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)

To identify correlates of virologic response and survival, the reverse transcriptase (RT) genotype and in vitro antiviral susceptibility of human immunodeficiency virus (HIV) isolates from 20 patients treated with didanosine were studied. Patients had advanced HIV disease and were intolerant to or had failed zidovudine. Neither RT genotype nor antiviral susceptibility testing, as determined by a peripheral blood mononuclear cell-based assay, correlated with a virologic response to didanosine, as determined previously by quantitative serum culture. Only one (8%) of 12 isolates obtained after 6-12 months of treatment showed mutation at codon 74 conferring didanosine resistance. Reversions were seen in three of five patients with pre-treatment zidovudine resistance mutations at codons 70, but in none of eight with mutations at codon 215. Pretreatment isolates encoding mutations at RT codon 215 or encoding codon 123 asp were associated with both significantly greater CD4 lymphocyte depletion and shorter survival. In this cohort of patients with advanced HIV disease, neither rapid emergence of didanosine resistance nor rapid reversion of zidovudine resistance was observed. To better understand the relationship between virologic response and in vitro susceptibility to didanosine, more precise tools may be needed.
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PMID:Reverse transcriptase genotype and antiretroviral susceptibility of human immunodeficiency virus isolates from patients with advanced disease treated with didanosine: correlation with virologic response and survival. 887 63

Deoxyribonucleic acid (DNA) strand breaks as a characteristic of apoptosis, and Fas antigen (Fas)/Fas ligand (FasL) expression may participate in acute immune complex alveolitis in mice. Male Institute for Cancer Research (ICR) mice were injected intravenously with immunoglobulin G (IgG) antibodies against ovalbumin and inhaled an aerosolized oval albumin (OA) solution. They were killed at 4, 6, 12, 24, 48 h and 7 days after aerosolization. We assessed DNA fragmentation by agarose gel electrophoresis and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labelling (TUNEL). The expression of Fas and FasL messenger ribonucleic acid (mRNA) in lung tissues was assessed by reverse transcriptase (RT) polymerase chain reaction, and by in situ hybridization (ISH) to localize Fas mRNA, and RT in situ polymerase chain reaction to localize FasL mRNA. The fragmentation of DNA extracted from lung tissue was found 6-24 h after OA inhalation. TUNEL detected positive signals in bronchial and alveolar epithelial, endothelial and inflammatory cells in the lung tissue. These positive signals had disappeared 7 days after OA inhalation. TUNEL also detected positive signals in apoptotic neutrophils in bronchoalveolar lavage fluid at 6-12 h. Fas mRNA was expressed in the alveolar epithelial and inflammatory cells, while the expression of FasL mRNA appeared to be upregulated in infiltrating inflammatory cells at 6-24 h. These results suggest that apoptosis may be associated with the resolution of inflammation and with tissue repair and also suggest the involvement of the Fas antigen/Fas ligand pathway in acute immune complex alveolitis in mice.
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PMID:Apoptosis and Fas/Fas ligand mRNA expression in acute immune complex alveolitis in mice. 938 64

In a phase II study of 6-12 months of adefovir dipivoxil treatment in human immunodeficiency virus (HIV)-infected patients, HIV from 8 of 29 patients developed mutations in reverse transcriptase (RT) potentially attributable to adefovir dipivoxil therapy. Recombinant HIV from pre- and posttreatment plasma samples from these 8 patients showed no change or minor decreases in adefovir susceptibility, consistent with the durable antiviral effect observed. Additionally, HIV from 8 patients developed the M184V RT mutation because of concomitant lamivudine use. Recombinant HIV pairs from all 4 patients with zidovudine-resistant HIV showed statistically significant increases in adefovir susceptibility of 3- to 4-fold (to near wild type IC50), and HIV pairs from 2 of 4 patients with zidovudine-sensitive HIV showed a 2- to 3-fold increase in susceptibility. In growth kinetics studies, expression of the M184V RT mutation resulted in attenuated viral growth in peripheral blood mononuclear cell cultures. These studies suggest that patients possessing HIV with zidovudine and lamivudine resistance mutations may benefit from adefovir dipivoxil therapy.
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PMID:Human immunodeficiency virus type 1 expressing the lamivudine-associated M184V mutation in reverse transcriptase shows increased susceptibility to adefovir and decreased replication capability in vitro. 984 27

