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Gas therapy has emerged as a promising approach for treating cancer, with gases like NO, H 2 S, and CO showing positive effects. Among these, NO is considered a key gas molecule with significant potential in stopping cancer progression. However, due to its high reactivity and short half-life, delivering NO directly to tumors is crucial for enhancing cancer treatment. NO-driven nanomedicines (NONs) have been developed to effectively deliver NO donors to tumors, showing great progress in recent years. This review provides an overview of the latest advancements in NO-based cancer nanotherapeutics. It discusses the types of NO donors used in current research, the mechanisms of action behind NO therapy for cancer, and the different delivery systems for NO donors in nanotherapeutics. It also explores the potential of combining NO donors with other treatments for enhanced cancer therapy. Finally, it examines the future prospects and challenges of using NONs in clinical settings for cancer treatment., (© 2024. The Author(s).)

Melanoma is an aggressive skin cancer notorious for high levels of drug resistance. Additionally, current treatments such as immunotherapies are often associated with numerous adverse side effects. The use of nitric oxide (NO) may represent an attractive treatment for melanoma due to NO's various anticancer properties, unlikeliness to foster resistance, and limited toxicity toward healthy tissues. The anticancer effects of chemical NO donors have been explored previously but with limited understanding of the needed characteristics for exerting optimal antimelanoma activity. Herein, the in vitro therapeutic efficacy of three macromolecular NO donor systems (i.e., cyclodextrin, mesoporous silica nanoparticles, and hyaluronic acid) with tunable NO-release kinetics was explored by evaluating skin permeation along with toxicity against melanoma and healthy skin cells. Cytotoxicity against melanoma cells was dependent on NO payload and not donor identity or NO-release kinetics. In contrast, cytotoxicity against healthy cells was primarily influenced by the macromolecular NO donor, with cyclodextrin- and hyaluronic acid-based NO donors having the highest therapeutic indices. In vitro skin permeation was influenced by both the size and charge of the NO donor, with smaller, more neutral donors resulting in greater permeation. A Pluronic F127 organogel was optimized for the delivery of a cyclodextrin-based NO donor. Delivery of the NO donor in this manner resulted in increased in vitro skin permeation and reduced tumor growth in an in vivo model.

Nitric oxide (NO) plays a crucial role as a messenger or effector in the body, yet it presents a dual impact on cardio-cerebrovascular health. Under normal physiological conditions, NO exhibits vasodilatory effects, regulates blood pressure, inhibits platelet aggregation, and offers neuroprotective actions. However, in pathological situations, excessive NO production contributes to or worsens inflammation within the body. Moreover, NO may combine with reactive oxygen species (ROS), generating harmful substances that intensify physical harm. This paper succinctly reviews pertinent literature to clarify the in vivo and in vitro origins of NO, its regulatory function in the cardio-cerebrovascular system, and the advantages and disadvantages associated with NO donor drugs, NO delivery systems, and vascular stent materials for treating cardio-cerebrovascular disease. The findings provide a theoretical foundation for the application of NO in cardio-cerebrovascular diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Medical device-associated infections are a pervasive global healthcare concern, often leading to severe complications. Bacterial biofilms that form on indwelling medical devices, such as catheters, are significant contributors to infections like bloodstream and urinary tract infections. This study addresses the challenge of biofilms on medical devices by introducing a portable antimicrobial catheter insert (PACI) designed to be efficient, biocompatible, and anti-infective. The PACI utilizes nitric oxide (NO), known for its potent antimicrobial properties, to deter bacterial adhesion and biofilm formation. To achieve this, a photoinitiated NO donor, S-nitroso-N-acetylpenicillamine (SNAP), is covalently linked to a polydimethylsiloxane (PDMS) polymer. This design allows for higher NO loading for long-term impact and prevents premature donor leaching, a common challenge with SNAP-blended polymers. The SNAP-PDMS material was applied to a side-glowing fiber optic and connected to a wearable light module emitting 450 nm light, creating a functional antimicrobial insert. Activation of the fiber optic, accomplished with a one-click mechanism, enables real-time NO release, maintaining controlled NO levels for a minimum of 24  hours. The therapeutic levels of NO released via photocatalysis from the PACI demonstrated remarkable efficacy, with >90 % reduction in bacterial viability against S. aureus, S. epidermidis, and P. mirabilis without any cytotoxic impact on mammalian cells. This study underscores the potential of the NO-releasing insert in clinical settings, providing a portable and adaptable solution for preventing catheter-associated infections., Competing Interests: Declaration of competing interest Dr. Elizabeth J. Brisbois is the founder of a startup company involved in exploring the possibility of using nitric oxide-releasing materials for medical applications., (Copyright © 2024. Published by Elsevier B.V.)

The prevalence of retinal neovascular diseases necessitates novel treatments beyond current therapies like laser surgery or anti-VEGF treatments, which often carry significant side effects. A novel therapeutic approach is introduced using copper-containing layered double hydroxides (Cu-LDH) nanozymes integrated with nitric oxide-releasing molecules (GSHNO), forming Cu-LDH@GSHNO aimed at combating oxidative stress within the retinal vascular system. Combination of synthetic chemistry and biological testing, Cu-LDH@GSHNO are synthesized, characterized, and assessed for curative effect in HUVECs and an oxygen-induced retinopathy (OIR) mouse model. The results indicate that Cu-LDH@GSHNO demonstrates SOD-CAT cascade catalytic ability, accompanied with GSH and nitric oxide-releasing capabilities, which significantly reduces oxidative cell damage and restores vascular function, presenting a dual-function strategy that enhances treatment efficacy and safety for retinal vascular diseases. The findings encourage further development and clinical exploration of nanozyme-based therapies, promising a new horizon in therapeutic approaches for managing retinal diseases driven by oxidative stress., (© 2024 Wiley‐VCH GmbH.)

Recently, nitric oxide (NO) has been shown to induce immunogenic cell death (ICD) in tumor cells through endoplasmic reticulum (ER) stress and mitochondrial outer membrane permeabilization (MOMP). However, NO is unstable, making direct delivery difficult. In this study, we developed a cell-penetrating polypeptide-based NO donor, poly(l-guanidine) (PLG). Given that the guanidine structure can be catalyzed by reactive oxygen species (ROS) to produce NO, helical PLG plays three roles: spontaneous cell penetration, intracellular ROS generation to produce NO, and induction of ICD. The results revealed that helical PLG generates NO inside the cell by self-inducible guanidine oxidation and that NO effectively elicits ICD by ER stress- and MOMP-dependent intertwined mechanisms.

Nitric oxide (NO) has received growing attention as an effective antibacterial agent with broad-spectrum activity and a low risk of resistance. However, it remains challenging to develop effective, controllable, and biocompatible NO-releasing materials. Here, we report a novel NO nanogenerator (AL-BNN6-PEG) self-assembled by lignin, a UV-absorbing and hydrophobic NO donor ( N , N '-di sec -butyl- N , N '-dinitroso-1,4-phenylenediamine, BNN6), and PEG-DSPE 2000 . It was discovered that upon visible light irradiation (450-460 nm), BNN6 can be decomposed by lignin within micellar nanoparticles via a photoinduced electron transfer mechanism in the aqueous medium. Lignin not only served as a sustainable carrier, enhancing the water dispersity of BNN6, but also acted as a biocompatible photosensitizer, triggering BNN6 decomposition with the concomitant release of NO. As a result, the micellar nanoparticles displayed superior antibacterial effects against Gram-negative and Gram-positive bacteria upon visible light illumination. Moreover, MTT assay revealed the negligible cytotoxic effect of the micellar nanoparticles to the mouse fibroblast cells (L929). This research provides more insight into the BNN6 decomposition mechanism and demonstrates a straightforward, effective, and biocompatible strategy for controlled NO-mediated antibacterial applications.

