High Concentrations Of Nitric Oxide Research Articles

Amino Acid Functionalized SrTiO3 Nanoarrays with Enhanced Osseointegration Through Programmed Rapid Biofilm Elimination and Angiogenesis Controlled by NIR-Driven Gas Therapy.

Bacterial biofilm formation is closely associated with persistent infections of medical implants, which can lead to implantation failure. Additionally, the reconstruction of the vascular network is crucial for achieving efficient osseointegration. Herein, an anti-biofilm nanoplatform based on L-arginine (LA)/new indocyanine green (NICG) that is anchored to strontim titanium oxide (SrTiO3) nano-arrays on a titanium (Ti) substrate by introducing polydopamine (PDA) serving as the interlayer is designed and successfully fabricated. Near-infrared light (NIR) is used to excite NICG, generating reactive oxygen species (ROS) that react with LA to release nitric oxide (NO) molecules. Utilizing the concentration-dependent effect of NO, high power density NIR irradiation applied during the early stage after implantation to release a high concentration of NO, which synergized with the photothermal effect of PDA to eliminate bacterial biofilm. Subsequently, the irradiation power density can be finely down-regulated to reduce the NO concentration in subsequent treatment for accelerating the reconstruction of blood vessels. Meanwhile, SrTiO3 nano-arrays improve the hydrophilicity of the implant surface and slowly release strontium (Sr) ions for continuously optimizing the osteogenic microenvironment. Effective biofilm elimination and revascularization alongside the continuous optimization of the osteogenic microenvironment can significantly enhance the osseointegration of the functionalized Ti implant in in vivo animal experiments.

Ferrihydrite regulated tire-wear microplastics biofilm for enhanced nitrogen transformation in surface water

Tire-wear microplastics (T-MPs) are increasingly present in surface water, which can intact with ferrihydrite and influence biofilm formation on T-MPs. However, the interaction of T-MPs and ferrihydrite on biofilm formation and its effect on nitrogen transformation in surface water is still unknown. In this paper, four sets of experiments were set up in simulated surface water inoculated with precultured bacteria, respectively, A: simulated surface water, B: addition of ferrihydrite, C: addition of T-MPs, and D: addition of both T-MPs and ferrihydrite. Characterization results showed that co-exposure of T-MPs and ferrihydrite increased roughness and decreased hydrophobicity in the surface of T-MPs, and resulted in higher biomass and EPS values in biofilm of T-MPs with ferrihydrite. Under co-exposure, the nitrate removal efficiency for 12 h was increased by 32.37 % and 25.74 % comparing with single ferrihydrite and T-MPs, and the accumulation and removal of nitrite as well as the production of higher concentrations of nitrous oxide indicated that the co-exposure contributed to the denitrification and stimulated nitrogen transformation. Furthermore, α-diversity index characterized a rich microbial community, especially the enrichment of functional microorganisms Firmicutes and Thauera, which were altered to enhance nitrogen transformation function (glutamine synthetase, nitronate monooxygenase). Ferrihydrite promoted complete denitrification process in the system and strengthened the role of nitrogen transformation microorganisms in the T-MPs biofilm. The abundance of key enzymes and functional genes (napA, nrtC, nirB, nosZ) increased with co-exposure T-MPs and ferrihydrite, and genes associated with nitrate and nitrite reduction (narG, narI) exhibited higher abundance in biofilm of T-MPs compared to the surrounding water. This research provided important insights into the effects of T-MPs co-exposure interactions with ferrihydrite on nitrogen transformation in surface water.

