Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Liver biopsies from patients with alcoholic hepatitis, chemical hepatitis, or viral hepatitis types A, B, or non-A, non-B were examined by electron microscopy. Circular, fused, cytoplasmic membranes were observed in hepatocytes of 17% of patients with hepatitis type B and 92% of patients with hepatitis type non-A, non-B. The membrane alterations were not observed in hepatocytes of patients with the other types of hepatitis. The greater frequency of altered cytoplasmic membranes in hepatocytes of patients with non-A, non-B hepatitis was shown to be statistically significant (p less than 0.05) when compared to that in patients with viral hepatitis type B.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Association of human hepatocellular membrane fusions with non-A, non-B hepatitis. 287 55

Nitric oxide is now established as a biological mediator of clinical relevance. The present study investigated the production of nitric oxide by lympho-mononuclear leukocytes from alcoholic patients with either hepatitis or cirrhosis. The study included 42 patients, 12 without any liver disease and 30 alcoholic patients, 13 of whom had histologically confirmed cirrhosis and 17 alcoholic hepatitis. Cells were obtained from peripheral blood by density gradient and incubated in sterile conditions in RPMI 1640 for 6 h at 37 degrees C. Culture supernatants were assayed for nitrite concentration using the Griess reaction. Cells from cirrhotic but not from hepatopathic patients showed significantly higher nitrite production than controls (cirrhotic, 0.36 +/- 0.07; hepatopathic, 0.13 +/- 0.02; control: 0.25 +/- 0.05 nmol/10(6) cells/6 h). In cirrhotic patients L-Nitro-arginine methylester inhibited nitrite production (0.18 +/- 0.05). These data suggest that alcoholic cirrhotic but nonhepatopathic patients show an increased nitric oxide production by blood lymphomononuclear cells. This production could be involved in the systemic vasodilation in cirrhotic patients.
J Mol Med (Berl) 1995 Jan
PMID:Nitric oxide production by mononuclear leukocytes in alcoholic cirrhosis. 763 39

Perturbations in keratin intermediate filament organization and Mallory body (MB) formation are associated with alcoholic hepatitis. Inducible heat shock proteins (HSPs) are expressed in a variety of liver diseases including alcoholic liver disease. Therefore, we investigated whether heat shock protein induction can lead to MB formation. Mice were primed by a 5-month feeding of griseofulvin (GF) or diethyl 1,4-dehydro-2,4,6-trimethyl-3,5-pyridinedicarboxylate (DDC) followed by drug withdrawal for 1 month. The animals were then subjected to an in vivo heat shock treatment or sham heat treatment. Liver morphology, HSP expression, liver regeneration (PCNA-labeled nuclei), and MB formation were monitored during a 7-day posttreatment period. Numerous MBs developed in the livers of mice exposed to GF or DDC for 5 months, but very few small MBs remained after 1-month withdrawal of either drug. No MBs were found at Day 1 post heat shock, whereas numerous MBs were observed at Day 7. The frequency of PCNA-labeled nuclei increased during the same period. At Day 1 posttreatment, a variable liver centrilobular necrosis was observed accompanied by a prominent increase in HSP-25 and HSP70 expression, but HSP-90 expression was not increased. In drug-primed mouse liver, a heat shock treatment induces the expression of specific HSPs prior to the formation of MBs, indicating that HSP expression may play a role in the pathogenesis of MB formation. We speculate that this role is through the protein unfolding function of HSP, which leads to the aggregation of the cytokeratins to form MBs as well as to polyubiquitin binding to these proteins in a manner analogous to amyloid formation.
Exp Mol Pathol 1995 Aug
PMID:Heat shock in vivo induces Mallory body formation in drug primed mouse liver. 875 55

