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Zeid Kayali Jason Herring Pedro Baron Edson Franco Okechukwu Ojogho Jason Smith Gregory Watkins Douglas Smith Victor Lamin Thanh Hoang Rajiv Sharma Meleah Mathahs Lawrance Sowers Kyle E Brown Warren N Schmidt 《Journal of gastroenterology and hepatology》2009,24(6):1030-1037
Background and Aims: Increased levels of nitric oxide (NO) are hypothesized to contribute to renal dysfunction in patients with decompensated cirrhosis. In this study, we examined whether splanchnic and/or peripheral NO levels and L-arginine (L-Arg) correlate with progressive renal dysfunction in cirrhotics.
Methods: Serum NO metabolites (NOx) and L-Arg were measured in: controls ( n = 10); organ donors ( n = 12); compensated cirrhotics ( n = 17), cirrhotics with ascites ( n = 25), refractory ascites ( n = 11) or hepatorenal syndrome type II (HRS) ( n = 11) and chronic renal failure patients ( n = 18).
Results: Plasma NOx and L-Arg levels rose progressively with worsening renal function in decompensated cirrhotics. Both NOx and L-Arg levels were highest in patients with HRS ( P < 0.001 and P < 0.025, respectively). While there were no differences in NOx levels related to the site of sampling, L-Arg levels were lowest in hepatic venous blood. There were significant relationships of NOx and L-Arg with Model for End-Stage Liver Disease score and Child–Pugh scores ( P < 0.04 and P < 0.01, respectively). Multivariate analysis showed a significant relationship between NOx, L-Arg and HRS.
Conclusion: Worsening renal function in decompensated cirrhosis is accompanied by progressive elevation in plasma NOx and L-Arg. These findings support the hypothesis that NO-mediated vasodilation is probably linked with the mechanism of progressive renal failure in decompensated cirrhotics. 相似文献
Methods: Serum NO metabolites (NOx) and L-Arg were measured in: controls ( n = 10); organ donors ( n = 12); compensated cirrhotics ( n = 17), cirrhotics with ascites ( n = 25), refractory ascites ( n = 11) or hepatorenal syndrome type II (HRS) ( n = 11) and chronic renal failure patients ( n = 18).
Results: Plasma NOx and L-Arg levels rose progressively with worsening renal function in decompensated cirrhotics. Both NOx and L-Arg levels were highest in patients with HRS ( P < 0.001 and P < 0.025, respectively). While there were no differences in NOx levels related to the site of sampling, L-Arg levels were lowest in hepatic venous blood. There were significant relationships of NOx and L-Arg with Model for End-Stage Liver Disease score and Child–Pugh scores ( P < 0.04 and P < 0.01, respectively). Multivariate analysis showed a significant relationship between NOx, L-Arg and HRS.
Conclusion: Worsening renal function in decompensated cirrhosis is accompanied by progressive elevation in plasma NOx and L-Arg. These findings support the hypothesis that NO-mediated vasodilation is probably linked with the mechanism of progressive renal failure in decompensated cirrhotics. 相似文献
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Hepatic nonalcoholic fatty liver disease (NAFLD) is known to exacerbate liver injury due to chronic hepatitis C infection. Heme oxygenase-1 (HO-1) is an important protective antioxidative defense enzyme that is known to be induced in response to NAFLD and other liver injuries. The aim of this study was to evaluate HO-1 expression in HCV infected human livers with concomitant NAFLD.MethodsWe compared levels of HO-1 in NAFLD liver biopsies from patients with or without chronic HCV infection using immunohistochemistry, immunoblots and real time RT-PCR. We also evaluated frozen sections of liver with dihydroethidium (DHE) or dichlorofluorescein (DCF) fluorescence staining to evaluate O2? and peroxide production respectively.ResultsHO-1 expression was only increased in NAFLD livers without HCV infection, while HCV infected livers showed reduced HO-1 levels, regardless whether NAFLD was present. In uninfected livers with NAFLD, HO-1 expression was primarily localized in hepatocytes containing fat and areas of injury around the central vein. However, both NAFLD with and without concomitant HCV infection showed high levels of O2? or peroxide production compared to normal human liver control samples.ConclusionsThese findings support the hypothesis that NAFLD is an important process for hepatocyte oxidative stress and injury in liver diseases. They also suggest that HCV can repress HO-1 induction in vivo even when other inducers of HO-1 are present. 相似文献
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Hickman MA Rusche LN 《Proceedings of the National Academy of Sciences of the United States of America》2010,107(45):19384-19389
