Tuning the nitric oxide release from CPO-27 MOFs.
Ontology highlight
ABSTRACT:
SUBMITTER: Cattaneo D
PROVIDER: S-EPMC4786954 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tendon regeneration is still a great challenge due to its avascular structure and low self-renewal capability. The nitric oxide (NO) therapy emerges as a promising treatment for inducing the regeneration of injured tendon by angiogenesis. Here, in this study, a system that NO-loaded metal-organic frameworks (MOFs) encapsulated in polycaprolactone (PCL)/gelatin (Gel) aligned coaxial scaffolds (NMPGA) is designed and prepared for tendon repair. In this system, NO is able to be released in vitro at a slow and stable average speed of 1.67 nM h-1 as long as 15 d without a burst release stage in the initial 48 h. Furthermore, NMPGA can not only improve the tubular formation capability of endothelial cells in vitro but also obviously increase the blood perfusion near the injured tendon in vivo, leading to accelerating the maturity of collagen and recovery of biomechanical strength of the regenerated tendon tissue. As a NO-loaded MOFs therapeutic system, NMPGA can promote tendon regeneration in a shorter healing period with better biomechanical properties in comparison with control group by angiogenesis. Therefore, this study not only provides a promising scaffold for tendon regeneration, but also paves a new way to develop a NO-based therapy for biomedical application in the future.
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Project description:We report the ability to readily tune NO release from N-diazeniumdiolate-encapsulated liposomal structures by altering the NO donor molecule structure and/or phospholipid composition (independently or in combination). While encapsulating more stable NO donors expectedly enhanced the NO release (up to 48 h) from the liposomes, the phospholipid headgroup surface area proved equally useful in controlling NO-release kinetics by influencing the water uptake and concomitant N-diazeniumdiolate NO donor breakdown (to NO). The potential therapeutic utility of the NO-releasing liposomes was further assessed in biological/proteinaceous fluids. The NO-release kinetics were similar in buffer and serum.
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Project description:We have investigated the kinetics of NO escape from Geobacillus stearothermophilus nitric oxide synthase (gsNOS). Previous work indicated that NO release was gated at position 223 in mammalian enzymes; our kinetics experiments include mutants at that position along with measurements on the wild type enzyme. Employing stopped-flow UV-vis methods, reactions were triggered by mixing a reduced enzyme/N-hydroxy-l-arginine complex with an aerated buffer solution. NO release kinetics were obtained for wt NOS and three mutants (H134S, I223V, H134S/I223V). We have confirmed that wt gsNOS has the lowest NO release rate of known NOS enzymes, whether bacterial or mammalian. We also have found that steric clashes at positions 223 and 134 hinder NO escape, as judged by enhanced rates in the single mutants. The empirical rate of NO release from the gsNOS double mutant (H134/I223V) is nearly as rapid as that of the fastest mammalian enzymes, demonstrating that both positions 223 and 134 function as gates for escape of the product diatomic molecule.
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Project description:Nitric oxide (NO) derived from nitric oxide synthase (NOS) is an important paracrine effector that maintains vascular tone. The release of NO mediated by NOS isozymes under various O(2) conditions critically determines the NO bioavailability in tissues. Because of experimental difficulties, there has been no direct information on how enzymatic NO production and distribution change around arterioles under various oxygen conditions. In this study, we used computational models based on the analysis of biochemical pathways of enzymatic NO synthesis and the availability of NOS isozymes to quantify the NO production by neuronal NOS (NOS1) and endothelial NOS (NOS3). We compared the catalytic activities of NOS1 and NOS3 and their sensitivities to the concentration of substrate O(2). Based on the NO release rates predicted from kinetic models, the geometric distribution of NO sources, and mass balance analysis, we predicted the NO concentration profiles around an arteriole under various O(2) conditions. The results indicated that NOS1-catalyzed NO production was significantly more sensitive to ambient O(2) concentration than that catalyzed by NOS3. Also, the high sensitivity of NOS1 catalytic activity to O(2) was associated with significantly reduced NO production and therefore NO concentrations, upon hypoxia. Moreover, the major source determining the distribution of NO was NOS1, which was abundantly expressed in the nerve fibers and mast cells close to arterioles, rather than NOS3, which was expressed in the endothelium. Finally, the perivascular NO concentration predicted by the models under conditions of normoxia was paradoxically at least an order of magnitude lower than a number of experimental measurements, suggesting a higher abundance of NOS1 or NOS3 and/or the existence of other enzymatic or nonenzymatic sources of NO in the microvasculature.
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Project description:Nitric oxide (NO) shows high potential in the cardiovascular system with anticoagulant and antibacterial efficacy. Cu based metal organic frameworks with amino modification (CuMOFs) were found to have an extraordinary high NO loading, but at the expense of framework stability in ambient moisture. Nano CuMOFs was synthesized by hydrothermal method in this work, and treated with stearic acid (SA) creating a hydrophobic form. It was found that the structure of the particles was not affected after treatment with SA, and the treated CuMOFs had tunable hydrophobicity. Both CuMOFs and SA modified CuMOFs adsorbed NO with the reaction of the amino group and NO to form a NONOate. SA modification enhanced stability of the CuMOFs in phosphate buffer solution (PBS, pH = 7.4), slowed down the interaction between the NO loading unit and H2O, and thus NO releasing was prolonged. The resulting NO-loaded CuMOFs inhibited platelet activation dramatically, prolonged the coagulation time and displayed excellent antibacterial properties. They could be envisioned as a good candidate for application in blood contacting implants.
