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Crambescin C1 Acts as A Possible Substrate of iNOS and eNOS Increasing Nitric Oxide Production and Inducing In Vivo Hypotensive Effect.

ABSTRACT: Crambescins are guanidine alkaloids from the sponge Crambe crambe. Crambescin C1 (CC) induces metallothionein genes and nitric oxide (NO) is one of the triggers. We studied and compared the in vitro, in vivo, and in silico effects of some crambescine A and C analogs. HepG2 gene expression was analyzed using microarrays. Vasodilation was studied in rat aortic rings. In vivo hypotensive effect was directly measured in anesthetized rats. The targets of crambescines were studied in silico. CC and homo-crambescine C1 (HCC), but not crambescine A1 (CA), induced metallothioneins transcripts. CC increased NO production in HepG2 cells. In isolated rat aortic rings, CC and HCC induced an endothelium-dependent relaxation related to eNOS activation and an endothelium-independent relaxation related to iNOS activation, hence both compounds increase NO and reduce vascular tone. In silico analysis also points to eNOS and iNOS as targets of Crambescin C1 and source of NO increment. CC effect is mediated through crambescin binding to the active site of eNOS and iNOS. CC docking studies in iNOS and eNOS active site revealed hydrogen bonding of the hydroxylated chain with residues Glu377 and Glu361, involved in the substrate recognition, and explains its higher binding affinity than CA. The later interaction and the extra polar contacts with its pyrimidine moiety, absent in the endogenous substrate, explain its role as exogenous substrate of NOSs and NO production. Our results suggest that CC serve as a basis to develop new useful drugs when bioavailability of NO is perturbed.

SUBMITTER: Rubiolo JA

PROVIDER: S-EPMC8312399 | biostudies-literature |

REPOSITORIES: biostudies-literature

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iNOS-derived nitric oxide promotes glycolysis by inducing pyruvate kinase M2 nuclear translocation in ovarian cancer.

Project description:Aerobic glycolysis is essential for tumor growth and survival. Activation of multiple carcinogenic signals contributes to metabolism reprogramming during malignant transformation of cancer. Recently nitric oxide has been noted to promote glycolysis but the mechanism remains elusive. We report here the dual role of nitric oxide in glycolysis: low/physiological nitric oxide (? 100 nM) promotes glycolysis for ATP production, oxidative defense and cell proliferation of ovary cancer cells, whereas excess nitric oxide (? 500 nM) inhibits it. Nitric oxide has a positive effect on glycolysis by inducing PKM2 nuclear translocation in an EGFR/ERK2 signaling-dependent manner. Moreover, iNOS induced by mild inflammatory stimulation increased glycolysis and cell proliferation by producing low doses of nitric oxide, while hyper inflammation induced iNOS inhibited it by producing excess nitric oxide. Finally, iNOS expression is abnormally increased in ovarian cancer tissues and is correlated with PKM2 expression. Overexpression of iNOS is associated with aggressive phenotype and poor survival outcome in ovarian cancer patients. Our study indicated that iNOS/NO play a dual role of in tumor glycolysis and progression, and established a bridge between iNOS/NO signaling pathway and EGFR/ERK2/PKM2 signaling pathway, suggesting that interfering glycolysis by targeting the iNOS/NO/PKM2 axis may be a valuable new therapeutic approach of treating ovarian cancer.

| S-EPMC5464849 | biostudies-literature

Recipient iNOS but not eNOS deficiency reduces luminal narrowing in tracheal allografts.

Project description:Chronic airway rejection is characterized by prolonged inflammation, epithelial damage, and eventual luminal obliterative bronchiolitis (OB). In cardiac allografts, the inducible nitric oxide synthase (iNOS) promotes acute rejection but paradoxically reduces neointimal formation, the hallmark of chronic rejection. The specific roles of NOS isoforms in modulating lymphocyte traffic and airway rejection are not known. Using a double lumen mouse tracheal transplant model, tracheal grafts from B10.A (allo) or C57BL/6J (iso) mice were transplanted into cyclosporine-treated wild-type (WT) iNOS(-/-) or endothelial NOS (eNOS)(-/-) recipients. OB was observed in WT tracheal allografts at 3 weeks (53 +/- 2% luminal occlusion vs. 17 +/- 1% for isografts, P < 0.05) with sites of obstructive lesion formation coinciding with areas of CD3(+) CD8(+) T cell-rich lymphocytic bronchitis. In contrast, allografts in iNOS(-/-) recipients exhibited reductions in local expression of proinflammatory chemokines and cytokines, graft T cell recruitment and apoptosis, and luminal obliteration (29 +/- 2%, P < 0.05 vs. WT allografts). Recipient eNOS deficiency, however, suppressed neither chemokine expression, lymphocyte infiltration, nor airway occlusion (54 +/- 2%). These data demonstrate that iNOS exacerbates luminal obliteration of airway allografts in contrast with the known suppression by iNOS of cardiac allograft vasculopathy. Because iNOS(-/-) airways transplanted into WT allograft hosts are not protected from rejection, these data suggest that iNOS expressed by graft-infiltrating leukocytes exerts the dominant influence on airway rejection.

| S-EPMC2193988 | biostudies-literature

Simvastatin induces a central hypotensive effect via Ras-mediated signalling to cause eNOS up-regulation.