The multifaceted role nitric oxide (NO) plays in human physiology and pathophysiology has opened new scenarios in biomedicine by exploiting this free radical as an unconventional therapeutic against important diseases. The difficulties in handling gaseous NO and the strict dependence of the biological effects on its doses and location have made the light-activated NO precursors, namely NO photodonors (NOPDs), very appealing by virtue of their precise spatiotemporal control of NO delivery. The covalent integration of NOPDs and additional functional components within the same molecular skeleton through suitable linkers can lead to an intriguing class of multifunctional photoactivatable molecular hybrids. In this Perspective, we provide an overview of the recent advances in these molecular constructs, emphasizing those merging NO photorelease with targeting, fluorescent reporting, and phototherapeutic functionalities. We will highlight the rational design behind synthesizing these molecular hybrids and critically describe the advantages, drawbacks, and opportunities they offer in biomedical research.

Developing quantitative biosensors of superoxide (O 2 •- ) and nitric oxide (NO) anion is crucial for pathological research. As of today, the main challenge for electrochemical detection is to develop high-selectivity nano-mimetic materials to replace natural enzymes. In this study, the dendritic-like morphological structure of silver organic framework (Ag-MOF) was successfully synthesized via a solvothermal strategy. Owing to the introduction of polymeric composites results in improved electrical conductivity and catalytic activity, which promotes mass transfer and leads to faster electron efficiency. For monitoring the electrochemical signals of O 2 •- and NO, the Ag-MOF electrode substrate was produced by drop-coating, and composites were designed by cyclic voltammetric potential cycles. The designed electrode substrates demonstrate high sensitivity, wide linear concentrations of 1 nM-1000 μM and 1 nM-850 μM, and low detection limits of 0.27 nM and 0.34 nM (S/N = 3) against O 2 •- and NO. Aside from that, the sensor successfully monitored the cellular release of O 2 •- , and NO from HepG2 and RAW 264.7 living cells and has the potential to monitor exogenous NO release from donors of Diethylamine (DEA)-NONOate and sodium nitroprusside (SNP). Additionally, the developed system was applied to the analysis of O 2 •- and NO in real biological fluid samples, and the results were good satisfactory (94.10-99.57 ± 1.23%). The designed system provides a novel approach to obtaining a good electrochemical biosensor platform that is highly selective, stable, and flexible. Finally, the proposed method provides a quantitative way to follow the dynamic changes in O 2 •- and NO in biological systems., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Based on the synergistic therapeutic effect of nitric oxide (NO) and Rho-associated protein kinase (ROCK) inhibitors on glaucoma, a series of NO-donating Netarsudil derivatives were designed, synthesized, and their activities in vitro and in vivo were evaluated. Among them, ( S )- 10e released an appropriate amount of NO in aqueous humor in vitro and displayed potent ROCK inhibition. Topical administration of ( S )- 10e significantly lowered intraocular pressure in an acute ocular hypertension rabbit model and protected retinal ganglion cells in a magnetic microbead occlusion mouse model. A metabolism investigation revealed that ( S )- 10e released 7a , a metabolite after NO releasing, and 13 , an active metabolite of ( S )-Netarsudil, in rabbit eyes. Notably, introducing an NO donor moiety attenuated ROCK inhibition-induced ocular irritation in an sGC-independent manner, suggesting that the attenuated conjunctival hyperemia effect of ( S )- 10e is related to the NO-induced protein S-nitrosation of phosphodiesterase 3A (PDE3A). Overall, ( S )- 10e is a promising candidate for glaucoma treatment.

We describe here the design and antitumor evaluation of benzofuroxan-based nitric oxide (NO)-donor hybrid derivatives targeting human carbonic anhydrases (hCAs) IX and XII. The most effective compounds, 27 and 28 , demonstrated potent dual action, exhibiting low nanomolar inhibition constants against hCA IX and significant NO release. Notably, compound 27 showed significant antiproliferative effects against various cancer cell lines, particularly renal carcinoma A-498 cells. In these cells, it significantly reduced the expression of CA IX and iron-regulatory proteins, inducing apoptosis via mitochondrial caspase activity and ferroptosis pathways, as evidenced by increases in ROS, nitrite, and down-regulated expression of ferritin-encoding genes. In three-dimensional tumor models, compound 27 effectively reduced spheroid size and viability. In vivo toxicity studies in mice indicated that the compounds were well-tolerated, with no significant alterations in kidney function. These findings underscore the potential of benzofuroxan-based CA inhibitors for further preclinical evaluations as therapeutic agents targeting renal cell carcinoma.

Healthcare associated infections (HCAI) represent a significant burden worldwide contributing to morbidity and mortality and result in substantial economic consequences equating to billions annually. Although the impacts of HCAI have been felt for many years, the coronavirus pandemic has had a profound effect, escalating rates of HCAI, even with extensive preventative measures such as vaccination, personal protective equipment, and deep cleaning regimes. Therefore, there is an urgent need for new solutions to mitigate this serious health emergency. In this paper, the fabrication of nitric oxide (NO) releasing dual action polymer coatings for use in healthcare applications is described. The coatings are doped with the NO donor S -nitroso- N -acetylpenicillamine (SNAP) and release high payloads of NO in a sustained manner for in excess of 50 hours. These coatings are extensively characterized in multiple biologically relevant solutions and the antibacterial/antiviral efficacy is studied. For the first time, we assess antibacterial activity in a time course study (1, 2, 4 and 24 h) in both nutrient rich and nutrient poor conditions. Coatings exhibit excellent activity against Pseudomonas aeruginosa and methicillin resistant Staphylococcus aureus (MRSA), with up to complete reduction observed over 24 hours. Additionally, when tested against SARS-CoV-2, the coatings significantly reduced active virus in as little as 10 minutes. These promising results suggest that these coatings could be a valuable addition to existing preventative measures in the fight against HCAIs.

Nitric oxide (NO), a gasotransmitter, is known for its wide range of effects in vasodilation, cardiac relaxation, and angiogenesis. This diatomic free radical also plays a pivotal role in reducing the risk of platelet aggregation and thrombosis. Furthermore, NO demonstrates promising potential in cancer therapy as well as in antibacterial and antibiofilm activities at higher concentrations. To leverage their biomedical activities, numerous NO donors have been developed. Among these, N -nitrosamines are emerging as a notable class, capable of releasing NO under suitable photoirradiation and finding a broad range of therapeutic applications. This review discusses the design, synthesis, and biological applications of polymeric N -nitrosamines, highlighting their advantages over small molecular NO donors in terms of stability, NO payload, and target-specific delivery. Additionally, various small-molecule N -nitrosamines are explored to provide a comprehensive overview of this burgeoning field. We anticipate that this review will aid in developing next-generation polymeric N -nitrosamines with improved physicochemical properties.

