Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

There is accumulating evidence that leptin has a pleiotropic role in hematopoiesis, immune response, fibrogenesis, and hepatocarcinogenesis. We investigated the expression of leptin and leptin receptor (OB-R) at the protein level by flow cytometry and also quantified by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) the two major leptin receptor isoforms (OB-Rl, OB-Rs) in peripheral blood mononuclear cells (PBMCs) of patients with hepatitis B (HBV; n = 31), hepatitis C (HCV; n = 34), and nonviral liver disease (n = 25), and healthy controls (n = 36), as well as in liver tissues of HBV (n = 8), HCV (n = 7), and healthy individuals (n = 6). Serum leptin levels were measured in all participants (N = 126). We observed significantly lower OB-Rl and OB-Rs mRNA levels in PBMCs of HBV and HCV patients compared with healthy controls and nonviral liver disease patients (P < 0.05). Flow cytometry analysis confirmed the real-time RT-PCR results. Expression of leptin and OB-Rl was significantly increased in viral hepatitis liver tissues compared with healthy tissues (P < 0.01). OB-Rl mRNA levels were not associated with hepatitis patients' clinical status (inactive, chronic hepatitis, or cirrhosis). We also found decreased serum leptin in HBV and HCV patients compared with healthy individuals and the nonviral liver disease group. Leptin was expressed in 3 of 34 HCV (8.8%) and 19 of 25 (76%) nonviral liver disease patients. Moreover, expression of OB-Rl and OB-Rs were associated when all individuals were grouped together (r = 0.78, P < 0.001). In conclusion, our findings may suggest the involvement of the leptin system in the immunopathology of chronic viral hepatitis.
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PMID:Leptin receptor isoforms mRNA expression in peripheral blood mononuclear cells from patients with chronic viral hepatitis. 1706 Jun 87

Chronic hepatitis B continues to be a major cause of end-stage liver disease and hepatocellular carcinoma worldwide. Nucleos(t)ide analogues have proven to be effective in controlling the disease and perhaps decreasing the incidence of hepatocellular carcinoma. However, development of drug resistance is a major limitation to their long-term effectiveness. Understanding the mechanisms of drug resistance are important for designing new agents and devising strategies to manage and prevent the development of antiviral drug resistance. The development of resistance is determined by an interplay of viral, host, and drug characteristics Homology of the HBV polymerase to the human immunodeficiency virus-1 reverse transcriptase has allowed predictions to be made on the effect mutations have on HBV polymerase structure. In vitro functional studies provide complementary information. Several broad principles on the mechanism of resistance have emerged from these studies. First, most of the primary mutations cluster in the vicinity of the incoming nucleotide and act by directly affecting the position or stability of the bound substrate, template, or primer. In contrast, secondary mutations tend to occur away from the nucleotide-binding pocket. Finally, the structural and functional consequences of mutations are quite variable among the different agents. This paper reviews the key mutations and mechanisms associated with resistance to the nucleos(t)ide analogues approved for clinical use and discuss new targets for drug development.
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PMID:Drug targets and molecular mechanisms of drug resistance in chronic hepatitis B. 1740 58

HIV infection worsens the course and the natural history of chronic hepatitis B (HBV) leading to rapid progression to cirrhosis and to end-stage liver disease. Highly active antiretroviral therapy (HAART) regimens including nucleoside and/or nucleotide analogues with activity against both HIV reverse transcriptase and hepatitis B virus polymerase have clearly improved the survival rates of HIV/HBV-coinfected patients. How HAART beneficially affects the natural course of chronic hepatitis B in coinfected patients is not known. We report a biopsy-proven case of reversal of HBV-related cirrhosis in a coinfected patient, paralleling long-term suppression of HBV replication with tenofovir disoproxil fumarate as part of a HAART. Pathological reversibility of cirrhosis was ascertained by normalization of biochemical (platelet count) and morphological (abdominal ultrasonography and gastrointestinal endoscopy) tests as well as non-invasive markers of fibrosis. In conclusion, a HAART regimen including tenofovir disoproxil fumarate in a HBV/HIV-coinfected cirrhotic patient might lead to sustained HBV viral suppression and result in cirrhosis reversal.
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PMID:Reversibility of cirrhosis in HIV/HBV coinfection. 1750 71