Project description:Background and purposeClinical studies indicate that statins have a BP-lowering effect in hypercholesterolemic individuals with hypertension. Specifically, statins modulate BP through the up-regulation of endothelial NOS (eNOS) activation in the brain. However, the signalling mechanisms through which statins enhance eNOS activation remain unclear. Therefore, we examined the possible signalling pathways involved in statin-mediated BP regulation in the nucleus tractus solitarii (NTS).Experimental approachTo investigate the involvement of Ras and other signalling pathways in simvastatin-induced effects on BP, BP and renal sympathetic nerve activity (RSNA) were determined in spontaneously hypertensive rats (SHRs) before and after i.c.v. administration of simvastatin in the absence and presence of a Ras-specific inhibitor (farnesyl thiosalicylic acid, FTS), a geranylgeranyltransferase inhibitor (GGTI-2133), a PI3K inhibitor (LY294002) or a MAPK-ERK kinase (MEK) inhibitor (PD98059).Key resultsFTS significantly attenuated the decrease in BP and increased NO evoked by simvastatin and reversed the decrease in basal RSNA induced by simvastatin. Immunoblotting and pharmacological studies showed that inhibition of Ras activity by FTS significantly abolished simvastatin-induced phosphorylation of ERK1/2, ribosomal protein S6 kinase (RSK), Akt and decreased eNOS phosphorylation. Likewise, administration of Akt and ERK1/2 signalling inhibitors, LY294002 and PD98059, attenuated the reduction in BP evoked by simvastatin. Furthermore, i.c.v. simvastatin decreased Rac1 activation and the number of ROS-positive cells in the NTS.Conclusions and implicationsSimvastatin modulates central BP control in the NTS of SHRs by increasing Ras-mediated activation of the PI3K-Akt and ERK1/2-RSK signalling pathways, which then up-regulates eNOS activation.

| S-EPMC3799598 | biostudies-literature

Identification of hamster inducible nitric oxide synthase (iNOS) promoter sequences that influence basal and inducible iNOS expression.

Project description:IFN-?/LPS-activated hamster (Mesocricetus auratus) macrophages express significantly less iNOS (NOS2) than activated mouse macrophages, which contributes to the hamster's susceptibility to intracellular pathogens. We determined a mechanism responsible for differences in iNOS promoter activity in hamsters and mice. The HtPP (1.2 kb) showed low basal and inducible promoter activity when compared with the mouse, and sequences within a 100-bp region (-233 to -133) of the mouse and hamster promoters influenced this activity. Moreover, within this 100 bp, we identified a smaller region (44 bp) in the mouse promoter, which recovered basal promoter activity when swapped into the hamster promoter. The mouse homolog (100-bp region) contained a cis-element for NF-IL-6 (-153/-142), which was absent in the hamster counterpart. EMSA and supershift assays revealed that the hamster sequence did not support the binding of NF-IL-6. Introduction of a functional NF-IL-6 binding sequence into the hamster promoter or its alteration in the mouse promoter revealed the critical importance of this transcription factor for full iNOS promoter activity. Furthermore, the binding of NF-IL-6 to the iNOS promoter (-153/-142) in vivo was increased in mouse cells but was reduced in hamster cells after IFN-?/LPS stimulation. Differences in the activity of the iNOS promoters were evident in mouse and hamster cells, so they were not merely a result of species-specific differences in transcription factors. Thus, we have identified unique DNA sequences and a critical transcription factor, NF-IL-6, which contribute to the overall basal and inducible expression of hamster iNOS.

| S-EPMC3382312 | biostudies-literature

The genetic association between iNOS and eNOS polymorphisms and gastric cancer risk: a meta-analysis.

