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)

Competitive inhibitors of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG-CoA) reductase are currently used to treat patients with hypercholesterolaemia. These inhibitors affect not only cholesterol biosynthesis, but also the production of non-steroidal mevalonate derivatives, that are involved in a number of growth-regulatory processes. As a consequence, their potential use as anticancer drugs has been suggested. In order to examine long-term effects of this potential therapeutic approach, we cultivated the gastric carcinoma cell line, EPG85-257, and the breast tumour cell line, MDA-MB231, in the presence of increasing concentrations of the HMG-CoA reductase inhibitor, pravastatin. For both cell lines, this procedure led to the selection of resistant variants able to proliferate in more than 1000 microM inhibitor. By competitive reverse transcriptase/polymerase chain reaction assay (cRT-PCR), the expression of the mRNA for two key proteins of cellular cholesterol metabolism, HMG-CoA reductase and low-density lipoprotein (LDL) receptor, were analysed in sensitive and resistant cells. Despite similar growth rates, MDA-MB231 cells expressed approximately four times more HMG-CoA reductase mRNA than EPG85-257 cells and over 30 times more LDL receptor mRNA. Both mRNA species were coordinately regulated in the parental and in the pravastatin-resistant variant cells. Expression was highly stimulated (3- to 4-fold for the HMG-CoA reductase and 2- to 3-fold for the LDL receptor) in the resistant variants when cultured in lipoprotein-deficient medium in the presence of 1000 microM pravastatin. Immunocytological analysis of the expression of the HMG-CoA reductase and LDL receptor protein were in accordance with the data on specific mRNA expression obtained by cRT-PCR. Southern blot analysis revealed a 1.5-fold amplification of the HMG-CoA reductase gene in resistant MDA-MB231 cells, but not in the resistant EPG85-257 variant. Our data provide evidence for resistance mechanisms to pravastatin that are independent of the amplification of the HMG-CoA reductase gene. By analogy to the cell-culture models employed in this study, it is conceivable that similar mechanisms might occur in human tumour cells in vivo during long-term treatment with HMG-CoA reductase inhibitors. This might limit their application as chemotherapeutic anticancer agents.
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PMID:Effects of pravastatin, a hydroxymethylglutaryl-CoA reductase inhibitor, on two human tumour cell lines. 779 99

1. We administered the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor pravastatin at a daily dose of 1 mg kg(-1) body weight to cholesterol-fed (0.03%) heterozygous Watanabe heritable hyperlipidaemic rabbits, an animal model for heterozygous familial hypercholesterolaemia. 2. After 12 months of cholesterol treatment, immunohistochemistry with the monoclonal antibody 9D9 was used to detect hepatic low density lipoprotein (LDL) receptors, which were quantified by densitometry. In addition we determined LDL receptor mRNA by competitive reverse transcriptase polymerase chain reaction. The cholesterol precursor lathosterol and the plant sterol campesterol were analysed by gas-liquid chromatography. 3. The drug reduced total plasma cholesterol levels by 51% (P=0.04), when compared to the control group. Unexpectedly, hepatic LDL receptor density and mRNA showed no significant differences between the groups. Total plasma levels of lathosterol and campesterol also revealed no significant differences between the groups, if expressed relative to plasma cholesterol. 4. The findings suggest that mechanisms other than induced hepatic LDL receptors are responsible for the cholesterol-lowering effect of pravastatin in this animal model. We propose a reduced cholesterol absorption efficiency compatible with similar campesterol levels between both groups observed in our study.
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PMID:Effects of pravastatin on cholesterol metabolism of cholesterol-fed heterozygous WHHL rabbits. 964 43

HIV-positive patients receiving antiretroviral therapy with HIV-1 protease-inhibitors (PI) frequently show insulin-resistance, impaired glucose tolerance, hypertriglyceridaemia and lipodystrophy (LD). LD has often been reported only after the beginning of PI therapy. Some authors link LD to HIV chronic infection, some others suggest that PIs increase pre-existent disturb. Preliminary data of an observational study drawn in IV day-hospital of Spallanzani Institute in Rome showed hypertriglyceridaemia in 36.4% and hyperglycaemia in 11.2% of patients treated with PI. Carr suggests that such drugs should have this lipid-increasing effect because of their inhibition of low density lipoprotein-receptor-related protein, cytoplasmic retinoic-acid binding protein type 1 and P450 3A cytochrome. This theory doesn't explain why both untreated patients and treated with only reverse transcriptase inhibitors show sometimes the same disorders. According to another hypothesis Tumor necrosis factor-alpha, through inhibition of lipoprotein-lipase, would determine high fat-storage in the adipose tissue. Cardiovascular risk factors have always to be assessed before starting a therapy with PI. Glycaemia, triglyceridaemia, cholesterolaemia have to be performed every three months during the treatment and, if necessary, C-Peptide and insulinaemia too. A treatment with lipid-lowering drugs is always recommended in patients with hypertriglyceridaemia > 500 mg/dl and/or hypercholesterolaemia LDL > 190 mg/dl in two following checks. Fibrates have proven to be effective in reducing hypertriglyceridaemia, but there is no certainty that such therapies could have good effects on the LD itself too.
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PMID:[Dysmetabolic syndrome related to HIV-1 protease inhibitors. Review of the literature and personal data]. 1074 53