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Project description:Amine-based diazeniumdiolates (NONOates) have garnered widespread use as nitric oxide (NO) donors, and their potential for nitroxyl (HNO) release has more recently been realized. While NO release rates can vary significantly with the type of amine, half-lives of seconds to days under physiological conditions, there is as yet no way to determine a priori the NO or HNO production rates of a given species, and no discernible trends have manifested other than that secondary amines produce only NO (i.e., no HNO). As a step to understanding these complex systems, here we describe a procedure for modeling amine-based NONOates in water solvent that provides an excellent correlation (R(2) = 0.94) between experimentally measured dissociation rates of seven secondary amine species and their computed NO release activation energies. The significant difference in behavior of NONOates in the gas and solvent phases is also rigorously demonstrated via explicit additions of quantum mechanical water molecules. The presented results suggest that the as-yet unsynthesized simplest amine-based NONOate, the diazeniumdiolated ammonia anion [H2N-N(O)?NO(-)], could serve as an unperturbed HNO donor. These results provide a step forward toward the accurate modeling of general NO and/or HNO donors as well as for the identification of tailored prodrug candidates.
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Project description:The in vivo glucose recovery of subcutaneously implanted nitric oxide (NO)-releasing microdialysis probes was evaluated in a rat model using saturated NO solutions to steadily release NO. Such methodology resulted in a constant NO flux of 162 pmol cm(-2) s(-1) from the probe membrane over 8 h of perfusion daily. The in vivo effects of enhanced localized NO were evaluated by monitoring glucose recovery over a 14 day period, with histological analysis thereafter. A difference in glucose recovery was observed starting at 7 days for probes releasing NO relative to controls. Histological analysis at 14 days revealed lessened inflammatory cell density at the probe surface and decreased capsule thickness. Collectively, the results suggest that intermittent sustained NO release from implant surfaces may improve glucose diffusion for subcutaneously implanted sensors by mitigating the foreign body reaction.
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Project description:The release of the main vasodilator nitric oxide (NO) by the endothelial NO synthase (eNOS) is a hallmark of endothelial function. We aim at elucidating the underlying mechanism how eNOS activity depends on cortical stiffness (?(cortex)) of living endothelial cells. It is hypothesized that cortical actin dynamics determines ?(cortex) and directly influences eNOS activity. By combined atomic force microscopy and fluorescence imaging we generated mechanical and optical sections of single living cells. This approach allows the discrimination between ?(cortex) and bulk cell stiffness (?(bulk)) and, additionally, the simultaneous analysis of submembranous actin web dynamics. We show that ?(cortex) softens when cortical F-actin depolymerizes and that this shift from a gel-like stiff cortex to a soft G-actin rich layer, triggers the stiffness-sensitive eNOS activity. The results implicate that stiffness changes in the ?100 nm phase of the submembranous actin web, without affecting ?(bulk), regulate NO release and thus determines endothelial function.
| S-EPMC3402397 | biostudies-literature
Project description:Implantable glucose biosensors provide real-time information about blood glucose fluctuations, but their utility and accuracy are time-limited due to the foreign body response (FBR) following their insertion beneath the skin. The slow release of nitric oxide (NO), a gasotransmitter with inflammation regulatory properties, from a sensor surface has been shown to dramatically improve sensors' analytical biocompatibility by reducing the overall FBR response. Indeed, work in a porcine model suggests that as long as the implants (sensors) continue to release NO, even at low levels, the inflammatory cell infiltration and resulting collagen density are lessened. While these studies strongly support the benefits of NO release in mitigating the FBR, the mechanisms through which exogenous NO acts on the surrounding tissue, especially under the condition of hyperglycemia, remain vague. Such knowledge would inform strategies to refine appropriate NO dosage and release kinetics for optimal therapeutic activity. In this study, we evaluated mediator, immune cell, and mRNA expression profiles in the local tissue microenvironment surrounding implanted sensors as a function of NO release, diabetes, and implantation duration. A custom porcine wound healing-centric multiplex gene array was developed for nanoString barcoding analysis. Tissues adjacent to sensors with sustained NO release abrogated the implant-induced acute and chronic FBR through modulation of the tissue-specific immune chemokine and cytokine microenvironment, resulting in decreased cellular recruitment, proliferation, and activation at both the acute (7-d) and chronic (14-d) phases of the FBR. Further, we found that sustained NO release abrogated the implant-induced acute and chronic foreign body response through modulation of mRNA encoding for key immunological signaling molecules and pathways, including STAT1 and multiple STAT1 targets including MAPK14, IRAK4, MMP2, and CXCL10. The condition of diabetes promoted a more robust FBR to the implants, which was also controlled by sustained NO release.
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Project description:The purpose of this study is to comprehensively elucidate the role of nitric oxide and nitric oxide synthase isoforms in pulmonary emphysema using cap analysis of gene expression (CAGE) sequencing.
2021-01-18 | GSE164521 | GEO