Ruthenium nitrosyl (Ru-NO) complexes are of interest as photoactive nitric oxide (NO) donor candidates for local therapeutic applications. NO plays a crucial regulatory role in skin homeostasis, concentration-dependently affecting processes like the proliferation, apoptosis, autophagy and redox balance. In this context, we investigated HE-10, a ruthenium-based photoinducible NO donor, for its pro-oxidant and cytotoxic effects under light and dark conditions in VH10 human foreskin fibroblast cells. We also tested its intracellular and extracellular NO-releasing function. Our study reveals a significant dose-dependent cytotoxic effect of HE-10, an increase in intracellular reactive oxygen and nitrogen species, and the occurrence of apoptosis in skin fibroblast cells. Furthermore, exposure to both increasing doses of HE-10 and white LED light led to substantial cellular events, including a significant induction of autophagy and G2/M phase cell cycle arrest. Paradoxically, these effects were not solely attributable to NO release based on DAF2-DA NO probe results, suggesting that intracellular photochemical reactions additional to NO photolysis contribute to HE-10's biological activity. This study shows that HE-10 exhibits both cytotoxic and potential therapeutic effects, depending on concentration and light exposure. These findings are crucial for developing targeted Ru-NO complex treatments for skin diseases and potentially certain types of skin cancer, where controlled NO release could be beneficial.

Therapies for wound infections require medications with antibacterial and wound-healing functions. However, it remains a challenge to produce a single drug that can perform dual functions. Nitric oxide (NO), with its antibacterial and wound-healing activities, is an ideal solution to address this challenge. However, many controlled-release strategies for NO rely on external probes for tracing the release in situ, making it difficult to precisely assess the location and magnitude. To address this issue, this study describes a novel NO donor, DHU-NO1, capable of efficiently releasing NO under mild conditions (450 nm illumination). Simultaneously, DHU-NO1 generates the fluorophore Azure B (AZB), which enables direct, non-consumptive tracing of the NO release by monitoring the fluorescence and absorption changes in AZB. Given that NO can be conveniently traced, the amount of released NO can be controlled during biological applications, thereby allowing both functions of NO to be performed. When applied to the affected area, DHU-NO1, illuminated by both a simple light-emitting diode (LED) light source and natural light, achieves significant antibacterial effects against wound infections and promotes wound healing in mice. This study offers a novel and effective approach for treating wound infections., (© 2024 Wiley‐VCH GmbH.)

The combination of nitric oxide (NO) donors with nanomaterials has emerged as a promising approach to reduce postharvest losses. The encapsulation of NO donors provides protection from rapid degradation and controlled release, enhancing the NO effectiveness in postharvest treatments. Moreover, the application method can also influence postharvest responses. In this study, two application methods were evaluated, spraying and immersion, using S-nitrosoglutathione (GSNO, a NO donor) in free and encapsulated forms on papaya fruit. Our hypothesis was that GSNO encapsulated in chitosan nanoparticles would outperform the free form in delaying fruit senescence. In addition, this study marks the pioneering characterization of chitosan nanoparticles containing GSNO within the framework of a postharvest investigation. Overall, our findings indicate that applying encapsulated GSNO (GSNO-NP-S) through spraying preserves the quality of papaya fruit during storage. This method not only minimizes weight loss, ethylene production, and softening, but also stimulates antioxidant responses, thereby mitigating oxidative damage. Consequently, it stands out as the promising technique for delaying papaya fruit senescence. This innovative approach holds the potential to enhance postharvest practices and advance sustainable agriculture., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024. Published by Elsevier Inc.)

Cardiovascular diseases pose a significant global health challenge, contributing to high mortality rates and impacting overall well-being and quality of life. Nitric oxide (NO) plays a pivotal role as a vasodilator, regulating blood pressure and enhancing blood flow-crucial elements in preventing cardiovascular diseases, making it a prime therapeutic target. Herein, metal-based nanozymes (NZs) designed to induce NO release from both endogenous and exogenous NO-donors are investigated. Successful synthesis of gold, platinum (Pt) and cerium oxide NZs is achieved, with all three NZs demonstrating the ability to catalyze the NO release from various NO sources, namely S-nitrosothiols and diazeniumdiolates. Pt-NZs exhibit the strongest performance among the three NZ types. Further exploration involved investigating encapsulation and coating techniques using poly(lactic-co-glycolic acid) nanoparticles as experimental carriers for Pt-NZs. Both strategies showed efficiency in serving as platforms for Pt-NZs, successfully showing the ability to trigger NO release., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. The funders had no role in the design of the study nor in the decision to publish the results., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

IQ-1 (11 H -indeno[1,2- b ]quinoxalin-11-one oxime) is a specific c-Jun N-terminal kinase (JNK) inhibitor with anticancer and neuro- and cardioprotective properties. Because aryloxime derivatives undergo cytochrome P450-catalyzed oxidation to nitric oxide (NO) and ketones in liver microsomes, NO formation may be an additional mechanism of IQ-1 pharmacological action. In the present study, electron paramagnetic resonance (EPR) of the Fe 2+ complex with diethyldithiocarbamate (DETC) as a spin trap and hemoglobin (Hb) was used to detect NO formation from IQ-1 in the liver and blood of rats, respectively, after IQ-1 intraperitoneal administration (50 mg/kg). Introducing the spin trap and IQ-1 led to signal characteristics of the complex (DETC) 2 -Fe 2+ -NO in rat liver. Similarly, the introduction of the spin trap components and IQ-1 resulted in an increase in the Hb-NO signal for both the R- and the T-conformers in blood samples. The density functional theory (DFT) calculations were in accordance with the experimental data and indicated that the NO formation of IQ-1 through the action of superoxide anion radical is thermodynamically favorable. We conclude that the administration of IQ-1 releases NO during its oxidoreductive bioconversion in vivo .

Triple-negative breast cancer (TNBC) is a highly lethal malignancy, and its clinical management encounters severe challenges due to its high metastatic propensity and the absence of effective therapeutic targets. To improve druggability of aurovertin B (AVB), a natural polyketide with a significant antiproliferative effect on TNBC, a series of NO donor/AVB hybrids were synthesized and tested for bioactivities. Among them, compound 4d significantly inhibited the proliferation and metastasis of TNBC in vitro and in vivo with better safety than that of AVB. The structure-activity relationship analysis suggested that the types of NO donor and the linkers had considerable effects on the activities. Mechanistic investigations unveiled that 4d induced apoptosis and ferroptosis by the reduction of mitochondrial membrane potential and the down-regulation of GPX4, respectively. The antimetastatic effect of 4d was associated with the upregulation of DUSP1. Overall, these compelling results underscore the tremendous potential of 4d for treating TNBC.

Herein, we report the synthesis of a new hybrid compound based on a 2'-deoxyuridine nucleoside conjugated with a NO photo-donor moiety (dU-t-NO) via CuAAC click chemistry. Hybrid dU-t-NO, as well as two previously reported 2'-deoxyadenosine based hybrids (dAdo-S-NO and dAdo-t-NO), were evaluated for their cytotoxic and cytostatic activities in selected cancer cell lines. dAdo-S-NO and dAdo-t-NO hybrids displayed higher activity with respect to dU-t-NO. All hybrids showed effective release of NO in the micromolar range. The photochemical behavior of the newly reported hybrid, dU-t-NO, was studied in the RKO colon carcinoma cell line, whereas the dAdo-t-NO hybrid was tested in both colon carcinoma RKO and hepatocarcinoma Hep 3B2.1-7 cell lines to evaluate the potential effect of NO released upon irradiation on cell viability. A customized irradiation apparatus for in vitro experiments was also designed.