Solid organ transplantation in human immunodeficiency virus (HIV)-infected individuals requiring concomitant use of immunosuppressants (IS) (e.g. cyclosporine [CsA], sirolimus [SrL], tacrolimus [FK]) and antiretrovirals (ARVs) (e.g. protease inhibitors [PIs] and/or nonnucleoside reverse transcriptase inhibitors [NNRTIs]) is complicated by significant drug interactions. To assist in appropriate clinical management, we describe the pharmacokinetics and dosing modifications in 35 patients (20 kidney, 13 liver and two kidney-liver HIV-infected subjects with end-stage kidney or liver disease), on both IS and NNRTIs, PIs, and combined NNRTIs + PIs, in studies done at weeks 2-4 and/or 12 weeks after transplantation or after a change in IS or ARV drug regimen (n = 97 studies). CsA, SrL and FK concentrations were measured in whole blood by LC/MS. HIV-infected transplant recipients using PIs with IS had marked increases in CsA, FK or SrL trough levels compared to those on NNRTIs alone or to patients not on ARVs, necessitating either a reduction in dose or an increase in dosing interval. Subjects on efavirenz (EFV) and CsA required much higher doses of CsA than those using any other ARV. Changes in antiretroviral therapy should be carefully managed to avoid insufficient immunosuppression or toxicity due to drug interactions.
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PMID:Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. 1794 60

Despite the development of new therapeutic options, treatment of chronic hepatitis B remains a clinical challenge because of the need for long-term treatment in most patients. Treatment with pegylated interferon is the only option that allows a defined duration of treatment. Nonetheless, approximately 70% of the patients treated do not have a prolonged treatment response. A variety of nucleoside analog viral polymerase (reverse transcriptase) inhibitors have been developed (lamivudine, adefovir dipivoxil, entecavir, telbivudine); they can be administered orally and are well tolerated. These antiviral agents effectively induce viral suppression, which is accompanied by an improvement in transaminases and hepatic histology. Nonetheless, the rates of HBe and HBs seroconversion remain low with nucleoside analogs, and the absence of these immunologic events necessitates prolonged antiretroviral treatment. Treatment with nucleoside analogs leads to selection of resistant mutant viruses. They therefore require close clinical and virologic follow-up to enable early screening for resistance and adaptation of treatment before the liver disease worsens. The development of these different treatment options has made possible very significant improvements in the management of patients with chronic hepatitis B, by preventing aggravation of liver disease in most of them.
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PMID:[Current data on the treatment of chronic hepatitis B]. 1804 41

Hepatitis E virus (HEV) is the main cause of enterically transmitted non-A hepatitis worldwide. Infection is endemic in developing countries. Disease course is benign, and severe jaundice is rarely reported. Three patients presented to our department with symptomatic acute hepatitis. Two of them had recently travelled to endemic areas. Jaundice was very marked in all patients. HEV infection was documented by HEV antibodies and by HEV-RNA detection in serum and stools. In the autochthonous case, immunoglobulin-M was absent, and diagnosis was established on HEV-RNA amplification by real-time reverse transcriptase-PCR. Comprehensive investigation for concomitant causes of liver disease was negative in all patients. Histological features showed marked cholestasis with multiple bile plugs in dilated canaliculi. In conclusion, acute hepatitis E may be autochthonous in developed countries and patients may present with severe jaundice. HEV-RNA detection by real-time reverse transcriptase-PCR is a very efficacious diagnostic tool in anti-HEV immunoglobulin-M-negative cases.
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PMID:Acute hepatitis E with severe jaundice: report of three cases. 1804 73

Hepatitis E indigenous to developed countries (hepatitis EIDC) is a form of hepatitis E in persons with no travel history to highly endemic areas. It has been recognized recently as an emerging clinical entity in a significant number of economically developed countries including UK. However, it is still perceived as a rare disease and routine laboratory testing for hepatitis E is not performed. A series of 13 cases of hepatitis EIDC, diagnosed in a 13-month period from June 2005 within a single center in South Hampshire, UK, is presented. These patients were identified after implementing a novel-screening algorithm that introduced routine hepatitis E serological investigations. Patients were middle aged or elderly and males were affected more commonly. Four patients (31%) required hospital admission. All reverse transcriptase-polymerase chain reaction (RT-PCR) confirmed cases carried hepatitis E virus (HEV) genotype-3, which bore close sequence homology to HEV circulating in UK pigs. None of these patients recalled eating undercooked pork products or close contact with pigs during the 2 months preceding the onset of acute hepatitis. In comparison, during the same period, only two cases of hepatitis A and five cases of acute hepatitis B were diagnosed. These data illustrate the importance of introducing routine hepatitis E testing in all patients with unexplained acute liver disease and absence of relevant travel history. Routine testing can clarify hepatitis E epidemiology whilst improving the clinical management of patients with acute liver disease.
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PMID:Unexpectedly high incidence of indigenous acute hepatitis E within South Hampshire: time for routine testing? 1809 34

