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)

Macrophage colony-stimulating factor (M-CSF) is a multifunctional cytokine attributed with key biological functions beyond the first discovered role in promoting proliferation of myeloid cell lineage. The human pancreatic cancer cell line MIA PaCa-2, from which the M-CSF gene was originally cloned, was used to study regulation of M-CSF expression. Expression of M-CSF was inducible by interleukin-1alpha (IL-1alpha), lipopolysaccharide (LPS) and PMA as demonstrated by a biological activity assay, Northern-blot analysis and reverse transcriptase (RT) PCR. Treatment of the cells with forskolin or dibutyryl-cAMP attenuated the expression of M-CSF induced by IL-1alpha or LPS, but not by PMA. Electromobility shift assays showed that IL-1alpha predominantly activated nuclear factor kappaB (NF-kappaB), while PMA preferentially activated activator protein-1 (AP-1). The activation of NF-kappaB, but not AP-1, could be attenuated by cAMP elevation. Relative RT-PCR demonstrated that the expression of a 1.6-kb M-CSF mRNA transcript was more effectively induced by IL-1alpha than a 4.0-kb transcript. By and large the induced expression of both mRNA transcripts could be attenuated by cAMP. M-CSF promoter-driven luciferase reporter-gene assays revealed that cAMP elevation attenuated the IL-1-induced transcription activation of the M-CSF promoter, but it had no effect on PMA-induced transcription. Our findings suggest that cAMP regulates M-CSF gene expression at the transcriptional level and that its inhibitory effect involves NF-kappaB signalling pathway.
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PMID:cAMP attenuates interleukin-1-stimulated macrophage colony-stimulating factor (M-CSF) expression. 1092 34

Macrophage-colony-stimulating factor (M-CSF) regulates the survival, proliferation and differentiation of the mononuclear phagocyte lineage. Osteopetrotic (op/op) mice defective in producing functional M-CSF were used in order to investigate the role of M-CSF on the development of microglia and brain macrophages and the expression of scavenger receptor (SR). Adult op/op and littermate mice at 10-47 weeks of age were investigated by immunohistochemistry with a panel of monoclonal antibodies (F4/80, Mac-1, anti-major histocompatibility complex (MHC) class II and anti-SR), electron microscopy and reverse transcriptase-polymerase chain reaction (RT-PCR). Microglia were weakly immunolabeled with F4/80 and Mac-1 in op/op and littermate mice, but the number of microglia in op/op mice was reduced in the cerebrum, cerebellum and brainstem compared with that of normal littermates. The numbers of Mac-1-positive microglia in op/op mice was 39% (pons) and 30% (cerebellar cortex) lower than that in normal littermates (P<0.05). In addition, the microglia cell processes in op/op mice were often shorter than those in control mice. In op/op and littermate mice, both MHC class II and SR were present in perivascular cells and macrophages of the leptomeninx and choroid plexus. Ultrastructurally, perivascular cells appeared to be immature, since their cytoplasm was narrow and contained few inclusion bodies compared with those of control mice. Reverse transcriptase-polymerase chain reaction showed a weak expression for SR mRNA in the brains of op/op mice as well as littermate mice. These results indicate that microglia are partly dependent on M-CSF for their proliferation and differentiation and that M-CSF has no significant effect on the expression of SR in the physiological brain. The study also suggests that M-CSF affects the maturation of perivascular cells at the ultrastructural level.
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PMID:Effects of macrophage-colony-stimulating factor deficiency on the maturation of microglia and brain macrophages and on their expression of scavenger receptor. 1093 50

(S)-2-ethyl-7-fluoro-3-oxo-3, 4-dihydro-2H-quinoxaline-carboxylic acid isopropylester (GW420867X) inhibits HIV-1 reverse transcriptase and could be used for the treatment of HIV infection. This study quantified the movement of [14C]GW420867X into the CNS by means of a guinea-pig brain perfusion technique. Results indicated that [14C]GW420867X can enter the brain (Kin: 38.4+/-7.7 microl min(-1) g(-1)) and cerebrospinal fluid (CSF; Kin: 1.2+/-0.1 microl min(-1) g(-1)). Self-inhibition studies also suggested the presence of a saturable transport system for [14C]GW420867X at the blood-brain barrier (BBB). Thus [14C]GW420867X can enter the brain via the BBB and, compared with the blood-CSF barrier, this route is the predominant pathway for the brain entry of this drug. This would suggest that GW420867X is a promising drug for the treatment of HIV infection within the brain.
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PMID:Brain and CSF entry of the novel non-nucleoside reverse transcriptase inhibitor, GW420867X. 1111 96