The assembly of 6-12 subunits of Ca(2+)/calmodulin-dependent kinase II (CaM kinase II) into holoenzymes is an important structural feature of the enzyme and its postulated role as a molecular detector of Ca(2+) oscillations. Using single cell reverse transcriptase-polymerase chain reaction, we show that alpha- and beta-CaM kinase II mRNAs are simultaneously present in the majority of hippocampal neurons examined and that co-assembly of their protein products into heteromers is therefore possible. The subunit composition of CaM kinase II holoenzymes was analyzed by immunoprecipitation with subunit-specific monoclonal antibodies. Rat forebrain CaM kinase II consists of heteromers composed of alpha and beta subunits at a ratio of 2:1 and homomers composed of only alpha subunits. We examined the functional effect of the heteromeric assembly by analyzing the calmodulin dependence of autophosphorylation. Recombinant homomers of alpha- or beta-CaM kinase II, as well as of alternatively spliced beta isoforms, have distinct calmodulin dependences for autophosphorylation based on differences in their calmodulin affinities. Half-maximal autophosphorylation of alpha is achieved at 130 nM calmodulin, while that for beta occurs at 15 nM calmodulin. In CaM kinase II isolated from rat forebrain, however, the calmodulin dependence for autophosphorylation of the beta subunits is shifted toward that of alpha homomers. This suggests that Thr(287) in beta subunits is phosphorylated by alpha subunits present in the same holoenzyme. Once autophosphorylated, beta-CaM kinase II traps calmodulin by reducing the rate of calmodulin dissociation.
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PMID:Functional implications of the subunit composition of neuronal CaM kinase II. 1042 54

Little is known about treatment of hepatitis C virus (HCV) infection in "other groups" than the general population, namely patients with hematologic or renal disorders and patients with human immune deficiency (HIV) co-infection. The aim was to better define HCV therapies in these groups. We analyzed the medical literature focusing on treatment of HCV infection in other populations to suggest conclusions about indications based on tolerance and efficacy. As in the general population, the decision to treat should be based mainly on liver pathology, and to a lesser extent on virologic profiles (genotype, quantitative viremia). Hemophilia does not modify therapeutic strategies which combine interferon-alpha and ribavirin. Similar combinations should be discussed in patients with inherited hemoglobin disorders but iron overload (secondary hemochromatosis) associated with multiple transfusions may decrease the potential efficacy of interferon-alpha and chronic anemia may limit the use of ribavirin. In hemodialyzed patients, therapy by interferon-alpha is feasible with 3 MU subcutaneously after each hemodialysis three times weekly for 6-12 months. Virologic results are at least similar to those obtained in the general population with frequent pathological improvement. Combinations are not possible because ribavirin is contraindicated for pharmacokinetic reasons. In kidney recipients, interferon-alpha is deleterious and inefficient; ribavirin monotherapy has a potential interest which remains to be evaluated. In HIV co-infected patients, treatment is mandatory given the high rate of cirrhosis and the improved survival related to multiple anti-HIV therapies (which have no clear efficacy for quantitative HCV viremia). Due to the limited efficacy of interferon-alpha monotherapy, the combination of interferon-alpha and ribavirin appears to be the logical treatment. An important point is the in vitro inhibition of phosphorylation by ribavirin of HIV reverse transcriptase inhibitors which has to be analyzed in vivo before the combination can be recommended. On the basis of the results of liver biopsy, antiviral treatments may be proposed for HCV-infected patients with hematologic or renal disorders as well as for HIV co-infected patients. The choice of therapy (monotherapy or combined therapies) should be based on the clinical situation (contraindicated with chronic anemia or renal failure, for example) and its duration on the virologic factors of response as in the general population.
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PMID:Treatment of chronic hepatitis C in special groups. 1062 89