The development of drug-resistant microorganisms is taking a heavy toll on the biomedical world. Clinical infections are costly and becoming increasingly dangerous as bacteria that once responded to standard antibiotic treatment are developing resistance mechanisms that require innovative treatment strategies. Nitric oxide (NO) is a gaseous molecule produced endogenously that has shown potent antibacterial capabilities in numerous research studies. Its multimechanistic antibacterial methods prevent the development of resistance and have shown potential as an alternative to antibiotics. However, there has yet to be a direct comparison study evaluating the antibacterial properties of NO against antibiotic susceptible and antibiotic-resistant clinically isolated bacterial strains. Herein, standardized lab and clinically isolated drug-resistant bacterial strains are compared side-by-side for growth and viability following treatment with NO released from S-nitrosoglutathione (GSNO), an NO donor molecule. Evaluation of growth kinetics revealed complete killing of E. coli lab and clinical strains at 17.5 mM GSNO, though 15 mM displayed >50% killing and significantly reduced metabolic activity, with greater dose dependence for membrane permeability. Clinical P. aeruginosa showed greater susceptibility to GSNO during growth curve studies, but metabolic activity and membrane permeability demonstrated similar effects for 12.5 mM GSNO treatment of lab and clinical strains. MRSA lab and clinical strains exhibited total killing at 17.5 mM treatment, though metabolic activity was decreased, and membrane permeation began at 12.5 mM for both strains. Lastly, both S. epidermidis strains were killed by 15 mM GSNO, with sensitivities in metabolic activity and membrane permeability at 12.5 mM GSNO. The mirrored antibacterial effects seen by the lab and clinical strains of two Gram-negative and two Gram-positive bacteria reveal the translational success of NO as an antibacterial therapy and potential alternative to standard antibiotic treatment., (© 2024 The Author(s). Journal of Biomedical Materials Research Part B: Applied Biomaterials published by Wiley Periodicals LLC.)

Berberine was used as the lead compound in the present study to design and synthesize novel berberine derivatives by splicing bromine bridges of different berberine carbon chain lengths coupled nitric oxide donors, and their lipid lowering activities were assessed in a variety of ways. This experiment synthesized 17 new berberine nitric oxide donor derivatives. Compared with berberine hydrochloride, most of the compounds exhibited certain glycerate inhibitory activity, and compounds 6a, 6b, 6d, 12b and 12d showed higher inhibitory activity than berberine, with 6a, 6b and 6d having significant inhibitory activity. In addition, compound 6a linked to furazolidone nitric oxide donor showed better NO release in experiments; In further mechanistic studies, we screened and got two proteins, PCSK9 and ACLY, and docked two proteins with 17 compounds, and found that most of the compounds bound better with ATP citrate lyase (ACLY), among which there may be a strong interaction between compound 6a and ACLY, and the interaction force was better than the target drug Bempedoic Acid, which meaning that 6a may exert hypolipidemic effects by inhibiting ACLY; moreover, we also found that 6a may had the better performance in gastrointestinal absorption, blood-brain barrier permeability, Egan, Muegge class drug principle model calculation and bioavailability., Competing Interests: Declaration of competing interest This Project Supported by Natural Science Foundation of Heilongjiang Province(LH2022H013)., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The acidic byproducts of bacteria in plaque around orthodontic brackets contribute to white spot lesion (WSL) formation. Nitric oxide (NO) has antibacterial properties, hindering biofilm formation and inhibiting the growth of oral microbes. Materials that mimic NO release could prevent oral bacteria-related pathologies. This study aims to integrate S-nitroso-acetylpenicillamine (SNAP), a promising NO donor, into orthodontic elastomeric ligatures, apply an additional polymer coating, and evaluate the NO-release kinetics and antimicrobial activity against Streptococus mutans . SNAP was added to clear elastomeric chains (8 loops, 23 mm long) at three concentrations (50, 75, 100 mg/mL, and a control). Chains were then coated, via electrospinning, with additional polymer (Elastollan ® ) to aid in extending the NO release. NO flux was measured daily for 30 days. Samples with 75 mg/mL SNAP + Elastollan ® were tested against S. mutans for inhibition of biofilm formation on and around the chain. SNAP was successfully integrated into ligatures at each concentration. Only the 75 mg/mL SNAP chains maintained their elasticity. After polymer coating, samples exhibited a significant burst of NO on the first day, exceeding the machine's reading capacity, which gradually decreased over 29 days. Ligatures also inhibited S. mutans growth and biofilm formation. Future research will assess their mechanical properties and cytotoxicity. This study presents a novel strategy to address white spot lesion (WSL) formation and bacterial-related pathologies by utilizing nitric oxide-releasing materials. Manufactured chains with antimicrobial properties provide a promising solution for orthodontic challenges, showing significant potential for academic-industrial collaboration and commercial viability.

The effect of a promising NO donor, a binuclear nitrosyl iron complex (NIC) with 3,4-dichlorothiophenolyls [Fe 2 (SC 6 H 3 Cl 2 ) 2 (NO) 4 ], on the adenylate cyclase and soluble guanylate cyclase enzymatic systems was studied. In in vitro experiments, this complex increased the concentration of important secondary messengers, such as cAMP and cGMP. An increase of their level by 2.4 and 4.5 times, respectively, was detected at NIC concentration of 0.1 mM. The ligand of the complex, 3,4-dichlorothiophenol, produced a less pronounced effect on adenylate cyclase. It was shown that the effect of this complex on the activity of soluble guanylate cyclase was comparable to the effect of anionic nitrosyl complex with thiosulfate ligands that exhibits vasodilating and cardioprotective properties., (© 2024. Springer Science+Business Media, LLC, part of Springer Nature.)

