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:4.6.1.2 (guanylate cyclase)
8,497 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously reported that a crude aqueous extract of the bitter melon (Momordica charantia) has both cytostatic and cytotoxic activities, and is a competitive inhibitor of guanylate cyclase activity. This crude preparation kills human leukemic lymphocytes in a dose-dependent manner while not affecting the viability of normal human lymphocytes at these same doses. In this report we describe the purification and characterization of one of these cytostatic factors which also exhibits anti-viral activity. The partially purified factor was both cytostatic to BHK-21 cells and inhibitory to VSV plaque formation in a dose-dependent manner. This preparation was inhibitory to both viral and host cell RNA and protein synthesis as early as 30 min after addition to these samples. As determined by gel filtration and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), this purified factor is a single component with a molecular weight corresponding to 40,000 daltons. The factor is sensitive to boiling and to pre-treatments with trypsin, but not ribonuclease (RNAse), or deoxyribonuclease (DNAse). As determined by radioactive precursor uptake and incorporation studies, the purified factor inhibits both RNA and protein synthesis in intact tissue culture cells and inhibits protein synthesis in a cell-free wheat germ system. DNA synthesis was slightly stimulated. The purified factor is cytostatic for both BHK-21 and for the IM9 leukemic cell lines for at least 120 h. The cytostatic component had no effect on cellular cyclic GMP metabolism.
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PMID:Purification and characterization of a cytostatic factor with anti-viral activity from the bitter melon. 619 72

Cyclic GMP and activators (acetylcholine, E. coli heat-stable toxin) of guanylate cyclase were capable of completely replacing the helper cell or interleukin 2 requirement for gamma-interferon (IFN gamma) production by Lyt-1-,2+ cells from C57BL/6 mouse spleen cells. The cyclic GMP help was independent of DNA synthesis or proliferation in the IFN gamma-producing cells, because cyclic GMP reversed mitomycin C blockage of IFN gamma production but did not reverse the inhibition of DNA synthesis. Thus, the findings presented here are unrelated to the question of the second messenger role of cyclic GMP in the activation of lymphocytes for DNA synthesis and cellular proliferation. The cyclic GMP help for IFN gamma production was antagonized by cyclic AMP and inducers (isoproterenol) of adenylate cyclase.
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PMID:Cyclic GMP as the second messenger in helper cell requirement for gamma-interferon production. 629 93

Leukotrienes B4, C4, and D4 were capable of replacing the helper cell or interleukin 2 requirement for gamma-interferon (IFN gamma) production by Lyt-1-,2+ cells from C57BL/6 mouse spleen cells at leukotriene concentrations as low as 0.002 microM. An antioxidant inhibitor (butylated hydroxyanisole) of lipoxygenase metabolism of arachidonic acid suppressed IFN gamma production. The suppression was significantly reversed by leukotriene C4, which further suggests that leukotrienes and possibly other substances produced by the lipoxygenase pathway of arachidonic acid metabolism play an important role in the regulation of IFN gamma production. All of these events may be related to activation of guanylate cyclase activity, since cyclic GMP also significantly reversed the suppressor effects of butylated hydroxyanisole in IFN gamma production. The leukotriene help for IFN gamma production was independent of DNA synthesis or cellular proliferation. The data are consistent with the hypothesis that lipxoygenase products of arachidonic acid metabolism may play a role in the mediation of interleukin 2 help in IFN gamma production. Cells that are rich sources of leukotrienes, then, should play important roles in positive regulation of lymphokine production.
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PMID:Leukotrienes: positive signals for regulation of gamma-interferon production. 631 47

Ammonium sulfate-precipitated supernatants of classical enteropathogenic Escherichia coli strains were negative when investigated for enterotoxin production in rabbit ligated ileal loops, rabbit skin vascular permeability factor tests, suckling mice, and Y-1 adrenal cells. They also failed to stimulate guanylate cyclase activity in homogenates of rabbit, rat, and infant mouse intestines. Furthermore, DNA from enteropathogenic E. coli lacked sequences that encode heat-labile and heat-stable enterotoxins. These studies fail to show conventional enterotoxin synthesis by classical enteropathogenic E. coli.
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PMID:Failure to detect conventional enterotoxins in classical enteropathogenic (serotyped) Escherichia coli strains of proven pathogenicity. 675 24

