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)

During the past two decades, the essentiality of zinc for man has been established. Deficiency of zinc in man due to nutritional factors and several diseased states has been recognized. High phytate content of cereal proteins decreases availability of zinc; thus the prevalence of zinc deficiency is likely to be high in a population subsisting mainly on cereal proteins. Alcoholism is known to cause hyperzincuria and thus may play a role in producing zinc deficiency in man. Malabsorption, cirrhosis of the liver, chronic renal disease and other chronically debilitating diseases may similarly induce zinc deficiency in human subjects. A severe deficiency of zinc has recently been recognized to occur in patients with sickle cell anemia and a beneficial effect of zinc therapy in such patients has been reported. Growth retardation, male hypogonadism, skin changes, poor appetite, mental lethargy and delayed wound healing are some of the manifestations of chronically zinc-deficient human subjects. Taste abnormalities, correctable with zinc supplementation, have been observed in uremic subjects. Recently, abnormal dark adaptation related to zinc deficiency in patients with cirrhosis of the liver and sickle cell disease has been reported. In severely zinc-deficient patients, dermatological manifestations, diarrhea, alopecia, mental disturbances and intercurrent infections predominate and if untreated the condition becomes fatal. Zinc deficiency is known to affect testicular functions adversely in man and animals. This effect of zinc is at the end organ level and it appears that zinc is essential for spermatogenesis and testosterone steroidogenesis. Zinc is involved in many biochemical functions. Several zinc metalloenzymes have been recognized in the past decade. Zinc is required for each step of cell cycle in microorganisms and is essential for DNA synthesis. Thymidine kinase, RNA polymerase, DNA-polymerase from various sources and RNA-dependent DNA polymerase from viruses have been shown to be zinc-dependent enzymes. Zinc also regulates the activity of RNase; thus the catabolism of RNA appears to be zinc-dependent. The effect of zinc on protein synthesis may be attributable to its vital role in nucleic acid metabolism. The activities of many zinc-dependent enzymes have been shown to be affected adversely in zinc-deficient tissues. Three enzymes, alkaline phosphatase, carboxypeptidase and thymidine kinase, appear to be most sensitive to zinc restriction in that their activities are affected adversely within three to six days of institution of a zinc-deficient diet to experimental animals.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Zinc deficiency in human subjects. 636 78

Hepatitis C virus (HCV) is the leading cause of non-A, non-B hepatitis among renal allograft recipients. We sought to identify and describe a proteinuric renal disease occurring in our HCV-infected renal transplant patients. Patients with proteinuria exceeding 1 g/day were identified from a cohort of 98 HCV-infected kidney recipients. Qualitative and quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and restriction fragment-length polymorphism of the amplified RT-PCR product was performed to detect circulating HCV RNA, viral titer, and strain type, respectively. An immune complex nephritis (ICN) of the membranoproliferative pattern (MPGN) was found on five of eight biopsies. Two patients infected with the Hutch strain-type developed nephrotic-range proteinuria within three months posttransplant while the remaining three MPGN patients had been transplanted greater than 5 years prior to the onset of proteinuria. Testing for rheumatoid factors, cryoglobulins, hypocomplementemia, and circulating immune complexes failed to show a consistent pattern. Sucrose density gradient (SDG) equilibrium centrifugation was used to determine the buoyant-density of HCV virions from control (HCV-infected nonproteinuric recipients; n = 5) and nephrotic patients (n = 5). Whereas HCV virions from the control patients had a low buoyant density on sucrose gradients, a substantial percentage of the circulating HCV RNA from the MPGN patients was present in the high-density fractions in association with IgM and IgG. Treatment of the pooled high-density layers with NP40 followed by recentrifugation resulted in a shift of the HCV RNA to the medium-density layers. In conclusion, MPGN developed in five HCV-infected kidney recipients despite pharmacologic immunosuppression. Both the physicochemical properties of the HCV virions on SDG and their association with IgG and IgM in the high-density layers provide indirect evidence for the presence of circulating complexes of anti-HCV antibody and HCV antigen(s).
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PMID:De novo membranoproliferative glomerulonephritis in hepatitis C virus-infected renal allograft recipients. 754 75

