TY - JOUR. T1 - Distribution and function of recombinant endothelial nitric oxide synthase in transplanted hearts. AU - Yap, J.. AU - OBrien, T.. AU - Pellegrini, C.. AU - Barber, D. A.. AU - Tazelaar, H. D.. AU - Severson, S. R.. AU - Miller, V. M.. AU - McGregor, C. G.A.. PY - 1999/6/1. Y1 - 1999/6/1. N2 - Introducing recombinant genes into donor hearts may offer a therapeutic intervention that could potentially attenuate the complications of heart transplantation, including rejection, infection and accelerated atherosclerosis. In the cardiovascular system, reduced bioactivity of endothelial nitric oxide is a feature of atherosclerosis and vascular injury. Nitric oxide is an arterial vasodilator that also inhibits proliferation of vascular smooth muscle cells and platelet aggregation. Experiments were designed to determine the distribution of adenoviral-mediated transfer of recombinant endothelial nitric oxide synthase gene (eNOS) and the effect of recombinant gene expression on the function ...
A new use for HMG-CoA reductase inhibitors is provided. In the instant invention, HMG-CoA reductase inhibitors are found to upregulate endothelial cell Nitric Oxide Synthase activity through a mechanism other than preventing the formation of oxidative-LDL. As a result, HMG-CoA reductase inhibitors are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include pulmonary hypertension, ischemic stroke, impotence, heart failure, hypoxia-induced conditions, insulin deficiency, progressive renal disease, gastric or esophageal motility syndrome, etc. Subjects thought to benefit mostly from such treatments include nonhyperlipidemics and nonhypercholesterolemics, but not necessarily exclude hyperlipidemics and hypercholesterolemics.
A use for rho GTPase function inhibitors is provided. In the instant invention, rho GTPase function inhibitors are found to upregulate endothelial cell Nitric Oxide Synthase activity. As a result, rho GTPase function inhibitors are useful in treating or preventing conditions that result from the abnormally low expression and/or activity of endothelial cell Nitric Oxide Synthase. Such conditions include pulmonary hypertension, ischemic stroke, impotence, heart failure, hypoxia-induced conditions, insulin deficiency, progressive renal disease, gastric or esophageal motility syndrome, etc. Subjects thought to benefit mostly from such treatments include nonhyperlipidemics and nonhypercholesterolemics, but do not necessarily exclude hyperlipidemics and hypercholesterolemics.
Mitochondrial nitric oxide synthase (mtNOS) is expressed constitutively, although it might be induced. Nitric oxide (NO) is a physiological regulator of mitochondrial respiration. Melatonin prevents mitochondrial oxidative damage and inhibits iNOS expression induced by bacterial lipopolysaccharide (LPS). The loss of melatonin with age may be related to the age-dependent mitochondrial damage. Thus, we examined the protective role of melatonin against the effects of LPS on mtNOS and on respiratory complexes activity in liver and lung mitochondria from young and old rats. The activity of mtNOS in control lung was low and did not change with age. LPS administration (10 mg/kg, i.v.) significantly increased mtNOS expression and activity and NO production in lung mitochondria, and the effect was greater in old rats. LPS administration also reduced the age-dependent decrease of the respiratory complexes I and IV. Melatonin administration (60 mg/kg, i.p.) prevented the LPS toxicity, decreasing ...
Curcumin inhibits nitric oxide synthase gene expression. Curcumin is a naturally occurring, dietary polyphenolic phytochemical that has been shown to inhibit cancer among other things. With respect to inflammation, it inhibits the activation of free radical activated transcription factors, and reduces the production of proinflammatory cytokines such as tumor necrosis factor-alpha (TNF), interleukin-1 and interleukin-8). Upon inflammation, an enzyme is induced (nitric oxide synthase) that catalyzes the production of nitric oxide (NO), a molecule that may lead to carcinogenesis. In this study in mouse immune cells curcumin reduced the production of nitric oxide in a concentration-dependent manner. Furthermore, curcumin reduced nitric oxide expression in the livers of mice by 50-70%. Investigators were able to obtain potency at nanomoles per gram of body weight, even though it is believed that curcumin needs to be given at dosages that are unattainable through diet to produce an in vivo effect. ...