Nitric oxide (NO) is a key signalling molecule released by vascular endothelial cells that is essential for vascular health. Low NO bioactivity is associated with cardiovascular diseases, such as hypertension, atherosclerosis, and heart failure and NO donors are a mainstay of drug treatment. However, many NO donors are associated with the development of tolerance and adverse effects, so new formulations for controlled and targeted release of NO would be advantageous. Herein, we describe the design and characterisation of a novel NO delivery system via the reaction of acidified sodium nitrite with thiol groups that had been introduced by cysteamine conjugation to porous graphene oxide nanosheets, thereby generating S-nitrosated nanosheets. An NO electrode, ozone-based chemiluminescence and electron paramagnetic resonance spectroscopy were used to measure NO released from various graphene formulations, which was sustained at >5 × 10 -10  mol cm -2 min -1 for at least 3 h, compared with healthy endothelium (cf. 0.5-4 × 10 -10  mol cm -2 min -1 ). Single cell Raman micro-spectroscopy showed that vascular endothelial and smooth muscle cells (SMCs) took up graphene nanostructures, with intracellular NO release detected via a fluorescent NO-specific probe. Functionalised graphene had a dose-dependent effect to promote proliferation in endothelial cells and to inhibit growth in SMCs, which was associated with cGMP release indicating intracellular activation of canonical NO signalling. Chemiluminescence detected negligible production of toxic N-nitrosamines. Our findings demonstrate the utility of porous graphene oxide as a NO delivery vehicle to release physiologically relevant amounts of NO in vitro, thereby highlighting the potential of these formulations as a strategy for the treatment of cardiovascular diseases., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Addressing the pervasive issue of bacteria and biofilm infections is crucial in the development of advanced antifouling wound dressings. In this study, a novel wound healing treatment using sulfobetaine (SBMA) decorated electrospun fibrous membrane based on polycaprolactone (PCL)/nitric oxide (NO) donors was developed. The fabrication involved a dual strategy, first integrating NO donors into mesoporous polydopamine (MPDA) and complexed with PCL/PEI to electrospin nanofibers. The fibrous membrane exhibited a potent antibacterial response upon irradiation at 808 nm, owing to a combination of NO and photothermal effect that effectively targets bacteria and disrupts biofilms. Surface functionalization of the membrane with PEI allowed for the attachment of SBMA via Michael addition, fabricating a zwitterionic surface, which significantly hinders protein adsorption and reduces biofilm formation on the wound dressing. In vitro and in vivo assessments confirmed the rapid bactericidal capabilities and its efficacy in biofilm eradication. Combining photothermal activity, targeted NO release and antifouling surface, this multifaceted wound dressing addresses key challenges in bacterial infection management and biofilm eradication, promoting efficient wound healing., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Biomedical devices are vulnerable to infections and biofilm formation, leading to extended hospital stays, high expenditure, and increased mortality. Infections are clinically treated via the administration of systemic antibiotics, leading to the development of antibiotic resistance. A multimechanistic strategy is needed to design an effective biomaterial with broad-spectrum antibacterial potential. Recent approaches have investigated the fabrication of innately antimicrobial biomedical device surfaces in the hope of making the antibiotic treatment obsolete. Herein, we report a novel fabrication strategy combining antibacterial nitric oxide (NO) with an antibiofilm agent N -acetyl cysteine (NAC) on a polyvinyl chloride surface using polycationic polyethylenimine (PEI) as a linker. The designed biomaterial could release NO for at least 7 days with minimal NO donor leaching under physiological conditions. The proposed surface technology significantly reduced the viability of Gram-negative Escherichia coli (>97%) and Gram-positive Staphylococcus aureus (>99%) bacteria in both adhered and planktonic forms in a 24 h antibacterial assay. The composites also exhibited a significant reduction in biomass and extra polymeric substance accumulation in a dynamic environment over 72 h. Overall, these results indicate that the proposed combination of the NO donor with mucolytic NAC on a polymer surface efficiently resists microbial adhesion and can be used to prevent device-associated biofilm formation.

Nitric oxide (NO) is an important biological messenger as well as a signaling molecule that participates in a broad range of physiological events and therapeutic applications in biological systems. However, due to its very short half-life in physiological conditions, its therapeutic applications are restricted. Efforts have been made to develop an enormous number of NO-releasing molecules (NORMs) and motifs for NO delivery to the target tissues. These NORMs involve organic nitrate, nitrite, nitro compounds, transition metal nitrosyls, and several nanomaterials. The controlled release of NO from these NORMs to the specific site requires several external stimuli like light, sound, pH, heat, enzyme, etc. Herein, we have provided a comprehensive review of the biochemistry of nitric oxide, recent advancements in NO-releasing materials with the appropriate stimuli of NO release, and their biomedical applications in cancer and other disease control., Competing Interests: Declaration of competing interest “There are no conflicts to declare”., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

S-Nitroso-N-acetylpenicillamine (SNAP) is among the most common nitric oxide (NO)-donor molecules and its solid-state photolytic decomposition has potential for inhaled nitric oxide (iNO) therapy. The photochemical NO release kinetics and mechanism were investigated by exposing solid-state SNAP to a narrow-band LED as a function of nominal wavelength and intensity of incident light. The photolytic efficiency, decomposition products, and the photolytic pathways of the SNAP were examined. The maximum light penetration depth through the solid layer of SNAP was determined by an optical microscope and found to be within 100-200 μm, depending on the wavelength of light. The photolysis of solid-state SNAP to generate NO along with the stable thiyl (RS·) radical was confirmed using Electron Spin Resonance (ESR) spectroscopy. The fate of the RS· radical in the solid phase was studied both in the presence and absence of O 2 using NMR, IR, ESR, and UPLC-MS. The changes in the morphology of SNAP due to its photolysis were examined using PXRD and SEM. The stable thiyl radical formed from the photolysis of solid SNAP was found to be reactive with another adjacent thiyl radical to form a disulfide (RSSR) or with oxygen to form various sulfonyl and sulfonyl peroxyl radicals {RS(O) x O·, x = 0 to 7}. However, the thiyl radical did not recombine with NO to reform the SNAP. From the PXRD data, it was found that the SNAP loses its crystallinity by generating the NO after photolysis. The initial release of NO during photolysis was increased with increased intensity of light, whereas the maximum light penetration depth was unaffected by light intensity. The knowledge gained about the photochemical reactions of SNAP may provide important insight in designing portable photoinduced NO-releasing devices for iNO therapy., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Nitric oxide (NO) is a gaseous molecule that has a central role in signaling pathways involved in numerous physiological processes (e.g., vasodilation, neurotransmission, inflammation, apoptosis, and tumor growth). Due to its gaseous form, NO has a short half-life, and its physiology role is concentration dependent, often restricting its function to a target site. Providing NO from an external source is beneficial in promoting cellular functions and treatment of different pathological conditions. Hence, the multifaceted role of NO in physiology and pathology has garnered massive interest in developing strategies to deliver exogenous NO for the treatment of various regenerative and biomedical complexities. NO-releasing platforms or donors capable of delivering NO in a controlled and sustained manner to target tissues or organs have advanced in the past few decades. This review article discusses in detail the generation of NO via the enzymatic functions of NO synthase as well as from NO donors and the multiple biological and pathological processes that NO modulates. The methods for incorporating of NO donors into diverse biomaterials including physical, chemical, or supramolecular techniques are summarized. Then, these NO-releasing platforms are highlighted in terms of advancing treatment strategies for various medical problems., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

The nitric oxide/cyclic guanosine monophosphate (NO/cGMP) signaling pathway is an effective mechanism involved in the treatment of hypertension. In our search for potential antihypertensive agents, a series of novel NO-donor derivatives of the 4-chromanone skeleton were designed and synthesized by coupling furoxans or nitrooxy NO-donor moieties. All derivatives showed enhanced nitric oxide releasing capacity and vasodilator activity with EC 50 values ranging from 0.0215 μM to 1.46 μM, obviously superior to those of precursor 3. These biological evaluations indicated that all compounds displayed an important vasorelaxant effect, and several compounds (9c, 14b, 14c, 14d) presented good vasodilator activity, with 14c being the best. Furthermore, molecular modeling studies revealed that compound 14c occupied the pocket well with the phosphodiesterase 5 domain in a favorable conformation. In conclusion, we observed that these novel compounds can act as structural templates for the design and subsequent development of new vasodilators and antihypertensive drugs., (© 2022 John Wiley & Sons Ltd.)

