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)

It has been reported in the literature that biological membranes arising from HIV-induced cell fusion, as well as syncytium formation between infected and non-infected cells and those involved in transduction, viral DNA nuclear import and virion budding from the host cell, are all made of proteins, a phospholipid (P) bilayer and cholesterol (C). However, the P/C molar ratio is higher in the retroviral envelope than in the plasma membrane where they originate, and higher than in the nuclear envelope. Mechanisms are described which elucidate this puzzling fact, as well as cholesterol-dependent leakage and pore formation during cell fusion. Fatty acylation of viral and host cell proteins is required to direct them to membranes. Detergent-insoluble microdomains enriched in cholesterol and sphingolipids, termed either DIGs (detergent-insoluble glycolipid-enriched complexes), DRMs (detergent resistant membranes), TIFFs (Triton-insoluble floating fractions) or GEMs (glycolipid-enriched membranes), function as platforms for attachment of proteins in the process of signal transduction. HIV-SUgp120 (HIV-surface glycoprotein), T-cell receptor (TCR)-CD4+ and co-receptors promote aggregation of these lipid "rafts" which concentrate the Src family tyrosine kinases SFKs (PTK, Lyn, Fyn, Lck), GPI (glycosyl phosphatidylinositol)-anchored proteins, and phosphatidylinositol kinases PI(3)K and PI(4)K, inducing cell signalling. HIV-SUgp120 transduces the activation signal and provokes the formation of polyunsaturated fatty acid (PUFA) metabolites, i.e. the prostaglandin PGE2 suppressor of immune function and inhibitor of cytotoxic T-lymphocyte (CTL) proliferation, while PGB2 activates SFKs and increases mRNA expression, as well as NFkappaB (nuclear transcription factor) translocation to nucleus. HIV nuclear import, DNA integration, chromatin template capacity may be mediated by the lipid environment. The lipid-enriched microdomains from which HIV-1 buds, may explain the high level of cholesterol and sphingolipids in the viral envelope, since host cell rafts become a viral coat. HIV-1 infection induces alteration of cellular lipids: (1) shift in phospholipid synthesis to neutral lipids associated with the viral load, polyunsaturated fatty acid (PUFA) peroxidation, and n-3 deficiency with deregulation of cytokines and PPAR-gamma (peroxisome proliferator-activated receptor-gamma), and (2) alloimmune phospholipid antibody production in which antibodies to cardiolipin and to phosphatidylserine are most prevalent, due to the destruction of mitochondrial membranes and progression of lymphocyte apoptosis. The current highly active anti-retroviral therapy, including both viral reverse transcriptase (RT) inhibitors (NRTIs and NNRTIs, nucleoside and non-nucleoside RT inhibitors) and protease inhibitors (PIs), induces side-effects in the long term. Lipodystrophy (LD), consists of peripheral lipoatrophy associated with central fat accumulation (called "crixbelly" and "buffalo hump"), insulin resistance, elevation of very low density lipoproteins, decrease in high density lipoproteins and inhibition of adipocyte differentiation. LD syndrome appears to be induced by PIs that inhibit GLUT4, glucose transporter isoform, and by NRTIs which provoke mitochondrial failure. New therapeutic strategies assessed: (1) inhibition of the viral integrase and/or HIV entry into cells through natural products or their derivatives, (2) inhibition of HIV-1 entry into macrophages pretreated with Gram-negative bacterial lipopolysaccharide, (3) vaccination with multi-lipopeptides, i.e. sequences of HIV-1 peptides with CD4+ T-cell and B-cell epitopes, modified by adding a lipid tail to one end, which produce HIV-specific CTL and multispecific immune responses in most of the vaccinated subjects and (4) stimulation of antiviral drug activity with lipid-prodrugs targeting viral RT, polymerase, integrase, or aspartyl-protease.
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PMID:Human immunodeficiency virus and host cell lipids. Interesting pathways in research for a new HIV therapy. 1169 68

Previous studies have demonstrated that cyclopentenone prostaglandins (cyPG) inhibit human immunodeficiency virus type 1 (HIV-1) replication in various cell types. We investigated the role of PG in the replication of HIV-1 in primary macrophages. The cyPG, PGA(1) and PGA(2), inhibited HIV-1 replication in acutely infected human monocyte-derived macrophages (MDM). Because PGA(1) and PGA(2) have previously been shown to be peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, we examined the effect of synthetic PPARgamma agonists on HIV replication. The PPARgamma agonist ciglitazone inhibited HIV-1 replication in a dose-dependent manner in acutely infected human MDM. In addition, cyPG and ciglitazone reduced HIV replication in latently infected and viral entry-independent U1 cells, suggesting an effect at the level of HIV gene expression. Ciglitazone also suppressed HIV-1 mRNA levels as measured by reverse transcriptase PCR, in parallel with the decrease in reverse transcriptase activity. Co-transfection of PPARgamma wild type vectors and treatment with PPARgamma agonists inhibited HIV-1 promoter activity in U937 cells. Activation of PPARgamma also decreased HIV-1 mRNA stability following actinomycin D treatment. In summary, our experimental findings implicate PPARgamma as an important factor in the suppression of HIV-1 gene expression in MDM by cyPG. Thus natural and synthetic PPARgamma agonists may play a role in controlling HIV-1 infection in macrophages.
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PMID:Peroxisome proliferator-activated receptor gamma agonists inhibit HIV-1 replication in macrophages by transcriptional and post-transcriptional effects. 1184 31