TY - JOUR. T1 - Prevention of nitric oxide synthase induction in vascular smooth muscle cells by microtubule depolymerizing agents. AU - Marczin, Nándor. AU - Papapetropoulos, Andreas. AU - Jilling, Tamás. AU - Catravas, John D.. PY - 1993/1/1. Y1 - 1993/1/1. N2 - We investigated the role of microtubules in the induction of nitric oxide synthase in cultured vascular smooth muscle cells. We found that like interleukin‐1α, lipopolysaccharide elicited a time and concentration‐dependent accumulation of cyclic GMP via induction of nitric oxide synthase. Nocodazole and colchicine, two chemically distinct microtubule depolymerizing agents, completely prevented lipopolysaccharide‐ and interleukin‐induced (and nitric oxide‐mediated) cyclic GMP generation. In contrast to lipopolysaccharide and interleukin‐1α, cyclic GMP accumulation in response to sodium nitroprusside, an exogenous nitrovasodilator, was not altered by either nocodazole or colchicine. Our findings demonstrate that ...
1.Nitric oxide is a potent vasodilator which plays a major role in the control of blood pressure. The hyperdynamic circulation of cirrhosis has been linked to nitric oxide.. 2.We measured neutrophil nitric oxide synthase activity in relation to the level of hepatic dysfunction in patients with liver disease of varying aetiology and severity.. 3.Neutrophils were isolated from 21 patients (7 Child-Pugh score A, 6 grade B and 8 grade C) aged 28-76 (median 49) years. Nitric oxide synthase activity was measured using the conversion of oxyhaemoglobin to methaemoglobin by nitric oxide and expressed in terms of cell protein. Blood pressure and biochemical indices were recorded. Data were assessed using Kruskal-Wallis one-way analysis of variance, Mann-Whitney U-test or Pearson correlation as appropriate.. 4.Systolic, mean arterial and diastolic blood pressures decreased with increasing hepatic damage (P = 0.031, P = 0.01 and P = 0.038 respectively). Nitric oxide synthase activity increased with the ...
Pu-erh tea undergoes a unique fermentation process and contains theabrownins, polysaccharides and caffeine; although it is unclear about which component is associated with the down regulation of nitric oxide levels or how this process is mediated. To address this question we examined the effects of pu-erh tea on nitric oxide synthase (NOS) genes. Cohorts of rats were separately given four-week treatments of water as control, pu-erh tea, or the tea components: theabrownins, caffeine or polysaccharides. Five experimental groups were injected with lipopolysaccharides (LPS) to induce nitric oxide (NO) production, while the corresponding five control groups were injected with saline as a negative control. The serum and liver NO concentrations were examined and the NOS expression of both mRNA and protein was measured in liver. The results showed that the rats which were fed pu-erh tea or polysaccharides had lower levels of NO which corresponded with the down-regulation of inducible nitric oxide synthase (iNOS
Effects of Nerve Growth Factor and Nitric Oxide Synthase Inhibitors on Amyloid Precursor Protein mRNA Levels and Protein Stability
This study demonstrates for the first time that expression of a recombinant protein in the adventitia by in vivo adenovirus-mediated gene transfer can result in a biological effect. Our results indicate that delivery of adenoviral vectors encoding the β-galactosidase and eNOS genes to the periarterial sheath of rabbit carotid arteries results in adventitia-specific gene transfer and expression. Expression of recombinant eNOS in the adventitia resulted in marked increase in calcium-dependent NOS activity, an elevation of cGMP levels, and a diminished sensitivity to phenylephrine. Furthermore, the recombinant eNOS is responsive to stimulation by calcium ionophore and acetylcholine, as manifested by enhanced relaxations to these agents.. Gene transfer to the adventitia by adenoviral vectors has been demonstrated by Rios and coworkers9 in monkey femoral and carotid arteries. We obtained similar adventitia-specific gene transfer in rabbit carotid arteries by instilling adenoviral vectors into the ...
