A self-supplying nitric oxide coating on Mg alloy for vascular stents promotes re-endothelialization.

Six nickel( ii ) complexes of two 4-bromobenzhydrazones have been synthesized and characterized. They show distorted octahedral geometry with rich supramolecular interactions, and promising binding affinity towards B-DNA and SARS-CoV-2 M pro .

In 1987, it was demonstrated that nitric oxide (NO) is the endothelium-derived relaxing factor (EDRF). This opened a long history of confirming that NO is synthesized in all tissues through constitutive synthases in the endothelium and nervous system, and inducible synthases in cells of the immune system. In parallel, it was proven that nitrovasodilators (NVDs), such as nitroglycerin (NTG), are transformed into NO and develop their vasodilatory action through the action of the NO/cGMP pathway. In 1990, we verified that transdermic NTG, in addition to relaxing smooth muscle cells, also had anti-inflammatory effects in inflammatory processes accessible via this route, such as superficial thrombophlebitis or supraspinatus tendonitis. Ten years later, other authors began to confirm this effect of transdermal NTG, but in recent years, the types of chemical molecules that have been used as vehicles for both NTG and other nitrated compounds capable of delivering NO in large doses to very precise locations while avoiding its systemic effect, have expanded. In fact, nanoliposomal NTG is indicated as a potent anti-inflammatory substance. New fields are opening up in the treatment of neurodegenerative diseases, cancer, and inflammatory joint processes such as rheumatoid arthritis and osteoarthritis. The use of NO/titanium nitride as a coating for stents and pacemaker or defibrillator leads is now common, reducing thrombotic complications.

ABSTRACTProinflammatory cytokine interleukin (IL)‐1β is a key mediator of the inflammatory response in atherosclerosis. Targeting IL‐1β represents a new approach for the anti‐inflammatory therapy of cardiovascular diseases. Based on our previous data demonstrating that cardioprotective 6‐piperazinyl purines can effectively inhibit IL‐1β release in vascular cells, in this study, we present the synthesis of a next generation of purine analogues bearing either a furoxan moiety as a nitric oxide (NO) donor, or a (methylsulfonyl)thio group, a benzothioamide, or a 5‐phenyl‐3H‐1,2‐dithiole‐3‐thione as putative hydrogen sulfide (H2S) donor moieties. NO and H2S are gaseous signaling molecules that can reduce vascular inflammation. The new purine analogues were evaluated for their anti‐inflammatory activity by assessing their inhibitory effect on the secretion of lipopolysaccharide (LPS)‐induced IL‐1β in human aortic smooth muscle cells (HAoSMCs). Our initial findings revealed that compounds bearing a [methylsulfonyl)thio]propanoyl or [methylsulfonyl)thio]hexanoyl group (compounds MK175 and MK169, respectively) could effectively inhibit LPS‐induced IL‐1β release in HAoSMCs.

Chitosan-SNAP composite coating with sustained NO release for microbial killing and tomato preservation.

Photodynamic therapy (PDT) is often constrained by the insufficient therapeutic effect of reactive oxygen species (ROS) and poor stability of photosensitizers. To address these challenges, PdRu bimetallic nanoalloys (PdRu@PL) loaded with L-arginine (L-arg) as a nitric oxide (NO) donor were developed for synergistic PDT. A series of distinct morphologies-nanospheres, nanoflowers, and nanosheets-were synthesized, with the highly stable and uniformly alloyed PdRu NPs selected for further functionalization via PEGylation and L-arg loading. Under 808 nm laser irradiation, the PdRu nanoalloys exhibit excellent photothermal properties and generate ROS, including singlet oxygen and superoxide anions (˙O2-). The produced ˙O2- reacts with NO released from L-arg, forming highly cytotoxic peroxynitrite, a reactive nitrogen species. This cascade is further enhanced by catalase-like activities of the nanoalloys, which modulate the tumor microenvironment by decomposing hydrogen peroxide and alleviating hypoxia. In vitro experiments demonstrated efficient cellular uptake, concentration-dependent cytotoxicity against 4T1 cancer cells, and significant induction of apoptosis under laser exposure. In vivo studies in 4T1 tumor-bearing mice confirmed effective tumor accumulation of PdRu@PL, leading to nearly complete tumor ablation following treatment, without evident systemic toxicity. This work highlights PdRu bimetallic nanoalloys as a promising multifunctional platform for synergistic photodynamic and NO-based gas therapy, offering a strategy for enhanced anticancer efficacy.

