Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0406810 (NAME)
 13,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ginsenosides have been shown to stimulate nitric oxide (NO) production in aortic endothelial cells. However, the signaling pathways involved have not been well studied in human aortic endothelial cells. The present study was designed to examine whether purified ginsenoside Rb1, a major active component of ginseng could actually induce NO production and to clarify the signaling pathway in human aortic endothelial cells. NO production was rapidly increased by Rb1. The rapid increase in NO production was abrogated by treatment with nitric oxide synthetase inhibitor, L-NAME. Rb1 stimulated rapid phosphorylation of Akt (Ser473), ERK1/2 (Thr202/Thr204) and eNOS (Ser1177). Rapid phosphorylation of eNOS (Ser1177) was prevented by SH-5, an Akt inhibitor or wortmannin, PI3-kinase inhibitor and partially attenuated by PD98059, an upstream inhibitor for ERK1/2. Interestingly, NO production and eNOS phosphorylation at Ser1177 by Rb1 were abolished by androgen receptor antagonist, nilutamide. The results suggest that PI3kinase/Akt and MEK/ERK pathways and androgen receptor are involved in the regulation of acute eNOS activation by Rb1 in human aortic endothelial cells.
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PMID:Signaling pathway of nitric oxide production induced by ginsenoside Rb1 in human aortic endothelial cells: a possible involvement of androgen receptor. 1719 33

LCY-2-CHO has anti-inflammatory actions on macrophages. To understand its therapeutic implication in atherosclerosis, we examined its effects on the expressions of anti-inflammatory and inflammatory proteins in cultured rat aortic vascular smooth muscle cells (VSMC). LCY-2-CHO is able to induce heme oxygenase-1 (HO-1) protein expression through a transcriptional action. The HO-1 inducting effect of LCY-2-CHO was inhibited by SB203580, N(G)-nitro-l-arginine methylester (l-NAME), and wortmannin, but was not affected by U0126 or SP600125. In accordance LCY-2-CHO increased protein phosphorylation of p38, Akt, and eNOS. Nrf2 is a transcription factor essential for HO-1 gene induction and we showed that LCY-2-CHO is able to cause Nrf2 nuclear translocation and this action depends on p38, Akt and eNOS. In addition to induce anti-inflammatory HO-1, LCY-2-CHO reduced interleukin-1beta (IL-1beta)-induced inflammatory mediators, inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), growth-related oncogene protein-alpha (GRO-alpha), and interleukin-8 (IL-8). Inhibitory effect on IL-1beta-mediated NF-kappaB activation was evidenced by the diminishment of IkappaB kinase (IKK) phosphorylation and IkappaBalpha degradation. In contrast, IL-1beta-mediated ERK and JNK activations were not changed by LCY-2-CHO, while p38 activation by IL-1beta and LCY-2-CHO displayed the non-additivity. Taken together, given the overall anti-inflammatory properties of LCY-2-CHO in VSMC, in terms to induce HO-1 gene expression and inhibit inflammatory gene expression, these results highlight the therapeutic potential of LCY-2-CHO in atherosclerosis.
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PMID:The anti-inflammatory actions of LCY-2-CHO, a carbazole analogue, in vascular smooth muscle cells. 1749 20

Neuropeptide Y (NPY) is a 36 amino acid peptide widely present in the CNS, including the retina. Previous studies have demonstrated that NPY promotes cell proliferation of rat post-natal hippocampal and olfactory epithelium precursor cells. The aim of this work was to investigate the role of NPY on cell proliferation of rat retinal neural cells. For this purpose, primary retinal cell cultures expressing NPY, and NPY Y(1), Y(2), Y(4) and Y(5) receptors [Alvaro et al., (2007) Neurochem. Int., 50, 757] were used. NPY (10-1000 nM) stimulated cell proliferation through the activation of NPY Y(1), Y(2) and Y(5) receptors. NPY also increased the number of proliferating neuronal progenitor cells (BrdU(+)/nestin(+) cells). The intracellular mechanisms coupled to NPY receptors activation that mediate the increase in cell proliferation were also investigated. The stimulatory effect of NPY on cell proliferation was reduced by L-nitroarginine-methyl-esther (L-NAME; 500 microM), a nitric oxide synthase inhibitor, 1H-[1,2,4]oxadiazolo-[4, 3-a]quinoxalin-1-one (ODQ; 20 microM), a soluble guanylyl cyclase inhibitor or U0126 (1 microM), an inhibitor of the extracellular signal-regulated kinase 1/2 (ERK 1/2). In conclusion, NPY stimulates retinal neural cell proliferation, and this effect is mediated through nitric oxide-cyclic GMP and ERK 1/2 pathways.
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PMID:Neuropeptide Y stimulates retinal neural cell proliferation--involvement of nitric oxide. 1833 83

