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)

The idiopathic inflammatory myopathies (IIM) are a group of autoimmune diseases characterized by chronic lymphocytic and macrophagic infiltration in muscle. Because the mechanism for recruitment of these cells probably involves chemokines, we focused on the study of the expression pattern of some beta chemokines and receptors because it may provide a basis for selective immunotherapy. The expression of CCL3 (MIP-1alpha), CCL4 (MIP-1beta), CCL5 (RANTES) and their main receptors (CCR1 and CCR5) was studied by semi-quantitative reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry in a series of 16 IIM and five controls (four normal muscles and one tonsil). Except for CCL5, strong expression was observed by RT-PCR with all molecules in all IIM subtypes in comparison to control muscle. Immunohistochemistry revealed diffuse CCL4 expression in all vessels in dermatomyositis. In both polymyositis and sporadic inclusion body myositis (s-IBM) it was restricted to vessels in the vicinity of inflammatory exudates. CCL5 expression was low, restricted to a few inflammatory cells in all IIM; CCR1 expression was mainly restricted to macrophages and s-IBM endothelial cells, whereas CCR5 was localized in inflammatory cells invading non-necrotic muscle fibres. Expressions of both receptors were also recorded in few muscle fibres. In conclusion, the upregulation of beta chemokines and receptors in IIM and their differential expression by various cells may contribute to chronic inflammation and to the peculiar distribution of inflammatory exudates in these diseases.
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PMID:Expression of the beta chemokines CCL3, CCL4, CCL5 and their receptors in idiopathic inflammatory myopathies. 1563 33

Involvement of excessive Th1 cell functions and heat shock protein expression in the pathogenesis of Behcet's disease (BD) has been reported. In this study we have characterized immune responses in intestinal lesions of BD. Peripheral blood lymphocytes (PBL) of BD and healthy controls (HC) and tissue specimens of intestinal Behcet's disease (intestinal BD), Crohn's disease (CD) and ulcerative colitis (UC) were analysed for mRNA and protein expression by reverse transcriptase-polymerase chain reaction (PCR) and immunohistochemistry, respectively. PBL of BD patients expressed the Th1-related chemokine receptor, CCR5 and CXCR3 preferentially compared with those of healthy controls. Intestinal lesions of BD expressed interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha and interleukin (IL)-12 mRNA, indicating Th1 skewed responses in vivo. mRNA of Txk, a Tec family tyrosine kinase specific to Th1 cells, was expressed in the lesions, suggesting its contribution to the Th1-dominant responses. In the intestinal samples, CCR5 was detected in all the cases with BD, whereas Th2-related CCR3 and CCR4 were detected randomly, mainly in the cases with inactive BD and those receiving large amounts of prednisolone, indicating the Th1-dominant immune responses in the intestinal lesions. As the ligands of CCR5, MIP1alpha and MIP1beta were detected, whereas RANTES was not. Heat shock protein (HSP) 60 was expressed in PBL and intestinal tissues of BD. Th1-dominant immune responses and HSP60 expression may induce the inflammatory responses and thus be associated with the pathogenesis of intestinal BD.
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PMID:Involvement of Th1 cells and heat shock protein 60 in the pathogenesis of intestinal Behcet's disease. 1565 37

Mycophenolate mofetil (MMF), the bioavailable form of mycophenolic acid (MPA), has been proposed as adjuvant therapy for human immunodeficiency virus type 1 (HIV-1) infection. MPA can inhibit viral replication and might blunt virus-induced immunopathology. However, other effects of this inhibitor might be detrimental in an HIV-infected patient. We therefore studied the effect of MPA on selected cellular processes of relevance to HIV infection. We found that MPA did not alter the expression of the primary HIV coreceptor CCR5 on primary resting lymphocytes, but modestly increased CCR5 expression after activation. Conversely, MPA modestly decreased the secretion of the CCR5 ligand RANTES in resting lymphocytes, but had no effect after activation. It has been suggested that the use of inhibitors of host nucleoside metabolism may enhance clinical toxicities induced by HIV-1 nucleoside reverse transcriptase inhibitors (NRTIs). We found no evidence that MPA induced mitochondrial dysfunction or enhanced dysfunction induced by NRTIs in an HepG2 cell line model of mitochondrial toxicity. Further, MPA did not selectively enhance apoptosis in HIV-1-infected lymphocytes. Our findings support the testing of MMF to augment suppression of viral replication. However, careful study will be required to demonstrate that MMF is beneficial when used without antiretroviral therapy, to inhibit residual replication, or to deplete the pool of latently infected nonactivated cells.
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PMID:Ex vivo modeling of the effects of mycophenolic acid on HIV infection: considerations for antiviral therapy. 1572 50