Superoxide dismutase (SOD) in renal tissue biopsy specimens obtained from patients with immunoglobulin A nephropathy (13 cases) and non-immunoglobulin A mesangial proliferative glomerulonephritis (nine cases) was studied at the protein level by an enzyme-linked immunosorbent assay method and at the mRNA level by the reverse transcriptase-polymerase chain reaction (RT-PCR) assay. Total SOD activity in the tissue supernatant was measured by applying an electron paramagnetic resonance/spin trapping method. Normal renal tissues obtained from kidneys removed for malignancies (six cases) were included as healthy controls. The copper and zinc form of SOD (Cu,Zn-SOD) activity at both the protein and mRNA levels was lower in the moderately or severely damaged tissues compared with that in the normal or mildly damaged tissues. On the other hand, manganese SOD (Mn-SOD) values at either the protein level or the mRNA level did not differ significantly between control and patient samples. In the histochemical study using a polyclonal rabbit anti-Cu,Zn-SOD antibody, the staining intensity for Cu,Zn-SOD antigen was lower in the areas with advanced histologic damage than in the intact tissues. A follow-up study showed that renal function deterioration was proportionately slower in patients whose SOD activity was within the range of healthy tissue levels at the time of biopsy. Our data suggest that a lower level of SOD activity, whether as a cause or a consequence of the disease process, might induce a decrease in the scavenger reaction of superoxide (O2-) thus causing the tissue to become more vulnerable to oxidative stress.
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PMID:Superoxide dismutase activity in human glomerulonephritis. 871 10

Proximal tubular epithelial cells are the most abundant cells in the renal cortex, and recent studies suggest that they may play an important role in initiating pathological changes in renal disease. Transforming growth factor (TGF)-beta 1 has been implicated as a major factor controlling the development and progression of renal fibrosis in numerous diseases, including diabetic nephropathy. We have recently demonstrated that human proximal tubular epithelial cells synthesize and secrete TGF-beta 1 after the sequential addition of both 25 mmol/L D-glucose and platelet-derived growth factor (PDGF). The present study examines the control of this synthesis and in particular the polar requirements of the stimulation and the direction of release of the protein. A proximal tubular cell line (LLC-PK1) was cultured on porous tissue culture inserts. Confluent cells were exposed to 25 mmol/L D-glucose on either their apical or basolateral aspect. TGF-beta 1 mRNA induction (reverse transcriptase polymerase chain reaction) occurred only after basolateral exposure. Similarly, TGF-beta 1 synthesis and secretion was induced only by the subsequent addition of PDGF to the basolateral aspect of the cells. In contrast, TGF-beta 1 protein secretion was detected equally in the apical and basolateral compartments. This effect was maximal after 12-hour PDGF stimulation and represented a threefold increase over controls for TGF-beta 1 in both the apical and basolateral compartments (n = 3, P < 0.05 versus control). The glucose transporter inhibitors phlorizin and phloretin were used to investigate the role of specific D-glucose transport proteins. Application of either basolateral phlorizin or phloretin at the time of addition of 25 mmol/L D-glucose to the same compartment inhibited TGF-beta 1 synthesis in response to PDGF. Maximal inhibition was achieved at 0.5 mmol/L of either inhibitor (phlorizin percent inhibition of apical TGF-beta 1, 75%, P = 0.015, and of basolateral TGF-beta 1, 78%, P = 0.015; phloretin percent inhibition of apical TGF-beta 1, 68%, P = 0.03, and of basolateral TGF-beta 1, 79%, P = 0.001, n = 5, P versus control). No inhibition was seen with apical application of either inhibitor. These data demonstrate that the priming of proximal tubular cells for TGF-beta 1 synthesis occurs only after basolateral exposure of the cells to 25 mmol/L D-glucose. This mechanism is dependent on the activity of the basolateral D-glucose transporter GLUT-1. In another series of experiments, TGF-beta 1 synthesis in response to the addition of basolateral PDGF was also induced after basolateral pretreatment with D-galactose but not 2-deoxy-D-glucose. This priming effect demonstrates the dependence of this response on glucose metabolism by the cells, not simply the activity of the GLUT-1 transporter, as both 2-deoxy-D-glucose and D-galactose are transported by GLUT-1, although only the latter is metabolized. The extrapolation of these results to diabetic nephropathy would suggest that it is changes in the interstitial concentration of glucose rather than the urinary glucose level that likely modulate the synthesis of the profibrotic cytokine TGF-beta 1 and thereby influence the progression of interstitial fibrosis.
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PMID:Polarity of stimulation and secretion of transforming growth factor-beta 1 by cultured proximal tubular cells. 906 Aug 45

We describe the frist reported case in Switzerland of HIV-associated nephropathy (HIVAN). HIVAN shows a typical combination of clinical findings: black race, proteinuria, large hyper-echogenic kidneys, normal blood pressure, positive HIV serology and no autoantibodies. The histologic findings are typical: focal segmental glomerulosclerosis of the collapsing variant, often with marked interstitial nephritis. The disease normally appears before AIDS symptoms develop and follows a very aggressive course to end-stage renal disease. Therapy consists of a combination of nucleoside reverse transcriptase and proteinase inhibitors, ACE inhibitors, and possibly steroids. In end-stage renal disease patients can be managed by haemodialysis, continuous ambulatory peritoneal dialysis (CAPD) or kidney transplantation.
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PMID:[A patient with rapidly progressing renal failure, florid syphilis and positive HIV serology]. 986 91

