Large Amounts Of NO Research Articles

Enhanced Glycosylation Caused by Overexpression of Rv1002c in a Recombinant BCG Promotes Immune Response and Protects against Mycobacterium tuberculosis Infection.

Tuberculosis (TB) is a major global health threat despite its virtual elimination in developed countries. Issues such as drug accessibility, emergence of multidrug-resistant strains, and limitations of the current BCG vaccine highlight the urgent need for more effective TB control measures. This study constructed BCG strains overexpressing Rv1002c and found that the rBCG-Rv1002c strain secreted more glycosylated proteins, significantly enhancing macrophage activation and immune protection against Mycobacterium tuberculosis (M. tb). These results indicate that Rv1002c overexpression promotes elevated levels of O-glycosylation in BCG bacteriophages, enhancing their phagocytic and antigenic presentation functions. Moreover, rBCG-Rv1002c significantly upregulated immune regulatory molecules on the macrophage surface, activated the NF-κB pathway, and facilitated the release of large amounts of NO and H2O2, thereby enhancing bacterial control. In mice, rBCG-Rv1002c immunization induced greater innate and adaptive immune responses, including increased production of multifunctional and long-term memory T cells. Furthermore, rBCG-Rv1002c-immunized mice exhibited reduced lung bacterial load and histological damage upon M. tb infection. This result shows that it has the potential to be an excellent candidate for a preventive vaccine against TB.

Emission characteristics and formation mechanisms of PM2.5 and gases from different geological maturities coals combustion

To evaluate the influence of geological maturity on coal combustion pollutant emissions, six chunk coals and corresponding briquettes (volatile matter [VM] content from 8.0% to 39.9%) were selected for simulated residential combustion in a carefully designed chamber, and the formation mechanism involved was investigated. VM was revealed to have a nonlinear effect on the emission factors (EFs) of particulate matter with an aerodynamic diameter of <2.5 μm (PM2.5), polycyclic aromatic hydrocarbons (PAHs), elemental carbon (EC), and organic carbon (OC), with the highest EFs observed in VM of 15.8% and 26.8%. Coal tar yield and air-supply from VM combustion in its initial stage was found to be a key factor influencing PM2.5 and PAH emissions when compared with the char combustion and burnout stages. The highest PM2.5 and PAH EFs were observed in coal with 15.8% VM. Additionally, significant amounts of hydrogen cyanide (HCN) were detected at stage 1 and were released as volatile-N through the pyrolysis of coal-N. N2O and NOx were also emitted through homogeneous gas-phase HCN reactions. However, only a small proportion of NOx was produced, indicating that the contribution of VM to HCN and N2O emissions is greater than that of NOx. In the char reaction stage (stage 2), char-N reacted with O2 to form large amounts of NO, and the reaction length of the entire coal combustion process exhibited a positive relationship with coal maturity (correlation coefficient 0.69, p < 0.05), suggesting that the contribution of NO from char-N to overall NO emissions increased with the coal’s geological maturity due to the increase in coal-N retention in char. Furthermore, coal briquetting was found to decrease the EFs of pollutants, which may be explained by an increase in MCE (modified combustion efficiency) and the conversion from coal tar to carbon and hydrogen. This study elucidated the effects of geological maturity on pollutant emissions from coal combustion and examined relevant underlying mechanism. These data can serve as the foundation for a clean coal project in China or other counties concerned with coal combustion emissions.