Leptin, a pleiotropic cytokine secreted by adipocytes but also identified in salivary glands and saliva, is recognized as an important element of oral mucosal defense. Here, we report that in sublingual salivary glands leptin protects the acinar cells of against ethanol cytotoxicity. We show that ethanol- induced cytotoxicity, characterized by a marked drop in the acinar cell capacity for NO production, arachidonic acid release and prostaglandin generation, was subject to suppression by leptin. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with cyclooxygenase inhibitor, indomethacin and nitric oxide synthase (cNOS) inhibitor, L-NAME, as well as PP2, an inhibitor of Src kinase. Indomethacin, while not affecting leptin-induced arachidonic acid release, caused the inhibition in PGE2 generation, pretreatment with L-NAME led to the inhibition in NO production, whereas PP2 exerted the inhibitory effect on leptin-induced changes in NO, arachidonic acid, and PGE2. The leptin-induced changes in arachidonic acid release and PGE2 generation were blocked by ERK inhibitor, PD98059, but not by PI3K inhibitor, wortmannin. Further, leptin suppression of ethanol cytotoxicity was reflected in the increased Akt and cNOS phosphorylation that was sensitive to PP2. Moreover, the stimulatory effect of leptin on the acinar cell cNOS activity was inhibited not only by PP2, but also by Akt inhibitor, SH-5, while wortmannin had no effect. Our findings demonstrate that leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of MAPK/ERK and Akt that result in up-regulation of the respective prostaglandin and nitric oxide synthase pathways.
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PMID:Leptin protection of salivary gland acinar cells against ethanol cytotoxicity involves Src kinase-mediated parallel activation of prostaglandin and constitutive nitric oxide synthase pathways. 1834 Apr 8

Redox regulation of inducible nitric oxide synthase (iNOS) expression was investigated in lipopolysaccharide and interferon-gamma (LPS + IFNgamma)-stimulated microvascular endothelial cells from mouse skeletal muscle. Unstimulated endothelial cells produced reactive oxygen species (ROS) sensitive to inhibition of NADPH oxidase (apocynin and DPI), mitochondrial respiration (rotenone) and NOS (L-NAME). LPS + IFNgamma caused a marked increase in ROS production; this increase was abolished by inhibition of NADPH oxidase (apocynin, DPI and p47phox deficiency). LPS + IFNgamma induced substantial expression of iNOS protein. iNOS expression was prevented by the antioxidant ascorbate and by NADPH oxidase inhibition (apocynin, DPI and p47phox deficiency), but not by inhibition of mitochondrial respiration (rotenone) and xanthine oxidase (allopurinol). iNOS expression also was prevented by selective antagonists of ERK, JNK, Jak2, and NFkappaB activation. LPS + IFNgamma stimulated activation/phosphorylation of ERK, JNK, and Jak2 and activation/degradation of IkappaB, but only the activation of JNK and Jak2 was sensitive to ascorbate, apocynin and p47phox deficiency. Ascorbate, apocynin and p47phox deficiency also inhibited the LPS + IFNgamma-induced DNA binding activity of transcription factors IRF1 and AP1 but not NFkappaB. In conclusion, LPS + IFNgamma-induced NFkappaB activation is necessary for iNOS induction but is not dependent on ROS signaling. LPS + IFNgamma-stimulated NADPH oxidase activity produces ROS that activate the JNK-AP1 and Jak2-IRF1 signaling pathways required for iNOS induction. Since blocking either NFkappaB activation or NADPH oxidase activity is sufficient to prevent iNOS expression, they are separate targets for therapeutic interventions that aim to modulate iNOS expression in sepsis.
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PMID:iNOS expression requires NADPH oxidase-dependent redox signaling in microvascular endothelial cells. 1848 Dec 58

