ABSTRACT
The effect of a promising NO donor, a binuclear nitrosyl iron complex (NIC) with 3,4-dichlorothiophenolyls [Fe2(SC6H3Cl2)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.
Subject(s)
Cyclic AMP , Cyclic GMP , Cyclic GMP/metabolism , Cyclic AMP/metabolism , Animals , Iron/metabolism , Iron/chemistry , Adenylyl Cyclases/metabolism , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/chemistry , Soluble Guanylyl Cyclase/metabolism , Nitrogen Oxides/pharmacology , Nitrogen Oxides/metabolism , Nitrogen Oxides/chemistry , RatsABSTRACT
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.
Subject(s)
Fibroblasts , Nitric Oxide , Humans , Fibroblasts/drug effects , Fibroblasts/metabolism , Nitric Oxide/metabolism , Cell Line , Cell Survival/drug effects , Ruthenium/chemistry , Photosensitizing Agents/pharmacology , Photosensitizing Agents/chemistry , Reactive Oxygen Species/metabolism , Apoptosis/drug effects , Autophagy/drug effects , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/chemistry , Dose-Response Relationship, Drug , LightABSTRACT
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.
Subject(s)
Biofilms , Elastomers , Nitric Oxide , Streptococcus mutans , Streptococcus mutans/drug effects , Streptococcus mutans/growth & development , Elastomers/chemistry , Nitric Oxide/chemistry , Nitric Oxide/metabolism , Biofilms/drug effects , S-Nitroso-N-Acetylpenicillamine/pharmacology , S-Nitroso-N-Acetylpenicillamine/chemistry , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/chemical synthesis , Orthodontic Brackets/microbiology , Microbial Sensitivity Tests , Anti-Infective Agents/pharmacology , Anti-Infective Agents/chemistry , Anti-Infective Agents/chemical synthesis , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/chemical synthesis , HumansABSTRACT
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.
Subject(s)
Antineoplastic Agents , Apoptosis , Ferroptosis , Nitric Oxide Donors , Triple Negative Breast Neoplasms , Animals , Female , Humans , Mice , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/therapeutic use , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Discovery , Drug Screening Assays, Antitumor , Ferroptosis/drug effects , Mice, Inbred BALB C , Mice, Nude , Molecular Structure , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/therapeutic use , Nitric Oxide Donors/chemical synthesis , Structure-Activity Relationship , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Triple Negative Breast Neoplasms/metabolism , Oxadiazoles/chemistry , Oxadiazoles/pharmacology , Pyrans/chemistry , Pyrans/pharmacologyABSTRACT
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.
Subject(s)
Antineoplastic Agents , Nitric Oxide Donors , Nitric Oxide , Nucleosides , Humans , Cell Line, Tumor , Antineoplastic Agents/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/chemical synthesis , Nitric Oxide/metabolism , Nitric Oxide/chemistry , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/chemistry , Nucleosides/chemistry , Nucleosides/pharmacology , Cell Survival/drug effects , Click Chemistry , Cell Proliferation/drug effects , Molecular Structure , Deoxyuridine/chemistry , Deoxyuridine/pharmacology , Deoxyuridine/analogs & derivativesABSTRACT
Developing quantitative biosensors of superoxide (O2â¢-) 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 O2â¢- 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 O2â¢- and NO. Aside from that, the sensor successfully monitored the cellular release of O2â¢-, 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 O2â¢- 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 O2â¢- and NO in biological systems.
Subject(s)
Biosensing Techniques , Electrochemical Techniques , Nitric Oxide , Superoxides , Biosensing Techniques/methods , Nitric Oxide/analysis , Nitric Oxide/chemistry , Humans , Superoxides/analysis , Superoxides/chemistry , Electrochemical Techniques/methods , Mice , Animals , Hep G2 Cells , RAW 264.7 Cells , Catalysis , Limit of Detection , Metal-Organic Frameworks/chemistry , Silver/chemistry , Biomarkers/analysis , Nitric Oxide Donors/chemistryABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Escherichia coli , Nitric Oxide , Nitric Oxide/pharmacology , Nitric Oxide/chemistry , Nitric Oxide/metabolism , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Escherichia coli/drug effects , Escherichia coli/growth & development , Humans , S-Nitrosoglutathione/pharmacology , S-Nitrosoglutathione/chemistry , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/chemistry , Drug Resistance, Bacterial/drug effects , Microbial Sensitivity Tests , Pseudomonas aeruginosa/drug effects , Pseudomonas aeruginosa/growth & developmentABSTRACT
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.
Subject(s)
Acetylcysteine , Anti-Bacterial Agents , Biofilms , Escherichia coli , Nitric Oxide , Staphylococcus aureus , Acetylcysteine/chemistry , Acetylcysteine/pharmacology , Nitric Oxide/chemistry , Nitric Oxide/metabolism , Nitric Oxide/pharmacology , Staphylococcus aureus/drug effects , Escherichia coli/drug effects , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Biofilms/drug effects , Polyethyleneimine/chemistry , Polyethyleneimine/pharmacology , Biocompatible Materials/chemistry , Biocompatible Materials/pharmacology , Microbial Sensitivity Tests , Polyvinyl Chloride/chemistry , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/pharmacologyABSTRACT
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.
