Τετάρτη 12 Ιουνίου 2019

Nitric Oxide

Compensatory mechanisms in myoglobin deficient mice preserve NO homeostasis

Publication date: 1 September 2019

Source: Nitric Oxide, Volume 90

Author(s): Ji Won Park, Barbora Piknova, Soumyadeep Dey, Constance T. Noguchi, Alan N. Schechter

Abstract

The mechanism for nitric oxide (NO) generation from reduction of nitrate (NO3) and nitrite (NO2) has gained increasing attention due to the potential beneficial effects of NO in cardiovascular diseases and exercise performance. We have previously shown in rodents that skeletal muscle is the major nitrate reservoir in the body and that exercise enhances the nitrate reduction pathway in the muscle tissue and have proposed that nitrate in muscle originates from diet, the futile cycle of nitric oxide synthase 1 (NOS1) and/or oxidation of NO by oxymyoglobin. In the present study, we tested the hypothesis that lack of myoglobin expression would decrease nitrate levels in skeletal muscle. We observed a modest but significant decrease of nitrate level in skeletal muscle of myoglobin deficient mice compared to littermate control mice (17.3 vs 12.8 nmol/g). In contrast, a NOS inhibitor, L-NAME or a low nitrite/nitrate diet treatment led to more pronounced decreases of nitrate levels in the skeletal muscle of both control and myoglobin deficient mice. Nitrite levels in the skeletal muscle of both types of mice were similar (0.48 vs 0.42 nmol/g). We also analyzed the expression of several proteins that are closely related to NO metabolism to examine the mechanism by which nitrate and nitrite levels are preserved in the absence of myoglobin. Western blot analyses suggest that the protein levels of xanthine oxidoreductase and sialin, a nitrate transporter, both increased in the skeletal muscle of myoglobin deficient mice. These results are compatible with our previously reported model of nitrate production in muscle and suggest that myoglobin deficiency activates compensatory mechanisms to sustain NO homeostasis.

Graphical abstract

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Nitric oxide releasing two-part creams containing S-nitrosoglutathione and zinc oxide for potential topical antimicrobial applications

Publication date: 1 September 2019

Source: Nitric Oxide, Volume 90

Author(s): Joshua C. Doverspike, Yang Zhou, Jianfeng Wu, Xiaojuan Tan, Chuanwu Xi, Mark E. Meyerhoff

Abstract

Currently, most antimicrobial topical treatments utilize antibiotics to prevent or treat infection at a wound site. However, with the ongoing evolution of multi-drug resistant bacterial strains, there is a high demand for alternative antimicrobial treatments. Nitric oxide (NO) is an endogenous gas molecule with potent antimicrobial activity, which is effective against a wide variety of bacterial strains. In this study, the potential for creating NO releasing creams containing the naturally occurring NO carrier, S-nitrosoglutathione (GSNO), are characterized and evaluated. GSNO is shown to have prolonged stability (>300 days) when mixed and stored within Vaseline at 24 °C. Further, enhanced proliferation of NO from GSNO using zinc oxide nanoparticles (ZnO) is demonstrated. Triggering NO release from the GSNO/Vaseline mixture using a commercial zinc oxide-containing cream exhibits first-order NO release kinetics with the highest %NO release over the first 6 h. Significant killing effects against S. aureusS. epidermidis, and P. aeruginosa are demonstrated for the GSNO/Vaseline/ZnO cream mixtures in a proportional manner dependent upon the concentration of GSNO in the final mixture.

Graphical abstract

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The role of nitric oxide signaling in pulmonary circulation of high- and low-altitude newborn sheep under basal and acute hypoxic conditions

Publication date: 1 August 2019

Source: Nitric Oxide, Volume 89

Author(s): Emilio A. Herrera, Germán Ebensperger, Ismael Hernández, Emilia M. Sanhueza, Aníbal J. Llanos, Roberto V. Reyes

