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:2.7.7.48 (transcriptase)
9,479 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, nitric oxide (NO) has been shown to suppress dengue virus (DENV) RNA and protein accumulation in infected cells. In this report, the potential target of the inhibitory effect of NO was studied at the molecular level. The NO donor, S-nitroso-N-acetylpenicillamine (SNAP), showed an inhibitory effect on RNA accumulation at around 8-14 h post-infection, which corresponded to the step of viral RNA synthesis in the DENV life cycle. The activity of the viral replicase isolated from SNAP-treated DENV-2-infected cells was suppressed significantly compared with that of the negative-control N-acetyl-DL-penicillamine (NAP)-treated cells. Further investigations on the molecular target of NO action showed that the activity of recombinant DENV-2 NS5 in negative-strand RNA synthesis was affected in the presence of 5 mM SNAP in in vitro RNA-dependent RNA polymerase (RdRp) assays, whereas the RNA helicase activity of DENV-2 NS3 was not inhibited up to a concentration of 15 mM SNAP. These results suggest that the inhibitory effect of NO on DENV infection is partly via inhibition of the RdRp activity, which then downregulates viral RNA synthesis.
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PMID:Antiviral action of nitric oxide on dengue virus type 2 replication. 1696 59

We have previously shown that the endocannabinoid anandamide and its metabolically stable analog (R)-methanandamide produce vasorelaxation in rabbit aortic ring preparations in an endothelium-dependent manner that could not be mimicked by other CB(1) cannabinoid receptor agonists (Am J Physiol 282: H2046-H2054, 2002). Here, we show that (R)-methanandamide and abnormal cannabidiol stimulated nitric oxide (NO) production in rabbit aortic endothelial cells (RAEC) in a dose-dependent manner but that other CB(1) and CB(2) receptor agonists, such as cis-3R-[2-hydroxy-4-(1,1-dimethylheptyl)phenyl]-trans-4R-3(3-hydroxypropyl)-1R-cyclohexanol (CP55940) and (R)-(+)-[2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-[1,2,3-d,e]-1,4-benzoxazin-6-yl]-1-naphthalenyl-methanone (WIN55212-2), failed to do so. CB(1) antagonists rimonabant [also known as SR141716; N-piperidin-1-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide] and 6-methoxy-2-(4-methoxyphenyl)benzo[b]-thien-3-yl][4-cyanophenyl]methanone (LY320135) and CB(2) antagonist N-[(1S)-endo-1,3,3,-trimethylbicyclo[2.2.1]heptan-2-yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-pyrazole-3-carboxamide (SR144528) failed to block (R)-methanandamide-mediated NO production in RAEC. However, anandamide receptor antagonist (-)-4-(3-3,4-trans-p-menthadien-(1,8)-yl)-orcinol (O-1918) blocked (R)-methanandamide-mediated NO production in RAEC. Reverse transcriptase-polymerase chain reaction and Western blot analyses failed to detect the CB(1) receptor in RAEC, making this a good model to study non-CB(1) responses to anandamide. (R)-Methanandamide produced endothelial nitric-oxide synthase (eNOS) phosphorylation via the activation of phosphoinositide 3-kinase-Akt signaling. Inhibition of G(i) signaling with pertussis toxin, or phosphatidylinositol 3-kinase activity with 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), resulted in a decrease in (R)-methanandamide-induced Akt phosphorylation and NO production. Results from this study suggest that in RAEC, (R)-methanandamide acts on a novel non-CB(1) and non-CB(2) anandamide receptor and signals through G(i) and phosphatidylinositol 3-kinase, leading to Akt activation, eNOS phosphorylation, and NO production.
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PMID:Anandamide-mediated CB1/CB2 cannabinoid receptor--independent nitric oxide production in rabbit aortic endothelial cells. 1737 72