Lifetime of nitric oxide produced by surface dielectric barrier discharge in controlled atmospheres: Role of O2 content

Nitric oxide (NO) is an invaluable multifunctional chemical in agri-food applications; for example, it plays a role in plant growth, development, and stress tolerance. One of the interesting implications of NO is the suppression of fruit ripening and the resulting increase in shelf life. Since a high concentration of NO is producible in atmospheric plasmas, increasing attempts in plasma agriculture have been made to study several types of plasma reactors operated in air. However, as NO is rapidly oxidized by oxygen (O2) and/or ozone (O3), the use of NO produced in atmospheric plasmas is naturally nontrivial, and the lifetime of NO is highly sensitive to the reactor environments. Here, we investigated the time development of O3 and nitrogen oxides (NOx=1–3) in a surface dielectric barrier discharge (sDBD) reactor with respect to the O2 content of the controlled atmosphere (N2+O2). In situ optical absorption spectroscopy enabled the observation of the dynamics of O3 and NOx under gas-tight conditions. In these plasma reactors, NO became a dominant species after the chemical mode transition from O3 to NO occurred. We found that a lower O2 content correlated to a faster appearance of NO in the plasma reactor. The NO lifetime significantly increased as the O2 content decreased from 20 to 5 % in the plasma reactor, while the maximum concentration of NO decreased. Our findings indicated that the appropriate control of the O2 content is essential in atmospheric plasma reactors dependent on O3 and/or NOx applications.

Synthesis of NO by rotating sliding arc discharge reactor with conical-spiral electrodes

The present work investigates the potential applications of nitrogen oxides (NO x ), particularly nitric oxide (NO) and nitrogen dioxide (NO2), generated through discharge plasma in diverse sectors such as medicine, nitrogen fixation, energy, and environmental protection. In this study, a rotating sliding arc discharge reactor was initially employed to produce high concentrations of gaseous NO x , followed by the utilization of a molybdenum wire redox reactor for NO2-to-NO conversion. The outcomes reveal that the discharge states and generations of NO x are affected by varying parameters, including the applied energies, frequencies and airflow states (1.3–2.6 m/s are the laminar flow, 2.6–5.2 m/s are the transition state, 5.2–6.5 m/s are the turbulent flow), and the concentrations of NO x within the arc discharge are higher than that in the spark discharge. Moreover, the concentrations of NO, NO2 and NO x gradually increased, and the concentration ratios of NO/NO2 and NO x /NO2 decreased with increasing the applied energy for one cycle from 14.8 mJ to 24.3 mJ. Meanwhile, the concentrations of NO, NO2 and NO x gradually decreased, and the concentration ratios of NO/NO2 and NO x /NO2 first decreased and then increased with increasing the applied frequencies from 5.0 kHz to 9.0 kHz. Further, the concentrations of NO, NO2 and NO x gradually decreased, and the concentration ratios of NO/NO2 and NO x /NO2 first increased and then decreased with increasing the air flow speeds from 1.3 m/s to 6.5 m/s. Lastly, the concentrations of NO increased and NO2 decreased with increasing temperature from 25 °C to 400 °C using molybdenum converted. These findings provide experimental support for the application of plasma in the fields of medicine, nitrogen fixation, energy and environmental protection.

Novel 131-iodine labeled and ultrasound-responsive nitric oxide and reactive oxygen species controlled released nanoplatform for synergistic sonodynamic/nitric oxide/chemodynamic/radionuclide therapy

Nitric oxide (NO) and reactive oxygen species (ROS) embody excellent potential in cancer therapy. However, as a small molecule, their targeted delivery and precise, controllable release are urgently needed to achieve accurate cancer therapy. In this paper, a novel US-responsive bifunctional molecule (SD) and hyaluronic acid-modified MnO2 nanocarrier was developed, and a US-responsive NO and ROS controlled released nanoplatform was constructed. US can trigger SD to release ROS and NO simultaneously at the tumor site. Thus, SD served as acoustic sensitizer for sonodynamic therapy and NO donor for gas therapy. In the tumor microenvironment, the MnO2 nanocarrier can effectively deplete the highly expressed GSH, and the released Mn2+ can make H2O2 to produce .OH by Fenton-like reaction, which exhibited a strong chemodynamic effect. The high concentration of ROS and NO in cancer cell can induce cancer cell apoptosis ultimately. In addition, toxic ONOO–, which was generated by the reaction of NO and ROS, can effectively cause mitochondrial dysfunction, which induced the apoptosis of tumor cells. The 131I was labeled on the nanoplatform, which exhibited internal radiation therapy for tumor therapy. In −vitro and −vivo experiments showed that the nanoplatform has enhanced biocompatibility, and efficient anti-tumor potential, and it achieves synergistic sonodynamic/NO/chemodynamic/radionuclide therapy for cancer.