Cobalt (Co) toxicity poses a serious constraint on plant growth by inducing oxidative stress and disrupting cellular and physiological processes. This study investigated the interactive effects of Co and sodium nitroprusside (SNP), a nitric oxide (NO) donor, on two lettuce varieties (Lactuca sativa L.): curly (var. crispa) and Romaine (var. longifolia) under controlled hydroponic conditions. Plants were exposed to Co and SNP treatments, and growth parameters, oxidative stress indicators, antioxidant enzyme activities, and Co accumulation in roots and shoots were evaluated. Co exposure markedly reduced shoot and root biomass and increased membrane permeability, hydrogen peroxide (H2O2), malondialdehyde (MDA), proline accumulation, and Co concentrations in both varieties. Co+SNP application partially alleviated Co-induced stress relative to Co treatment alone, as evidenced by moderated membrane permeability (MP), reduced lipid peroxidation (MDA), and modulation of antioxidant enzyme activities (CAT and APX), particularly in Romaine lettuce. In contrast, the response of curly lettuce to SNP application was limited, likely due to its higher Co accumulation and greater oxidative burden. Overall, the results demonstrate genotype-dependent responses to SNP application under high-dose Co stress. Although SNP modulated several stress-related parameters, Co accumulation in edible shoot tissues highlights potential food safety concerns. Therefore, the findings should be interpreted within the context of controlled hydroponic systems and provide insight into genotype-dependent stress responses rather than recommendations for food production in Co-contaminated environments.

Injectable hydrogels have made remarkable progress in the treatment of periodontitis. However, an excessively high swelling ratio causes the hydrogels to expand excessively within the periodontal pocket. Uncontrolled swelling within the confined periodontal pocket can exert detrimental pressure on surrounding tissues, leading to poor blood circulation and tissue hypoxia in the periodontal area, and may even exacerbate the inflammatory response. In this study, injectable low-swelling hydrogels with an interpenetrating polymer network structure were designed based on polysaccharides. The hydrogels were formed through the Schiff base reaction between chitosan and oxidized hyaluronic acid, and interpenetration with methacrylated sodium alginate by UV polymerization. A nitric oxide (NO) donor and epigallocatechin gallate (EGCG) were encapsulated in hydrogels to provide synergistic bioactivity. The results indicated that the hydrogels maintained a low swelling ratio in the oral environment, which also effectively inhibited bacterial growth and scavenged reactive oxygen species (ROS) through the synergistic action of NO and EGCG, thereby promoting the repair and regeneration of periodontal tissue. This research provides a new perspective for the application of injectable hydrogels in periodontitis treatment.

Although conventional immunotherapies have significantly transformed cancer treatment, their efficacy is still fundamentally limited by the immunosuppressive tumor microenvironment and systemic toxicity. In this study, we propose a Gas-Metal Synergy Strategy, which integrates immune activation and biosafety, by engineering a pH-responsive manganese-based zeolitic imidazolate framework (named MRPH) nanoplatform co-loaded with the nitric oxide (NO) donor RRX-001. MRPH selectively dissociates in the acidic TME, releasing Mn²⁺ and NO, which together amplify the activation of the cGAS-STING pathway through a synergistic mechanism: NO induces mitochondrial damage and the cytosolic release of mtDNA, while Mn²⁺ enhances the sensitivity of cGAS to mtDNA. Simultaneously, PEG-HA-modified nanoparticles enable tumor-targeted delivery, and this spatiotemporal coordination triggers immunogenic cell death, dendritic cell maturation, and CD8⁺ T cell infiltration, while inhibiting CD47-mediated immunosuppression and promoting tumor vascular normalization. Furthermore, our findings indicate that manganese-related genes are linked to immune modulation and tumor microenvironment remodeling in osteosarcoma patients. Both in vitro and in vivo studies demonstrate that MRPH significantly enhances gas-amplified metalloimmunotherapy. This work pioneers a low-toxicity paradigm that integrates gas therapy and metal-based immunotherapy, offering a transformative approach to solid tumor immunotherapy.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12951-025-03950-6.