Peroxisome proliferator-activated receptor (PPAR) alpha is a ligand-activated transcription factor that has been linked with rodent hepatocarcinogenesis. It has been suggested that PPARalpha mRNA expression levels are an important determinant of rodent hepatic tumorigenicity. Previous work in rat mammary gland epithelial cells showed significantly increased PPARalpha mRNA expression in carcinomas, suggesting the possible role of this isoform in rodent mammary gland carcinogenesis. In this study we sought to determine whether PPARalpha is expressed and dynamically regulated in human breast cancer MCF-7 and MDA-MB-231 cells. Having established the presence of PPARalpha in both cell types, we then examined the consequence of PPARalpha activation, by its ligands Wy-14,643 and clofibrate, on proliferation. With real-time reverse transcriptase-polymerase chain reaction, we showed that PPARalpha mRNA was dynamically regulated in MDA-MB-231 cells and that PPARalpha activation significantly increased proliferation of the cell line. In contrast, PPARalpha expression in MCF-7 cells did not change with proliferation during culture and was present at significantly lower levels than in MDA-MB-231 cells. However, PPARalpha ligand activation still significantly increased the proliferation of MCF-7 cells. The promotion of proliferation in breast cancer cell lines following PPARalpha activation was in stark contrast to the effects of PPARgamma-activating ligands that decrease proliferation in human breast cancer cells. Our results established the presence of PPARalpha in human breast cancer cell lines and showed for the first time that activation of PPARalpha in human breast cancer cells promoted proliferation. Hence, this pathway may be significant in mammary gland tumorigenesis.
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PMID:Peroxisome proliferator-activated receptor alpha in the human breast cancer cell lines MCF-7 and MDA-MB-231. 1220 67

We have cloned a cDNA coding for a novel steroid receptor co-activator protein termed SRAP from a rat prostate library. Although the nucleotide sequence of the SRAP has 78.2% identity to that of the human steroid receptor RNA activator (SRA), a novel RNA molecule which was reported to act as an RNA transcript without being translated into protein [Lanz, McKenna, Onate, Albrecht, Wong, Tsai, Tsai and O'Malley (1999) Cell 97, 17-27], the cDNA of SRAP is capable of generating a functional protein. Glutathione S-transferase pull-down assays showed that SRAP associates with the partial androgen receptor (AR) protein composed of a DNA-binding domain and an activation function 2. Luciferase assays demonstrated that SRAP enhances the transactivation activity of the AR, the glucocorticoid receptor and the peroxisome proliferator-activated receptor gamma(1) in a ligand-dependent manner. Using a green fluorescent protein (GFP) fusion-protein construct, we demonstrated in vivo translation of the GFP-SRAP fusion protein in HeLa cells co-transfected with pSG5AR and reporter gene in the presence of 5 alpha-dihydrotestosterone (DHT). Co-transfection of the GFP-SRAP fusion protein expression plasmid enhanced the transactivation activity of AR whereas incorporation of mutations in SRAP of the fusion protein resulted in loss of enhancement of the transactivation activity. Northern blot analysis and reverse transcriptase PCR assays showed that SRAP and SRA are expressed in rat and human prostate cancer cell lines respectively. In HeLa cells and the human prostate cancer cells line DU-145, co-transfected with SRAP, the DHT-dependent transactivation activities of AR were not completely inhibited by the anti-androgen flutamide, but the transactivation activities still remained high even in the presence of 5 microM flutamide, suggesting that SRAP may play an important role in enhancing AR activity in prostate cancer.
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PMID:A novel steroid receptor co-activator protein (SRAP) as an alternative form of steroid receptor RNA-activator gene: expression in prostate cancer cells and enhancement of androgen receptor activity. 1235 Feb 25

