High Concentrations Of Nitric Oxide Research Articles

Thermoacoustic Imaging-Guided Thermo-Chemotherapy for Hepatocellular Carcinoma Sensitized by a Microwave-Responsive Nitric Oxide Nanogenerator.

Imaging-guided percutaneous microwave thermotherapy has been regarded as an important alternative nonsurgical therapeutic strategy for hepatocellular carcinoma (HCC) that provides excellent local tumor control and favorable survival benefit. However, providing a high-resolution, real-time, and noninvasive imaging technique for intraoperative guidance and controlling postoperative residual tumor recurrence are urgent needs for the clinical setting. In this study, a cisplatin (CDDP)-loaded nanocapsule (NPs@CDDP) with microwave responsive property was prepared to simultaneously serve as a contrast agent of emerging thermoacoustic imaging and a sensitizing agent of microwave thermo-chemotherapy. Accompanying the enzymolysis in the tumor microenvironment, the NPs@CDDP responsively release l-arginine (l-Arg) and CDDP. l-Arg with excellent microwave-absorbing property allowed it to serve as a thermoacoustic imaging contrast agent for accurately delineating the tumor and remarkably increasing tumor temperature under ultralow power microwave irradiation. Apart from the chemotherapeutic effect, CDDP elevated the intracellular H2O2 level through cascade reactions and further accelerated the continuous transformation of l-Arg to nitric oxide (NO), which endowed the NPs@CDDP with NO-generation capability. Notably, the high concentration of intracellular NO was proved to aggravate lipid peroxidation and greatly improved the efficacy of microwave thermo-chemotherapy. Thereby, NPs@CDDP was expected to serve as a theranostic agent integrating the functions of tumor microenvironment-responsive drug delivery system, contrast agent of thermoacoustic imaging, thermal sensitizing agent, and NO nanogenerator, which was promising to provide a potential imaging-guided therapeutic strategy for HCC.

Inducible Nitric Oxide Synthase Embedded in Alginate/Polyethyleneimine Hydrogel as a New Platform to Explore NO-Driven Modulation of Biological Function.

Nitric oxide (NO), a small free radical molecule, turned out to be pervasive in biology and was shown to have a substantial influence on a range of biological activities, including cell growth and apoptosis. This molecule is involved in signaling and affects a number of physiologic functions. In recent decades, several processes related to cancer, such as angiogenesis, programmed cell death, infiltration, cell cycle progression, and metastasis, have been linked with nitric oxide. In addition, other parallel work showed that NO also has the potential to operate as an anti-cancer agent. As a result, it has gained attention in cancer-related therapeutics. The nitric oxide synthase enzyme family (NOS) is required for the biosynthesis of nitric oxide. It is becoming increasingly popular to develop NO-releasing materials as strong tumoricidal therapies that can deliver sustained high concentrations of nitric oxide to tumor sites. In this paper, we developed NO-releasing materials based on sodium alginate hydrogel. In this regard, alginate hydrogel discs were modified by adsorbing layers of polyethyleneimine and iNOS-oxygenase. These NO-releasing hydrogel discs were prepared using the layer-by-layer film building technique. The iNOS-oxygenase is adsorbed on the positively charged polyethyleneimine (PEI) matrix layer, which was formed on a negatively charged sodium alginate hydrogel. We show that nitric oxide is produced by enzymes contained within the hydrogel material when it is exposed to a solution containing all the components necessary for the NOS reaction. The electrostatic chemical adsorption of the layer-by-layer process was confirmed by FTIR measurements as well as scanning electron microscopy. We then tested the biocompatibility of the resulting modified sodium alginate hydrogel discs. We showed that this NOS-PEI-modified hydrogel is overall compatible with cell growth. We characterized the NOS/hydrogel films and examined their functional features in terms of NO release profiles. However, during the first 24 h of activity, these films show an increase in NO release flux, followed by a gradual drop and then a period of stable NO release. These findings show the inherent potential of using this system as a platform for NO-driven modulation of biological functions, including carcinogenesis.