The origin recognition complex (ORC) defines origins of replication and also interacts with heterochromatin proteins in a variety of species, but how ORC functions in heterochromatin assembly remains unclear. The largest subunit of ORC, Orc1, is particularly interesting because it contains a nucleosome-binding BAH domain and because it gave rise to Sir3, a key silencing protein in Saccharomyces cerevisiae, through gene duplication. We examined whether Orc1 possessed a Sir3-like silencing function before duplication and found that Orc1 from the yeast Kluyveromyces lactis, which diverged from S. cerevisiae before the duplication, acts in conjunction with the deacetylase Sir2 and the histone-binding protein Sir4 to generate heterochromatin at telomeres and a mating-type locus. Moreover, the ability of KlOrc1 to spread across a silenced locus depends on its nucleosome-binding BAH domain and the deacetylase Sir2. Interestingly, KlOrc1 appears to act independently of the entire ORC, as other subunits of the complex, Orc4 and Orc5, are not strongly associated with silenced domains. These findings demonstrate that Orc1 functioned in silencing before duplication and suggest that Orc1 and Sir2, both of which are broadly conserved among eukaryotes, may have an ancient history of cooperating to generate chromatin structures, with Sir2 deacetylating histones and Orc1 binding to these deacetylated nucleosomes through its BAH domain. 相似文献
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Lesliam Quirós-Alcalá Jessie P. Buckley Meleah Boyle 《International journal of hygiene and environmental health》2018,221(4):652-660
Background
Emerging experimental studies suggest that parabens could affect metabolism by altering the microbiome or signaling pathways involved in adipocyte differentiation. While human exposure to parabens is widespread, epidemiologic studies assessing the role of these chemicals on adiposity measures are scarce.Objective
We examined associations of parabens with adiposity measures among adults and children in the U.S. general population.Methods
We conducted covariate-adjusted linear and logistic regression models to examine associations between urinary biomarker concentrations of four parabens (butyl-BP, ethyl-EP, methyl-MP, and propyl paraben-PP) and measures of adiposity (obesity; body mass index, BMI or BMI z-score; and waist circumference) among 4730 adults (2007–2014) and 1324 children (2007–2012), participating in the National Health and Nutrition Examination Survey. We also assessed heterogeneity of associations by gender.Results
We generally observed significant inverse associations between adiposity measures and paraben biomarker concentrations among adults (BP, EP, MP, PP) and children (MP). For example, adjusted prevalence odds ratios (95% confidence intervals, CI) for obesity per a ten-fold increase in MP concentrations were 0.64 (95% CI: 0.55, 0.73) for adults and 0.71(95% CI: 0.52, 0.95) for children. Strength of inverse associations typically increased monotonically with increasing paraben exposure quartiles; and, in general, inverse associations were more pronounced among females. Associations remained when controlling for other phenolic compounds previously linked with adiposity measures.Conclusions
In this cross-sectional study of adiposity measures and parabens, we observed consistent inverse associations in a representative sample of U.S adults and children. Further studies are warranted to confirm our findings, examine the potential role of paraben sequestration in adipose tissue, and elucidate mechanisms by which parabens could alter metabolism. 相似文献9.
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Zhu Z Wilson AT Luxon BA Brown KE Mathahs MM Bandyopadhyay S McCaffrey AP Schmidt WN 《Hepatology (Baltimore, Md.)》2010,52(6):1897-1905
Induction of heme oxygenase-1 (HO-1) inhibits hepatitis C virus (HCV) replication. Of the products of the reaction catalyzed by HO-1, iron has been shown to inhibit HCV ribonucleic acid (RNA) polymerase, but little is known about the antiviral activity of biliverdin (BV). Herein, we report that BV inhibits viral replication and viral protein expression in a dose-dependent manner in replicons and cells harboring the infectious J6/JFH construct. Using the SensoLyte 620 HCV Protease Assay with a wide wavelength excitation/emission (591 nm/622 nm) fluorescence energy transfer peptide, we found that both recombinant and endogenous nonstructural 3/4A (NS3/4A) protease from replicon microsomes are potently inhibited by BV. Of the tetrapyrroles tested, BV was the strongest inhibitor of NS3/4A activity, with a median inhibitory concentration (IC(50)) of 9 μM, similar to that of the commercial inhibitor, AnaSpec (Fremont, CA) #25346 (IC(50) 5 μM). Lineweaver-Burk plots indicated mixed competitive and noncompetitive inhibition of the protease by BV. In contrast, the effects of bilirubin (BR) on HCV replication and NS3/4A were much less potent. Because BV is rapidly converted to BR by biliverdin reductase (BVR) intracellularly, the effect of BVR knockdown on BV antiviral activity was assessed. After greater than 80% silencing of BVR, inhibition of viral replication by BV was enhanced. BV also increased the antiviral activity of α-interferon in replicons. Conclusion: BV is a potent inhibitor of HCV NS3/4A protease, which likely contributes to the antiviral activity of HO-1. These findings suggest that BV or its derivatives may be useful in future drug therapies targeting the NS3/4A protease. 相似文献