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)

Zalcitabine is an analogue of the nucleoside deoxycytidine which, when intracellularly converted to an active triphosphate metabolite, inhibits replication of human immunodeficiency virus (HIV). Zalcitabine is thought to act in the early phase of HIV replication by inhibiting reverse transcriptase and terminating the viral DNA chain. In vitro, zalcitabine is one of the more effective nucleoside analogues currently in clinical use for HIV infection, with 0.5 mumol/L concentrations completely inhibiting HIV replication in human T lymphocyte cell lines. In clinical trials, p24 antigen levels decreased and CD4 cell counts increased in patients with acquired immunodeficiency syndrome (AIDS) receiving zalcitabine > or = 0.03 mg/kg/day as monotherapy. Dose-dependent adverse effects that include peripheral neuropathy, stomatitis and rash, restrict long term use at higher dosages, and it is unclear whether zalcitabine monotherapy is as effective as zidovudine in extending survival in HIV-infected patients. Alternating or concomitant therapy with zalcitabine and zidovudine provides effective inhibition of viral replication and disease progression (as measured by improvements in CD4 cell counts) with lower and less toxic dosage regimens. At present, therefore, zalcitabine has a place in AIDS therapy both in combination with zidovudine, and as monotherapy for patients unable to tolerate zidovudine.
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PMID:Zalcitabine. A review of its pharmacology and clinical potential in acquired immunodeficiency syndrome (AIDS). 128 Oct 77

This article outlines steps in the development of antiviral drugs, with particular emphasis on therapeutic regimens for infections with human T-lymphotropic virus type III (HTLV-III). Inhibitors of reverse transcriptase activity, including suramin, antimoniotungstate (HPA-23), and trisodium phosphonorformate have shown in vitro activity against HTLV-III in early clinical trials. Other significant antiviral agents are recombinant interferon alpha-A, ribavirin, and ansamycin. Recent evidence suggests that antibodies to envelope protein, gp120, may be essential for neutralization. Combinations of antiviral agents may prove additive or synergistic, eg, interferons plus reverse transcriptase inhibitors or interferons plus ribavirin. Alternating, sequential antiviral regimens may be useful in reducing resistance and toxicity. However, antiviral agents will not be effective without additonal immunostimulatory therapy for viral control and immune reconstitution.
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PMID:Prospects of therapy for infections with human T-lymphotropic virus type III. 241 93

Zalcitabine (ddC) was the first drug to be approved under the US Food and Drug Administration's (FDA's) accelerated drug approval process. Zalcitabine is a potent nucleoside analogue inhibitor of reverse transcriptase used in the treatment of HIV infection. It is approximately 10-fold more potent than zidovudine (AZT) on a molar basis in vitro. Zalcitabine is well absorbed orally and reaches maximal plasma concentrations within 1 to 2 hours. In humans it is mainly eliminated by renal excretion of unchanged drug, and patients with renal failure may exhibit a prolonged half-life. A variety of clinical trials have evaluated the efficacy of zalcitabine based on improved survival and decreased frequency of opportunistic infections and on a surrogate marker of HIV disease, the CD4 count, or the concentration of an antigen associated with HIV, p24. Alternating zalcitabine therapy with zidovudine therapy was associated with increased CD4+ lymphocyte counts and reduced plasma p24 antigen levels. Zalcitabine can cause peripheral neuropathy (in 17 to 31% of patients), which is dose-related and is completely reversible when the drug is discontinued. Zalcitabine will continue to play a role in chemotherapeutic approaches to HIV.
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PMID:Zalcitabine. Clinical pharmacokinetics and efficacy. 761 75

We report the isolation of a novel mouse gene which encodes a putative hyaluronan synthase. The cDNA was identified using degenerate reverse transcriptase-polymerase chain reaction. Degenerate primers were designed based upon an alignment of the amino acid sequences of Streptococcus pyogenes HasA, Xenopus laevis DG42, and Rhizobium meliloti NodC. A mouse embryo cDNA library was screened with the resultant polymerase chain reaction product, and multiple cDNA clones spanning 3 kilobase pairs (kb) were isolated. The open reading frame predicted a 63-kDa protein with several transmembrane sequences, multiple consensus phosphorylation sites, and four putative hyaluronan binding motifs. The amino acid sequence displayed 55% identity to mouse HAS, 56% identity to Xenopus DG42, and 21% identity to Streptococcus HasA. Northern analysis identified transcripts of 4.8 kb and 3.2 kb, which were expressed highly in the developing mouse embryo and at lower levels in adult mouse heart, brain, spleen, lung, and skeletal muscle. Transfection experiments demonstrated that mouse Has2 could direct hyaluronan coat biosynthesis in transfected COS cells, as evidenced by a classical particle exclusion assay. These results suggest that mammalian HA synthase activity is regulated by at least two related genes. Accordingly, we propose the name Has2 for this gene.
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PMID:Molecular cloning and characterization of a putative mouse hyaluronan synthase. 879 45

