Search Results (378)

Cerebral vasospasm (CVS) following a subarachnoid hemorrhage (SAH) is a critical complication driven by imbalances between vasodilators and vasoconstrictors. This review explores the bidirectional interplay between nitric oxide (NO) and endothelin-1 (ET-1) in CVS pathogenesis. NO, a potent vasodilator mainly produced by endothelial and neuronal nitric oxide synthase (eNOS/nNOS) under normal physiological conditions, is scavenged early after SAH by hemoglobin derivatives, leading to microcirculatory dysfunction, pericyte constriction, and impaired neurovascular coupling. Conversely, ET-1 exacerbates vasoconstriction by suppressing NO synthesis via ROS-dependent eNOS uncoupling and Rho-kinase activation. The NO/ET-1 axis further influences delayed cerebral ischemia (DCI) through mechanisms like 20-HETE-mediated cGMP suppression and oxidative stress. Emerging therapies—including NO donors, NOS gene therapy, and ET-1 receptor antagonists—aim to restore this balance. Understanding these pathways offers translational potential for mitigating CVS and improving outcomes post-SAH. Full article

Aging, one of the main factors associated with cardiovascular diseases, induces vascular modifications through nitric oxide (NO) release and oxidative stress. Based on the antioxidant properties of the non-enzymatic spirulina extract (non-Enz-Spir-E) and that degrading enzymes enhances the extract bioactivity, the aim of this study was to analyze the in vitro effect of an Alcalase-assisted Enz-Spir-E on the vasodilator function of conduit and resistance arteries (which differently contribute to blood pressure regulation) in aging. Therefore, thoracic aorta (TA) and mesenteric arteries (MA) from male Sprague–Dawley rats (20–22 months-old) were divided into two groups: non-incubated vessels and vessels exposed to Enz-Spir-E (0.1% w/v) for 3 h. The vasodilation to acetylcholine (ACh), sodium nitroprusside (SNP, a NO donor), carbon-monoxide-releasing molecule (CORM), and cromakalim (a potassium channel opener), as well as NO and superoxide anion production, were studied. Enz-Spir-E increased the ACh-, SNP-, and CORM-induced responses in both types of arteries, while the cromalakim-induced relaxation was increased only in MA. Enz-Spir-E increased NO release (TA: 5.69-fold; MA: 1.79-fold), while it reduced superoxide anion formation (TA: 0.52-fold; MA: 0.66-fold). These results indicate that Enz-Spir-E improves aging-associated vasodilation through increasing NO release/bioavailability in both types of arteries and hyperpolarizing mechanisms only in MA. Full article

Priapism is a frequent and debilitating complication in patients with sickle cell disease (SCD), characterized by recurrent ischemic episodes that can culminate in fibrosis of the erectile tissue and irreversible erectile dysfunction. Despite significant advancements in the management of acute episodes, current therapies remain largely ineffective in preventing recurrences, emphasizing the need for novel strategies that target the underlying pathophysiology. This narrative review describes the mechanistic links between oxidative stress and nitric oxide (NO) dysregulation in the pathogenesis of SCD-associated priapism, with a particular focus on the NO–cyclic guanosine monophosphate (cGMP)–phosphodiesterase type 5 (PDE5) signaling axis. We analyze preclinical evidence supporting resveratrol, a natural polyphenolic compound, as well as its NO-donor hybrid derivatives, as emerging therapeutic candidates. Additionally, we discuss the potential of combining resveratrol with current treatment approaches, and address the translational challenges that must be overcome to move from preclinical data to clinical application. Taken together, the evidence presented in this review supports resveratrol-based therapies as a promising approach for oxidative-stress-driven priapism in SCD and delineates critical perspectives for their further investigation. Full article

