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 granulocyte-derived hemoregulatory peptide pyroGlu-Glu-Asp-Cys-Lys = pEEDCK is known to keep hematopoietic cells quiescent. When oxidized to its dimeric form (pEEDCK)2, it activates growth of hematopoietic progenitors in association with stroma-derived cytokines. (pEEDCK)2 has a Cys-Cys motif which is also a typical feature of the macrophage inflammatory protein (MIP-1alpha). The present study was designed to analyze differences between the response of normal and leukemic progenitor cells to (pEEDCK)2 or MIP-1alpha. When long-term bone marrow cultures (LTBMCs) were incubated with (pEEDCK)2 or MIP-1alpha and/or cytokines, the stimulatory effect on colony-forming units-granulocyte/erythroid/macrophage/megakaryocyte of LTBMC from chronic myeloid leukemia (CML) patients was less than 50% compared to LTBMC from healthy humans. No difference in oncogene expression could be observed in LTBMC from CML patients regarding reduction of Philadelphia chromosome-associated transcription of the BCR-ABL gene. With respect to the expression of growth and differentiation-associated genes (Galpha16, 5-lipoxygenase, phospholipaseA2, c-kit, and CD34), which were analyzed from LTBMC by semiquantitative reverse transcriptase-polymerase chain reaction, the same transcription rate was observed in CML patients and healthy donors. However, two isoforms of a key enzyme of oxidative metabolism, carnitine palmitoyltransferase (CPT1A and CPT1B), showed 50-fold higher expression rates in LTBMC cells of healthy donors compared to CML patients. It is known that a decrease in oxidative metabolism is associated with an increase in redox equivalents in malignancy. This might result in a reduction of disulphide bonds in (pEEDCK)2 or MIP-1alpha, thus inducing a downregulation of these factors in bone marrow from CML patients.
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PMID:Effect of the hemoregulatory peptide (pEEDCK)2 (pyroGlu-Glu-Asp-Cys-Lys)2 and MIP-1alpha is reduced in bone marrow cultures from patients with chronic myeloid leukemia (CML). 1146 52

The chemokine receptors CXCR4 and CCR5 are used as co-receptors by the T cell-tropic (X4) and macrophage-tropic (R5) HIV-1 strains, respectively, for entering their host cells. Viral entry can be inhibited by the natural ligands for CXCR4, the CXC chemokine SDF-1 and CCR5, the CC chemokines RANTES, MIP-1alpha and MIP-1beta. Several peptidic compounds, T22 (an 18-mer), T134 (a 14-mer), ALX40-4C (a 9-mer) and CGP 64222 (also a 9-mer), have been identified as CXCR4 antagonists and show anti-HIV activity. Also, the HIV-1 tat protein has been described as a 'natural' CXCR4 antagonist with anti-HIV-1 activity. The most potent and specific CXCR4 antagonists are the bicyclam derivatives, which also potently block X4 HIV replication. AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks the outgrowth of all X4 HIV and dual-tropic (R5/X4) variants that use CXCR4 for entering the cells (cell lines, CXCR4-transfected cell lines, lymphocytes or monocytes/ macrophages). From the bicyclam analogues, AMD3100 was selected as the clinical drug candidate, which, after initial Phase I (safety) studies, has proceeded to Phase II (efficacy) trials. The first non-peptidic compound that interacts with CCR5, and not with CXCR4, is a quaternary ammonium derivative, called TAK-779, which also has potent but variable anti-HIV activity. We believe that HIV entry/fusion inhibitors will become important new antiviral agents to combat AIDS. However, like the current clinically approved agents, they will need to be used in combinations consisting of antivirals that target other aspects of the HIV replication cycle, such as reverse transcriptase and protease, to obtain optimum therapeutic effects.
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PMID:Inhibition of HIV infection by CXCR4 and CCR5 chemokine receptor antagonists. 1159 85