Nitric oxide and Nitrous oxide accumulation, oxygen production during nitrite denitrification in an anaerobic/anoxic sequencing batch reactor: exploring characteristics and mechanism.

Nitrite denitrification has received increasing attention due to its high efficiency, low energy consumption, and sludge yield. However, the nitric oxide (NO) and nitrous oxide (N2O) which are harmful to the environment, microorganisms, and humans are produced in this process. In order to mitigate NO and N2O production, the biological mechanisms of NO and N2O accumulation, as well as NO detoxification during nitrite denitrification in a sequencing batch reactor were studied. Results showed that the peak of NO accumulation increased from 0.29 [Formula: see text] 0.01 to 3.12 [Formula: see text] 0.34mg L-1 with the increase of carbon to nitrogen ratio (COD/N), which is caused by the sufficient electron donor supply for NO2--N reduction process at high COD/N. Furthermore, the result suggested that NO accumulation with no pH adjustment was 12 times higher than that with pH adjustment. It is related to the inhibition on NO reductase caused by the high free nitrous acid (FNA) and NO concentration with no pH adjustment. The pathways of NO detoxification included NO emission, reduction, and dismutation, and the more NO produced, the high proportion of NO dismutation pathway. Result showed that the maximum of oxygen production during NO dismutation reached to 1.39mg L-1. N2O accumulation was mainly associated with FNA and NO inhibition, COD/N. The peak of N2O accumulation presented a completely opposite trend at pH adjustment and no pH adjustment, it is because that the higher FNA and NO concentration at high COD/N without pH adjustment will inhibit the N2O reductase activity, resulting in the N2O reduction was hindered during nitrite denitrification.

Curcumin-Added Whey Protein Positively Modulates Skeletal Muscle Inflammation and Oxidative Damage after Exhaustive Exercise.

(1) Background: Exhaustive exercise can induce muscle damage. The consumption of nutritional compounds with the ability to positively influence the oxidative balance and an exacerbated inflammatory process has been previously studied. However, little is known about the nutritional value of curcumin (CCM) when mixed with whey protein concentrate (WPC). This study was developed to evaluate the effect of CCM-added WPC on inflammatory and oxidative process control and histopathological consequences in muscle tissue submitted to an exhaustive swimming test (ET). (2) Methods: 48 animals were randomly allocated to six groups (n = 8). An ET was performed 4 weeks after the start of the diet and animals were euthanized 24 h post ET. (3) Results: WPC + CCM and CCM groups reduced IL-6 and increased IL-10 expression in muscle tissue. CCM reduced carbonyl protein after ET compared to standard AIN-93M ET and WPC + CCM ET diets. Higher nitric oxide concentrations were observed in animals that consumed WPC + CCM and CCM. Consumption of WPC + CCM or isolated CCM reduced areas of inflammatory infiltrate and fibrotic tissue in the muscle. (4) Conclusions: WPC + CCM and isolated CCM contribute to the reduction in inflammation and oxidative damage caused by the exhaustive swimming test.

The metabolic phenotype of the patient influences the reduction in carotid intima-media thickness achieved following metabolic surgery.

To determine whether metabolic phenotype is associated with the change in carotid intima-media thickness (CIMT) in patients undergoing bariatric /metabolic surgery (BMS). We performed a case-control study of BMS candidates who had metabolically unhealthy obesity (MUO) or metabolically healthy obesity (MHO). We measured the change in CIMT during the 9 months following BMS. The plasma tumor necrosis factor-α, interleukin-1β, adiponectin, leptin, nitric oxide (NO), vascular endothelial growth factor A (VEGF-A), and malondialdehyde concentrations were determined, adipocyte area was measured histologically, and adipose tissue area was estimated using computed tomography. Fifty-six patients (mean age 44.5 years, mean body mass index 44.9 kg/m2, 53% women, and 53% had MUO) were studied. Nine months following BMS, the MUO phenotype was not associated with a significant reduction in CIMT, and that of the MHO group was larger. In addition, fewer participants achieved a 10% reduction in CIMT in the MUO group. A CIMT reduction was associated with lower VEGF-A and NO in the MUO group, while that in the MHO group was associated with a higher NO concentration. The metabolic phenotype of patients may influence their change in CIMT following BMS, probably through circulating vasodilatory and pro-inflammatory molecules.

