sequences and also identifies the enzyme classes and subclasses at the finest resolution. A tenfold cross-validation result shows accuracy between 97 and 99% at different levels in the hierarchy of enzyme classification, which is superior to comparable methods. We applied ECemble to predict the entire complements of enzymes from ten sequenced proteomes including the human proteome. We also applied this method to predict enzymes encoded by the human gut microbiome from gut metagenomic samples, and to study the role played by the microbe-derived enzymes in the human metabolism. After mapping the known and predicted enzymes to canonical human pathways, we identified 48 pathways that have at least one bacteria-encoded enzyme, which demonstrates the complementary role of gut microbiome in human gut metabolism. These pathways are primarily involved in metabolizing dietary nutrients such as carbohydrates, amino acids, lipids

  17. A new kinetic model for human iodine metabolism

    International Nuclear Information System (INIS)

    Ficken, V.J.; Allen, E.W.; Adams, G.D.

    1985-01-01

    A new kinetic model of iodine metabolism incorporating preferential organification of tyrosil (TYR) residues of thyroglobulin is developed and evaluated for euthyroid (n=5) and hyperthyroid (n=11) subjects. Iodine and peripheral T4 metabolims were measured with oral /sup 131/I-NaI and intravenous /sup 125/I-74 respectively. Data (obtained over 10 days) and kinetic model are analyzed using the SAAM27 program developed by Berman (1978). Compartment rate constants (mean rate per hour +- ISD) are tabulated in this paper. Thyroid and renal iodide clearance compare favorably with values reported in the literature. TYR rate constants were not unique; however, values obtained are within the range of rate constants determined from the invitro data reported by others. Intraluminal iodine as coupled TYR is predicted to be 21% for euthyroid and 59% for hyperthyroid subjects compared to analytical chemical methods of 30% and 51% respectively determined elsewhere. The authors plan to evaluate this model as a method of predicting the thyroid radiation dose from orally administered I/sup 131/

  18. 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.

  19. Ecophysiological consequences of alcoholism on human gut microbiota: implications for ethanol-related pathogenesis of colon cancer.

    Science.gov (United States)

    Tsuruya, Atsuki; Kuwahara, Akika; Saito, Yuta; Yamaguchi, Haruhiko; Tsubo, Takahisa; Suga, Shogo; Inai, Makoto; Aoki, Yuichi; Takahashi, Seiji; Tsutsumi, Eri; Suwa, Yoshihide; Morita, Hidetoshi; Kinoshita, Kenji; Totsuka, Yukari; Suda, Wataru; Oshima, Kenshiro; Hattori, Masahira; Mizukami, Takeshi; Yokoyama, Akira; Shimoyama, Takefumi; Nakayama, Toru

    2016-06-13

    Chronic consumption of excess ethanol increases the risk of colorectal cancer. The pathogenesis of ethanol-related colorectal cancer (ER-CRC) is thought to be partly mediated by gut microbes. Specifically, bacteria in the colon and rectum convert ethanol to acetaldehyde (AcH), which is carcinogenic. However, the effects of chronic ethanol consumption on the human gut microbiome are poorly understood, and the role of gut microbes in the proposed AcH-mediated pathogenesis of ER-CRC remains to be elaborated. Here we analyse and compare the gut microbiota structures of non-alcoholics and alcoholics. The gut microbiotas of alcoholics were diminished in dominant obligate anaerobes (e.g., Bacteroides and Ruminococcus) and enriched in Streptococcus and other minor species. This alteration might be exacerbated by habitual smoking. These observations could at least partly be explained by the susceptibility of obligate anaerobes to reactive oxygen species, which are increased by chronic exposure of the gut mucosa to ethanol. The AcH productivity from ethanol was much lower in the faeces of alcoholic patients than in faeces of non-alcoholic subjects. The faecal phenotype of the alcoholics could be rationalised based on their gut microbiota structures and the ability of gut bacteria to accumulate AcH from ethanol.

  20. Chemical reaction vector embeddings: towards predicting drug metabolism in the human gut microbiome.

    Science.gov (United States)

    Mallory, Emily K; Acharya, Ambika; Rensi, Stefano E; Turnbaugh, Peter J; Bright, Roselie A; Altman, Russ B

    2018-01-01

    Bacteria in the human gut have the ability to activate, inactivate, and reactivate drugs with both intended and unintended effects. For example, the drug digoxin is reduced to the inactive metabolite dihydrodigoxin by the gut Actinobacterium E. lenta, and patients colonized with high levels of drug metabolizing strains may have limited response to the drug. Understanding the complete space of drugs that are metabolized by the human gut microbiome is critical for predicting bacteria-drug relationships and their effects on individual patient response. Discovery and validation of drug metabolism via bacterial enzymes has yielded >50 drugs after nearly a century of experimental research. However, there are limited computational tools for screening drugs for potential metabolism by the gut microbiome. We developed a pipeline for comparing and characterizing chemical transformations using continuous vector representations of molecular structure learned using unsupervised representation learning. We applied this pipeline to chemical reaction data from MetaCyc to characterize the utility of vector representations for chemical reaction transformations. After clustering molecular and reaction vectors, we performed enrichment analyses and queries to characterize the space. We detected enriched enzyme names, Gene Ontology terms, and Enzyme Consortium (EC) classes within reaction clusters. In addition, we queried reactions against drug-metabolite transformations known to be metabolized by the human gut microbiome. The top results for these known drug transformations contained similar substructure modifications to the original drug pair. This work enables high throughput screening of drugs and their resulting metabolites against chemical reactions common to gut bacteria.

  1. 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.

  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. 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.

  4. Caffeine and human DNA metabolism: the magic and the mystery

    Energy Technology Data Exchange (ETDEWEB)

    Kaufmann, William K.; Heffernan, Timothy P.; Beaulieu, Lea M.; Doherty, Sharon; Frank, Alexandra R.; Zhou Yingchun; Bryant, Miriam F.; Zhou Tong; Luche, Douglas D.; Nikolaishvili-Feinberg, Nana; Simpson, Dennis A.; Cordeiro-Stone, Marila

    2003-11-27

    The ability of caffeine to reverse cell cycle checkpoint function and enhance genotoxicity after DNA damage was examined in telomerase-expressing human fibroblasts. Caffeine reversed the ATM-dependent S and G2 checkpoint responses to DNA damage induced by ionizing radiation (IR), as well as the ATR- and Chk1-dependent S checkpoint response to ultraviolet radiation (UVC). Remarkably, under conditions in which IR-induced G2 delay was reversed by caffeine, IR-induced G1 arrest was not. Incubation in caffeine did not increase the percentage of cells entering the S phase 6-8 h after irradiation; ATM-dependent phosphorylation of p53 and transactivation of p21{sup Cip1/Waf1} post-IR were resistant to caffeine. Caffeine alone induced a concentration- and time-dependent inhibition of DNA synthesis. It inhibited the entry of human fibroblasts into S phase by 70-80% regardless of the presence or absence of wildtype ATM or p53. Caffeine also enhanced the inhibition of cell proliferation induced by UVC in XP variant fibroblasts. This effect was reversed by expression of DNA polymerase {eta}, indicating that translesion synthesis of UVC-induced pyrimidine dimers by DNA pol {eta} protects human fibroblasts against UVC genotoxic effects even when other DNA repair functions are compromised by caffeine.

  5. Caffeine and human DNA metabolism: the magic and the mystery

    International Nuclear Information System (INIS)

    Kaufmann, William K.; Heffernan, Timothy P.; Beaulieu, Lea M.; Doherty, Sharon; Frank, Alexandra R.; Zhou Yingchun; Bryant, Miriam F.; Zhou Tong; Luche, Douglas D.; Nikolaishvili-Feinberg, Nana; Simpson, Dennis A.; Cordeiro-Stone, Marila

    2003-01-01

    The ability of caffeine to reverse cell cycle checkpoint function and enhance genotoxicity after DNA damage was examined in telomerase-expressing human fibroblasts. Caffeine reversed the ATM-dependent S and G2 checkpoint responses to DNA damage induced by ionizing radiation (IR), as well as the ATR- and Chk1-dependent S checkpoint response to ultraviolet radiation (UVC). Remarkably, under conditions in which IR-induced G2 delay was reversed by caffeine, IR-induced G1 arrest was not. Incubation in caffeine did not increase the percentage of cells entering the S phase 6-8 h after irradiation; ATM-dependent phosphorylation of p53 and transactivation of p21 Cip1/Waf1 post-IR were resistant to caffeine. Caffeine alone induced a concentration- and time-dependent inhibition of DNA synthesis. It inhibited the entry of human fibroblasts into S phase by 70-80% regardless of the presence or absence of wildtype ATM or p53. Caffeine also enhanced the inhibition of cell proliferation induced by UVC in XP variant fibroblasts. This effect was reversed by expression of DNA polymerase η, indicating that translesion synthesis of UVC-induced pyrimidine dimers by DNA pol η protects human fibroblasts against UVC genotoxic effects even when other DNA repair functions are compromised by caffeine

  6. [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.

  7. 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.

  8. 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

  9. Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

    International Nuclear Information System (INIS)

    Winkler, Sandra; Borkham-Kamphorst, Erawan; Stock, Peggy; Brückner, Sandra; Dollinger, Matthias; Weiskirchen, Ralf; Christ, Bruno

    2014-01-01

    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

  10. 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

  11. 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.

  12. 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

    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......, 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...

  13. 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

    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 t...... imply a healthy gut microbial ecosystem and points at colonic transit time as a highly important factor to consider in microbiome and metabolomics studies.......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...... 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...

  14. 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

    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......  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...

  15. Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats.

    Science.gov (United States)

    Li, Songtao; Liao, Xilu; Meng, Fanyu; Wang, Yemei; Sun, Zongxiang; Guo, Fuchuan; Li, Xiaoxia; Meng, Man; Li, Ying; Sun, Changhao

    2014-01-01

    Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model. Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR)-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

  16. Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats.

    Directory of Open Access Journals (Sweden)

    Songtao Li

    Full Text Available BACKGROUND: Non-alcoholic fatty liver disease (NAFLD is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA, an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD-induced obese non-alcoholic fatty liver disease (NAFLD rat model. METHODOLOGY/PRINCIPAL FINDINGS: Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA-supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator-activated receptor (PPAR-α was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-α significantly inhibited the anti-steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. CONCLUSIONS/SIGNIFICANCE: These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-α involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD.

  17. Cytochrome P450 isoform selectivity in human hepatic theobromine metabolism

    Science.gov (United States)

    Gates, Simon; Miners, John O

    1999-01-01

    Aims The plasma clearance of theobromine (TB; 3,7-dimethylxanthine) is known to be induced in cigarette smokers. To determine whether TB may serve as a model substrate for cytochrome P450 (CYP) 1A2, or possibly other isoforms, studies were undertaken to identify the individual human liver microsomal CYP isoforms responsible for the conversion of TB to its primary metabolites. Methods The kinetics of formation of the primary TB metabolites 3-methylxanthine (3-MX), 7-methylxanthine (7-MX) and 3,7-dimethyluric acid (3,7-DMU) by human liver microsomes were characterized using a specific hplc procedure. Effects of CYP isoform-selective xenobiotic inhibitor/substrate probes on each pathway were determined and confirmatory studies with recombinant enzymes were performed to define the contribution of individual isoforms to 3-MX, 7-MX and 3,7-DMU formation. Results The CYP1A2 inhibitor furafylline variably inhibited (0–65%) 7-MX formation, but had no effect on other pathways. Diethyldithiocarbamate and 4-nitrophenol, probes for CYP2E1, inhibited the formation of 3-MX, 7-MX and 3,7-DMU by ≈55–60%, 35–55% and 85%, respectively. Consistent with the microsomal studies, recombinant CYP1A2 and CYP2E1 exhibited similar apparent Km values for 7-MX formation and CYP2E1 was further shown to have the capacity to convert TB to both 3-MX and 3,7-DMU. Conclusions Given the contribution of multiple isoforms to 3-MX and 7-MX formation and the negligible formation of 3,7-DMU in vivo, TB is of little value as a CYP isoform-selective substrate in humans. PMID:10215755

  18. Understanding arsenic metabolism through spectroscopic determination of arsenic in human urine

    OpenAIRE

    Brima, Eid I.; Jenkins, Richard O.; Haris, Parvez I.

    2006-01-01

    In this review we discuss a range of spectroscopic techniques that are currently used for analysis of arsenic in human urine for understanding arsenic metabolism and toxicity, especially in relation to genetics/ethnicity, ingestion studies and exposure to arsenic through drinking water and diet. Spectroscopic techniques used for analysis of arsenic in human urine include inductively coupled plasma mass spectrometry (ICP-MS), hydride generation atomic absorption spectrometry (HG-AAS), hydride ...

  19. Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

    OpenAIRE

    Specht, Andrew; Fiske, Laurie; Erger, Kirsten; Cossette, Travis; Verstegen, John; Campbell-Thompson, Martha; Struck, Maggie B.; Lee, Young Mok; Chou, Janice Y.; Byrne, Barry J.; Correia, Catherine E.; Mah, Cathryn S.; Weinstein, David A.; Conlon, Thomas J.