1. Chemokine expression and function was monitored in an experimental model of granulomatous tissue formation after injection of croton oil in complete Freund's adjuvant (CO/CFA) into mouse dorsal air-pouches up to 28 days. 2. In the first week, mast cell degranulation and leukocyte influx (mononuclear cell, MNC, and polymorphonuclear cell, PMN) were associated with CXCR2, KC and macrophage inflammatory protein (MIP)-2 mRNA expression, as determined by TaqMan reverse transcriptase-polymerase chain reaction. KC ( approximately 400 pg x mg protein(-1), n=12) and MIP-2 (approximately 800 pg x mg protein(-1), n=12) proteins peaked at day 7, together with myeloperoxidase (MPO) activity. Highest MIP-1alpha (>1 ng x mg protein(-1), n=12) levels were measured at day 3. 3. After day 7, a gradual increase in CCR2 and CCR5 mRNA, monocyte chemoattractant protein (MCP)-1 mRNA and protein expression was measured. MCP-1 protein peaked at day 21 (approximately 150 pg x mg protein(-1), n=12) and was predominantly expressed by mast cells. A gradual increase in N-acetyl-beta-D-glucosaminidase (NAG) activity (maximal at 28 days) was also measured. 4. An antiserum against MIP-1alpha did not modify the inflammatory response measured at day 7 (except for a 50% reduction in MIP-1alpha levels), but provoked a significant increase in MPO, NAG and MCP-1 levels as measured at day 21 (n=6, P<0.05). An antiserum to MCP-1 reduced NAG activity at day 21 but increased MPO activity values (n=8, P<0.05). 5. In conclusion, we have shown that CO/CFA initiates a complex inflammatory reaction in which initial expression of MIP-1alpha serves a protective role whereas delayed expression of MCP-1 seems to have a genuine pro-inflammatory role.
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PMID:Analysis of the temporal expression of chemokines and chemokine receptors during experimental granulomatous inflammation: role and expression of MIP-1alpha and MCP-1. 1170 36

Interleukin-18 (IL-18) is a proinflammatory monokine structurally related to IL-1beta that stimulates interferon-gamma (IFN-gamma) production. IL-18 is synthesized as an inactive precursor, pro-IL-18, which is cleaved by IL-1beta-converting enzyme (ICE)/caspase-1 in a mature protein. In view of the proposed use of IL-18 in cancer immuno/gene therapy, we have studied the expression of IL-18 in tumor cells. IL-18 mRNA was detected by reverse transcriptase polymerase chain reaction in all human ovarian carcinoma cell lines tested (9/9) and in one-half of tumor cell populations obtained from ovarian carcinoma patients (4/8). ICE mRNA was expressed in a smaller fraction of samples (3/9 cell lines and 3/8 samples from patients). IL-18 protein was also found in 7/13 ovarian carcinoma solid tumors by immunohistochemic analysis. In tumor cell lines we were able to detect abundant intracellular pro-IL-18 (24 kDa) by Western blotting, whereas the mature form of IL-18 was undetectable, irrespective of the presence of ICE mRNA and protein. Only pro-IL-18 was also found in the ovarian carcinoma cell supernatants, which did not display any IL-18 biologic activity in functional assays. Normal cultured ovarian epithelial cells revealed the presence of both IL-18 and ICE mRNA in all samples (5/5) and IL-18 protein was expressed by the thin epithelial cell layer surrounding normal ovary. More importantly, normal ovarian epithelial cells released low but detectable amounts of mature IL-18 in the culture supernatant, which displayed IL-18-like biologic activity in functional assays. These data suggest that mature biologically active IL-18 production is a feature of the normal ovarian surface epithelium lost during neoplastic transformation.
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PMID:Expression of interleukin-18 in human ovarian carcinoma and normal ovarian epithelium: evidence for defective processing in tumor cells. 1194 65

Chemokines are important mediators of cell trafficking during immune inductive and effector activities, and dysregulation of their expression might contribute to the pathogenesis of human immunodeficiency virus type 1 and the related simian immunodeficiency virus (SIV). To understand better the effects of SIV infection on lymphoid tissues in rhesus macaques, we examined chemokine messenger RNA (mRNA) expression patterns by using DNA filter array hybridization. Of the 34 chemokines examined, the interferon gamma (IFN-gamma)-inducible chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma (CXCL9/Mig) was one of the most highly up-regulated chemokines in rhesus macaque spleen tissue early after infection with pathogenic SIV. The relative levels of expression of CXCL9/Mig mRNA in spleen and lymph nodes were significantly increased after infection with SIV in both quantitative image capture and analysis and real-time reverse transcriptase-polymerase chain reaction assays. In addition, in situ hybridization for CXCL9/Mig mRNA revealed that the patterns of expression were altered after SIV infection. Associated with the increased expression of CXCL9/Mig were increased numbers of IFN-gamma mRNA-positive cells in tissues and reduced percentages of CXC chemokine receptor (CXCR) 3(+)/CD3(+) and CXCR3(+)/CD8(+) lymphocytes in peripheral blood. We propose that SIV replication in vivo initiates IFN-gamma-driven positive-feedback loops in lymphoid tissues that disrupt the trafficking of effector T lymphocytes and lead to chronic local inflammation, thereby contributing to immunopathogenesis.
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PMID:Increased expression of the inflammatory chemokine CXC chemokine ligand 9/monokine induced by interferon-gamma in lymphoid tissues of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome. 1196 73