Design, synthesis, and biological studies of nitric oxide-donating piperlongumine derivatives triggered by lysyl oxidase as anti-triple negative breast cancer agents

Nitric oxide (NO) is an important gas messenger molecule with a wide range of biological functions. High concentration of NO exerts promising antitumor effects and is regarded as one of the hot spots in cancer research, that have limitations in their direct application due to its gaseous state, short half-life (seconds) and high reactivity. Lysyl oxidase (LOX) is a copper-dependent amine oxidase that is responsible for the covalent bonding between collagen and elastin and promotes tumor cell invasion and metastasis. The overexpression of LOX in triple-negative breast cancer (TNBC) makes it an attractive target for TNBC therapy. Herein, novel NO donor prodrug molecules were designed and synthesized based on the naturally derived piperlongumine (PL) skeleton, which can be selectively activated by LOX to release high concentrations of NO and PL derivatives, both of them play a synergistic role in TNBC therapy. Among them, the compound TM-1 selectively released NO in highly invasive TNBC cells (MDA-MB-231), and TM-1 was also confirmed as a potential TNBC cell line inhibitor with an inhibitory concentration of 2.274 μM. Molecular docking results showed that TM-1 had a strong and selective binding affinity with LOX protein.

Knockdown of trem2 promotes proinflammatory microglia and inhibits glioma progression via the JAK2/STAT3 and NF-κB pathways

BackgroundIn the tumor immune microenvironment (TIME), triggering receptor expressed on myeloid cells 2 (trem2) is widely considered to be a crucial molecule on tumor-associated macrophages(TAMs). Multiple studies have shown that trem2 may function as an immune checkpoint in various malignant tumors, mediating tumor immune evasion. However, its specific molecular mechanisms, especially in glioma, remain elusive.MethodsLentivirus was transfected to establish cells with stable knockdown of trem2. A Transwell system was used for segregated coculture of glioma cells and microglia. Western blotting, quantitative real-time polymerase chain reaction (qRT‒PCR), and immunofluorescence (IF) were used to measure the expression levels of target proteins. The proliferation, invasion, and migration of cells were detected by colony formation, cell counting kit-8 (CCK8), 5-ethynyl-2’-deoxyuridine (EdU) and transwell assays. The cell cycle, apoptosis rate and reactive oxygen species (ROS) level of cells were assessed using flow cytometry assays. The comet assay and tube formation assay were used to detect DNA damage in glioma cells and angiogenesis activity, respectively. Gl261 cell lines and C57BL/6 mice were used to construct the glioma orthotopic transplantation tumor model.ResultsTrem2 was highly overexpressed in glioma TAMs. Knocking down trem2 in microglia suppressed the growth and angiogenesis activity of glioma cells in vivo and in vitro. Mechanistically, knockdown of trem2 in microglia promoted proinflammatory microglia and inhibited anti-inflammatory microglia by activating jak2/stat1 and inhibiting the NF-κB p50 signaling pathway. The proinflammatory microglia produced high concentrations of nitric oxide (NO) and high levels of the proinflammatory cytokines TNF-α, IL-6, and IL-1β, and caused further DNA damage and promoted the apoptosis rate of tumor cells.ConclusionsOur findings revealed that trem2 in microglia plays a significant role in the TIME of gliomas. Knockdown of trem2 in microglia might help to improve the efficiency of inhibiting glioma growth and delaying tumor progression and provide new ideas for further treatment of glioma.

Coumarin-Furoxan Hybrid Suppressed the Proliferation and Metastasis of Triple-Negative Breast Cancer by Activating Mitochondrial Stress and Cell Apoptosis.