Diesel exhaust particles (DEPs) at three concentrations (5, 35, and 50 mg/kg body weight) were instilled into rats intratracheally. We studied gene expression at 1, 7, and 30 days postexposure in cells obtained by bronchoalveolar lavage (BAL) and in lung tissue. Using real-time reverse transcriptase-polymerase chain reaction (RT-PCR), we measured the mRNA levels of eight genes [interleukin (IL)-1beta, IL-6, IL-10, iNOS (inducible nitric oxide synthase), MCP-1 (monocyte chemoattractant protein-1), MIP-2 (macrophage inflammatory protein-2), TGF-beta1 (transforming growth factor-beta1), and TNF-alpha (tumor necrosis factor-alpha )] in BAL cells and four genes [IL-6, ICAM-1 (intercellular adhesion molecule-1), GM-CSF (granulocyte/macrophage-colony stimulating factor), and RANTES (regulated upon activation normal T cell expressed and secreted)] in lung tissue. In BAL cells on day 1, high-dose exposure induced a significant up-regulation of IL-1beta, iNOS, MCP-1, and MIP-2 but no change in IL-6, IL-10, TGF-beta1, and TNF-alpha mRNA levels. There was no change in the mRNA levels of IL-6, RANTES, ICAM-1, and GM-CSF in lung tissue. Nitric oxide production and levels of MCP-1 and MIP-2 were increased in the 24-hr culture media of alveolar macrophages (AMs) obtained on day 1. IL-6, MCP-1, and MIP-2 levels were also elevated in the BAL fluid. BAL fluid also showed increases in albumin and lactate dehydrogenase. The cellular content in BAL fluid increased at all doses and at all time periods, mainly due to an increase in polymorphonuclear leukocytes. In vitro studies in AMs and cultured lung fibroblasts showed that lung fibroblasts are a significant source of IL-6 and MCP-1 in the lung.
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PMID:Time course of gene expression of inflammatory mediators in rat lung after diesel exhaust particle exposure. 1586 72

As a result of their close association with the blood-brain barrier, astrocytes play an important role in regulating the homing of different leukocyte subsets to the inflamed central nervous system (CNS). In this study, we investigated whether human astrocytes produce chemokines that promote the migration of myeloid dendritic cells (DCs). By reverse transcriptase-polymerase chain reaction and enzyme-linked immunosorbent assay, we show that cultured human astrocytes stimulated with interleukin-1beta and tumor necrosis factor produce CCL2, CCL3, CCL4, CCL5, CCL20, and CXCL12 that act on immature DCs, but not CCL19 and CCL21, 2 chemokines specific for mature DCs. Compared with controls, supernatants of cytokine-stimulated astrocytes are more effective in promoting the migration of immature monocyte-derived DCs (iMDDCs). Desensitization of CXCR4 (receptor for CXCL12), CCR1-3-5 (shared receptors for CCL3-4-5), and CCR6 (receptor for CCL20) on iMDDC reduces cell migration toward astrocyte supernatants, indicating that astrocytes release biologically relevant amounts of iMDDC-attracting chemokines. By immunohistochemistry, we show that CXCL12 and, to a lesser extent, CCL20 are expressed by reactive astrocytes in multiple sclerosis lesions. These data lend support to the idea that astrocyte-derived chemokines may contribute to immature DC recruitment to the inflamed CNS.
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PMID:Astrocytes produce dendritic cell-attracting chemokines in vitro and in multiple sclerosis lesions. 1610 19