    2011-01-01

    A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size,...

  20. Genome-Wide RNAi Ionomics Screen Reveals New Genes and Regulation of Human Trace Element Metabolism

    OpenAIRE

    Malinouski, Mikalai; Hasan, Nesrin M.; Zhang, Yan; Seravalli, Javier; Lin, Jie; Avanesov, Andrei; Lutsenko, Svetlana; Gladyshev, Vadim N.

    2017-01-01

    Trace elements are essential for human metabolism and dysregulation of their homeostasis is associated with numerous disorders. Here we characterize mechanisms that regulate trace elements in human cells by designing and performing a genome-wide high-throughput siRNA/ionomics screen, and examining top hits in cellular and biochemical assays. The screen reveals high stability of the ionomes, especially the zinc ionome, and yields known regulators and novel candidates. We further uncover fundam...

  1. Metabolic mapping of functional activity in human subjects with the [18F]fluorodeoxyglucose technique

    International Nuclear Information System (INIS)

    Greenberg, J.H.; Reivich, M.; Alavi, A.

    1981-01-01

    The 2-[ 18 F]fluoro-2-deoxy-D-glucose technique was used to measure regional cerebral glucose utilization by human subjects during functional activation. Normal male volunteers subjected to one or more sensory stimuli exhibited focal increases in glucose metabolism in response to the stimulus. These results demonstrate that the technique is capable of providing functional maps in vivo related to both body region and submodality of sensory information in the human brain

  2. A Metabolic Biofuel Cell: Conversion of Human Leukocyte Metabolic Activity to Electrical Currents

    Directory of Open Access Journals (Sweden)

    Cui X Tracy

    2011-05-01

    Full Text Available Abstract An investigation of the electrochemical activity of human white blood cells (WBC for biofuel cell (BFC applications is described. WBCs isolated from whole human blood were suspended in PBS and introduced into the anode compartment of a proton exchange membrane (PEM fuel cell. The cathode compartment contained a 50 mM potassium ferricyanide solution. Average current densities between 0.9 and 1.6 μA cm-2 and open circuit potentials (Voc between 83 and 102 mV were obtained, which were both higher than control values. Cyclic voltammetry was used to investigate the electrochemical activity of the activated WBCs in an attempt to elucidate the mechanism of electron transfer between the cells and electrode. Voltammograms were obtained for the WBCs, including peripheral blood mononuclear cells (PBMCs - a lymphocyte-monocyte mixture isolated on a Ficoll gradient, a B lymphoblastoid cell line (BLCL, and two leukemia cell lines, namely K562 and Jurkat. An oxidation peak at about 363 mV vs. SCE for the PMA (phorbol ester activated primary cells, with a notable absence of a reduction peak was observed. Oxidation peaks were not observed for the BLCL, K562 or Jurkat cell lines. HPLC confirmed the release of serotonin (5-HT from the PMA activated primary cells. It is believed that serotonin, among other biochemical species released by the activated cells, contributes to the observed BFC currents.

  3. Lack of evidence for metabolism of p-phenylenediamine by human hepatic cytochrome P450 enzymes

    International Nuclear Information System (INIS)

    Stanley, Lesley A.; Skare, Julie A.; Doyle, Edward; Powrie, Robert; D'Angelo, Diane; Elcombe, Clifford R.

    2005-01-01

    p-Phenylenediamine (PPD) is a widely used ingredient in permanent hair dyes; however, little has been published on its metabolism, especially with respect to hepatic cytochrome P450 (CYP)-mediated oxidation. This is regarded as a key step in the activation of carcinogenic arylamines that ultimately leads to the development of bladder cancer. Most epidemiology studies show no significant association between personal use of hair dyes and bladder cancer, but one recent study reported an increased risk of bladder cancer in women who were frequent users of permanent hair dyes. The aim of the present study was to use intact human hepatocytes, human liver microsomes, and heterologously expressed human CYPs to determine whether PPD is metabolised by hepatic CYPs to form an N-hydroxylamine. p-Phenylenediamine was N-acetylated by human hepatocytes to form N-acetylated metabolites, but there was no evidence for the formation of mono-oxygenated metabolites or for enzyme-mediated covalent binding of 14 C-PPD to microsomal protein. In contrast, 2-aminofluorene underwent CYP-mediated metabolism to ≥4 different hydroxylated metabolites. The lack of evidence for hepatic CYP-mediated metabolism of PPD is inconsistent with the hypothesis that this compound plays a causal role in the development of bladder cancer via a mode of action involving hepatic metabolism to an N-hydroxyarylamine

  4. Simulating the physiology of athletes during endurance sports events: modelling human energy conversion and metabolism

    NARCIS (Netherlands)

    van Beek, J.H.G.M.; Supandi, F.B.; Gavai, Anand; de Graaf, A.A.; 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

  5. 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

  6. Brain, nutrition and metabolism : Studies in lean, obese and insulin resistant humans

    NARCIS (Netherlands)

    Versteeg, R.I.

    2017-01-01

    This thesis describes studies on the effects of obesity, weight loss and meal timing on the human brain and glucose metabolism. We investigated effects of meal timing during a hypocaloric diet and weight loss on brain serotonin transporters (SERT) and dopamine transporters (DAT), neuronal activity

  7. Human taurine metabolism: fluxes and fractional extraction rates of the gut, liver, and kidneys

    NARCIS (Netherlands)

    van Stijn, Mireille F. M.; Vermeulen, Mechteld A. R.; Siroen, Michiel P. C.; Wong, Leanne N.; van den Tol, M. Petrousjka; Ligthart-Melis, Gerdien C.; Houdijk, Alexander P. J.; van Leeuwen, Paul A. M.

    2012-01-01

    Taurine is involved in numerous biological processes. However, taurine plasma level decreases in response to pathological conditions, suggesting an increased need. Knowledge on human taurine metabolism is scarce and only described by arterial-venous differences across a single organ. Here we present

  8. 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

    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. As the prolif......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...... number and could be explained by reduced incorporation into diacyl- and triacylglycerols. The levels of long-chain acyl-CoA esters decreased with increased passage number. Late-passage, non-proliferating, myoblast cultures showed strong senescence-associated β-galactosidase activity indicating...... 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....

  9. 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.

    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,

  10. Abnormalities in Human Brain Creatine Metabolism in Gulf War Illness Probed with MRS

    Science.gov (United States)

    2014-12-01

    TYPE Final 3. DATES COVERED 30 Sep 2012 - 29 Sep 2014 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Abnormalities in Human Brain Creatine Metabolism in...levels of total creatine (tCr) in veterans with Gulf War Illness have been observed in prior studies. The goal of this research is to estimate amounts and

  11. 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.

  12. Killing in More-than-human Spaces: Pasteurisation, Fungi, and the Metabolic Lives of Wine

    Directory of Open Access Journals (Sweden)

    Brice, Jeremy

    2014-05-01

    Full Text Available What place might killing occupy in a more-than-human world, where human life is always-already entangled among nonhumans? In this article I attempt to unsettle the assumption that only individual organisms can be killed, and to render other sites and spaces of killing visible. Drawing on ethnographic fieldwork among winemakers in South Australia I examine pasteurisation, a killing practice that acts not on organisms but on the fluids within which they live. Examining the pasteurisation of wine damaged by the fungus Botrytis cinerea, I argue that this practice shifts the locus of killing from botrytis’ body to metabolic life processes which embrace extracellular enzymes diffused throughout the wine. I suggest that pasteurisation thus displaces killing into spaces, such as wine-in-the-making, within which many metabolic lives coexist and interpenetrate. Pasteurisation therefore renders killing an intervention into the metabolic relationships that tie together numerous species of microbes living within wine. In acting on wine as a whole it kills rather indiscriminately, simultaneously terminating multiple lives that relate to humans in different ways. Pasteurisation therefore both protects and spoils wine, reconfiguring multiple human-nonhuman relationships in conflicting and sometimes economically costly ways. In so doing, it illustrates that in a more-than-human world killing becomes difficult to confine to a single unwanted organism or species. Killing instead becomes disturbingly mobile and communicable, prone to rebound upon the valued human lives of those who kill in unsettling and potentially harmful ways.

  13. Metabolic Modeling of Common Escherichia coli Strains in Human Gut Microbiome

    Directory of Open Access Journals (Sweden)

    Yue-Dong Gao

    2014-01-01

    Full Text Available The recent high-throughput sequencing has enabled the composition of Escherichia coli strains in the human microbial community to be profiled en masse. However, there are two challenges to address: (1 exploring the genetic differences between E. coli strains in human gut and (2 dynamic responses of E. coli to diverse stress conditions. As a result, we investigated the E. coli strains in human gut microbiome using deep sequencing data and reconstructed genome-wide metabolic networks for the three most common E. coli strains, including E. coli HS, UTI89, and CFT073. The metabolic models show obvious strain-specific characteristics, both in network contents and in behaviors. We predicted optimal biomass production for three models on four different carbon sources (acetate, ethanol, glucose, and succinate and found that these stress-associated genes were involved in host-microbial interactions and increased in human obesity. Besides, it shows that the growth rates are similar among the models, but the flux distributions are different, even in E. coli core reactions. The correlations between human diabetes-associated metabolic reactions in the E. coli models were also predicted. The study provides a systems perspective on E. coli strains in human gut microbiome and will be helpful in integrating diverse data sources in the following study.

  14. Thorium-232 in human tissues: Metabolic parameters and radiation doses

    International Nuclear Information System (INIS)

    Stehney, A.F.

    1994-01-01

    Higher than environmental levels of 232 Th have been found in autopsy samples of lungs and other organs from four former employees of a Th refinery. Working periods of the subjects ranged from 3 to 24 years, and times from end of work to death ranged from 6 to 31 years. Concentrations of 232 Th in these samples and in tissues from two cases of non-occupational exposure were examined for compatibility with dosimetric models in Publication 30 of the International Commission on Radiological Protection (ICPP 1979a). The concentrations of 232 Th in the lungs of the Th workers relative to the concentrations in bone or liver were much higher than calculated from the model for class Y aerosols of Th and the exposure histories of the subjects, and concentrations in the pulmonary lymph nodes were much lower than calculated for three of the Th workers and both non-occupational cases. Least-squares fits to the measured concentrations showed that the biological half-times of Th in liver, spleen, and kidneys are similar to the half-time in bone instead of the factor of 10 less suggested in Publication 30, and the fractions translocated from body fluids were found to be about 0.03, 0.02, and 0.005, respectively, when the fraction to bone was held at the suggested value of 0.7. Fitted values of the respiratory parameters differed significantly between cases and the differences were ascribable to aerosol differences. Average inhalation rates calculated for individual Th workers ranged from 50 to 110 Bq 232 Th y -1 , and dose equivalents as high as 9.3 Sv to the lungs, 2.0 Sv to bone surfaces, and 1.1 Sv effective dose equivalent were calculated from the inhalation rates and fitted values of the metabolic parameters. The radiation doses were about the same when calculated from parameter values fitted with an assumed translocation fraction of 0.2 from body fluids to bone instead of 0.7

  15. 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.

  16. In vitro and occupational induction of sister-chromatid exchanges in human lymphocytes with furfuryl alcohol and furfural

    Energy Technology Data Exchange (ETDEWEB)

    Gomez-Arroyo, S.; Souza, V.

    1985-06-01

    Sister-chromatid exchanges (SCEs) in human lymphocytes were studied using the FPG technique in order to determine the cytogenetic effect of furfural and furfuryl alcohol. The induction of SCEs was also investigated in workers occupationally exposed to these solvents that are commonly used in the manufacture of furoic resins. The results obtained from the in vitro treatments show that furfural increased the number of SCEs, while furfuryl alcohol did not. In exposed workers, neither of these solvents increased the spontaneous frequency of SCEs per metaphase.

  17. Estradiol stimulation of inositolphospholipid metabolism in human endometrial fibroblasts

    International Nuclear Information System (INIS)

    Iida, K.; Imai, A.; Tamaya, T.

    1989-01-01

    Stimulated inositolphospholipid turnover has been proposed to constitute a signal-transducing mechanism in many cell types. To determine the inositolphospholipid turnover during stimulation by 17 beta-estradiol, the turnover kinetics of phospholipids was investigated in human endometrial fibroblasts. In cells incubated with [ 32 P] phosphate for 1 h, estradiol rapidly and persisitently (for at least 30 min) enhanced the rate of 32 P-labeling of phosphatidic acid (PA). On the other hand, after a lag time of 5 min, 32 P-labeling of phosphatidylinositol (PI) was also increased also. These sequential 32 P-labeling of PA and PI demonstrated that inositolphospholipid turnover was stimulated in fibroblasts exposed to estradiol. The rapid estrogen-stimulated inositolphospholipid turnover may not be through the mechanism associated with classical action of estrogen

  18. Alterations in calcium metabolism during human monocyte activation

    International Nuclear Information System (INIS)

    Scully, S.P.