Triple-negative breast cancer (TNBC) typically manifests as higher invasive carcinoma correlated with a worse prognosis that primarily relies on chemotherapy. There is growing evidence that nitric oxide (NO) donor drugs have the potential for anticancer therapy. On this basis, we constructed and evaluated a novel coumarin-furoxan hybrid 4A93 as an effective antitumor candidate drug. 4A93 exhibits low IC50 values in three TNBC cell lines and inhibits colony formation and DNA synthesis, probably due to the release of high concentrations of NO in mitochondria, which induces oxidative stress, mitochondrial dysfunction, and apoptosis. Further research suggests that 4A93 might destroy mitochondria by opening the mitochondrial permeability transition pore (mPTP), depolarizing the mitochondrial membrane potential (MMP), and promoting the release of cytochrome c into the cytoplasm. Intrinsic apoptosis is induced finally, along with Akt/Erk signaling suppression. Additionally, 4A93 underregulates the Epithelial-mesenchymal transition process to inhibit cell migration and invasion. In 4T1 subcutaneous and hematogenous models of mice, 4A93 therapy suppresses the tumor growth and prevented lung metastasis with favorable biosafety. Our results provide insights into 4A93 in TNBC treatment and validate the contribution of NO donors in tumor therapy.

Mitochondrial Targeted Thermosensitive Nanocarrier for Near-Infrared-Triggered Precise Synergetic Photothermal Nitric Oxide Chemotherapy.

Nitric oxide (NO) intervenes, that is, a potential treatment strategy, and has attracted wide attention in the field of tumor therapy. However, the therapeutic effect of NO is still poor, due to its short half-life and instability. Therapeutic concentration ranges of NO should be delivered to the target tissue sites, cell, and even subcellular organelles and to control NO generation. Mitochondria have been considered a major target in cancer therapy for their essential roles in cancer cell metabolism and apoptosis. In this study, mesoporous silicon-coated gold nanorods encapsulated with a mitochondria targeted and the thermosensitive lipid layer (AuNR@MSN-lipid-DOX) served as the carrier to load NO prodrug (BNN6) to build the near-infrared-triggered synergetic photothermal NO-chemotherapy platform (AuNR@MSN(BNN6)-lipid-DOX). The core of AuNR@MSN exhibited excellent photothermal conversion capability and high loading efficiency in terms of BNN6, reaching a high value of 220 mg/g (w/w), which achieved near-infrared-triggered precise release of NO. The outer biocompatible lipid layer, comprising thermosensitive phospholipid DPPC and mitochondrial-targeted DSPE-PEG2000-DOX, guided the whole nanoparticle to the mitochondria of 4T1 cells observed through confocal microscopy. In the mitochondria, the nanoparticles increased the local temperature over 42 °C under NIR irradiation, and a high NO concentration from BNN6 detected by the NO probe and DSPE-PEG2000-DOX significantly inhibited 4T1 cancer cells in vitro and in vivo under the synergetic photothermal therapy (PTT)-NO therapy-chemotherapy modes. The built NIR-triggered combination therapy nanoplatform can serve as a strategy for multimodal collaboration.

A coumarin-furoxan hybrid as novel nitric oxide donor induced cell apoptosis and ferroptosis in NSCLC by promoting S-nitrosylation of STAT3 and negative regulation of JAK2-STAT3 pathway

Non-small cell lung cancer (NSCLC) still lacks effective treatment because of its extensive mutation diversity and frequent drug resistance. Therefore, it is urgent to develop new therapeutic strategies for NSCLC. In this study, we evaluated the inhibitory effect of a new coumarin-furoxan hybrid compound 9, a nitric oxide (NO) donor drug, on NSCLC proliferation and its mechanism. Our results show that compound 9 can inhibit the growth of four NSCLC cell lines and H1975 xenograft model in a dose-dependent manner. Compound 9 effectively releases high concentrations of NO within the mitochondria, leading to cellular oxidative stress, mitochondrial dysfunction, and apoptosis. Moreover, compound 9 inhibits JAK2/STAT3 protein phosphorylation and induces S-nitrosylation modification of STAT3, ultimately resulting in endogenous apoptosis in NSCLC. Additionally, compound 9 significantly induces NSCLC ferroptosis by depleting intracellular GSH, elevating MDA levels, inhibiting SLC7A11/GSH protein expression, and negatively regulating the JAK2/STAT3 pathway. In summary, this study elucidates the inhibitory effects of compound 9 on NSCLC proliferation and provides insights into the underlying mechanisms, offering new possibilities for NSCLC treatment strategies.

