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)

Adriamycin is a potent, broad-spectrum chemotherapeutic agent effective against solid tumors and malignant hematological disease. The major limiting factor for adriamycin is its cardiotoxicity. Thus, the objective of this study was to investigate the role of cardiomyocyte and endothelial cell apoptosis in adriamycin-induced cardiomyopathy, in vivo and in vitro. For in vivo study, intraperitoneal injections of adriamycin were administered to nine adult male Wistar rats and normal saline to six rats as control. Eight of the nine rats in the adriamycin group, but none in the control group, developed marked ascites and DNA ladders in agarose gel electrophoresis of genomic DNA extracted from the rat hearts (P<0.001). The ratio of apoptotic nuclei in the cardiomyocytes was significantly higher for the adriamycin-treated rats (162+/-149/10(6) cells) than for the controls (4.2+/-1.3/10(6) cells; P<0.01) by TUNEL assay. Increased endothelial cell apoptosis was detected in the small coronary vessels of the myocardium of the adriamycin-treated rats. Increased immuno-reactive Caspase-3 expression was also noted for both cardiomyocytes and endothelial cells of adriamycin-treated rats. In vitro adriamycin treatment for cultured neonatal rat cardiomyocytes and human umbilical vein endothelial cells, respectively, showed a dose-related increase in apoptosis as determined by flowcytometry, DNA ladder analysis, TUNEL assay and/or electron-microscope examination. A dose-related increase in the expression of Fas antigen, Bax and Caspase-3, as well as a decrease in the expression of Bcl-2, were determined for the adriamycin-treated cardiomyocytes using Northern blot analysis, reverse transcriptase polymerase chain reaction (RT-PCR) and ribonuclease protection assay. RT-PCR also revealed increased Fas antigen expression, decreased Bcl-2 expression, and no change in Bax expression for the adriamycin-treated human umbilical vein cells. Further, pretreatment with broad caspase inhibitor, but not neutralizing FasL antibody, resulted in inhibition of adriamycin-induced endothelial cell apoptosis. In conclusion, these results indicate that both adriamycin-induced cardiomyocyte and endothelial cell death can occur via apoptosis which is dose-related, and can occur both in vitro and in vivo with changes in the expression of the apoptosis-related genes. Adriamycin-induced endothelial cell apoptosis is mediated by caspase activation but is Fas/FasL signal pathway independent. Our data provides evidence that both cardiomyocyte and endothelial cell apoptosis may play an important role in adriamycin-induced cardiomyopathy.
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PMID:Adriamycin-induced cardiomyocyte and endothelial cell apoptosis: in vitro and in vivo studies. 1250 58

Staphylococcal infection-producing superantigens, such as staphylococcal enterotoxin B (SEB), are presumed to play an important role of inflammatory processes in atopic dermatitis (AD). The aim of this study was to elucidate the apoptotic response of peripheral blood mononuclear cells (PBMCs) from children with AD. PBMCs from AD children were sampled and cultured with SEB stimulation. Levels of apoptosis and Fas expression were measured using flow cytometry; the soluble Fas ligand (sFasL) was also measured using the enzyme-linked immunosorbent assay method, and the expression of FasL in PBMCs was observed using reverse transcriptase-polymerase chain reaction. There was no difference in the initial levels of apoptosis and Fas expression in precultured PBMCs of AD patients and healthy donors. After culturing for 48 h under SEB stimulation, the apoptosis level and Fas expression were significantly upregulated in the PBMCs from AD children compared with that from the normal controls. In patients, the sFasL was significantly increased, and the expression of FasL was observed in messenger RNA of peripheral monocytes. These results suggest that the Fas/FasL system is involved in the apoptosis induced by SEB in AD, with simultaneous increases in sFasL and expression of FasL.
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PMID:Staphylococcal enterotoxin B upregulates fas-mediated apoptosis of peripheral blood mononuclear cells in childhood atopic dermatitis. 1254 99