Chilling injury (CI) is a major constraint to the postharvest shelf-life of tomato fruit (Solanum lycopersicum L.), leading to severe quality deterioration, which is closely linked to cell membrane damage. While individual postharvest treatments with the elicitors, such as methyl salicylate (MeSA), methyl jasmonate (MeJA), and the nitric oxide donor sodium nitroprusside (SNP), alleviate cold stress, their synergistic potential in combination has not been systematically explored. The present study evaluated the postharvest efficacy of 1 mM MeSA, MeJA, SNP, and their combinations (MeSA + MeJA, MeSA + SNP, MeJA + SNP) on ‘Vivalto RZ’ tomato fruits stored for 20 days at 2 °C, followed by a 2-day shelf-life period at 20 °C. All treatments effectively mitigated quality loss and CI incidence compared to the control. Notably, the MeSA + SNP and MeJA + SNP combinations demonstrated the highest efficacy, resulting in the lowest CI indices (1.2–1.4 vs. 3.4 in control) and the best preservation of firmness and titratable acidity. This enhanced tolerance was correlated with improved membrane integrity (lower malondialdehyde content and ion leakage) and the strongest upregulation of the antioxidant system, specifically achieving the highest ascorbate peroxidase (APX) activity. The combined application of MeSA or MeJA with SNP exerts a synergistic effect that provides superior chilling tolerance, representing a highly effective and commercially viable strategy to extend the postharvest shelf-life of tomato fruit.

Acute pulmonary embolism (PE) is the third leading cause of cardiovascular mortality after ischemic heart disease and stroke. Along with thrombolysis, reducing pulmonary vascular resistance in PE is one of the important pathogenetic ways of treating this pathology. The article presents a review of current literature data on the prospects for fundamental research into potential pulmonary vasodilators. A vasodilator used in clinical practice should be selective, if possible, for pulmonary vessels, not contribute to the aggravation of arterial hypotension, and not have a negative inotropic effect on the heart. The purpose of this study was to analyze the available literature data on experimental research aimed at using vasodilators in modeling of PE in animals. The publications were retrieved from such databases as PubMed, Scopus, Web of Science, and Russian Science Citation Index. Since the development of pulmonary vasoconstriction in PE is promoted by neurogenic, humoral, and local mechanisms, it is impossible to single out the only key 'target' for the use of a vasodilator. Promising areas of research may include the search for new nitric oxide donors and the study of the vasodilator properties of such compounds as 1.2-propanediol and N-nitroso-N-morpholino-amino-acetonitrile. It is also necessary to study the vasodilator properties of argon as a potential agonist of GABA receptors in pulmonary vascular smooth muscle cells. Selective action on Ca2+, K+, and Na+ ion channels in pulmonary vascular smooth muscle cells could be a potential method of vasodilation in pulmonary thromboembolism. Piezo1 mechanosensitive channels of the pulmonary vascular endothelium may be a pharmacological target for vasodilation in PE. Further study of the mechanisms regulating intrapulmonary and bronchopulmonary shunt blood flow is also necessary to find new approaches to reducing pulmonary vascular resistance in PE. The effects of vasodilators in PE could be more pronounced if pathogenetic constrictor neurogenic mechanisms are eliminated simultaneously with their use. One of the approaches to reducing the neurogenic component of the constrictor reaction of pulmonary vessels in PE conditions could be the effect on inhibitory presynaptic receptors located at the endings of sympathetic nerves.