Cystathionine γ-lyase (CSE) is a pyridoxal 5′-phosphate (PLP)-dependent enzyme that catalyzes the final step of the transsulfuration pathway, converting cystathionine into cysteine. Additionally, CSE is also essential for the formation of cysteine hydropolysulfide (Cys-S-(S)n-H), known as supersulfides, by metabolizing cystine under pathological conditions. We previously reported that, during cystine metabolism, CSE undergoes self-inactivation through polysulfidation at the Cys136 residue. Here, contrary to the anticipated role of L-S-nitrosocysteine (L-CysNO) as a nitric oxide (NO) donor, we demonstrate that it serves as a substrate for CSE and that its metabolites inhibit the activity of the enzyme during L-CysNO metabolism. The in vitro incubation of CSE—but not the Cys136/171Val mutant—with L-CysNO resulted in the dose-dependent inhibition of supersulfide production, which was not reversed by the reducing agents. Notably, CSE activity remained unchanged upon preincubation with other NO donors, such as S-nitrosoglutathione or D-CysNO, but was inhibited when coincubated with cysteine. Furthermore, when PLP was removed from the CSE/L-CysNO premix, L-CysNO no longer inhibited CSE activity, suggesting that CSE metabolizes L-CysNO and that its metabolites contribute to enzyme inactivation. Indeed, we identified thionitrous acid and pyruvate as the primary CSE/L-CysNO reaction products. Thus, we establish L-CysNO as a CSE substrate and demonstrate that its metabolites act as enzyme inhibitors through a novel irreversible modification at the Cys136/171 residues. Full article

Dinitrosyl iron complexes (DNICs) are the most abundant nitric oxide (NO) metabolites in NO-producing cells and can be used as a platform for photochemical vehicles for NO donors. However, not much is known about the photochemical dynamics of DNICs. This study investigates the photoexcitation dynamics of a mononuclear DNIC ligated with 2-mercaptoethanol, [(HOCH₂CH₂S)₂Fe(NO)₂]⁻, in D₂O solution through femtosecond infrared spectroscopy. Approximately 70% of the excited [(HOCH₂CH₂S)₂Fe(NO)₂]⁻ at 400 nm relaxes back to the ground state with a time constant of 270 ps, and the remaining dissociates NO⁻ with a time constant of 630 ps. The resulting mononitrosyl iron complex, [(HOCH₂CH₂S)₂Fe(NO)(D₂O)₂], formed by a rapid coordination of D₂O molecule to the nascent photoproduct, [(HOCH₂CH₂S)₂Fe(NO)], reacts with the abundant thiolate, HOCH₂CH₂S⁻, in solution, producing [(HOCH₂CH₂S)₃Fe(NO)]⁻ with a rate constant of 1.3 × 10⁷ M⁻¹s⁻¹. The detailed photochemical dynamics described herein lays the groundwork for the development of NO⁻ donors using DNICs with controlled and tunable photoreactivity for potential therapeutic applications. Full article

The gas transmitters nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) play important roles in physiological regulation, including adrenal function. Among them, only NO has been directly implicated in controlling catecholamine biosynthesis. This study examined whether CO and H₂S exert similar effects by treating PC12 cells with a CO donor (CORM-2) or an H₂S donor (NaHS), with or without glucocorticoid stimulation. Gene expression of tyrosine hydroxylase (Th), dopamine β-hydroxylase (Dbh), and phenylethanolamine N-methyltransferase (Pnmt) was assessed by RT-qPCR, and catecholamine release was measured by ELISA. We found that exogenous CO decreased Th and Dbh expression, attenuated glucocorticoid-induced upregulation of catecholamine biosynthesis genes, and differentially modulated dopamine and norepinephrine release. In contrast, exogenous H₂S treatment had no significant effect. These findings identify CO as a novel regulator of catecholamine biosynthesis and highlight important differences among gas transmitters in stress-related signaling. Full article

Localized therapeutic action and targeted drug release offer compelling advantages over traditional systemic drug administration. This is particularly important for nitric oxide (NO), whose biological effects vary greatly depending on concentration and cellular environment. Light-sensitive NO donors are promising for achieving precise, on-demand NO release. However, their efficiency and photostability are limited by competing photophysical processes and the generation of reactive oxygen species (ROS). In this study, we investigate hybrid systems composed of photosensitive nitric oxide (NO) donors and silver island films (SIFs). The influence of localized surface plasmon on non-radiative relaxation pathways and ROS generation is the main focus of the paper. Upon excitation at 500 nm, we observed several-fold increase in NO release, attributed to resonant interactions between the plasmonic field and the dye molecules. By tuning the thickness of a SiO₂ buffer layer, we identified key parameters affecting process efficiency: the spectral overlap between the plasmon resonance and the sensitizer’s absorption band, and the distance between the nanoparticle and the molecule. Additionally, singlet oxygen generation increase was observed. These findings demonstrate the potential of plasmonic enhancement to controllably boost photochemical activity in organic systems, paving the way for advanced applications in phototherapy and biomedical diagnostics. Full article