The Fas / Fas-ligand (FasL) system is an important death signal pathway in the liver. An enhanced local inflammatory response prompted by FasL expression, which contributes to neutrophil recruitment and interleukin-1 beta (IL-1beta) release, seems to be crucial to chronic liver damage, persistence of viral infections, and probably initiation and / or promotion of HCC. In order to evaluate the expression of Fas, FasL, and IL-1beta in different stages of human liver disease and to determine whether hepatitis B virus (HBV) and hepatitis C virus (HCV) infections modulate their expression, also in relation to apoptosis, we examined 87 liver samples obtained from patients with: chronic hepatitis (CH) (n.42), cirrhosis (n.9) and hepatocellular carcinoma (HCC) (n.16) and corresponding peritumoural tissues (n.16); histologically-normal liver (n.4) as controls. Fas, FasL and IL-1beta mRNA were quantified using reverse transcriptase-polymerase chain reaction. The apoptotic index was evaluated by TUNEL analysis. Our data showed a progressive Fas / FasL increase from CH to cirrhosis followed by a decline from the latter to HCC. In histological sections apoptosis was detected in HCC. A significant difference emerged between HCV and HBV-related disease for IL-1beta expression only in CH. A significant positive correlation between IL-1beta and FasL in HCV-related disease (P = 0.014) and an inverse correlation between IL-1beta and Fas in HBV-related disease (P = 0.021) were observed. The different pattern of IL-1beta, Fas and FasL expression found in HCV- and HBV-mediated liver disease, points to a different modulation of immune response B and C virus induced, while the decline in Fas / FasL expression in HCC may be related to defence mechanisms adopted by HCC cells against the immune system.
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PMID:Fas / FasL system, IL-1beta expression and apoptosis in chronic HBV and HCV liver disease. 1833 Dec 50

Polycystic kidney (PCK) rats are a spontaneous model of autosomal recessive polycystic kidney disease that exhibit cholangiocyte-derived liver cysts. We have previously reported that in normal cholangiocytes a subset of vesicles contain three proteins (ie, the water channel AQP1, the chloride channel CFTR, and the anion exchanger AE2) that account for ion-driven water transport. Thus, we hypothesized that altered expression and location of these functionally related proteins contribute to hepatic cystogenesis. We show here that under basal conditions and in response to secretin and hypotonicity, cysts from PCK rats expanded to a greater degree than cysts formed by normal bile ducts. Quantitative reverse transcriptase-polymerase chain reaction, immunoblot analysis, and confocal and immunoelectron microscopy all indicated increased expression of these three proteins in PCK cholangiocytes versus normal cholangiocytes. AQP1, CFTR, and AE2 were localized preferentially to the apical membrane in normal rats while overexpressed at the basolateral membrane in PCK rats. Exposure of the cholangiocyte basolateral membrane to CFTR inhibitors [5-nitro-2-(3-phenylpropylamino)-benzoic acid and CFTRinh172], or Cl(-)/HCO(3)(-) exchange inhibitors (4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid disodium salt hydrate and 4-acetamido-4'-isothiocyanato-2,2'-stilbenedisulfonic acid disodium salt hydrate) blocked secretin-stimulated fluid accumulation in PCK but not in normal cysts. Our data suggest that hepatic cystogenesis in autosomal recessive polycystic kidney disease may involve increased fluid accumulation because of overexpression and abnormal location of AQP1, CFTR, and AE2 in cystic cholangiocytes. Therapeutic interventions that block the activation of these proteins might inhibit cyst expansion in polycystic liver disease.
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PMID:Hepatic cystogenesis is associated with abnormal expression and location of ion transporters and water channels in an animal model of autosomal recessive polycystic kidney disease. 1898 97

Orthotopic liver transplantation (OLT) continues to be the only remedy for end-stage liver disease. In an attempt to decrease the ever-widening gap between organ donor and recipient numbers, and ultimately make more livers amenable to transplantation, we characterized the healthy human liver's response to ischemia and reperfusion-induced injury during transplantation. This was carried out by transcriptional profiling using cDNA microarray to identify genes whose expression was modulated at the 1-h postreperfusion time point. We observed that the map kinase phosphatase-1/dual-specificity phosphatase-1 (MKP-1/DUSP1) mRNA was strongly and significantly upregulated. Validation of this observation was carried out using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting and immunohistochemistry. In addition, we characterized the signaling pathways regulating MKP-1 expression using the human hepatoma cell line HepG2. Finally, by combining MKP-1 silencing with reperfusion-associated stresses, we reveal the preferential role of this protein in attenuating the activity of the JNK and p38(MAPK) pathways, and the resulting apoptosis, making MKP-1 a potential target for therapeutic intervention.
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PMID:The MAP kinase phosphatase-1 MKP-1/DUSP1 is a regulator of human liver response to transplantation. 1903 24


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