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

The regulation of sinusoidal resistance is dependent on the contraction of hepatic stellate cells (HSC) around sinusoidal endothelial cell (SEC) through paracrine cross-talk of vasoconstrictor and vasodilator agents. Hydrogen sulfide (H2S), a recently discovered gas neurotransmitter, is a putative vasodilator whose role in hepatic vascular regulation and portal hypertension is unexplored. Four-week bile duct-ligated (BDL) rats with cirrhosis and control rats were treated daily with NaHS (56 micromol/kg) for 5 days. Isolated livers were perfused first with NaHS for 20 minutes and then with norepinephrine (NE) and the intrahepatic resistance studied. In normal rats and animals with cirrhosis, administration of NE resulted in a dose-dependent increase of portal pressure. This effect was attenuated by H2S treatment (P < .05). The H2S-induced relaxation of hepatic microcirculation was attenuated by glibenclamide, an adenosine triphosphate (ATP)-sensitive K+ channel inhibitor. L-Cysteine, a substrate of cystathionine-gamma-lyase (CSE), decreased vasoconstriction in normal rat livers (P < .05) but failed to do so in livers with cirrhosis. BDL resulted in a downregulation of CSE mRNA/protein levels and activity (P < .05). Our in vitro data demonstrate that CSE is expressed in hepatocytes, HSCs, but not in sinusoidal endothelial cells (SEC). HSC activation downregulates CSE mRNA expression, resulting in a defective production of H2S and abrogation of relaxation induced by L-cysteine. In conclusion, CSE-derived H2S is involved in the maintenance of portal venous pressure. The reduction of CSE expression in the liver with cirrhosis contributes to the development of increased intrahepatic resistance and portal hypertension.
 ...
PMID:The third gas: H2S regulates perfusion pressure in both the isolated and perfused normal rat liver and in cirrhosis. 1610 46

Herbal medicines have been used in the treatment of liver diseases for a long time. A number of herbal preparations are available in the market. This article reviews four commonly used herbal preparations: (1) Phyllanthus, (2) Silybum marianum (milk thistle), (3) glycyrrhizin (licorice root extract), and (4) Liv 52 (mixture of herbs). Phyllanthus has a positive effect on clearance of HBV markers and there are no major adverse effects; there are no data from randomized controlled trials on clinically relevant outcomes, such as progression of chronic hepatitis to cirrhosis and/or liver cancer, and on survival. Silymarin does not reduce mortality and does not improve biochemistry and histology among patients with chronic liver disease; however, it appears to be safe and well tolerated. Stronger neominophagen C (SNMC) is a Japanese preparation that contains 0.2% glycyrrhizin, 0.1% cysteine, and 2% glyceine. SNMC does not have antiviral properties; it primarily acts as an anti-inflammatory or cytoprotective drug. It improves mortality in patients with subacute liver failure and improves liver functions in patients with subacute hepatic failure, chronic hepatitis, and cirrhosis with activity. SNMC does not reduce mortality among patients with cirrhosis with activity. SNMC may prevent the development of hepatocellular carcinoma in patients with chronic hepatitis C, however, prospective data are lacking. Liv 52, an Ayurvedic hepatoprotective agent, is not useful in the management of alcohol-induced liver disease. Standardization of herbal medicines has been a problem and prospective, randomized, placebo-controlled clinical trials are lacking to support their efficacy. The methodological qualities of clinical trials of treatment with herbal preparations are poor. The efficacy of these herbal preparations need to be evaluated in rigorously designed, larger randomized, double-blind, placebo-controlled multicenter trials.
 ...
PMID:Herbal medicines for liver diseases. 1618 78