HIV-1 protease inhibitors have contributed significantly to the reduction in morbidity and mortality associated with HIV-1 disease. Some of their clinical benefit may be attributed to inhibition of non-viral pathogen proteases and mammalian proteases involved in apoptosis. Our objective was to investigate the effect of HIV-1 protease inhibitors on two different mechanisms of apoptosis in cells not exposed to HIV-1. Modulation of apoptosis induced in U937 or Jurkat cells by CD95 (Fas-ligand) or TNF-alpha was measured using flow cytometry using the 7-AAD and annexin/propidium iodide methods. - HIV-1 protease inhibitors reduced TNF-alpha mediated cell death in a dose-dependent manner, with a maximum inhibition ranging between 38% and 60% observed for 100 microM indinavir. Saquinavir and ritonavir, but not nelfinavir also inhibited TNF-alpha induced cell death. Nevirapine (an HIV-1 reverse transcriptase inhibitor) showed no effect. The TNF-alpha activity was also inhibited by the caspase inhibitors Z-VAD-fmk at concentrations of 10 microM or less, and by DEVD-cmk. In contrast, HIV-1 protease inhibitors did not affect CD95 induced apoptosis in Jurkat cells at any of the concentrations tested. Our findings indicate that HIV-1 protease inhibitors may act on mammalian proteases involved in the regulation of apoptosis; whether this is relevant in the clinical setting remains to be established. Identification of the pathways involved may lead to a better understanding of the clinical impact of this drug class and their role in HAART associated toxicities.
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PMID:Inhibition of TNF-alpha mediated cell death by HIV-1 specific protease inhibitors. 1257 50

This study was designed to detect apoptosis in both human senile cataracts and cataracts associated with diabetic retinopathy (DR) and to elucidate the signaling pathway involved in its regulation. Samples of human cataracts were obtained from 56 patients (senile cataracts, n = 40; cataracts with DR, n = 16) and were analyzed by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method, transmission electron microscopy, immunohistochemistry, and reverse transcriptase-polymerase chain reaction (RT-PCR) assay of apoptotic modulators. The TUNEL study demonstrated that the percentage of TUNEL-positive cells in the cataracts with proliferative DR was higher than in the senile cataracts ( P < 0.05). The immunohistochemistry and RT-PCR assay showed a higher level of Fas expression and Fas mRNA in the cataracts with DR than in the senile cataracts, although there was no difference in the expression level of the Fas ligand, Bcl-2, and their mRNAs between both groups. The number of dark cells, which were characterized by a convoluted nucleus and chromatin condensation with abundant free 3'-OH DNA ends, was higher in the cataracts with DR than in the senile cataracts ( P < 0.01). Apoptosis plays an important role in the development of cataracts with DR, but not in senile cataracts, and may be induced by Fas-mediated signaling.
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PMID:Fas-mediated apoptosis in human lens epithelial cells of cataracts associated with diabetic retinopathy. 1265 58

Nelarabine, prodrug of arabinosylguanine (ara-G), has demonstrated T-lymphoblastic antileukemic activity in cell lines and in the clinic. To investigate the mechanism for lineage-specific toxicity, the effects of ara-G were compared in CEM (T-lymphoblast), Raji (B-lymphoblast), and ML-1 (myeloid) cell lines. CEM cells were the most sensitive to ara-G-induced apoptosis and accumulated the highest levels of ara-G triphosphate (ara-GTP). However, compared with myeloid and B-lineage cell lines, CEM cells incorporated fewer ara-G molecules-which were at internucleotide positions in all 3 cell lines- into DNA. Ara-G induced an S-phase arrest in both Raji and ML-1, while in CEM the S-phase cells decreased with a concomitant increase in the sub-G1 population. Within 3 hours of ara-G treatment, the levels of soluble Fas ligand (sFasL) in the medium increased significantly in CEM cultures. In parallel, an induction of FasL gene expression was observed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Pretreatment of CEM cells with a Fas antagonistic antibody inhibited ara-G-mediated cell death. These results demonstrate that high ara-GTP accumulation in T cells results in an S phase-dependent apoptosis induced by ara-G incorporation into DNA, which may lead to a T cell-specific signal for the induction and liberation of sFasL. Subsequently, the sFasL induces an apoptotic response in neighboring non-S-phase cells. In contrast, myeloid and B cells accumulated lower levels of ara-GTP and arrested in S phase, blocking any apoptotic signaling.
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PMID:Mechanisms for T-cell selective cytotoxicity of arabinosylguanine. 1275 Jan 68