Nitric oxide (NO) activates the soluble isoform of guanylate cyclase in platelets and inhibits platelet function. Several studies suggest the existence of a pathway for NO synthesis in platelets as a form of feedback inhibition, but the identity of the NO synthase (NOS) isoform present within platelets is unknown. We isolated human platelets, and synthesized cDNA from platelet RNA for analysis by PCR. Primers for human neuronal or inducible NOS failed to yield a PCR signal. However, primers specific for endothelial NOS (ecNOS) amplified a DNA band of the expected size. Analysis of nucleotide sequence revealed that the amplified DNA is ecNOS. NOS enzyme activity was detected in the platelet particulate subcellular fraction, as previously demonstrated for ecNOS in other cells. Thus, ecNOS is present in human platelets, and may play a role in the regulation of platelet function by an endogenous NO pathway.
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PMID:Expression of constitutive endothelial nitric oxide synthase in human blood platelets. 747 56

The present study was aimed to test the role of endothelin-1 (ET-1) as a possible autocrine/paracrine growth factor for cardiac fibroblasts, and to examine its interaction with cardiac natriuretic hormones. Expression of preproET-1 (ppET-1) mRNA by cultured cardiac fibroblasts from neonatal rats was demonstrated by Northern blot analysis using cDNA for rat ppET-1 as a probe. Angiotensin II (ANG II) and ET-1 transiently (30 min) increased steady-state ppET-1 mRNA levels in cardiac fibroblasts. Both ET-1 and ANG II significantly stimulated [3H] thymidine incorporation into cardiac fibroblasts, whose effects were dose-dependently inhibited by an ETA receptor antagonist (BQ123), BQ123 also inhibited both ET-1- and ANG II-induced ppET-1 mRNA expression. Both atrial and brain natriuretic peptides (ANP, BNP), which activate particulate guanylate cyclase, inhibited ppET-1 mRNA expression and [3H]thymidine incorporation stimulated by ANG II and ET-1. Sodium nitroprusside, a soluble guanylate cyclase activator, and 8-bromocyclic GMP, a membrane-permeable cGMP derivative, similarly inhibited ppET-1 mRNA expression and [3H]-thymidine incorporation. BNP was more potent than ANP to inhibit ANG II- and ET-1-stimulated DNA synthesis, whereas BNP and ANP were almost equipotent in stimulating cGMP generation in cardiac fibroblasts. Our data demonstrated that ANG II and ET-1 upregulate ET-1 gene expression in rat cardiac fibroblasts partly via cyclic GMP-dependent mechanism, and that natriuretic peptides inhibit ANG II-stimulated proliferation of cardiac fibroblasts, possibly by inhibiting ET-1 gene expression. Our data suggest the possible role of endogenous ET-1 as an autocrine/paracrine growth factor for cardiac fibroblasts and its close interaction with natriuretic peptides in the regulation of cardiac fibrosis.
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PMID:Natriuretic peptides inhibit angiotensin II-induced proliferation of rat cardiac fibroblasts by blocking endothelin-1 gene expression. 763 42

Endothelium-derived nitric oxide (NO) relaxes fetal pulmonary arterial vessels through activation of guanylate cyclase and increasing smooth muscle cyclic guanosine 3', 5'-monophosphate (cGMP). Exogenous NO administered as a gas at low concentrations shares this effect, decreasing pulmonary artery resistance and increasing in pulmonary blood flow. NO, endogenously synthesized or inhaled as a gas, may affect cellular growth in the underlying pulmonary vascular smooth muscle media. We report the effects of NO and cGMP upon DNA synthesis and proliferation of passaged pulmonary vascular smooth muscle cells from fetal rats. Smooth muscle cells from rat fetal pulmonary artery (RFPASM; 18-19 day gestation; term 21 days) were treated in culture with sodium nitroprusside (SNP), isosorbide dinitrite (ISDN)--both NO-generating vasodilators--or 8-bromo-cGMP, a cell-permeant cGMP analog. All agents inhibited thymidine uptake at concentrations of 10(-3)-10(-2) M. Lower concentrations (10(-5)-10(-4) M) of SNP and ISDN increased [3H]-thymidine ([3H]TdR) uptake, an effect not seen with cGMP at similar concentrations. Exposing RFPASM to authentic NO gas in a deoxygenated medium inhibited [3H]TdR uptake only. NO appears to have a biphasic effect on DNA synthesis in passaged RFPASM, with stimulation at micromolar concentrations and inhibition at higher levels. NO may thus alter vascular smooth muscle growth and pulmonary vascular remodeling in conditions complicated by pulmonary hypertension and treated with inhaled NO.
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PMID:The effect of nitric oxide on fetal pulmonary artery smooth muscle growth. 764 91