Abstract

Nitric oxide (NO) is the main vasodilator agent that drives the rapid decrease of pulmonary vascular resistance for the respiratory onset during the fetal to neonatal transition. Nevertheless, the enhanced NO generation by the neonatal pulmonary arterial endothelium does not prevent development of hypoxic pulmonary hypertension in species without an evolutionary story at high altitude. Therefore, this study aims to describe the limits of the NO function at high-altitude during neonatal life in the sheep as an animal model without tolerance to perinatal hypoxia. We studied the effect of blockade of NO synthesis with l-NAME in the cardiopulmonary response of lowland (580 m) and highland (3600 m) newborn lambs basally and under an episode of acute hypoxia. We also determined the pulmonary expression of proteins that mediate the actions of the NO vasodilator pathway in the pulmonary vasoactive tone and remodeling. We observed an enhanced nitrergic function in highland lambs under basal conditions, evidenced as a markedly greater increase in basal mean pulmonary arterial pressure (mPAP) and resistance (PVR) under blockade of NO synthesis. Further, acute hypoxic challenge in lowland lambs infused with l-NAME markedly increased their mPAP and PVR to values greater than baseline, whilst in highland animals under NO synthesis blockade, these variables did not show additional increase in response to low PO2. Highland animals showed increased pulmonary RhoA expression, decreased PSer188-RhoA fraction, increased PSer311-p65-NFқβ fraction and up-regulated smooth muscle α-actin, relative to lowland controls. Taken together our data suggest that NO-mediated vasodilation is important to keep a low pulmonary vascular resistance under basal conditions and acute hypoxia at low-altitude. At high-altitude, the enhanced nitrergic signaling partially prevents excessive pulmonary hypertension but does not protect against acute hypoxia. The decreased vasodilator efficacy of nitrergic tone in high altitude lambs could be in part due to increased RhoA signaling that opposes to NO action in the hypoxic pulmonary circulation.



Targeting nitric oxide as a key modulator of sepsis, arthritis and pain

Publication date: 1 August 2019

Source: Nitric Oxide, Volume 89

Author(s): Fernando Spiller, Rodrigo Oliveira Formiga, Jonathan Fernandes da Silva Coimbra, Jose Carlos Alves-Filho, Thiago Mattar Cunha, Fernando Queiroz Cunha

Abstract

Nitric oxide (NO) is produced by enzymatic activity of neuronal (nNOS), endothelial (eNOS), and inducible nitric oxide synthase (iNOS) and modulates a broad spectrum of physiological and pathophysiological conditions. The iNOS isoform is positively regulated at transcriptional level and produces high levels of NO in response to inflammatory mediators and/or to pattern recognition receptor signaling, such as Toll-like receptors. In this review, we compiled the main contributions of our group for understanding of the role of NO in sepsis and arthritis outcome and the peripheral contributions of NO to inflammatory pain development. Although neutrophil iNOS-derived NO is necessary for bacterial killing, systemic production of high levels of NO impairs neutrophil migration to infections through inhibiting neutrophil adhesion on microcirculation and their locomotion. Moreover, neutrophil-derived NO contributes to multiple organ dysfunction in sepsis. In arthritis, NO is chief for bacterial clearance in staphylococcal-induced arthritis; however, it contributes to articular damage and bone mass degradation. NO produced in inflammatory sites also downmodulates pain. The mechanism involved in analgesic effect and inhibition of neutrophil migration is dependent on the activation of the classical sGC/cGMP/PKG pathway. Despite the increasing number of studies performed after the identification of NO as an endothelium-derived relaxing factor, the underlying mechanisms of NO in inflammatory diseases remain unclear.



Nitric oxide and interactions with reactive oxygen species in the development of melanoma, breast, and colon cancer: A redox signaling perspective

Publication date: 1 August 2019

Source: Nitric Oxide, Volume 89

Author(s): Hugo P. Monteiro, Elaine G. Rodrigues, Adriana K.C. Amorim Reis, Luiz S. Longo, Fernando T. Ogata, Ana I.S. Moretti, Paulo E. da Costa, Ana C.S. Teodoro, Maytê S. Toledo, Arnold Stern

Abstract

Cancer development is closely related to chronic inflammation, which is associated with identifiable markers of tumor progression, such as uncontrolled cell proliferation, angiogenesis, genomic instability, chemotherapeutic resistance, and metastases. Redox processes mediated by reactive oxygen species (ROS) and nitric oxide (NO) within the inflammatory tumor microenvironment play an essential role in directly influencing intercellular and intracellular signaling. These reactive species originating in the cancer cell or its microenvironment, mediate the epithelial-mesenchymal transition (EMT) and the mesenchymal-epithelial transition (MET). However, intracellular interactions between NO and ROS must be controlled to prevent cell death. Melanoma, breast, and colon cancer cells have developed a mechanism to survive and adapt to oxidative and nitrosative stress. The mechanism involves a spatial-temporal fine adjustment of the intracellular concentrations of NO and ROS, thereby guaranteeing the successful development of cancer cells. Physiological concentrations of NO and supra physiological concentrations of ROS are prevalent in cancer cells at the primary site. The situation reverses in cancer cells undergoing the EMT prior to being released into the blood stream. Intracellular supra physiological concentrations of NO found in circulating cancer cells endow them with anoikis resistance. When the anoikis-resistant cancer cells arrive at a metastatic site they undergo the MET. Endogenous supra physiological concentrations of ROS and physiological NO concentrations are prevalent in these cells. Understanding tumor progression from the perspective of redox signaling permits the characterization of new markers and approaches to therapy. The synthesis and use of compounds with the capacity of modifying intracellular concentrations of NO and ROS may prove effective in disrupting a redox homeostasis operative in cancer cells.