Mesothelial cells are of mesenchymal origin, although they also have epithelial characteristics. Such cells obtained from benign effusions are not terminally differentiated and can be kept in short-term cultures. These cultures grow with an either epithelial or fibroblast-like phenotype, a pattern which is stable through the early passages. Several factors have been associated with mesothelial differentiation. The Wilms' tumour susceptibility gene 1 (WT1) is expressed during transitions of mesenchyme to epithelial tissues, as in the embryonic kidney, and it has been suggested as a marker for the mesothelial lineage. The proteoglycans (PGs) and hyaluronan are also differentially synthesised by epithelial and fibroblastic malignant mesothelioma cells and the cell surface PGs seem to indicate phenotypic differentiation even in epithelial tumours. To investigate how the epithelial and fibroblast-like differentiation of benign mesothelial cells was correlated to WT1, PGs and hyaluronan synthase, we studied their expression by semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) analyses. The expressions of these genes were all associated with a variation in phenotypic differentiation. Cell lines with epithelial morphology expressed more mRNA coding for WT1 and cell surface PGs than did the fibroblastic ones, the difference being greatest for syndecan-4 and glypican. The increase in WT1-associated mRNA was about as great as that of syndecans. Fibroblast-like cells, on the other hand, expressed substantially more of the matrix PGs versican and biglycan, while decorin expression was detected in only trace amounts in both morphological phenotypes. Hyaluronan synthase varied individually between the cell lines, although epithelial cells often expressed higher levels. The results indicate that the regulation of mesothelial differentiation is multifactorial and also involves WT1 and several PGs.
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PMID:Expression of genes coding for proteoglycans and Wilms' tumour susceptibility gene 1 (WT1) by variously differentiated benign human mesothelial cells. 1055 May 42

Aseptic loosening of prosthetic components, the most common long-term complication after total hip replacement (THR), is characterized by the formation of a synovial membrane-like interface tissue (SMLIT). It was hypothesized that the hyaluronan synthase (HAS)/hyaluronan (HA)/HA receptor CD44 signalling system is responsible for the synovial-like differentiation of the interface membrane. SMLIT was therefore compared with osteoarthritis (OA) synovial membrane by using reverse transcriptase polymerase chain reaction (RT-PCR) of HAS 1, 2 and 3, histochemical HA assay, and immunohistochemistry of CD44 and its non-HA ligands. All three isoforms of HAS were found in these samples. HA and CD44 were most abundant in the lining, but the signal was actually stronger in aseptic loosening than in OA (p<0.01). The non-HA CD44 ligands, collagen type VI, fibronectin, osteopontin, and MCP-1, had a similar distribution pattern in both tissues. These results confirm the synovial-like structure of the interface tissue lining. The pressure waves and movement of the HA-rich pseudosynovial fluid seem to drive HA into the implant-to-host interface, which itself also produces HA. HA may be responsible for the induction of a synovial-like lining at the interface through HA-CD44 signalling.
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PMID:Hyaluronan synthases, hyaluronan, and its CD44 receptor in tissue around loosened total hip prostheses. 1143 72

To elucidate the effects of interleukin-1beta (IL-1beta) on osteogenic protein-1 (OP-1) gene expression in a polylayer culture of rabbit articular chondrocytes, we measured rabbit OP-1 mRNA using quantitative TaqMan reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. Rabbit articular chondrocytes were isolated and cultured in minimum essential medium eagle alpha modification containing 10% fetal bovine serum for 7 days. IL-1beta was then added and cultures were continued for 48 or 96 hours. OP-1 gene expression was detected in cell cultures both with and without addition of IL-1beta. However, the level of expression was very low in the control group. OP-1 gene expression was significantly increased about 450- to 800-fold in IL-1beta-treated groups (0.1, 1, and 10 ng/ml) versus the control group. Evaluation of serial changes in OP-1 expression after addition of IL-1beta (10 ng/ml) revealed that OP-1 gene expression increased rapidly after addition of IL-1beta, reaching a peak at 48 hours, and then decreasing. Simultaneous assay of CD44 expression demonstrated a rapid increase, similar to that of OP-1 expression, following addition of IL-1beta: this was followed by a more gradual increase. Assay of hyaluronan synthase-2 (HAS-2) expression following addition of IL-1beta showed an increase after OP-1 expression had already reached a peak. Our results demonstrate that OP-1 expression is induced by IL-1beta and suggest that this expression, like that of HAS-2, may play a role as a protective mechanism against inflammatory cytokines.
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PMID:Induction of osteogenic protein-1 expression by interleukin-1beta in cultured rabbit articular chondrocytes. 1223 82

