Candidate molecules as alternative nitric oxide donors with better antibacterial property against Escherichia coli and Staphylococcus aureus.

Nitric Oxide

Nitric oxide: physiology and pharmacology.

Nitric oxide releasing poly(vinylidene fluoride-co-hexafluoropropylene) films using a fluorinated nitric oxide donor to greatly decrease chemical leaching

Nitric oxide (NO) has a wide range of functions in the skin, and topical NO donors have several potential clinical applications. However, currently available donors are either unstable on the skin surface, release low concentrations of NO, or have a short duration of action. Endogenous S-nitrosothiols (RSNOs) store and transport NO within the body and can be used as exogenous sources of NO. To study in vitro and in vivo the chemical and biological behaviour of two RSNO species, S-nitrosoglutathione (GSNO) and S-nitroso-N-acetylcysteine (SNAC), in an easily applied hydrogel, and to correlate dermal nitrite concentration with erythema following application of the RSNOs. To assess the suitability of GSNO and SNAC as biologically effective NO donors for clinical research and as potential therapeutic agents. GSNO (0.3 mol g(-1)) and SNAC (0.6 mol g(-1)) were incorporated in Synperonic F-127 hydrogels (Uniquema, Belgium). The in vitro kinetics of decomposition were measured by spectrophotometry at 37 degrees C. The RSNO-containing hydrogels were applied to the forearm skin of eight subjects. Blood flow was measured by laser Doppler for 3 h following application of NO donors and dermal nitrite simultaneously measured in microdialysate in four subjects. The mean peak blood flow achieved was 250. At blood flow values of < 250, dermal nitrite correlated closely with blood flow and could be defined by the equation: blood flow = (nitrite concentration x 0.66) + 120, (P = 0.013). At higher blood flows there was a paradoxical fall in dermal nitrite concentration. Topical RSNOs produce a consistent, sustained and biologically effective release of NO on human skin in vivo, which offers advantages over currently available topical NO donors. Dermal nitrite concentration--the oxidation product of NO--is directly correlated with blood flow at low and moderate levels of blood flow. At high levels of blood flow, there is a reduction in dermal nitrite, which is presumed to be due to increased blood scavenging.

S-nitrosothiols have been implicated as intermediary transducers of nitric oxide bioactivity; however, the mechanisms by which these compounds affect cellular functions have not been fully established. In this study, we have examined the effect of S-nitrosothiol transport on intracellular thiol status and upon the activity of a target protein (caspase-3), in bovine aortic endothelial cells. We have previously demonstrated that the specific transport of amino acid-based S-nitrosothiols (S-nitroso-L-cysteine and S-nitrosohomocysteine) occurs via amino acid transport system L to generate high levels of intracellular protein S-nitrosothiols (Zhang, Y., and Hogg, N. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 7891-7896). In this study, we demonstrate that the transport of S-nitrosothiols is essential for these compounds to affect intracellular thiol levels and to modify intracellular protein activity. Importantly, the ability of these compounds to affect intracellular processes occurs independently of nitric oxide formation. These findings suggest that the major action of these compounds is not to liberate nitric oxide in the extracellular space but to be specifically transported into cells where they are able to modify cellular functions through nitric oxide-independent mechanisms.

Nitric oxide decreases IGF-1 receptor function in vitro; glutathione depletion enhances this effect in vivo

Chapter 2 - Biomedical applications of polymeric nitric oxide (NO) donors

Novel quantum dots–carboxymethyl chitosan nanocomposite nitric oxide donors capable of detecting release of nitric oxide in situ

Nitro-aniline based tripodal nitric oxide (NO) releasing molecule and light-triggered cytotoxicity in cancer cells

The rapid decomposition of nitric oxide (NO) donors in aqueous environments remains a limitation for applications requiring extended NO release. Herein, we report the synthesis of dipalmitoylphosphatidylcholine-based liposomes capable of extended NO release using low molecular weight NO donors and a reverse-phase evaporation technique. The encapsulation of the NO donors within the liposomes enabled both prolonged NO release and enhanced storage compared to free NO donors alone. The NO-releasing liposomes also demonstrated enhanced efficacy against human pancreatic cancer cells. These NO-release vehicles represent attractive anticancer therapeutics due to their potential to store the majority of their NO payload until reaching cancerous tissue at which time the lower pH inherent to such environments will trigger an avalanche of NO.

