Nitric oxide : biology and chemistry最新文献

The highly porous morphology of chitosan cryogels, with submicrometric-sized pore cell walls, provides a large surface area which leads to fast water absorption and elevated swelling degrees. These characteristics are crucial for the applications of nitric oxide (NO) releasing biomaterials, in which the release of NO is triggered by the hydration of the material. In the present study, we report the development of chitosan cryogels (CS) with a porous structure of interconnected cells, with wall thicknesses in the range of 340–881 nm, capable of releasing NO triggered by the rapid hydration process. This property was obtained using an innovative strategy based on the functionalization of CS with two previously synthesized S-nitrosothiols: S-nitrosothioglycolic acid (TGA(SNO)) and S-nitrosomercaptosuccinic acid (MSA(SNO)). For this purpose, CS was previously methacrylated with glycidyl methacrylate and subsequently submitted to photocrosslinking and freeze-drying processes. The photocrosslinked hydrogels thus obtained were then functionalized with TGA(SNO) and MSA(SNO) in reactions mediated by carbodiimide. After functionalization, the hydrogels were frozen and freeze-dried to obtain porous S-nitrosated chitosan cryogels with high swelling capacities. Through chemiluminescence measurements, we demonstrated that CS-TGA(SNO) and CS-MSA(SNO) cryogels spontaneously release NO upon water absorption at rates of 3.34 × 10⁻² nmol mg⁻¹ min⁻¹ and 1.27 × 10⁻¹ nmol mg⁻¹ min⁻¹, respectively, opening new perspectives for the use of CS as a platform for localized NO delivery in biomedical applications.

Carbon monoxide (CO) poisoning is a leading cause of poison-related morbidity and mortality worldwide. By binding to hemoglobin and other heme-containing proteins, CO reduces oxygen delivery and produces tissue damage. Prompt treatment of CO-poisoned patients is necessary to prevent acute and long-term complications. Oxygen therapy is the only available treatment. Visible light has been shown to selectively dissociate CO from hemoglobin with high efficiency without affecting oxygen affinity. Pulmonary phototherapy has been shown to accelerate the rate of CO elimination in CO poisoned mice and rats when applied directly to the lungs or via intra-esophageal or intra-pleural optical fibers. The extracorporeal removal of CO using a membrane oxygenator with optimal characteristic for blood exposure to light has been shown to accelerate the rate of CO illumination in rats with or without lung injury and in pigs. The development of non-invasive techniques to apply pulmonary phototherapy and the development of a compact, highly efficient membrane oxygenator for the extracorporeal removal of CO in humans may provide a significant advance in the treatment of CO poisoning.

Cardiac surgeries under cardiopulmonary bypass (CPB) are complex procedures with high incidence of complications, morbidity and mortality. The inhaled nitric oxide (iNO) has been frequently used as an important composite of perioperative management during cardiac surgery under CPB. We conducted a meta-analysis of published randomized clinical trials (RCTs) to assess the effects of iNO on reducing postoperative complications, including the duration of postoperative mechanical ventilation, length of intensive care unit (ICU) stay, length of hospital stay, mortality, hemodynamic improvement (the composite right ventricular failure, low cardiac output syndrome, pulmonary arterial pressure, and vasoactive inotropic score) and myocardial injury biomarker (postoperative troponin I levels). Subgroup analyses were performed to assess the effect of modification and interaction. These included iNO dosage, the timing and duration of iNO therapy, different populations (children and adults), and comparators (other vasodilators and placebo or standard care). A comprehensive search for iNO and cardiac surgery was performed on online databases. Twenty-seven studies were included after removing the duplicates and irrelevant articles. The results suggested that iNO could reduce the duration of mechanical ventilation, but had no significance in the ICU stay, hospital stay, and mortality. This may be attributed to the small sample size of the most included studies and heterogeneity in timing, dosage and duration of iNO administration. Well-designed, large-scale, multicenter clinical trials are needed to further explore the effect of iNO in improving postoperative prognosis in cardiovascular surgical patients.