In this study, a series of novel furoxan-based nitric oxide (NO) releasing derivatives of pyranocarbazole alkaloids were designed, synthesized, and biologically evaluated against human cancer cell lines. The derivatives showed considerable antiproliferative activities (IC 50  = 0.05-7.55 μM) and most compounds showed higher activity in MDA-MB-231 than H460 and HeLa. Especially, the most active derivative 7a (IC 50  = 0.05 μM) against MDA-MB-231 was about 60 times stronger than lead compound, as well as equivalent to positive control taxol, and produced high levels of NO in MDA-MB-231. Furthermore, 7a could significantly inhibit the growth of MDA-MB-231 tumors in vivo with low toxicity and the PI3K/Akt signaling pathway. These results indicated that compound 7a could be a promising lead for further studies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Hypothesis: Alginate is widely used in biomedical applications due to its high biocompatibility as well as structural and mechanical similarities to human tissue. Further, simple ionic crosslinking of alginate allows for the formation of alginate beads capable of drug delivery. S-nitrosoglutathione is a water-soluble molecule that releases nitric oxide in physiological conditions, where it acts as a potent antimicrobial gas, among other functions. As macrophages and endothelial cells endogenously produce nitric oxide, incorporating nitric oxide donors into polymers and hydrogels introduces a biomimetic approach to mitigate clinical infections, including those caused by antibiotic-resistant microorganisms. The incorporation of S-nitrosoglutathione into macro-scale spherical alginate beads is reported for the first time and shows exciting potential for biomedical applications., Experiments: Herein, nitric oxide-releasing crosslinked alginate beads were fabricated and characterized for surface and cross-sectional morphology, water uptake, size distribution, and storage stability. In addition, the NO release was quantified by chemiluminescence and its biological effects against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus were investigated. The biocompatibility of the alginate beads was tested against 3T3 mouse fibroblast cells., Findings: Overall, nitric oxide-releasing alginate beads demonstrate biologically relevant activities without eliciting a cytotoxic response, revealing their potential use as an antimicrobial material with multiple mechanisms of bacterial killing., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Physical incorporation of nitric oxide (NO) releasing materials in biomedical grade polymer matrices to fabricate antimicrobial coatings and devices is an economically viable process. However, achieving long-term NO release with a minimum or no leaching of the NO donor from the polymer matrix is still a challenging task. Herein, ( N -acetyl- S -nitrosopenicillaminyl)- S -nitrosopenicillamine (SNAP-SNAP), a penicillamine dipeptide NO-releasing molecule, is incorporated into a commercially available biomedical grade silicone rubber (SR) to fabricate a NO-releasing coating (SNAP-SNAP/SR). The storage stabilities of the SNAP-SNAP powder and SNAP-SNAP/SR coating were analyzed at different temperatures. The SNAP-SNAP/SR coatings with varying wt % of SNAP-SNAP showed a tunable and sustained NO release for up to 6 weeks. Further, S -nitroso- N -acetylpenicillamine (SNAP), a well-explored NO-releasing molecule, was incorporated into a biomedical grade silicone polymer to fabricate a NO-releasing coating (SNAP/SR) and a comparative analysis of the NO release and S -nitrosothiol (RSNO) leaching behavior of 10 wt % SNAP-SNAP/SR and 10 wt % SNAP/SR was studied. Interestingly, the 10 wt % SNAP-SNAP/SR coatings exhibited ∼36% higher NO release and 4 times less leaching of NO donors than the 10 wt % SNAP/SR coatings. Further, the 10 wt % SNAP-SNAP/SR coatings exhibited promising antibacterial properties against Staphylococcus aureus and Escherichia coli due to the persistent release of NO. The 10 wt % SNAP-SNAP/SR coatings were also found to be biocompatible against NIH 3T3 mouse fibroblast cells. These results corroborate the sustained stability and NO-releasing properties of the SNAP-SNAP in a silicone polymer matrix and demonstrate the potential for the SNAP-SNAP/SR polymer in the fabrication of long-term indwelling biomedical devices and implants to enhance biocompatibility and resist device-related infections.

An overview on the design of nitric oxide (NO) delivering surfaces for biomedical purposes is provided, with a focus on the advances of the past 5 years. A localized supply of NO is of a particular interest due to the pleiotropic biological effects of this diatomic compound. Depending on the generated NO flux, the surface can mimic a physiological release profile to provide an activity on the vascular endothelium or an antibacterial activity. Three requirements are considered to describe the various strategies leading to a surface delivering NO. Firstly, the coating must be selected in accordance with the properties of the substrate (nature, shape, dimensions…). Secondly, the releasing and/or generating kinetics of NO should match the targeted biological application. Currently, the most promising structures are developed to provide an adaptable NO supply driven by pathophysiological needs. Finally, the biocompatibility and the stability of the surface must also be considered regarding the expected residence time of the device. A critical point of view is proposed to help readers in the design of the NO delivering surface according to its expected requirement and therapeutic purpose., (© 2022 Wiley-VCH GmbH.)

Cyclic guanosine monophosphate (cGMP) is a second messenger involved in the regulation of numerous physiological processes. The modulation of cGMP is important in many diseases, but reliably assaying cGMP in live cells in a plate-based format with temporal resolution is challenging. The Förster/fluorescence resonance energy transfer (FRET)-based biosensor cGES-DE5 has a high temporal resolution and high selectivity for cGMP over cAMP, so we converted it to use bioluminescence resonance energy transfer (BRET), which is more compatible with plate-based assays. This BRET variant, called CYGYEL (cyclic GMP sensor using YFP-PDE5-Rluc8), was cloned into a lentiviral vector for use across different mammalian cell types. CYGYEL was characterised in HEK293T cells using the nitric oxide donor diethylamine NONOate (DEA), where it was shown to be dynamic, reversible, and able to detect cGMP with or without the use of phosphodiesterase inhibitors. In human primary vascular endothelial and smooth muscle cells, CYGYEL successfully detected cGMP mediated through either soluble or particulate guanylate cyclase using DEA or C-type natriuretic peptide, respectively. Notably, CYGYEL detected differences in kinetics and strength of signal both between ligands and between cell types. CYGYEL remained selective for cGMP over cAMP, but this selectivity was reduced compared to cGES-DE5. CYGYEL streamlines the process of cGMP detection in plate-based assays and can be used to detect cGMP activity across a range of cell types.

Nitric oxide (NO) has an important class of endogenous diatomic molecules that play a key regulatory role in many physiological and biochemical processes. However, the type of nitrosamine NO donor stimulated by light has many advantages compared to the conventional NO donors such as diazeniumdiolates and S -nitrosothiols compounds, including easy synthesis, good stability, and controllable release. In addition, NO release can be regulated by light induction with a built-in calibration mechanism fluorescence. Here, we report that the migration and proliferation of human umbilical vein vascular endothelial cells could be accelerated by the light-triggered NO donors, leading to the angiogenesis. Meanwhile, the screened NO donor 3a with Levofloxacin (Lev) showed synergistic effects to eradicate Methicillin-resistant Staphylococcus aureus (MRSA) biofilms in vitro and treat bacteria-infected wound in vivo.

In modern chemical and biochemical studies, special attention is paid to molecular systems capable of generating nitric oxide (NO), which is one of the most important signalling molecules in the body and can trigger a whole cascade of reactions. Despite the importance of this molecule, the mechanisms of its formation in living organisms remain a subject of debate. This review combines the most important methods of releasing NO from endogenous and exogenous sources. The history of endogenous NO donors dates back more than 150 years, since the synthesis of nitroglycerin, which remains the standard vasodilator today, even though it is known that it and many other similar compounds lead to the development of a nitrate tolerance. Particular awareness is devoted to the mechanisms of NO formation without the participation of enzymes, since these methods are most important for creating exogenous sources of NO as drugs. The study of NO formation methods is centred on both the creation of new NO donors and understanding the mechanisms of tolerance to them., (Copyright © 2021 Elsevier Inc. All rights reserved.)