Peroxisome proliferator-activated receptor gamma (PPARgamma), a member of a nuclear transcription factor family, has been previously demonstrated to have antiinflammatory activity. The effects of PPARgamma activation in the development of an immune response are less well characterized. Through evaluation of PPARgamma heterozygote mice (PPARgamma(+/-) and specific PPARgamma agonist ligand binding, we evaluated the immunologic effects of PPARgamma activation in a well-described model of colitis. Increased susceptibility to dextran sodium sulfate (DSS)-induced colitis as defined by body weights, histologic injury, and survival was observed in the PPARgamma(+/-) mice in comparison to wild-type mice. Three different PPARgamma ligands (troglitazone, pioglitazone, and rosiglitazone) demonstrated beneficial dose-related treatment effects when administered prior to the onset of colitis. However, no protection was observed when PPARgamma ligand activation occurred after the onset of colitis. The reduction in DSS-induced inflammation noted with PPARgamma ligand treatment was associated with decreased interferon-gamma and tumor necrosis factor-alpha and increased interleukin (IL)-4 and IL- 10 levels as assessed by quantitative reverse transcriptase-polymerase chain reaction. Consistent with this shift towards a T helper (Th2) cytokine dominance, PPARgamma ligand treatment stimulated increased GATA-3 expression. These results indicate that the protective effects exhibited by PPARgamma ligands in intestinal inflammation may be due to immune deviation away from Th1 and towards Th2 cytokine production.
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PMID:Peroxisome proliferator-activated receptor gamma agonist ligands stimulate a Th2 cytokine response and prevent acute colitis. 1247 48

Genes induced or suppressed by oxidized low-density lipoproteins (oxLDL) in human monocytic THP-1 cells were searched using the differential display reverse transcriptase polymerase chain reaction. One of the differentially expressed (up-regulated) cDNA fragments was found to contain sequences corresponding to monocyte chemotactic protein-3 (MCP-3). The stimulatory effect of the oxLDL on the expression of MCP-3 mRNA was both time- and dose-dependent. Treatment with GF109203X and genistein, inhibitors of protein kinase C and tyrosine kinase, respectively, had no effect on the induction of MCP-3 mRNA by oxLDL, while treatment with cycloheximide inhibited the induction. The induction was reproduced by the lipid components in oxLDL such as 9-HODE and 13-HODE, which are known to activate the peroxisome proliferator-activated receptor gamma (PPARgamma). Introduction of an endogenous PPARgamma ligand, 15d-PGJ2, in the culture of THP-1 cells resulted in the induction of MCP-3 gene expression. Furthermore, analyses of human atherosclerotic plaques revealed that the expressional pattern of MCP-3 in the regions of neointimal and necrotic core overlapped with that of PPARgamma. These results suggest that oxLDL delivers its signal for MCP-3 expression via PPARgamma, which may be further related to the atherogenesis.
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PMID:Oxidized low-density lipoproteins may induce expression of monocyte chemotactic protein-3 in atherosclerotic plaques. 1538 Oct 85

Lipodystrophic syndrome is a major side effect of highly active antiviral therapy. Fat tissue redistribution is associated with changes in adipocyte gene expression and in circulating levels of adipocytokines involved in the development of insulin resistance. However, the evidence that HIV drugs accumulate into human adipocytes and have a direct effect on the expression of adipocyte-specific genes is still lacking. To address these questions, we used adipocytes derived from adult stem (hMADS) cells isolated from human adipose tissue. We showed by ELISA that two inhibitors of the HIV protease, lopinavir and ritonavir, accumulated at similar levels during the development of hMADS cells in adipocytes, whereas a non-nucleoside reverse transcriptase inhibitor, the nevirapine, accumulated at lower levels. Two fluorescent protease inhibitors then have been generated to investigate their subcellular localization. The data showed that HIV drugs accumulated into adipocytes and displayed various effects on hMADS cell-derived adipocytes. Indinavir, amprenavir, and nevirapine did not alter differentiation of precursor cells. In contrast, lopinavir, saquinavir, and ritonavir inhibited the development of preadipocytes into adipocytes. In adipocytes, amprenavir increased leptin expression and ritonavir was able to up-regulate tumor necrosis factor-alpha, interleukin 6, and leptin expression and down-regulate the expression of peroxisome proliferator-activated receptor gamma and adiponectin. Intracellular accumulation and localization of HIV drugs into human adipocytes strongly suggest that adipose tissues store these drugs. Because ritonavir can alter the expression of insulin resistance-related cytokines in human adipocytes in a way parallel to the situation observed in vivo upon treatment of HIV-infected patients, we propose that protease inhibitors participate in insulin resistance through a direct effect on adipocytes.
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PMID:Human immunodeficiency virus protease inhibitors accumulate into cultured human adipocytes and alter expression of adipocytokines. 1552 48

