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)

Methionine adenosyltransferase (MAT) is an ubiquitous enzyme that catalyzes the synthesis of S-adenosylmethionine from methionine and ATP. In mammals, there are two genes coding for MAT, one expressed exclusively in the liver and a second enzyme present in all tissues. Molecular studies indicate that liver MAT exists in two forms: as a homodimer and as a homotetramer of the same oligomeric subunit. The liver-specific isoenzymes are inhibited in human liver cirrhosis, and this is the cause of the abnormal metabolism of methionine in these subjects.
 ...
PMID:S-adenosylmethionine synthesis: molecular mechanisms and clinical implications. 917 57

Familial and secondary deficiency of plasma lecithin-cholesterol acyltransferase (LCAT) produce circulating lipoprotein particles with gross structural and compositional abnormalities; these have adverse effects on a variety of cellular functions. Factors affecting hepatic synthesis and secretion of this plasma enzyme are largely unknown but, potentially, some of them can be investigated with monospecific antibodies. In the present study, enzymically active LCAT was purified 40,000-fold from human plasma and then used to raise polyclonal antibodies in New Zealand White rabbits. Addition of this antiserum (1 microliter) to human plasma (25 microlitres) completely inhibited LCAT activity, although it was less effective against plasma from other species. The antibodies appeared to be monospecific to plasma LCAT. They gave a single precipitin arc by crossed immunoelectrophoresis, while immunodiffusion established that there was no cross-reactivity with several apolipoproteins or with serum albumin. Moreover, the antiserum was successfully used to detect LCAT in normal human plasma by Laurell rocket immunoelectrophoresis. By contrast, Western blotting of plasma proteins using whole LCAT antiserum was largely unsuccessful because of high background staining, although this could be substantially reduced by use of an IgG fraction. However, the whole antiserum readily immunoprecipitated LCAT secreted into the culture medium of HepG2 cells, a human hepatoblastoma cell line, pre-labelled with [35S]methionine, the [35S]-labelled LCAT appearing as a narrow 65-kDa protein band by electrophoresis and fluorography. We conclude that polyclonal antibodies may be an important tool to investigate the characteristics and underlying mechanisms of secondary LCAT deficiencies, including those associated with hepatic cirrhosis and schistosomiasis.
 ...
PMID:Characterization and potential uses of rabbit polyclonal antibodies against human plasma lecithin-cholesterol acyltransferase. 918 Oct 76

The study was conceived to evaluate if S-adenosil-L-methionine, a substance commonly used in the treatment of cholestasis in patients with cirrhosis and chronic hepatitis, exerts any immunological effect and of it is able to counterbalance bile acid-mediated immunosuppression. Proliferation and interleukin 2 and interferon-gamma secretion of human lymphocytes, collected from healthy subjects and exposed to mitogenic stimuli (phytohemagglutinin, pokeweed and anti-CD3 monoclonal antibodies), were analysed in the basal condition or after exposure to S-adenosil-L-methionine and/or chenodeoxycholic acid. Chenodeoxycholic acid inhibited phytohemagglutinin-induced lymphocyte proliferation and interferon-gamma secretion, and phytohemagglutinin and pokeweed-mediated interleukin 2 secretion. S-adenosil-L-methionine did not affect lymphocyte proliferation while it reduced interleukin 2 secretion upon phytohemagglutinin and pokeweed stimulation and interferon-gamma secretion upon all stimuli tested. Moreover, S-adenosil-L-methionine counteracted chenodeoxycholic acid-mediated inhibition of lymphocyte proliferation and interleukin 2 secretion. The results of our study confirm the immunosuppressive role of chenodeoxycholic acid on both secretive and proliferative lymphocyte functions and provide evidence of immunomodulatory activities of S-adenosil-L-methionine and its capacity to antagonize chenodeoxycholic acid-mediated inhibition of lymphocyte proliferation and interleukin 2 secretion.
 ...
PMID:S-adenosil-L-methionine is able to reverse the immunosuppressive effects of chenodeoxycholic acid in vitro. 930 55

Cirrhosis and hepatocellular carcinoma occur as long-term complications of chronic hepatitis B virus (HBV) infection. Antiviral therapy is potentially a successful approach for the treatment of patients with HBV infection, which includes the nucleoside analog, lamivudine [(-)2'-deoxy-3'-thiacytidine, 3TC]. Although resistance to lamivudine therapy has been reported in several HBV-infected patients, the pattern of resistance-associated mutations in HBV has not been fully characterized. We report a DNA sequence database that includes a 500-base pair region of the HBV polymerase gene from 20 patients with clinical manifestations of lamivudine resistance. Analysis of the database reveals two patterns of amino acid substitutions in the tyrosine, methionine, aspartate, aspartate (YMDD) nucleotide-binding locus of the HBV polymerase. HBV DNA from the sera of patients in Group I exhibits a substitution of valine for methionine at residue 552, accompanied by a substitution of methionine for leucine at residue 528. Patients in Group II had only an isoleucine-for-methionine substitution at position 552. Reconstruction of these mutations in an HBV replication-competent plasmid was performed in a transient transfection cell assay to determine the function/relevance of these mutations to lamivudine resistance. Both Group I and Group II mutations resulted in a substantial decrease in sensitivity to lamivudine treatment (> 10,000-fold shift in IC50 over wild-type [wt] IC50), strongly indicating that these mutations were involved in resistance to lamivudine. A hypothetical model of the HBV reverse transcriptase has been generated for further study of the role of these mutations in lamivudine resistance.
 ...
PMID:Identification and characterization of mutations in hepatitis B virus resistant to lamivudine. Lamivudine Clinical Investigation Group. 962 Mar 41