The degradation of rat hepatic intermediate filament (IF) proteins cytokeratin A (CK-A, 55-kDa) and cytokeratin D (CK-D, 48-kDa) by purified rat liver calcium-activated proteases (calpains I and II) was evaluated in vitro. Calpain-mediated IF proteolysis was monitored by SDS-PAGE and Western blotting with antibodies to CK-A and CK-D and compared to microtubule protein actin. Both cytokeratins underwent rapid yet limited proteolysis by calpain I and II. Despite the conserved nature of cytokeratins and limited substrate specificity for calpains, distinct fragmentation patterns were obtained for calpain I) CK-A, 46- and 43-kDa/CK-D, 41-, and 39-kDa; and calpain II) CK-A, 46- and 43-kDa/CK-D 41-kDa. The 46-kDa CK-A fragment was the predominant fragment for both calpains. Two-dimensional electrophoresis (IEF/SDS-PAGE) of CK fragments revealed the presence of classic "staircase" patterns consistent with endogenous proteases. Furthermore, proteolytic fragments showed a 2-D electrophoretic shift to lower pI suggesting that the limited hydrolysis occurred within the N-terminal arginine-rich region of CK, a region believed essential for IF interactions in vivo. Thus, calpains may represent an initial step in the turnover of these stable and long-lived proteins and as such, may be relevant to diseases characterized by abnormal disruption and bundling of IF such as formation of Mallory bodies in alcoholic hepatitis.
Res Commun Mol Pathol Pharmacol 1998 Sep
PMID:Degradation of cytokeratin intermediate filaments by calcium-activated proteases (calpains) in vitro: implications for formation of Mallory bodies. 987 79

In a clinical study in which patients with alcoholic hepatitis were treated with prednisone for 1 month, posttreatment liver biopsies showed diminished inflammation, but Mallory bodies were not diminished. This suggested that steroid treatment may reduce inflammation by inhibiting NFkappaB activation. Sparing of Mallory bodies suggests that NFkappaB activation may not be involved mechanistically in Mallory body formation. To test this idea, we induced Mallory body formation in drug-primed mice with or without dexamethasone treatment. As predicted, dexamethasone decreased NFkappaB activation; however, Mallory body formation was increased. Surprisingly, TNFalpha and iNOS, which normally increase as a result of NFkappaB activation, were upregulated by the dexamethasone treatment. It was concluded that NFkappaB activation is not involved in Mallory body formation. Despite this, induced increases in TNFalpha, iNOS, c-jun/API and c-myc expression indicate that oxidative stress is likely involved in Mallory body formation.
Exp Mol Pathol 2000 Dec
PMID:Dexamethasone enhances mallory body formation in drug-primed mouse liver. 1111 61

Human liver contains estrogen receptors (ER) which render it sensitive to estrogen. Chronic ethanol ingestion in humans and rats results in alterations of circulating sex steroid levels and expression of sex hormone-dependent phenotype. The analysis and quantitation of hepatic estrogen receptor (ER) activity and sex hormone-responsive proteins have been performed over the past two decades. Alcohol abuse appears to induce an increase in ER content of human liver, especially in patients with alcoholic hepatitis actively drinking. This observation is reproduced in an experimental model of chronic alcohol feeding of rats. In male rat liver, the increased ER expression induced by alcohol is associated with an elevated proliferation rate of the hepatocytes. In female liver, the ER content is not affected by alcohol intake and apoptosis prevails over proliferation. The feminization of the liver in males may protect the liver from the severe alcohol-induced liver injury seen in females.
Mol Cell Endocrinol 2002 Jul 31
PMID:Hepatic estrogen receptors and alcohol intake. 1216 Oct 8

Mallory bodies (MBs) are aggresomes, composed of cytokeratin and various other proteins, which form in diseased liver because of disruption in the ubiquitin-proteasome protein degradation pathway. Heat shock proteins (hsp's) are thought to be involved in this process because it was discovered that MB formation is induced by heat shock in drug-primed mice. It has been reported that ubiquitin and a mutant form of ubiquitin (UBB(+1)) are found in aggresomes formed in the neurons in Alzheimer's disease and in the liver MBs in various liver diseases. In addition, hsp 70 has been found in aggresomes in Alzheimer's and in MBs in drug-primed mice. Therefore, we hypothesized that hsp's might be involved in MB formation in human liver diseases. Liver biopsy sections were double-stained using ubiquitin and hsp 70 or 90b antibodies. Both hsps 70 and 90b were found in MBs in all liver diseases investigated including primary billiary cirrhosis, nonalcoholic steatohepatitis, hepatitis B and C, idiopathic cirrhosis, alcoholic hepatitis, and hepatocellular carcinoma. Ubiquitin and the hsp's colocalized in all MBs in the diseased liver sections. These results indicate that hsp involvement in MB formation is similar to that seen in aggresome formation in other conformational diseases.
Exp Mol Pathol 2003 Apr
PMID:Heat shock proteins are present in mallory bodies (cytokeratin aggresomes) in human liver biopsy specimens. 1271 Sep 48