We have succeeded in stably maintaining the entire genome of SIVmac239 as a plasmid clone. Supercoiled proviral plasmid DNA was inoculated intramuscularly into two adult rhesus macaques and into a neonate. All three animals became viremic and seroconverted. Viral kinetics were followed prospectively by quantitative competitive reverse transcriptase polymerase chain reaction (QC-RT-PCR), measurement of proviral DNA load in peripheral blood mononuclear cells (PBMCs) by PCR, and virus isolation by cocultivation. The infant developed high virus loads and succumbed to AIDS and SIV-associated nephropathy at 10 weeks postinoculation. Both adults are still living but have progressed to AIDS; one adult has also developed severe thrombocytopenia. We conclude that infection through intramuscular inoculation of cloned plasmid DNA encoding the entire proviral genome is reproducible and will provide a useful tool for studying viral pathogenesis.
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PMID:Viremia and AIDS in rhesus macaques after intramuscular inoculation of plasmid DNA encoding full-length SIVmac239. 1019 54

Indinavir is a protease inhibitor used in the treatment of patients with HIV infection. Combination antiretroviral therapy with indinavir plus 2 nucleoside reverse transcriptase inhibitors (NRTIs) is associated with greater reductions in viral load, greater increases in CD4+ cell counts, and reduced morbidity and mortality when compared with 2 NRTIs alone. In the landmark clinical trial ACTG 320, the rate of progression to AIDS or death (primary end-point) among zidovudine-experienced patients treated with indinavir, zidovudine and lamivudine was approximately half that of patients who received only zidovudine plus lamivudine (6 vs 11%; p < 0.001). The durability of an indinavir-containing regimen was demonstrated in Merck protocol 035, an ongoing trial in which a significant proportion of patients had sustained viral suppression for up to 3 years. Merck protocol 039, also an ongoing trial, showed a greater effect on surrogate markers of HIV disease progression with indinavir-based triple therapy than with zidovudine plus lamivudine or indinavir monotherapy in patients with advanced disease (median baseline CD4+ count 15 cells/microL). Numerous additional clinical trials have established the beneficial antiviral and immunological effects of indinavir in both antiretroviral-naive and -experienced patients with HIV infection. Indinavir is associated with various drug class-related adverse events, including gastrointestinal disturbances (e.g. nausea, diarrhoea), headache and asthenia/fatigue. A lipodystrophy syndrome has been commonly reported with indinavir and other protease inhibitors combined with NRTIs, but it has also been reported in many protease inhibitor-naive patients, and a definitive causal link has not been established between the syndrome and protease inhibitors. Nephrolithiasis may develop in about 9% of patients receiving indinavir but does not appear to be associated with other protease inhibitors; <0.5% of patients receiving indinavir discontinue the drug because of nephrolithiasis, which may be the extreme end of a continuum of crystal-related renal syndromes. Additional renal problems (e.g. nephropathy) have been reported in small numbers of patients receiving indinavir. In summary, indinavir is a protease inhibitor with well documented efficacy when used as part of combined therapy in patients with HIV infection. Both US and UK treatment guidelines continue to recommend protease inhibitor-based regimens including indinavir as a first-line option. Indinavir is being studied as a twice daily and once daily regimen with a low dosage of ritonavir as a way to alleviate tolerability, drug interaction and patient compliance/adherence issues. Indinavir-containing triple therapy has demonstrated positive effects not only on surrogate markers of disease progression, but also on clinical end-points of mortality and morbidity in patients with HIV disease. Protease inhibitors are a significant advance in the care of patients with HIV infection, and, in an era of evidence-based medicine, indinavir represents an important component of antiretroviral treatment strategies.
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PMID:Indinavir: a review of its use in the management of HIV infection. 1065 94

Acyclovir is an antiviral agent that causes termination of viral DNA synthesis by inhibiting viral reverse transcriptase. Acyclovir is used therapeutically to treat herpes simplex, cytomegalovirus, Epstein-Barr, and varicella-Zoster. Although acyclovir is thought to be low in toxicity, it has caused an obstructive nephropathy from accumulation of crystals in renal tissue. A retrospective review (January 1995 through March 2000) was conducted of acyclovir toxicoses in dogs reported to the ASPCA National Animal Poison Control Center. Of 105 ingestions, 10 were considered cases of acyclovir toxicosis. The most common signs seen were vomiting, diarrhea, anorexia, and lethargy. Ingested dosages ranged from 40 to 2195 mg/kg bw. Polyuria and polydipsia were reported in I dog. In 6/10 cases, signs developed within 3 h of ingestion. Treatment included standard decontamination procedures, (ie induction of emesis, administration of activated charcoal), diuresis, and supportive care.
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PMID:Accidental ingestion of acyclovir in dogs: 105 reports. 1111 48