In order to investigate the neuropathological effects on the developing rat brain after intrauterine infection, identification of glail fibrillary acidic protein (GFAP), 2', 3'-cyclic nucleotide phosphodiesterase (CNPase), and neurofilament (NF) was observed. Escherichia coli (E. coli) was inoculated into uterine horn of pregnant rats when gestation was 70% complete (15 days) and the control group was inoculated with normal saline. Immunohistochemistry was used for evaluation of GFAP, CNPase, and NF expression in pup brains at postnatal day 7 (P7) and reverse transcriptase-PCR (RT-PCR) to analyze macrophage inflammatory protein-1 alpha mRNA (MIP-1 alpha mRNA), macrophage inflammatory protein-1 beta mRNA (MIP-1beta mRNA), the regulated upon activation normal T expressed and secreted chemokine mRNA (RANTES mRNA) and Eotaxin mRNA expression in pup brains at P1, P3 and P7. The numbers of GFAP-positive cells of the E. coli-treated group pups were marked increased in periventricular white matter and hippocampus at P7 compared with the control group but no significant different levels of GFAP expression in corpus callosum were found between two groups. The integrate density (ID) of CNPase-positive staining of the Escherichia coli-treated group pups were marked decreased in periventricular white matter and corpus callosum at P7 compared with the control group. The ID of NF-positive staining of the Escherichia coli-treated group pups were marked decreased in periventricular white matter at P7 compared with the control group and no significant different levels of NF expression in corpus callosum were found between two groups. The expression of MIP-1 alpha mRNA and MIP-1 beta mRNA in brain of the E. coli-treated pup rat were higher than the control at P1, but the expression of MIP-1 alpha mRNA and MIP-1 beta mRNA in brain of the pup rat at P3 and P7 had no significant difference between two groups. The alteration of expression of GFAP, CNPase, and NF in the brain of neonatal rats after intrauterine infection suggested that intrauterine infection could cause neonatal white matter damage. Moreover, the transient increase in expression of chemokine such as MIP-1 alpha, MIP-1 beta in neonatal brain after intrauterine infection indicated that MIP-1 alpha, MIP-1 beta may be a mechanism mediating between the neonatal white matter damage and the intrauterine infection.
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PMID:White matter damage and chemokine induction in developing rat brain after intrauterine infection. 1623 36

The first small-molecule CCR5 antagonist, TAK-779, could not be developed as an anti-human immunodeficiency virus type (anti-HIV-1) agent because of its poor oral bioavailability. TAK-652 is an orally bioavailable TAK-779 derivative with potent anti-HIV-1 activity. TAK-652 inhibited the binding of RANTES (regulated on activation, normal T-cell expressed and secreted), macrophage inflammatory protein 1alpha (MIP-1alpha), and MIP-1beta to CCR5-expressing cells at nanomolar concentrations. TAK-652 could also suppress the binding of monocyte chemotactic protein 1 (MCP-1) to CCR2b-expressing cells. However, its inhibitory effect on ligand binding to other chemokine receptors was limited. TAK-652 was active against CCR5-using (R5) HIV-1 but totally inactive against CXCR4-using (X4) HIV-1. The compound was active against R5 HIV-1 clinical isolates containing reverse transcriptase and protease inhibitor-resistant mutations, with a mean 50% effective concentration (EC50) and EC90 of 0.061 and 0.25 nM, respectively. In addition, recombinant R5 viruses carrying different subtype (A to G) envelope proteins were equally susceptible to TAK-652. A single oral administration of TAK-652 up to 100 mg was safe and well tolerated in humans. The compound displayed favorable pharmacokinetics, and its plasma concentration was 7.2 ng/ml (9.1 nM) even 24 h after the administration of 25 mg. Thus, TAK-652 is a promising candidate as a novel entry inhibitor of HIV-1.
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PMID:TAK-652 inhibits CCR5-mediated human immunodeficiency virus type 1 infection in vitro and has favorable pharmacokinetics in humans. 1625 Dec 99