The effects of methylene blue, an inhibitor of the activation of the soluble guanylyl cyclase by nitric oxide (NO), were studied on blood pressure (BP) and on hyporesponsiveness to norepinephrine (NE) induced by Escherichia coli lipopolysaccharide (LPS) in pentobarbital-anesthetized rats. Methylene blue intravenous (i.v.) injection (3 mg/kg) produced a transient increase in BP which, in LPS-treated rats, was followed by a more sustained increase in BP. Methylene blue restored the reactivity to NE in LPS-treated rats but did not change either BP or reactivity to NE in saline-infused control rats. Cyclic GMP level was significantly increased in small femoral resistance arteries removed from LPS-treated rats as compared with controls (125.2 +/- 19.5 and 83.5 +/- 18.8 fmol/mg DNA, respectively, n = 8). In rats receiving methylene blue, there was no significant difference in cyclic GMP content of the arteries of LPS-treated rats as compared with controls (59.4 +/- 8.1 and 78.5 +/- 6.1 fmol/mg DNA, respectively, n = 8). These results support the involvement of increased stimulation of arterial guanylyl cyclase in hyporeactivity to NE elicited by LPS. They show that in vivo administration of methylene blue is able to restore both vascular cyclic GMP level and pressor responses to NE to control levels in LPS-treated rats.
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PMID:Effects of methylene blue on blood pressure and reactivity to norepinephrine in endotoxemic rats. 768 18

When cellular stimulants such as neurotransmitters, hormones, autacoids, cytokines and growth factors stimulate their respective specific receptors in the plasma membranes of cells, a variety of responses are elicited. GTP-binding proteins are also involved in the reactions between receptors and cellular effectors. Stimulation of receptors are subsequently coupled to the activation of ion channels, turnover of inositol phospholipid metabolism, adenylate cyclase and guanylate cyclase, inhibition of adenylate cyclase and potentiation of all proliferation. Active substances such as the so-called second messengers are produced in the cells. In this article, two findings are described: 1) Ca2+, which increases by stimulation of receptors with neurotransmitters and hormones, stimulated Ca2+/calmodulin-dependent protein kinase II in cell systems such as NG108-15 neuroblastoma x glioma hybrid cells and primarily cultured neuronal cells of rat hippocampus. 2) Coupling preferences and possible transduction mechanisms from experiments on NG108-15 cells and NL308 neuroblastoma x fibroblast hybrid cells which have been stably transfected with DNA for m1, m2, m3 and m4 muscarinic acetylcholine receptors were examined. These results may provide a useful research model for examining and evaluating the effects and mechanisms of the drugs on a living system and may help develop useful methodology for the discovery of innovative drugs.
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PMID:[Cellular reactions after stimulation of receptors: research model for evaluation of effects and action mechanisms of drugs for discovery of innovative drugs]. 769 94

An indazole derivative, YC-1, was identified in this study to be capable of reversibly and effectively inhibiting proliferation of rat A10 vascular smooth-muscle cells (VSMCs) in vitro. YC-1 (1-100 microM) dose-dependently inhibited [3H]thymidine incorporation into DNA in rat A10 VSMCs that were synchronized by serum depletion and then restimulated by addition of 10% foetal calf serum (FCS), whereas FCS-induced [3H]thymidine incorporation into rat synchronized endothelial cells was unaffected by this agent. The dose of YC-1 required to cause inhibition of FCS-induced proliferation was similar to that necessary for the formation of cellular cyclic GMP (cGMP). Guanylate cyclase activity in soluble fractions of VSMCs was activated by YC-1 (1-100 microM), whereas cGMP-specific phosphodiesterase activity was unaffected by this compound. The anti-proliferative effect of YC-1 was mimicked by 8-bromo-cGMP, a membrane-permeable cGMP analogue, and was antagonized by KT 5823 (0.2 microM), a selective inhibitor of protein kinase G. The anti-proliferative effect of YC-1 was also antagonized by Methylene Blue (50 microM), a guanylate cyclase inhibitor, and was potentiated by 3-isobutyl-1-methylxanthine (500 microM), a phosphodiesterase inhibitor. These results verified that YC-1 is a direct soluble guanylate cyclase activator in A10 VSMCs, and the anti-proliferative effect of YC-1 is mediated by cGMP. YC-1 still inhibited FCS-induced DNA synthesis even when added 10-18 h after restimulation of the serum-deprived A10 VSMCs with 10% FCS. Flow cytometry in synchronized populations revealed an acute blockage of FCS-inducible cell-cycle progression at a point in the G1/S-phase in YC-1 (100 microM)-treated cells. The inhibition of proliferation by YC-1 was demonstrated to be independent of cell damage, as documented by several criteria of cell viability. In conclusion, YC-1 reversibly and effectively inhibited the proliferation of VSMCs, suggesting that it has potential as a therapeutic agent in the prevention of vascular diseases.
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PMID:Mechanism of anti-proliferation caused by YC-1, an indazole derivative, in cultured rat A10 vascular smooth-muscle cells. 984 40


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