Mechanical stress is known to activate signaling cascades, including mitogen-activated protein kinase (MAPK) pathways. Although mechanical stress has been implicated in hepatic cirrhosis and liver regeneration following hepatectomy, the signaling pathway(s) that may be activated in hepatocytes in response to mechanical stress have not been determined. Using primary cultured rat hepatocytes to examine cellular signaling in response to mechanical stress associated with medium change, we observed that the phosphorylation status of extracellular signal-regulated kinase 1/2 (ERK1/2), Jun N-terminal kinase and p38 MAPK, but not Akt, was altered. MAPK activation, especially ERK1/2, was rapidly increased within 5 min, followed by a subsequent decrease to below basal levels between 30 min and 1 h following medium change. MAPK/ERK kinase (MEK1/2) phosphorylation followed the same pattern. The phosphorylation of Raf-1 in response to medium change was also consistent with Raf-1 serving as an upstream regulator of MEK1/2-ERK1/2 signaling. Phosphorylation of ERK1/2 was increased by mechanical stress alone, suggesting that mechanical stress may be primarily responsible for ERK1/2 activation in response to medium change. Medium change produced a marked decline in oxidized glutathione and malondialdehyde levels, and the antioxidant N-acetyl-L-cysteine decreased basal ERK1/2 phosphorylation, suggesting a role for oxidative stress in maintaining basal ERK1/2 phosphorylation in cultured hepatocytes. These data suggest that medium change results in immediate activation of the MAPK signaling pathway due to mechanical stress, followed by a subsequent inactivation of MAPK signaling due to a reduction in oxidative stress levels. These processes may be associated with alteration of hepatic hemodynamic circulation observed in hepatic diseases and in liver transplantation.
 ...
PMID:Role of mechanical and redox stress in activation of mitogen-activated protein kinases in primary cultured rat hepatocytes. 1624 70

Intestinal failure-associated liver disease develops in 40% to 60% of infants who require long-term total parenteral nutrition (TPN) for intestinal failure and 15% to 40% of adults on home parenteral nutrition. The clinical spectrum includes hepatic steatosis, cholestasis, cholelithiasis, and hepatic fibrosis. Progression to biliary cirrhosis and the development of portal hypertension and liver failure occurs in a minority but is more common in infants and neonates than in adults. The pathogenesis is multifactorial. In infants it is related to prematurity, low birth weight, duration of PN, short bowel syndrome requiring multiple laparotomies, and recurrent sepsis. Other important mechanisms include lack of enteral feeding, which leads to reduced gut hormone secretion; reduction of bile flow and biliary stasis, which leads to the development of cholestasis; and biliary sludge and gallstones, which exacerbate hepatic dysfunction. In adults, IFALD is less common and related to age, length of time on PN, total caloric intake, and lipid or glucose overload. In preterm infants, a deficiency of taurine or cysteine may play a role, whereas in both adults and children, choline deficiency may exacerbate IFALD. Lipid emulsions, choline deficiency, and manganese toxicity are associated with both hepatic steatosis and cholestasis in adults and children. Management strategies for the prevention of intestinal failure-induced liver disease include early enteral feeding, a multidisciplinary approach to the management of parenteral nutrition, and aseptic catheter techniques to reduce sepsis. The addition of choline, taurine, and cysteine to PN solutions may also play a role. Oral administration of ursodeoxycholic acid may improve bile flow and reduce gallbladder stasis. Survival after either isolated small bowel or combined liver and small bowel transplantation is approximately 50% at 5 years, making this an acceptable therapeutic option in adults and children with irreversible liver and intestinal failure.
 ...
PMID:Intestinal failure-associated liver disease: what do we know today? 1647 75

Hepatitis C virus (HCV) is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma worldwide-and is the main cause of adult liver transplants in developed nations. We have identified a class of novel and specific inhibitors of HCV NS5B RNA-dependent RNA polymerase (RdRp) activity in vitro. Characterization of two such inhibitors, COMPOUND1 (5-(4-chlorophenylmethylene)-3-(benzenesulfonylamino)-4-oxxo-2-thionothiazolidine) and COMPOUND2 (5-(4-bromophenylmethylene)-3-(benzenesulfonylamino)-4-oxxo-2-thionothiazolidine), is reported here. With IC(50) values of 0.54muM and 0.44muM, respectively, they are reversible and non-competitive with nucleotides. Biochemical and structural studies have suggested that these compounds can inhibit the initiation of the RdRp reaction. Interestingly, these inhibitors appear to form a reversible covalent bond with the NS5B cysteine 366, a residue that is not only conserved among all HCV genotypes and a large family of viruses but also required for full NS5B RdRp activity. This may reduce the potential resistance of the viruses to this class of inhibitors.
 ...
PMID:Novel inhibitors of hepatitis C virus RNA-dependent RNA polymerases. 1647 48