An atom- and step-economical electrochemical method for the synthesis of aliphatic nitro-NNO-azoxy compounds from the corresponding nitroso compounds was developed employing ammonium dinitramide, a prospective green oxidant for aerospace propulsion applications, as both electrolyte and source of a =NNO2 group. The developed method is green, practical, and scalable due to constant current electrolysis in an undivided cell at high current densities. Synthesized products demonstrated pronounced NO-donor activity and fungicidal activity against phytopathogenic fungi.

BackgroundMigraine impacts 15% of the global population, predominantly women. Previous studies have shown a role for prolactin in animal migraine models induced by either stimulation of the dura mater or repeated stress exposure. However, the site of prolactin action is not fully known nor are its downstream mechanisms. This study investigated the potential downstream mechanisms and the cell types involved in prolactin- and repeated stress-induced migraine-like responses.MethodsTwo preclinical migraine models were used in this study, dural stimulation and repeated restraint stress. Dural injections in mice enabled drug delivery to the dura mater through the intersection of the lambdoidal and sagittal sutures. Additionally, a model of repeated stress-induced periorbital hypersensitivity and priming to a subthreshold nitric oxide donor was used. Von Frey filaments were used to measure periorbital mechanical thresholds before and after dural administration of prolactin or stress.ResultsConditional knockout of prolactin receptors in Nav1.8-expressing sensory neurons partially but significantly blocked the periorbital hypersensitivity caused by dural application of prolactin (0.5 µg) to female mice. Depletion of macrophages using clodronate liposome injections before dural prolactin significantly blocked the prolactin responses. The inducible nitric-oxide synthase (iNOS) inhibitor AR-C102222 (ARC; 15 mg/kg) significantly blocked the dural prolactin-induced responses. To determine whether macrophages and iNOS contribute to repetitive stress-induced periorbital hypersensitivity and priming to SNP, clodronate liposomes or ARC were given before or after repetitive stress exposure. Macrophage depletion prior to or following stress significantly inhibited stress-induced periorbital hypersensitivity in both males and females. However, ARC only blocked stress-induced migraine-like behaviors in females.ConclusionThis study demonstrates that dural prolactin acts through both neuronal and immune cell mechanisms and is dependent on iNOS activity. In response to repeated stress, macrophages contribute to behavioral responses in both sexes while iNOS is only required in females. These findings suggest that interactions between the immune and nervous systems are important for the effects of prolactin and stress on migraine-relevant mechanisms and demonstrate further sex differences in specific pathways.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-025-02261-3.

Nitric oxide-releasing dextran surface with enhanced albumin affinity mitigates infection and foreign body reaction

Androgenetic alopecia (AGA) is recognized as a prevalent androgen-mediated disorder characterized by progressive follicular miniaturization and irreversible hair loss, primarily driven by the pathological elevation of dihydrotestosterone (DHT) that disrupts hair follicle microenvironment and induces follicular cells damage. This condition frequently results in profound psychosocial distress and diminished quality of life among affected individuals. In this study, we introduced a novel microneedle-based drug delivery system (CK/GSNO@Lip MN) for the synergistic treatment of AGA. The system was ingeniously engineered for the co-delivery of Ginsenoside Compound K (CK) and S-nitrosoglutathione (GSNO), which possessed distinct hydrophobicities and release kinetics. Specifically, the hydrophobic drug CK activated the PI3K-AKT signaling pathway to upregulate β-catenin expression, while concurrently modulating reactive oxygen species (ROS) levels and alleviating excessive inflammatory responses. Meanwhile, the hydrophilic nitric oxide (NO) donor GSNO released NO to enhance angiogenesis and synergistically regulated inflammatory homeostasis in conjunction with CK, thereby creating a favorable microenvironment for hair regeneration. Ultimately, CK/GSNO@Lip MN achieved significant hair regeneration by modulating the hair follicle microenvironment and promoting the proliferation of follicular cells. This innovative therapeutic strategy provided a comprehensive approach to AGA treatment, with promising potential for broader dermatological applications. Graphical Supplementary InformationThe online version contains supplementary material available at 10.1186/s12951-025-03944-4.

