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)

The structural characteristics of oversulfated chondroitin/dermatan sulfates (C/DSs) in the fibrous lesions of the rat liver with cirrhosis were examined. Long-Evans Cinnamon rats were subjected to the present study as the model animals with cirrhosis. The serial polyester wax sections of liver with cirrhosis were processed into the fibrous lesions and the nonfibrous lesions. The oversulfated C/DSs in the tissue sections on a glass slide were degraded to unsaturated disaccharides by chondroitinase ABC and ACII digestion in the presence of bacterial collagenase. Subsequently, the resulting unsaturated disaccharides were determined by the reversed-phase ion-pair high-performance liquid chromatography with fluorometric postcolumn derivatization using 2-cyanoacetamide as a reagent. Through these in situ investigations, we found some facts as follows: (i) in the fibrous lesion, the remarkable increase of the oversulfated C/DSs content and the decrease of the oversulfation degree of the C/DSs were observed compared with those in the nonfibrous lesion, (ii) the proportion of the iduronic acid content in the C/DSs in the fibrous lesion was significantly low compared with that in the nonfibrous lesion, and (iii) in the nonfibrous lesion close to the fibrous lesion, both quantitative and qualitative alterations of C/DSs were not observed at all. These findings indicate that the oversulfated C/DSs with low iduronic acid content are possible marker for the fibrogenesis of liver with cirrhosis.
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PMID:Structural characteristics of oversulfated chondroitin/dermatan sulfates in the fibrous lesions of the liver with cirrhosis. 1051 Feb 72

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.
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PMID:Alcoholic liver disease: new insights in pathogenesis lead to new treatments. 1072 99

In the past, alcoholic liver disease was attributed exclusively to dietary deficiencies, but experimental and judicious clinical studies have now established alcohol's hepatotoxicity. Despite an adequate diet, it can contribute to the entire spectrum of liver diseases, mainly by generating oxidative stress through its microsomal metabolism via cytochrome P4502E1 (CYP2E1). It also interferes with nutrient activation, resulting in changes in nutritional requirements. This is exemplified by methionine, one of the essential amino acids for humans, which needs to be activated to S-adenosylmethionine (SAMe), a process impaired by liver disease. Thus, SAMe rather than methionine is the compound that must be supplemented in the presence of significant liver disease. In baboons, SAMe attenuated mitochondrial lesions and replenished glutathione; it also significantly reduced mortality in patients with Child A or B cirrhosis. Similarly, decreased phosphatidylethanolamine methyltransferase activity is associated with alcoholic liver disease, resulting in phosphatidylcholine depletion and serious consequences for the integrity of membranes. This can be offset by polyenylphosphatidylcholine (PPC), a mixture of polyunsaturated phosphatidylcholines comprising dilinoleoylphosphatidylcholine (DLPC), which has high bioavailability. PPC (and DLPC) opposes major toxic effects of alcohol, with down-regulation of CYP2E1 and reduction of oxidative stress, deactivation of hepatic stellate cells, and increased collagenase activity, which in baboons, results in prevention of ethanol-induced septal fibrosis and cirrhosis. Corresponding clinical trials are ongoing.
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PMID:ALCOHOL: its metabolism and interaction with nutrients. 1094 Mar 40

Liver cirrhosis represents a worldwide health problem and is a major cause of mortality. Cirrhosis is the result of extensive hepatocyte death and fibrosis induced by chronic alcohol abuse and hepatitis B and C viruses. Successful gene therapy approaches to this disease may require both reversal of fibrosis and stimulation of hepatocyte growth. Urokinase-type plasminogen activator (uPA) may serve this function, as it is an initiator of the matrix proteolysis cascade and induces hepatocyte growth factor expression. In a rat cirrhosis model, a single iv administration of a replication-deficient adenoviral vector encoding a nonsecreted form of human uPA resulted in high production of functional uPA protein in the liver. This led to induction of collagenase expression and reversal of fibrosis with concomitant hepatocyte and improved liver function. Thus, uPA gene therapy may be an effective strategy for treating cirrhosis in humans.
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PMID:Liver cirrhosis is reverted by urokinase-type plasminogen activator gene therapy. 1112 55