Molecular mechanism of Chuanxiong Rhizoma in treating coronary artery diseases

ObjectiveMost of the studies on the herb Chuanxiong Rhizoma (CR) have focused on the l-arginine-nitric oxide (NO) pathway, but the nitrate-nitrite-NO (NO3−–NO2−–NO) pathway was rarely investigated. Therefore, the aim of this study was to evaluate the effects and mechanisms of action of CR in coronary artery disease (CAD). MethodsThe NO3−, NO2− and NO levels were examined in the NO3−–NO2−–NO pathway. High-performance ion chromatography was used to quantify NO3− and NO2− levels. Then, NO was quantified using a multifunctional enzyme marker with a fluorescent probe. The tension of aortic rings was measured using a multi myograph system. ResultsHigh content of NO3− and low content of NO2− was found in CR, and which could potently convert NO3− to NO2− in the presence of endogenous reductase enzyme. Incubating human coronary artery endothelial cells (HCAECs) with CR-containing serum showed that CR significantly decreased the NO3− content and increased the levels of NO2− and NO in the cells under hypoxic conditions. In addition, CR significantly relaxed isolated aortic rings when the l-arginine –NO pathway was blocked. The optimal concentration of CR for relaxation was 200 mg/mL. ConclusionCR supplements large amounts of NO in cells and vessels to achieve relaxation via the NO3−–NO2−–NO pathway, thereby making up for the deficiency caused by the lack of NO after the l-arginine-NO pathway is suppressed. This study also supports the potential use of a traditional Chinese herb for future drug development.

General Strategy for Integrated Bioorthogonal Prodrugs: Pt(II)-Triggered Depropargylation Enables Controllable Drug Activation In Vivo.

Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of O/N-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug 16, in which a Pt(IV) moiety is covalently connected with an O2-propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O2-propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.

Nitric Oxide Modulates Metabolic Remodeling in Inflammatory Macrophages through TCA Cycle Regulation and Itaconate Accumulation

SummaryClassical activation of macrophages (M(LPS+IFNγ)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1β production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage.

4-Hydroxy-2-Nonenal, Indused Nitric Oxide Synthase Statues in Hypertension Patients

The oxidative stress is one of the main cause for cardiovascular diseases (like Hypertension) also one of the results of these diseases. This study involved 56 subjects matched ages and sex divided into two groups; 28 hypertensive subject and 28 healthy subject as control group. The following analysis was done: 4-Hydroxy-2-nonenal (4HNE), Induced nitric oxide synthase (iNOS) and albumin. The results show that there is a significant increase in (4HNE) between patients group and control group. INOS was significantly higher in patients compared to controls while there were no significant difference found in albumin between patient and control group. The increase in 4HNE which is a product of lipid peroxidation is attributed to destruction in body cell caused by due to the increase in stress events. And the increase in iNOS because iNOS produces large amounts of NO as a defense mechanism in response to cytokines and is an important factor in the response of the body to attack by parasites, bacterial infection, and tumor growth. It has been concluded that is important nappy on ideal weight, because obesity considered main factors for heart disease and hardening of the arteries. There is a positive relationship between oxidation results from hypertension and their developments. The aim of this study was to investigate the relationship between of some oxidative stress markers and cardiovascular diseases

Role of Oxidative Stress in the Pathophysiology of Pneumococcal Meningitis

Pneumococcal meningitis is a life-threatening disease characterized by an acute purulent infection affecting the pia mater, the arachnoid, and the subarachnoid spaces. Streptococcus pneumoniae crosses the blood-brain barrier (BBB) by both transcellular traversal and disruption of the intraepithelial tight junctions to allow intercellular traversal. During multiplication, pneumococci release their bacterial products, which are highly immunogenic and may lead to an increased inflammatory response in the host. Thus, these compounds are recognized by antigen-presenting cells through the binding of toll-like receptors. These receptors induce the activation of myeloid differentiation factor 88 (MyD88), which interacts with various protein kinases, including IL-1 receptor-associated kinase-4 (IRAK4), which is phosphorylated and dissociated from MyD88. These products also interact with tumor necrosis factor receptor-associated factor 6 dependent signaling pathway (TRAF6). This cascade provides a link to NF-κB-inducing kinase, resulting in the nuclear translocation of NF-κB leading to the production of cytokines, chemokines, and other proinflammatory molecules in response to bacterial stimuli. Consequently, polymorphonuclear cells are attracted from the bloodstream and then activated, releasing large amounts of NO•, O2 •, and H2O2. This formation generates oxidative and nitrosative stress, subsequently, lipid peroxidation, mitochondrial damage, and BBB breakdown, which contributes to cell injury during pneumococcal meningitis.

