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:3.1.27.1 (RNase)
16,360 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dihydropyridine-sensitive voltage-gated (l-type) Ca2+ channels play an essential role in cardiac and smooth muscle excitation-contraction coupling. Transcripts for the two pore-forming subunits of l-type Ca2+ channels, alpha 1C and alpha 1D have been detected in heart and lung; however, distribution, structure and regulated expression of these channel subunit mRNAs have not been examined in detail. Here we use RNase protection and RT-PCR assays to identify cardiac-specific features of expression of the two channel mRNAs. First, expression of alpha 1D mRNA is found in lung, aorta and atrium, but is not detected in ventricle. Limited expression of alpha 1D mRNA is also seen in enriched preparations of cardiac myocytes: it is significant in atrial myocytes, but not in ventricular myocytes. Second, RT-PCR analyses indicate that atrial alpha 1D channels exclusively contains the 15-amino acid insertion between third and fourth segments in repeat IV. Finally, expression of alpha 1C mRNA, but not alpha 1D mRNA, is up-regulated by glucocorticoids in atrium and ventricle: adrenalectomy and subsequent injection of the glucocorticoid agonist dexamethasone decreased and increased the channel message, respectively. Dexamethasone also significantly increased the number of dihydropyridine-binding sites in ventricle. In contrast, alpha 1C mRNA levels were glucocorticoid-insensitive in lung and aorta. Thus, basal and glucocorticoid-induced expression, and splicing of the two l-type Ca2+ channel alpha 1 subunit transcripts are tissue specifically controlled in atria and ventricles of rat heart.
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PMID:Distribution, splicing and glucocorticoid-induced expression of cardiac alpha 1C and alpha 1D voltage-gated Ca2+ channel mRNAs. 940 78

Dexamethasone (DEX) increases the expression of neurotrophin-3 (NT-3) in normal rat hippocampal neurons, whereas transient forebrain ischemia reduces the NT-3 mRNA level. The effect of DEX on the expression of NT-3 mRNA in injured brain cells after ischemia has not been investigated, however. Using in situ hybridization and ribonuclease protection assay methods, we studied NT-3 mRNA expression in rats with and without DEX administration after transient forebrain ischemia. Without DEX treatment, NT-3 mRNA was down-regulated in the hippocampal neurons at 2, 4, 12 h and returned to basal levels 24 h following ischemia. With DEX treatment, however, NT-3 mRNA showed no change at 2, 4 and 12 h and increased 24 h after ischemia. The results indicate that DEX inhibits ischemia-induced NT-3 mRNA down-regulation during the first 12 h and up-regulates NT-3 mRNA 24 h after ischemia. DEX administration might be effective in influencing some of the pathophysiological effects of ischemia in the hippocampus.
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PMID:Dexamethasone inhibits ischemia-induced transient reduction of neurotrophin-3 mRNA in rat hippocampal neurons. 985 2

T cell activation is enhanced by the costimulatory interaction of B7 on antigen-presenting cells and CD28 on T cells, resulting in long-term T cell proliferation, differentiation and production of large amounts of cytokines, such as interleukin (IL)-2. CTLA-4 is a co-stimulation receptor that shares 31% homology with CD28 and binds B7 family members with higher affinity. CTLA-4 is transiently expressed intracellularly and on the cell surface following activation of T cells. We have studied the kinetics of CTLA-4 expression and the effects of dexamethasone on CTLA-4 expression during T cell activation in cultures of mouse spleen cells stimulated by a mixture of immobilized anti-CD3 and anti-CD28 monoclonal antibodies (anti-CD3/CD28 mAb) or concanavalin A (ConA). CTLA-4 expression peaked on day 2 and returned to background levels after 7 days. Dexamethasone was found to potentiate CTLA-4 expression in a dose-dependent manner with an EC50 effective concentration 50%) of about 10(-8) M. In contrast, other immunosuppressive agents, such as rapamycin or cyclosporin A had no or an inhibitory effect on CTLA-4 expression, respectively. Dexamethasone also stimulated CD28 expression, but inhibited IL-2R expression during anti-CD3/CD28 mAb-induced mouse splenic T cell activation. Western blot analyses of lysates of activated mouse T cells showed that dexamethasone increased CTLA-4 protein levels twofold during anti-CD3/CD28 mAb-induced activation. Dexamethasone also enhanced CTLA-4 messenger RNA twofold as quantified by ribonuclease protection assay. The effects of dexamethasone on CTLA-4 expression were glucocorticoid-specific and completely inhibited by the glucocorticoid receptor antagonist mifepristone (RU486), indicating that the effect of dexamethasone on CTLA-4 expression is mediated through the glucocorticoid receptor. In conclusion, the immunosuppressive agent dexamethasone actually stimulates CTLA-4 expression, which is involved in downregulation of T cell activation.
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PMID:Dexamethasone enhances CTLA-4 expression during T cell activation. 1052 80