The intimate relation between amino acids and protein and nitrogen requirements is well recognized. Nutrition research has focused on the capacity of food to meet the need for nitrogen and indispensable amino acids (IAA) and led to the conclusion that the quality, not just the quantity, of protein is critical. This is especially relevant in regard to the sulfur amino acids (SAA) methionine and cysteine because of the increased understanding of their relation to chronic diseases (e.g., cardiovascular disease, dementia, cirrhosis), immunomodulation, DNA transcription, and RNA translation. Considerable effort has been expended to determine whether and to what extent cysteine can spare the requirement for the IAA methionine. In vivo studies in humans generally concur that the dietary requirement of the SAA ranges between 13 and 16 mg.kg(-1).d(-1), but how much can be met by cysteine relative to methionine remains controversial. This review examines the current status of in vivo estimates of methionine and cysteine requirements in human adults and considers needs beyond what is necessary for protein synthesis. Factors influencing the utilization of methionine and cysteine, especially those conditions that lead to toxicity on the one hand or beneficial effects on the other, are discussed. Data on alternative dietary sources of methyl groups (e.g., betaine, choline, phosphatidylcholine, S-adenosylmethionine, S-methylmethionine) or sulfur (e.g., N-acetylcysteine or L-2-oxothiazolidine-4-carboxylic acid) support a role for the SAA "beyond protein." Other pathways may influence the specific requirement for methionine and/or cysteine, especially when the person is challenged by disease, inadequate availability of food, or environmental stress.
 ...
PMID:Sparing of methionine requirements: evaluation of human data takes sulfur amino acids beyond protein. 1670 39

Hepatitis C virus is a major global health problem affecting an estimated 170 million people worldwide. Chronic infection is common and can lead to cirrhosis and liver cancer. There is no vaccine available and current therapies have met with limited success. The viral RNA genome encodes a polyprotein that includes two proteases essential for virus replication. The NS2-3 protease mediates a single cleavage at the NS2/NS3 junction, whereas the NS3-4A protease cleaves at four downstream sites in the polyprotein. NS3-4A is characterized as a serine protease with a chymotrypsin-like fold, but the enzymatic mechanism of the NS2-3 protease remains unresolved. Here we report the crystal structure of the catalytic domain of the NS2-3 protease at 2.3 A resolution. The structure reveals a dimeric cysteine protease with two composite active sites. For each active site, the catalytic histidine and glutamate residues are contributed by one monomer, and the nucleophilic cysteine by the other. The carboxy-terminal residues remain coordinated in the two active sites, predicting an inactive post-cleavage form. Proteolysis through formation of a composite active site occurs in the context of the viral polyprotein expressed in mammalian cells. These features offer unexpected insights into polyprotein processing by hepatitis C virus and new opportunities for antiviral drug design.
 ...
PMID:Structure of the catalytic domain of the hepatitis C virus NS2-3 protease. 1713 77

Cytokeratins (CK) constitute a family of cytoskeletal intermediate filament proteins that are typically expressed in epithelial cells. An abnormal structure and function are effects that are clearly related to liver diseases as non-alcoholic steatohepatitis, cirrhosis and hepatocellular carcinoma. We have previously observed that sodium arsenite (SA) induced the synthesis of CK18 protein and promotes a dose-related disruption of cytoplasmic CK18 filaments in a human hepatic cell line. Both abnormal gene expression and disturbance of structural organization are toxic effects that are likely to cause liver disease by interfering with normal hepatocyte function. To investigate if a disruption in the CK18 expression pattern is associated with arsenite liver damage, we investigated CK18 mRNA and protein levels in liver slices treated with low levels of SA. Organotypic cultures were incubated with 0.01, 1 and 10 microM of SA in the absence and presence of N-acetyl cysteine (NAC). Cell viability and inorganic arsenic metabolism were determined. Increased expression of CK18 was observed after exposure to SA. The addition of NAC impeded the oxidative effects of SA exposure, decreasing the production of thiobarbituric acid-reactive substances and significantly diminishing the up regulation of CK18 mRNA and protein. Liver arsenic levels correlated with increased levels of mRNA. Mice treated with intragastric single doses of 2.5 and 5 mg/kg of SA showed an increased expression of CK18. Results suggest that CK18 expression may be a sensible early biomarker of oxidative stress and damage induced by arsenite in vitro and in vivo. Then, during SA exposure, altered CK expression may compromise liver function.
 ...
PMID:Arsenite induced oxidative damage in mouse liver is associated with increased cytokeratin 18 expression. 1734 Jan 20