Excessive nitric oxide impairs wound collagen accumulation

BackgroundNitric oxide (NO) plays a major regulatory role in wound collagen synthesis. We hypothesized that this regulatory role is tightly controlled by the levels of NO in the wound environment and that supranormal wound NO generation impairs wound collagen accumulation. Materials and methodsWe used the model of turpentine-induced granuloma in male Sprague–Dawley rats as a sterile inflammatory stimulus generating large amounts of NO. In this environment, NO generation increased by 260%, whereas collagen deposition was significantly reduced by 38.5% (729.7 ± 81.5 versus 449.4 ± 76.3 μg hydroxyproline/100 mg sponge, P<0.05). Inhibition of NO synthase activity using 300 mM L-N6-(1-iminoethyl)-lysine, a highly potent and selective inhibitor of inducible NO synthase, significantly reduced NO elevation by 43.3% and increased wound collagen deposition by 37.3% (P<0.05). These effects occurred without any anti-inflammatory effects of L-N6-(1-iminoethyl)-lysine as assessed by the white blood cell counts and levels of interleukins 1 and 6. ConclusionsThe data show that high levels of NO within the wound environment significantly reduce wound collagen deposition. Inhibition of NO generation restores collagen levels to normal levels. The regulatory effects of NO on wound collagen appear to be highly correlated with the amount of NO generated.

Oxidative stress and pyrogenic fever pathogenesis

The causative/regulatory connections between changes in tissue redox state and fever induction were investigated herein. Wherefore, LPS, the primary element of bacterial cell wall, in addition to inducing pro-inflammatory cytokines, activated macrophages and other leukocytes to secrete hydroxyl radical (OH), nitric oxide metabolites (NO x −), superoxide (O 2 ) and other reactive oxygen/nitrogen species. Furthermore, inflammation response-associated hypoxia stimulated glutamate release, which caused excitotoxicity of cells by increasing extracellular Ca 2+. Cytokines and glutamate in turn also triggered the release of large amounts of NO x −, OH, O 2 , and other radicals. Those reactive nitrogen species in turn caused cellular injury via the peroxidation of membrane lipids and oxidative damage of proteins and DNA. Glutamate, NO x −, OH and antioxidants participated in the pathogenesis and regulation of LPS- or cytokines-induced fever. In particular, to highlight the role of glutamate, prostaglandin E 2, NO x − and OH generated in the hypothalamus during pyrogenic fever was attempted hereby. To find the link among the signaling with the glutamate, NO x − and OH /prostaglandin E 2 in the hypothalamus during pyrogenic fever will be challenging and could now clinically suppress pyrogenic fever.

Direct EPR Detection of Nitric Oxide in Mice Infected with the Pathogenic Mycobacterium Mycobacterium tuberculosis.

It has been shown that treatment of mice preinfected with Mycobacterium tuberculosis with spin NO traps (iron complexes with diethyldithiocarbamate) enables detection of large amounts of NO in internal organs 2 and 4 weeks after infection (up to 55–57 μmol/kg of wet lung tissue accumulated with spin NO traps during 30 min). The animals were infected with the drug-sensitive laboratory strain H37Rv and a clinical isolate nonrespondent to antituberculous drugs (the multidrug-resistant strain of M. tuberculosis) obtained from a patient with an active form of tuberculosis. Two weeks after infection with the multidrug-resistant strain, the NO level in the lungs, spleen, liver and kidney increased sharply concurrently with slight lesions of lung tissue. A reverse correlation, i.e., low level of NO in the lungs and other internal organs and extensive injury of lung tissue, was established for H37Rv-infected mice. Four weeks after infection, NO production in the lungs increased dramatically for both M. tuberculosis strains resulting in 80–84% damage of lung tissue. The lesion is suggested to be due to the development of defense mechanisms in M. tuberculosis counteracting NO effects.