Angiogenesis takes place during embryogenesis, characterized by the formation of new blood vessels from pre-existing ones. This biological process is also found in the female reproductive system, wound healing, and cancer development. Apoptosis, programmed cell death, is a physiological process in development, tissue homeostasis, and disease. Apoptosis is a normal event in several reproductive tissues including human placenta. In these studies, we investigated whether aberrant angiogenesis and apoptosis are associated with recurrent pregnancy loss (RPL). We compared the gene expression level for angiogenesis- and apoptosis-related genes in chorionic villi from RPL patients and those from normal controls. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis revealed that 7 angiogenesis- and 12 apoptosis-related genes were abnormally expressed in chorionic villi from RPL patients. Angiogenesis-related genes that showed aberrant expression level are matrix metalloproteinase-2 (MMP-2), plasminogen activator inhibitor (PAI), integrin, transforming growth factor-beta (TGF-beta), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and leptin receptor. Expression levels for these genes, except for leptin receptor, showed less in chorionic villi from RPL patients than those from normal controls. In contrast, higher expression levels of 12 apoptosis-related genes (caspase 3, 6, 7, 8, 9, 10, 12, BAD, BAX, BID, Fas, and FasL) were shown in chorionic villi from RPL patients than those from normal controls. Taken all together, it is likely that the lower expression of angiogenesis-related genes and the excessive expression of apoptosis-related genes are associated with RPL.
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PMID:Expression of angiogenesis- and apoptosis-related genes in chorionic villi derived from recurrent pregnancy loss patients. 1287 95

The Fas ligand (FasL) pathway is one of the two major effector mechanisms of T-cell-mediated cell death. FasL expression by extralymphatic tissues is thought to maintain a status of immunity. Accordingly, it has been proposed that tumor cells express FasL as a mechanism of immunologic escape. However, data regarding FasL expression in normal or neoplastic tissues remain controversial. In the present study, we investigated the expression of FasL in normal peripheral blood B lymphocytes or malignant cells of the B-lymphocyte lineage to elucidate a possible immunologic counterattack mechanism. FasL gene expression was analyzed by reverse transcriptase polymerase chain reaction in two non-Hodgkin's lymphoma (NHL) entities: the highly aggressive Burkitt's lymphoma (BL) and indolent NHL chronic lymphocytic leukemia (CLL). FasL expression was found to be consistently negative in all BL cell lines and purified samples from patients with CLL. FasL is not constitutively expressed in normal peripheral blood or neoplastic B lymphocytes making the Fas counterattack, as described for gastrointestinal cancer, unlikely as a mechanism of immunologic escape of lymphoma cells.
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PMID:Fas ligand is not constitutively expressed in low-grade B-cell lymphoma and B-lymphoblastoid cells. 1293 Mar 19