Aqueous Electroreduction of Nitric Oxide to Ammonia at Low Concentration via Vacancy Engineered FeOCl

AbstractElectroreduction of nitric oxide (NO) to NH3 (NORR) has gained extensive attention for the sake of low carbon emission and air pollutant treatment. Unfortunately, NORR is greatly hindered by its sluggish kinetics, especially under low concentrations of NO. Herein, we developed a chlorine (Cl) vacancy strategy to overcome this limitation over FeOCl nanosheets (FeOCl‐VCl). Density functional theory (DFT) calculations revealed that the Cl vacancy resulted in defective Fe with sharp d‐states characteristics in FeOCl‐VCl to enhance the absorption and activation of NO. In situ X‐ray absorption near‐edge structure (XANES) and attenuated total reflection‐infrared spectroscopy (ATR‐IR) verified the lower average oxidation state of defective Fe to enhance the electron transfer for NO adsorption/activation and facilitate the generation of key NHO and NHx intermediates. As a result, the FeOCl‐VCl exhibited superior NORR activities with the NH3 Faradaic efficiency up to 91.1 % while maintaining a high NH3 yield rate of 455.4 μg cm−2 h−1 under 1.0 vol % NO concentration, competitive with those of previously reported literatures under higher NO concentration. Further, the assembled Zn‐NO battery utilizing FeOCl‐VCl as cathode delivered a record peak power density of 6.2 mW cm−2, offering a new route for simultaneous NO removal, NH3 production, and energy supply.

Aqueous Electroreduction of Nitric Oxide to Ammonia at Low Concentration via Vacancy Engineered FeOCl.

Electroreduction of nitric oxide (NO) to NH3 (NORR) has gained extensive attention for the sake of low carbon emission and air pollutant treatment. Unfortunately, NORR is greatly hindered by its sluggish kinetics, especially under low concentrations of NO. Herein, we developed a chlorine (Cl) vacancy strategy to overcome this limitation over FeOCl nanosheets (FeOCl-VCl ). Density functional theory (DFT) calculations revealed that the Cl vacancy resulted in defective Fe with sharp d-states characteristics in FeOCl-VCl to enhance the absorption and activation of NO. In situ X-ray absorption near-edge structure (XANES) and attenuated total reflection-infrared spectroscopy (ATR-IR) verified the lower average oxidation state of defective Fe to enhance the electron transfer for NO adsorption/activation and facilitate the generation of key NHO and NHx intermediates. As a result, the FeOCl-VCl exhibited superior NORR activities with the NH3 Faradaic efficiency up to 91.1 % while maintaining a high NH3 yield rate of 455.4 μg cm-2 h-1 under 1.0 vol % NO concentration, competitive with those of previously reported literatures under higher NO concentration. Further, the assembled Zn-NO battery utilizing FeOCl-VCl as cathode delivered a record peak power density of 6.2 mW cm-2 , offering a new route for simultaneous NO removal, NH3 production, and energy supply.