The random arbitrary primed (RAP) polymerase chain reaction (PCR) differential display (DD) method was applied to isolate genes related to cholesterol metabolism from exogenously hypercholesterolemic (ExHC) rats and the progenitor, SD rats. Forty-seven trials of RAP-PCR DD resulted in the isolation of 37 clones differing in strain, cholesterol supplementation or their interaction. Among their fingerprints, five clones gave reproducible patterns by a Northern blotting analysis. The sequence of two clones with lower mRNA abundance in ExHC rats than in SD rats was homologous to that of fatty acid synthase and oxalyl-CoA decarboxylase. Two other clones with higher mRNA on the n-cholesterol diet were matrin F/G protein and the NMDA receptor glutamate-binding subunit. The other clone with higher mRNA abundance in ExHC rats on the cholesterol diet was myelodysplasia/myeloid leukemia factor 2. Fifteen trials of reverse transcriptase (RT)-PCR DD yielded 10 clones, but none of the fingerprints were reproduced by the Northern blotting analysis. These results indicate that RAP-PCR DD is an appropriate alternative to RT-PCR DD for isolating the genes involved in hypercholesterolemia.
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PMID:Application of the random arbitrary primed polymerase chain reaction differential display method to isolate genes of cholesterol metabolism-related proteins from rat liver. 1087 81

We prospectively followed 20 consecutive patients with human immunodeficiency virus type 1 (HIV-1) with viral loads of <200 RNA copies/mL. These patients had been treated with 2 nucleoside reverse transcriptase inhibitors and > or =1 HIV-1 protease inhibitor for > or =3 months; they developed body changes consistent with lipodystrophy and requested they be switched from protease inhibitor to efavirenz. At baseline and every 3 months, we assessed the following: body mass index, waist-to-hip ratio, regional fat thickness (assessed by sonography), fasting total and high-density lipoprotein cholesterol, triglycerides, glucose, insulin, CD4(+) cells, and viral load. At baseline, hypertriglyceridemia (> or =200 mg/dL) was present in 17 (85%) patients, hypercholesterolemia (> or =200 mg/dL) in 14 (70%), and impaired fasting glucose (> or =110 mg/dL) in 8 (40%); CD4(+) T cells were 280x10(6) cells/L (range, 64-942x10(6) cells/L). HIV-1 RNA had been at <200 copies/mL for a median of 14 months (range, 3-24 months). Six months after switching to efavirenz, there was a reduction in triglyceride levels (a decrease of 31%; P=.03) and fasting insulin resistance index (a decrease of 28%; P=.03), but total and high-density lipoprotein cholesterol and glucose did not change. Waist-to-hip ratio decreased from 0.92 to 0.87 (P=.06). Subcutaneous fat thickness did not change. CD4(+) cells remained stable (363x10(6) cells/L; range, 102-741x10(6) cells/L; P=.65). Nineteen patients (95%) had HIV-1 RNA levels that remained at <200 copies/mL. Although CD4(+) response and viral suppression remained preserved after 6 months of switching from protease inhibitor to efavirenz, the benefits of this approach on the evolution of lipodystrophy were limited, and our findings do not support its routine recommendation to treat lipodystrophy.
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PMID:Impact of switching from human immunodeficiency virus type 1 protease inhibitors to efavirenz in successfully treated adults with lipodystrophy. 1107 62

Macrophage migration inhibitory factor (MIF) has been shown to play an important role in macrophage-mediated diseases. We investigate the potential role of MIF in atherogenesis using a hypercholesterolemic rabbit model. New Zealand White rabbits fed with a 2% cholesterol diet developed hypercholesterolemia and early fatty streaks at 1 month. The lesions became advanced at 3 months and were associated with de novo MIF expression by vascular endothelial cells (VECs) and smooth muscle cells (SMCs), as demonstrated by immunohistochemistry, reverse transcriptase-polymerase chain reaction, and in situ hybridization. By contrast, there was no increase in MIF levels in rabbits fed a normal diet. In early atherogenesis, marked upregulation of MIF mRNA and protein by VECs and some intimal cells were closely associated with CD68(+) monocyte adhesion onto and subsequent migration into subendothelial space. Of significance, the accumulation of macrophages was exclusively localized to areas of strong MIF expression, which may be associated with the macrophage-rich fatty streak lesion formation. Upregulation of MIF by SMCs is transient during atherogenesis. Importantly, strong MIF expression by activated macrophages may be responsible for the development of foam cell-rich lesions. Finally, the ability of MIF to induce intercellular adhesion molecule-1 expression by VECs implicates its pathogenic role in atherogenesis. In conclusion, the present study provides the first demonstration that MIF is markedly upregulated during atherogenesis. Upregulation of MIF by VECs and SMCs may play a role in macrophage adhesion, transendothelial migration, accumulation, and, importantly, transformation into foam cells. Furthermore, strong MIF expression by macrophages may both initiate and amplify the atherogenesis process.
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PMID:De novo expression of macrophage migration inhibitory factor in atherogenesis in rabbits. 1123 Jan 14