Endotoxin tolerance (ET) is the hyporesponsiveness to lipopolysaccharide (LPS) after prior exposure. It is characterized by the downregulation of pro-inflammatory cytokine levels. Although ET protects against inflammation, its abolishment or recovery is critical for immunity. Nitric oxide (NO) plays various roles in the development of ET; however, its specific role in ET recovery remains unknown. To induce ET, RAW264.7 cells (a murine macrophage cell line) were pre-exposed to LPS (LPS₁, 100 ng/mL for 24 h) and subsequently re-stimulated with LPS (LPS₂, 100 ng/mL for 24 h). Expression of cytokines, NO, nitrite and inducible NO synthase (iNOS) were measured after 0, 12, 24, and 36 h of resting after LPS₁ treatment with or without the iNOS-specific inhibitor, 1400W. LPS₂-induced tumor necrosis factor-⍺ (TNF-⍺) and interleukin-6 (IL-6) were downregulated after LPS₁ treatment, confirming the development of ET. Notably, TNF-⍺ and IL-6 levels spontaneously rebounded after 12–24 h of resting following LPS₁ treatment. In contrast, levles of NO, nitrite and iNOS increased during ET development and decreased during ET recovery. Moreover, 1400W inhibited ET development and blocked the early production of NO (<12 h) during ET recovery. Our findings suggest a negative correlation between iNOS-induced NO and cytokine levels in the abolishment of ET.

Background

Cardiopulmonary bypass (CPB) is associated with intravascular hemolysis which depletes endogenous nitric oxide (NO). The impact of hemolysis on pulmonary arterial compliance (PAC) and right ventricular systolic function has not been explored yet. We hypothesized that decreased NO availability is associated with worse PAC and right ventricular systolic function after CPB.

Methods

This is a secondary analysis of an observational cohort study in patients undergoing cardiac surgery with CPB at Massachusetts General Hospital, USA (2014–2015). We assessed PAC (stroke volume/pulmonary artery pulse pressure ratio), and right ventricular function index (RVFI) (systolic pulmonary arterial pressure/cardiac output), as well as NO consumption at 15 min, 4 h and 12 h after CPB. Patients were stratified by CPB duration. Further, we assessed the association between changes in NO consumption with PAC and RVFI between 15min and 4 h after CPB.

Results

PAC was lowest at 15min after CPB and improved over time (n = 50). RVFI was highest -worse right ventricular function- at CPB end and gradually decreased. Changes in hemolysis, PAC and RVFI differed over time by CPB duration. PAC inversely correlated with total pulmonary resistance (TPR). TPR and PAC positively and negatively correlated with RVFI, respectively. NO consumption between 15min and 4 h after CPB correlated with changes in PAC (−0.28 ml/mmHg, 95%CI −0.49 to −0.01, p = 0.012) and RVFI (0.14 mmHg*L⁻¹*min, 95%CI 0.10 to 0.18, p < 0.001) after multivariable adjustments.

Conclusion

PAC and RVFI are worse at CPB end and improve over time. Depletion of endogenous NO may contribute to explain changes in PAC and RVFI after CPB.

The mammalian brain is exquisitely vulnerable to lack of oxygen. However, the mechanism underlying the brain's sensitivity to hypoxia is incompletely understood. In this narrative review, we present a case for sulfide catabolism as a key defense mechanism of the brain against acute oxygen shortage. We will examine literature on the role of sulfide in hypoxia/ischemia, deep hibernation, and leigh syndrome patients, and present our recent data that support the neuroprotective effects of sulfide catabolism and persulfide production. When oxygen levels become low, hydrogen sulfide (H₂S) accumulates in brain cells and impairs the ability of these cells to use the remaining, available oxygen to produce energy. In recent studies, we found that hibernating ground squirrels, which can withstand very low levels of oxygen, have high levels of sulfide:quinone oxidoreductase (SQOR) and the capacity to catabolize hydrogen sulfide in the brain. Silencing SQOR increased the sensitivity of the brain of squirrels and mice to hypoxia, whereas neuron-specific SQOR expression prevented hypoxia-induced sulfide accumulation, bioenergetic failure, and ischemic brain injury in mice. Excluding SQOR from mitochondria increased sensitivity to hypoxia not only in the brain but also in heart and liver. Pharmacological agents that scavenge sulfide and/or increase persulfide maintained mitochondrial respiration in hypoxic neurons and made mice resistant to ischemic injury to the brain or spinal cord. Drugs that oxidize hydrogen sulfide and/or increase persulfide may prove to be an effective approach to the treatment of patients experiencing brain injury caused by oxygen deprivation or mitochondrial dysfunction.