This study shows that adult hypertensive SHR exhibit higher cNOS activity in the heart than normotensive WKY rats. In contrast, in young SHR, in which high blood pressure is not yet established, cNOS activity was similar to that in young and adult WKY rats. These findings indicate that increased cNOS activity in the heart is related to hypertension and not to differences in age or strain. The left and right ventricles hold the highest differential pressure in the cardiovascular system18 ; this difference is higher in hypertension.18 19 The cNOS activity, selectively assessed in both sides of the heart, indicated that in hypertensive animals the left side has higher enzyme activity than the right side. In normotensive rats, on the other hand, the activities of the enzyme were similar in both sides of the heart. Whole hearts of adult WKY rats showed no enhanced cNOS activity compared with those of young rats, while blood pressure was significantly higher. These observations suggest that within the ...
PURPOSE: Inducible nitric oxide synthase has been implicated in the pathogenesis of cerebral ischemic damage, in the angiogenic process and in diabetic vascular damage. This study was undertaken to determine whether inducible nitric oxide synthase is present in the retinas from human subjects with diabetes mellitus. METHODS: This was an experimental immunohistochemical prospective study. Ten postmortem eyes from five subjects with diabetes mellitus, 10 eyes from five subjects without diabetes and without known ocular disease, and two eyes from one subject with unilateral ocular ischemic syndrome secondary to severe carotid artery obstruction were examined. We used immunohistochemical techniques and antibodies directed against inducible nitric oxide synthase, glial fibrillary acidic protein, and vimentin. The main outcome measure was immunoreactivity for these antibodies. RESULTS: Immunoreactivity for inducible nitric oxide synthase was not observed in retinas from all subjects without diabetes ...
In previous studies, we showed that in vivo infusion of angiotensin II (Ang II) to adult rats induced vascular changes in gene expression, and this effect did not depend solely on blood pressure elevation. To determine whether nitric oxide can influence the effects of Ang II on the vessel wall, we administered to rats Ang II separately or in combination with the arginine analogue N omega-nitro-L-arginine methyl ester, which inhibits nitric oxide synthase chronically when given in vivo. We measured changes in aortic medial thickness, the association of macrophages with the endothelial surface of the aorta, the presence of proliferating cell nuclear antigen in the intima and adventitia as an index of aortic cell cycle changes, and the expression of immunodetectable fibronectin as an index of changes in the extra-cellular matrix. After 18 days of nitric oxide inhibition, the major changes were increased medial thickness and a 3.5-fold increase in the number of adherent macrophages. Rats treated with two
Looking for online definition of Nitrogen monoxide in the Medical. peripheral nerves by a constitutive nitric oxide synthase,. (see SILDENAFIL). nitric oxide.Background Inhaled nitric oxide improves gas exchange in neonates, but the efficacy of low-dose inhaled nitric oxide in reducing the need for extracorporeal membrane.The inhalation of nitric oxide. Saleh D. Reduced expression of endothelial nitric oxide synthase in. et al. Hemodynamic response to sildenafil, nitric oxide,.PubMed comprises more than 26 million citations for biomedical literature from MEDLINE, life science journals, and online books.Treatment of Pulmonary Arterial Hypertension With Sildenafil:. of sildenafil.. The Internet Journal of Pulmonary Medicine. 2005 Volume 6 Number 1. Abstract.Endothelial Dysfunction in the Human Umbilical Artery due to Preeclampsia.Top online canadia pharmacy - cialis, viagra, propecia, diflucan and other tablets.When you feel fatigued in the gym, do you think of taking a nitric oxide ...
TY - JOUR. T1 - Increased organ blood flow in chronic endotoxemia is reversed by nitric oxide synthase inhibition. AU - Meyer, J.. AU - Hinder, F.. AU - Stothert, J.. AU - Traber, L. D.. AU - Herndon, David. AU - Flynn, J. T.. AU - Traber, D. L.. PY - 1994. Y1 - 1994. N2 - We evaluated regional blood flows in a hyperdynamic sepsis model and the reversal of increased flows by blockade of nitric oxide (NO) synthase. Seven awake sheep were continuously infused with Escherichia coli endotoxin [lipopolysaccharide (LPS), 10 ng · kg-1 · min-1] for 48 h. The NO synthase inhibitor N(ω)-nitro-L-arginine methyl ester (L-NAME, 25 mg/kg) was injected after 24 h. Blood flows to systemic organs were determined with the radioactive microsphere technique. LPS induced elevation of cardiac index by 36% (P , 0.05) and a fall in systemic vascular resistance index by 37% (P , 0.05) at 0 h [time of L-NAME administration, 24 h after infusion of LPS had begun]. L-NAME administration normalized cardiac index [6.1 ± ...