Nitric oxide (NO) and carbon monoxide (CO) synthesized from L-arginine by NO synthase and from heme by heme oxygenase, respectively, are the well-known neurotransmitters and are also involved in the regulation of vascular tone. Recent studies suggest that hydrogen sulfide (H(2)S) is the third gaseous mediator in mammals. H(2)S is synthesized from L-cysteine by either cystathionine beta-synthase (CBS) or cystathionine gamma-lyase (CSE), both using pyridoxal 5'-phosphate (vitamin B(6)) as a cofactor. H(2)S stimulates ATP-sensitive potassium channels (K(ATP)) in the vascular smooth muscle cells, neurons, cardiomyocytes and pancreatic beta-cells. In addition, H(2)S may react with reactive oxygen and/or nitrogen species limiting their toxic effects but also, attenuating their physiological functions, like nitric oxide does. In contrast to NO and CO, H(2)S does not stimulate soluble guanylate cyclase. H(2)S is involved in the regulation of vascular tone, myocardial contractility, neurotransmission, and insulin secretion. H(2)S deficiency was observed in various animal models of arterial and pulmonary hypertension, Alzheimer's disease, gastric mucosal injury and liver cirrhosis. Exogenous H(2)S ameliorates myocardial dysfunction associated with the ischemia/reperfusion injury and reduces the damage of gastric mucosa induced by anti-inflammatory drugs. On the other hand, excessive production of H(2)S may contribute to the pathogenesis of inflammatory diseases, septic shock, cerebral stroke and mental retardation in patients with Down syndrome, and reduction of its production may be of potential therapeutic value in these states.
 ...
PMID:Hydrogen sulfide (H2S) - the third gas of interest for pharmacologists. 1737 2

Hepatitis C virus (HCV) is a major cause of chronic hepatitis that can lead to cirrhosis and hepatocellular carcinoma. To study the effects of HCV protein expression on host cells, we established conditional expression of the full-length open reading frame (ORF) of an infectious cDNA clone of HCV (genotype 1a, H77 strain) in the nontransformed human hepatocyte line cell HH4 using the ecdysone receptor regulatory system. Treatment with the ecdysone analog ponasterone-A induced tightly regulated and dose-dependent full-length HCV ORF expression and properly processed HCV proteins. HCV Core, NS3, and NS5A colocalized in perinuclear regions and associated with the early endosomal protein EEA1. HCV ORF expression caused marked growth inhibition, increased intracellular reactive oxygen species, up-regulation of glutamate-l-cysteine ligase activity, increased glutathione level, and activation of nuclear factor kappaB. Although it was not directly cytotoxic, HCV ORF expression sensitized HH4 cells to Fas at certain concentrations but not to tumor necrosis factor-related apoptosis-inducing ligand. HCV ORF expression in HH4 cells up-regulated genes involved in innate immune response/inflammation and oxidative stress responses and down-regulated cell growth-related genes. Expression of HCV ORF in host cells may contribute to HCV pathogenesis by producing oxidative stress and increasing the expression of genes related to the innate immune response and inflammation.
 ...
PMID:Responses of nontransformed human hepatocytes to conditional expression of full-length hepatitis C virus open reading frame. 1799 16


<< Previous 1 2 3 4 5 6 7 8 Next >>