From unstable crystals to relatively stable monohydrate crystals, many researchers have been working on S-nitrosocaptopril for more than two decades. S-nitrosocaptopril monohydrate (Cap-NO·H 2 O) is a novel crystal form of S-nitrosocaptopril (Cap-NO), and is not only a nitric oxide (NO) donor, but also an angiotensin-converting enzyme inhibitor (ACEI). Yet, a method for long-term storage has never been reported. In order to determine the optimal storage conditions, Plackett-Burman (PB) design was performed to confirm the critical factors. Response surface methodology (RSM) was employed to determine the optimal Cap-NO·H 2 O storage condition, based on the rough interval determined by the path of steepest ascent experiment. The optimized storage condition was denoted as nitrogen purity of 97%, temperature of -10 °C and 1.20 g deoxidizer. In this case, a final preservation rate of 97.91 ± 0.59% could be obtained. In specific storage conditions, Cap-NO·H 2 O was found to be stable for at least 6 months in individual PE package, procreating a potentially applicable avenue.

It has been previously demonstrated that metal nanoparticles embedded into polymeric materials doped with nitric oxide (NO) donor compounds can accelerate the release rate of NO for therapeutic applications. Despite the advantages of elevated NO surface flux for eradicating opportunistic bacteria in the initial hours of application, metal nanoparticles can often trigger a secondary biocidal effect through leaching that can lead to unfavorable cytotoxic responses from host cells. Alternatively, copper-based metal organic frameworks (MOFs) have been shown to stabilize Cu 2+/1+ via coordination while demonstrating longer-term catalytic performance compared to their salt counterparts. Herein, the practical application of MOFs in NO-releasing polymeric substrates with an embedded NO donor compound was investigated for the first time. By developing composite thermoplastic silicon polycarbonate polyurethane (TSPCU) scaffolds, the catalytic effects achievable via intrapolymeric interactions between an MOF and NO donor compound were investigated using the water-stable copper-based MOF H 3 [(Cu 4 Cl) 3 (BTTri) 8 -(H 2 O) 12 ]·72H 2 O (CuBTTri) and the NO donor S -nitroso- N -acetyl-penicillamine (SNAP). By creating a multifunctional triple-layered composite scaffold with CuBTTri and SNAP, the surface flux of NO from catalyzed SNAP decomposition was found tunable based on the variable weight percent CuBTTri incorporation. The tunable NO surface fluxes were found to elicit different cytotoxic responses in human cell lines, enabling application-specific tailoring. Challenging the TSPCU-NO-MOF composites against 24 h bacterial growth models, the enhanced NO release was found to elicit over 99% reduction in adhered and over 95% reduction in planktonic methicillin-resistant Staphylococcus aureus , with similar results observed for Escherichia coli . These results indicate that the combination of embedded MOFs and NO donors can be used as a highly efficacious tool for the early prevention of biofilm formation on medical devices.

Lignin is an important component of the healing tissue in fruits. In this study, we treated muskmelon (Cucumis melo L. cv. "Manao") fruit with exogenous nitric oxide (NO) donor sodium nitroprusside (SNP) to observe and analyze its effect on lignin synthesis and accumulation during healing. Results showed that SNP treatment enhanced the contents of endogenous NO and H 2 O 2 , increased the activities of phenylalanine ammonia lyase, cinnamate 4 hydroxylase, cinnamyl alcohol dehydrogenase, and peroxidase, and raised the contents of sinapyl alcohol, coniferyl alcohol, coumaryl alcohol, and lignin. SNP augmented the hardness of the healing tissue and decreased its resilience, springiness, and cohesiveness. In addition, SNP treatment effectively reduced the weight loss and disease index of wounded muskmelons. All these results suggest that lignin metabolism mediated by NO play a crucial role in wound healing of muskmelons., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

In this study, eleven new 3- and 7-positions modified scopoletin derivatives (18a-k) were designed, synthesized, and biologically evaluated against human breast cancer cell lines. Most compounds showed improved antiproliferative activity against MCF-7 and MDA-MB-231 cells and weaker cytotoxicity on human breast epithelial cell line MCF-10A than lead compound 5. Among them, compound 18e exhibited the most potent antiproliferative activity against MCF-7 cells (IC 50  = 0.37 ± 0.05 μM). Particularly, 18e produced the highest levels of nitric oxide (NO) intracellularly, and its antiproliferation effect was attenuated by hemoglobin (an NO scavenger). Further pharmacological research showed that 18e blocked the cell cycle at the G 2 /M phase, downregulated the phosphorylation of PI3K and Akt in MCF-7 cells and regulated the expressions of the apoptosis proteins to induce apoptosis. Moreover, 18e inhibited the growth of MCF-7 in vivo. Overall, 18e is a novel anticancer agent with the abilities of high concentration of NO releasing and the inhibition of PI3K/Akt signaling pathway, and may be a promising agent against MCF-7 human breast cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Drug resistance and the serious side effects caused by classical chemotherapy drugs necessitate the development of novel targeted drug delivery systems. The high lipophilicity and short half-life of nitric oxide (NO), a gas with strong antitumor activity, make it difficult to reach the tumor site and result in a poor therapeutic effect in vivo . In order to overcome the deficiencies of the existing NO donors and NO delivery vehicles, a novel strategy was proposed to deliver NO for cancer chemotherapy by the prodrug dimer self-assembly nanoparticles of NO donors. Specifically, phenylsulfonylfuroxan (FZ) was chosen as the NO donor to synthesize the prodrug dimer precursor (FZ-SS-FZ) by disulfide linkages and ester bonds. The insertion of disulfide linkages promotes the self-assembly of FZ-SS-FZ in water. After this, the dual-responsive and tumor-targeting NO delivery system (FZ-SS-FZ@FA NPs) will finally be fabricated by further introducing folic acid on the surface of nanoparticles. FZ-SS-FZ can self-assemble to form uniform nanoparticles in water, which can effectively deliver NO to the tumor site and be uptaken by tumor cells, thus resulting in specific NO release in tumor cells and inducing tumor cell apoptosis. FZ-SS-FZ@FA NPs significantly improve the drug loading and delivery efficiencies of NO for chemotherapy, while enhancing its efficacy, providing a novel strategy for the tumor-targeted delivery of NO and at the same time laying a theoretical basis for the clinical translation of NO-based gas chemotherapy, opening up a new approach for cancer chemotherapy.