The SRY-related gene SOX9 is involved in the differentiation of Sertoli cells in male gonads of vertebrates with different kinds of sex determination. In the olive ridley Lepidochelys olivacea, a species with temperature sex determination (TSD), the SOX9 protein is expressed at stages 21-24 in medullary cells in gonads of embryos incubated at both male-(MPT) or female-promoting temperatures (FPT). However, at FPT the expression of SOX9 protein decreases at stage 25 and disappears at stage 26, suggesting this as the critical period for SOX9 regulation by temperature. Here, we used reverse transcriptase polymerase chain reaction (RT-PCR) to detect SOX9 transcripts in gonads of embryos switched from MPT to FPT at stage 23 and sampled at days 6-14. Simultaneously, groups of embryos were switched back to MPT and gonadal sex was established. SOX9 transcripts were detected at days 6-12 of switching, when embryos reached stage 25 and were no longer detected at day 14, when the embryos were at stage 26. Embryos switched back to MPT at days 6 or 8 formed testes, whereas embryos switched at days 10 or 14 developed ovaries. Results suggest that at MPT the male sex-determining pathway that maintains SOX9 expression in male gonads is established at stage 24. In contrast, at FPT, the female sex-determining pathway involved in downregulation of SOX9 in female gonads occurs within two days at stage 25. J. Exp. Zool. 290:498-503, 2001.
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PMID:Timing of SOX9 downregulation and female sex determination in gonads of the sea turtle Lepidochelys olivacea. 1155 57

Effects of lead nitrate (LN), a hepatic mitogen, on hepatic gene expressions of lanosterol 14alpha-demethylase (CYP51) and the sterol regulatory element binding proteins (SREBP-1a, SREBP-1c and SREBP-2), which are thought to be transcription factors for hepatic CYP51 gene, were examined by the methods of Northern blot and/or real time reverse transcriptase-polymerase chain reaction (RT-PCR). In both immature (4-week-old) and mature (7-week-old) rats, LN treatment resulted in definite increases in hepatic gene expression of CYP51 at 12 h and in the liver weight at 48 h. As for transcription factors for the CYP51 gene, enhanced gene expression of SREBP-2 was observed 6-12 h after LN treatment, whereas no enhanced gene expression of other SREBPs, SREBP-1a and SREBP-1c, was observed at any time after the treatment; for SREBP-1a, there was no significant change; for SREPB-1c, there was a drastic decrease. In addition, the serum total cholesterol level was increased 12 h after LN treatment to 7-week-old rats, and the increased level was maintained at least up to 48 h later. In the present study, we demonstrate for the first time that LN, a heavy-metal ion, activates the expression of the SREBP-2 and CYP51 genes without decreasing the serum total cholesterol level and further suggest that only SREBP-2 among SREBPs might play an important role in the LN-enhanced CYP51 gene expression.
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PMID:Altered gene expression of hepatic lanosterol 14alpha-demethylase (CYP51) in lead nitrate-treated rats. 1211 Oct 4