    1984-01-01

    Human peripheral blood monocytes have been prepared from plateletpheresis residues by counterflow centrifugal elutriation in sufficient quantities to enable quantitative studies of cell calcium. Kinetic analysis of 45 Ca exchange data in resting monocytes was compatible with a model of cellular calcium containing three exchangeable calcium pools. These pools are thought to represent a putative ectocellular pool, a putative cytoplasmic chelated pool, and a putative organelle sequestered pool. Exposure of monocytes to the plant lectin Con A at a concentration that maximally simulated superoxide production caused an increase in the size and a doubling in the exchange rate of the putative cytoplasmic pool without a change in the other cellular pools. The cytoplasmic ionized calcium, [Ca]/sub i/, measured with the fluorescent probe, Quin 2 rose from a resting level of 83 nM to 165 mN within 30 sec of exposure to Con A. This increase in cytoplasmic calcium preceded the release of superoxide radicals. Calcium transport and calcium ATPase activities were identified and characterized in plasma membrane vesicles prepared from monocytes. Both activities were strictly dependent on ATP and Mg, had a Km/sub Ca/ in the submicromolar range and were stimulated by calmodulin. Thus, it seems that monocyte calcium is in a dynamic steady state that is a balance between efflux and influx rates, and that the activation of these cells results in the transition to a new steady state. The alteration in [Ca]/sub i/ that accompany the new steady state are essential for superoxide production by human monocytes

  19. Comparative Metabolism Study of Five Protoberberine Alkaloids in Liver Microsomes from Rat, Rhesus Monkey, and Human.

    Science.gov (United States)

    Li, Yan; Zhou, Yanyan; Si, Nan; Han, Lingyu; Ren, Wei; Xin, Shaokun; Wang, Hongjie; Zuo, Ran; Wei, Xiaolu; Yang, Jian; Zhao, Haiyu; Bian, Baolin

    2017-11-01

    Protoberberine alkaloids including berberine, palmatine, jatrorrhizine, coptisine, and epiberberine are major components in many medicinal plants. They have been widely used for the treatment of cancer, inflammation, diabetes, depression, hypertension, and various infectious areas. However, the metabolism of five protoberberine alkaloids among different species has not been clarified previously. In order to elaborate on the in vitro metabolism of them, a comparative analysis of their metabolic profile in rat, rhesus monkey, and human liver microsomes was carried out using ultrahigh-performance liquid chromatography coupled with a high-resolution linear trap quadrupole-Orbitrap mass spectrometer (UHPLC-electrospray ionization-Orbitrap MS) for the first time. Each metabolite was identified and semiquantified by its accurate mass data and peak area. Fifteen metabolites were characterized based on accurate MS/MS spectra and the proposed MS/MS fragmentation pathways including demethylation, hydroxylation, and methyl reduction. Among them, the content of berberine metabolites in human liver microsomes was similar with those in rhesus monkey liver microsomes, whereas berberine in rat liver microsomes showed no demethylation metabolites and the content of metabolites showed significant differences with that in human liver microsomes. On the contrary, the metabolism of palmatine in rat liver microsomes resembled that in human liver microsomes. The content of jatrorrhizine metabolites presented obvious differences in all species. The HR-ESI-MS/MS fragmentation behavior of protoberberine alkaloids and their metabolic profile in rat, rhesus monkey, and human liver microsomes were investigated for the first time. The results demonstrated that the biotransformation characteristics of protoberberine alkaloids among different species had similarities as well differences that would be beneficial for us to better understand the pharmacological activities of protoberberine alkaloids

  20. Human neutrophil peptide-1 promotes alcohol-induced hepatic fibrosis and hepatocyte apoptosis.

    Directory of Open Access Journals (Sweden)

    Rie Ibusuki

    Full Text Available Neutrophil infiltration of the liver is a typical feature of alcoholic liver injury. Human neutrophil peptide (HNP-1 is an antimicrobial peptide secreted by neutrophils. The aim of this study was to determine if HNP-1 affects ethanol-induced liver injury and to examine the mechanism of liver injury induced by HNP-1.Transgenic (TG mice expressing HNP-1 under the control of a β-actin-based promoter were established. Ethanol was orally administered to HNP-1 TG or wild-type C57BL/6N (WT mice. SK-Hep1 hepatocellular carcinoma cells were used to investigate the effect of HNP-1 on hepatocytes in vitro.After 24 weeks of ethanol intake, hepatic fibrosis and hepatocyte apoptosis were significantly more severe in TG mice than in WT mice. Levels of CD14, TLR4, and IL-6 in liver tissues were higher in TG mice than in WT mice. Apoptosis was accompanied by higher protein levels of caspase-3, caspase-8, and cleaved PARP in liver tissue. In addition, phosphorylated ASK1, ASK1, phosphorylated JNK, JNK1, JNK2, Bax, Bak and Bim were all more abundant in TG mice than in WT mice. In contrast, the level of anti-apoptotic Bcl2 in the liver was significantly lower in TG mice than in WT mice. Analysis of microRNAs in liver tissue showed that miR-34a-5p expression was significantly higher in TG mice than in WT mice. Furthermore, in the presence of ethanol, HNP-1 increased the apoptosis with the decreased level of Bcl2 in a concentration-dependent manner in vitro.HNP-1 secreted by neutrophils may exacerbate alcohol-induced hepatic fibrosis and hepatocyte apoptosis with a decrease in Bcl2 expression and an increase in miR-34a-5p expression.

  1. Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis

    Science.gov (United States)

    Watanabe, Miki; Muraleedharan, Ranjithmenon; Lambert, Paul F.; Lane, Andrew N.; Romick-Rosendale, Lindsey E.; Wells, Susanne I.

    2017-01-01

    The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos). To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA) that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth. PMID:28558019

  2. Effects of superfoods on risk factors of metabolic syndrome: a systematic review of human intervention trials.

    Science.gov (United States)

    van den Driessche, José J; Plat, Jogchum; Mensink, Ronald P

    2018-04-25

    Functional foods can be effective in the prevention of metabolic syndrome and subsequently the onset of cardiovascular diseases and type II diabetes mellitus. More recently, however, another term was introduced to describe foods with additional health benefits: "superfoods", for which, to date, no generally accepted definition exists. Nonetheless, their consumption might contribute to the prevention of metabolic syndrome, for example due to the presence of potentially bioactive compounds. This review provides an overview of controlled human intervention studies with foods described as "superfoods" and their effects on metabolic syndrome parameters. First, an Internet search was performed to identify foods described as superfoods. For these superfoods, controlled human intervention trials were identified until April 2017 investigating the effects of superfood consumption on metabolic syndrome parameters: waist circumference or BMI, blood pressure, or concentrations of HDL cholesterol, triacylglycerol or glucose. Seventeen superfoods were identified, including a total of 113 intervention trials: blueberries (8 studies), cranberries (8), goji berries (3), strawberries (7), chili peppers (3), garlic (21), ginger (10), chia seed (5), flaxseed (22), quinoa (1), cocoa (16), maca (1), spirulina (7), wheatgrass (1), acai berries (0), hemp seed (0) and bee pollen (0). Overall, only limited evidence was found for the effects of the foods described as superfoods on metabolic syndrome parameters, since results were not consistent or the number of controlled intervention trials was limited. The inconsistencies might have been related to intervention-related factors, such as duration or dose. Furthermore, conclusions may be different if other health benefits are considered.

  3. Overexpression of the human DEK oncogene reprograms cellular metabolism and promotes glycolysis.

    Directory of Open Access Journals (Sweden)

    Marie C Matrka

    Full Text Available The DEK oncogene is overexpressed in many human malignancies including at early tumor stages. Our reported in vitro and in vivo models of squamous cell carcinoma have demonstrated that DEK contributes functionally to cellular and tumor survival and to proliferation. However, the underlying molecular mechanisms remain poorly understood. Based on recent RNA sequencing experiments, DEK expression was necessary for the transcription of several metabolic enzymes involved in anabolic pathways. This identified a possible mechanism whereby DEK may drive cellular metabolism to enable cell proliferation. Functional metabolic Seahorse analysis demonstrated increased baseline and maximum extracellular acidification rates, a readout of glycolysis, in DEK-overexpressing keratinocytes and squamous cell carcinoma cells. DEK overexpression also increased the maximum rate of oxygen consumption and therefore increased the potential for oxidative phosphorylation (OxPhos. To detect small metabolites that participate in glycolysis and the tricarboxylic acid cycle (TCA that supplies substrate for OxPhos, we carried out NMR-based metabolomics studies. We found that high levels of DEK significantly reprogrammed cellular metabolism and altered the abundances of amino acids, TCA cycle intermediates and the glycolytic end products lactate, alanine and NAD+. Taken together, these data support a scenario whereby overexpression of the human DEK oncogene reprograms keratinocyte metabolism to fulfill energy and macromolecule demands required to enable and sustain cancer cell growth.

  4. In vitro metabolism of [14C]-toluene by human and rat liver microsomes and liver slices

    International Nuclear Information System (INIS)

    Chapman, D.E.; Moore, T.J.; Michener, S.R.; Powis, G.

    1990-01-01

    Toluene metabolites produced by liver microsomes from six human donors included benzylalcohol (Balc), benzaldehyde (Bald) and benzoic acid (Bacid). Microsomes from only one human donor metabolized toluene to p-cresol and o-cresol. Human liver microsomes also metabolized Balc to Bald. Balc metabolism required NADPH, was inhibited by carbon monoxide, and was decreased at a buffer pH of 10. Balc metabolism was not inhibited by ADP-ribose or sodium azide. These results suggest that cytochrome P450 is responsible for the in vitro metabolism of Balc by human liver microsomes. Toluene metabolites formed by human liver slices and released into the incubation media included hippuric acid, and Bacid. Cresols or cresol-conjugates were not detected in liver slice incubation media from any human donor. Toluene metabolism by human liver was compared to metabolism by comparable liver preparations from male Fischer F344 rats. Rates of toluene metabolism by human liver microsomes and liver slices were 9-fold and 1.3-fold greater than for rat liver, respectively. Covalent binding of toluene to human liver microsomes and liver slices was 21-fold and 4-fold greater than for comparable rat liver preparations. Covalent binding of toluene to human microsomes required NADPH, was significantly decreased by coincubation with 4 mM cysteine or 4 mM glutathione, and radioactivity associated with microsomes was decreased by subsequent digestion of microsomes with protease. These results suggest that toluene metabolism and covalent binding of toluene are underestimated if the male Fischer 344 rat is used as a model for human toluene metabolism

  5. Alcohol: A Nutrient with Multiple Salutary Effects

    Directory of Open Access Journals (Sweden)

    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.

  6. Endocrine and metabolic disorders associated with human immune deficiency virus infection.

    Science.gov (United States)

    Unachukwu, C N; Uchenna, D I; Young, E E

    2009-01-01

    Many reports have described endocrine and metabolic disorders in the human immunodeficiency virus (HIV) infection. This article reviewed various reports in the literature in order to increase the awareness and thus the need for early intervention when necessary. Data were obtained from MEDLINE, Google search and otherjournals on 'HIV, Endocrinopathies/Metabolic Disorders' from 1985 till 2007. Studies related to HIV associated endocrinopathies and metabolic disorders in the last two decades were reviewed. Information on epidemiology, pathogenesis, diagnosis and treatment of the target organ endocrinopathies and metabolic disorders in HIV/AIDS were extracted from relevant literature. Endocrine and metabolic disturbances occur in the course of HIV infection. Pathogenesis includes direct infection of endocrine glands by HIV or opportunistic organisms, infiltration by neoplasms and side effects of drugs. Adrenal insufficiency is the commonest HIV endocrinopathy with cytomegalovirus adrenalitis occurring in 40-88% of cases. Thyroid dysfunction may occur as euthyroid sick syndrome or sub-clinical hypothyroidism. Hypogonadotrophic dysfunction accounts for 75% of HIV-associated hypogonadism, with prolonged amenorrhoea being three times more likely in the women. Pancreatic dysfunction may result in hypoglycaemia or diabetes mellitus (DM). Highly active antiretroviral therapy (HAART) especially protease inhibitors has been noted to result in insulin resistance and lipodystrophy. Virtually every endocrine organ is involved in the course of HIV infection. Detailed endocrinological and metabolic evaluation and appropriate treatment is necessary in the optimal management of patients with HIV infection in our environment.

  7. 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.

  8. 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...... inosine 5'-monophosphate (IMP) formation. After exercise, blood flow to one leg was occluded. Muscle biopsies (vastus lateralis) were taken before and 3.6 +/- 0.2 min after exercise from the occluded leg and 0.7 +/- 0.0, 1.1 +/- 0.0, and 2.9 +/- 0.1 min postexercise in the nonoccluded leg. Exercise...... activated AMPD; at exhaustion IMP was 3.5 +/- 0.4 mmol/kg dry muscle. Before exercise, 16.0 +/- 1.6% of AMPD cosedimented with the myosin fraction; the extent of AMPD:myosin binding was unchanged by exercise. Inosine content increased about threefold during exercise and twofold more during recovery; by 2...