Simultaneous detection of three chemical species (NO, O, O2) using a single broadband femtosecond laser

Simultaneous nitric oxide (NO) laser-induced fluorescence (LIF), atomic oxygen (O) two-photon LIF (TPLIF), and molecular oxygen (O2) LIF were demonstrated using a single broadband femtosecond (fs) laser in methane- and hydrogen-fueled flames. An amplified Ti:Sapphire laser with ∼80-fs pulse duration was used to pump an optical parametric amplifier (OPA) to generate 226.1-nm pulses having 2.3 nm (∼450 cm−1) bandwidth to excite all three species simultaneously. The specific excitation transitions are NO A-X (0,0) system, O 3p3P←←2p3P two-photon transition, and O2B3Σu−−X3Σg− Schumann-Runge system. Detailed emission characterization was performed using a 1D imaging spectrometer to identify suitable emission bands for interference-free detection of each species. A simultaneous detection system consisting of a visible and a UV camera provided the optimal detection of all three species. Imaging studies revealed high concentrations of NO, O, and O2 at the edge of the flame cone of Bunsen flames because NO and O are produced at the hot flame front. O2 LIF signal was present only at the flame front because of the strong temperature dependence of the O2 Schumann-Runge system. Direct imaging of O TPLIF enabled single-shot as well as high-fidelity shot-averaged line images in stable laminar flames. Equivalence ratio scans in the CH4/air Hencken flames showed good agreements for O and O2 with Cantera equilibrium predictions performed using GRI-Mech 3.0. Although the NO measurements deviated from the equilibrium calculations on the fuel-rich side, it agreed well with previously reported NO LIF measurements in a similar flame. This discrepancy is likely due to Prompt NO, which was not considered in the simulation. NO LIF measurements as a function of height-above-the-burner in the H2/air Hencken flames agreed well with calculated NO mole fractions using the UNICORN flame code. The present study lays the foundation for single-laser imaging of three critical flame species in NO formation pathways in combustion systems.

Alginate/Polyethyleneimine-Based Nitric Oxide-Releasing Hydrogel As a Potential Platform to Study the Effects of NO on Carcinogenesis

Numerous biological functions are affected by the functions of nitric oxide (NO), such as cell proliferation and programmed cell death. NOis a ubiquitous free radical gas that exerts a wide range of biological effects and acts as a signaling molecule in the body. Recent studies have indicated that nitric oxide regulates multiple cancer-related processes, such as angiogenesis, apoptosis, cell cycle, invasion, and metastasis. Alternatively, it is also emerging as a potential anti-oncogenic agent under other conditions. Nitric oxide is synthesized by a complex family of nitric oxide synthase (NOS) enzymes. There is encouraging interest in developing NO-releasing materials as potent tumoricidal agents in which high and localized concentrations of NO may be directly released in a sustained manner to the tumor site. The goal of this project is to develop a hydrogel that incorporates inducible nitric oxide synthase (iNOS) using a layer-by-layer building strategy to form layers of polyethyleneimine (PEI) and iNOSoxy as NO-releasing coatings on alginate hydrogel. When the hydrogel coated with PEI/iNOSoxy films are exposed to arginine, a source of reducing equivalents, and other required ingredients, nitric oxide is formed and released. In this work, FTIR spectroscopy was employed to characterize the functional groups of pristine sodium alginate (SA), polyethyleneimine (PEI) and SA/PEI composite hydrogels. We also used scanning electron microscopy (SEM) for surface characterization. Cyclic voltammetry was used to determine the amount of electroactive heme-enzyme adsorbed on the modified surfaces. We examine how the electroactive heme enzyme in the thin films correlates with the enzymatic NOS activity in terms of NO release fluxes from PEI/NOS-coated hydrogels. After the structural characterization of the NOS/hydrogel films using spectroscopy, we examined their function in terms of NO release profiles. We observed an initial “burst” of NO release during the first 4 hours of activity, followed by a decline and then stable NO release for up to 144 hours possibility to interrogate the role of NO on the balance of cell proliferation and cell death in these cell lines. The measured fluxes are higher than what have been reported in the literature for other inorganic NO-releasing systems. This data will allow us to build NOS-alginate hydrogels with defined NO release profiles for application in cell biology to test the effect of sustained NO release on cell proliferation and cell death on specific cancer cell lines.