Mathematical model of NO and O 2 transport in an arteriole facilitated by hemoglobin based O 2 carriers

The increasing demand for donated human blood has spurred research to develop hemoglobin-based O 2 carriers (HBOCs) that can be used as red blood cell (RBC) substitutes. However, in vivo studies of acellular HBOCs have shown an increase in mean arterial pressure following transfusion that has been attributed to the HBOC's ability to scavenge NO (an important vasodilator that is synthesized by endothelial cells in the blood vessel wall that signals neighboring smooth muscle cells to relax). In this study, a mathematical model was developed to describe NO and O 2 transport in an arteriole containing a mixture of acellular HBOCs and RBCs. The acellular HBOCs studied in this work possessed a wide range of O 2 affinities, O 2 dissociation rate constants and NO reactivities in order to evaluate their effect on O 2 tension and NO concentration in the arteriole tissue region. By focusing on the concentration of NO that is localized in the arteriole smooth muscle cell region, the model can predict the vasopressor response of HBOCs. The results of this study confirmed that acellular HBOCs scavenge large amounts of NO from the entire arteriole (~ 50% or more NO compared to RBCs only). A recombinant Hb, rHb3011, displayed the least NO reactivity and consequently left the most NO remaining in the arteriole. The NO concentration in the arteriole with respect to the other HBOCs studied was proportional to their NO reactivity. Therefore, the results of this study demonstrate that NO scavenging is an unavoidable consequence of transfusing HBOCs. To prevent or reduce vasodilatation, we suggest administration of NO by either inhaling NO or transfusing nitrite into the blood stream followed by transfusion of HBOC.

Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium

The endothelium lines the luminal surface of every blood vessel, allowing it contact with circulating blood elements, as well as the underlying vascular smooth muscle layer. In healthy vessels, the endothelium expresses constitutive forms of nitric oxide synthase (NOSIII) and cyclo-oxygenase (COX-1), which produce the vasoactive hormones NO and prostacyclin, respectively. Both NO and prostacyclin relax blood vessels and inhibit platelet activation. The actions of prostacyclin are mediated by cell surface prostacyclin (IP) receptors and/or intracellular peroxisome proliferator-activated receptors (PPAR) beta. The actions of NO are mediated predominately by activation of intracellular guanylyl cyclase, leading to the formation of cGMP. In platelets, the actions of NO and prostacyclin are synergistic, but in vessels their actions are additive. In diseased vessels, inducible forms of NOS (NOSII) and cyclo-oxygeanse (COX-2) are expressed in vascular smooth muscle, resulting in the release of large amounts of NO, prostacyclin and prostaglandin E2. The relative contribution of NOSII and COX-2 to vascular inflammation is still debated, but is likely to result in both protective and damaging responses. The relative contribution of constitutive forms of NOS and COX, as well as interactions between IP, PPAR beta and guanylyl cyclase pathways in vessels and platelets, is discussed.

LA419, a Novel Nitric Oxide Donor, Prevents Cardiac Remodeling Via the Endothelial Nitric Oxide Synthase Pathway

The discovery of NO as the endothelium-derived relaxing factor unleashed new horizons. NO is a ubiquitous radical exerting both hemodynamic and tissue growth–modifying effects. The vasodilative and antiproliferative properties of NO produced by endothelial NO synthase are considered to act beneficially within the cardiovascular system. However, under certain circumstances, the inducible NO synthase produces large quantities of NO that may be harmful.1 Most NO effects can be attributed to the activation of soluble guanylate cyclase and the subsequent cascade of events including enhanced cGMP concentration, activation of cGMP-dependent kinase-1, and reduced intracellular calcium levels in target cells. NO acts as a principal regulator of vascular function. Venodilatation and arterial relaxation result in a decrease of left ventricular pressure and chamber size, leading to attenuation of oxygen consumption. NO dilates epicardial coronary arteries, enhances collateral flow, and inhibits platelet aggregation. Moreover, NO was shown to inhibit collagen synthesis and to reduce cardiomyocyte growth. NO, thus, represents an opposing force to vasoconstrictors and growth-promoting substances, such as angiotensin II and endothelin. The depression of NO signaling, including downregulated expression and attenuated enzymatic activity of NO synthase and scavenging of NO by oxygen-derived free radicals, seems to be a principal disorder in endothelial dysfunction. NO deficiency is, therefore, related to many cardiovascular pathologies, such as coronary atherosclerosis with myocardial ischemia, arterial hypertension with left ventricular hypertrophy, or heart failure. It is obvious that NO plays an important role in the circulatory physiology. Nevertheless, the impact of therapeutically increased NO bioactivity on cardiovascular morbidity and mortality is unclear. In the Gruppo Italiano per lo Studio della Streptochinasi nell’Inffarto Miocardico 3 and International Study of Infarct Survival 4 trials, nitrates failed to reduce mortality when given after myocardial infarction.2 Although the effect of the combination of isosorbide dinitrate and hydralazine in the Vasodilator-Heart …

Macrophage biology and immunology: man is not a mouse.