Inhibition of phosphatidylcholine-specific phospholipase C (PC-PLC) has previously been shown to be a potential target for novel cancer therapeutics. One downstream consequence of PC-PLC activity is the activation of NF-κB, a nuclear transcription factor responsible for transcribing genes related to oncogenic traits, such as proliferation, angiogenesis, metastasis, and cancer cell survival. Another biological pathway linked to NF-κB is the exogenous delivery of nitric oxide (NO), which decreases NF-κB activity through an apparent negative-feedback loop. In this study, we designed and synthesised 13 novel NO-releasing derivatives of our previously reported class of PC-PLC inhibitors, 2-morpholinobenzoic acids. These molecules contained a secondary benzylamine group, which was readily nitrosylated and subsequently confirmed to release NO in vitro using a DAF-FM fluorescence-based assay. It was then discovered that these NO-releasing derivatives possessed significantly improved anti-proliferative activity in both MDA-MB-231 and HCT116 cancer cell lines compared to their non-nitrosylated parent compounds. These results confirmed that the inclusion of an exogenous NO-releasing functional group onto a known PC-PLC inhibitor enhances anti-proliferative activity and that this relationship can be exploited in order to further improve the anti-proliferative activity of current/future PC-PLC inhibitors.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are a major cause of upper gastro-intestinal (GI) ulceration and bleeding as well as cardiovascular (CV) diseases (e.g., myocardial infarction and stroke). A feature common to both these adverse events is a variety of vascular reactions. One approach to overcome these side effects has been the development of nitric-oxide (NO)-donating NSAIDs. The NO is considered to overcome some of these vascular reactions caused by NSAIDs. Unfortunately, the NO-NSAIDs developed so far have not had the expected benefits compared with NSAIDs alone., Objectives: Using in vitro preparations it is hoped to gain insight into the vascular and smooth muscle reactions induced by NO-NSAIDs compared with NSAIDs as a basis for improving the protective responses attributed to the NO-donating properties of these drugs., Methods: A range of NO-NSAIDs was synthesized based on the esterification of NSAIDs with the nitro-butoxylate as a prototype of an NO-donor. These compounds, as well as NO-donor agents and NSAIDS, were examined for their possible effects on isolated segments of digital arteries of fallow deer, which provide a robust model for determining the effects of vasodilator and vasoconstrictor activities, in comparison with those of standard pharmacological agents., Results: The NO-NSAIDs were found to antagonise the smooth muscle contractions produced by 5-hydroxytryptamine (serotonin, 5-HT). However, while almost all their parent NSAIDs had little or no effect, with the exception of the R-(-)-isomers of both ibuprofen and flurbiprofen, which caused vasodilatation, all the NO-NSAIDs tested antagonised the increase in tension produced by 5-HT., Conclusions: R-(-)-ibuprofen and R-(-)-flurbiprofen, along with the nitro-butoxyl esters of the NSAIDs examined, produce relaxation of segments of deer digital artery smooth muscle in vitro. The evidence presented suggests that their mechanism involves the release of NO or its products., (© 2021. The Author(s).)

Skin necrosis is the most serious complication of flap plastic surgery, which means the failure of the operation. Systemic administration rarely benefits the local area and can lead to side effects, while topical administration has poor permeability due to the skin barrier function. Currently, few of these common medical interventions can totally respond to the blood supply of the skin after surgery. Herein, a soluble microneedle (MN) patch made of hyaluronic acid was used to target the ischemic area in a painless and precise manner for transdermal drug delivery. Based on the important role of nitric oxide (NO) in angiogenesis, the thermosensitive NO donor (BNN6) and gold nanorods (GNRs) acting as photothermal agents were introduced into the microneedles (MNs). The hyperthermia induced by GNRs under near infrared (NIR, 808 nm) irradiation could enhance the penetration of drugs and facilitate NO release from BNN6. A series of corresponding experiments proved that the system played a significant promotion role in vascular regeneration, providing a painless, precise and NO-assisted treatment method for the ischemic perforator flaps.

The development of novel therapeutic strategies for combating Alzheimer's disease (AD) is challenging but imperative. Multifunctional nanoparticles are promising tools for regulating complex pathological dysfunctions for AD treatment. Herein, we constructed multifunctional nanoparticles consisting of regadenoson (Reg), nitric oxide (NO) donor, and YC-1 in a single molecular entity that can spontaneously self-assemble into nanoparticles and load donepezil to yield Reg-nanoparticles (Reg-NPs). The Reg moiety enabled the Reg-NPs to effectively regulate tight junction-associated proteins in the blood-brain barrier, thus facilitating the permeation of donepezil through the barrier and its accumulation in the brain. Moreover, the released NO and YC-1 activated the NO/cGMP/CREB signaling pathway by stimulating soluble guanylyl cyclase and inhibiting phosphodiesterase activity, which finally reduced cytotoxicity induced by aggregated Aβ in the neurons and was beneficial for synaptic plasticity and memory formation.

Despite technological advancement, nosocomial infections are prevalent due to the rise of antibiotic resistance. A combinatorial approach with multimechanistic antibacterial activity is desired for an effective antibacterial medical device surface strategy. In this study, an antimicrobial peptide, nisin, is immobilized onto biomimetic nitric oxide (NO)-releasing medical-grade silicone rubber (SR) via mussel-inspired polydopamine (PDA) as a bonding agent to reduce the risk of infection. Immobilization of nisin on NO-releasing SR (SR-SNAP-Nisin) and the surface characteristics were characterized by Fourier transform infrared spectroscopy and scanning electron microscopy with energy-dispersive X-ray spectroscopy and contact angle measurements. The NO release profile (7 days) and diffusion of SNAP from SR-SNAP-Nisin were quantified using chemiluminescence-based nitric oxide analyzers and UV-vis spectroscopy, respectively. Nisin quantification showed a greater affinity of nisin immobilization toward SNAP-doped SR. Matrix-assisted laser desorption/ionization mass spectrometry analysis on surface nisin leaching for 120 h under physiological conditions demonstrated the stability of nisin immobilization on PDA coatings. SR-SNAP-Nisin shows versatile in vitro anti-infection efficacy against Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus in the planktonic and adhered states. Furthermore, the combination of NO and nisin has a superior ability to impair biofilm formation on polymer surfaces. SR-SNAP-Nisin leachates did not elicit cytotoxicity toward mouse fibroblast cells and human umbilical vein endothelial cells, indicating the biocompatibility of the material in vitro . The preventative and therapeutic potential of SR-SNAP-Nisin dictated by two bioactive agents may offer a promising antibacterial surface strategy.

Gasotransmitters belong to the subfamily of endogenous gaseous signaling molecules, which find a wide range of biomedical applications. Among the various gasotransmitters, nitric oxide (NO) has an enormous effect on the cardiovascular system. Apart from this, NO showed a pivotal role in neurological, respiratory, and immunological systems. Moreover, the paradoxical concentration-dependent activities make this gaseous signaling molecule more interesting. The gaseous NO has negligible stability in physiological conditions (37 °C, pH 7.4), which restricts their potential therapeutic applications. To overcome this issue, various NO delivering carriers were reported so far. Unfortunately, most of these NO donors have low stability, short half-life, or low NO payload. Herein, we review the synthesis of NO delivering motifs, development of macromolecular NO donors, their advantages/disadvantages, and biological applications. Various NO detection analytical techniques are discussed briefly, and finally, a viewpoint about the design of polymeric NO donors with improved physicochemical characteristics is predicted.

Nitric oxide (NO) produced in plant cells has the unique ability to interact with various other biomolecules, thereby facilitating its own as well as their signaling and associated actions at their sites of biosynthesis and at other sites via transcellular long distance transport of the molecular complexes. Melatonin (Mel) is one such biomolecule produced in plant cells which has fascinated plant biologists with regard to its molecular crosstalk with other molecules to serve its roles as a growth regulator. Present work reports the synthesis of N-nitrosomelatonin (NOMela) and its preferential uptake by Arabidopsis seedlings roots and long distance transport to the leaves through vascular strands. Equimolar (250 μM) concentrations of NOMela and S-nitrosoglutathione (GSNO) in aqueous solutions bring about 52.8% more release of NO from NOMela than from GSNO. Following confocal laser scanning microscopic (CLSM) imaging, Pearson's correlation coefficient analysis of the Scatter gram of endogenously taken up NOMela demonstrates significant NO signal in roots emanating from mitochondria. NOMela (250 μM) taken up by Arabidopsis seedling roots also proved more efficient as a NO transporter from primary root to leaves than 250 μM of GSNO. These novel observations on NOMela thus hold promise to decipher its crucial role as a NO carrier and reservoir in plant cells, and also as a facilitator of melatonin action in plant development., (Copyright © 2021 Elsevier Inc. All rights reserved.)