Ginseng has beneficial effects on the cardiovascular system, but its underlying mechanism is unclear. This study investigated the effects of ginsenoside Rb1, a major constituent of ginseng, on the changes of lactate dehydrogenase (LDH) activity, nitric oxide (NO), tissue-type plasminogen activator (t-PA), and plasminogen activator inhibitor-1 (PAI-1) in oxidized low-density lipoprotein (oxLDL)-injuring endothelial cells. Human umbilical vein endothelial cells were cultured and divided into 6 groups (n = 6): control group, oxLDL alone group (100 mg/L), ginsenoside Rb1 alone group (10 microg/mL), oxLDL plus ginsenoside Rb1 groups (0.1, 1.0, and 10 microg/mL, respectively.). Twenty-four hours after treatment, LDH activity and concentrations of NO, t-PA, and PAI-1 in culture medium were measured while the expressions of endothelial nitric oxide synthase (eNOS), t-PA, and PAI-1 mRNA in endothelial cells were detected by reverse-transcriptase polymerase chain reaction. Compared with control group, oxLDL (100 mg/L) caused LDH activity, the expressions of eNOS and t-PA mRNA, and concentrations of NO and t-PA to significantly decrease (P < 0.05, respectively), and it also led to dramatic increase of PAI-1 mRNA and concentration (P < 0.05, respectively). Ginsenoside Rb1 alone did not demonstrate this ability. High-dose Rb1 (10 microg/mL) could block the effects of oxLDL on LDH activity, mRNA of eNOS, t-PA, and PAI-1, and concentrations of NO, t-PA, and PAI-1 (P < 0.05, respectively), and neither low-dose Rb1 (0.1 microg/mL) nor medium-dose Rb1 (1.0 microg/mL) demonstrated this ability. We conclude that ginsenoside Rb1 has protective effects on oxLDL-injuring human vascular endothelial cells and can reverse the effects of oxLDL on NO, t-PA, and PAI-1.
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PMID:Protective effects of ginsenoside Rb1 on human umbilical vein endothelial cells in vitro. 1787 61

The present study was designed to determine whether N-acetylcysteine (NAC), a potent antioxidant, modulates nitric oxide (NO) production stimulated by lipopolysaccharide (LPS) and tumor necrosis factor-alpha (TNF-alpha) in adipocytes. Stimulation by the combination of 5 microg/ml of LPS and 100 ng/ml of TNF-alpha (LT) significantly enhanced NO production in 3T3-L1 adipocytes. Preincubation of the cells with NAC (5-20 mM) for 24 h suppressed the increased NO production in a dose-dependent manner. The production of NO was decreased by 49% at the concentration of 20 mM of NAC. The decrease in NO production by NAC was accompanied by a decrease in inducible nitric oxide synthase (iNOS) protein, detected by immunoblot analysis, and iNOS mRNA, determined by real-time reverse-transcriptase coupled polymerase chain reaction analysis. Nuclear factor-kappa B (NF-kappa B) was significantly activated by LT-treatment, while the pretreatment with 20 mM of NAC prevented the activity by 42%. Pyrrolidine dithiocarbamate (PDTC), a NF-kappaB inhibitor, also inhibited the LT-mediated NO production dose-dependently. One hundred microM of PDTC inhibited the NO production by 46%. We also investigated the effect of NAC and PDTC on the production of interleukein-6 (IL-6), which is regulated transcriptionally by NF-kappa B in 3T3-L1 adipocytes. IL-6 production was markedly increased by LT stimulus, and the enhanced secretion of IL-6 was suppressed in a dose-dependent manner by pretreatment with NAC or PDTC. These results suggest that NAC regulates iNOS expression and NO production in adipocytes through the modulating activation of NF-kappa B.
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PMID:N-acetylcysteine inhibits induction of nitric oxide synthase in 3T3-L1 adipocytes. 1817 Sep 62

Microglial cells are the prime effectors in immune and inflammatory responses of the central nervous system (CNS). During pathological conditions, the activation of these cells helps restore CNS homeostasis. However, chronic microglial activation endangers neuronal survival through the release of various proinflammatory molecules and neurotoxins. Thus, negative regulators of microglial activation have been considered as potential therapeutic candidates to target neurodegeneration, such as that in Alzheimer's and Parkinson's diseases. Shikonin, a naphthoquinone pigment from the root of Lithospermum erythrorhizon, has long been used as an ointment for wound healing in traditional oriental medicine. Shikonin has been reported to have antibacterial, antitumor, and anti-inflammatory effects. The aim of this study was to examine whether shikonin represses microglial activation. In a study of shikonin and five of its derivatives, isobutyrylshikonin (IBS) and isovalerylshikonin (IVS) were the most effective at inhibiting LPS-induced nitric oxide (NO) release from microglial cells. Reverse transcriptase real-time PCR analysis revealed that pretreatment of rat brain microglia with IBS and IVS attenuated the LPS-induced expression of mRNAs encoding inducible NO synthase, tumor necrosis factor (TNF)-alpha, interleukin-1beta, and cyclooxygenase-2. In rat brain microglia, IBS and IVS reduced the LPS-stimulated production of TNF-alpha and prostaglandin E2. In addition, IBS and IVS significantly decreased LPS-induced IkappaB-alpha phosphorylation and NF-kappaB DNA binding activity, as well as the phosphorylation of the ERK1/2 and Akt signaling proteins. In organotypic hippocampal slice cultures, propidium iodide staining revealed prominent cell death in the hippocampal layer after 72h of LPS treatment. Both IBS and IVS clearly blocked the effect of LPS on hippocampal cell death and inhibited LPS-induced NO production in culture medium. These results suggest that IBS and IVS provide neuroprotection by reducing the release of various proinflammatory molecules from activated microglia.
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PMID:Shikonins attenuate microglial inflammatory responses by inhibition of ERK, Akt, and NF-kappaB: neuroprotective implications. 1865 51