The effect of dexamethasone on angiotensin-converting enzyme (ACE) in primary culture of adult cardiac fibroblasts was analyzed in this study. ACE is central to cardiac remodeling in conditions such as myocardial infarction (MI). Some studies indicate that glucocorticoids are often increased post-MI, whereas other studies suggest that glucocorticoids stimulate ACE activity in various cell types. Most cardiac cells are fibroblasts, which have an important function in cardiac remodeling. Therefore, we studied the effects of glucocorticoids on ACE activity and mRNA levels in primary cultures of adult rat cardiac fibroblasts. Steady-state ACE activity was very low, but it increased sixfold with dexamethasone (1 microM for 48 h) treatment. ACE activation occurred within 12 h and peaked at 96 h, after treatment. RNase-protection assays revealed an associated threefold increase (P < 0.05) in ACE mRNA. Dexamethasone's stimulatory effect was abolished by an RNA synthesis inhibitor (actinomycin D, 5 microg/ml) but was potentiated by a protein synthesis inhibitor (cycloheximide, 5 microg/ml). The glucocorticoid-mediated response appears to be specific, because mineralocorticoid treatment did not alter ACE activity. These findings indicate that both transcriptional and posttranscriptional mechanisms are involved in glucocorticoid regulation of ACE expression in rat cardiac fibroblasts.
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PMID:Glucocorticoid regulation of angiotensin-converting enzyme in primary culture of adult cardiac fibroblasts. 1112 30

Monocrotaline-induced pulmonary hypertension (PH) in rats is preceded by an inflammatory response in the lungs, and interleukin-6 (IL-6) is expressed in response to inflammation. To evaluate the role of IL-6 in monocrotaline-induced PH, rats received a single subcutaneous injection of monocrotaline (60 mg/kg) or an equivalent amount of normal saline. Pulmonary artery pressure (Ppa), right ventricular hypertrophy (RVH), expression of IL-6 mRNA, and bioactivity of IL-6 in the lungs of these rats were examined 48 hours and 1 and 2 weeks after administration of monocrotaline. The effects of dexamethasone treatment on monocrotaline-induced PH also were evaluated. Two weeks after administration of monocrotaline, significant PH and RVH developed in these rats. Reverse transcription-polymerase chain reaction (RT-PCR) revealed expression of IL-6 mRNA in the lungs 48 hours and 1 and 2 weeks after administration of monocrotaline. This was confirmed using ribonuclease protection assay. The bioactivity of IL-6 in lung extracts progressively increased. Dexamethasone markedly inhibited expression of IL-6 mRNA and IL-6 bioactivity in the lungs, with concomitant attenuation of monocrotaline-induced PH and RVH. Our data show that monocrotaline induces expression of IL-6 mRNA in rat lungs and that inhibition of IL-6 results in attenuation of PH. These findings indicate that IL-6 may play a role in the pathogenesis of PH.
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PMID:Monocrotaline induces interleukin-6 mRNA expression in rat lungs. 1172 Jun 14

Although CYP2C8, CYP2C9, and CYP2C19 play an important role in drug biotransformation, factors influencing the expression and activity of these CYP2C P450s in human liver remain largely undefined. We used primary cultures of human hepatocytes from 15 subjects to assess the inducibility of CYP2C enzyme expression by prototypical inducer agents, including rifampicin, dexamethasone, and phenobarbital. After culture for 72 h in serum-free medium on collagen, Western blotting revealed that CYP2C9 was the only CYP2C enzyme expressed at appreciable levels in untreated hepatocytes. Subsequent treatment with 25 microMrifampicin for 48 h elicited marked increases in CYP2C8 (700 +/- 761%), CYP2C19 (854%), and CYP2C9 (209 +/- 176%) protein content versus a 550 +/- 170% enhancement of CYP3A4 enzyme levels. Parallel increases in CYP2C mRNAs, measured by Northern blotting and/or RNase protection, were found in rifampicin-treated hepatocytes, with CYP2C8, CYP2C9, and CYP2C19 transcripts exhibiting increases of 688 +/- 635, 207 +/- 49, and 230 +/- 60%, respectively, versus an 8.8-fold enhancement of CYP3A4 mRNA levels. Dexamethasone (10 microM) treatment enhanced CYP2C8 mRNA (360 +/- 100%) and protein (274%) content, although this steroid had less effect on CYP2C9 and CYP2C19 transcripts (23 +/- 21% and 21 +/- 36%, respectively) and enzyme levels (55 and 143%, respectively). Phenobarbital (100 microM) was a powerful inducer of CYP2C9 (850%) and CYP2C19 (735%) mRNA content, and also increased CYP2C8 (610%) and CYP3A4 (205%) transcripts. Our results show that CYP2C enzyme expression in human hepatocytes is highly inducible by rifampicin, dexamethasone, and phenobarbital. Because these xenobiotics are ligands and/or activators of the pregnane X receptor and/or constitutive androstane receptor, such orphan nuclear receptors and their response elements may partake in regulating CYP2C gene expression in humans.
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PMID:Expression and induction of CYP2C P450 enzymes in primary cultures of human hepatocytes. 1213 Jul 4