  9. Role of aminotransferases in glutamate metabolism of human erythrocytes

    Energy Technology Data Exchange (ETDEWEB)

    Ellinger, James J. [University of Wisconsin-Madison, Department of Biochemistry (United States); Lewis, Ian A. [Princeton University, Lewis-Sigler Institute for Integrative Genomics (United States); Markley, John L., E-mail: markley@nmrfam.wisc.edu [University of Wisconsin-Madison, Department of Biochemistry (United States)

    2011-04-15

    Human erythrocytes require a continual supply of glutamate to support glutathione synthesis, but are unable to transport this amino acid across their cell membrane. Consequently, erythrocytes rely on de novo glutamate biosynthesis from {alpha}-ketoglutarate and glutamine to maintain intracellular levels of glutamate. Erythrocytic glutamate biosynthesis is catalyzed by three enzymes, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and glutamine aminohydrolase (GA). Although the presence of these enzymes in RBCs has been well documented, the relative contributions of each pathway have not been established. Understanding the relative contributions of each biosynthetic pathway is critical for designing effective therapies for sickle cell disease, hemolytic anemia, pulmonary hypertension, and other glutathione-related disorders. In this study, we use multidimensional {sup 1}H-{sup 13}C nuclear magnetic resonance (NMR) spectroscopy and multiple reaction mode mass spectrometry (MRM-MS) to measure the kinetics of de novo glutamate biosynthesis via AST, ALT, and GA in intact cells and RBC lysates. We show that up to 89% of the erythrocyte glutamate pool can be derived from ALT and that ALT-derived glutamate is subsequently used for glutathione synthesis.

  10. Microbial metaproteomics for characterizing the range of metabolic functions and activities of human gut microbiota.

    Science.gov (United States)

    Xiong, Weili; Abraham, Paul E; Li, Zhou; Pan, Chongle; Hettich, Robert L

    2015-10-01

    The human gastrointestinal tract is a complex, dynamic ecosystem that consists of a carefully tuned balance of human host and microbiota membership. The microbiome is not merely a collection of opportunistic parasites, but rather provides important functions to the host that are absolutely critical to many aspects of health, including nutrient transformation and absorption, drug metabolism, pathogen defense, and immune system development. Microbial metaproteomics provides the ability to characterize the human gut microbiota functions and metabolic activities at a remarkably deep level, revealing information about microbiome development and stability as well as their interactions with their human host. Generally, microbial and human proteins can be extracted and then measured by high performance MS-based proteomics technology. Here, we review the field of human gut microbiome metaproteomics, with a focus on the experimental and informatics considerations involved in characterizing systems ranging from low-complexity model gut microbiota in gnotobiotic mice, to the emerging gut microbiome in the GI tract of newborn human infants, and finally to an established gut microbiota in human adults. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Genome-scale metabolic model of Pichia pastoris with native and humanized glycosylation of recombinant proteins.

    Science.gov (United States)

    Irani, Zahra Azimzadeh; Kerkhoven, Eduard J; Shojaosadati, Seyed Abbas; Nielsen, Jens

    2016-05-01

    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 prediction of protein yield, demonstrates the effect of the different types of N-glycosylation of protein yield, and can be used to predict potential targets for strain improvement. The model represents a step towards a more complete description of protein production in P. pastoris, which is required for using these models to understand and optimize protein production processes. © 2015 Wiley Periodicals, Inc.

  12. Explant culture of human peripheral lung. I. Metabolism of benzo[alpha]pyrene

    DEFF Research Database (Denmark)

    Stoner, G.D.; Harris, C.C.; Autrup, Herman

    1978-01-01

    the predominant alveolar epithelial cell type. Lamellar inclusion bodies were released from the type 2 cells and accumulated in the alveolar spaces. The metabolism of benzo[alpha]pyrene (BP) in human lung explants cultured for up to 7 days was investigated. Human lung explants had measurable aryl hydrocarbon......Human lung explants have been maintained in vitro for a period of 25 days. Autoradiographic studies indicated that the broncholar epithelial cells, type 2 alveolar epithelial cells, and stromal fibroblasts incorporated 3H-thymidine during the culture. After 7 to 10 days, type 2 cells were...... hydroxylase activity and could metabolize BP into forms that were bound to cellular DNA and protein. Peripheral lung had significantly lower aryl hydrocarbon hydroxylase activity than cultured bronchus but both tissues had similar binding levels of BP to DNA. Radioautographic studies indicated that all cell...

  13. Quantifying Diet-Induced Metabolic Changes of the Human Gut Microbiome

    DEFF Research Database (Denmark)

    Shoaie, Saeed; Ghaffari, Pouyan; Kovatcheva-Datchary, Petia

    2015-01-01

    The human gut microbiome is known to be associated with various human disorders, but a major challenge is to go beyond association studies and elucidate causalities. Mathematical modeling of the human gut microbiome at a genome scale is a useful tool to decipher microbe-microbe, diet...... of single bacteria and whole communities in vitro. Focusing on metabolic interactions between the diet, gut microbiota, and host metabolism, we demonstrated the predictive power of the toolbox in a diet-intervention study of 45 obese and overweight individuals and validated our predictions by fecal...... and blood metabolomics data. Thus, modeling could quantitatively describe altered fecal and serum amino acid levels in response to diet intervention....

  14. The pharmacokinetics and metabolism of lumiracoxib in chimeric humanized and murinized FRG mice.

    Science.gov (United States)

    Dickie, A P; Wilson, C E; Schreiter, K; Wehr, R; Wilson, E M; Bial, J; Scheer, N; Wilson, I D; Riley, R J

    2017-07-01

    The pharmacokinetics and metabolism of lumiracoxib were studied, after administration of single 10mg/kg oral doses to chimeric liver-humanized and murinized FRG mice. In the chimeric humanized mice, lumiracoxib reached peak observed concentrations in the blood of 1.10±0.08μg/mL at 0.25-0.5h post-dose with an AUC inf of 1.74±0.52μgh/mL and an effective half-life for the drug of 1.42±0.72h (n=3). In the case of the murinized animals peak observed concentrations in the blood were determined as 1.15±0.08μg/mL at 0.25h post-dose with an AUC inf of 1.94±0.22μgh/mL and an effective half-life of 1.28±0.02h (n=3). Analysis of blood indicated only the presence of unchanged lumiracoxib. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles obtained in humanized mice were different compared to murinized animals with e.g., a higher proportion of the dose detected in the form of acyl glucuronide metabolites and much reduced amounts of taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57bl/6J mice and humans, revealed a greater though not complete match between chimeric humanized mice and humans, such that the liver-humanized FRG model may represent a useful approach to assessing the biotransformation of such compounds in humans. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Long Non-Coding RNAs Associated with Metabolic Traits in Human White Adipose Tissue

    Directory of Open Access Journals (Sweden)

    Hui Gao

    2018-04-01

    Full Text Available Long non-coding RNAs (lncRNAs belong to a recently discovered class of molecules proposed to regulate various cellular processes. Here, we systematically analyzed their expression in human subcutaneous white adipose tissue (WAT and found that a limited set was differentially expressed in obesity and/or the insulin resistant state. Two lncRNAs herein termed adipocyte-specific metabolic related lncRNAs, ASMER-1 and ASMER-2 were enriched in adipocytes and regulated by both obesity and insulin resistance. Knockdown of either ASMER-1 or ASMER-2 by antisense oligonucleotides in in vitro differentiated human adipocytes revealed that both genes regulated adipogenesis, lipid mobilization and adiponectin secretion. The observed effects could be attributed to crosstalk between ASMERs and genes within the master regulatory pathways for adipocyte function including PPARG and INSR. Altogether, our data demonstrate that lncRNAs are modulators of the metabolic and secretory functions in human fat cells and provide an emerging link between WAT and common metabolic conditions. Keywords: White adipose tissue, Adipocytes, Long non-coding RNAs, Metabolic traits, Lipolysis, Adiponectin

  16. An association study between polymorphism of alcohol ...

    African Journals Online (AJOL)

    Jane

    2011-09-28

    Sep 28, 2011 ... factors which include alcohol metabolizing genes and ... Association research proves that c2 allele is a risk factor for ..... polymorphism in alcohol liver cirrhosis and alcohol chronic pancreatitis among Polish individuals.S cand ...

  17. 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.

  18. Sympathetic influence on cerebral blood flow and metabolism during exercise in humans

    DEFF Research Database (Denmark)

    Seifert, Thomas; Secher, Niels H

    2011-01-01

    This review focuses on the possibility that autonomic activity influences cerebral blood flow (CBF) and metabolism during exercise in humans. Apart from cerebral autoregulation, the arterial carbon dioxide tension, and neuronal activation, it may be that the autonomic nervous system influences CBF...... perfusion and reduces the near-infrared determined cerebral oxygenation at rest, but not during exercise associated with an increased cerebral metabolic rate for oxygen (CMRO(2)), suggesting competition between CMRO(2) and sympathetic control of CBF. CMRO(2) does not change during even intense handgrip...

  19. 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.

  20. Bioactivation of food genotoxicants 5-hydroxymethylfurfural and furfuryl alcohol by sulfotransferases from human, mouse and rat: a comparative study.

    Science.gov (United States)

    Sachse, Benjamin; Meinl, Walter; Sommer, Yasmin; Glatt, Hansruedi; Seidel, Albrecht; Monien, Bernhard H

    2016-01-01

    5-Hydroxymethylfurfural (HMF) and furfuryl alcohol (FFA) are moderately potent rodent carcinogens that are present in thermally processed foodstuffs. The carcinogenic effects were hypothesized to originate from sulfotransferase (SULT)-mediated bioactivation yielding DNA-reactive and mutagenic sulfate esters, a confirmed metabolic pathway of HMF and FFA in mice. It is known that orthologous SULT forms substantially differ in substrate specificity and tissue distribution. This could influence HMF- and FFA-induced carcinogenic effects. Here, we studied HMF and FFA sulfoconjugation by 30 individual SULT forms of humans, mice and rats. The catalytic efficiencies (k cat/K M) of HMF sulfoconjugation of human SULT1A1 (13.7 s(-1) M(-1)), mouse Sult1a1 (15.8 s(-1) M(-1)) and 1d1 (4.8 s(-1) M(-1)) and rat Sult1a1 (5.3 s(-1) M(-1)) were considerably higher than those of all other SULT forms investigated (≤0.73 s(-1 )M(-1)). FFA sulfoconjugation was monitored using adenosine as a nucleophilic scavenger for the reactive 2-sulfoxymethylfuran (t 1/2 = 20 s at 37 °C). The resulting adduct N (6)-((furan-2-yl)methyl)-adenosine (N (6)-MF-A) was quantified by isotope-dilution UPLC-MS/MS. The rates of N (6)-MF-A formation showed that hSULT1A1 and its orthologues in mice and rats were also the most important contributors to FFA sulfoconjugation in each of the species. Taken together, the catalytic capacity of hSULT1A1 is comparable to that of mSult1a1 in mice, the species in which carcinogenic effects of HMF and FFA were detected. This is of primary concern due to the expression of hSULT1A1 in many different tissues.

  1. Ketone body metabolism in normal and diabetic human skeletal muscle

    International Nuclear Information System (INIS)

    Nosadini, R.; Avogaro, A.; Sacca, L.

    1985-01-01

    Although the liver is considered the major source of ketone bodies (KB) in humans, these compounds may also be formed by nonhepatic tissues. To study this aspect further, 3-[ 14 C]hydroxybutyrate (BOH) or [3- 14 C]acetoacetate (AcAc) were constantly infused after a priming dose and contemporaneous arterial and venous samples were taken at splanchnic, heart, kidney, and leg sites in eight normal subjects (N) undergoing diagnostic catheterization and at the forearm site in five normal and six ketotic diabetic (D) subjects. After 70 min of infusion, tracer and tracee levels of AcAc and BOH reached a steady state in the artery and vein in both normal and diabetic subjects. The venous-arterial (V-A) difference at the forearm step for cold KB was negligible both in normal and diabetic subjects, whereas for labeled KB it was approximately 10-fold higher in diabetic subjects (V-A AcAc, -31 +/- 7 and -270 +/- 34 dpm/ml in N and D, respectively; V-A BOH, -38 +/- 6 and -344 +/- 126 dpm/ml in N and D, respectively). The authors assumed that the V-A difference in tracer concentration was consistent with dilution of the tracer by newly synthesized tracee inside the muscle and calculated that the forearm muscle produces KB at a rate of 16.2 +/- 3.3 mumol/min in D and 0.9 +/- 0.9 mumol/min in N. These findings can be accounted for by the hypothesis that the disappearance flux of KB from circulation was replaced by an equivalent flux of KB entering the vein at the muscle step in D but not in N. Moreover, in N KB were not only produced but also utilized by the splanchnic area (39 +/- 9 mumol/min)

  2. Metabolism of azo dyes by human skin microbiota.

    Science.gov (United States)

    Stingley, Robin L; Zou, Wen; Heinze, Thomas M; Chen, Huizhong; Cerniglia, Carl E

    2010-01-01

    Reduction of Methyl Red (MR) and Orange II (Or II) by 26 human skin bacterial species was monitored by a rapid spectrophotometric assay. The analysis indicated that skin bacteria, representing the genera Staphylococcus, Corynebacterium, Micrococcus, Dermacoccus and Kocuria, were able to reduce MR by 74-100 % in 24 h, with only three species unable to reduce completely the dye in that time. Among the species tested, only Corynebacterium xerosis was unable to reduce Or II to any degree by 24 h, and only Staphylococcus delphini, Staphylococcus sciuri subsp. sciuri and Pseudomonas aeruginosa were able to reduce completely this dye within 24 h. MR reduction started with early-exponential growth in Staphylococcus aureus and Staphylococcus epidermidis, and around late-exponential/early-stationary growth in P. aeruginosa. Reduction of Or II, Ponceau S and Ponceau BS started during late-exponential/early-stationary growth for all three species. Using liquid chromatography/electrospray ionization mass spectrometry analyses, MR metabolites produced by Staph. aureus, Staph. epidermidis and P. aeruginosa were identified as N,N-dimethyl-p-phenylenediamine and 2-aminobenzoic acid. Searches of available genomic and proteomic data revealed that at least four of the staphylococci in this study, Staphylococcus haemolyticus, Staph. epidermidis, Staphylococcus cohnii and Staphylococcus saprophyticus, have hypothetical genes with 77, 76, 75 and 74 % sequence identity to azo1 encoding an azoreductase from Staph. aureus and hypothetical proteins with 82, 80, 72 and 74 % identity to Azo1, respectively. In addition, Staphylococcus capitis has a protein with 79 % identity to Azo1. Western analysis detected proteins similar to Azo1 in all the staphylococci tested, except Staph. delphini, Staph. sciuri subsp. sciuri and Staphylococcus auricularis. The data presented in this report will be useful in the risk assessment process for evaluation of public exposure to products containing these dyes.