It is well known that the mitogen-activated protein kinase (MAPK) signal transduction pathways is involved in the regulation of inducible nitric oxide synthase (iNOS) in many cellular systems. However, sufficient information describing the role of MAPKs on iNOS expression in rat Schwann cells (SCs) is lacking. Therefore the paper was sought to investigate the role of MAPK cascades in iNOS expression following treatment of lipopolysaccharide (LPS) in a rat Schwann cell line RSC 96. Reverse transcriptase-PCR analysis (RT-PCR) and immunocytochemical staining were performed to detect iNOS expression following LPS induction. Next RT-PCR and Western blot analysis were employed to study expression of iNOS after using inhibitors selective for ERK (PD98059), JNK/SAPK (SP600125) and p38 (SB202190). The production of nitric oxide (NO) was measured by nitrate reductase method. LPS could significantly induce the expression of iNOS located in the cytoplasm in RSC 96 with a concentration- and time-dependent manner. Administration of inhibitors individually and combinations of the three inhibitors at micromolar concentrations suppressed the expression of iNOS and the production of NO. Based on these observations, it is proposed that LPS may activate the rat Schwann cell line RSC 96 to express iNOS and release NO via the MAPK signal transduction pathways.
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PMID:Role of mitogen-activated protein kinase cascades in inducible nitric oxide synthase expression by lipopolysaccharide in a rat Schwann cell line. 1866 65

Nitric oxide (NO) is a bioactive molecule involved in several growth and developmental processes in plants. These processes are mostly characterized by changes in primary and secondary metabolism. Here, the effect of NO on cellulose synthesis in tomato (Solanum lycopersicum) roots was studied. The phenotype of roots, cellulose content, the incorporation of 14C-glucose into cellulosic fraction and the expression of tomato cellulose synthase (CESA) transcripts in roots treated with the NO donor sodium nitroprusside (SNP) were analysed. Nitric oxide affected cellulose content in roots in a dose dependent manner. Low concentrations of SNP (pmoles of NO) increased cellulose content in roots while higher concentrations of SNP (nmoles of NO) had the opposite effect. This result correlated with assays of 14C-glucose incorporation into cellulose in roots. The effect of NO on 14C-glucose incorporation into cellulose was transient and reversible. Microscopic analysis of roots suggested that NO affected primary cell wall cellulose synthesis. Three tomato cellulose synthase (SICESA) transcripts were identified. Reverse transcriptase polymerase chain reaction experiments were carried out and indicated that SICESA1 and SICESA3 levels were affected by high NO concentrations. Together, these results support the hypothesis that variations in NO levels influence cellulose synthesis and content in roots.
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PMID:Nitric oxide: an active nitrogen molecule that modulates cellulose synthesis in tomato roots. 1863 43

The antiulcer effect of bisdemethoxycurcumin, a yellow pigment found mainly in rhizomes of Curcuma longa, was compared with curcumin in gastric ulcer model systems to validate its clinical application as a remedy for peptic ulcer. Western blot analysis of mouse macrophage cell line RAW 264.7 activated with lipopolysaccharide showed that bisdemethoxycurcumin inhibited inducible nitric oxide synthase (iNOS) production significantly but had no effect on tumor necrosis factor-alpha (TNF-alpha) production, whereas curcumin showed stronger suppression of iNOS protein production and inhibited TNF-alpha protein production significantly. However, bisdemethoxycurcumin and curcumin possessed similar potency in scavenging nitric oxide generated from mouse macrophage cell line RAW 264.7. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that both curcuminoids inhibited the induction of iNOS dose-dependently at the transcriptional level and curcumin also appeared to inhibit the induction of TNF-alpha at post-transcriptional level. In an animal model, intraduodenal administration of bisdemethoxycurcumin (5-80 mg/kg body wt.) showed a strong inhibitory effect on gastric acid secretion in pylorus-ligated rats whereas curcumin (5-20 mg/kg body wt.) showed a less inhibitory effect, with maximum potency at a dose of 20mg/kg body wt. Moreover, oral administration of bisdemethoxycurcumin at doses of 20-80 mg/kg body wt. twice daily for 10 days showed a significant curative efficacy in accelerating the healing of acetic acid-induced chronic gastric ulcer and promotion of mucosal regeneration in the ulcerated portion in a dose-related manner with potency equal to curcumin. In contrast, the curative potency of curcumin tended to decrease at doses over 160 mg/kg body wt./day. Western blot analysis in ulcerated gastric mucosa showed that bisdemethoxycurcumin dose-dependently reduced the increased protein expression level of iNOS but not TNF-alpha. These results indicated that bisdemethoxycurcumin directly accelerates gastric ulcer healing with potency equal to curcumin. Its antiulcer effect might be due to its properties of decreasing gastric acid secretion and enhancing the mucosal defensive mechanism through suppression of iNOS-mediated inflammation.
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PMID:Comparative antiulcer effect of bisdemethoxycurcumin and curcumin in a gastric ulcer model system. 1918 55

