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)

Assessment of liver regeneration with endogenous genes that are expressed during DNA replication is physiological, specific and direct. To determine whether H3 histone messenger RNA expression (which is tightly coupled with DNA synthesis) could be used for this purpose, we initially examined liver regeneration in a mouse model. After partial hepatectomy, RNA transblot studies showed induction of H3 histone messenger RNA expression in regenerating mouse livers. In situ molecular hybridization demonstrated that the overall pattern of H3 histone messenger RNA expression correlated with [3H]thymidine labeling of hepatocytes. After partial hepatectomy, H3 histone messenger RNA expression in hepatocytes peaked at 48 hr (greater than 60 times greater than at 24 hr; p less than 0.001) and then rapidly declined. Although hepatocyte labeling with [3H]thymidine showed similar kinetics of liver regeneration, use of this parameter resulted in overestimation of the proliferative compartment when it was compared with H3 histone messenger RNA expression. Next we determined whether H3 histone messenger RNA expression could be used to study hepatocellular proliferation in archival human material. H3 histone messenger RNA-expressing hepatocytes were identified on in situ hybridization in patients with acute or chronic active hepatitis and active cirrhosis, but not inactive cirrhosis. These studies demonstrate that H3 histone messenger RNA is expressed in a phasic manner during liver regeneration. Use of H3 histone messenger RNA expression to evaluate hepatocellular proliferation should facilitate clinical studies and greatly advance our understanding of the pathophysiology of liver regeneration.
 ...
PMID:Analysis of hepatocellular proliferation: study of archival liver tissue is facilitated by an endogenous marker of DNA replication. 139 4

Sera of 78 patients with different chronic liver diseases were examined for the presence of anti-histone activity using an enzyme-linked immunosorbent assay. Eighteen patients had primary biliary cirrhosis (PBC), 20 had chronic active hepatitis, and 40 had cirrhosis. Anti-histone antibodies were detected in 34 patients (43.6%), distributed among all liver disease entities studied. When antibodies of specific isotypes (IgG, IgM, and IgA) were measured, even higher frequencies were noted--50% for IgG and 53.8% for IgA. Antibodies to histone subfractions H1, H2a, H2b, H3, and H4 were also observed in all liver disorders investigated (in 22-32% of patients)--H1 and H3 being the prominent fractions involved. Of the various disease entities examined PBC was the one disclosing the highest frequency of anti-histone antibodies.
 ...
PMID:Autoantibodies to histones and their subfractions in chronic liver diseases. 278 64

Chronic hepatitis resulting from hepatitis C virus (HCV) infection develops into cirrhosis in at least half of infected patients and increases the risk of hepatocellular carcinoma. The pathogenic effects of a number of viruses result from the disturbance of intracellular signal cascades caused by viral antigens. Therefore, we investigated the interaction of nonstructural protein 3 (NS3) of HCV with the cyclic AMP-dependent signal pathway. We found a similarity between the HCV sequence Arg-Arg-Gly-Arg-Thr-Gly-Arg-Gly-Arg-Arg-Gly-Ile-Tyr-Arg localized in NS3 and the general consensus sequence of protein kinase A (PKA). Consequently, the catalytic (C) subunit of PKA bound to a bacterially expressed fragment of HCV polyprotein containing amino acid residues 1189 to 1525. When this fragment was introduced into cells, it inhibited the translocation of the C subunit into the nucleus after stimulation with forskolin. The result of this inhibition was significantly reduced histone phosphorylation. Therefore, the presence of NS3 in the cytoplasm of infected cells may affect a wide range of PKA functions and contribute to the pathogenesis of the diseases caused by HCV.
 ...
PMID:Nonstructural protein 3 of hepatitis C virus blocks the distribution of the free catalytic subunit of cyclic AMP-dependent protein kinase. 906 Jun 39

In vivo histoautoradiographic study of cerebral accumulation of exogenous histone after its intracarotid infusion to anesthetized rats with intact liver and animals with experimental cirrhosis showed that histone penetrates brain capillary endotheliocyte membranes and gets into the nervous tissue.
 ...
PMID:Accumulation of exogenous histone in rat brain parenchyma. 1114 May 81

Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine and adenine salvage pathways. In mammals, the liver plays a central role in methionine metabolism, and this essential function is lost in the progression from liver cirrhosis to hepatocarcinoma. Deficient MTAP gene expression has been recognized in many transformed cell lines and tissues. In the present work, we have studied the expression of MTAP in human and experimental liver cirrhosis and hepatocarcinoma. We observe that MTAP gene expression is significantly reduced in human hepatocarcinoma tissues and cell lines. Interestingly, MTAP gene expression was also impaired in the liver of CCl4-cirrhotic rats and cirrhotic patients. We provide evidence indicating that epigenetic mechanisms, involving DNA methylation and histone deacetylation, may play a role in the silencing of MTAP gene expression in hepatocarcinoma. Given the recently proposed tumor suppressor activity of MTAP, our observations can be relevant to the elucidation of the molecular mechanisms of multistep hepatocarcinogenesis.
 ...
PMID:Methylthioadenosine phosphorylase gene expression is impaired in human liver cirrhosis and hepatocarcinoma. 1551 35

Hepatocellular carcinoma is often diagnosed at an advanced stage, when it is not amenable to curative therapies. There is no effective chemotherapy. Advances in cancer biology suggest that a limited number of pathways are responsible for initiating and maintaining dysregulated cell proliferation, which is the major cellular alteration responsible for the cancer phenotype. New treatments in development target several of these critical pathways, including agents targeting the receptor tyrosine kinase pathways, the Wnt/beta-catenin signaling pathway, the ubiquitin/proteasome degradation pathway, the epigenetic DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, and telomerase. Several of these approaches hold significant promise for improving the long-term outcome of patients with advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, these approaches must be coupled with new strategies for halting or reversing the progression of chronic liver disease.
 ...
PMID:Hepatocellular carcinoma: molecular pathways and new therapeutic targets. 1591 49

Hepatocellular carcinoma is often diagnosed at an advanced stage, when potentially curative surgical or local ablative therapies are not feasible. There is no effective chemotherapy for hepatocellular carcinoma. Recent advances in cancer biology suggest that a limited number of signalling pathways may be responsible for uncontrolled cell proliferation, the major cellular alteration responsible for the cancer phenotype. Novel anticancer agents target these critical pathways, including the receptor tyrosine kinase pathways, the Wnt/beta-catenin signalling pathway, the ubiquitin/proteasome degradation pathway, the DNA methylation and histone deacetylation pathways, the PI3 kinase/AKT/mTOR pathway, angiogenic pathways, telomerase and the cell cycle. These agents hold promise for improving the outcome of patients with intermediate and advanced hepatocellular carcinoma. Because of the high prevalence of liver cirrhosis in hepatocellular carcinoma patients, to achieve long-term survival of the majority of patients, targeted anticancer therapies will need to be coupled with strategies aimed at reversing the progression of chronic liver disease.
 ...
PMID:Emerging drugs for hepatocellular carcinoma. 1693 86

Despite aggressive treatment, sarcoidosis may be debilitating and progressive. The role of tumor necrosis factor (TNF)-a in the genesis of granulomas is ambiguous. It has proven to be critical in the formation and maintenance of granulomatous inflammation and its antagonist, Infliximab, has therefore been used with success in the treatment of patients with sarcoidosis. There are, however, reports of onset of sarcoidosis in patients in treatment for other conditions and that had no outbursts before submission to this therapy. We used Infliximab in the treatment of patients with sarcoidosis who either didn't respond to corticosteroids and other conventional drugs or developed unacceptable side effects to these drugs. The initial dose was 5mg/Kg body weight and subsequent doses were given at weeks 2, 4 and then every other 8 weeks for a total period of one year. We treated ten patients with biopsy proven sarcoidosis, five men and five women, with a mean age of 47.1 years ranging from 28 to 63 years of age. Three patients had severe neurological symptoms, two had hepatic cirrhosis, one had granulomatous inflammation of the lachrymal gland and had already been submitted to many surgeries, one had extensive pulmonary involvement (stage III), one had disfiguring lupus pernio and two presented disabling cutaneous nodules. In four patients the dosage of corticosteroids or other immunosuppressive drugs was suspended, in three the dosage was reduced and in one, corticosteroids were added to the Infliximab therapy. In five of the patients there was a significant improvement. One of the patients with neurological symptoms displayed a complete recovery, while another had significant improvement of vision deficit enabling her to read again. Two patients withdrew from therapy, one due to lack of improvement of neurological symptoms and the other due to the onset of organizing pneumonia spawned by Infliximab. Two patients developed anti-histone antibodies during treatment. Infliximab seems effective in treating patients who are either refractory or develop side effects to a standard regimen of corticosteroids and immunosuppressive agents. These patients, treated with Infliximab, should be under tight surveillance in order to quickly identify possible secondary effects.
 ...
PMID:Infliximab for treating sarcoidosis patients, Portuguese experience. 2147 72