  3. Plasma metabolism of apolipoprotein A-IV in humans

    International Nuclear Information System (INIS)

    Ghiselli, G.; Krishnan, S.; Beigel, Y.; Gotto, A.M. Jr.

    1986-01-01

    As assessed by molecular sieve chromatography and quantitation by a specific radioimmunoassay, apoA-IV is associated in plasma with the triglyceride-rich lipoproteins, to a high density lipoprotein (HDL) subfraction of smaller size than HDL3, and to the plasma lipoprotein-free fraction (LFF). In this study, the turnover of apoA-IV associated to the triglyceride-rich lipoproteins, HDL and LFF was investigated in vivo in normal volunteers. Human apoA-IV isolated from the thoracic duct lymph chylomicrons was radioiodinated and incubated with plasma withdrawn from normal volunteers after a fatty meal. Radioiodinated apoA-IV-labeled triglyceride-rich lipoproteins, HDL, and LFF were then isolated by chromatography on an AcA 34 column. Shortly after the injection of the radioiodinated apoA-IV-labeled triglyceride-rich lipoproteins, most of the radioactivity could be recovered in the HDL and LFF column fractions. On the other hand, when radioiodinated apoA-IV-labeled HDL or LFF were injected, the radioactivity remained with the originally injected fractions at all times. The residence time in plasma of 125 I-labeled apoA-IV, when injected in association with HDL or LFF, was 1.61 and 0.55 days, respectively. When 125 I-labeled apoA-IV was injected as a free protein, the radioactivity distributed rapidly among the three plasma pools in proportion to their mass. The overall fractional catabolic rate of apoA-IV in plasma was measured in the three normal subjects and averaged 1.56 pools per day. The mean degradation rate of apoA-IV was 8.69 mg/kg X day

  4. Age dependent in vitro metabolism of bifenthrin in rat and human hepatic microsomes.

    Science.gov (United States)

    Nallani, Gopinath C; Chandrasekaran, Appavu; Kassahun, Kelem; Shen, Li; ElNaggar, Shaaban F; Liu, Zhiwei

    2018-01-01

    Bifenthrin, a pyrethroid insecticide, undergoes oxidative metabolism leading to the formation of 4'-hydroxy-bifenthrin (4'-OH-BIF) and hydrolysis leading to the formation of TFP acid in rat and human hepatic microsomes. In this study, age-dependent metabolism of bifenthrin in rats and humans were determined via the rates of formation of 4'-OH-BIF and TFP acid following incubation of bifenthrin in juvenile and adult rat (PND 15 and PND 90) and human (18years) liver microsomes. Furthermore, in vitro hepatic intrinsic clearance (CL int ) of bifenthrin was determined by substrate consumption method in a separate experiment. The mean V max (±SD) for the formation of 4'-OH-BIF in juvenile rat hepatic microsomes was 25.0±1.5pmol/min/mg which was significantly lower (pbifenthrin occurs primarily via oxidative pathway with relatively lesser contribution (~30%) from hydrolytic pathway in both rat and human liver microsomes. The CL int values for bifenthrin, determined by monitoring the consumption of substrate, in juvenile and adult rat liver microsomes fortified with NADPH were 42.0±7.2 and 166.7±20.5μl/min/mg, respectively, and the corresponding values for human liver microsomes were 76.0±4.0 and 21.3±1.2μl/min/mg, respectively. The data suggest a major species difference in the age dependent metabolism of bifenthrin. In human liver microsomes, bifenthrin is metabolized at a much higher rate in juveniles than in adults, while the opposite appears to be true in rat liver microsomes. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Methods of Assessing Human Tendon Metabolism and Tissue Properties in Response to Changes in Mechanical Loading

    DEFF Research Database (Denmark)

    Heinemeier, Katja M; Kjaer, Michael; Magnusson, S Peter

    2016-01-01

    expression as well as protein synthesis rate. Further the (14)C bomb-pulse method has provided data on long-term tissue turnover in human tendon. Non-invasive techniques allow measurement of tendon metabolism (positron emission tomography (PET)), tendon morphology (magnetic resonance imaging (MRI......In recent years a number of methodological developments have improved the opportunities to study human tendon. Microdialysis enables sampling of interstitial fluid in the peritendon tissue, while sampling of human tendon biopsies allows direct analysis of tendon tissue for gene- and protein...

  6. Predictive Utility of Brief Alcohol Use Disorders Identification Test (AUDIT) for human immunodeficiency virus antiretroviral medication nonadherence.

    Science.gov (United States)

    Broyles, Lauren Matukaitis; Gordon, Adam J; Sereika, Susan M; Ryan, Christopher M; Erlen, Judith A

    2011-10-01

    Alcohol use negatively affects adherence to antiretroviral therapy (ART), thus human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) care providers need accurate, efficient assessments of alcohol use. Using existing data from an efficacy trial of 2 cognitive-behavioral ART adherence interventions, the authors sought to determine if results on 2 common alcohol screening tests (Alcohol Use Disorders Identification Test--Consumption [AUDIT-C] and its binge-related question [AUDIT-3]) predict ART nonadherence. Twenty-seven percent of the sample (n = 308) were positive on the AUDIT-C and 34% were positive on the AUDIT-3. In multivariate analyses, AUDIT-C-positive status predicted ART nonadherence after controlling for race, age, conscientiousness, and self-efficacy (P = .036). Although AUDIT-3-positive status was associated with ART nonadherence in unadjusted analyses, this relationship was not maintained in the final multivariate model. The AUDIT-C shows potential as an indirect screening tool for both at-risk drinking and ART nonadherence, underscoring the relationship between alcohol and chronic disease management.

  7. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    Science.gov (United States)

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-06-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.

  8. Effect of obesity and metabolic syndrome on plasma oxysterols and fatty acids in human.

    Science.gov (United States)

    Tremblay-Franco, Marie; Zerbinati, Chiara; Pacelli, Antonio; Palmaccio, Giuseppina; Lubrano, Carla; Ducheix, Simon; Guillou, Hervé; Iuliano, Luigi

    2015-07-01

    Obesity and the related entity metabolic syndrome are characterized by altered lipid metabolism and associated with increased morbidity risk for cardiovascular disease and cancer. Oxysterols belong to a large family of cholesterol-derived molecules known to play crucial role in many signaling pathways underlying several diseases. Little is known on the potential effect of obesity and metabolic syndrome on oxysterols in human. In this work, we questioned whether circulating oxysterols might be significantly altered in obese patients and in patients with metabolic syndrome. We also tested the potential correlation between circulating oxysterols and fatty acids. 60 obese patients and 75 patients with metabolic syndrome were enrolled in the study along with 210 age- and sex-matched healthy subjects, used as control group. Plasma oxysterols were analyzed by isotope dilution GC/MS, and plasma fatty acids profiling was assessed by gas chromatography coupled with flame ionization detection. We found considerable differences in oxysterols profiling in the two disease groups that were gender-related. Compared to controls, males showed significant differences only in 4α- and 4β-hydroxycholesterol levels in obese and metabolic syndrome patients. In contrast, females showed consistent differences in 7-oxocholesterol, 4α-hydroxycholesterol, 25-hydroxycholesterol and triol. Concerning fatty acids, we found minor differences in the levels of these variables in males of the three groups. Significant changes were observed in plasma fatty acid profile of female patients with obesity or metabolic syndrome. We found significant correlations between various oxysterols and fatty acids. In particular, 4β-hydroxycholesterol, which is reduced in obesity and metabolic syndrome, correlated with a number of saturated and mono-unsaturated fatty acids that are end-products of de novo lipogenesis. Our data provide the first evidence that obesity and metabolic syndrome are associated with

  9. A computer model simulating human glucose absorption and metabolism in health and metabolic disease states [version 1; referees: 2 approved, 1 approved with reservations

    Directory of Open Access Journals (Sweden)

    Richard J. Naftalin

    2016-04-01

    Full Text Available A computer model designed to simulate integrated glucose-dependent changes in splanchnic blood flow with small intestinal glucose absorption, hormonal and incretin circulation and hepatic and systemic metabolism in health and metabolic diseases e.g. non-alcoholic fatty liver disease, (NAFLD, non-alcoholic steatohepatitis, (NASH and type 2 diabetes mellitus, (T2DM demonstrates how when glucagon-like peptide-1, (GLP-1 is synchronously released into the splanchnic blood during intestinal glucose absorption, it stimulates superior mesenteric arterial (SMA blood flow and by increasing passive intestinal glucose absorption, harmonizes absorption with its distribution and metabolism. GLP-1 also synergises insulin-dependent net hepatic glucose uptake (NHGU. When GLP-1 secretion is deficient post-prandial SMA blood flow is not increased and as NHGU is also reduced, hyperglycaemia follows. Portal venous glucose concentration is also raised, thereby retarding the passive component of intestinal glucose absorption.   Increased pre-hepatic sinusoidal resistance combined with portal hypertension leading to opening of intrahepatic portosystemic collateral vessels are NASH-related mechanical defects that alter the balance between splanchnic and systemic distributions of glucose, hormones and incretins.The model reveals the latent contribution of portosystemic shunting in development of metabolic disease. This diverts splanchnic blood content away from the hepatic sinuses to the systemic circulation, particularly during the glucose absorptive phase of digestion, resulting in inappropriate increases in insulin-dependent systemic glucose metabolism.  This hastens onset of hypoglycaemia and thence hyperglucagonaemia. The model reveals that low rates of GLP-1 secretion, frequently associated with T2DM and NASH, may be also be caused by splanchnic hypoglycaemia, rather than to intrinsic loss of incretin secretory capacity. These findings may have therapeutic

  10. Alcohol and Health. Fifth Special Report to the U.S. Congress from the Secretary of Health and Human Services.

    Science.gov (United States)

    National Inst. on Alcohol Abuse and Alcoholism (DHHS), Rockville, MD.

    This report is divided into an overview of alcohol and health, and eight chapters which deal with various aspects of alcohol use and abuse. The epidemiology of alcohol abuse and alcoholism is discussed. Data are presented on self-reported consumption of alcohol among youths and adults; alcohol consumption during pregnancy; alcohol-related…

  11. Alcohol Alert

    Science.gov (United States)

    ... of Alcohol Consumption Alcohol's Effects on the Body Alcohol Use Disorder Fetal Alcohol Exposure Support & Treatment Alcohol Policy Special ... 466 KB] No. 81: Exploring Treatment Options for Alcohol Use Disorders [ PDF - 539K] No. 80: Alcohol and HIV/AIDS: ...

  12. [ALLELES C282Y AND H63D HFE GENE, INSULIN RESISTANCE AND SUSCEPTIBILITY TO DISTURBANCE OF PORPHYRIN METABOLISM IN NON-ALCOHOLIC FATTY LIVER DISEASE].