Delivery of carbon monoxide via halogenated ether anesthetics

Publication date: 1 August 2019

Source: Nitric Oxide, Volume 89

Author(s): Christopher P. Hopper, Jakob Wollborn



Light-induced release of nitric oxide from the nitric oxide-bound CDGSH-type [2Fe–2S] clusters in mitochondrial protein Miner2

Publication date: 1 August 2019

Source: Nitric Oxide, Volume 89

Author(s): Yiming Wang, Jeonghoon Lee, Huangen Ding

Abstract

Human mitochondrial matrix protein Miner2 hosts two [2Fe–2S] clusters via two CDGSH (Cys-Asp-Gly-Ser-His) motifs. Unlike other iron-sulfur clusters in proteins, the reduced CDGSH-type [2Fe–2S] clusters in Miner2 are able to bind nitric oxide (NO) and form stable NO-bound [2Fe–2S] clusters without disruption of the clusters. Here we report that the NO-bound Miner2 [2Fe–2S] clusters can quickly release NO upon the visible light excitation. The UV–visible and Electron Paramagnetic Resonance (EPR) measurements show that the NO-bound Miner2 [2Fe–2S] clusters are converted to the reduced Miner2 [2Fe–2S] clusters upon the light excitation under anaerobic conditions, suggesting that NO binding in the reduced Miner2 [2Fe–2S] clusters is reversible. Additional studies reveal that binding of NO effectively inhibits the redox transition of the Miner2 [2Fe–2S] clusters, indicating that NO may modulate the physiological activity of Miner2 in mitochondria by directly binding to the CDGSH-type [2Fe–2S] clusters in the protein.



Nitric oxide and abscisic acid protects against PEG-induced drought stress differentially in Brassica genotypes by combining the role of stress modulators, markers and antioxidants

Publication date: 1 August 2019

Source: Nitric Oxide, Volume 89

Author(s): Seema Sahay, Ehasanullah Khan, Meetu Gupta

Abstract

The present study was designed to see the effect of exogenous nitric oxide (NO) and abscisic acid (ABA) and their interaction on physiological and biochemical activities in leaves and roots of two Indian mustard (Brassica juncea) cultivars [cv. Pusa Jagannath (PJN) and Varuna (VAR)] exposed to polyethylene glycol (PEG)-induced drought stress. Seven days old hydroponically grown seedlings were treated with PEG (10%), sodium nitroprusside, a NO donor [NO (100 μM)] and abscisic acid [ABA (10 μM)], using different combinations as: Control, ABA, NO, PEG, PEG + ABA, PEG + NO, and PEG + NO + ABA. Results revealed that in response to PEG-induced drought stress leaf relative water content, chlorophyll, carotenoid and protein content decreased with increased production of O2−●, MDA, H2O2, cysteine content and non-enzymatic antioxidants (including proline, flavonoid, phenolic, anthocyanin, and ascorbic acid), whereas, the enzymatic antioxidants (including SOD, CAT, APX, GR) showed the response range from no effect to increase or decrease in certain enzymes in both Brassica cultivars. The application of NO or/and ABA in PEG-stressed cultivars showed that both enzymatic and non-enzymatic antioxidants responded differently to attenuate oxidative stress in leaves and roots of both cultivars. Overall, PJN had the antioxidant protection mainly through the accumulation of non-enzymatic antioxidants, whereas VAR showed tolerance by the enhancement of both enzymatic and non-enzymatic antioxidant activities. Altogether, the study concluded that the independent NO and its interaction with ABA (PEG + NO and PEG + NO + ABA) were much effective than independent ABA (PEG + ABA) in lowering PEG-drought stress in Brassica cultivars.



