Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Extracorporeal shock wave lithotripsy (ESWL) is a safe, effective method to treat urinary lithiasis. The success rate in ESWL depends on stone location, size, number, and fragility as well as calceal anatomy and patency of the urinary tract. An association of calcineurin inhibitors and uric acid urolithiasis has been reported in renal allograft recipients, but the mechanism remains unknown. Herein we have reported the case of 68-year-old male patient who developed cryptogenic cirrhosis and underwent liver transplantation. Seven years after transplantation, the patient was admitted to the hospital with right renal colic. An 8.9-mm radiolucent stone at the pyeloureteric junction was associated with moderate consecutive hydronephrosis. The second stone was located in a lower renal calyx. After a failed attempt at retrograde ureteral stenting, we performed a percutaneous nephrostomy. Antegrade pyelography with following ESWL treatment resulted in disintegration of the obstructive stone at the pyeloureteric junction. Afterward, we performed antegrade placement of a double-J stent. Residual stones in the lower renal calyx were successfully treated with a 3-month course of oral intake of a dissolution agent-potassium sodium hydrogen citrate. In this case, we have discussed ESWL and oral dissolution therapy of radiolucent stones in a hydronephrotic right kidney, which resulted in stone-free disease after 3 months of combined therapy. There was neither clinical nor biochemical damage to the transplanted liver.
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PMID:Extracorporeal shock wave lithotripsy of impacted radiolucent stone at the right pyeloureteric junction and oral dissolution therapy in a patient with transplanted liver: a case report. 1808 30

Understanding the mechanism of saturated fatty acid-induced hepatocyte toxicity may provide insight into cures for diseases such as obesity-associated cirrhosis. Trehalose, a nonreducing disaccharide shown to protect proteins and cellular membranes from inactivation or denaturation caused by different stress conditions, also protects hepatocytes from palmitate-induced toxicity. Our results suggest that trehalose serves as a free radical scavenger and alleviates damage from hydrogen peroxide secreted by the compromised cells. We also observe that trehalose protects HepG2 cells by interacting with the plasma membrane to counteract the changes in membrane fluidity induced by palmitate. The experimental results are supported by molecular dynamics simulations of model cell membranes that closely reflect the experimental conditions. Simulations were performed to understand the specific interactions between lipid bilayers, palmitate, and trehalose. The simulations results reveal the early stages of how palmitate induces biophysical changes to the cellular membrane and the role of trehalose in protecting the membrane structure.
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PMID:Experimental and computational studies investigating trehalose protection of HepG2 cells from palmitate-induced toxicity. 1809 30

MTAP (5'-methylthioadenosine phosphorylase) catalyses the reversible phosphorolytic cleavage of methylthioadenosine leading to the production of methylthioribose-1-phosphate and adenine. Deficient MTAP activity has been correlated with human diseases including cirrhosis and hepatocellular carcinoma. In the present study we have investigated the regulation of MTAP by ROS (reactive oxygen species). The results of the present study support the inactivation of MTAP in the liver of bacterial LPS (lipopolysaccharide)-challenged mice as well as in HepG2 cells after exposure to t-butyl hydroperoxide. Reversible inactivation of purified MTAP by hydrogen peroxide results from a reduction of V(max) and involves the specific oxidation of Cys(136) and Cys(223) thiols to sulfenic acid that may be further stabilized to sulfenyl amide intermediates. Additionally, we found that Cys(145) and Cys(211) were disulfide bonded upon hydrogen peroxide exposure. However, this modification is not relevant to the mediation of the loss of MTAP activity as assessed by site-directed mutagenesis. Regulation of MTAP by ROS might participate in the redox regulation of the methionine catabolic pathway in the liver. Reduced MTA (5'-deoxy-5'-methylthioadenosine)-degrading activity may compensate for the deficient production of the precursor S-adenosylmethionine, allowing maintenance of intracellular MTA levels that may be critical to ensure cellular adaptation to physiopathological conditions such as inflammation.
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PMID:Redox regulation of methylthioadenosine phosphorylase in liver cells: molecular mechanism and functional implications. 1823 76