Although much has been learned about the role of the amygdala in Pavlovian fear conditioning, relatively little is known about the signaling pathway involved in the acquisition of an active avoidance reaction. The aim of this study is to investigate the potentiating effects of the NO-guanylate cyclase activator YC-1 on learning and memory of shuttle avoidance test in rats. YC-1 enhanced the induction of long-term potentiation (LTP) in amygdala through NO-cGMP-PKG-ERK pathway and the increase of BDNF expression. The Western blot and PCR methods were used to examine the signaling pathways involved in fear memory. It was found that YC-1 increased the avoidance responses during learning period and the memory retention lasted longer than one week. The enhancement of learning behavior by YC-1 was antagonized by intracerebroventricular injection of NOS inhibitor l-NAME, PKG inhibitor Rp-8-Br-PET-cGMPS and MEK inhibitor PD98059, indicating that NO-cGMP-PKG and ERK pathways are involved in the learning potentiating action of YC-1. In addition, YC-1 increased the activation of ERK and Akt 30 min after Day-1 training in amygdala. YC-1 also potentiated the expression of BDNF and CREB in response to fear memory test. Taken together, these findings suggest that NO-cGMP-PKG-ERK signaling pathway is involved in the action of YC-1 in enhancing the fear memory.
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PMID:Enhancement of active shuttle avoidance response by the NO-cGMP-PKG activator YC-1. 1859 Jul 24

Advances in understanding the functional aspects of leptin in the processes affecting peripheral tissues have brought to the forefront the role of this pluripotent cytokine in the processes of gastric mucosal defense and repair. Here, we report that leptin protects the gastric mucosal cells against ethanol cytotoxicity. We show that ethanol cytotoxicity, characterized by a marked drop in the mucosal cells capacity for NO production, arachidonic acid release and prostaglandin generation, was subject to suppression by leptin. The loss in countering capacity of leptin on the ethanol-induced cytotoxicity was attained with cyclooxygenase inhibitor, indomethacin and nitric oxide synthase (cNOS) inhibitor, L-NAME, as well as PP2, an inhibitor of Src kinase. Indomethacin caused the inhibition in PGE(2) generation, pretreatment with L-NAME led to the inhibition in NO production, whereas PP2 exerted the inhibitory effect on leptin-induced changes in NO, arachidonic acid and PGE(2). The leptin-induced changes in arachidonic acid release and PGE(2) generation were blocked by ERK inhibitor, PD98059, but not by PI3K inhibitor, wortmannin. Moreover, the stimulatory effect of leptin on the mucosal cells cNOS activity was inhibited not only by PP2, but also by Akt inhibitor, SH-5. Our findings demonstrate that leptin protection of gastric mucosa against ethanol cytotoxicity involves Src kinase-mediated bifurcated activation of MAPK/ERK and Akt that leads to up-regulation of the respective prostaglandin and nitric oxide synthase pathways.
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PMID:Src kinase-mediated parallel activation of prostaglandin and constitutive nitric oxide synthase pathways in leptin protection of gastric mucosa against ethanol cytotoxicity. 1862 47

Ginsenosides have been reported to release nitric oxide (NO) and decrease intracellular free Ca(2+) in cardiovascular system, which play important roles in antihypertrophic effect. This study investigated the potential inhibitory effect of total ginsenosides (TG) on right ventricular hypertrophy induced by monocrotaline (MCT, 60 mg/kg/d) and examined the possible antihypertrophic mechanism in male Sprague Dawley rats. MCT-intoxicated animals were treated with TG (20, 40, 60 mg/kg/d) for 18 d. TG treatment ameliorated MCT-induced elevations in right ventricular peak systolic pressure, right ventricular hypertrophy and the expression of atrial natriuretic peptide; N(G)-nitro-L-arginine-methyl ester (L-NAME), an NO synthase (NOS) inhibitor, had no influence on these inhibitory effects of TG 40 mg/kg/d, and TG at this dose had no any effect on the eNOS mRNA expression, suggesting the limited rule of NO in TG's effects. To further examine the mechanisms of the protection, the expression of calcineurin and its catalytic subunit CnA, as well as extracellular signal-regulated kinase-1 (ERK-1) and mitogen-activated protein kinase (MAPK) Phosphatase-1 (MKP-1) was examined. TG treatment significantly suppressed MCT-induced elevations of these signaling pathways in a dose-dependent manner. In summary, TG is effective in protecting against MCT-induced right ventricle hypertrophy, possibly through lowering pulmonary hypertension. Multiple molecular mechanisms appeared to be involved in this protection, such as the suppression of MCT-activated calcineurin and ERK signaling pathways.
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PMID:Total ginsenosides inhibit the right ventricular hypertrophy induced by monocrotaline in rats. 1867 84