Project description:Objective:There are a number of susceptible factors for an increased risk of gastric cancer. Nitric oxide (NO) is considered to be associated with the development of a range of cancers. In particular, inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) are known to play a central role in the production of NO. Published studies relating to the association between eNOS rs1799983, rs2070744, and iNOS rs2297518 polymorphisms and the risk of gastric cancer risk are conflicting and inconclusive and require further analysis. Materials and methods:This study involved a meta-analysis of case-control studies relating to eNOS rs1799983, rs2070744, and iNOS rs2297518 polymorphisms published prior to January 2018. Literature searches were carried out in PubMed, Embase, Web of Science, the Cochrane Library databases, and the Chinese National Knowledge Infrastructure. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to evaluate the strength of association based on genotype data. Results:A total of 1,356 cases and 1,791 controls were included from nine case-control studies involving eNOS rs1799983 (G894T), rs2070744 (T-786C), and iNOS rs2297518 (C150T) polymorphisms. Data analysis indicated that iNOS rs2297518 was a risk factor for Helicobacter pylorus-positive gastric cancer when compared with H. pylorus-negative gastric cancer (p=0.003, OR [95% CI] =2.19 [1.31-3.66]). In addition, the allelic, dominant, and recessive models of eNOS rs2070744 were significantly associated with a risk of gastric cancer (allelic model: p<0.00001, OR [95% CI] =0.23 [0.16-0.34]; dominant model: p<0.00001, OR [95% CI] =0.25 [0.15-0.42]; recessive model: p<0.00001, OR [95% CI] =0.16 [0.08-0.30]). No association was identified between eNOS rs1799983 and the risk of gastric cancer (p>0.05). Conclusion:iNOS rs2297518 and eNOS rs2070744 polymorphisms may represent susceptible factors for gastric cancer.

| S-EPMC5939909 | biostudies-literature

eNOS/iNOS and endoplasmic reticulum stress-induced apoptosis in the placentas of patients with preeclampsia.

Project description:Disruption of nitric oxide pathway and endoplasmic reticulum (ER) stress had been observed in preeclampsia (PE). However, the correlation and overall detailed expression profiles of ER stress-related markers and endothelial nitric oxide synthase/inducible nitric oxide synthase (eNOS/iNOS) in patients with PE were poorly understood. In this study, placental protein expression of ER stress-related markers as well as eNOS/iNOS in normotensive control (n=32) and PE pregnancies (n=32) was examined by western blot. In addition, apoptosis was detected by terminal deoxynucleotidyl transferase-mediated nick-end labelling (TUNEL) staining in placentas. Compared with control, we found elevated ER stress response was agreeable with iNOS upregulation in placenta tissue of PE patients. Placental protein expression of ER stress-related markers, including GRP78, GRP94, p-PERK, eIF2a, p-eIF2a, XBP1, CHOP, Ire1, p-Ire1 and iNOS, was higher, and eNOS expression was lower in PE (P<0.05 for all); however, the expression of ATF6 and PERK was similar in the PE and control groups. Upregulation of CHOP and iNOS was consistent of apoptosis increasing indicated by TUNEL staining and caspase 4 expression upregulation in PE placenta. Our datas suggest that the exaggerated ER stress response and upregulated iNOS are probably associated with increased apoptosis in placenta of PE patients and may contribute to the pathophysiology of PE.

| S-EPMC5144123 | biostudies-literature

DIESEL particulate exposed macrophages alter endothelial cell expression of eNOS, iNOS, MCP1, and glutathione synthesis genes.

Project description:There is considerable debate regarding inhaled diesel exhaust particulate (DEP) causing impairments in vascular reactivity. Although there is evidence that inhaled particles can translocate from the lung into the systemic circulation, it has been suggested that inflammatory factors produced in the lung following macrophage particle engulfment also pass into the circulation. To investigate these differing hypotheses, we used in vitro systems to model each exposure. By using a direct exposure system and a macrophage-endothelial cell co-culture model, we compared the effects of direct DEP exposure and exposure to inflammatory factors produced by DEP-treated macrophages, on endothelial cell mRNA levels for eNOS, iNOS, endothelin-1, and endothelin-converting-enzyme-1. As markers of oxidative stress, we measured the effects of DEP treatment on glutathione (GSH) synthesis genes and on total GSH. In addition, we analyzed the effect of DEP treatment on monocyte chemo-attractant protein-1. Direct DEP exposure increased endothelial GCLC and GCLM as well as total GSH in addition to increased eNOS, iNOS, and Mcp1 mRNA. Alternatively, inflammatory factors released from DEP-exposed macrophages markedly up-regulated endothelial iNOS and Mcp1 while modestly down-regulating eNOS. These data support both direct exposure to DEP and the release of inflammatory cytokines as explanations for DEP-induced impairments in vascular reactivity.

| S-EPMC3217165 | biostudies-literature

Nitric oxide-dependent Src activation and resultant caveolin-1 phosphorylation promote eNOS/caveolin-1 binding and eNOS inhibition.