A recent article by Shibata et al. [1] and an interview with the senior investigator Kobayashi [2], both in the October 2006 issue of Journal of Leukocyte Biology, discuss the role of macrophage-derived NO in the clearance of apoptotic cells. We were surprised that neither in the original paper nor in the accompanying interview was it discussed that these results rely entirely on data obtained in murine macrophages. It is, however, evident that there are differences in macrophage NO production and regulation among different species [3, 4]. Several years ago, we and others [5–7] described fundamental differences between macrophages from mice and humans regarding NO synthase (NOS) activity. Murine macrophages produce large amounts of NO and L-citrulline from L-arginine via induction of the inducible form of NOS (iNOS). In parallel, murine macrophages synthesize the obligatory cofactor tetrahydrobiopterin (BH4), essential for stabilization and function of the iNOS enzyme protein [8, 9]. Human as well as macrophages from other animal species, such as rabbits, goats, or Syrian hamsters, do not have NOS activity nor do they synthesize BH4 [7, 10, 11]. In addition, murine macrophages consume most of the L-arginine by another enzyme—arginase—and convert it into L-ornithine. This arginase is not active in human macrophages too [7, 9, 12]. A lot of research has since been done to demonstrate nitrite production in human macrophages. Recent reviews claim that human macrophages have iNOS activity, albeit induced by other stimuli rather than those inducing nitrite production in murine macrophages [13]. We evaluated several of these stimuli and could show that nitrite was not produced by iNOS activity in human macrophages. The nitrite measured came from other noncellular sources [14]. None of the articles cited as proof for iNOS activity in human macrophages provides sound biochemical data about L-arginine consumption, BH4 synthesis, and L-citrulline production [13]. Moreover, they do not control for nitrite generation from other nonmacrophage sources [14]. The only report that demonstrates nitrite production from NOS activity in human macrophage-like cells is an article by Bertholet et al. [15]. There, the U937 monoblastic leukemia cell line was transfected with a plasmid containing a functional iNOS gene. Nitrite production by these cells, however, totally depended on substitution of the cofactor BH4 and additional substrate [15]. As species differences are not confined to NOS activity and are fundamental in many aspects of immunology [3, 16, 17], we propose that the species involved should be mentioned in the title and abstract of articles dealing with common aspects of immunity.

New functional aspects of the L-arginine-nitric oxide metabolism within the circulating blood

Nitric oxide (NO) is a signaling molecule of major importance modulating not only the function of the vascular wall but also that of blood cells, such as platelets and leukocytes. The synthesis of NO in the circulation has been attributed mainly to the vascular endothelium. Red blood cells (RBC) have been demonstrated to carry a non-functional NOS and--due to their huge haemoglobin content--have been assumed to metabolize large quantities of NO. More recently, however, RBC have been identified to reversibly bind, transport, and release NO within the cardiovascular system. We provide evidence that RBC from humans express an active and functional endothelial type NOS. RBC NOS activity may regulate deformability of RBC, and inhibits activation of platelets. This review aims to discuss the potential role of RBC NOS in the circulation and new concepts of NO research in the microcirculation.