    Science.gov (United States)

    Krivosheev, A B; Maximov, V N; Voevoda, M I; Kuimov, A D; Kondratova, M A; Tuguleva, T A; Koval, O N; Bezrukova, A A; Bogorianova, P A; Rybina, O V

    2015-01-01

    The aim of the present work was to study the frequency of genotypes and alleles of C282Y and H63D HFE gene that may be associated with impaired porphyrin metabolism, as well as possible reasons for the formation of dysmetabolism porphyrins with NAFLD. The study involved 65 patients (52 men and 13 women) aged 21 to 69 years (mean age 48.5±1.5 years). Excretion uroporphyrin, coproporphyrin, 6-aminolevulinic acid of porphobilinogen in urine was determined by chromatography and spectrophotometry calculated total excretion of porphyrins. Allele frequencies C282Y and H63D were determined during the molecular genetic analysis of DNA using the polymerase chain reaction followed by analysis of length polymorphism restraktsionnyh fragments. Condition of carbohydrate metabolism was evaluated by the level of fasting blood glucose and standard glucose tolerance test. Diagnosis of insulin resistance was performed according to the criteria proposed by the European Group for the Study of insulin resistance (EGIR). Skill test for the C282Y mutation carriage and H63D in the HFE gene in 65 patients with non-alcoholic fatty liver disease. Disturbances in the metabolism of porphyrins were recorded in 43 (66.2%) patients. H63D and C282Y mutations were found in 18 (27.7%) patients, of whom 13 (72.2%) people with different options dismetabolism porphyrins and signs of insulin resistance. In 47 (72.3%) patients without mutations studied porphyrin metabolism disorders were detected in 30 (63.8 %), of which insulin resistance is registered only in 16 (34.0 %). Detection of mutations C282Y and H63D in the HFE gene in combination with disorders of porphyrin metabolism on the background of insulin resistance is likely to allow such patients considered as candidates for inclusion in the higher risk of formation of diabetes.

  13. Molecular Basis of Alcohol-Related Gastric and Colon Cancer.

    Science.gov (United States)

    Na, Hye-Kyung; Lee, Ja Young

    2017-05-24

    Many meta-analysis, large cohort studies, and experimental studies suggest that chronic alcohol consumption increases the risk of gastric and colon cancer. Ethanol is metabolized by alcohol dehydrogenases (ADH), catalase or cytochrome P450 2E1 (CYP2E1) to acetaldehyde, which is then further oxidized to acetate by aldehyde dehydrogenase (ALDH). Acetaldehyde has been classified by the International Agency for Research on Cancer (IARC) as a Group 1 carcinogen to humans. The acetaldehyde level in the stomach and colon is locally influenced by gastric colonization by Helicobacter pylori or colonic microbes, as well as polymorphisms in the genes encoding tissue alcohol metabolizing enzymes, especially ALDH2. Alcohol stimulates the uptake of carcinogens and their metabolism and also changes the composition of enteric microbes in a way to enhance the aldehyde level. Alcohol also undergoes chemical coupling to membrane phospholipids and disrupts organization of tight junctions, leading to nuclear translocation of β-catenin and ZONAB, which may contributes to regulation of genes involved in proliferation, invasion and metastasis. Alcohol also generates reactive oxygen species (ROS) by suppressing the expression of antioxidant and cytoprotective enzymes and inducing expression of CYP2E1 which contribute to the metabolic activation of chemical carcinogens. Besides exerting genotoxic effects by directly damaging DNA, ROS can activates signaling molecules involved in inflammation, metastasis and angiogenesis. In addition, alcohol consumption induces folate deficiency, which may result in aberrant DNA methylation profiles, thereby influencing cancer-related gene expression.

  14. Effects of hyperthermia on cerebral blood flow and metabolism during prolonged exercise in humans

    DEFF Research Database (Denmark)

    Nybo, Lars; Møller, Kirsten; Volianitis, Stefanos

    2002-01-01

    The development of hyperthermia during prolonged exercise in humans is associated with various changes in the brain, but it is not known whether the cerebral metabolism or the global cerebral blood flow (gCBF) is affected. Eight endurance-trained subjects completed two exercise bouts on a cycle...... ergometer. The gCBF and cerebral metabolic rates of oxygen, glucose, and lactate were determined with the Kety-Schmidt technique after 15 min of exercise when core temperature was similar across trials, and at the end of exercise, either when subjects remained normothermic (core temperature = 37.9 degrees C...... with control at the end of exercise (43 +/- 4 vs. 51 +/- 4 ml. 100 g(-1). min(-1); P glucose, and the cerebral metabolic rate was therefore higher at the end...

  15. Impact of training state on fasting-induced regulation of adipose tissue metabolism in humans

    DEFF Research Database (Denmark)

    Bertholdt, Lærke; Gudiksen, Anders; Stankiewicz, Tomasz

    2018-01-01

    Recruitment of fatty acids from adipose tissue is essential during fasting. However, the molecular mechanisms behind fasting-induced metabolic regulation in human adipose tissue and the potential impact of training state in this are unknown. Therefore, the aim of the present study was to investig......Recruitment of fatty acids from adipose tissue is essential during fasting. However, the molecular mechanisms behind fasting-induced metabolic regulation in human adipose tissue and the potential impact of training state in this are unknown. Therefore, the aim of the present study...... was to investigate 1) fasting-induced regulation of lipolysis and glyceroneogenesis in human adipose tissue as well as 2) the impact of training state on basal oxidative capacity and fasting-induced metabolic regulation in human adipose tissue. Untrained (VO2max 55ml......RNA content were higher in trained subjects than untrained subjects. In addition, trained subjects had higher adipose tissue hormone sensitive lipase Ser660 phosphorylation and adipose triglyceride lipase protein content as well as higher plasma free fatty acids concentration than untrained subjects during...

  16. The human hepatocyte cell lines IHH and HepaRG: models to study glucose, lipid and lipoprotein metabolism.

    Science.gov (United States)

    Samanez, Carolina Huaman; Caron, Sandrine; Briand, Olivier; Dehondt, Hélène; Duplan, Isabelle; Kuipers, Folkert; Hennuyer, Nathalie; Clavey, Véronique; Staels, Bart

    2012-07-01

    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 stimuli is often lost. Here, we characterize two human hepatocyte cell lines, IHH and HepaRG, by analysing the expression and regulation of genes involved in glucose and lipid metabolism. Our results show that the glycolysis pathway is activated by glucose and insulin in both lines. Gluconeogenesis gene expression is induced by forskolin in IHH cells and inhibited by insulin in both cell lines. The lipogenic pathway is regulated by insulin in IHH cells. Finally, both cell lines secrete apolipoprotein B-containing lipoproteins, an effect promoted by increasing glucose concentrations. These two human cell lines are thus interesting models to study the regulation of glucose and lipid metabolism.

  17. Sex-specific metabolic interactions between liver and adipose tissue in MCD diet-induced non-alcoholic fatty liver disease.

    Science.gov (United States)

    Lee, Yun-Hee; Kim, Sou Hyun; Kim, Sang-Nam; Kwon, Hyun-Jung; Kim, Jeong-Dong; Oh, Ji Youn; Jung, Young-Suk

    2016-07-26

    Higher susceptibility to metabolic disease in male exemplifies the importance of sexual dimorphism in pathogenesis. We hypothesized that the higher incidence of non-alcoholic fatty liver disease in males involves sex-specific metabolic interactions between liver and adipose tissue. In the present study, we used a methionine-choline deficient (MCD) diet-induced fatty liver mouse model to investigate sex differences in the metabolic response of the liver and adipose tissue. After 2 weeks on an MCD-diet, fatty liver was induced in a sex-specific manner, affecting male mice more severely than females. The MCD-diet increased lipolytic enzymes in the gonadal white adipose tissue (gWAT) of male mice, whereas it increased expression of uncoupling protein 1 and other brown adipocyte markers in the gWAT of female mice. Moreover, gWAT from female mice demonstrated higher levels of oxygen consumption and mitochondrial content compared to gWAT from male mice. FGF21 expression was increased in liver tissue by the MCD diet, and the degree of upregulation was significantly higher in the livers of female mice. The endocrine effect of FGF21 was responsible, in part, for the sex-specific browning of gonadal white adipose tissue. Collectively, these data demonstrated that distinctively female-specific browning of white adipose tissue aids in protecting female mice against MCD diet-induced fatty liver disease.

  18. Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism

    International Nuclear Information System (INIS)

    Ucciferri, Nadia; Sbrana, Tommaso; Ahluwalia, Arti

    2014-01-01

    Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell–cell or cell–tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

  19. Metabolomics analysis of metabolic effects of nicotinamide phosphoribosyltransferase (NAMPT inhibition on human cancer cells.

    Directory of Open Access Journals (Sweden)

    Vladimir Tolstikov

    Full Text Available Nicotinamide phosphoribosyltransferase (NAMPT plays an important role in cellular bioenergetics. It is responsible for converting nicotinamide to nicotinamide adenine dinucleotide, an essential molecule in cellular metabolism. NAMPT has been extensively studied over the past decade due to its role as a key regulator of nicotinamide adenine dinucleotide-consuming enzymes. NAMPT is also known as a potential target for therapeutic intervention due to its involvement in disease. In the current study, we used a global mass spectrometry-based metabolomic approach to investigate the effects of FK866, a small molecule inhibitor of NAMPT currently in clinical trials, on metabolic perturbations in human cancer cells. We treated A2780 (ovarian cancer and HCT-116 (colorectal cancer cell lines with FK866 in the presence and absence of nicotinic acid. Significant changes were observed in the amino acids metabolism and the purine and pyrimidine metabolism. We also observed metabolic alterations in glycolysis, the citric acid cycle (TCA, and the pentose phosphate pathway. To expand the range of the detected polar metabolites and improve data confidence, we applied a global metabolomics profiling platform by using both non-targeted and targeted hydrophilic (HILIC-LC-MS and GC-MS analysis. We used Ingenuity Knowledge Base to facilitate the projection of metabolomics data onto metabolic pathways. Several metabolic pathways showed differential responses to FK866 based on several matches to the list of annotated metabolites. This study suggests that global metabolomics can be a useful tool in pharmacological studies of the mechanism of action of drugs at a cellular level.

  20. Allometric scaling and cell ratios in multi-organ in vitro models of human metabolism

    Directory of Open Access Journals (Sweden)

    Nadia eUcciferri

    2014-12-01

    Full Text Available Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step towards building an integrated picture of systemic metabolism and signalling in physiological or pathological conditions. However the rational design of in vitro models of cell-cell or cell-tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here we analyse the physiologic relationship between cells, cell metabolism and exchange in the human body using allometric rules, downscaling them to an organ-on-a plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (Cell Number Scaling Model, CNSM, and Metabolic and Surface Scaling model, MSSM are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions which can be extrapolated to the in vivo

  1. Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism.

    Science.gov (United States)

    Ucciferri, Nadia; Sbrana, Tommaso; Ahluwalia, Arti

    2014-01-01

    Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell-cell or cell-tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

  2. Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism

    Energy Technology Data Exchange (ETDEWEB)

    Ucciferri, Nadia [CNR Institute of Clinical Physiology, Pisa (Italy); Interdepartmental Research Center “E. Piaggio”, University of Pisa, Pisa (Italy); Sbrana, Tommaso [Interdepartmental Research Center “E. Piaggio”, University of Pisa, Pisa (Italy); Ahluwalia, Arti, E-mail: arti.ahluwalia@unipi.it [CNR Institute of Clinical Physiology, Pisa (Italy); Interdepartmental Research Center “E. Piaggio”, University of Pisa, Pisa (Italy)

    2014-12-17

    Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell–cell or cell–tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

  3. Metabolism of nitrogen-13 labelled ammonia in different conditions in dogs, human volunteers and transplant patients

    International Nuclear Information System (INIS)

    Bormans, G.; Maes, A.; Langendries, W.; Nuyts, J.; Vrolix, M.; Vanhaecke, J.; Schiepers, C.; Roo, M. de; Mortelmans, L.; Verbruggen, A.

    1995-01-01

    To investigate the rate of metabolism of nitrogen-13 labelled ammonia ( 13 NH 3 ) in different conditions, we have determined the relative amount of unchanged 13 NH 3 in the blood of dogs, volunteers and transplant patients at different times following injection. In dogs, the determinations were made under basal conditions, during adenosine administration and after coronary occlusion. The results show that adenosine administration increases the metabolic rate whereas coronary occlusion does not affect 13 NH 3 metabolism. For both human volunteers and transplant patients the metabolic rate of 13 NH 3 was assessed under basal conditions and during adenosine administration. 13 NH 3 metabolism proceeds faster in transplant patients than in volunteers under both conditions. Adenosine administration causes a faster 13 NH 3 turnover in volunteers but not in transplant patients. Application of individual metabolite correction resulted in a 16% decrease in the calculated blood flow compared to uncorrected values. A smaller difference (5%) was observed between correction with mean metabolite values and individually acquired metabolite values. (orig.)