Nitric oxide (NO) is produced in most cells in the skin and is an important regulator of essential cutaneous functions, including responses to UV irradiation, microbial defense, wound healing, melanogenesis and epidermal permeability barrier homeostasis. Harnessing the physiological activities of NO for therapeutic use is difficult because the molecule is highly reactive and unstable. A variety of exogenous NO delivery platforms have been developed and evaluated; however, they have limited clinical applications in dermatology due to instability and poor cutaneous penetration. NO-releasing nanomaterials overcome these limitations, providing targeted tissue delivery, and sustained and controlled NO release. This review provides a comprehensive and up-to-date evaluation of the use of NO-releasing nanomaterials in dermatology for the treatment of skin and soft tissue infections and wound healing.

Emerging data from clinical studies have shown pro-inflammatory effects associated with e-cigarette use. Fractional exhaled nitric oxide (FeNO) is a biomarker of pulmonary type 2 (T2) inflammation. The effect of chronic e-cigarette use on FeNO is unclear. The aim of this study was to compare FeNO levels in COPD ex-smokers who use e-cigarettes (COPDE + e-cig) to COPDE ex-smokers (COPDE) and COPD current smokers (COPDS). FeNO levels were significantly higher in COPDE + e-cig (median 16.2 ppb) and COPDE (median 18.0 ppb) compared to COPDS (median 7.6 ppb) (p = 0.0003 and p < 0.0001 respectively). There was no difference in FeNO levels between COPDE + e-cig compared to COPDE (p > 0.9). The importance of our results is that electronic cigarette use does not alter the interpretation of FeNO results, and so does not interfere with the use of FeNO as a practical biomarker of T2 inflammation, unlike current cigarette smoking in COPD. Whilst the effect of electronic cigarette use on FeNO levels is not the same as cigarette smoke, this cannot be taken as evidence that electronic cigarettes are harmless. These differential pulmonary effects can be attributed to differences in the chemical composition of the two products.

Background

Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia. Methods: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice. Results: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception. Conclusion: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of K_ATP channels on peripheral nociceptors.

Neuronal differentiation of adipose tissue-derived stem cells (ASCs) is greatly promoted by valproic acid (VPA) with cAMP elevating agents thorough NO signaling pathways, but its mechanism is not fully understood. In the present study, we investigate the involvement of protein S-nitrosylation in the VPA-promoted neuronal differentiation of ASCs. The whole amount of S-nitrosylated protein was increased by the treatment with VPA alone for three days in ASCs. An inhibitor of thioredoxin reductase (TrxR), auranofin, further increased the amount of S-nitrosylated protein and enhances the VPA-promoted neuronal differentiation in ASCs. On the contrary, another inhibitor of TrxR, dinitrochlorobenzene, inhibited the VPA-promoted neuronal differentiation in ASCs even with cAMP elevating agents, which was accompanied by unexpectedly decreased S-nitrosylated protein. It was considered from these results that increased protein S-nitrosylation is involved in VPA-promoted neuronal differentiation of ASCs. By the proteomic analysis of S-nitrosylated protein in VPA-treated ASCs, no identified proteins could be specifically related to VPA-promoted neuronal differentiation. The identified proteins, however, included those involved in the metabolism of substances regulating neuronal differentiation, such as aspartate and glutamate.