Renin secretion can be stimulated by ATP via purinergic P2Y receptors. ATP is a cotransmitter with norepinephrine and is released from the cytosol during cell damage. Such release could account for the de novo renin expression seen in the proximal tubule in renal disease and in myocardial infarct borders. Whereas most P2Y purinoceptor subtypes utilize phosphoinositide signal-transduction pathways, the effector mechanisms of the subtype P2Y(11) also involve increases in cAMP, a well-known renin secretagogue and stimulus to renin production. The present study tested the effect of ATP on human renin gene (REN) promoter activity and the role of P2Y(11). By means of reverse transcriptase-polymerase chain reaction, we found that renin-expressing Calu-6 cells express P2Y(11) mRNA. Expression was also detected in the brain, kidney, testis, muscle, liver, and spleen. We made a novel cell line (Calu-6/P2Y11) in which P2Y(11) cDNA, under the control of a strong promoter, was stably integrated into genomic DNA. These cells produced P2Y(11) mRNA during culture. Treatment of Calu-6/P2Y11 cells with 1 mmol/L ATP caused a 3-fold increase in renin mRNA and protein over 36 hours. Transient transfection of Calu-6/P2Y11 cells with constructs containing 896 bp of human REN 5'-flanking DNA linked to the luciferase reporter gene led to a 5.8+/-0.6-fold increase (mean+/-SEM) in reporter activity in response to ATP (P=0.0015). In contrast, UTP produced only a 1.4+/-0.1-fold increase (P=0.016). For ADP, it was 1.7+/-0.1-fold (P=0.011). The response profile was ATP>ADP>AMP=adenosine=0, consistent with a P2Y(11) effect. Mutation of the cAMP response element (CRE) located at -222 in the REN promoter DNA abolished the effect of ATP. Furthermore, ATP induced a rapid, time-dependent increase in the phosphorylation of CRE binding protein (CREB) and activating transcription factor-1. These data implicate a cAMP pathway in mediation of the P2Y(11) effect. In conclusion, we have made a novel cell line that overexpresses the P2Y(11) purinoceptor. Stimulation of these cells by ATP activates a cAMP signal-transduction pathway that phosphorylates CREB and stimulates renin promoter activity via the CRE at -222. The data raise the possibility of a contribution of ATP/P2Y(11) effects to sympathetic stimulation of renin, as well as to responses in renin seen after tissue damage, such as in kidney disease and myocardial infarction.
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PMID:Capacity for purinergic control of renin promoter via P2Y(11) receptor and cAMP pathways. 1111 31

Connective tissue growth factor (CTGF) is a member of the CCN family of immediate early genes, which are involved in cell proliferation, migration, and matrix production. Recently, CTGF was observed to be strongly upregulated in human proliferative and fibrogenic renal disease. By in situ hybridization and reverse transcriptase-PCR, the expression of CTGF was investigated in experimental proliferative glomerulonephritis induced by injection of anti-Thy-1.1 antibody in the rat. CTGF expression in cultured rat mesangial cells and glomerular visceral epithelial cells (GVEC) was studied in response to transforming growth factor beta (TGF-beta), an essential pathogenetic factor in this model. In normal rat kidneys, only some GVEC expressed CTGF mRNA. In anti-Thy-1.1 nephritis, CTGF mRNA expression was strongly increased in extracapillary and mesangial proliferative lesions and in areas of periglomerular fibrosis. Early glomerular CTGF overexpression in GVEC coincided with a striking upregulation of TGF-beta2 and to a lesser extent of TGF-beta3. Glomerular CTGF mRNA expression was maximal at day 7, in association with increased TGF-beta1 mRNA and protein expression. CTGF mRNA overexpression by parietal epithelial cells preceded the periglomerular appearance of alpha-smooth muscle actin-positive fibroblasts. In cultured mesangial cells, TGF-beta1, -beta2, and -beta3 transiently increased the CTGF/glyceraldehyde phosphate dehydrogenase mRNA ratio up to threefold versus control at 4 h. In GVEC, upregulation of CTGF mRNA by these TGF-beta isoforms was more sustained, being 8- to 16-fold versus control at 24 h. The kinetics of CTGF expression strongly suggest a role in glomerular repair, possibly downstream of TGF-beta, in this model of transient renal injury.
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PMID:Kinetics of connective tissue growth factor expression during experimental proliferative glomerulonephritis. 1118 95


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