Decorin is a small extracellular matrix proteoglycan. It binds and modulates transforming growth factor (TGF)-beta 1 action, the major stimulator of fibrogenesis. Its role in the pathogenesis of human liver cirrhosis is unknown. Therefore, we studied the relationship of the 2 proteins in normal human liver and in 43 chronic hepatitis and liver cirrhosis specimens. To understand the mechanism that maintains matrix deposition in stage IV hepatitis, we studied expression of tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2, as well as the activities of type IV collagenases. Gene expression was analyzed on messenger RNA and protein level by morphologic and biochemical approaches. Decorin proved to be an early marker of fibrogenesis, and its deposition increased parallel to that of TGF-beta 1 and to inflammatory activity. Liver fibrosis progressed despite high temporospatial expression of decorin with TGF-beta 1. Neither decorin nor TGF-beta 1 protein deposition increased further in cirrhosis with low inflammatory activity, suggesting that impaired extracellular matrix catabolism rather than active production plays a role in this stage. This possibility was supported by high message levels of metalloproteinase inhibitors, no 72-kd collagenase activities, and low 92-kd collagenase activities.
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PMID:Expression of decorin, transforming growth factor-beta 1, tissue inhibitor metalloproteinase 1 and 2, and type IV collagenases in chronic hepatitis. 1134 37

Since the authors reported the presence of collagenase in the liver as well as its increased activity in the early stage of hepatic fibrosis and its reduced activity in advanced fibrosis in rats induced by chronic CCl4 intoxication, in baboons fed alcohol chronically and in patients with alcoholic fibrosis, other investigators have demonstrated the same tendency of collagenase activity biologically and histochemically. Very recently, the authors demonstrated definite gene expression of collagenase during the recovery from experimental hepatic fibrosis using Northern blotting and in situ hybridization. The findings of in situ hybridization not only demonstrated the cells expressing collagenase, but also suggested much information on the mechanism of the recovery from fibrosis. Hepatic stellate cells play a key role not only in fibrogenesis but also in fibrolysis. The authors' recent observation revealed that collagenase (matrix metalloproteinase-13 (MMP-13)) gene expression appears very early in the process of recovery from liver fibrosis, and that both stellate cells and hepatocytes express MMP-13. Recovery from liver cirrhosis requires the gene expression of collagenase, increased production of the collagenase enzyme, and activation of the enzyme balanced with the specific inhibitors of collagenase. The understanding of molecular mechanisms of MMP-1 gene expression which is under investigation in our laboratory may provide us a new strategy for the treatment of liver fibrosis including the possibility of gene therapy.
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PMID:Reversibility of hepatic fibrosis: from the first report of collagenase in the liver to the possibility of gene therapy for recovery. 1145 May 93

The activated hepatic stellate cell (HSC) is central to liver fibrosis as the major source of collagens I and III and the tissue inhibitors of metalloproteinase-1 (TIMP-1). During spontaneous recovery from liver fibrosis, there is a decrease of TIMP expression, an increase in collagenase activity, and increased apoptosis of HSC, highlighting a potential role for TIMP-1 in HSC survival. In this report, we use tissue culture and in vivo models to demonstrate that TIMP-1 directly inhibits HSC apoptosis. TIMP-1 demonstrated a consistent, significant, and dose-dependent antiapoptotic effect for HSC activated in tissue culture and stimulated to undergo apoptosis by serum deprivation, cycloheximide exposure, and nerve growth factor stimulation. A nonfunctional mutated TIMP-1 (T2G mutant) in which all other domains are conserved did not inhibit apoptosis, indicating that inhibition of apoptosis was mediated through MMP inhibition. Synthetic MMP inhibitors also inhibited HSC apoptosis. Studies of experimental liver cirrhosis demonstrated that persistent expression of TIMP-1 mRNA determined by PCR correlated with persistence of activated HSC quantified by alpha smooth muscle actin staining, while in fibrosis, loss of activated HSC correlated with a reduction in TIMP-1 mRNA. We conclude that TIMP-1 inhibits apoptosis of activated HSC via MMP inhibition.
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PMID:Inhibition of apoptosis of activated hepatic stellate cells by tissue inhibitor of metalloproteinase-1 is mediated via effects on matrix metalloproteinase inhibition: implications for reversibility of liver fibrosis. 1179 25