Combinations of two nucleoside analogue reverse transcriptase inhibitors plus a third agent represent the current standard for antiretroviral therapy. Stavudine is a nucleoside analogue that demonstrates in vitro activity against human immunodeficiency virus type 1 (HIV-1) and HIV-2 within an acceptable therapeutic index in a range of T lymphocyte and haematopoietic precursor cell lines. It is additive or synergistic in vitro with a number of other antiretrovirals including protease inhibitors in two and three way combinations and is active against zidovudine-resistant virus. It exhibits excellent oral bioavailability, with CSF penetration. In clinical use, stavudine exhibits antiretroviral activity as a monotherapy similar to zidovudine, and is of proven clinical benefit in zidovudine-pretreated patients. In combination with didanosine and/or nelfinavir it results in more substantial and durable responses in immunological and virological markers than reported with either drug alone. Comparative trials in zidovudine-experienced patients suggest a similar frequency of adverse events to that observed with zidovudine. Peripheral neuropathy is the most common dose-limiting toxicity with haematological and hepatic function disturbance being infrequent. Reasons for stavudine failure are not established, with no consistent genotypic pattern being associated with changes in stavudine sensitivity in vitro or in vivo. The role of stavudine is as a component of triple therapy regimens both in initial therapy and in patients with prior zidovudine experience.
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PMID:The role of stavudine in the management of adults with HIV infection. 1132 40

A cDNA encoding feline granulocyte colony stimulating factor (fG-CSF) was cloned from alveolar macrophages using the reverse transcriptase-polymerase chain reaction. The cDNA is 949 bp in length and encodes a predicted mature protein of 174 amino acids. Recombinant fG-CSF was expressed as a glutathione S-transferase fusion and purified by affinity chromatography. Biological activity of the recombinant protein was demonstrated using the murine myeloblastic cell line GNFS-60, which showed an ED50 for fG-CSF of approximately 2 ng/ml.
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PMID:Isolation, nucleotide sequence and expression of a cDNA encoding feline granulocyte colony-stimulating factor. 1149 96

Mucosal macrophages have been implicated in the pathogenesis of inflammatory bowel disease (IBD). Macrophage-colony stimulating factor (M-CSF) influences monocyte/macrophage proliferation, differentiation, and activation. Serum levels are increased in active IBD, but little is known about its role in mucosal inflammation. This study was undertaken to determine the distribution, frequency, and level of M-CSF expression in normal and IBD-affected intestine. RNA and tissue were studied from patients with Crohn's disease (CD) and ulcerative colitis (UC) as well as from histologically normal colon. Tissue from intestinal tuberculosis and ischaemic colitis patients served as controls. M-CSF mRNA and protein were examined by semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR), in situ hybridisation, and immunohistochemistry, respectively. M-CSF mRNA and protein were detected in histologically normal intestine, but their expression was largely confined to the mucosa. In active IBD, the frequency of M-CSF-expressing cells was significantly increased and their distribution markedly altered, although no increase in mucosal M-CSF mRNA levels in intestinal tissue was observed. The changes were not specific to IBD, as there were similar findings in intestinal tuberculosis and ischaemic colitis. The marked alteration observed in M-CSF expression in IBD and the importance of this cytokine in stimulating macrophage functions suggest that M-CSF may contribute to the pathogenesis of the IBD lesion.
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PMID:Expression of macrophage-colony stimulating factor in normal and inflammatory bowel disease intestine. 1174 98

The brain and CSF distribution of the HIV reverse transcriptase inhibitor, 2'3'-dideoxycytidine (ddC), was investigated by the in situ brain perfusion and isolated incubated choroid plexus methods in the guinea pig. Multiple-time brain perfusions indicated that the distribution of [3H]ddC to the brain and CSF was low and the unidirectional rate constant (K(in)) for the brain uptake of this nucleoside analogue (0.52 +/- 0.10 microL/min/g) was not significantly different to that for the vascular marker, [14C]mannitol (0.44 +/- 0.09 microL/min/g). The influence of unlabelled ddC, six organic anion transport inhibitors and 3'-azido 3'-deoxythymidine (AZT) on the CNS uptake of [3H]ddC was examined in situ and in vitro. ddC, probenecid and 2,4-dichlorophenoxyacetic acid altered the distribution of [3H]ddC into the brain and choroid plexuses, indicating that the limited distribution of [3H]ddC was a result of an organic anion efflux transporter, in addition to the low lipophilicity of this drug (octanol-saline partition coefficient, 0.047 +/- 0.001). The CNS distribution was also sensitive to p-aminohippurate and deltorphin II, but not digoxin, suggesting the involvement of organic anion transporters (OAT1/OAT3-like) and organic anion transporting polypeptides (OATP1/OATPA-like). AZT did not effect the accumulation of [3H]ddC, indicating that when these nucleoside analogues are used in anti-HIV combination therapy, the CNS distribution of ddC is unchanged.
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PMID:The distribution of the anti-HIV drug, 2'3'-dideoxycytidine (ddC), across the blood-brain and blood-cerebrospinal fluid barriers and the influence of organic anion transport inhibitors. 1190 88

