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Chemical biology of nitric oxide (NO). The nitrosylation/denitrosylation reactions play important role in the maintenance of NO levels in the mammalian cells. An excessive nitrosylation can lead to protein misfolding, oxidative stress and impairment of NO synthesis by the nitric oxide synthase (NOS) enzymes
Source publication
Nitric oxide (NO), a gaseous small molecule generated by the nitric oxide synthase (NOS) enzymes, plays key roles in signal transduction. The thiol groups present in many proteins and small molecules undergo nitrosylation to form the corresponding S-nitrosothiols. The release of NO from S-nitrosothiols is a key strategy to maintain the NO levels in...
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Citations
... NO release from samples was also detected using electron paramagnetic resonance (EPR) spectrometry. As described in previous studies [51][52][53], DETC 2 Fe was used for NO trapping. NaDETC (250 mM, 5 ml) and iron(II) sulfate (FeSO 4 ·7H 2 O, 50 mM, 5 ml) were separately dissolved in degassed Milli-Q water. ...
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.
... GSNO, a NO donor, was reported to release NO for cancer treatment at a rate affected by temperature, metal ions (e.g., Cu + ) and light [45][46][47]. As shown in Figure S7, GSNO with or without GSNO showed little release of NO. ...
Background
Immunogenic cell death (ICD) induced by different cancer treatments has been widely evaluated to recruit immune cells and trigger the specific antitumor immunity. However, cancer associated fibroblasts (CAFs) can hinder the invasion of immune cells and polarize the recruited monocytes to M2-type macrophages, which greatly restrict the efficacy of immunotherapy (IT).
Methods
In this study, an injectable hydrogel induced by copper (Cu) has been designed to contain antibody of PD-L1 and nitric oxide (NO) donor. The therapeutic efficacy of hydrogel was studied in 4T1 cells and CAFs in vitro and 4T1 tumor-bearing mice in vivo. The immune effects on cytotoxic T lymphocytes, dendritic cells (DCs) and macrophages were analyzed by flow cytometry. Enzyme-linked immunosorbent assay, immunofluorescence and transcriptome analyses were also performed to evaluate the underlying mechanism.
Results
Due to the absorbance of Cu with the near-infrared laser irradiation, the injectable hydrogel exhibits persistent photothermal effect to kill cancer cells. In addition, the Cu of hydrogel shows the Fenton-like reaction to produce reactive oxygen species as chemodynamic therapy, thereby enhancing cancer treatment and amplifying ICD. More interestingly, we have found that the released NO can significantly increase depletion of CAFs and reduce the proportion of M2-type macrophages in vitro. Furthermore, due to the amplify of ICD, injectable hydrogel can effectively increase the infiltration of immune cells and reverse the immunosuppressive tumor microenvironment (TME) by regulating CAFs to enhance the therapeutic efficacy of anti-PD-L1 in vivo.
Conclusions
The ion induced self-assembled hydrogel with NO could enhance immunotherapy via amplifying ICD and regulating CAFs. It provides a novel strategy to provoke a robust antitumor immune response for clinical cancer immunotherapy.
Graphical Abstract
... NO precursors such as N-diazeniumdiolates, S-nitrosothiols, organic nitrates, have been intensively studied for biomedical purposes [17][18][19]. Phenylsulfonyl furoxan (PSF) is a NO precursor molecule that releases NO in response to glutathione (GSH) [20]. Similar to most NO precursors, PSF is a hydrophobic molecule and needs a carrier to deliver itself in order to achieve optimal efficacy. ...
Self-assembled drug-polymer micelles are attractive candidates for drug delivery. In this study, amphiphilic floxuridine (FdU)-poly ε-caprolactone (PCL) conjugates containing ester bond were synthesized and self-assembled with phenylsulfonyl furoxan (PSF) to form drug-loading micelles. The micelles had an average size of 91.2 nm and a critical micelle concentration (CMC) of 8.56 μg mL−1. The Micelles were stable in physiological environment, but would decompose under intracellular conditions, releasing chemotherapeutic drug FdU and NO precursor PSF in cancer cells. Intracellular glutathione (GSH) triggered NO release from the PSF, with which the FdU inhibited cancer cells synergistically. In vitro cell and in vivo small animal experiments demonstrated that the Micelles could accumulate in the tumor and be internalized by cancer cells. The micelles inhibited the cancer cell proliferation by releasing FdU and NO. The NO acted as an MDR reversal agent and hence increased the intracellular FdU concentration, through which synergistic therapy was achieved. This drug-polymer conjugate-based micelles had high therapeutic efficacy for cancer with low side effects, providing a new approach to cancer chemotherapy.