Cell-based extracorporeal liver support is an option to assist or replace the failing organ until regeneration or until transplantation can be performed. The use of porcine cells or tumor cell lines is controversial. Primary human liver cells, obtained from explanted organs found to be unsuitable for transplantation, are a desirable cell source as they perform human metabolism and regulation. The Modular Extracorporeal Liver Support (MELS) concept combines different extracorporeal therapy units, tailored to suit the individual and intra-individual clinical needs of the patient. A multi-compartment bioreactor (CellModule) is loaded with human liver cells obtained by 5-step collagenase liver perfusion. A cell mass of 400 g - 600 g enables the clinical application of a liver lobe equivalent hybrid organ. A detoxification module enables single pass albumin-dialysis via a standard high-flux dialysis filter, and continuous veno-venuous hemodiafiltration may be included if required. Cells from 54 human livers have been isolated (donor age: 56 +/- 13 years, liver weight: 1862 +/- 556 g resulting in a viability of 55.0 +/- 15.9%). These grafts were not suitable for LTx, due to steatosis (54%), cirrhosis (15%), fibrosis (9%), and other reasons (22%). Out of 36 prepared bioreactors, 10 were clinically used to treat 8 patients with liver failure. The overall treatment time was 7-144 hours. No adverse events were observed. Initial clinical applications of the bioreactor evidenced the technical feasibility and safety of the system.
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PMID:Primary human liver cells as source for modular extracorporeal liver support--a preliminary report. 1245 42

In laboratory animals, intrasplenic hepatocyte transplantation corrects the physiologic abnormalities associated with decompensated liver disease. The clinical experience with hepatocyte transplantation for cirrhosis has been disappointing when compared with laboratory experience. The route of hepatocyte delivery may influence hepatocyte engraftment and function. Outbred pigs were recipients of allogeneic pig hepatocytes. Donor hepatocytes were isolated by collagenase perfusion and labeled using 5(6)-carboxyfluorescein diacetate succinimidyl-ester (CMFSE). Cells were introduced into pig spleens by infusion through the splenic artery or by direct splenic puncture. Direct intrasplenic injection produced engraftment that was far superior to that obtained using splenic artery infusion. Splenic artery infusion produced a gastric erosion and large areas of splenic necrosis secondary to vascular occlusion with hepatocytes, whereas direct splenic injection was associated with clinically insignificant intraabdominal hemorrhage. The route of hepatocyte delivery may influence hepatocyte engraftment and explain the disparity in efficacy of hepatocyte transplantation between the laboratory and clinic.
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PMID:Route of hepatocyte delivery affects hepatocyte engraftment in the spleen. 1297 19

TGFbeta controls hepatocyte growth through cell cycle arrest and apoptosis, and resistance to TGFbeta is a mechanism of malignant transformation. The aim of this study was to assess differences in TGFbeta-mediated growth inhibition in normal and cirrhotic hepatocytes. Cirrhosis was induced in mice and normal and cirrhotic hepatocytes were isolated by collagenase perfusion and treated with or without TGFbeta (5 ng/ml). DNA synthesis, Smad protein expression, and DNA binding activity were determined. TGFbeta reduced DNA synthesis to a greater degree in normal hepatocytes than in cirrhotic hepatocytes (87% vs. 68%; p<0.05). Smad protein expression was decreased in cirrhotic hepatocytes and Smad 2/3/4 complex formation was suppressed. Furthermore, cirrhotic hepatocytes had decreased DNA binding activity at 120 min following TGFbeta treatment. In conclusion, decreased Smad protein expression may impair TGFbeta-mediated growth inhibition in cirrhotic hepatocytes.
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PMID:Cirrhotic hepatocytes exhibit decreased TGFbeta growth inhibition associated with downregulated Smad protein expression. 1469 24


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