Abstract: Treatment of rat cerebellar astrocyte-enriched primary cultures with dexamethasone enhances the nitric oxide-dependent cyclic GMP formation induced by noradrenaline in a time-(,6 h) and concentration-dependent manner (half-maximal effect at 1 nM). Stimulation of cyclic GMP formation by the calcium ionophore A23187 is similarly enhanced. In contrast, cyclic GMP accumulation in cells treated with lipopolysaccharide is inhibited by dexamethasone. The potentiating effect of dexamethasone is prevented by the protein synthesis inhibitor cycloheximide and is not due to increased soluble guanylate cyclase activity. Agonist stimulation of [3H]arginine to [3H]citrulline conversion is enhanced by dexamethasone in astrocytes but not in cerebellar granule cells. These results indicate that glucocorticoids may up-regulate astroglial calcium-dependent nitric oxide synthase while preventing expression of inducible nitric oxide synthase and are the first report of a differential long-term regulation of ...
As described in Chapter 42, niric oxide (NO) is synthesized from the amino acid l-arginine by the actions of a family of enymes, the NO synthases (NOS), each isoform of which is encoded by a separate gene. Two NOS isoforms are calcium-dependent and constitutively expressed and produce low levels of NO: NOS1 (neuronal NOS or nNOS), which is found mostly in neurons and skeletal muscle, and NOS3 (endothelial NOS or eNOS), which is found mostly in endothelial cells. NOS1 is critical for neurotransmission and learning, and NOS3 regulates vascular tone and adhesion of circulating cells. Inducible NOS (iNOS or NOS2) is transcriptionally induced by proinflammatory cytokines (such as tumor necrosis factor-α [TNF-α] and interferon-γ [IFN-γ]) and microbial products (e.g., lipoplysaccharide [LPS]). iNOS is calciumindependent, expressed by many cell types (especially mononuclear phagocytes, hepatocytes, chondrocytes and smooth muscle cells) and is responsible for high output NO production (1-3). While ...
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TY - JOUR. T1 - Myeloperoxidase up-regulates the catalytic activity of inducible nitric oxide synthase by preventing nitric oxide feedback inhibition. AU - Galijasevic, Semira. AU - Saed, Ghassan M.. AU - Diamond, Michael P.. AU - Abu-Soud, Husam M.. PY - 2003/12/9. Y1 - 2003/12/9. N2 - Kinetic and structure analysis of inducible nitric oxide synthase (iNOS) revealed that, in addition to the increase of iNOS expression in inflamed areas, the major pathway causing overproduction of NO is destabilization of the iNOS-nitrosyl complex(es) that form during steady-state catalysis. Formation of such a complex allows iNOS to operate at only a fraction (20-30%) of its maximum activity. Thus, bioavailability of NO scavengers at sites of inflammation may play an essential role in up-regulation of the catalytic activity of iNOS, by preventing the catalytic activity inhibition that is attributed to nitrosyl complex formation. Myeloperoxidase (MPO), a major NO scavenger, is a pivotal enzyme involved in ...
The present study was performed to investigate the effects of chronic administration of nonylphenol (NP) on the expression of inflammation-related genes in the brains of mice. NP was given orally by gavages at 0, 50, 100, and 200 mg/kg/d. The expression of inflammatory enzymes, inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), was evaluated by immunohistochemistry and immunoblotting assays. The nitric oxide (NO) level and nitric oxide synthase (NOS) activity were also measured by biochemical analyses. The results showed that NP at a high dose (200 mg/kg/d) significantly increased the expression of iNOS and COX-2 in both the hippocampus and cortex. In parallel with the increase in iNOS expression, the NO level was significantly greater at the dose of 200 mg/kg/d, compared to the control. The activity of NOS was also increased in the brain of mice at the dose of 100 and 200 mg/kg/d. These findings demonstrate that NP may have the potential to induce the chronic inflammation or cause
TY - JOUR. T1 - Distribution of nitric oxide synthase in the human cerebral blood vessels and brain tissues. AU - Tomimoto, Hidekazu. AU - Nishimura, Masaki. AU - Suenaga, Toshihiko. AU - Nakamura, Sinichi. AU - Akiguchi, Ichiro. AU - Wakita, Hideaki. AU - Kimura, Jun. AU - Mayer, Bernd. PY - 1994/11. Y1 - 1994/11. N2 - The distribution of nitric oxide synthase was investigated in human cerebral blood vessels and brain tissues. NADPH-diaphorase histochemistry, which is a marker for nitric oxide synthase in neurons and endothelial cells, revealed periadventitial nerve fibers in the arteries of the circle of Willis and their cortical branches, as well as the common carotid and subclavian arteries. The fibers were mostly nonvaricose in the periadventitial nerve trunk and were varicose within the adventitia. Patchy reaction products were distributed in the perinuclear region of each endothelial cell. Smooth muscle cells in the tunica media were weakly stained. Staining was particularly intense in ...