Exogenous l-ARGININE does not stimulate production OF NO or cGMP within the rat corporal smooth muscle cells in culture

Publication date: 1 August 2019

Source: Nitric Oxide, Volume 89

Author(s): Monica G. Ferrini, Andrea Abraham, Sabine Nguyen, Robert Luna, Manuel Flores, Jorge N. Artaza, Leslie Graciano, Jacob Rajfer

Abstract
Background and aim

Nitric oxide (NO) is the intracellular chemical responsible for initiating a penile erection. Despite conflicting clinical data, it continues to be publicized and promoted that orally administered l-arginine, the putative substrate for NO, enhances the erectile response presumably by stimulating NO production by the corporal tissues resulting in an increase in cGMP production. To shed light on this issue, an in vitro study was conducted to explore the effect of direct exogenous administration of l-arginine as well as its precursor and metabolite, l-citrulline, on the NO-cGMP pathway within the cavernosal smooth muscle (CSM) cell.

Materials and methods

CSM cells obtained from 8 to 10 week old Sprague-Dawley rats were grown in Dulbecco media with 20% fetal calf serum and then incubated with or without l-arginine (L-ARG) or l-citrulline (L-CIT) in a time course and dose-response manner. Sildenafil (0.4 mM), IBMX (1 mM), l-NAME (3 μM), ODQ (5 μM) and Deta Nonoate (10 μM) were used as either inhibitors or stimulators of the NO-cGMP pathway. mRNA and protein were extracted and used for the determination of the phosphodiesterase 5 (PDE5). PDE5 activity was determined by luminometry. cGMP content was determined by ELISA. Nitrite formation, an indicator of NO production, was measured in the cell culture media by a colorimetric assay. The cationic (CAT-1) and neutral (SNAT-1) amino acid transporters for L-ARG and L-CIT, respectively, were determined by Western blot.

Results

When compared to untreated CSM cells, incubation with 0.25–4.0 mM of L-ARG or 0.3–4.8 mM of L-CIT anywhere between 3 and 24 h did not result in any additional nitrite or cGMP production. The addition of l-NAME, IBMX or ODQ to these L-ARG and L-CIT treated cells did not alter these results. L-CIT but not L-ARG increased PDE5 mRNA and protein content as well as the activity of the PDE5 enzyme. Both CAT-1 and SNAT-1 were expressed in the CSM cells.

Conclusions

This in vitro study demonstrates that exogenous administration of L-ARG or L-CIT failed to stimulate production of either NO or cGMP by the corporal CSM cells. A re-evaluation of the presumptive role of the exogenous administration of L-ARG in improving the synthesis of NO at least at the level of the CSM cells appears warranted.



Dietary nitrate supplementation alters the oral microbiome but does not improve the vascular responses to an acute nitrate dose

Publication date: 1 August 2019

Source: Nitric Oxide, Volume 89

Author(s): Mia Burleigh, Luke Liddle, David J. Muggeridge, Christopher Monaghan, Nicholas Sculthorpe, John Butcher, Fiona Henriquez, Chris Easton

Abstract

Nitrate (NO3) contained in food and beverages can transiently increase nitric oxide (NO) availability following a stepwise reduction to nitrite (NO2) by commensal bacteria in the oral cavity. We tested the hypothesis that regular ingestion of dietary NO3 would influence the oral microbiome, the capacity to reduce NO3 to NO2 in saliva, and the vascular responses to an acute dose of NO3. The abundance of bacterial species on the tongue, the availability of NO markers, and vascular function were assessed in 11 healthy males before and after 7 days of supplementation with NO3-rich beetroot juice and a NO3-depleted placebo. As expected, saliva and plasma NO2 and NO3 were significantly elevated after NO3 supplementation (all P < 0.05) but not placebo. We found that NO3 supplementation increased salivary pH (7.13 ± 0.54 to 7.39 ± 0.68, P = 0.043) and altered the abundance of some bacteria previously implicated in NO3 reduction: Neisseria (from 2% ± 3%–9% ± 5%, P < 0.001), Prevotella (from 34% ± 17%–23% ± 11%, P = 0.001) and Actinomyces (from 1% ± 1%–0.5% ± 0.4%). Despite these alterations to the oral microbiota, an acute dose of NO3 increased salivary and plasma NO2, reduced systolic blood pressure and increased the response to flow mediated dilation to a similar extent before and after 7 days of supplementation (P > 0.05). Our study establishes that supplementing the diet with NO3 for a sustained period can alter the oral environment in favour of health but does not impact the response to an acute NO3 dose. Acute ingestion of NO3 results in transient improvements in vascular function but the dietary induced adaptations to the oral bacteria did not enhance these effects.



Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
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