Subject(s)
Berberine , Hypolipidemic Agents , Nitric Oxide Donors , Berberine/pharmacology , Berberine/analogs & derivatives , Berberine/chemical synthesis , Berberine/chemistry , Hypolipidemic Agents/pharmacology , Hypolipidemic Agents/chemical synthesis , Hypolipidemic Agents/chemistry , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/chemical synthesis , Nitric Oxide Donors/chemistry , Humans , Molecular Structure , ATP Citrate (pro-S)-Lyase/antagonists & inhibitors , ATP Citrate (pro-S)-Lyase/metabolism , Proprotein Convertase 9/metabolism , Molecular Docking Simulation , Animals , Blood-Brain Barrier/drug effects , Nitric Oxide/metabolism , PCSK9 InhibitorsABSTRACT
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.
Subject(s)
Anti-Bacterial Agents , Bandages , Betaine , Biofilms , Indoles , Nanofibers , Polyesters , Wound Healing , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/administration & dosage , Biofilms/drug effects , Animals , Wound Healing/drug effects , Polyesters/chemistry , Indoles/chemistry , Indoles/pharmacology , Betaine/chemistry , Betaine/pharmacology , Betaine/analogs & derivatives , Nanofibers/chemistry , Polymers/chemistry , Nitric Oxide/metabolism , Staphylococcus aureus/drug effects , Biofouling/prevention & control , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/chemistry , Mice , Surface Properties , Escherichia coli/drug effects , Polyethyleneimine/chemistryABSTRACT
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.
Subject(s)
Graphite , Nitric Oxide , Graphite/chemistry , Nitric Oxide/metabolism , Humans , Nanostructures/chemistry , Porosity , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/pharmacology , Nitric Oxide Donors/administration & dosage , Cell Proliferation/drug effects , Cardiovascular Diseases/drug therapy , Endothelial Cells/metabolism , Endothelial Cells/drug effects , Human Umbilical Vein Endothelial Cells , Myocytes, Smooth Muscle/metabolism , Myocytes, Smooth Muscle/drug effectsABSTRACT
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.
Subject(s)
Nanostructures , Neoplasms , Humans , Nitric Oxide/chemistry , Nitric Oxide Donors/chemistry , Drug Carriers/chemistry , Neoplasms/drug therapyABSTRACT
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 O2 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)xO·, 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.
Subject(s)
Nitric Oxide , Tandem Mass Spectrometry , S-Nitroso-N-Acetylpenicillamine/pharmacology , Nitric Oxide/metabolism , Photolysis , Chromatography, Liquid , Nitric Oxide Donors/chemistry , OxygenABSTRACT
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.
Subject(s)
Neoplasms , Nitric Oxide , Humans , Nitric Oxide/metabolism , Nitric Oxide Donors/therapeutic use , Nitric Oxide Donors/chemistry , Signal Transduction , Biocompatible Materials/chemistry , GasesABSTRACT
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 EC50 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.
Subject(s)
Nitric Oxide , Vasodilator Agents , Vasodilator Agents/pharmacology , Vasodilator Agents/chemistry , Nitric Oxide/metabolism , Nitric Oxide Donors/chemistry , Antihypertensive Agents/pharmacology , Antihypertensive Agents/chemistryABSTRACT
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 (IC50 = 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 (IC50 = 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.
Subject(s)
Alkaloids , Antineoplastic Agents , Carbazoles , Drug Design , Nitric Oxide Donors , Nitric Oxide , Humans , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Screening Assays, Antitumor , Molecular Structure , Nitric Oxide/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Structure-Activity Relationship , Nitric Oxide Donors/chemistry , Nitric Oxide Donors/pharmacology , Carbazoles/chemistry , Carbazoles/pharmacology , Alkaloids/chemistry , Alkaloids/pharmacologyABSTRACT
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.
Subject(s)
Anti-Infective Agents , Gasotransmitters , Mice , Animals , Humans , Alginates/chemistry , Nitric Oxide Donors/chemistry , Nitric Oxide/metabolism , S-Nitrosoglutathione , Biomimetics , Endothelial Cells , Cross-Sectional Studies , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/chemistry , Hydrogels/chemistry , Polymers/chemistry , WaterABSTRACT
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 â¼36% 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.
Subject(s)
Nitric Oxide , Silicone Elastomers , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Escherichia coli/metabolism , Mice , Nitric Oxide/chemistry , Nitric Oxide Donors/chemistry , Nitroso Compounds , Polymers/chemistry , S-Nitroso-N-Acetylpenicillamine/chemistry , S-Nitroso-N-Acetylpenicillamine/pharmacologyABSTRACT
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.
Subject(s)
Nitric Oxide Donors , Nitric Oxide , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Endothelium, Vascular , Nitric Oxide/chemistry , Nitric Oxide Donors/chemistryABSTRACT
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.