Photobiomodulation at 830 nm Reduced Nitrite Production by Peripheral Blood Mononuclear Cells Isolated from Multiple Sclerosis Subjects.

Background: Multiple sclerosis (MS) is a neurodegenerative condition characterized by high concentration of nitric oxide leading to the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), a condition known as nitrosative stress. ROS and RNS produce the inhibition of the mitochondrial electron transport chain leading to mitochondrial dysfunction, reduction of adenosine triphosphate, and death of neurons, producing severe and irreversible damage in the central nervous system of people with MS (PwMS). Current drug treatments for MS focus on the regulation of immune response in acute stages of disease, but they do not regulate nitrosative stress which is present in the acute and chronic stages of disease. Previously, our laboratory showed that photobiomodulation (PBM) on experimental autoimmune encephalomyelitis mice, the animal model of MS, reduced clinical severity of disease, gene expression of inducible nitric oxide synthase (iNOS), and the levels of nitrite in in vivo and in vitro experiments. Objective: We evaluated the effect of PBM on the regulation of nitrosative stress in PwMS. Methods: PBM was applied on peripheral blood mononuclear cells (PBMCs) obtained from PwMS to evaluate PBM on the regulation of nitrate as a marker of nitrosative stress. Results: PBM at 830 nm (10 J/cm2 at 72 h) reduced the levels of nitrite and this reduction was in relationship with the increase of interleukin-10 and the reduction of interferon-γ produced by the PBMCs regardless of the severity of disease present in the participants. Conclusions: PBM at 830 nm can potentially be used to reduce nitrosative stress at any point of disease in PwMS.

Abstract 1848: Ultra-high concentrations of gaseous nitric oxide show rapid cytotoxic capabilities against colon, breast, pancreatic and other cancer cells in vitro