  4. Metabolism of oxycodone in human hepatocytes from different age groups and prediction of hepatic plasma clearance

    Directory of Open Access Journals (Sweden)

    Timo eKorjamo

    2012-01-01

    Full Text Available Oxycodone is commonly used to treat severe pain in adults and children. It is extensively metabolized in the liver in adults, but the maturation of metabolism is not well understood. Our aim was to study the metabolism of oxycodone in cryopreserved human hepatocytes from different age groups (3 days, 2 and 5 months, 4 years, adult pool and predict hepatic plasma clearance of oxycodone using these data. Oxycodone (0.1, 1 and 10 µM was incubated with hepatocytes for 4 hours, and 1 µM oxycodone also with CYP3A inhibitor ketoconazole (1 µM. Oxycodone and noroxycodone concentrations were determined at several time points with liquid chromatography-mass spectrometry. In vitro clearance of oxycodone was used to predict hepatic plasma clearance, using the well-stirred model and published physiological parameters. Noroxycodone was the major metabolite in all batches and ketoconazole inhibited the metabolism markedly in most cases. A clear correlation between in vitro oxycodone clearance and CYP3A4 activity was observed. The predicted hepatic plasma clearances were typically much lower than the published median total plasma clearance from pharmacokinetic studies. In general, this in vitro to in vivo extrapolation method provides valuable information on the maturation of oxycodone metabolism that can be utilized in the design of clinical pharmacokinetic studies in infants and young children.

  5. Mass spectrometry characterization of circulating human serum albumin microheterogeneity in patients with alcoholic hepatitis.

    Science.gov (United States)

    Naldi, Marina; Baldassarre, Maurizio; Domenicali, Marco; Giannone, Ferdinando Antonino; Bossi, Matteo; Montomoli, Jonathan; Sandahl, Thomas Damgaard; Glavind, Emilie; Vilstrup, Hendrik; Caraceni, Paolo; Bertucci, Carlo

    2016-04-15

    Human serum albumin (HSA) is the most abundant plasma protein, endowed with several biological properties unrelated to its oncotic power, such as antioxidant and free-radicals scavenging activities, binding and transport of many endogenous and exogenous substances, and regulation of endothelial function and inflammatory response. These non-oncotic activities are closely connected to the peculiarly dynamic structure of the albumin molecule. HSA undergoes spontaneous structural modifications, mainly by reaction with oxidants and saccharides; however, patients with cirrhosis show extensive post-transcriptional changes at several molecular sites of HSA, the degree of which parallels the severity of the disease. The present work reports the development and application of an innovative LC-MS analytical method for a rapid and reproducible determination of the relative abundance of HSA isoforms in plasma samples from alcoholic hepatitis (AH) patients. A condition of severe oxidative stress, similar to that observed in AH patients, is associated with profound changes in circulating HSA microheterogeneity. More interestingly, the high resolution provided by the analytical platform allowed the monitoring of novel oxidative products of HSA never reported before. Copyright © 2016 Elsevier B.V. All rights reserved.

  6. Network Thermodynamic Curation of Human and Yeast Genome-Scale Metabolic Models

    Science.gov (United States)

    Martínez, Verónica S.; Quek, Lake-Ee; Nielsen, Lars K.

    2014-01-01

    Genome-scale models are used for an ever-widening range of applications. Although there has been much focus on specifying the stoichiometric matrix, the predictive power of genome-scale models equally depends on reaction directions. Two-thirds of reactions in the two eukaryotic reconstructions Homo sapiens Recon 1 and Yeast 5 are specified as irreversible. However, these specifications are mainly based on biochemical textbooks or on their similarity to other organisms and are rarely underpinned by detailed thermodynamic analysis. In this study, a to our knowledge new workflow combining network-embedded thermodynamic and flux variability analysis was used to evaluate existing irreversibility constraints in Recon 1 and Yeast 5 and to identify new ones. A total of 27 and 16 new irreversible reactions were identified in Recon 1 and Yeast 5, respectively, whereas only four reactions were found with directions incorrectly specified against thermodynamics (three in Yeast 5 and one in Recon 1). The workflow further identified for both models several isolated internal loops that require further curation. The framework also highlighted the need for substrate channeling (in human) and ATP hydrolysis (in yeast) for the essential reaction catalyzed by phosphoribosylaminoimidazole carboxylase in purine metabolism. Finally, the framework highlighted differences in proline metabolism between yeast (cytosolic anabolism and mitochondrial catabolism) and humans (exclusively mitochondrial metabolism). We conclude that network-embedded thermodynamics facilitates the specification and validation of irreversibility constraints in compartmentalized metabolic models, at the same time providing further insight into network properties. PMID:25028891

  7. Insights into the impact of silver nanoparticles on human keratinocytes metabolism through NMR metabolomics.

    Science.gov (United States)

    Carrola, Joana; Bastos, Verónica; Ferreira de Oliveira, José Miguel P; Oliveira, Helena; Santos, Conceição; Gil, Ana M; Duarte, Iola F

    2016-01-01

    Due to their antimicrobial properties, silver nanoparticles (AgNPs) are increasingly incorporated into consumer goods and medical products. Their potential toxicity to human cells is however a major concern, and there is a need for improved understanding of their effects on cell metabolism and function. Here, Nuclear Magnetic Resonance (NMR) metabolomics was used to investigate the metabolic profile of human epidermis keratinocytes (HaCaT cell line) exposed for 48 h to 30 nm citrate-stabilized spherical AgNPs (10 and 40 μg/mL). Intracellular aqueous extracts, organic extracts and extracellular culture medium were analysed to provide an integrated view of the cellular metabolic response. The specific metabolite variations, highlighted through multivariate analysis and confirmed by spectral integration, suggested that HaCaT cells exposed to AgNPs displayed upregulated glutathione-based antioxidant protection, increased glutaminolysis, downregulated tricarboxylic acid (TCA) cycle activity, energy depletion and cell membrane modification. Importantly, most metabolic changes were apparent in cells exposed to a concentration of AgNPs which did not affect cell viability at significant levels, thus underlying the sensitivity of NMR metabolomics to detect early biochemical events, even in the absence of a clear cytotoxic response. It can be concluded that NMR metabolomics is an important new tool in the field of in vitro nanotoxicology. Copyright © 2015 Elsevier Inc. All rights reserved.

  8. Effects of extracellular modulation through hypoxia on the glucose metabolism of human breast cancer stem cells

    Science.gov (United States)

    Yustisia, I.; Jusman, S. W. A.; Wanandi, S. I.

    2017-08-01

    Cancer stem cells have been reported to maintain stemness under certain extracellular changes. This study aimed to analyze the effect of extracellular O2 level modulation on the glucose metabolism of human CD24-/CD44+ breast cancer stem cells (BCSCs). The primary BCSCs (CD24-/CD44+ cells) were cultured under hypoxia (1% O2) for 0.5, 4, 6, 24 and 48 hours. After each incubation period, HIF1α, GLUT1 and CA9 expressions, as well as glucose metabolism status, including glucose consumption, lactate production, O2 consumption and extracellular pH (pHe) were analyzed using qRT-PCR, colorimetry, fluorometry, and enzymatic reactions, respectively. Hypoxia caused an increase in HIF1α mRNA expressions and protein levels and shifted the metabolic states to anaerobic glycolysis, as demonstrated by increased glucose consumption and lactate production, as well as decreased O2 consumption and pHe. Furthermore, we demonstrated that GLUT1 and CA9 mRNA expressions simultaneously increased, in line with HIF1α expression. In conclusion, modulation of the extracellular environment of human BCSCs through hypoxia shifedt the metabolic state of BCSCs to anaerobic glycolysis, which might be associated with GLUT1 and CA9 expressions regulated by HIFlα transcription factor.

  9. In Vitro Disease Model of Microgravity Conditioning on Human Energy Metabolism

    Science.gov (United States)

    Snyder, Jessica; Culbertson, C.; Zhang, Ye; Emami, K.; Wu, H.; Sun, Wei

    2010-01-01

    NASA and its partners are committed to introducing appropriate new technology to enable learning and living safely beyond the Earth for extended periods of time in a sustainable and possibly indefinite manner. In the responsible acquisition of that goal, life sciences is tasked to tune and advance current medical technology to prepare for human health and wellness in the space environment. The space environment affects the condition and function of biological systems from organ level function to shape of individual organelles. The objective of this paper is to study the effect of microgravity on kinetics of drug metabolism. This fundamental characterization is meaningful to (1) scientific understanding of the response of biology to microgravity and (2) clinical dosing requirements and pharmacological thresholds during long term manned space exploration. Metabolism kinetics of the anti-nausea drug promethazine (PMZ) were determined by an in vitro ground model of 3-dimensional aggregates of human hepatocytes conditioned to weightlessness using a rotating wall bioreactor. The authors observed up-regulated PMZ conversion in model microgravity conditions and attribute this to effect to model microgravity conditioning acting on metabolic mechanisms of the cells. Further work is necessary to determine which particular cellular mechanisms are governing the experimental observations, but the authors conclude kinetics of drug metabolism are responsive to gravitational fields and further study of this sensitivity would improve dosing of pharmaceuticals to persons exposed to a microgravity environment.

  10. The Effect of Piceatannol from Passion Fruit (Passiflora edulis Seeds on Metabolic Health in Humans

    Directory of Open Access Journals (Sweden)

    Munehiro Kitada

    2017-10-01

    Full Text Available Animal studies have shown the beneficial effects of piceatannol on metabolic health; however, there is a lack of human studies designed to examine these effects. The objective of this study was to investigate the effects of piceatannol on metabolic health in humans. This randomized, placebo-controlled study was conducted on 39 subjects, including 10 overweight men and 9 overweight women (BMI ≥ 25, as well as 10 non-overweight men and 10 non-overweight women (BMI < 25. Subjects received piceatannol (20 mg/day or placebo capsules for eight weeks in a random order. The primary outcome was the effect of piceatannol on glucose-metabolism, including insulin sensitivity. The secondary outcomes were the effects on other parameters, including blood pressure (BP, heart rate (HR, endothelial function, lipids, inflammation, oxidative stress, mood status, and Sirt1 and phospho-AMP-activated kinase (p-AMPK expression in isolated peripheral blood mononuclear cells (PBMNCs. Supplementation with piceatannol in overweight men reduced serum insulin levels, HOMA-IR, BP and HR. Other groups, including non-overweight men, as well as overweight and non-overweight women, showed no beneficial effects on insulin sensitivity, BP and HR. Furthermore, piceatannol is not associated with other data, including body weight (BW, body composition, endothelial function, lipids, inflammation, oxidative stress, mood status, and Sirt1/p-AMPK expression in PBMNCs. In conclusion, supplementation with piceatannol can improve metabolic health, including insulin sensitivity, BP and HR, in overweight men.

  11. Comparative metabolism of honokiol in mouse, rat, dog, monkey, and human hepatocytes.

    Science.gov (United States)

    Jeong, Hyeon-Uk; Kim, Ju-Hyun; Kong, Tae Yeon; Choi, Won Gu; Lee, Hye Suk

    2016-04-01

    Honokiol has antitumor, antioxidative, anti-inflammatory, and antithrombotic effects. Here we aimed to identify the metabolic profile of honokiol in mouse, rat, dog, monkey, and human hepatocytes and to characterize the enzymes responsible for the glucuronidation and sulfation of honokiol. Honokiol had a high hepatic extraction ratio in all five species, indicating that it was extensively metabolized. A total of 32 metabolites, including 17 common and 15 different metabolites, produced via glucuronidation, sulfation, and oxidation of honokiol allyl groups were tentatively identified using liquid chromatography-high resolution quadrupole Orbitrap mass spectrometry. Glucuronidation of honokiol to M8 (honokiol-4-glucuronide) and M9 (honokiol-2'-glucuronide) was the predominant metabolic pathway in hepatocytes of all five species; however, interspecies differences between 4- and 2'-glucuronidation of honokiol were observed. UGT1A1, 1A8, 1A9, 2B15, and 2B17 played major roles in M8 formation, whereas UGT1A7 and 1A9 played major roles in M9 formation. Human cDNA-expressed SULT1C4 played a major role in M10 formation (honokiol-2'-sulfate), whereas SULT1A1*1, 1A1*2, and 1A2 played major roles in M11 formation (honokiol-4-sulfate). In conclusion, honokiol metabolism showed interspecies differences.