Biphasic Action of Inducible Nitric Oxide Synthase in a Hindlimb Ischemia Model

We investigated the influence of inducible nitric oxide synthase (iNOS) on acute ischemic injury and chronic angiogenesis. In a hindlimb ischemia model, NO produced by endothelial NO synthase (eNOS) reduces ischemic injury and promotes angiogenesis. However, the effect of the large amounts of NO generated by induced iNOS is unclear. Experimental groups of mice were as follows: (1) wild-type group (Wild), (2) iNOS-knockout group (iNOS-KO), and (3) aminoguanidine-treated wild-type group (Wild + AG), which received aminoguanidine from day 0 to day 3 after ischemia. Acute ischemic injury was evaluated by measuring the plasma CK value and ischemic score. Chronic angiogenesis was evaluated by microangiography and with a non-contact type Doppler blood flowmeter on day 3. Compared with the Wild group (251 ± 34.7 IU/l), the CK value was significantly elevated in the iNOS-KO (497 ± 126.7 IU/l) and Wild + AG (587.2 ± 128.7 IU/l) groups. The ischemic score was significantly increased in the iNOS-KO (92%) and Wild ± AG (66.6%) groups compared with the Wild group (23%). Blood flow was significantly increased in the iNOS-KO group (58.7 ± 15.3%) compared with the Wild (38.1 ± 15.9%) and Wild ± AG (43.5 ± 9.8%) groups in the chronic stage. Microangiography revealed a significantly increased number of blood vessels in the iNOS-KO (0.29 ± 0.02) group compared with the Wild (0.12 ± 0.01) and Wild + AG (0.15 ± 0.02) groups. Our findings indicate that NO generated by iNOS has a biphasic action, reducing acute ischemic injury and inhibiting angiogenesis in the chronic stage.

The Role of Rho-Associated Kinase in Differential Regulation by Statins of Interleukin-1β- and Lipopolysaccharide-Mediated Nuclear Factor κB Activation and Inducible Nitric-Oxide Synthase Gene Expression in Vascular Smooth Muscle Cells

An optimal level of NO has protective effects in atherosclerosis, whereas large amounts contribute to septic shock. To study how statins, the potent inhibitors of cholesterol synthesis, regulate NO in the vascular wall, we determined their effects on interleukin-1beta (IL-1beta)- and lipopolysaccharide (LPS)-induced NO production in aortic vascular smooth muscle cells (VSMCs). Compared with the large amounts of NO and inducible NO synthase (iNOS) protein expression induced by LPS, the responses of IL-1beta were modest. Various statins were found to inhibit LPS-induced iNOS expression and NO production, although they potentiated IL-1beta responses. In addition, fluvastatin increased IL-1beta-induced p65 nuclear translocation and nuclear factor kappaB (NF-kappaB) activity, although it inhibited those induced by LPS. To address the role of small G proteins in statin's actions, farnesyl transferase inhibitors [alpha-hydroxyfarne-sylphosphonic acid and (2S)-2-[[(2S)-2-[(2S,3S)-2-[(2R)-2-amino-3-mercaptopropyl]amino]-3-methylpentyl]oxy]-1-oxo-3-phenylpropyl]amino]-4-(methylsulfonyl)-butanoic acid 1-methylethyl ester (L-744382)], Rac inhibitor (NSC23766), and Rho-associated kinase (ROCK) inhibitor [N-(4-pyridyl)-4-(1-aminoethyl)cyclohexanecarboxamide dihydrochloride (Y-27632)] were used. We found that Y-27632 potentiated IL-1beta-induced iNOS expression, p65 nuclear translocation, IkappaB kinase (IKK), and NF-kappaB activation, whereas it had minimal effects on LPS-induced responses. In contrast, farnesyl transferase inhibitors blocked iNOS protein expression induced by LPS and IL-1beta, whereas NSC23766 had no effect. Further studies showed that LPS down-regulated Rho and ROCK activity, whereas IL-1beta increased them, suggesting a negative role of Rho and ROCK signaling, which is regulated in contrary manners by IL-1beta and LPS, in IKK/NF-kappaB activation. Through abrogating this negative signaling, statins differentially regulate iNOS expression induced by LPS and IL-1beta in VSMCs. These differential actions of statins on iNOS gene regulation might provide an additional explanation for the pleiotropic beneficial effects of statins.

NO x ground concentration at a station at high altitude in relation to cloud-to-ground lightning flashes