Bradykinin 2 receptor (B2R) deficiency predisposes to cardiac hypertrophy and hypertension. The pathways mediating these effects are not known. Two-month-old B2R knockout (KO) and wild-type (WT) mice were assigned to 4 treatment groups (n = 12-14/group): control (vehicle); nitro-L-arginine methyl ester (L-NAME) an NO synthase inhibitor; simvastatin (SIM), an NO synthase activator; and SIM+L-NAME. Serial echocardiography was performed and blood pressure (BP) at 6 weeks was recorded using a micromanometer. Myocardial eNOS and mitogen-activated protein kinase (MAPK, including ERK, p38, and JNK) protein expression were measured. Results showed that (i) B2RKO mice had significantly lower ejection fraction than did WT mice (61% +/- 1% vs. 73% +/- 1%), lower myocardial eNOS and phospho-eNOS, normal systolic BP, and higher LV mass, phospho-p38, and JNK; (ii) L-NAME increased systolic BP in KO mice (117 +/- 19 mm Hg) but not in WT mice and exacerbated LV hypertrophy and dysfunction; and (iii) in KO mice, SIM decreased hypertrophy, p38, and JNK, improved function, increased capillary eNOS and phospho-eNOS, and prevented L-NAME-induced LV hypertrophy without lowering BP. We conclude that disruption of the B2R causes maladaptive cardiac hypertrophy with myocardial eNOS downregulation and MAPK upregulation. SIM reverses these abnormalities and prevents the development of primary cardiac hypertrophy as well as hypertrophy secondary to L-NAME-induced hypertension.
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PMID:Simvastatin reverses cardiac hypertrophy caused by disruption of the bradykinin 2 receptor. 1875 13

Oxidative stress causes cardiomyocyte death and subsequent ventricular dysfunction and cardiac remodeling after myocardial infarction (MI), thus contributing to high mortality in chronic heart failure patients. We investigated the effects of kallistatin in cardiac remodeling in a chronic MI rat model and in primary cardiac cells. Human kallistatin gene was injected intramyocardially 20 min after ligation of the left coronary artery. At 4 weeks after MI, expression of human kallistatin in rat hearts was identified by reverse transcription-polymerase chain reaction, immunohistochemistry and ELISA. Kallistatin administration improved cardiac performance, increased mean arterial pressure, decreased myocardial infarct size and restored left ventricular wall thickness. Kallistatin treatment significantly attenuated cardiomyocyte size and atrial natriuretic peptide expression. Kallistatin also reduced collagen accumulation, collagen fraction volume and expression of collagen types I and III, transforming growth factor-beta1 (TGF-beta1) and plasminogen activator inhibitor-1 in the myocardium. Inhibition of cardiac hypertrophy and fibrosis by kallistatin was associated with increased cardiac nitric oxide (NO) levels and decreased superoxide formation, NADH oxidase activity and p22-phox expression. Moreover, in both primary cultured rat cardiomyocytes and myofibroblasts, recombinant kallistatin inhibited intracellular superoxide formation induced by H(2)O(2), and the antioxidant effect of kallistatin was abolished by Nomega-nitro-L-arginine methyl ester (L-NAME), indicating a NO-mediated event. Kallistatin promoted survival of cardiomyocytes subjected to H(2)O(2) treatment, and inhibited H(2)O(2)-induced Akt and ERK phosphorylation, as well as NF-kappaB activation. Furthermore, kallistatin abrogated TGF-beta-induced collagen synthesis and secretion in cultured myofibroblasts. This is the first study to demonstrate that kallistatin improves cardiac performance and prevents post-MI-induced cardiac hypertrophy and fibrosis through its antioxidant action.
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PMID:Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction. 1876 77


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