Data suggest that mineralocorticoid selectivity is differentially regulated in epithelial target tissues. We investigated whether the level of dietary NaCl intake influenced the expression and tissue distribution of 11-beta-hydroxysteroid dehydrogenase type 2 (11betaHSD-2), aldosterone receptor (MR), and glucocorticoid receptor (GR) in rat colon, kidney, and cardiovascular tissue. Rats were fed a diet with 0.01 or 3% NaCl for 10 days. Messenger RNAs were analyzed with ribonuclease protection assay, 11betaHSD-2 protein by Western blot analysis, and localization of GR and 11betaHSD-2 by immunohistochemistry. NaCl restriction elevated plasma renin and aldosterone concentration, whereas corticosterone was unaltered. In distal colon, 11betaHSD-2 mRNA and protein were augmented significantly by low-NaCl intake and immunolabeling was widely distributed in crypt and surface epithelium. The MR mRNA level was decreased, whereas GR mRNA was unaltered in distal colon. MR, GR, and 11betaHSD-2 mRNAs were not changed in kidney cortex and medulla, left cardiac ventricle, and aorta. Immunofluorescence labeling showed that GR and 11betaHSD-2 localization was mutually exclusive in kidney. In colon epithelium, nuclear staining for GR subsided as perinuclear 11betaHSD-2 immunoreactivity increased with NaCl restriction. As a functional correlate of increased 11betaHSD-2 expression in colon, the GR-stimulated sodium-hydrogen exchanger NHE-3 was lowered by NaCl restriction. Inhibition of 11betaHSD-2 activity by carbenoxolone during NaCl restriction stimulated NHE-3 expression in colon. Dexamethasone stimulated NHE-3 both in colon and kidney. These data indicate that mineralocorticoid selectivity is physiologically regulated by NaCl intake at the level of 11betaHSD-2 expression and tissue distribution in the distal colon, but not in the kidney.
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PMID:Stimulation of 11-beta-hydroxysteroid dehydrogenase type 2 in rat colon but not in kidney by low dietary NaCl intake. 1284 61

The host response during resolution of Pneumocystis murina infection following withdrawal of Dexamethasone (Dex) induced immunosuppression was analyzed. Mice were inoculated with P. murina and treated with Dex for 4 weeks. Treatment was stopped and mice were sacrificed at d1, d7, and d14. Control mice were treated in the same manner, but were inoculated with nonviable P. murina. P. murina was actively cleared from the lungs following withdrawal of Dex treatment. No P. murina was detected in control mice. Significantly more neutrophils, lymphocytes, macrophages, and eosinophils were recovered from the lungs of mice that had been infected with P. murina than from control mice at d7, but only neutrophils remained significantly elevated at d14. Significantly more CD4+ and CD8+ T cells were purified from the lungs of mice that had been infected with P. murina mice at d7 and d14. Cytokine levels were measured in lung lavage fluid by ELISA. TNF-alpha, IFN-gamma, IL-1, and IL-6 levels were higher in mice that had been inoculated with P. murina at all three time points. TNF-alpha and IL-1 levels did not change significantly following withdrawal of Dex treatment. Low levels of IL 6 were detected at d1, but increased significantly by d7 and d14. IFN-gamma levels peaked at d14. Chemokine message levels were measured in lung tissue by ribonuclease protection assay. MIP-1beta and IP-10 message increased between d1 and d7 and then decreased by d14. RANTES message levels increased from d1 to d7 and remained elevated at d14. Withdrawal of Dex induced immunosuppression from P. murina infected mice resulted in activation of many arms of the host response that lead to resolution of the infection.
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PMID:Resolution of Pneumocystis murina infection following withdrawal of corticosteroid induced immunosuppression. 1632 97


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