Macrophage colony-stimulating factor (M-CSF) enhances the susceptibility of macrophages to infection with HIV-1, in part by increasing the expression of CD4 and CCR5. Human monocyte-derived macrophages (MDMs) infected in vitro with HIV-1 endogenously produce M-CSF, with kinetics paralleling virus replication, which can lead to enhanced spreading of the infection. AZT and ritonavir both inhibit HIV replication, but their impact on M-CSF production by HIV-infected human MDMs is unknown. The dose response and kinetics of virus replication in the presence of AZT and ritonavir were determined for HIV-infected MDMs from HIV-seronegative donors. Harvested supernatants were monitored for reverse transcriptase activity, M-CSF production, and HIV proteins. Our data suggest that threshold levels of HIV replication must occur before maximum M-CSF production is induced. Addition of AZT or ritonavir before or after establishment of productive HIV infection dramatically reduces virus replication and M-CSF production by human MDMs. However, ongoing virus replication and M-CSF production are slow to return to baseline levels after addition of AZT or ritonavir, suggesting that HIV replication and virion release from infected macrophages continue long after initiation of antiretroviral therapy. Our results suggest that, in human macrophages, HIV-1 replication and M-CSF production are inextricably linked, such that inhibition of one leads to a concomitant reduction of the other. Low-level HIV replication and M-CSF release during ongoing antiretroviral therapies may facilitate the survival and maintenance of infected macrophages and suggests that additional therapies targeting M-CSF may be critical for elimination of macrophage reservoirs.
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PMID:Inhibition of HIV replication and macrophage colony-stimulating factor production in human macrophages by antiretroviral agents. 1207 57

An earlier study reported that human gingival epithelial cells in primary culture and oral epithelial cell lines KB and HSC-2 cells were devoid of membrane CD14 (mCD14) and did not show enhanced production of interleukin (IL)-8 or granulocyte macrophage-colony stimulating factor (GM-CSF) upon stimulation with bacterial cell-surface components such as lipopolysaccharide (LPS), lipoteichoic acid (LTA), peptidoglycan (PGN) and synthetic muramyldipeptide (MDP) even in the presence of serum. The present study demonstrated that after treatment with interferon (IFN)-gamma for 3 days, these cells secreted IL-8 and GM-CSF in response to the bacterial components. Treatment with IFN-gamma enhanced Toll-like receptor (TLR) 2, TLR4, MD-2 and MyD88 mRNA expression as determined by reverse transcriptase PCR. Anti-TLR2 and anti-TLR4 monoclonal antibodies (MAbs) inhibited the IL-8 production induced by PGN and LTA as well as LPS, respectively, in IFN-gamma-primed oral epithelial cells, whereas neither MAb inhibited IL-8 production induced by MDP. These findings suggested that IFN-gamma primed oral epithelial cells to produce cytokines upon stimulation with various bacterial components by up-regulation of the TLR system.
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PMID:Priming of human oral epithelial cells by interferon-gamma to secrete cytokines in response to lipopolysaccharides, lipoteichoic acids and peptidoglycans. 1217 Dec 92

Using a combination of cross species reverse transcriptase-polymerase chain reaction and 3' rapid amplification of cDNA ends techniques, we cloned the cDNA encoding gerbil granulocyte/macrophage colony-stimulating factor (GM-CSF). The open reading frame had 81% nucleotide identity with its mouse counterpart, while the mature protein had 80% homology with mature mouse GM-CSF. COS-7 cells transfected with gerbil GM-CSF cDNA secreted high levels of bioactive GM-CSF, as their supernatant stimulated gerbil bone-marrow cell proliferation and colony formation in semi-solid medium.
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PMID:Molecular cloning and expression of gerbil granulocyte/macrophage colony-stimulating factor. 1223 85


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