Similarly to the short-lived messenger nitric oxide (NO), the more stable carbon monoxide (CO) molecule can also activate soluble guanylyl cyclase (sGC) to increase cGMP levels. However, CO-induced cGMP production is much less efficient. Using an accessible invertebrate model, we dissect a potential interaction between the canonical NO/sGC/cGMP and CO signalling pathways during development. The embryonic midgut of locusts is innervated by neurons that migrate in four discrete chains on its outer surface. Transcellular diffusing NO stimulates enteric neuron migration via cGMP signalling. The application of an NO donor results in virtually all enteric neurons being cGMP-immunoreactive while CO increases cGMP production only in approximately 33% of the migrating neurons. Cellular CO release appears to act as a slow down signal for motility. We quantify how CO specifically increases the interneuronal distance during chain migration. Moreover, time-lapse microscopy shows that CO reduces the directionality of the migrating neurons. These findings support the function of NO and CO as antagonistic signals for the coordination of collective cell migration during the development of the enteric nervous system. These experiments and the resulting insights into basic scientific questions prove once more that locust embryos are not only preparations for basic research, but also relevant models for screening of drugs targeting NO and CO signalling pathways as well as for isolating compounds affecting neuronal motility in general. Full article

Oxidative stress in hypoxic conditions impairs the regenerative process in chronic wounds, highlighting the potential of reactive oxygen species (ROS) scavengers to accelerate wound healing. Nitric oxide (NO) in particular plays a pivotal role as an endogenous gasotransmitter and as a signaling molecule involved in regulating hypoxia. In this review, we examine hydrogel-based wound healing strategies for delivering gaseous NO molecules stably to the wound site. As carriers of NO donors, these hydrogels facilitate the controlled and sustained release of NO and offer high biocompatibility and hydrophilicity. First, we first introduce the hypoxic physiology of chronic wounds and elucidate the beneficial and detrimental effects of ROS. In addition, we discuss the role of NO in angiogenesis and the wound healing process. Finally, we review various NO donors and their incorporation into hydrogels for therapeutic applications. Given the extensive use of hydrogels in wound healing, this review will provide valuable avenues for the consideration of new functional hydrogels in regenerative treatments. Full article

L-type Ca²⁺ channels, particularly Ca_V1.2, play a crucial role in cardiac excitation-contraction coupling and are known to exhibit mechanosensitivity. However, the mechanisms regulating their response to mechanical stress remain poorly understood. To investigate the mechanosensitivity and nitric oxide (NO)-dependent regulation of L-type Ca²⁺ channels in rat ventricular cardiomyocytes, we used RNA sequencing to assess isoform expression and whole-cell patch-clamp recordings to measure L-type Ca²⁺ current (I_Ca,L) under controlled mechanical and pharmacological conditions. RNA sequencing revealed predominant expression of Ca_V1.2 (TPM: 0.1170 ± 0.0075) compared to Ca_V1.3 (0.0021 ± 0.0002) and Ca_V1.1 (0.0002 ± 0.0002). Local axial stretch (6–10 μm) consistently reduced I_Ca,L in proportion to stretch magnitude. The NO donor SNAP (200 μM) had variable effects on basal I_Ca,L in unstretched cells (stimulatory, inhibitory, or biphasic) but consistently restored stretch-reduced I_Ca,L to control levels. Ascorbic acid (10 μM), which reduces S-nitrosylation, increased basal I_Ca,L and partially restored the reduction caused by stretch, implicating S-nitrosylation in channel regulation. The sGC inhibitor ODQ (5 μM) decreased I_Ca,L in both stretched and unstretched cells, indicating involvement of the NO–cGMP pathway. Mechanical stress modulates L-type Ca²⁺ channels through a complex interplay between S-nitrosylation and NO–cGMP signaling, with S-nitrosylation playing a predominant role in stretch-induced effects. This mechanism may represent a key component of cardiac mechanotransduction and could be relevant for therapeutic targeting in cardiac pathologies involving mechanically induced dysfunction. Full article