Project description:Endothelial nitric oxide synthase (eNOS)-mediated NO production plays a critical role in the regulation of vascular function and pathophysiology. Caveolin-1 (Cav-1) binding to eNOS holds eNOS in an inactive conformation; however, the mechanism of Cav-1-mediated inhibition of activated eNOS is unclear. Here the role of Src-dependent Cav-1 phosphorylation in eNOS negative feedback regulation is investigated. Using fluorescence resonance energy transfer (FRET) and coimmunoprecipitation analyses, we observed increased interaction between eNOS and Cav-1 following stimulation of endothelial cells with thrombin, vascular endothelial growth factor, and Ca(2+) ionophore A23187, which is corroborated in isolated perfused mouse lung. The eNOS/Cav-1 interaction is blocked by eNOS inhibitor L-N(G)-nitroarginine methyl ester (hydrochloride) and Src kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo [3, 4-d] pyrimidine. We also observe increased binding of phosphomimicking Y14D-Cav-1 mutant transduced in human embryonic kidney cells overexpressing eNOS and reduced Ca(2+)-induced NO production compared to cells expressing the phosphodefective Y14F-Cav-1 mutant. Finally, Src FRET biosensor, eNOS small interfering RNA, and NO donor studies demonstrate NO-induced Src activation and Cav-1 phosphorylation at Tyr-14, resulting in increased eNOS/Cav-1 interaction and inhibition of eNOS activity. Taken together, these data suggest that activation of eNOS promotes Src-dependent Cav-1-Tyr-14 phosphorylation and eNOS/Cav-1 binding, that is, eNOS feedback inhibition.

| S-EPMC3315804 | biostudies-literature

Inducible nitric oxide synthase (iNOS) regulatory region variation in non-human primates.

Project description:Inducible nitric oxide synthase (iNOS) is an enzyme that plays a key role in intracellular immune response against respiratory infections. Since various species of nonhuman primates exhibit different levels of susceptibility to infectious respiratory diseases, and since variation in regulatory regions of genes is thought to play a key role in expression levels of genes, two candidate regulatory regions of iNOS were mapped, sequenced, and compared across five species of nonhuman primates: African green monkeys (Chlorocebus sabaeus), pig-tailed macaques (Macaca nemestrina), cynomolgus macaques (Macaca fascicularis), Indian rhesus macaques (Macaca mulatta), and Chinese rhesus macaques (M. mulatta). In addition, we conducted an in silico analysis of the transcription factor binding sites associated with genetic variation in these two candidate regulatory regions across species. We found that only one of the two candidate regions showed strong evidence of involvement in iNOS regulation. Specifically, we found evidence of 13 conserved binding site candidates linked to iNOS regulation: AP-1, C/EBPB, CREB, GATA-1, GATA-3, NF-AT, NF-AT5, NF-?B, KLF4, Oct-1, PEA3, SMAD3, and TCF11. Additionally, we found evidence of interspecies variation in binding sites for several regulatory elements linked to iNOS (GATA-3, GATA-4, KLF6, SRF, STAT-1, STAT-3, OLF-1 and HIF-1) across species, especially in African green monkeys relative to other species. Given the key role of iNOS in respiratory immune response, the findings of this study might help guide the direction of future studies aimed to uncover the molecular mechanisms underlying the increased susceptibility of African green monkeys to several viral and bacterial respiratory infections.

| S-EPMC4361290 | biostudies-literature

mRNA expression and localization of bNOS, eNOS and iNOS in human cervix at preterm and term labour.

Project description:BACKGROUND: Preterm birth is the primary cause of the neonatal mortality and morbidity. There will be no preterm birth without a cervical softening. Nitric oxide (NO) is shown to be a mediator of term cervical ripening. The aim of this study was to investigate mRNA expression of the three isomers of NO synthases (NOS) and to identify them by immunohistochemistry in the human cervix at preterm birth compared to term. METHODS: The three isomers of NOS--inducible (iNOS), endothelial (eNOS) and neuronal (bNOS)--were investigated in the human cervix. The expression of mRNA was determined using Real-Time Multiplex RT-PCR. The localisation of synthases in the cervical tissue was analysed using immunohistochemistry. Cervical biopsies were obtained from 4 groups of women without clinical signs of infection: preterm (PTL), term labour (TL), preterm not in labour (PTnotL) and term not in labour (TnotL) patients. One-Way ANOVA, Kruskal-Wallis, Student t-test or Mann-Whitney test were applied as appropriate to determine statistically significant differences among the groups. RESULTS: Patients in preterm labour had significantly (p < 0.01) higher mRNA levels of all the three NOS isomers compared to those in term labour. Women not in labour, irrespective of gestational age, thus with unripe cervices, had significantly lower eNOS mRNA levels compared to those in labour (p < 0.01). Immunoreactivity for all three NO synthases was observed in each examined sample in all groups. The bNOS staining was the most prominent. CONCLUSION: The mRNA levels were higher in the preterm labour group compared to the women at term labour. The significant increase of the eNOS mRNA expression, from the unripe to the favourable cervical state during labour, may indicate a role of eNOS and supports the role of NO in the cervical ripening process. All the three synthases were identified by immunohistochemistry in all the groups of study.

| S-EPMC1188074 | biostudies-literature

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