Liver cirrhosis, an end-result of a wide variety of the liver diseases, is a world wide health problem. Because of its unique organ system, i.e., portal blood supply, bile formation and enterohepatic circulation, drug metabolism system, and sinusoidal lining cells such as Kupffer, endothelial and stellate cells, the liver is a target of a variety of hepatotoxic insults. Current data suggest that hepatocyte apoptosis is an essential feature contributing to liver injury in a wide range of acute and chronic liver diseases. With an improved understanding of the pathophysiological role of apoptosis in liver diseases, we are now entering an era where regulation of liver cell apoptosis is becoming a therapeutic possibility. Inhibition of hepatocyte apoptosis using a variety of different strategies may be therapeutically beneficial in liver injuries, such as alcoholic hepatitis, non-alcoholic steatohepatitis (NASH), viral hepatitis, and cholestatic liver diseases. Considering the link between hepatocyte apoptosis and liver fibrosis, inhibition of hepatocyte apoptosis may also be an anti-fibrotic therapeutic strategy. Moreover, selective induction of apoptosis of activated stellate cells would be a unique approach to induce the resolution the phase of liver fibrosis. These concepts merit further clinical and basic investigation.
Curr Mol Med 2003 Sep
PMID:Mechanisms of liver injury: an overview. 1452 80

Chronic ethanol ingestion leads to inhibition of proteasomal activity. As a consequence, proteins accumulate in liver cells. Cytokeratin accumulation as seen in alcoholic hepatitis could lead to the formation of Mallory bodies. In order to study the phenomenon of cytokeratin accumulation in liver cells, rats were fed ethanol or dextrose for 1 month and some were given the proteasome inhibitor, PS-341, to augment the inhibitory effect of ethanol feeding. This was done to study the involvement of proteasome inhibition in the process of cytokeratin accumulation. There was a marked increase in the accumulation of polyubiquitinated proteins, and heat shock proteins (hsp) 25 and 70 in the liver of rats treated with PS-341. Similarly, cytokeratin-8 (CK-8) levels were markedly increased in the liver homogenates of rats fed ethanol when given PS-341. When normal mouse cultured hepatocytes were transfected with cytokeratin-18 (CK-18) tagged with red fluorescent protein (RFP), CK-18 aggresomes formed because proteasome was overloaded. These data provide new evidence that proteasome inhibition is involved in cytokeratin accumulation, when aggresomes are formed in tissue culture. Accumulation of cytokeratin in this way may ultimately lead to Mallory body formation as seen in alcoholic hepatitis.
Exp Mol Pathol 2004 Apr
PMID:Proteasome inhibition induces cytokeratin accumulation in vivo. 1501 Feb 85

Tumor necrosis factor (TNF)-alpha-induced hepatocyte apoptosis is implicated in a wide range of liver diseases including viral hepatitis, alcoholic hepatitis, ischemia/reperfusion liver injury, and fulminant hepatic failure. TNF-alpha exerts a variety of effects that are mediated mainly by TNF-receptor 1 (TNF-R1) in cell death. The activation of TNF-R1 leads to the activation of multiple apoptotic pathways involving the activation of the pro-death Bcl-2 family proteins, reactive oxygen species, C-Jun NH2-terminal kinase, cathepsin B, acidic sphingomyelinase and neutral sphingomyelinase. These pathways are closely interlinked and mainly act on mitochondria, which release the apoptogenic factors and other events, resulting in apoptosis. This article reviews the recent progress in the molecular mechanisms of TNF-alpha-induced apoptosis in hepatocytes, and discusses how these molecular findings are shaping our understanding of the pathogenesis of liver diseases and our strategy to develop novel therapeutics.
J Cell Mol Med
PMID:Dissection of the multiple mechanisms of TNF-alpha-induced apoptosis in liver injury. 1560 73


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