Cytokines and beta-chemokines are important mediators of the immune system and are expressed in many infectious diseases. To study cytokine and beta-chemokine profiles during pathogenesis of lentiviral infection and progression to AIDS in rhesus macaques, we established new quantitative real-time reverse transcriptase-polymerase chain reaction (RT-PCR) assays based on TaqMan chemistry. Using synthetic RNA standards, we quantified mRNAs of IL-2, IL-4, IL-6, IL-10, IL-12 p40, interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), RANTES, macrophage inflammatory protein 1 alpha (MIP-1 alpha), and MIP-1 beta in unstimulated peripheral blood mononuclear cells (PBMCs) and lymph nodes from macaques chronically infected with SIV or SHIV. Viremic monkeys with decreased CD4(+) T cell counts (<500 cells/microl) had significantly higher IL-10 mRNA expression than uninfected controls, which parallels the findings in HIV-1-infected humans. In addition, MIP-1 alpha, MIP-1 beta, and RANTES mRNA expression increased in viremic monkeys with decreased CD4(+) T cell counts; gene expression was inversely correlated with CD4(+) T cell counts, but not viral load. The newly established quantitative real-time RT-PCR assays will allow the determination of cytokine and beta-chemokine patterns in rhesus macaques in studies of microbial pathogenesis or vaccine development.
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PMID:Quantitation of simian cytokine and beta-chemokine mRNAs, using real-time reverse transcriptase-polymerase chain reaction: variations in expression during chronic primate lentivirus infection. 1207 58

Apoptosis of histiocytes is a characteristic feature of necrotizing lymphadenitis (HNL). Recent studies have indicated that Fas and perforin-based pathways are involved in the apoptotic process of HNL. Elevated levels of serum interferon (IFN)-gamma are reported in HNL. The CXC chemokine interferon-gamma-inducible protein-10 (IP-10) and monokine induced by interferon-gamma (MIG) cause tissue necrosis, and interleukin (IL)-18 induces the expression of IFN-gamma and Fas ligand (FasL) by T and natural killer (NK) cells. This study was designed to determine the expression of IFN-gamma, IL-18, MIG and IP-10 in HNL. Ten cases of HNL were analyzed by using immunohistochemical staining and/or reverse transcriptase-polymerase chain reaction (RT-PCR). As a control, we included four cases of non-specific lymphadenitis. MIG and IP-10 proteins, which enhance the release of granzyme, showed a similar distribution pattern in viable tissues surrounding dead tissue, mostly within histiocytes, and lymphocytes in HNL. IL-18 was located within histiocytes, especially phagocytic histiocytes, but not within lymphocytes. In addition, IFN-gamma-positive lymphocytes were frequently detected in the surrounding dead tissue, and the lymphocytes in the same area were frequently positive for CXCR3, a specific receptor of MIG and IP-10. In non-specific lymphadenitis, MIG, IP-10 and IL-18 positive cells were detected, but their numbers were relatively small compared with HNL, while IFN-gamma positive cells were rarely encountered. Our findings suggest that the cytokine and chemokine pathways of IFN-gamma, IL-18, MIG and IP-10 play an important role in the pathogenesis of apoptosis associated with HNL.
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PMID:Interferon-gamma, interleukin-18, monokine induced by interferon-gamma and interferon-gamma-inducible protein-10 in histiocytic necrotizing lymphadenitis. 1214 94

Bone marrow abnormalities are frequently observed in HIV-1-infected individuals. Infection of marrow mesenchymal stem cells (MSCs) may abrogate their growth properties and hematopoietic supportive functions. To delineate the cell type infected, and factors responsible for the deleterious effects, human bone marrow cells were exposed to HIV-1 in vitro. By week 4, the ability of MSCs to form colonies of purely fibroblasts (CFU-F) and mixed colonies of fibroblasts and adipocytes (CFU-FA) was suppressed by 23 +/- 5 and 55 +/- 7%, respectively. The p24 concentration in culture supernatants steadily declined from 170 ng/ml in the inoculum to 134 +/- 30, 35 +/- 15, 2.3 +/- 3, and <0.02 ng/ml at the end of week 1, 2, 3, and 4, respectively. However, even at week 4, coculturing with MT-4 lymphocytes for 1 week dramatically increased p24 levels. Polymerase chain reaction (PCR) amplification, using HIV-1-specific primers, and in situ hybridization with an HIV-1 cDNA probe demonstrated the presence of virus-specific nucleic acids within stromal colonies. Coimmunostaining with antibody to CD83 implicated the presence of HIV-1 within dendritic progenitor cells. Immunostaining with HIV-1 Tat antibody demonstrated the presence of Tat protein and reverse transcriptase (RT)-PCR assays showed increased (160-220%) mRNA levels for inflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin 1beta [IL-1beta], IL-6, and macrophage inflammatory protein 1alpha [MIP-1alpha]). A concentration-dependent decrease in CFU-STROs was observed on incubation with either Tat protein (1-100 ng/ml) or with TNF-alpha or IL-1beta (0.025-25 ng/ml). These results suggest that HIV-1 infection of stromal cells may produce inhibitory factors that suppress the clonogenic potential of MSCs.
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PMID:Suppression of clonogenic potential of human bone marrow mesenchymal stem cells by HIV type 1: putative role of HIV type 1 tat protein and inflammatory cytokines. 1223 Sep 35