The interleukin-6 (IL-6)/gp-80 and hepatocyte growth factor (HGF)/met ligand/receptor systems have been shown to stimulate biliary epithelial cell (BEC) DNA synthesis in vitro. The mRNA and protein production of these two in vitro mitogens were mapped in vivo during the first week after bile duct ligation (BDL) when peak BEC DNA synthesis is seen. Changes around the biliary tree were compared with those seen in the peripheral liver using a combination of Northern blotting and a unique biliary tree isolation technique, in which the bile ducts and the surrounding portal stroma and inflammatory cells are separated from the hepatocytes by perfusion digestion. Further localization was performed with in situ hybridization and immunohistochemistry. In the normal liver, there is low-level expression of HGF mRNA by periportal stellate cells, and HGF protein localizes to these cells and to neutrophils; extracellular HGF protein is present in the bile. There is no detectable IL-6 mRNA by Northern analysis or IL-6 protein expression in the normal liver, but both met and IL-6 receptor (IL-6R) mRNA are detectable; met mRNA is expressed strongly in the biliary tree, and met protein is expressed weakly on hepatocytes and strongly on BEC. IL-6R mRNA is weakly expressed in the biliary tree, and IL-6R protein is detectable on hepatocytes, with a periportal-to-perivenular gradient, but not on BEC. During the first 3 days after BDL, HGF mRNA expression is increased in both the biliary tree and in the peripheral liver, and production is localized to stellate cells, periductal neutrophils, and stromal cells, which typically accompany the proliferating ductules. IL-6 mRNA and protein were detected only near the biliary tree after BDL, and not in the peripheral liver, and the production was localized to periductal hematolymphoid cells, which had the morphological appearance of macrophages and/or dendritic cells. There is also a distinct up-regulation of met and gp-80 mRNA and protein in the biliary tree, which is stronger than that seen in the peripheral liver. Met protein expression is increased, and IL-6R(gp-80) protein is induced on the proliferating BEC, consistent with the participation of both the HGF/met and IL-6/gp-80 systems in the early phases of type I ductular reactions. These observations show that periductal hematolymphoid and stromal cells are the source of BEC growth factors, and receptors for these factors are up-regulated on BEC during active ductular proliferation. Complex interactions between the inflammatory, stromal, and BEC results in a dysmorphogenic repair response that eventually leads to cirrhosis.
 ...
PMID:Interleukin-6, hepatocyte growth factor, and their receptors in biliary epithelial cells during a type I ductular reaction in mice: interactions between the periductal inflammatory and stromal cells and the biliary epithelium. 979 10

Heptral (S-adenosine-L-methionine) was given to 32 patients with chronic diffuse diseases of the liver and intrahepatic cholestasis. 16 of them had primary biliary cirrhosis (PBC). Phase I of the treatment lasted 16 days when the drug was injected intravenously in a dose 800 mg/day. It was followed by phase 2--1600 mg/day taken for 16 days. A response was registered in the majority of patients. They had relieved symptoms of asthenia, skin pruritus, jaundice. The patients with liver cirrhosis and chronic hepatitis exhibited a statistically significant fall in ALT, AST and GGTP. PBS patients showed insignificant lowering of cholesterol, bilirubin. No resistance was noted in repeated courses. Heptral tolerance was satisfactory.
 ...
PMID:[Clinical trial of heptral in patients with chronic diffuse liver disease with intrahepatic cholestasis syndrome]. 986 18

The impairment of transsulphuration during methionine degradation in hepatic failure can be counteracted by treatment with S-adenosylmethionine. Regarding the pathogenesis of hepatic encephalopathy, no convincing evidence exists for tryptophan, glutamine or glutamate being involved. Portal-systemic shunting-induced hyperammonaemia may reduce plasma branched-chain amino acids. The glucose effect on urea synthesis does not exist in cirrhosis.
 ...
PMID:Amino acid metabolism in liver disease. 1045 30