Endogenous Nitric Oxide Releases In Situ for RNS/ROS Synergistic Cancer Therapy

AbstractGas therapy, represented by nitric oxide (NO), has shown a powerful anti‐tumor effect. However, current NO therapy relies on NO precursors, which are often released prematurely during in vivo delivery, resulting in poor targeting and obvious toxic side effects. Herein, a core/shell‐structured nanocatalyst is designed and prepared to catalyze the generation of NO in tumor without introduction of NO donor. In this system, C‐Z@CM is prepared by coating the octahedron of Cu‐MOF with a nano‐ZnO, and camouflaging homologous tumor cell membrane. After the nanomedicine is taken up by tumor cells, ZnO reacts in situ with endogenous S‐nitrosoglutathione (GSNO), which is highly expressed in tumors, to continuously and stably generate NO. In addition, the dispersed copper ions in C‐Z@CM acts as the catalytic active centers of the Fenton‐like reaction, which catalyzes H2O2 to generate a large number of hydroxyl radicals (•OH). Importantly, the cascade of NO and reactive oxygen species (ROS) leads to the massive production of more lethal reactive nitrogen species (RNS), further enhancing the therapeutic effect. Catalytic production of high concentrations of NO in situ in the tumor, combined with the cascade generation of ROS and RNS, accompanied by glutathione (GSH) depletion, achieving effective tumor suppression.

The Effect of High Nitric Oxide Concentrations on Oxygenators in Cardiopulmonary Bypass Machines (Experimental Study)

The aim of the study. To study the effect of high nitric oxide concentrations on hollow polypropylene fibers of oxygenators.Materials and methods. The study was conducted in two stages. At the first stage, we evaluated the stability of oxygenator membrane made of hollow polypropylene fibers after six hours of exposure to air-oxygen mixture containing NO at 500 parts per million, or 500 pro pro mille (ppm) concentration, using mass spectrometry and infrared spectroscopy. At the second stage, an experiment with cardiopulmonary bypass (CPB) was conducted on 10 pigs. In the study group (n=5) animals sweep gas was supplied to the oxygenator as an air-oxygen mixture with NO at 100 ppm. In the control group animals (n=5) an air-oxygen mixture was used without NO. The CPB lasted for 4 hours, followed by observation for 12 hours. NO, NO2 (at the inlet and outlet of the oxygenator), and the dynamics of methemoglobin were evaluated. After weaning of animals from CPB, the oxygenators were tested for leakproofness, and scanning electron microscopy (SEM) was performed.Results. The oxygenator made of polypropylene hollow fibers retained its gas transfer parameters after six hours of exposure to air-oxygen mixture containing NO at 500 ppm. Based on IR-Fourier spectroscopy findings, NO did not affect structural integrity of polypropylene membranes. NO added to gas mixture at 100 ppm did not increase NO2 to toxic level of 2 ppm in 91% of control tests during 4 hours CPB in pigs; mean value was 1.58 ± 0.28 ppm. Methemoglobin concentration did not exceed the upper limit of permissible level (3%), and there were no statistically significant differences with the control group. All tested oxygenators have passed the leakproofness test. According to SEM findings, larger amounts of fibrin deposits were found in the control group oxygenators vs study group.Conclusion. There were no negative effects of NO at 500 ppm concentration on the oxygenator membrane made of hollow polypropylene fibers. NO at 100 ppm in a gas-mixture supplied to oxygenators did not lead to an exceedance of safe NO2 and methemoglobin concentrations in an animal model. Reduced fibrin deposits on hollow fibers of polypropylene oxygenator membranes were observed when with NO at a level of 100 ppm was added to a gas mixture.

Inhalable Nitric Oxide Delivery Systems for Pulmonary Arterial Hypertension Treatment.

Pulmonary arterial hypertension (PAH) is a severe medical condition characterized by elevated blood pressure in the pulmonary arteries. Nitric oxide (NO) is a gaseous signaling molecule with potent vasodilator effects; however, inhaled NO is limited in clinical practice because of the need for tracheal intubation and the toxicity of high NO concentrations. In this study, inhalable NO-releasing microspheres (NO inhalers) are fabricated to deliver nanomolar NO through a nebulizer. Two NO inhalers with distinct porous structures are prepared depending on the molecular weights of NO donors. It is confirmed that pore formation can be controlled by regulating the migration of water molecules from the external aqueous phase to the internal aqueous phase. Notably, open porous NO inhalers (OPNIs) can deliver NO deep into the lungs through a nebulizer. Furthermore, OPNIs exhibit vasodilatory and anti-inflammatory effects via sustained NO release. In conclusion, the findings suggest that OPNIs with highly porous structures have the potential to serve as tools for PAH treatment.