The objective of the present study was to elucidate whether luteolytic prostaglandin F(2alpha) (PGF) plays roles in regulating the nitric oxide (NO) generating system in luteal endothelial cells (LECs). Reverse transcriptase PCR, immunoblotting and immunostaining revealed the presence of PGF receptor mRNA (521 bp) and protein (64 kDa) in cultured LECs obtained from the mid-stage corpus luteum. When cultured LECs were exposed to 0.1 microM-10 microM PGF, NO production was significantly stimulated by PGF at 24 h. When LECs were exposed to 1 microM PGF for 2, 6 and 24 h, PGF did not affect the expressions of endothelial NO synthase (eNOS) mRNA and protein. On the other hand, PGF stimulated the expression of inducible NOS (iNOS) mRNA (P<0.05) and protein (P<0.05) at 2 h, but not at 6 and 24 h. By observing the conversion of [(3)C](L)-arginine to [(3)C](L)-citrulline, we found that PGF stimulated NOS activity in cultured LECs at 2 h (P<0.05). The overall findings indicate that bovine LECs are a target for PGF and that PGF stimulates iNOS expression and NOS activity in bovine LECs. Stimulation of the NO generating system and NOS activity by PGF may result in increasing local NO production followed by luteolysis.
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PMID:Prostaglandin F(2alpha) regulates the nitric oxide generating system in bovine luteal endothelial cells. 1940

Acid aspiration or intrapulmonary instillation of gastric particles causes lung inflammation leading to acute lung injury (ALI). Hypercapnia exerts different effects on ALI caused by various insults. The effects of hypercapnia on lung inflammation and injury due to acid aspiration are yet to be determined. The present study was designed to investigate the involvement of inducible nitric oxide synthase (iNOS) and other mediators in acid-aspiration-induced ALI. We also sought to evaluate the effects of hypercapnia on the lung and associated changes induced by acid aspiration. We used Spague-Dawley rats anesthetized with intraperitioneal pentobarbital (40 mg/kg). Gastric acid particles were prepared from the stomach contents of rats at necropsy. The rats were randomly assigned to receive intratracheal instillation of physiological saline solution (PSS) at pH 7.24 (Control group), PSS at pH 1.25 (Low pH, LPH group), gastric particles (GP group), and GP with low pH PSS (GPLPH group). There were 10 rats in each group. The animals were observed for 6 hrs. To evaluate the effects of hypercapnia, we carried out two series of experiments: one under normocapnia and the other under hypercapnia with alteration of CO2 fraction in inspired air. Arterial pressure (AP) was monitored from the femoral arterial catheter. Heart rate was obtained from AP traicing. We determined the blood gases and acid-base status. Lung weight to body weight (LW/BW) ratio, LW gain (LWG), protein concentration in bronchoalveolar lavage (PCBAL) and leakage of Evans blue dye tracer were measured. Plasma nitrate/nitrite, methyl guanidine (MG), myeloperoxidase (MPO), phospholipase A2 (PLA2), proinflammatory cytokines were assessed. Histopathological examination of the lung tissue was performed. We employed reverse-transcriptase polymerase chain reaction to detect the expression of iNOS mRNA. GP and GPLPH caused hypotension, decreases in PaO2, pH and SaO2, and an increase in PaCO2. The insults also elevated LW/BW, LWG, PCBAL and dye leakage, plasma nitrate/nitrite, MG, MPO, PLA2, tumor necrosis factor(alpha), interleukin-beta and interleukin-6. The lung pathology was characterized by alveolar edema and hemorrhage with inflammatory cells infiltration. Assessment of lung injury score revealed that GP and GPLPH caused ALI. Furthermore, hypercapnia significantly enhanced ALI and associated changes following LPH, GP and GPLPH. Intratracheal instillation of GP in normal or low pH PSS causes ALI accompanied with biochemical changes. The release of nitric oxide via iNOS isoform is detrimental to the lung. Hypercapnia tended to enhance ALI and associated changes induced by gastric acid instillation.
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PMID:Enhancement effects of hypercapnia on the acute lung injury caused by acid aspiration. 1977 97


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