Alcoholic liver disease (ALD) is characterized by steatosis or fat deposition in the liver and inflammation, which leads to cirrhosis and hepatocellular carcinoma. Induction of target genes without involving changes in DNA sequence seems to contribute greatly to liver injury. Chromatin modifications including alterations in histones and DNA, as well as post-transcriptional changes collectively referred to as epigenetic effects are altered by alcohol. Recent studies have pointed to a significant role for epigenetic mechanisms at the nucleosomal level influencing gene expression and disease outcome in ALD. Specifically, epigenetic alterations by alcohol include histone modifications such as changes in acetylation and phosphorylation, hypomethylation of DNA, and alterations in miRNAs. These modifications can be induced by alcohol-induced oxidative stress that results in altered recruitment of transcriptional machinery and abnormal gene expression. Delineating these mechanisms in initiation and progression of ALD is becoming a major area of interest. This review summarizes key epigenetic mechanisms that are dysregulated by alcohol in the liver. Alterations by alcohol in histone and DNA modifications, enzymes related to histone acetylation such as histone acetyltransferases, histone deacetylases and sirtuins, and methylation enzymes such as DNA methyltransferases are discussed. Chromatin modifications and miRNA alterations that result in immune cell dysfunction contributing to inflammatory cytokine production in ALD is reviewed. Finally, the role of alcohol-mediated oxidative stress in epigenetic regulation in ALD is described. A better understanding of these mechanisms is crucial for designing novel epigenetic based therapies to ameliorate ALD.
 ...
PMID:Epigenetic regulation in alcoholic liver disease. 2163 50

Hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths worldwide, and the incidence of this fatal disease is still on rise. The majority of HCCs emerge in the background of a chronic liver disease, such as chronic hepatitis and liver cirrhosis. The current understanding is that majority of HCCs evolve as a consequence of chronic inflammation and due to the presence of infection with hepatitis viruses. These underlying pathogenic stimuli subsequently induce a spectrum of genetic and epigenetic alterations in several cancer-related genes, which are involved in cell-cycle regulation, cell growth and adhesion. Such widespread genomic alterations cause disruption of normal cellular signaling and finally lead to the acquisition of a malignant phenotype in HCC. In general, the type of gene alterations, such as point mutations, deletion of chromosomal regions and abnormal methylation of gene promoters differ according to the individual targeted gene. In HCC, incidence of genetic alterations is relatively rare and is limited to a subset of few cancer-specific genes, such as the tumor suppressor p53, RB genes and oncogenes such as the CTNNB1. In contrast, epigenetic changes that involve aberrant methylation of genes and other post-transcriptional histone modifications occur far more frequently, and some of these epigenetic alterations are now being exploited for the development of molecular diagnostic signatures for HCC. In addition, recent findings of unique microRNA expression profiles also provide an evidence for the existence of novel mechanisms for gene expression regulation in HCC. In this review article, we will review the current state of knowledge on the activation of various oncogenic pathways and the inactivation of tumor suppressor pathways in HCC that result in the disruption of cancer-related gene function. In addition, we will specifically emphasize the clinical implication of some of these genetic and epigenetic alterations in the management of hepatocarcinogenesis.
 ...
PMID:Genetic and epigenetic signatures in human hepatocellular carcinoma: a systematic review. 2196 51


1 2 3 4 Next >>