Viral hepatitis is a persisting concern. Outbreaks of hepatitis A occur in developed countries where only 10% to 20% of the population is seroprotected. The disease may cause fulminant liver failure and death. People who are targeted for vaccination include intravenous drug users, homosexuals, and chronic hepatitis patients. Secondary prophylaxis of household contacts is an efficient way to prevent secondary cases. Universal vaccination is now in progress for hepatitis B. Vaccination failure may occur in low birth weight infants, or in infants infected in utero. Chronic carriers of viral hepatitis may progress to cirrhosis and hepatocarcinoma, the latter risk being most important for men infected at birth. Alcohol intake should be avoided in carrier adolescents. Interferon is able to triple the rate of hepatitis B e antigen loss and decouple the rate of hepatitis B s antigen loss after one year, shortening disease evolution and, it is to be hoped, decreasing the risk of unfavorable outcome. Similarly, lamivudine increases by four times the rate of hepatitis B e antigen loss in adults. However, precore mutants may be selected by immune pressure after seroconversion in children, and tyrosine-methionine-aspartate-aspartate (YMDD) mutations appear in 15% of patients treated with lamivudine after 1 year. Hepatitis C is mainly acquired during childhood via true vertical transmission. The risk of acquiring Hepatitis C is related to the presence and amount of RNA for hepatitis C virus in mothers at the time of birth. The infection rate for the hepatitis C virus is higher in children from mothers who have tested positive for HIV, and higher if these children are themselves coinfected with HIV. Treatment with interferon alone has a poor rate of efficiency, although pediatric studies remain scarce. Combination treatment using ribavirin plus interferon yield a higher rate of success in eradicating viral infection in adults.
 ...
PMID:Update on prevention and treatment of viral hepatitis in children. 1055 88

Carcinogenesis may be effected not only through exposure to exogenous stimuli but also by genetic and epigenetic influences derived from endogenous factors. In the latter case, the mechanisms are still largely obscure because of the limited availability of appropriate in vivo experimental models. However, continuous feeding of a diet deficient in choline and methionine is well known to cause hepatocellular carcinomas (HCC) in rats in the absence of any known exogenous carcinogens and can serve as a good research model. A semi-synthetic, choline-deficient, L-amino acid-defined (CDAA) diet, containing practically no choline and low methionine, induces HCC with a background of fatty liver and hepatocyte death, subsequent regeneration and fibrosis resulting in cirrhosis. Using the CDAA diet, we have revealed the participation of oxidative injury to DNA and other subcellular components and of alteration in intrahepatic signal transduction pathways in the mechanisms underlying this rat liver carcinogenesis model. In the present paper, the current understanding of endogenous rat liver carcinogenesis, due to dietary choline deficiency, is reviewed.
 ...
PMID:Endogenous liver carcinogenesis in the rat. 1063 23

Much progress has been made in the understanding of the pathogenesis of alcoholic liver disease, resulting in improvement of prevention and therapy, with promising prospects for even more effective treatments. The most successful approaches that one can expect to evolve are those that deal with the fundamental cellular disturbances resulting from excessive alcohol consumption. Two pathologic concepts are emerging as particularly useful therapeutically. Whereas it continues to be important to replenish nutritional deficiencies, when present, it is crucial to recognize that because of the alcohol-induced disease process, some of the nutritional requirements change. This is exemplified by methionine, which normally is one of the essential amino acids for humans, but needs to be activated to S-adenosylmethionine (SAMe), a process impaired by the disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. Indeed, SAMe was found to attenuate mitochondrial lesions in baboons, replenish glutathione, and significantly reduce mortality in patients with Child A or B cirrhosis. Similarly, polyenylphosphatidylcholine (PPC) corrects the ethanol-induced hepatic phospholipid depletion as well as the decreased phosphatidylethanolamine methyltransferase activity and opposes oxidative stress. It also deactivates hepatic stellate cells, whereas its dilinoleoyl species (DLPC) increases collagenase activity, resulting in prevention of ethanol-induced septal fibrosis and cirrhosis in the baboon. Clinical trials with PPC are ongoing in patients with alcoholic liver disease. Furthermore, enzymes useful for detoxification, such as CYP2E1, when excessively induced, become harmful and should be downregulated. PPC is one of the substances with anti-CYP2E1 properties that is now emerging. Another important aspect is the association of alcoholic liver disease with hepatitis C: a quarter of all patients with alcoholic liver disease also have markers of HCV infection, with an even higher incidence in some urban areas but, at present, no specific therapy is available since interferon is contraindicated in that population. However, in addition to antiviral medications, agents that oppose oxidative stress and fibrosis should also be tested for hepatitis C treatment since these two processes contribute much to the pathology and mortality associated with the virus. In addition to antioxidants (such as PPC, silymarin, alpha-tocopherol and selenium), anti-inflammatory medications (corticosteroids, colchicine, anticytokines) are also being tested as antifibrotics. Transplantation is now accepted treatment in alcoholics who have brought their alcoholism under control and who benefit from adequate social support but organ availability is still the major limiting factor and should be expanded more aggressively. Finally, abstinence from excessive drinking is always indicated; it is difficult to achieve but agents that oppose alcohol craving are becoming available and they should be used more extensively.
 ...
PMID:Alcoholic liver disease: new insights in pathogenesis lead to new treatments. 1072 99


<< Previous 1 2 3 4 5 6 7 8 9 10