Dietary fatty acid (FA) absorption across the gastrointestinal (GI) tract is of critical importance for sustenance, however, excessive FA absorption has also been linked to metabolic syndrome and associated disorders. The expression of isoforms that regulate the dietary FA absorption are not as well characterized in the GI tract as they are elsewhere. Peroxisome proliferator-activated receptors (PPARalpha, beta, and gamma) and 9-cis-retinoic acid receptors (RXRalpha, beta, and gamma) are nuclear hormone transcription factors that control FA homeostasis, in part through the regulation of expression of membrane-bound FA transporting proteins. The present study was designed to elucidate the expression of PPAR and RXR isoforms and FA transporting proteins (FABPpm and FAT/CD36) in the rat and human GI tracts using reverse transcriptase-polymerase chain reaction (RT-PCR), immunoblotting, and immunohistochemical staining. The results revealed rat GI expression of all the PPAR and RXR isoforms, FABPpm and FAT/CD36. PPARalpha, PPARbeta, PPARgamma, RXRalpha, FABPpm, and FAT/CD36 isoforms exhibited ubiquitous expression in human GI tract, whereas RXRbeta was not detected. RXRgamma was observed in a majority of the human GI samples. These results provide a physiological foundation for rational drug design and drug delivery for the mitigation of metabolic syndrome and associated disorders to normalize intestinal FA absorption.
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PMID:Expression of PPAR, RXR isoforms and fatty acid transporting proteins in the rat and human gastrointestinal tracts. 1561 17

A better understanding of the mechanism of adipose tissue differentiation is of paramount importance in the development of therapeutic strategies for the treatment and prevention of obesity and type 2 diabetes mellitus. Optimal results using tissue culture models can be expected only when the in vitro adipocyte resembles adipose tissue in vivo as closely as possible. In this study, we used tissue-engineering principles to develop a three-dimensional (3-D) culture system to mimic the geometry of adipose tissue in vivo. Mouse preadipocyte 3T3-L1 cells were seeded onto nonbiodegradable fibrous polyethylene terephthalate scaffolds and differentiated with a hormone cocktail consisting of insulin, dexamethasone, isobutylmethylxanthine, and fetal calf serum. Cell morphology, growth, differentiation, and function were studied by immunocytochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), Western blotting, enzyme-linked immunosorbent assay, and oil red O staining. Cells grown on 3-D fibrous scaffolds were differentiated in situ by hormone induction with high efficiency (approximately 90%) as shown by scanning electron microscopy. Immunocytochemistry, immunoblot analysis, and RT-PCR revealed that the 3-D constructs expressed adipocyte-specific genes, including peroxisome proliferator-activated receptor gamma, leptin, adipsin, aP2, adiponectin, GLUT4, and resistin. Adipocytes matured on 3-D constructs secreted leptin at levels even greater than that of fully differentiated adipocytes in 2-D conventional cell cultures. Finally, adipocyte-specific phenotypic function was demonstrated by accumulation of neutral lipids in larger fat droplets. In conclusion, preadipocytes grown on 3-D matrices acquire morphology and biological features of mature adipocytes. This new culture model should have significant utility for in vitro studies of adipocyte cell biology and development.
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PMID:Adipose tissue model using three-dimensional cultivation of preadipocytes seeded onto fibrous polymer scaffolds. 1586 24

Agonists of the nuclear receptors peroxisome proliferator-activated receptor (PPAR) gamma, PPARalpha, and liver X receptors (LXRs) reduce blood glucose in type 2 diabetic patients and comparable mouse models. Since the capacity of these drugs to normalize hepatic gene expression is not known, we compared groups of obese diabetic db/db mice treated with agonists for PPARgamma [rosiglitazone (Rosi); 10 mg/kg/day], PPARalpha [Wy 14643 (Wy; 4-chloro-6-(2,3-xylidino)-2-pyrimidinyl)thioacetic acid); 30 mg/kg/day], and LXR [T0901317 (T09; N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1(trifluoromethyl)-ethyl]phenyl]-benzenesulfonamide); 40 mg/kg/day] and from untreated nondiabetic litter mates (db/+) by oligonucleotide microarrays and quantitative reverse transcriptase-polymerase chain reaction. The 10-day treatment period of db/db mice with Rosi, Wy, and T09 altered expression of 300, 620, and 735 genes including agonist-specific target genes, respectively. However, from the 337 genes differentially regulated in untreated db/+ versus db/db animals, only 34 (10%), 51 (15%), and 82 (24%) were regulated in the direction of the db/+ group by Rosi, Wy, and T09, respectively. Gene expression normalization by drug treatment involved glucose homeostasis, lipid homeostasis, and local glucocorticoid activation. In addition, our data pointed to hitherto unknown interference of these nuclear receptors with growth hormone receptor gene expression and endoplasmic reticulum stress. However, many diabetes-associated gene alterations remained unaffected or were even aggravated by nuclear receptor agonist treatment. These results suggest that diabetes-induced gene expression is minimally reversed by potent blood glucose-lowering nuclear receptor agonists.
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PMID:Blood glucose-lowering nuclear receptor agonists only partially normalize hepatic gene expression in db/db mice. 1626 May 81


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