Deregulation of interleukin-6 (IL-6) expression caused the synthesis and release of many inflammatory mediators. It is involved in chronic inflammation, autoimmune diseases, and malignancy. Stephania tetrandra S. Moore is a Chinese medicinal herb which has been used traditionary as a remedy for neuralgia and arthritis in China. To investigate the anti-inflammatory effects of S. tetrandra S. Moore in vitro and in vivo, its effects on the production of IL-6 and inflammatory mediators were analysed. When human monocytes/macrophages stimulated with silica were treated with 0.1-10 mug/ml S. tetranda S. Moore, the production of IL-6 was inhibited up to 50%. At these concentrations, it had no cytotoxicity effect on these cells. It also suppressed the production of IL-6 by alveolar macrophages stimulated with silica. In addition, it inhibited the release of superoxide anion and hydrogen peroxide from human monocytes/macrophages. To assess the anti-fibrosis effects of S. tetrandra S. Moore, its effects on in vivo experimental inflammatory models were evaluated. In the experimental silicosis model, IL-6 activities in the sera and in the culture supernatants of pulmonary fibroblasts were also inhibited by it. In vitro and in vivo treatment of S. tetrandra S. Moore reduced collagen production by rat lung fibroblasts and lung tissue. Also, S. tetrandra S. Moore reduced the levels of serum GOT and GPT in the rat cirrhosis model induced by CCL(4), and it was effective in reducing hepatic fibrosis and nodular formation. Taken together, these data indicate that it has a potent anti-inflammatory and antifibrosis effect by reducing IL-6 production.
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PMID:Anti-inflammatory effects of Stephania tetrandra S. Moore on interleukin-6 production and experimental inflammatory disease models. 1847 41

Attempts have been made by conventional gene therapy to suppress hepatic fibrogenesis, but potential oncogenic activity may prevent its clinical use. Recently, a novel major approach has been developed for resolution of liver fibrosis and cirrhosis: inactivation of hepatic stellate cells (HSC) using the endogenous expressing gene, which could mediate the homeostatic adaptation of liver. Cytoglobin (Cygb), originally identified in cultured rat HSC, is in a new class of heme containing proteins known as the hexacoordinate globin superfamily. These proteins exhibit peroxidase activity against hydrogen peroxides and lipid hydroperoxides. Considerable attention has been focused on the potential benefits of use of Cygb in fibrosis therapy, as up-regulation of Cygb expression could reduce oxidant stress, suppress HSC differentiation to a myofibroblast-like phenotype and eventually prevent the progress of liver fibrosis. Cygb has also been found to be a candidate tumor suppressor gene that might provide a new option for cancer gene therapy. In this review we systematically analyze the potential of Cygb as a prospective gene medicine for curing fibrosis, cancer, and other diseases such as diabetes. The molecular structure, regulation and subcellular location of Cygb are reviewed as well.
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PMID:Cytoglobin: a novel potential gene medicine for fibrosis and cancer therapy. 1869 Oct 24

The Z variant of 1-antitrypsin (AT) polymerizes within the liver and gives rise to liver cirrhosis and the associated plasma deficiency leads to emphysema. In this work, a combinatorial approach based on the inhibitory mechanism of (alpha1)-AT was developed to arrest its pathogenic polymerization. One peptide, Ac-TTAI-NH(2), emerged as the most tight-binding ligand for Z (alpha1)-AT. Characterization of this tetrapeptide by gel electrophoresis and biosensor analysis revealed its markedly improved binding specificity and affinity compared with all previously reported peptide inhibitors. In addition, the peptide is not cytotoxic to lung cell lines. A model of the peptide-protein complex suggests that the peptide interacts with nearby residues by hydrogen bonds, hydrophobic interactions, and cavity-filling stabilization. The combinatorially selected peptide not only effectively blocks the polymerization but also promotes dissociation of the oligomerized (alpha1)-AT. These results are a significant step towards the potential treatment of Z (alpha1)-AT related diseases.
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PMID:Small-molecule peptides inhibit Z alpha1-antitrypsin polymerization. 1912 Jun 95

Spontaneous bacterial peritonitis (SBP), a common complication of cirrhosis of liver, might result from translocation of bacteria from the small bowel. However, there is scanty data on frequency of small intestinal bacterial overgrowth (SIBO) in patients with cirrhosis of the liver. There are no data on SIBO in patients with extra-hepatic portal venous obstruction (EHPVO) in the literature. A total of 174 patients with cirrhosis of the liver, 28 with EHPVO and 51 healthy controls were studied for SIBO using glucose hydrogen breath test (GHBT). Persistent rise in breath hydrogen 12 ppm above basal (at least two readings) was considered diagnostic of SIBO. Of 174 patients (age 47.2 +/- 11.9 years, 80.5% male) with cirrhosis due to various causes, 67 (38.5%) were in Child's class A, 70 (40.2%) class B and 37 (21.7%) class C. Of the 174 patients with cirrhosis, 42 (24.14%) had SIBO as compared to 1 of 51 (1.9%) healthy controls (P < 0.0001). Patients with EHPVO had similar frequency of SIBO compared to healthy controls [2/28 (7.14%) vs 1/51 (1.97%), P = ns]. Frequency of SIBO in Child's A, B and C was comparable [13 (18.6%) vs 16 (23.9%) and 13 (35.1%), respectively; P = ns]. Presence of SIBO were not related to ascites, etiology of cirrhosis, and degree of liver dysfunction. SIBO is common in patients with cirrhosis of the liver. Patients with EHPVO do not have higher frequency of SIBO than healthy subjects. SIBO in cirrhosis is not related to the degree of derangement in liver function or of portal hypertension.
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PMID:Frequency and factors associated with small intestinal bacterial overgrowth in patients with cirrhosis of the liver and extra hepatic portal venous obstruction. 1942 96