This review explores the emerging role of functionalized hydrogels in modulating the microbiome for therapeutic applications in tissue regeneration and infection control. The skin and gut microbiomes play crucial roles in maintaining tissue homeostasis, regulating immune responses, and influencing the healing process. Disruptions in microbial balance—such as those observed in chronic wounds, autoimmune conditions, or post-surgical environments—can impair regeneration and increase susceptibility to infection. Hydrogels, due to their tunable physical and chemical properties, serve as versatile platforms for delivering probiotics, prebiotics, antimicrobials, and immune-modulatory agents. The encapsulation of beneficial bacteria, such as Lactobacillus plantarum or Prevotella histicola, within hydrogels could enhance bacterial viability, targeted delivery, and immune tolerance. Additionally, hydrogels functionalized with silver nanoparticles, nitric oxide donors, and bacteriocins have demonstrated effective biofilm disruption and pathogen clearance. These systems also promote favorable immune responses, such as M2 macrophage polarization and the induction of regulatory T cells, which are essential for tissue repair. Innovative approaches, including 3D bioprinting, self-healing materials, and photothermal-responsive hydrogels, expand the clinical versatility of these systems. Full article

Nitric oxide is a gaseous signalling molecule produced by plants. Slight changes in endogenous NO levels have significant biochemical and physiological consequences. We investigated the structural and functional properties of NO-responsive antiporter genes in Arabidopsis thaliana. Phylogenetic analysis of 50 antiporter genes classified them into four subgroups based on the presence of NHX and CPA domains and the evolutionary similarity of the protein sequences. Antiporters were found scattered across the five chromosomes with unique physico-chemical properties and subcellular localisation in the plasma membrane, nucleus, chloroplasts, and vacuole. Furthermore, we performed QPCR analysis of eight different antiporter genes after infiltrating the plants with 1 mM CySNO (S-nitroso-L-cysteine), a nitric oxide donor, in WT and the loss-of-function atgsnor1-3 (disruptive S-nitrosoglutathione reductase 1 activity) plants. The AT1G79400 (CHX2), AT2G38170 (RCI4), and AT5G17400 (ER-ANT1) showed a significant increase in their expression in response to CySNO infiltration. However, their expression in atgsnor1-3 plants was found to be lower than in the WT plants, indicating a significant redundancy in the response of these genes to 1 mM levels of CySNO and physiological levels of SNOs in atgsnor1-3. On the other hand, a significant reduction in the expression of AT1G16380 (CHX1), AT2G47600 (MHX1), AT3G13320 (CAX2), and AT5G11800 (KEA6) was observed in WT plants after CySNO infiltration as well as in the leaves of atgsnor1-3 plants. Our study identified three NO-responsive antiporter genes in Arabidopsis, indicating their roles in stress responsiveness and ion homeostasis that could be used for further validation of their roles in NO signalling in plants. Full article