It is well known that lymphocytes play a major role in coronary plaque destabilization in acute coronary syndromes. The aim of this study was to evaluate circulating lymphocyte apoptosis in patients with non-ST elevation myocardial infarction (NSTEMI) in comparison with subjects with stable angina and with healthy controls. We considered spontaneous lymphomonocyte apoptosis (evaluated by ELISA), interleukin (IL)-2 production (evaluated by ELISA), Fas expression on T cells (evaluated by flow cytometry) and Fas ligand mRNA (evaluated by reverse transcriptase polymerase chain reaction), as well as Fas functionality. To evaluate T-cell activation, we also investigated T-cell subpopulations (CD4/CD8 ratio), T-cell surface HLA-DR and CD69 expression (evaluated by flow cytometry) in blood taken within 6 hours from onset of NSTEMI. Spontaneous apoptosis was significantly increased in NSTEMI patients in comparison with the two control groups and it was associated with an increased expression of Fas, an increased susceptibility to the Fas agonist (CH-11) and a normal production of IL-2 in cell cultures. We also found a significant increase of HLA-DR+ CD3+ and CD69+ CD4+ cells in NSTEMI patients. These data suggest that the enhanced apoptosis is due to a mechanism of "active" antigen-driven death, induced by the expression of death cytokines and not by the failure of cell growth factors. We conclude that in case of NSTEMI peripheral lymphocytes are activated and undergo an enhanced programmed cell death due to activation mechanisms. It is likely that lymphocyte activation occurs before the onset of acute ischemia and contributes to the plaque rupture and to the myocardial ischemic insult.
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PMID:[Lymphocyte apoptosis in non-ST segment elevation acute myocardial infarction ]. 1462 21

The aim of the present study was to investigate the prevalence of c-FLIP [cellular FLICE-inhibitory protein, where FLICE is Fas-associated death domain (FADD)-like interleukin-1beta-converting enzyme] expression in gastric adenocarcinoma and its possible implications for the progression of the cancer. Expression of c-FLIP in 48 gastric adenocarcinomas and their normal counterparts was analysed by reverse transcriptase PCR, Western blotting and immunohistochemistry. In situ cell apoptosis was detected by TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) assay. As a result, c-FLIP transcripts were constitutively expressed in gastric adenocarcinomas and their levels were significantly higher than those in matched normal tissues ( P < 0.01). Immunohistochemically, the c-FLIP protein was also found to be expressed in all gastric adenocarcinomas (48/48), and 68.8% (33/48) showed an intense immunostaining; in contrast, only 75% (36/48) of normal gastric mucosa showed positive staining and none of them immunostained intensely. The abundance of c-FLIP protein was significantly higher in carcinoma than in normal gastric mucosa (6.93 +/- 0.58 versus 3.19 +/- 0.26, P < 0.01) and showed a reverse correlation with apoptotic index in adenocarcinoma, but not in normal mucosa. In addition, abundance of c-FLIP was significantly associated with lymph node metastasis at both mRNA level ( P < 0.05) and protein level ( P < 0.01). Western-blot analysis showed that the expression levels of the long form of c-FLIP and the short form of c-FLIP in adenocarcinomas were 2.6-fold and 2.8-fold ( P < 0.01) higher than those in normal tissues respectively. However, no significant difference was found between the expression levels of the two isoforms in both adenocarcinomas or normal tissues. In conclusion, overexpression of c-FLIP is tumour specific, which may be one of the in vivo mechanisms by which tumour cells escape from apoptotic death during the malignant transformation, and plays an important role in lymph node metastasis of gastric adenocarcinoma, which ultimately contributes to the tumour progression.
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PMID:Overexpression of cellular FLICE-inhibitory protein (FLIP) in gastric adenocarcinoma. 1463 56

A convincing body of evidence indicates that estrogen has significant immunomodulatory properties, including induction of thymic involution. However, it is unclear whether or not estrogen induces thymic involution by triggering apoptosis depended on Fas-FasL interactions. In the present study, estradiol-17beta (E(2)) was used to treat rats by gavages at 10, 1, 0.1, 0.01, and 0 ng/kg/day, respectively. Atrophy of thymus was determined by in situ morphological examination. Apoptotic cells were identified by terminal deoxynucleotide transferase-mediated deoxy-UTP nick end labeling (TUNEL) assay. A semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) method was used to analyze Fas and FasL mRNA levels. The results showed that E(2) induced thymic atrophy, increased the rates of apoptotic death, and enhanced the Fas/FasL mRNA levels. These findings suggested that Fas/FasL-mediated apoptosis involved in the induction of thymic atrophy by E(2).
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PMID:Thymic atrophy via estrogen-induced apoptosis is related to Fas/FasL pathway. 1499 13


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