An adhesion of the subacromial bursa in the shoulder causes pain during joint motion and restricts the range of motion of the glenohumeral joint. To understand the biologic features of an adhesion, the gene expressions in adhesive subacromial bursa were analyzed by quantitative real-time reverse transcriptase-polymerase chain reaction. The gene expressions in adhesive subacromial bursae were approximately threefold to fourfold greater than those in nonadhesive bursae for the genes for Type I and Type III procollagens, CD34 antigen in vascular endothelium, hyaluronan synthase-3, and interferon-gamma. The gene expression of interleukin-8 was predominant in adhesive bursa. The gene expressions of hyaluronan synthase-1, hyaluronan synthase-2, and interleukin-10 which is an antiadhesive cytokine were predominant in nonadhesive bursae. Chromatography analysis revealed that a hyaluronan, of which molecular weight was more than 100 kDa, was present in the cavity of nonadhesive subacromial bursae. It is suggested that pathologic fibrosis and vascularization are maintained by the presence of interferon-gamma and interleukin-8 in adhesive subacromial bursae and that high molecular weight hyaluronan or interleukin-10 plays a role for antiadhesion.
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PMID:Pathologic gene expression in adhesive subacromial bursae of human shoulder. 1283 53

Unfettered hyaluronan (HA) production is a hallmark of rheumatoid arthritis. The discovery of three genes encoding hyaluronan synthases (HASs) allows for the investigation of the signaling pathways leading to the activation of these genes. Our objective is to further understanding of the regulation of these genes as well as to find ways to prevent undesired gene activation. Human fibroblast-like synoviocytes were used in these experiments. mRNA levels of HAS were monitored by reverse transcriptase-PCR. A series of specific kinase inhibitors were used to investigate intracellular pathways leading to the up-regulation of HAS1. Our experiments, testing a series of stimuli including tumor necrosis factor alpha (TNFalpha), demonstrate that TGF-beta is the most potent stimulus for HAS1 transcription. TGF-beta activates HAS1 in a dose-dependent manner with a maximum effect at a concentration of 0.5-1 ng/ml. TGF-beta-induced HAS1 mRNA can be detected within 60 min and reaches maximal levels at 6 h. Furthermore, TGF-beta treatment leads to an increase in synthase activity as determined by HA ELISA and by in vitro HA synthase assays. In contrast to the activatory effect on HAS1, TGF-beta dose-dependently suppresses HAS3 mRNA. As to the mode of action of TGF-beta-induced HAS1 mRNA activation, our experiments reveal that blocking p38 MAPK inhibited the TGF-beta effect by 90%, blocking the MEK pathway led to an inhibition by 40%, and blocking the JNK pathway had no effect. The presented data might contribute to a better understanding of the role of TGF-beta and of HA in the pathology of diseases.
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PMID:Differential effect of transforming growth factor beta (TGF-beta) on the genes encoding hyaluronan synthases and utilization of the p38 MAPK pathway in TGF-beta-induced hyaluronan synthase 1 activation. 1467 2

Hyaluronan is a major molecule in joint fluid and plays a crucial role in joint motion and the maintenance of joint homeostasis. The concentration and average molecular weight of hyaluronan in the joint fluids are reduced in osteoarthritis and rheumatoid arthritis. To elucidate the underlying mechanism, we analyzed the message expression of three isoforms of hyaluronan synthase and hyaluronidase from knee synovium, using real-time reverse transcriptase polymerase chain reaction. Synovia were obtained from 17 patients with osteoarthritis, 14 patients with rheumatoid arthritis, and 20 healthy control donors. The message expression of hyaluronan synthase-1 and -2 in the synovium of both types of arthritis was significantly less than in the control synovium, whereas that of hyaluronidase-2 in the synovium of both arthritides was significantly greater than in the control synovium. The decreased expression of the messages for hyaluronan synthase-1 and -2 and/or the increased expression of the message for hyaluronidase-2 may be reflected in the reduced concentration and decreased average molecular weight of hyaluronan in the joint fluids of patients with osteoarthritis and rheumatoid arthritis.
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PMID:Expression analysis of three isoforms of hyaluronan synthase and hyaluronidase in the synovium of knees in osteoarthritis and rheumatoid arthritis by quantitative real-time reverse transcriptase polymerase chain reaction. 1553 29


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