The roles of endothelial nitric oxide synthase (eNOS), and its putative association with protein kinase B (PKB), and inducible nitric oxide synthase (iNOS) are not well characterized in hypoxic cardiac cells and there is a lack of studies that measure nitric oxide (NO) directly. Objective: To measure NO production in cardiomyocytes and cardiac microvascular endothelial cells (CMECs) under baseline and hypoxic conditions and to evaluate the expression, regulation and activation of eNOS, iNOS and PKB. The effect of PI3-K/PKB inhibition on NO production and eNOS expression/activation was also investigated. Methods: Adult rat cardiomyocytes and rat CMECs were made hypoxic by cell pelleting and low PO2 incubation. Intracellular NO was measured by FACS analysis of DAF-2/DA fluorescence, and eNOS, iNOS and PKB were evaluated by Western blotting or flow cytometry. Upstream PKB inhibition was achieved with wortmannin. Results: (1) NO levels increased in both cell types after exposure to hypoxia. (2) In ...
The long range goal of this project is to study structure-function relationships in nitric oxide synthase (NOS) and to develop isoform selective NOS inhibitors...
OBJECTIVE: The aim of this study was to investigate the role of inducible nitric oxide synthase (iNOS) in lethal prostate cancer (PCa) by studying the iNOS immunoreactivity in tumor tissue from men diagnosed with localized PCa.. MATERIALS AND METHODS: This study is nested within a cohort of men diagnosed with incidental PCa undergoing transurethral resection of the prostate (the Swedish Watchful Waiting Cohort). To investigate molecular determinants of lethal PCa, men who died from PCa (n = 132) were selected as cases; controls (n = 168) comprised men with PCa who survived for at least 10 years without dying from PCa during follow-up. The immunoreactivity of iNOS in prostate tumor epithelial cells and in cells of the surrounding stroma was scored as low/negative, moderate or high. Logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs) for lethal PCa according to iNOS category.. RESULTS: There was no association between iNOS immunoreactivity in stroma ...
Nitric oxide synthase oxygenase. Computer model showing the dimeric structure of murine nitric oxide synthase oxygenase (yellow, pink-red). The heme groups (green) assist in creating nitric oxide. This enzyme catalyses the production of nitric oxide. - Stock Image C035/5452
Expression of Inducible Nitric Oxide Synthase and Nitrotyrosine in Multiple Sclerosis Lesions: Nitric oxide generated by the inducible form of nitric oxide synt
Infection with Helicobacter pylori is recognized as a primary factor in the etiology of gastric disease and its early pathogenic effects are manifested by up-regulation in proinflammatory cytokine release, enhancement in nitric oxide generation, and amplification of apoptotic events. We applied the animal model of H. pylori -induced gastritis to study the effect of a specific inhibitor of p38 mitogen-activated protein kinase (p38 MAPK), SB 203580, on the mucosal apoptotic processes, and the expression of inducible nitric oxide synthase (NOS-2) activity and soluble tumor necrosis factor-α (TNF-α). Groups of rats were pretreated intragastrically with SB 203580 (5, 10, and 20 mg/kg) or vehicle, followed 60 min later by intragastric application of H. pylori lipopolysaccharide at 50 μg/animal, and after 2 and 4 additional days on the twice daily regimen of SB 203580 or vehicle, the animals were killed and their gastric mucosal tissue subjected to histologic and biochemical assessment. In the absence of SB