Concentrations of both nitrogen oxides (NO x =NO+NO 2) observed at a station at high altitude (Puy de Dome (PDD), 1465 m) have been analyzed in relation with the cloud-to-ground (CG) lightning activity provided by the detection network Météorage. A first analysis of the time series of both types of data issued for 4 months of the 2003 summer shows a good correspondence between high values of NO x and stormy conditions in the area. During this 4-month period, NO x values exceeding 100 μg m −3 have been observed on 7 days and all of these days correspond to lightning activity in a 200×200 km 2 area around PDD. Thirty-three days of the period experience lightning activity in this area, and only 14 of these days (42%) correspond to NO x peak values exceeding 50 μg m −3. The presence of lightning activity is a necessary condition to have very large peak values of NO x at PDD, but this condition is not sufficient. Two days showed NO x exceeding 300 μg m −3 which represents a value between 176 and 270 ppbv according to the respective proportion of NO 2 and NO. Six days are analyzed in detail, using other information about the convective system and the wind conditions. The data of urban stations close to PDD have also been considered in the analysis for evaluating the possible transport by a plume from a city area. These days include the higher NO x cases, cases with high lightning activity, and cases with remote lightning activity. On each of these days, the location of the CG flashes, the time delays between lightning activity and NO x increase, and the air flow seem consistent with an interpretation of NO x produced by lightning. The higher values of NO x correspond with close and stationary thunderstorms which produced large proportions of positive CG flashes with low wind conditions. However, the characteristic increase seems to depend on several parameters of the CG flashes: their rate, location, and polarity. By comparing with the values given by other authors for aircraft measurements at altitude, our observations indicate that large quantities of NO x could be produced by the CG flash processes.

Pharmacology of nitric oxide: molecular mechanisms and therapeutic strategies.

NO is considered to be an ubiquitous endogenous system which takes part in body's homeostatic regulations and in pathological events. NO derives from a) the actions of enzymes, the NO Synthases (NOS), which are constitutives (endothelial NOS (eNOS) and nervous NOS (nNOS)) and generate small amounts of NO and have homeostatic functions: and b) from the actions of inducible NOS (iNOS), which generate large amounts of NO and exert protective actions against noxious agents but also toxic effects (e.g. inhibition of enzymes) through the production of peroxynitrite (ONOO-). Modulation of the L-Arg/NO system may be used to obtain favourable therapeutic results, either by promoting (e.g. with NO donors) or by reducing (e.g. with NOS inhibitors) the production of NO. The present chapter will consider two approaches and four groups of potential therapeutic agents: 1) The stimulation of NO production with; a) agents which improve the efficiency of the Kallikrein-Kinin System; b) NO donors. 2) The reduction of excessive NO production with: a) inhibitors of NO Synthases; b) agents that reduce the formation of reactive nitrogen/ oxygen species (RNS / ROS).

The influence of nitrate concentration and acidity on the electrocatalytic reduction of nitrate on platinum

A study was performed to determine the influence of nitrate concentration and acidity on the reaction rate and selectivity of the electrocatalytic nitrate reduction on platinum. There are two different nitrate reduction mechanisms on platinum: a direct mechanism (0.4–0.1 V vs. SHE) and an indirect mechanism (0.9–0.5 V vs. SHE). In the direct mechanism the dependence of the reaction rate on the nitrate concentration changes with increasing nitrate concentration. Whereas at low concentrations (<0.1 M) the reaction order in nitrate is positive, at high concentrations (>0.1 M) the reaction order is negative. This suggests that at high concentrations the amount of free surface sites determines the reaction rate. These free surface sites are needed either for the adsorption of a second species necessary for the reaction (water or hydrogen) or for the dissociation of nitrate to nitrite. Both at low and high nitrate concentrations the direct reduction is mainly selective towards ammonia, although small amounts of N 2O and N 2 were observed using differential electrochemical mass spectrometry (DEMS) at potentials between 0.4 and 0.2 V at high concentrations of nitrate. This N 2 and N 2O formation seems to be related to the NO ads coverage on the electrode. The indirect reduction mechanism is autocatalytic as is illustrated by its unusual stirring behavior. Large amounts of NO were observed using DEMS. This suggests that not nitrate but NO + (⇆ HNO 2) is involved in the actual electron transfer. NO + is reduced to NO, which then reacts with HNO 3 to reproduce NO +, resulting in an overall reaction of nitrate to nitrite. Both nitrite and a high acidity are needed for this mechanism to develop, but addition of nitrite is not necessary since nitrite is present in small amounts in HNO 3 solutions of concentrations over 4 M. The autocatalytic reduction mechanism slows down and eventually terminates when NO starts to react to N 2O, as was observed using DEMS.