  12. Genome-scale metabolic models applied to human health and disease.

    Science.gov (United States)

    Cook, Daniel J; Nielsen, Jens

    2017-11-01

    Advances in genome sequencing, high throughput measurement of gene and protein expression levels, data accessibility, and computational power have allowed genome-scale metabolic models (GEMs) to become a useful tool for understanding metabolic alterations associated with many different diseases. Despite the proven utility of GEMs, researchers confront multiple challenges in the use of GEMs, their application to human health and disease, and their construction and simulation in an organ-specific and disease-specific manner. Several approaches that researchers are taking to address these challenges include using proteomic and transcriptomic-informed methods to build GEMs for individual organs, diseases, and patients and using constraints on model behavior during simulation to match observed metabolic fluxes. We review the challenges facing researchers in the use of GEMs, review the approaches used to address these challenges, and describe advances that are on the horizon and could lead to a better understanding of human metabolism. WIREs Syst Biol Med 2017, 9:e1393. doi: 10.1002/wsbm.1393 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

  13. Detection of fluorotelomer alcohols in indoor environments and their relevance for human exposure.

    Science.gov (United States)

    Schlummer, Martin; Gruber, Ludwig; Fiedler, Dominik; Kizlauskas, Markus; Müller, Josef

    2013-07-01

    Fluorotelomer alcohols (FTOH) are important precursors of perfluorinated carboxylic acids (PFCA). These neutral and volatile compounds are frequently found in indoor air and may contribute to the overall human exposure to per- and polyfluorinated alkyl substances (PFAS). In this study air samples of ten workplace environments and a car interior were analysed. In addition, extracts and emissions from selected outdoor textiles were analysed in order to establish their potential contribution to the indoor levels of the above-mentioned compounds. Concentrations of FTOHs measured in air ranged from 0.15 to 46.8, 0.25 to 286, and 0.11 to 57.5ng/m(3) for 6:2, 8:2 and 10:2 FTOHs, respectively. The highest concentrations in air were identified in shops selling outdoor clothing, indicating outdoor textiles to be a relevant source of FTOH in indoor workplace environments. Total amounts of FTOH in materials of outdoor textiles accounted for selling outdoor textiles contains the highest levels of FTOH. Exposure of humans to perfluorooctanoic acid (PFOA) through absorption of FTOH and subsequent degradation is discussed on the basis of indoor air levels. Calculation of indoor air-related exposure using the median of the measured air levels revealed that exposure is on the same order of magnitude as the recently reported dietary intakes for a background-exposed population. On the basis of the 95th percentile, indoor air exposure to PFOA was estimated to exceed dietary exposure. However, indoor air-related intakes of FTOH are far below the tolerable daily intake (TDI) of PFOA, indicating that there is no risk to health, even when assuming an unrealistic complete degradation of FTOH into PFOA. Copyright © 2013 Elsevier Ltd. All rights reserved.

  14. Metabolic adaptation of a human pathogen during chronic infections - a systems biology approach

    DEFF Research Database (Denmark)

    Thøgersen, Juliane Charlotte

    modeling to uncover how human pathogens adapt to the human host. Pseudomonas aeruginosa infections in cystic fibrosis patients are used as a model system for under-­‐ standing these adaptation processes. The exploratory systems biology approach facilitates identification of important phenotypes...... by classical molecular biology approaches where genes and reactions typically are investigated in a one to one relationship. This thesis is an example of how mathematical approaches and modeling can facilitate new biologi-­‐ cal understanding and provide new surprising ideas to important biological processes....... and metabolic pathways that are necessary or related to establishment of chronic infections. Archetypal analysis showed to be successful in extracting relevant phenotypes from global gene expression da-­‐ ta. Furthermore, genome-­‐scale metabolic modeling showed to be useful in connecting the genotype...

  15. Human-Centered Development of an Online Social Network for Metabolic Syndrome Management.

    Science.gov (United States)

    Núñez-Nava, Jefersson; Orozco-Sánchez, Paola A; López, Diego M; Ceron, Jesus D; Alvarez-Rosero, Rosa E

    2016-01-01

    According to the International Diabetes Federation (IDF), a quarter of the world's population has Metabolic Syndrome (MS). To develop (and assess the users' degree of satisfaction of) an online social network for patients who suffer from Metabolic Syndrome, based on the recommendations and requirements of the Human-Centered Design. Following the recommendations of the ISO 9241-210 for Human-Centered Design (HCD), an online social network was designed to promote physical activity and healthy nutrition. In order to guarantee the active participation of the users during the development of the social network, a survey, an in-depth interview, a focal group, and usability tests were carried out with people suffering from MS. The study demonstrated how the different activities, recommendations, and requirements of the ISO 9241-210 are integrated into a traditional software development process. Early usability tests demonstrated that the user's acceptance and the effectiveness and efficiency of the social network are satisfactory.

  16. The human body metabolism process mathematical simulation based on Lotka-Volterra model

    Science.gov (United States)

    Oliynyk, Andriy; Oliynyk, Eugene; Pyptiuk, Olexandr; DzierŻak, RóŻa; Szatkowska, Małgorzata; Uvaysova, Svetlana; Kozbekova, Ainur

    2017-08-01

    The mathematical model of metabolism process in human organism based on Lotka-Volterra model has beeng proposed, considering healing regime, nutrition system, features of insulin and sugar fragmentation process in the organism. The numerical algorithm of the model using IV-order Runge-Kutta method has been realized. After the result of calculations the conclusions have been made, recommendations about using the modeling results have been showed, the vectors of the following researches are defined.

  17. Human mesenchymal stromal cell-secreted lactate induces M2-macrophage differentiation by metabolic reprogramming

    OpenAIRE

    Selleri, Silvia; Bifsha, Panojot; Civini, Sara; Pacelli, Consiglia; Dieng, Mame Massar; Lemieux, William; Jin, Ping; Bazin, Ren?e; Patey, Natacha; Marincola, Francesco M.; Moldovan, Florina; Zaouter, Charlotte; Trudeau, Louis-Eric; Benabdhalla, Basma; Louis, Isabelle

    2016-01-01

    Human mesenchymal stromal cells (MSC) have been shown to dampen immune response and promote tissue repair, but the underlying mechanisms are still under investigation. Herein, we demonstrate that umbilical cord-derived MSC (UC-MSC) alter the phenotype and function of monocyte-derived dendritic cells (DC) through lactate-mediated metabolic reprogramming. UC-MSC can secrete large quantities of lactate and, when present during monocyte-to-DC differentiation, induce instead the acquisition of M2-...

  18. The metabolism of the human brain studied with positron emission tomography

    International Nuclear Information System (INIS)

    Greitz, T.; Ingvar, D.H.; Widen, L.

    1985-01-01

    This volume presents coverage of the use of positron emission tomography (PET) to study the human brain. The contributors assess new developments in high-resolution positron emission tomography, cyclotrons, radiochemistry, and tracer kinetic models, and explore the use of PET in brain energy metabolism, blood flow, and protein synthesis measurements, receptor analysis, and pH determinations, In addition, they discuss the relevance and applications of positron emission tomography from the perspectives of physiology, neurology, and psychiatry

  19. Influence of dietary macronutrients on liver fat accumulation and metabolism

    OpenAIRE

    Parry, Siôn A; Hodson, Leanne

    2017-01-01

    The liver is a principal metabolic organ within the human body and has a major role in regulating carbohydrate, fat, and protein metabolism. With increasing rates of obesity, the prevalence of non-alcoholic fatty liver disease (NAFLD) is growing. It remains unclear why NAFLD, which is now defined as the hepatic manifestation of the metabolic syndrome, develops but lifestyle factors such as diet (ie, total calorie and specific nutrient intakes), appear to play a key role. Here we review the av...

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

    Energy Technology Data Exchange (ETDEWEB)

    Kaphalia, Lata [Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Boroumand, Nahal [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Hyunsu, Ju [Department of Preventive Medicine and Community Health, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Kaphalia, Bhupendra S., E-mail: bkaphali@utmb.edu [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 775555 (United States); Calhoun, William J. [Department of Internal Medicine, The University of Texas Medical Branch, Galveston, TX 775555 (United States)

    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 < 1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 μg/g in the lungs of ethanol-fed mice as compared to 1.5 μg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease. - Highlights: • Chronic

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

    International Nuclear Information System (INIS)

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

    2014-01-01

    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 < 1.0% in the controls. Acetaldehyde (oxidative metabolite of ethanol) was minimally, but significantly increased in ethanol-fed vs. pair-fed control mice. Total fatty acid ethyl esters (FAEEs, nonoxidative metabolites of ethanol) were 47.6 μg/g in the lungs of ethanol-fed mice as compared to 1.5 μg/g in pair-fed controls. Histological and immunohistological evaluation showed perivascular and peribronchiolar lymphocytic infiltration, and significant oxidative injury, in the lungs of ethanol-fed mice compared to pair-fed controls. Several fold increases for cytochrome P450 2E1, caspase 8 and caspase 3 found in the lungs of ethanol-fed mice as compared to pair-fed controls suggest role of oxidative stress in ethanol-induced lung injury. ER stress and unfolded protein response signaling were also significantly increased in the lungs of ethanol-fed mice. Surprisingly, no significant activation of inositol-requiring enzyme-1α and spliced XBP1 was observed indicating a lack of activation of corrective mechanisms to reinstate ER homeostasis. The data suggest that oxidative stress and prolonged ER stress, coupled with formation and accumulation of cytotoxic FAEEs may contribute to the pathogenesis of alcoholic lung disease. - Highlights: • Chronic

  2. Coordinated Expression of Phosphoinositide Metabolic Genes during Development and Aging of Human Dorsolateral Prefrontal Cortex.

    Directory of Open Access Journals (Sweden)

    Stanley I Rapoport

    Full Text Available Phosphoinositides, lipid-signaling molecules, participate in diverse brain processes within a wide metabolic cascade.Gene transcriptional networks coordinately regulate the phosphoinositide cascade during human brain Development and Aging.We used the public BrainCloud database for human dorsolateral prefrontal cortex to examine age-related expression levels of 49 phosphoinositide metabolic genes during Development (0 to 20+ years and Aging (21+ years.We identified three groups of partially overlapping genes in each of the two intervals, with similar intergroup correlations despite marked phenotypic differences between Aging and Development. In each interval, ITPKB, PLCD1, PIK3R3, ISYNA1, IMPA2, INPPL1, PI4KB, and AKT1 are in Group 1, PIK3CB, PTEN, PIK3CA, and IMPA1 in Group 2, and SACM1L, PI3KR4, INPP5A, SYNJ1, and PLCB1 in Group 3. Ten of the genes change expression nonlinearly during Development, suggesting involvement in rapidly changing neuronal, glial and myelination events. Correlated transcription for some gene pairs likely is facilitated by colocalization on the same chromosome band.Stable coordinated gene transcriptional networks regulate brain phosphoinositide metabolic pathways during human Development and Aging.

  3. Targeting Aberrant Glutathione Metabolism to Eradicate Human Acute Myelogenous Leukemia Cells*

    Science.gov (United States)

    Pei, Shanshan; Minhajuddin, Mohammad; Callahan, Kevin P.; Balys, Marlene; Ashton, John M.; Neering, Sarah J.; Lagadinou, Eleni D.; Corbett, Cheryl; Ye, Haobin; Liesveld, Jane L.; O'Dwyer, Kristen M.; Li, Zheng; Shi, Lei; Greninger, Patricia; Settleman, Jeffrey; Benes, Cyril; Hagen, Fred K.; Munger, Joshua; Crooks, Peter A.; Becker, Michael W.; Jordan, Craig T.

    2013-01-01

    The development of strategies to eradicate primary human acute myelogenous leukemia (AML) cells is a major challenge to the leukemia research field. In particular, primitive leukemia cells, often termed leukemia stem cells, are typically refractory to many forms of therapy. To investigate improved strategies for targeting of human AML cells we compared the molecular mechanisms regulating oxidative state in primitive (CD34+) leukemic versus normal specimens. Our data indicate that CD34+ AML cells have elevated expression of multiple glutathione pathway regulatory proteins, presumably as a mechanism to compensate for increased oxidative stress in leukemic cells. Consistent with this observation, CD34+ AML cells have lower levels of reduced glutathione and increased levels of oxidized glutathione compared with normal CD34+ cells. These findings led us to hypothesize that AML cells will be hypersensitive to inhibition of glutathione metabolism. To test this premise, we identified compounds such as parthenolide (PTL) or piperlongumine that induce almost complete glutathione depletion and severe cell death in CD34+ AML cells. Importantly, these compounds only induce limited and transient glutathione depletion as well as significantly less toxicity in normal CD34+ cells. We further determined that PTL perturbs glutathione homeostasis by a multifactorial mechanism, which includes inhibiting key glutathione metabolic enzymes (GCLC and GPX1), as well as direct depletion of glutathione. These findings demonstrate that primitive leukemia cells are uniquely sensitive to agents that target aberrant glutathione metabolism, an intrinsic property of primary human AML cells. PMID:24089526

  4. Impaired insulin action in the human brain: causes and metabolic consequences.

    Science.gov (United States)

    Heni, Martin; Kullmann, Stephanie; Preissl, Hubert; Fritsche, Andreas; Häring, Hans-Ulrich

    2015-12-01

    Over the past few years, evidence has accumulated that the human brain is an insulin-sensitive organ. Insulin regulates activity in a limited number of specific brain areas that are important for memory, reward, eating behaviour and the regulation of whole-body metabolism. Accordingly, insulin in the brain modulates cognition, food intake and body weight as well as whole-body glucose, energy and lipid metabolism. However, brain imaging studies have revealed that not everybody responds equally to insulin and that a substantial number of people are brain insulin resistant. In this Review, we provide an overview of the effects of insulin in the brain in humans and the relevance of the effects for physiology. We present emerging evidence for insulin resistance of the human brain. Factors associated with brain insulin resistance such as obesity and increasing age, as well as possible pathogenic factors such as visceral fat, saturated fatty acids, alterations at the blood-brain barrier and certain genetic polymorphisms, are reviewed. In particular, the metabolic consequences of brain insulin resistance are discussed and possible future approaches to overcome brain insulin resistance and thereby prevent or treat obesity and type 2 diabetes mellitus are outlined.

  5. Genome-Wid