Indirect evidence suggests that estrogen is involved in the etiology of breast cancer. Estrogen is also thought to modulate nitric oxide (NO) in human breast tumor tissue via regulation of inducible nitric oxide synthase (iNOS). Objectives of this study were to determine whether estradiol (E2) affects iNOS expression level in breast cancer cells and to study the effect of various concentrations of E2 on cell proliferation. Immunocytochemical technique was employed to assess iNOS expression level. Proliferation of parent and 10-6 M tamoxifen resistant cells (T47D/TAMR-6) were assessed by MTT assay in the presence of E2. Addition of E2 (10-12 to 10-8 M) increases the expression of iNOS in parent cells, but not T47D/TAMR-6, Further increase in concentrations of E2 (10-8 to 10-4 M) again decreases the expression of iNOS in parent cells, but increase that of the T47D/TAMR-6 cells. Expression of iNOS in parent cells in a medium containing 1% serum (low serum) is less than the cells grown in a medium
The results of the present study indicate that administration of bacterial endotoxin LPS to experimental animals resulted in an increase in the extent of cell injury as well as an increase in inducible NOS activity in epithelial cells harvested from the colonic mucosa. This confirms previous findings that LPS treatment would activate iNOS and the resultant NO thus liberated could account for the increase in colonic cellular damage (Tepperman et al., 1994). Furthermore, the present data indicate that LPS treatment results in an increase in the activity of PKC in the cells isolated from the colonic mucosa. The increase in PKC occurs within the 1st h after LPS treatment, whereas the increase in iNOS activity was not observed until 4 h after LPS injection, a time that corresponded to the increase in the extent of cell injury. This temporal relationship suggests that the increase in PKC may mediate the cellular injury via activation of iNOS. This suggestion is further supported by the finding that ...
Nerve growth factor (NGF) increases expression of nitric oxide synthase (NOS) isozymes leading to enhanced production of nitric oxide (NO). NOS inhibitors attenuate NGF-mediated increases in cholinergic gene expression and neurite outgrowth. Mechanisms underlying this are unknown, but the mitogen-activated protein (MAP) kinase pathway plays an important role in NGF signaling. Like NGF, NO donors activate Ras leading to phosphorylation of MAP kinase. The present study investigated the role of NO in NGF-mediated activation of MAP kinase in PC12 cells. Cells were treated with 50 ng/mL NGF to establish the temporal pattern for rapid and sustained activation phases of MAP kinase kinase (MEK)-1/2 and p42/p44-MAP kinase. Subsequently, cells were pretreated with NOS inhibitors Nomega-nitro-L-arginine methylester and s-methylisothiourea and exposed to NGF for up to 24 h. NGF-induced activation of MEK-1/2 and p42/p44-MAP kinase was not dependent on NO, but sustained phosphorylation of MAP kinase was modulated by
Nitric oxide synthases (EC 1.14.13.39) (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and peristalsis, and is involved in angiogenesis and neural development. It may function as a retrograde neurotransmitter. Nitric oxide is mediated in mammals by the calcium-calmodulin controlled isoenzymes eNOS (endothelial NOS) and nNOS (neuronal NOS). The inducible isoform, iNOS, is involved in immune response, binds calmodulin at physiologically relevant concentrations, and produces NO as an immune defense mechanism, as NO is a free radical with an unpaired electron. It is the proximate cause of septic shock and may function in autoimmune disease. NOS catalyzes the reaction: 2 L-arginine + 3 NADPH + 1 H+ + 4 O2 ⇌ {\displaystyle \rightleftharpoons } 2 citrulline +2 nitric oxide + 4 H2O + 3 NADP+ NOS isoforms catalyze other leak and side reactions, ...