Interleukin-16 (IL-16) and the beta-chemokines (RANTES, monocyte chemotactic protein-1 (MCP-1), macrophage inhibitory protein (MIP)-1alpha and (MIP)-1beta) are soluble in vitro suppressors of macrophage tropic HIV-1 strains. The reduction of HIV-1 RNA plasma levels in late-stage patients receiving protease inhibitors has been associated with increased concentrations of MIP-1alpha, MIP-1beta, RANTES and IL-16 and a decrease in levels of MCP-1. We determined plasma levels of MCP-1, MIP-1alpha, MIP-1beta, RANTES and IL-16 during the first 16 weeks of highly active antiretroviral therapy (HAART) in chronic HIV-1-infected patients. Patients were administered one of two therapeutic regimens based on either a protease inhibitor (PI) or a non-nucleoside reverse transcriptase inhibitor (NNRTI). No differences were seen in the levels of RANTES and IL-16 over the first 16 weeks of HAART in either treatment group. MCP-1 decreased significantly in the PI-treated group over the first 16 weeks of HAART (P = 0.0003). A significant increase was observed in the levels of MIP-1alpha and MIP-1beta in the NNRTI cohort (P = 0.0010 and P = 0.0012, respectively). A significant decrease in levels of MIP-1alpha and MIP-1beta (P = 0.0015 and P = 0.0299, respectively) was observed over the 16 weeks in the PI cohort. A significant difference was seen when the levels of MIP-1alpha and MIP-1beta were compared between the NNRTI and the PI cohorts at week 16 (P = 0.04 and P = 0.05, respectively). Evaluation of CCR5 expression ex vivo revealed no difference between the two treatment groups. Patients were genotyped for CCR5 Delta32 and the incidence of heterozygosity was lower than in the HIV-1 seronegative controls (3% compared to 19%).
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PMID:Impact of NNRTI compared to PI-based highly active antiretroviral therapy on CCR5 receptor expression, beta-chemokines and IL-16 secretion in HIV-1 infection. 1239 Mar 2

HIV entry within the cell involves the presence of at least two chemokine co-receptors, the CCR5 and CXCR4 receptors. Viral entry can be inhibited by the natural ligands for CXCR4, the CXC chemokine SDF-1 and CCR5, the CC chemokines RANTES, MIP-1alpha and MIP-1beta, respectively. Much research has been devoted ultimately to the development of small molecule chemokine antagonists that inhibit virus entry within the cell, and constitute in this way novel antiviral medications. The most potent and specific CXCR4 antagonists reported up to now are the bicyclam derivatives, which also potently block X4 HIV replication. One such compound, AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks the outgrowth of all X4 HIV and dual-tropic (R5/X4) variants that use CXCR4 for entering the cells. From such bicyclam analogues, AMD3100 was selected as the clinical candidate, which, after initial Phase I studies, proceeded to Phase II trials, but unfortunately showed significant cardiac side effects which lead to its withdrawal from further development. The first nonpeptidic compound that interacts with CCR5, but not with CXCR4, is a quaternary ammonium derivative, TAK-779, which also shows potent but variable anti-HIV activity. A large number of potent CCR5 antagonists from several classes of polycyclic derivatives have been recently disclosed. Many such derivatives showed nanomolar binding affinity to the receptor, and at least one of them, the oxime-piperidine derivative SCH-351125 has progressed to clinical evaluation. The development of such agents for clinical use may constitute an additional approach for the treatment of HIV infection, in addition to the classical one involving reverse transcriptase and protease inhibitors.
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PMID:Non-peptidic chemokine receptors antagonists as emerging anti-HIV agents. 1242 Jul 52


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