The chemokine receptor CCR5 provides a portal of entry for human immunodeficiency virus type 1 (HIV-1) into susceptible CD4(+) cells. Both monoclonal antibody (MAb) and small-molecule CCR5 inhibitors have entered human clinical testing, but little is known regarding their potential interactions. We evaluated the interactions between CCR5 MAbs, small-molecule CCR5 antagonists, and inhibitors of HIV-1 gp120, gp41, and reverse transcriptase in vitro. Inhibition data were analyzed for cooperative effects using the combination index (CI) method and stringent statistical criteria. Potent, statistically significant antiviral synergy was observed between the CCR5 MAb PRO 140 and the small-molecule CCR5 antagonists maraviroc (UK-427,857), vicriviroc (SCH-D), and TAK-779. High-level synergy was observed consistently across various assay systems, HIV-1 envelopes, CCR5 target cells, and inhibition levels. CI values ranged from 0.18 to 0.64 and translated into in vitro dose reductions of up to 14-fold. Competition binding studies revealed nonreciprocal patterns of CCR5 binding by MAb and small-molecule CCR5 inhibitors, suggesting that synergy occurs at the level of receptor binding. In addition, both PRO 140 and maraviroc synergized with the chemokine RANTES, a natural ligand for CCR5; however, additive effects were observed for both small-molecule CCR5 antagonists and PRO 140 in combination with other classes of HIV-1 inhibitors. The findings provide a rationale for clinical exploration of MAb and small-molecule CCR5 inhibitors in novel dual-CCR5 regimens for HIV-1 therapy.
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PMID:Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. 1700 7

We assessed the effect of voriconazole (VRC) on the expression and release of selected cytokines and chemokines in the THP-1 human monocytic cell line in response to Aspergillus fumigatus hyphal fragments (HF) by cDNA microarray analysis, reverse transcriptase (RT) PCR, and enzyme-linked immunosorbent assay. Stimulation of THP-1 cells by HF alone caused a significant up-regulation of CCL4 (MIP1B) and CCL16, while CCL2 (MCP1) was down-regulated. By comparison, in the presence of VRC, a large number of genes such as CCL3 (MIP1A), CCL4 (MIP1B), CCL5 (RANTES), CCL7 (MCP3), CCL11 (EOTAXIN), CCL15 (MIP1Delta), CXCL6, and CXCL13 were strongly up-regulated in THP-1 cells challenged by HF, whereas CCL20 (MIP3A) and CCL21 (MIP2) were down-regulated. Among five genes differentially expressed in THP-1 cells, IL12A, IL12B, and IL-16 were down-regulated whereas IL-11 and TGFB1 were significantly up-regulated in the presence of VRC. The inflammation-related genes IFNgamma, IL1R1, and TNFA were also up-regulated in THP-1 cells exposed to HF only in the presence of VRC. RT-PCR of four selected genes validated the results of microarrays. The release of interleukin 1beta (IL-1beta) and IL-12 was significantly increased from monocytes stimulated either by HF alone (P < 0.05) or in the presence of VRC (P < 0.01 and P < 0.05, respectively). In contrast, tumor necrosis factor alpha release from monocytes was enhanced only in the presence of VRC (P < 0.01). The chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1beta were decreased under both conditions (P < 0.01). These results demonstrate that in the presence of VRC, HF induces a more pronounced profile of gene expression in THP-1 cells than HF alone, potentially leading to more-efficient host resistance to A. fumigatus.
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PMID:Expression of immunomodulatory genes in human monocytes induced by voriconazole in the presence of Aspergillus fumigatus. 1717 97

The objective of this study is to test whether the activation of toll-like receptors (TLRs) 2 and 3 (innate immune receptors for gram-positive and viral pathogens, respectively) can induce preterm delivery. One uterine horn of preterm pregnant CD-1 mice at approximately 75% of gestation was injected with TLR-2 ligands (lipoteichoic acid [LTA] or peptidoglycan [PGN]) or the TLR-3 ligand polyinosinic:cytidylic acid (poly[I:C]). Preterm delivery was recorded. In a separate group of mice, tissue mRNAs were quantified by reverse transcriptase polymerase chain reaction 5 hours after treatment with PGN or poly(I:C). Intrauterine PGN and LTA induced preterm delivery, reaching 100% at maximal doses. Intraperitoneal PGN also induced preterm delivery but at lower rates (maximum = 55%). Intrauterine poly(I:C) induced preterm birth in up to 31% of mice. Poly(I:C) induced uterine interferon beta and chemokine (C-C motif) ligand 5 (CCL5, also known as RANTES) but not interleukin 1beta, tumor necrosis factor, or lipopolysaccharide-induced CXC chemokine. PGN did not alter these mRNAs when compared with saline. Neither treatment induced gene expression in fetal membranes. Activation of either TLR-2 or -3 can induce preterm delivery in the mouse. Activation of TLR-3 with poly(I:C) induces interferon beta and the chemokine CCL5 in uterine tissues but not in fetal membranes.
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PMID:Activation of toll-like receptors 2 or 3 and preterm delivery in the mouse. 1764 3


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