The type six secretion system (T6SS) is a macromolecular weapon used by many Gram-negative bacteria. The T6SS functions as a needle injection system that delivers effector proteins directly into neighboring bacterial cells, thereby affecting their gene expression and physiological processes. Pseudomonas aeruginosa possesses at least three distinct T6SSs, designated as H1-, H2-, and H3-T6SS. Although extensive studies have been carried out on these T6SS systems in recent years, the regulatory mechanisms of T6SS remain incomplete. Here, we report the identification of norCBD as an operon that modulates the transcriptional activity of H2-T6SS. Both transposon insertion at norCBD and the deletion of the norCBD genes significantly reduced the CTX-H2-T6SS reporter activity. The norCBD operon encodes nitric oxide reductase (NorCBD), which reduces nitric oxide (NO) to nitrous oxide (N2O), a crucial step in reducing the toxic level of intracellular NO and facilitating anaerobic respiration. As the transcriptional regulator Dnr activates H2-type VI secretion system (H2-T6SS) in response to NO, experiments were carried out to examine whether norCBD deletion caused intracellular NO accumulation, which in turn disrupted Dnr-dependent regulation of H2-T6SS and virulence factors. The NO levels and Dnr-regulated gene expression were measured, and several virulence-related phenotypes were examined. The effects of NO donor sodium nitroprusside (SNP) and NO scavenger carboxy-phenyl-tetramethylimidazolineoxyl (CPTIO) were also tested. The data obtained indicate that deletion of norCBD led to intracellular NO accumulation, reduced H2-T6SS expression, and affected motility, pyocyanin production, and biofilm formation. Complementation of norCBD on a plasmid in the deletion mutant was able to restore H2-T6SS expression and the examined phenotypes to the wild-type levels. Treatment with CPTIO also restored H2-T6SS expression in the PAO1(ΔnorCBD). These results indicate that NorCBD plays a critical role in maintaining NO homeostasis that is necessary for effective Dnr-mediated gene regulation and multiple virulence-related traits, highlighting the importance of redox balance in coordinating respiration and pathogenesis in P. aeruginosa.

Brucella are intracellular pathogens that use flexible respiratory strategies to adapt to oxygen-limited conditions. The nor operon encodes components of nitric oxide reductase (Nor), which are involved in denitrification and nitric oxide (NO) detoxification. In this study, the role of the norD gene in nitrate-dependent respiration, resistance to nitrosative stress, and intracellular persistence in B. abortus was evaluated. A non-polar ΔnorD mutant was generated in strain 2308W and its survival and growth under aerobic and anaerobic conditions, with and without nitrate, as well as its tolerance to NO donors, were analyzed. In addition, its behavior was evaluated in activated and non-activated murine RAW264.7 and human THP-1 macrophages and in a murine infection model. The deletion of norD did not affect viability or growth under any of the conditions tested, nor did it alter resistance to NO in vitro or within activated macrophages. Furthermore, the mutant showed virulence comparable to the wild-type strain in BALB/c mice. These results contrast with those described for other Brucella species, suggesting that norD is dispensable in B. abortus 2308W virulence and that in the Brucella genus, there are species-specific differences in the role of the nor operon during infection.

Research using Drosophila melanogaster has provided fundamental insights into how diet, reproduction, genetics, and environment interact to shape aging. We showed that lifespan and reproductive traits are highly sensitive to nutritional balance, and flies represent an ideal system to disentangle these trade-offs. Across studies, protein-carbohydrate ratios, rather than caloric intake alone, determine whether investment favors reproduction or longevity. Flies naturally select nutrient ratios that maximize fecundity at the expense of survival, while dietary manipulations reveal sex-specific and transgenerational influences on stress resistance, metabolism, and antioxidant defenses. Developmental conditions, including larval diet, sugar identity, and crowding stress, further program adult physiology through insulin/IGF and TOR pathways. Our studies showed that insulin-like peptides provide non-redundant regulation of feeding, macronutrient allocation, and metabolic resilience, with neuromodulators and gut progenitors serving as key integrators of systemic signaling. Mitochondrial function and redox balance are important since expression of alternative dehydrogenases or modulation of CncC/Keap1 reshape stress resistance and lifespan. Studies of environmental toxicants, such as aluminum salts or nitric oxide donors, reveal how oxidative and nitrosative stress impair survival, while interventions like alpha-ketoglutarate or mild mitochondrial uncoupling confer context-dependent protection. Plant extracts, trace elements, and nanomaterials act as hormetic modulators of lifespan, although their benefits are tightly constrained by dose, sex, and diet. More than fifty studies published within fifteen years reveals that nutrition, reproduction, signaling pathways, and environmental exposures converge to determine healthspan, providing mechanistic insights with broad relevance to gerontology and translational biology.