Endothelium-derived nitric oxide (NO) is primarily attributable to constitutive expression of the endothelial nitric oxide synthase (eNOS) gene. Although a more comprehensive understanding of transcriptional regulation of eNOS is emerging with respec
Inducible synthesis of nitric oxide (NO) by macrophages is an important mechanism of the host defense against intracellular infection in mice, but the evidence for significant levels of inducible NO production by human macrophages is controversial. Here we report that the human promyelocytic cell line HL-60, when differentiated to a macrophage-like phenotype, acquires the ability to produce substantial amounts of NO on stimulation with LPS or 1, 25-dihydroxyvitamin D3 (1,25-D3) in the absence of activating factors such as gamma interferon. Expression of the inducible nitric oxide synthase (NOS2) was confirmed by sequencing of the reverse transcription-PCR product from stimulated HL-60 cells. Kinetic studies after lipopolysaccharide stimulation show that NOS2 mRNA levels rise within 3 to 6 h, that conversion of [14C]arginine to [14C]citrulline is maximal at 5 to 6 days, and that levels of reactive nitrogen intermediates stabilize at around 20 microM at 7 to 8 days. We find that 1,25-D3 acts to suppress
Nitric oxide (NO) is a short-lived biologic mediator that is shown to be induced in various cell types and to cause many metabolic changes in target cells. Inhibition of tumor cell growth and antimicrobial activity has been attributed to the stimulation of the inducible type of the NO synthase (NOS). However, there is limited evidence for the existence of such inducible NOS in a human cell type. We show here the induction of NO biosynthesis in freshly isolated human hepatocytes (HC) after stimulation with interleukin 1, tumor necrosis factor (TNF), IFN-gamma, and endotoxin. Increased levels of nitrite (NO2-) and nitrate (NO3-) in culture supernatants were associated with NADPH-dependent NOS activity in the cell lysates. The production of NO2- and NO3- was inhibited by NG-monomethyl L-arginine and was associated with an increase in cyclic guanylate monophosphate release. The data presented here provide evidence for the existence of typical inducible NO biosynthesis in a human cell type. ...
Inducible nitric oxide synthase in response to bacterial challenge in nasal tissues of wild type, CX3CR1|sup|+/GFP|/sup| and CX3 CR1|sup|GFP/GFP|/sup| mice
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NO-mediated toxicity contributes to neuronal damage after hypoxia; however, the molecular mechanisms involved are still a matter of controversy. Since mitochondria play a key role in signalling neuronal death, we aimed to determine the role of nitrative stress in hypoxia-induced mitochondrial damage. Therefore, we analysed the biochemical and ultrastructural impairment of these organelles in the optic lobe of chick embryos after in vivo hypoxia?reoxygenation. Also, we studied the NO-dependence of damage and examined modulation of mitochondrial nitric oxide synthase (mtNOS) after the hypoxic event. A transient but substantial increase in mtNOS content and activity was observed at 0?2 h posthypoxia, resulting in accumulation of nitrated mitochondrial proteins measured by immunoblotting. However, no variations in nNOS content were observed in the homogenates, suggesting an increased translocation to mitochondria and not a general de novo synthesis. In parallel with mtNOS kinetics, mitochondria ...
4K5I: Structure of bovine endothelial nitric oxide synthase heme domain in complex with (R)-1,2-bis((2-amino-4-methylpyridin-6-yl)-methoxy)-propan-3-amine
Mono- and Stereopictres of 5.0 Angstrom coordination sphere of Arsenic atom in PDB 1d1x: Bovine Endothelial Nitric Oxide Synthase Heme Domain Complexed With 1, 4-Pbitu (H4B Bound)
Animal, Base-Sequence, Chromosome-Mapping, Crosses-Genetic, Enzyme-Induction, Genes-Structural, Human, Hybridization, Mice: ge, Mice-Inbred-C57BL, Mice-Inbred-NOD: ge, Molecular-Sequence-Data, Muridae: ge, Rats, Rats-Wistar, SUPPORT-NON-U-S-GOVT, SUPPORT-U-S-GOVT-P-H-S. ...
Emerging evidence shows that neuronal nitric oxide synthase (nNOS) plays several diverging roles in modulating cardiac function. This review examines the nitric oxide (NO) pathway and the regulatory mechanisms to which nNOS signalling is sensitive. These mechanisms are diverse and include regulation of gene expression, posttranscriptional regulation, protein trafficking, allosteric modulation of nNOS and redox modification to alter NO bioavailability once synthesised. Functionally, alteration in nNOS-NO signalling in the heart may correlate with different cardiac regulatory states. The idea of this being associated with exercise-trained states and myocardial disease is discussed.