Background: Coagulation disorders, including both bleeding and thrombotic complications, are common in patients undergoing hemodialysis (HD). Here, we aimed to characterize platelet function in patients undergoing hemodialysis three times per week, compared to healthy controls. Methods: Platelet function was assessed using the Multiplate analyzer (Roche), which is based on multiple electrode impedance aggregometry. Platelet aggregation was induced using adenosine diphosphate (ADP), and the area under the curve (AUC) served as the primary endpoint. In addition, platelet counts and C-reactive protein (CRP) levels were measured. To further evaluate nitric oxide (NO)-mediated inhibition of platelet aggregation, blood samples were incubated with the NO donor, sodium nitroprusside (SNP), and the phosphodiesterase 5A (PDE5A) inhibitor, sildenafil. Results: A total of 60 patients undergoing HD and 67 healthy controls were included in the analysis. Patients receiving HD treatment had significantly lower platelet counts compared to healthy controls (226.9 ± 53.47 vs. 246.7 ± 47.21 G/L, p = 0.029). Platelet aggregation was markedly reduced in patients undergoing HD compared to controls (462.0 ± 266.54 vs. 644.5 ± 254.44 AU × min, p < 0.001) with a significant correlation for platelet count (r = 0.42, p = 0.001) and systemic inflammation as indicated by CRP levels (r = 0.28, p = 0.035). Following SNP and sildenafil administration, inhibition of platelet aggregation remained more pronounced in patients undergoing HD. However, the change in platelet aggregation after SNP/sildenafil treatment did not differ significantly between the groups. Conclusions: Patients undergoing HD exhibit altered platelet function, indicated by reduced aggregation and platelet counts, as well as an association with systemic inflammation. Multiple electrode impedance aggregometry appears to be a feasible method for detecting platelet function alterations in patients receiving HD treatment. Responsiveness to NO donors was preserved in patients undergoing HD. Further studies are needed to identify the underlying mechanisms, particularly the role of NO signaling in platelet dysfunction in patients undergoing HD. Full article

Cold storage is widely used for the postharvest preservation of fruits and vegetables; however, okra, as a tropical vegetable, is susceptible to chilling injury under low-temperature storage conditions, leading to quality deterioration, reduced nutritional value, and significant economic losses. Nitric oxide (NO), as an important signaling molecule, plays a crucial role in the postharvest preservation of fruits and vegetables. To investigate the effects of different concentrations of nitric oxide on the postharvest quality of okra under cold storage, fresh okra pods were treated with sodium nitroprusside (SNP), a commonly used NO donor, at concentrations of 0 (control), 0.5 (T1), 1.0 (T2), 1.5 (T3), and 2.0 mmol·L⁻¹ (T4). The results showed that low-concentration NO treatment (T1) significantly reduced weight loss, improved texture attributes including hardness, springiness, chewiness, resilience, and cohesiveness, and suppressed the increase in adhesiveness. T1 treatment also effectively inhibited excessive accumulation of cellulose and lignin, thereby maintaining tissue palatability and structural integrity. Additionally, T1 significantly delayed chlorophyll degradation, preserved higher levels of soluble sugars and proteins, and enhanced the activities of key antioxidant enzymes, including superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), contributing to improved oxidative stress resistance and membrane stability. In contrast, high-concentration NO treatments (T3 and T4) led to pronounced quality deterioration, characterized by accelerated membrane lipid peroxidation as evidenced by increased malondialdehyde (MDA) content and relative conductivity, and impaired antioxidant defense, resulting in rapid texture degradation, chlorophyll loss, nutrient depletion, and oxidative damage. These findings provide theoretical insights and practical guidance for the precise application of NO in extending shelf life and maintaining the postharvest quality of okra fruits. Full article

Nitric oxide (NO) has a dual effect on mitochondria. Incubating liver mitochondria with NO improves oxidative phosphorylation (OXPHOS) efficiency by decreasing state 4 respiration more than ATP synthesis and preventing mitochondrial permeability transition pore (mPTP) opening. We evaluated the effect of L-arginine (L-arg), an NO donor, on isolated liver mitochondrial respiration and mPTP in sepsis. Male mice were subjected to cecal ligation and perforation (CLP) with saline resuscitation or sham. After 8, 24, and 48 h, with and without L-arg, we measured isolated liver mitochondrial respiration and cytochrome c oxidase (COX) activity using polarographic methods and calcium retention capacity (CRC) to assess the mPTP and NO metabolites via the Griess reaction. Mitochondrial NO synthase (mtNOS) was identified by Western blot. CLP decreased state 3 respiration at 24 and 48 h, decreased COX activity at 8, 24, and 48 h, and increased state 4 respiration and decreased the respiratory control ratio (RCR) and CRC at 48 h. L-arg increased NO levels at 8 h, decreased state 4 respiration more than state 3 respiration (−39% versus −12%) at 48 h, decreased the CRC in the CLP groups at 24 and 48 h, but did not improve RCR. Our data suggests that L-arg does not restore liver mitochondrial OXPHOS efficiency or prevent mPTP opening in the late or recovery phases of sepsis. Full article