In this study, a detailed spectroscopic and computational analysis was carried out on 5-azanidyl-3-(morpholin-4-yl)-1,2,3λ⁵-oxadiazol-3-ylium (Linsidomine), a well-established nitric oxide donor with significant therapeutic relevance in cardiovascular pharmacology. The compound was characterized experimentally using FT-IR, FT-Raman, UV–Visible, and NMR spectroscopy, supported by quantum chemical simulations at the HF and B3LYP/6-311 + + G(d, p) levels. The observed vibrational frequencies were systematically assigned and validated through theoretical data, including the identification of key functional group vibrations such as N = O, C–N, and N = N. Frontier molecular orbital analysis revealed a moderate HOMO–LUMO gap of 3.836 eV, indicating a balance between stability and reactivity. Electrostatic potential mapping and Mulliken charge distributions highlighted electrophilic and nucleophilic zones responsible for biological interaction and NO release mechanisms. The drug-likeness, pharmacokinetic parameters, and medicinal chemistry filters confirm the compound’s oral bioavailability, metabolic safety, and synthetic accessibility. Moreover, the simulated Vibrational Circular Dichroism (VCD) spectrum and NMR chemical shifts reinforced its conformational and stereoelectronic consistency. Together, these results demonstrate Linsidomine’s strong potential as a bioactive molecule, offering insights into its structure-activity relationships and supporting its continued development in NO-based cardiovascular therapeutics.

Post-harvest quality maintenance of bell peppers (Capsicum annuum L.) presents significant challenges in commercial agriculture due to their high perishability and sensitivity to cold storage conditions. While ethylene regulators show promise in extending storage life, the optimal timing and method of application remain unclear. To evaluate the effectiveness of two ethylene regulators (1-methylcyclopropene (1-MCP) and sodium nitroprusside (SNP) as a nitric oxide donor) applied at different developmental stages on quality retention and antioxidant preservation in bell peppers during cold storage. Green Bianca and Red California Wonder bell pepper cultivars were treated with either 1 µmol L-1 1-MCP or 5 µmol L-1 SNP at three timing intervals: pre-harvest, post-harvest, or both. Following a factorial design with three replications, fruits were stored at 7 ± 0.5 °C with 80–85% relative humidity for 28 days. Comprehensive analysis included physical attributes (firmness, weight loss, shape index), chemical properties (pH, titratable acidity, soluble solids), bioactive compounds (vitamin C, phenolics, flavonoids), pigments (chlorophylls, carotenoids, lycopene), and physiological responses (chilling injury, ion leakage, antioxidant capacity). Pre-harvest application of SNP proved most effective for both cultivars, with Green Bianca showing superior retention of vitamin C (73.19 mg100g-1), antioxidant capacity (61.06%), and minimal weight loss (0.19%). Red California Wonder demonstrated optimal response to pre-harvest NO treatment, maintaining high antioxidant activity (45.16%) and vitamin C content (99.92 mg100g-1). Treatment timing significantly influenced effectiveness, with pre-harvest applications showing particular efficacy in maintaining membrane integrity and reducing chilling injury while preserving bioactive compounds. This study establishes the timing-dependent efficacy of ethylene regulators in bell pepper preservation and provides valuable insights for developing cultivar-specific post-harvest protocols. The findings offer practical solutions for extending market life and maintaining nutritional quality of bell peppers during cold storage, with potential applications in commercial post-harvest management systems.Supplementary InformationThe online version contains supplementary material available at 10.1038/s41598-025-27407-w.