Overexpression of inducible nitric oxide synthase (iNOS) has been reported in several human cancers, including esophageal squamous cell carcinoma (SCC). Benzo[a]pyrene (B[a]P), a polycyclic hydrocarbon carcinogen found in tobacco smoke and in the environment, induces cancer in multiple organ sites in animals and may be a causative agent for certain human cancers, such as esophageal cancer. In the present study, the effects of B[a]P on the induction of iNOS and the signaling pathways that lead to the induction were investigated in cultured rat esophageal epithelial (RE-149) cells. Treatment of RE-149 cells with B[a]P led to a marked increase in the expression of iNOS. The induction of iNOS by B[a]P was found to occur through an extracellular signal-regulated protein kinases (ERKs)-dependent pathway, since inhibition of ERKs by either pretreatment of RE-149 cells with PD98059, an inhibitor of ERKs upstream kinase MEK1/2, or overexpression of DN-ERK2, blocked the induction of iNOS by B[a]P. ...
Nitric oxide synthases (NOS) are haem-containing oxidoreductases and exist as homodimers in three isoforms: endothelial (eNOS), neuronal (nNOS), and inducible (iNOS). They produce NO through a 5-step oxidation of its substrate L-arginine to L-citrulline, using molecular oxygen. The C-terminal reductase domain of NOS contains binding sites for FAD, FMN and the electron donor, NADPH (Fig 3). The N-terminal oxygenase domain contains the haem group and binding sites for the substrate, arginine and the cofactor, BH4. The reductase domain generates electron flow from NADPH through the flavins FAD and FMN and then transfers the electrons to the oxygenase domain of the other monomer, where L-arginine oxidation occurs at the haem group in the active site [4].. In the vasculature, eNOS is the main NOS isoform, constitutively expressed in normal endothelium, while iNOS expression is normally low but may be increased in certain disease states, such as atherosclerosis [88]. eNOS is localized to invaginations ...
A novel role of interleukin-1-converting enzyme in cytokine-mediated inducible nitric oxide synthase gene expression: Implications for neuroinflammatory disease
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Inactivation of nitric oxide synthase after prolonged incubation of mouse macrophages with IFN-γ and bacterial lipopolysaccharide Academic Article ...
This unexpected set of observations led the investigators to explore a role for APE1 in regulation of nitric oxide synthase activity. Within the vascular endothelium, endothelial nitric oxide synthase (eNOS) activity is affected by levels of expression and also by well-characterized signaling pathways that activate eNOS. Expression of eNOS cannot be the major determinant of the hypertensive phenotype of APE1+/− mice, because eNOS levels are actually increased in the vessels of these mice in spite of their impaired ability to generate nitric oxide. The effect seems to be at the level of eNOS activation. Based on the data presented in this report it is reasonable to conclude that this is due in part to upregulation of H-Ras, which lies upstream of the phosphoinositide-3 kinase/Akt kinase pathway that potently activates eNOS.. The investigators conclude that increased Akt activation occurs via APE1-dependent upregulation of H-Ras expression, although the effect on H-Ras is modest and other ...
In awake dogs, the inhibition of NOS activity by NMA resulted in a significant pressor response (29+/-4 mmHg) and a significant systemic vasoconstriction (18+/-3 dyn *symbol* s *symbol* cm sup -5 ) that lasted 2 h and 1 h, respectively (Figure 1). Although cardiac output initially increased by 0.26+/-0.19 l *symbol* min sup -1) a significant secondary decrease (0.32+/-0.08 l *symbol* min sup -1) was recorded between 10 and 60 min. N-methyl-L-arginine injections were also followed by immediate and transient significant increases in heart rate (25+/-5 beats *symbol* min sup -1) and the first derivative of left ventricular pressure (457+/-169 mmHg *symbol* s sup -1 ; Figure 1and Figure 2). The effects of NMA on local circulation consisted of an immediate but transient significant increase in coronary blood flow (82+/-17 ml *symbol* min sup -1) and significant decreases in hepatic (56+/-16 ml *symbol* min sup -1) and mesenteric (31+/-7 ml *symbol* min sup -1) blood flow. Carotid blood flow initially ...
Human Placenta stained using PolyTek Anti-Mouse & EMA; Clone E29. Magnification 200X. Available at https://www.scytek.com/products/855-PAT125-PolyTek-Anti-Mouse-Polymerized-Alk-Phos.asp & https://www.scytek.com/products/35.97-A00008-0002-Epithelial-Membrane-Antigen-Clone-E29-(Ready-To-Use). ...
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