Chlamydiae are obligate intracellular bacterial parasites that infect eukaryotic cells and live their entire life cycle within a cytoplasmic vacuole or inclusion. We have employed cDNA microarray and conventional biological approaches to study the pathogen-host cell interaction during C. pneumoniae infection of eukaryotic cells. Two host cell signaling pathways, MEK/ERK and PI 3-kinase/Akt, were activated within 5 and 20 minutes, respectively, following infection with chlamydiae. Pharmacological inhibition of these pathways blocked invasion of HEp2 cells indicating that activation of these pathways was required for infection. Rho family GTPase activity was essential for invasion, since the pan-Rho GTPase inhibitor, compactin, blocked infection of HEp2 cells. cDNA microarrays and reverse transcriptase PCR were used to study host cell and chlamydial gene expression during the replication cycle. Analysis of host cell gene expression following infection with C. pneumoniae indicated that genes coding for cytokines, growth factors, and signaling molecules were upregulated, as early as 2 hours postinfection. Analysis of chlamydial gene expression indicated a temporal regulation of transcription with distinct early-, mid-, and late-cycle classes of RNA transcripts. Newly discovered genes encoding three Ser/Thr protein kinases and one protein phosphatase were upregulated 6-12 hours postinfection. One protein kinase, designated CpnPK1, was first detected at 12 hours postinfection, accumulated in the inclusion throughout the replication cycle, and may be a type III effector molecule. An increased understanding of chlamydial host cell interactions, in particular the role of various chlamydial proteins in infection and identification of essential virulence factors should provide novel targets for the development of new antimicrobials.
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PMID:Chlamydiae host cell interactions revealed using DNA microarrays. 1253 65

New HIV therapies have significantly increased survival, but are associated with multiple metabolic changes, most of them related to the protease inhibitors (PIs). The objective of this study was to elucidate and compare morphological and metabolic alterations in HIV-infected antiretroviral-naive patients receiving two nucleosides plus the PI nelfinavir (NFV) or the nonnucleoside reverse transcriptase inhibitor nevirapine (NVP). Forty-three patients (NFV, n = 20; NVP, n = 23) receiving 6-12 months of treatment were analyzed. Morphological changes were evaluated by bioelectrical impedance analysis, standard anthropometrics, and clinical examination. Serum total cholesterol (TC), low-density and high- density (HDL-c) lipoprotein cholesterol, triglycerides, glucose, and insulin were determined, among other metabolic parameters. No baseline differences were observed between groups. TC increased in both arms (NVP, 11%; NFV, 17%). HDL-c also increased in both groups, although more markedly in those receiving NVP (44% vs. 20%); on-treatment levels were also elevated (1.57 vs. 1.28 mmol/liter). As a consequence of these changes, the TC/HDL-c ratio dropped by 22% in the NVP arm and remained stable in the NFV group. With the use of NFV, the TC/HDL-c ratio and attendant cardiovascular risk did not change. In contrast, NVP offered benefits regarding lipid status, as manifested by enhanced HDL-c concentrations and decreased TC/HDL-c ratios. Inclusion of NVP should be considered when deciding upon antiretroviral regimens for patients at high coronary risk.
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PMID:A comparison of the effects of nevirapine and nelfinavir on metabolism and body habitus in antiretroviral-naive human immunodeficiency virus-infected patients: a randomized controlled study. 1460 48

Changes in gene expression levels of hepatic sterol regulatory element binding protein-2 (SREBP-2) and 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR) after a single i.v. injection of lead nitrate (LN, 100 micromol kg(-1) body weight) were examined comparatively by real time reverse transcriptase-polymerase chain reaction (RT-PCR) in male and female rats. Significant increases in the gene expression level of SREBP-2, a transcription factor for the HMGR gene, occurred at 6-12 h in male and at 24-36 h in female rats after LN-treatment. The gene expression level of HMGR, a rate-limiting enzyme for cholesterol biosynthesis, significantly increased at 3-48 h in male rats and 12-48 h in female rats. Subsequently, significant increases in the amount of hepatic total cholesterol in male and female rats were also observed at 3-48 h and 24-48 h, respectively. The present findings demonstrate that increases in gene expressions of hepatic SREBP-2 and HMGR and the amount of hepatic total cholesterol by LN occur earlier in male rats than in the females, and that increases in the gene expression level of HMGR and the amount of hepatic total cholesterol occur prior to the increase in the gene expression level of SREBP-2 in either sex of rats.
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PMID:Gender-related difference in altered gene expression of a sterol regulatory element binding protein, SREBP-2, by lead nitrate in rats: correlation with development of hypercholesterolemia. 1670 68


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