... Similar to the previously reported examples, the fast shuffling of oxidation states at the copper center might be responsible for release of nitric oxide from GSNO at physiological pH. 56 3.4. Cytotoxicity and Luminescence Property in Mammalian Cells. ...
Copper nanoclusters (CuNCs) are emerging as an interesting class of materials for various biomedical applications. In this work, we have designed highly stable nucleobase-capped luminescent CuNCs and studied the effect of substituents on the cluster composition and photophysical properties. The NCs exhibit exceptional stability in ambient atmosphere and show significant variation in the emission properties with a change in position of substituents on the ligand, thiouracil. This study represents the first example of a nanocluster that functionally mimics the activity of a major antioxidant enzyme, superoxide dismutase (SOD). In addition to their enzyme-mimetic activity, the CuNCs evince controlled release of nitric oxide (NO), a key gaseous molecule of endothelial system from S-nitrosothiol, S-nitrosoglutathione (GSNO). Further, to a greater significance, these luminescent CuNCs are readily taken up by the mammalian cells and exhibit low toxicity. The superoxide dismutase and NO releasing activity of the fluorescent, biocompatible copper nanoclusters suggest their potential application in both therapeutics and bioimaging.
... Mugesh et al. recently reported the synthesis of Cu 2 O nanoparticles with three different morphologies: rhombic dodecahedra, cube, and octahedra (Figure 2a). [66] Octahedra-shaped nanoparticles showed two-to fivefold higher catalytic activity toward all examined RSNOs (e.g., GSNO, S-nitroso-N-acetylcysteine (SNAC), S-nitrosohomocysteine (HCysNO), and CysNO) compared to rhombic dodecahedra-and cube-like nanoparticles (Figure 2b,c). These observations indicate that particle catalytic activity is morphology-dependent. Enzyme-mimicking activity of particles has been known to depend on various factors, including size, morphology, and surface area. ...
The highly diverse biological roles of nitric oxide (NO) in both physiological and pathophysiological processes have prompted great interest in the use of NO as a therapeutic agent in various biomedical applications. NO can exert either protective or deleterious effects depending on its concentration and the location where it is delivered or generated. This double‐edged attribute, together with the short half‐life of NO in biological systems, poses a major challenge to the realization of the full therapeutic potential of this molecule. Controlled release strategies show an admirable degree of precision with regard to the spatiotemporal dosing of NO but are disadvantaged by the finite NO deliverable payload. In turn, enzyme‐prodrug therapy techniques afford enhanced deliverable payload but are troubled by the inherent low stability of natural enzymes, as well as the requirement to control pharmacokinetics for the exogenous prodrugs. The past decade has seen the advent of a new paradigm in controlled delivery of NO, namely localized bioconversion of the endogenous prodrugs of NO, specifically by enzyme mimics. These early developments are presented, successes of this strategy are highlighted, and possible future work on this avenue of research is critically discussed.
Cancer cells typically display redox imbalance compared with normal cells due to increased metabolic rate, accumulated mitochondrial dysfunction, elevated cell signaling, and accelerated peroxisomal activities. This redox imbalance may regulate gene expression, alter protein stability, and modulate existing cellular programs, resulting in inefficient treatment modalities. Therapeutic strategies targeting intra‐ or extracellular redox states of cancer cells at varying state of progression may trigger programmed cell death if exceeded a certain threshold, enabling therapeutic selectivity and overcoming cancer resistance to radiotherapy and chemotherapy. Nanotechnology provides new opportunities for modulating redox state in cancer cells due to their excellent designability and high reactivity. Various nanomaterials are widely researched to enhance highly reactive substances (free radicals) production, disrupt the endogenous antioxidant defense systems, or both. Here, the physiological features of redox imbalance in cancer cells are described and the challenges in modulating redox state in cancer cells are illustrated. Then, nanomaterials that regulate redox imbalance are classified and elaborated upon based on their ability to target redox regulations. Finally, the future perspectives in this field are proposed. It is hoped this review provides guidance for the design of nanomaterials‐based approaches involving modulating intra‐ or extracellular redox states for cancer therapy, especially for cancers resistant to radiotherapy or chemotherapy, etc.