Vascular complications in the course of human immunodeficiency virus (HIV) infection are multifactorial and may be caused by the virus itself or by the related opportunistic infections and neoplasms. Highly active antiretroviral therapy (HAART), which dramatically modifies the natural history of HIV disease, causes in a high proportion of patients a metabolic syndrome that includes body fat redistribution, hypercholesterolaemia, hypertriglyceridaemia and insulin resistance. These effects are particularly evident in patients treated with protease inhibitors (PIs). However, studies on the cardiovascular risk among HIV-infected individuals receiving PIs have not shown a consistent association. The pathogenesis of the HAART-associated metabolic syndrome has not been completely elucidated, but there is growing evidence that a synergistic effect between PIs and nucleoside reverse transcriptase inhibitors might play a significant role. All HIV-infected patients candidate to antiretroviral therapy and patients already under treatment should undergo an assessment that includes the evaluation of the cardiovascular risk with the available guidelines.
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PMID:HIV infection, antiretroviral therapy and cardiovascular risk. 1239 24

Data on the efficacy and tolerability of antiretrovirals in children are limited as, in contrast to adult studies, large paediatric cohort studies are lacking. Thus, data pertaining to adults are often extrapolated to children despite the acknowledgement that children are not little adults. This review summarises information gathered from existing reports and focuses on the tolerabilities of antiretrovirals in children infected with HIV-1. The efficacy of antiretrovirals is not included in the scope of the discussion. Taste of antiretrovirals should be an important factor when considering the tolerability of antiretrovirals in children. However, antiretroviral options are often limited in young children as only some of the antiretrovirals are available as paediatric formulations. All antiretrovirals have been associated with toxicities in children, but in general, they are relatively well tolerated. The gastrointestinal system including hepatic system is most prone to being affected by these drugs. Skin rashes and hypersensitivity reactions are also associated with antiretroviral use, particularly with the non-nucleoside reverse transcriptase inhibitors. Mitochondrial toxicities that lead to impairment of liver function, pancreatic function and lactic acidosis are associated with most of the nucleoside analogues. Haematological toxicity is often a dose limiting adverse effect especially of the nucleoside analogues, in particular zidovudine. The protease inhibitors are associated with gastrointestinal intolerance (diarrhoea) and metabolic derangements that can lead to hypercholesterolaemia and hypertriglyceridaemia, which in turn and can lead to changes in body habitus. The renal system is also affected by several drugs, the most important of which is indinavir, which has been associated with renal stones and damage to the renal tubules. Fortunately, with lower incidence of major toxicity and with the range of drugs now available for paediatric use, toxicities are usually not a barrier to effect antiretroviral therapy in children.
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PMID:Tolerabilities of antiretrovirals in paediatric HIV infection. 1240 30

In a prospective, multicentre, switch study to identify the most frequently occurring nucleoside reverse transcriptase inhibitor (NRTI)-associated toxicities that cause NRTI withdrawal in virologically suppressed HIV-infected patients, among those who underwent stavudine substitution by tenofovir, 271 had hypertriglyceridemia and 193 had hypercholesterolemia. After 12 weeks of switching from stavudine to tenofovir, triglyceride and cholesterol levels showed significant de-creases, which suggests that such a switch may reverse, at least partly, stavudine-associated dyslipidaemia.
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PMID:Improvement of dyslipidemia in patients switching from stavudine to tenofovir: preliminary results. 1519 28

Insulin resistance is accepted as the underlying fundamental defect that predates and ultimately leads to the development of type 2 (adult onset) diabetes mellitus in the general non-human immunodeficiency virus (HIV)-infected population. Insulin resistance is also a major component of the metabolic syndrome that, in association with other factors such as hypertension, hypercholesterolemia, and central obesity, defines a pre-diabetic atherogenic state that leads to adverse cardiovascular events. Growing evidence now suggests that mitochondrial dysfunction in skeletal muscle may be the mechanism whereby insulin resistance is induced. The prevalence of insulin resistance, glucose intolerance, and diabetes in the HIV-infected population has dramatically increased following the common use of highly active antiretroviral therapy (HAART). The development of insulin resistance in the HIV-infected population is likely to be multifactorial reflecting genetic predisposition, direct and indirect effects of both the protease inhibitor (PI) and nucleoside reverse transcriptase inhibitor (NRTI) class of antiretroviral therapy, and a possible contribution from chronic inflammatory changes induced by HIV. Indirect effects of antiretroviral therapy on insulin resistance may be mediated through both the visceral adiposity and peripheral fat depletion components of lipodystrophy as well as through fatty infiltration in liver and muscle. Based on current knowledge, mitochondrial dysfunction can be hypothesized to play a key role in each of these components.
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PMID:Insulin resistance in the HIV-infected population: the potential role of mitochondrial dysfunction. 1618 Nov 44


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