Abstract Background: Nitric oxide (NO) acts as a signaling molecule in various pathological conditions, including cancer. High concentrations of NO are known to have an anti-tumor effect. It is anticipated that NO induces cancer cell cytotoxicity through DNA damage induction, leading to apoptotic cell death. To examine the cytotoxic effect of gaseous NO (gNO) on various cancer types, we exposed 6 cancer cell lines to gNO at ultra-high concentrations, of 10,000-100,000 ppm. Methods: Four mouse cancer cell lines, colon (CT26), breast (4T1), melanoma (B16F10) and lung (LLC1), and 2 human cancer cell lines, pancreatic (Panc02.03) and ovarian (OVCAR-3), were exposed directly to gNO at 10,000 - 100,000 ppm for 10 - 600 seconds (n=3). Air and nitrogen controls were used to assess whether the effect is mediated by gas flow or lack of oxygen (n=3). Cell viability was measured 24 hours after exposure by an XTT-based cell proliferation method. Additionally, cells were examined after exposure using Annexin V and Propidium Iodide cell apoptosis assays to determine cell death mechanisms. Results: gNO resulted in significant death of cancer cells in a dose and time dependent manner as revealed by XTT assay: 1. At a concentration of 100,000 ppm gNO, cell viability of CT26, 4T1, B16F10, LLC1 and Panc02.03 was reduced by ~100% after 10 seconds of exposure compared to non-treated (NT) cells (p<0.001) and OVCAR-3 was reduced by 84%. 2. Exposure of cells to 25,000-50,000 ppm gNO resulted in complete eradication of CT26, 4T1, B16F10, LLC1, Panc02.03 and OVCAR-3 cell viability after 1 minute of exposure compared to NT cells (p<0.001). 3. Exposure to 10,000 ppm gNO resulted in elimination of CT26, 4T1, B16F10 LLC1 and Panc02.03 after 2.5 minutes compared to NT cells (p<0.001) with OVCAR-3 viability reduced by 94%. 4. Viability of cells exposed to both nitrogen and air was comparable to NT cells. Additionally, a longer exposure time to 50,000 ppm gNO resulted in an increase in late apoptosis phase for LLC1 (from ~16% for 10 seconds to ~85% for 1 minute). Conclusion: gNO treatment resulted in a dose dependent cytotoxic response on various cancer cell lines, with higher concentrations leading to near instant cell death and lower concentrations requiring a longer exposure period to elicit cell death. Together with the known ability of NO to activate and recruit the immune system, these results suggest that gNO may be a potent therapeutic agent for tumor treatment across a range of tumor types. Citation Format: Hila Confino, Matan Goldshtein, Shani Puyesky, Shay Yarkoni, Amir Avniel, Steve Lisi, Ido Wolf. Ultra-high concentrations of gaseous nitric oxide show rapid cytotoxic capabilities against colon, breast, pancreatic and other cancer cells in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1848.

Oxygen-Generating Hydrogels Overcome Tumor Hypoxia to Enhance Photodynamic/Gas Synergistic Therapy.

Hypoxic environment is a bottleneck of photodynamic therapy (PDT) in tumor treatment, as oxygen is the critical substrate for photosensitivity reaction. Herein, a sustained oxygen supply system based on cerium nanoparticles and hydrogel (GHCAC) was explored for enhanced synergistic PDT and gas therapy. Ceria nanoparticles were prepared as a drug carrier by self-assembly mediated by hyaluronic acid (HA), a targeting for CD44 on cervical cancer cells, followed by photosensitizer and l-arginine (l-Arg) loading. Then, the GHCAC system was developed by incorporating a prepared nanocarrier (HCePA) and O2-evolving agent calcium peroxide (CaO2) into the hydrogel (Gel) developed by a poloxamer. Gel in the system could moderately infiltrate H2O to react with CaO2 and generate sustained oxygen using the catalase-like activity of HCePA. The system could efficiently alleviate hypoxia in tumor environments for up to 7 days, meeting the "once injection, repeat irradiation" strategy and enhanced PDT efficacy. Besides, the generated singlet oxygen (1O2) in the PDT process could also oxidize l-Arg into high concentrations of nitric oxide for synergistic gas therapy. The developed oxygen supplied and drug delivery Gel system is a new strategy for synergistic PDT/gas therapy to overcome cervical cancer.

High Nitric Oxide Concentration Inhibits Photosynthetic Pigment Biosynthesis by Promoting the Degradation of Transcription Factor HY5 in Tomato.

Photosynthetic pigments in higher plants, including chlorophyll and carotenoid, are crucial for photosynthesis and photoprotection. Previous studies have shown that nitric oxide (NO) plays a dual role in plant photosynthesis. However, how pigment biosynthesis is suppressed by NO remains unclear. In this study, we generated NO-accumulated gsnor mutants, applied exogenous NO donors, and used a series of methods, including reverse transcription quantitative PCR, immunoblotting, chromatin immunoprecipitation, electrophoretic mobility shift, dual-luciferase, and NO content assays, to explore the regulation of photosynthetic pigment biosynthesis by NO in tomato. We established that both endogenous and exogenous NO inhibited pigment accumulation and photosynthetic capacities. High levels of NO stimulated the degradation of LONG HYPOCOTYL 5 (HY5) protein and further inactivated the transcription of genes encoding protochlorophyllide oxidoreductase C (PORC) and phytoene synthase 2 (PSY2)—two enzymes that catalyze the rate-limiting steps in chlorophyll and carotenoid biosynthesis. Our findings provide a new insight into the mechanism of NO signaling in modulating HY5-mediated photosynthetic pigment biosynthesis at the transcriptional level in tomato plants.