PolyQ-Expansion Causes Mitochondria Fragmentation Independent of Huntingtin and Is Distinct from Traumatic Brain Injury (TBI)/Mechanical Stress-Mediated Fragmentation Which Results from Cell Death.

Mitochondrial dysfunction has been reported in many Huntington's disease (HD) models; however, it is unclear how these defects occur. Here, we test the hypothesis that excess pathogenic huntingtin (HTT) impairs mitochondrial homeostasis, using Drosophila genetics and pharmacological inhibitors in HD and polyQ-expansion disease models and in a mechanical stress-induced traumatic brain injury (TBI) model. Expression of pathogenic HTT caused fragmented mitochondria compared to normal HTT, but HTT did not co-localize with mitochondria under normal or pathogenic conditions. Expression of pathogenic polyQ (127Q) alone or in the context of Machado Joseph Disease (MJD) caused fragmented mitochondria. While mitochondrial fragmentation was not dependent on the cellular location of polyQ accumulations, the expression of a chaperone protein, excess of mitofusin (MFN), or depletion of dynamin-related protein 1 (DRP1) rescued fragmentation. Intriguingly, a higher concentration of nitric oxide (NO) was observed in polyQ-expressing larval brains and inhibiting NO production rescued polyQ-mediated fragmented mitochondria, postulating that DRP1 nitrosylation could contribute to excess fission. Furthermore, while excess PI3K, which suppresses polyQ-induced cell death, did not rescue polyQ-mediated fragmentation, it did rescue fragmentation caused by mechanical stress/TBI. Together, our observations suggest that pathogenic polyQ alone is sufficient to cause DRP1-dependent mitochondrial fragmentation upstream of cell death, uncovering distinct physiological mechanisms for mitochondrial dysfunction in polyQ disease and mechanical stress.

Design, Synthesis, and Biological Evaluation of Esculetin-Furoxan-DEAC Ternary Hybrids for Anti-Triple Negative Breast Cancer.

Twelve new hybrid compounds of Esculetin with nitric oxide (NO) donors and/or mitochondrial targeting groups were designed, synthesized, and evaluated for their anti-tumor activity and mechanism in vitro and in vivo. Notably, the most potent compound A11 exhibited nanomolar antiproliferative activity on triple-negative breast cancer (TNBC) MDA-MB-231 cells (IC50 = 8 nM) with a strikingly selective inhibitory effect. The mechanism of A11 involves targeting MDA-MB-231 cells' mitochondria, releasing a high NO concentration, and increasing the expression of cyclophilin D (CypD), leading to increased reactive oxygen species (ROS) and triggering cancer cell apoptosis. Additionally, A11 could arrest the cell cycle at the G2/M phase to achieve anti-tumor effects. Moreover, A11 demonstrated a superior TNBC inhibition rate and diminished toxicity relative to doxorubicin (DOX) in vivo. In summary, A11 serves as a noteworthy contender for TNBC treatment with high potency and minimal toxicity.

Nitric oxide: an old drug but with new horizons in ophthalmology-a narrative review.

Based on basic knowledge and prior research on nitric oxide (NO), the potential of NO for treating eye diseases is reviewed, and the possibility of NO-based eye drops in clinical practice and the future potential of NO in ophthalmology are discussed. A PubMed search was performed for English-language original reports and reviews using the following key words: nitric oxide, eye, ocular, and drug. NO is synthesized in the human body by NO synthase (NOS) from L-arginine or through enzyme-dependent reduction of dietary nitrate. Three types of NOS (eNOS, nNOS, and iNOS) are abundantly expressed in the eye under normal physiologic or pathologic conditions. The biological effect of NO in the eye is dose dependent. Low intraocular NO concentrations, produced by eNOS or nNOS, have various cellular effects, including vasodilation, intraocular pressure (IOP) regulation, and neuroprotection. iNOS induced under pathologic ocular conditions produces high NO concentrations in the local environment and mediates tissue inflammation, ocular cell apoptosis, and neurodegeneration. In particular, increased iNOS has been reported in glaucoma and retinal ischemic or degenerative diseases. NO plays a vital role in ocular injury. NO can facilitate ocular surface wound healing while eradicating pathogens such as bacteria and Acanthamoeba in chemical burns or infectious keratitis. Furthermore, NO has antifibrotic activity via the cyclic guanosine monophosphate (cGMP) signaling pathway. NO causes smooth muscle relaxation, which can be used to inhibit myopia progression in children. NO can be a stem cell modulator and may help in treating ocular stem cell disorders. Because of its diverse biologic effects, NO can be a key player in regulating ocular inflammation in various ocular diseases, aiding ocular surface wound healing, controlling IOP in glaucoma, alleviating retinal disease, and suppressing myopia progression. Although there remain limitations to the effective use of highly unstable state, gaseous NO, the role of NO in the field of ophthalmology can be greatly expanded through the development of novel NO donors and effective delivery platforms.