Hepatitis C Virus (HCV) infection is the major cause of chronic liver disease, leading to cirrhosis and hepatocellular carcinoma, which affects more than 200 million people worldwide. Currently the only therapeutic regimens are subcutaneous interferon-alpha or PEG-interferon alone or in combination with oral ribavirin. Although combination therapy is reasonably successful with the majority of genotypes, its efficacy against the predominant genotype (genotype 1) is moderate at best, with only approximately 50% of the patients showing sustained virological response. We recently disclosed the discovery of Boceprevir, SCH 503034 (1), which is a novel, potent, selective, orally bioavailable NS3 protease inhibitor that has been shown to be efficacious in humans and is currently undergoing clinical trials. As second generation compounds, we have further explored various novel structures with the aim of improving enzyme and cellular binding activities of 1. Herein, we disclose our efforts toward the identification of a novel P(3) sulfonamide-capped inhibitor that demonstrated improved binding and cellular activity compared to 1. X-ray structure of one of these inhibitors bound to the enzyme revealed a hydrogen bond of the P(3) sulfonamide group to Cys-159 which resulted in improved binding and cellular potency.
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PMID:Discovery of novel P3 sulfonamide-capped inhibitors of HCV NS3 protease. Inhibitors with improved cellular potencies. 1948 46

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. While searching for new natural anti-HCV agents in agricultural products, we found a potent inhibitor of HCV RNA expression in extracts of blueberry leaves when examined in an HCV subgenomic replicon cell culture system. This activity was observed in a methanol extract fraction of blueberry leaves and was purified by repeated fractionations in reversed-phase high-performance liquid chromatography. The final purified fraction showed a 63-fold increase in specific activity compared with the initial methanol extracts and was composed only of carbon, hydrogen, and oxygen. Liquid chromatography/mass-ion trap-time of flight analysis and butanol-HCl hydrolysis analysis of the purified fraction revealed that the blueberry leaf-derived inhibitor was proanthocyanidin. Furthermore, structural analysis using acid thiolysis indicated that the mean degree of polymerization of the purified proanthocyanidin was 7.7, consisting predominantly of epicatechin. Proanthocyanidin with a polymerization degree of 8 to 9 showed the greatest potency at inhibiting the expression of subgenomic HCV RNA. Purified proanthocyanidin showed dose-dependent inhibition of expression of the neomycin-resistant gene and the NS-3 protein gene in the HCV subgenome in replicon cells. While characterizing the mechanism by which proanthocyanidin inhibited HCV subgenome expression, we found that heterogeneous nuclear ribonucleoprotein A2/B1 showed affinity to blueberry leaf-derived proanthocyanidin and was indispensable for HCV subgenome expression in replicon cells. These data suggest that proanthocyanidin isolated from blueberry leaves may have potential usefulness as an anti-HCV compound by inhibiting viral replication.
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PMID:Proanthocyanidin from blueberry leaves suppresses expression of subgenomic hepatitis C virus RNA. 1953 80

Myeloperoxidase (MPO) generates reactive halogenating species that can modify DNA. The aim of this study was to investigate the formation of 8-halogenated 2'-deoxyguanosines (8- halo-dGs) during inflammatory events. 8-Bromo-2'-dG (8-BrdG) and 8-chloro-2'-dG (8-CldG) were generated by treatment of MPO with hydrogen peroxide at physiological concentrations of Cl(-) and Br(-). The formation of 8-halo-dGs with other oxidative stress biomarkers in lipopolysaccharide-treated rats was assessed by liquid chromatography tandem mass spectrometry and immunohistochemistry using a novel monoclonal antibody (mAb8B3) to 8-BrdG-conjugated keyhole limpet hemocyanin. The antibody recognized both 8-BrdG and 8-CldG. In the liver of lipopolysaccharide-treated rats, immunostaining for 8-halo-dGs, halogenated tyrosines, and MPO were increased at 8 h, whereas those of 8-oxo-2'-dG (8-OxodG) and 3-nitrotyrosine were increased at 24 h. Urinary excretion of both 8-CldG and 8-BrdG was also observed earlier than those of 8-OxodG and modified tyrosines (3-nitrotyrosine, 3-chlorotyrosine, and 3- bromotyrosine). Moreover, the levels of the 8-halo-dGs in urine from human diabetic patients were 8-fold higher than in healthy subjects (n = 10, healthy and diabetic, p < 0.0001), whereas there was a moderate difference in 8-OxodG between the two groups (p < 0.001). Interestingly, positive mAb8B3 antibody staining was observed in liver tissue from hepatocellular carcinoma patients but not in liver tissue from human cirrhosis patients. These data suggest that 8-halo-dGs may be potential biomarkers of early inflammation.
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PMID:Chemical and immunochemical detection of 8-halogenated deoxyguanosines at early stage inflammation. 2008 Nov 97


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