After injury, wound healing is a complex sequential cascade of events essential for the proper recovery of the wound without the scar formation. Nitric oxide (NO) is a small, endogenous free-radical gas with antimicrobial, vasodilating and growth factor stimulating properties. NO has wide biomedical application especially in wound healing however, its usability is hindered due its administration problem as it is highly unstable. In this work, poly (l-lactic acid) microparticles encapsulated with NO donor S-nitroso-N-acetyl-D-penicillamine (SNAP) were prepared using water-in-oil-water double emulsion solvent evaporation method for controlled delivery for NO at the specific site. The NO release from SNAP-PLLA microparticles prepared at two different stirring speeds (500 and 2500 RPM) was evaluated using three main SNAP decomposition triggers i.e. light, copper and ascorbic acid. The light controlled on and off mechanism of nitric oxide release from the microparticles at different intensities was demonstrated that can be used to control the amount of NO release depending on the need. An average total NO release of 6.11 ± 1.71 x10-08 for 9 hrs. and 8.43 ± 2.92 x10-08 for 13 hrs. was observed from microparticle(500) andmicroparticle(2500) respectively on exposure to light, copper (II) and ascorbate. Furthermore, these SNAP-PLLA microparticles were embedded into thermosensitive chitosan-agarose hydrogel to form microparticle-hydrogel composite. These composites have demonstrated NO release on exposure to light. An ascorbic acid chitosan-agarose hydrogel composite system was also used to evaluate the NO release in the presence of only ascorbic acid from the microparticle hydrogel composite. A significant difference in average total NO release from both microparticles as well as microparticle-hydrogel composite was observed because of varying size parameter. These findings suggest that these microparticle as well as microparticle-hydrogel composite formulations may be useful for wound site administration of nitric oxide to accelerate wound healing process delayed due to dysfunction in endogenous NO production caused by pathological infection.

A Photo-triggered and photo-calibrated nitric oxide donor: Rational design, spectral characterizations, and biological applications

In the vasculature it is well established that cGMP is involved in the relaxant response to nitric oxide (NO) and NO donors. However, there is an increasing evidence that alternative/additional pathways that are cGMP-independent may also exist. A key criterion for a response to NO or a NO donor drug to be classified as cGMP-independent is lack of (or incomplete) inhibition by the selective inhibitor of soluble guanylate cyclase, ODQ (1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one). In many blood vessels cGMP-independent mechanisms contribute to the vasorelaxation, and in certain vascular beds cGMP-independent relaxation may be the predominant mechanism of action of NO and NO donors. NO donor drugs that generate NO "spontaneously", like authentic NO (i.e. solutions of NO gas), appear to exhibit a larger component of cGMP-independent vasorelaxation than do those drugs that require bioactivation in the tissue. The long lasting inhibition of responses to vasoconstrictors by S-nitrosothiols, persisting after removal of these NO donors, may be a cGMP-independent process, at least in some vessels. The mechanisms involved in the inhibition of vascular growth by NO and NO donors are predominantly cGMP-independent, as are the mechanisms responsible for the effects of NO donors on apoptosis in vascular smooth muscle and endothelial cells. The ability of NO and NO donors to inhibit platelet aggregation has a significant cGMP-independent component. cGMP-independent pathways are most often, though not exclusively, seen at high concentrations (microM - mM) of NO and NO donors. Hence, in relation to the actions of endogenous NO, these pathways may be particularly important in settings when the inducible isoform of NO-synthase is expressed. Furthermore, cGMP-independent pathways are enhanced in animal models of atherosclerosis and ischaemia. This suggests that it may be possible to target cGMP-independent mechanisms with selected NO donors in disease states.

Characterization of the influence of nitric oxide donors on intestinal absorption of macromolecules

Chitosan-encapsulated nitric oxide donors enhance physiological recovery of sugarcane plants after water deficit