The current scenario of furoxan hybrids with anticancer potential

AbstractCancer is one of the most common and deadliest diseases affecting millions of human beings globally. Treatment of cancer has achieved great advancements, and chemotherapy remains one of the most important means. However, the chemotherapy suffers from apparent limitations including drug resistance, systemic toxicity, adverse effects, and tumor recurrence, creating an urgent demand to develop novel anticancer chemotherapeutics. Furoxan derivatives could exert anticancer activity via releasing high concentrations of nitric oxide (NO), which could induce cellular apoptosis, arrest cell cycle, inhibit the migration and invasion of cells, and suppress angiogenesis. Hence, furoxan derivatives demonstrated potent in vitro and in vivo anticancer efficiency. In particular, furoxan hybrids, combination of other anticancer pharmacophores with furoxan moiety, demonstrated significant therapeutic effects on various cancers including drug‐resistant forms since these derivatives could act on multiple targets in cancer cells simultaneously. Accordingly, furoxan hybrids constitute an important source in the development of novel chemotherapeutic agents with anticancer activity. This review is to highlight the current scenario of furoxan hybrids with anticancer potential, covering articles published from 2012 to present. The structure–activity relationships and mechanisms of action are discussed to continuously open up a map for the remarkable exploration of more effective candidates.

Removal of NO at low concentrations from polluted air in semi-closed environments by activated biochars from renewables feedstocks

Efficient measures are urgently required in large cities for nitric oxide (NO) elimination from air in urban semi-closed environments (parking lots and tunnels), characterized by low NO concentrations (<10 ppmv) and temperatures. One of the most promising abatement alternatives is the NO oxidation to NO2, which can be further easily captured in an alkali solution or over a porous solid. However, most of the research devoted to this topic is focused on the elimination of NO from fuel exhaust gases, with high NO concentrations (400–2000 ppmv). In this work, sustainable and low-cost activated biochars of different origin and having very different ash contents were employed in NO removal at very low concentrations. Thus, low ash content forestry (oak woodchips, OAK) and high ash content from agriculture (oilseed rape straw, OSR) biochars were subjected to physical activation with CO2 at 900 °C (OAK550-A900CO2 and OSR700-A900CO2, respectively). The NO removal performance tests of such activated carbons were carried out at different experimental conditions: i.e., temperature, relative humidity (0–50 vol% RH), NO-containing gas (N2 or air), amount of activated carbon, and NO concentration, to assess how the activated biochar properties influence their NO removal capacity. The sample OSR700-A900CO2 contained a higher population of oxygen surface functionalities, which might play an important role in the NO removal efficiency in dry conditions since they could assist NO oxidation on carbon active sites when used above room temperature (50–75 °C). However, at room temperature (25 °C), the presence of narrow micropore size distribution at 6 Å became a more relevant property, since it facilitates an intimate contact between NO and O2. Accordingly, the activated biochar from OAK was much more efficient, achieving complete removal of NO from air flow (dry or with 50 vol% RH) at 25 °C during 400 min of testing, making it an ideal candidate as biofilter for purifying air streams of semi-closed spaces contaminated with low concentrations of NO.