Oxidized LDL (oxLDL) and oxysterols are known to play a crucial role in endothelial dysfunction (ED) by inducing endoplasmic reticulum stress (ERS), inflammation, and apoptosis. However, the precise molecular mechanisms underlying these pathophysiological processes remain incompletely understood. Emerging evidence strongly implicates excessive nitric oxide (NO) production in the progression of various pathological conditions. The accumulation of reactive nitrogen species (RNS) leading to nitrosative stress (NSS) and aberrant protein S-nitrosylation contribute to NO toxicity. Studies have highlighted the involvement of NSS and S-nitrosylation in perturbing ER signaling through the modification of ER sensors and resident isomerases in neurons. This review focuses on the existing evidence that strongly associates NO with ERS and the possible implications in the context of ED induced by oxLDL and oxysterols. The potential effects of perturbed NO synthesis on signaling effectors linking NSS with ERS in endothelial cells are discussed to provide a conceptual framework for further investigations and the development of novel therapeutic strategies targeting ED.
In recent years, antimicrobial resistance (AMR) has become one of the greatest threats to human health. There is an urgent need to develop new antibacterial agents to effectively treat AMR infection. Herein, a novel nanozyme platform (Cu,N‐GQDs@Ru‐NO) is prepared, where Cu,N‐doped graphene quantum dots (Cu,N‐GQDs) are covalently functionalized with a nitric oxide (NO) donor, ruthenium nitrosyl (Ru‐NO). Under 808 nm near‐infrared (NIR) light irradiation, Cu,N‐GQDs@Ru‐NO demonstrates nicotinamide adenine dinucleotide (NADH) dehydrogenase‐like activity for photo‐oxidizing NADH to NAD⁺, thus disrupting the redox balance in bacterial cells and resulting in bacterial death; meanwhile, the onsite NIR light‐delivered NO effectively eradicates the methicillin‐resistant Staphylococcus aureus (MRSA) bacterial and biofilms, and promotes wound healing; furthermore, the nanozyme shows excellent photothermal effect that enhances the antibacterial efficacy as well. With the combination of NADH dehydrogenase activity, photothermal therapy, and NO gas therapy, the Cu,N‐GQDs@Ru‐NO nanozyme displays both in vitro and in vivo excellent efficacy for MRSA infection and biofilm eradication, which provides a new therapeutic modality for effectively treating MRSA inflammatory wounds.
Nanozymes, nanomaterials with enzyme‐mimicking activity, have attracted tremendous interest in recent years owing to their ability to replace natural enzymes in various biomedical applications, such as biosensing, therapeutics, drug delivery, and bioimaging. In particular, the nanozymes capable of regulating the cellular redox status by mimicking the antioxidant enzymes in mammalian cells are of great therapeutic significance in oxidative‐stress‐mediated disorders. As the distinction of physiological oxidative stress (oxidative eustress) and pathological oxidative stress (oxidative distress) occurs at a fine borderline, it is a great challenge to design nanozymes that can differentially sense the two extremes in cells, tissues and organs and mediate appropriate redox chemical reactions. In this Review, we summarize the advances in the development of redox‐active nanozymes and their biomedical applications. We primarily highlight the therapeutic significance of the antioxidant and prooxidant nanozymes in various disease model systems, such as cancer, neurodegeneration, and cardiovascular diseases. The future perspectives of this emerging area of research and the challenges associated with the biomedical applications of nanozymes are described.
Nanozymes, nanomaterials with enzyme‐mimicking activity, have attracted tremendous interest in recent years owing to their ability to replace natural enzymes in various biomedical applications, such as biosensing, therapeutics, drug delivery, and bioimaging. In particular, the nanozymes capable of regulating the cellular redox status by mimicking the antioxidant enzymes in mammalian cells are of great therapeutic significance in oxidative‐stress‐mediated disorders. As the distinction of physiological oxidative stress (oxidative eustress) and pathological oxidative stress (oxidative distress) occurs at a fine borderline, it is a great challenge to design nanozymes that can differentially sense the two extremes in cells, tissues and organs and mediate appropriate redox chemical reactions. In this Review, we summarize the advances in the development of redox‐active nanozymes and their biomedical applications. We primarily highlight the therapeutic significance of the antioxidant and prooxidant nanozymes in various disease model systems, such as cancer, neurodegeneration, and cardiovascular diseases. The future perspectives of this emerging area of research and the challenges associated with the biomedical applications of nanozymes are described.