Glucose-Responsive ZIF-8 Nanocomposites for Targeted Cancer Therapy through Combining Starvation with Stimulus-Responsive Nitric Oxide Synergistic Treatment.

With the rapid development of nanomedicine, low side effects and high-efficiency green antitumor approaches have attracted great attention. Herein, we report a strategy for the in situ synthesis of graphene oxide@zeolitic imidazolate framework-8 (GOx@ZIF-8) composite nanoparticles with high catalytic efficiency, under mild conditions by adding GOx molecules to the precursor of ZIF-8, and use them as a carrier to achieve efficient loading of l-Arg. In addition. folic-acid-conjugated bovine serum albumin (FA-BSA) has been used to engineer the surface of GOx@ZIF-8-l-Arg composite nanoparticles to enhance their specific recognition of tumor cells. With the high glucose level and low pH in the tumor intracellular environment, FA-BSA/GOx@ZIF-8-l-Arg rapidly consumed the intracellular glucose and produced H2O2, which profusely deteriorated the intracellular environment. Subsequently, a large amount of l-Arg was continuously released from the nanoparticles, reacting with H2O2 to continuously produce a high concentration of nitric oxide (NO), which further damaged the tumor cells. The FA-BSA/GOx@ZIF-8-l-Arg composite nanoparticles were cleverly designed to kill cancer cells efficiently through a starvation-NO synergistic process. This emerging green antitumor method has a promising application prospect in targeted therapy for the efficient clearance of cancers.

THEORETICAL ASPECTS OF MODELING THE DISPERSION OF POLLUTANTS IN THE ATMOSPHERE

The paper analyzes the methods and models of the state of the environment and found that due to the versatility and diversity of approaches in building a unified classification of atmospheric models is a difficult task. It is determined that the Lagrange model calculates the dispersion of air pollution by calculating a continuous plume trajectory and this method can be used to calculate the profiles of ozone scattering in the surrounding area from a point source. To determine the level of purity, use fuzzy logic, then the concept of "level of purity" will become a linguistic variable. The Gaussian model makes it possible to calculate the concentration of pollutants in the simulation area in a straight line between the source and the calculation point for each hour and obtain a model of pollution by emissions at the main city territory.
 Statistical models are a useful tool for diagnosing and predicting air quality through the interpolation and extrapolation of measured data. We plan to use elements of urban canyon models to predict emission concentrations on highways over short time intervals (from several hours to days). The NO-NO2-O3 reaction requires very high nitric oxide concentrations and long residence times for the gases to have a significant effect. This can take place under stagnant weather conditions, when significant concentrations of pollutants are observed for several days. However, there are no models that satisfactorily describe this phenomenon.

Effectiveness and Safety of Elevated Dosages of Nitrous Oxide on Behavior Management in Pediatric Dentistry

To determine if administering a higher dosage of nitrous oxide (>50%), with a nasal hood in pediatric dental restorative procedures, can allow for a safe and more cooperative experience for the pediatric patient as measured by observable adverse reactions and the Frankl Behavior Rating Scale. A retrospective chart review was completed of 200 patients total, 100 for each nitrous oxide (N2O) dosage group (≤50% vs >50%). Adverse reactions and The Frankl Behavior Rating Scale during pediatric restorative procedures with N2O were compared between the two dosage groups. There were few adverse reactions for both nitrous oxide groups (≤50% vs >50%) and there was no statistical difference in the Frankl Behavior Rating Scale for each group. Patients given more than 50% of nitrous oxide were not found to have an increase in adverse events. Higher concentrations of nitrous oxide (>50%) were not found to be associated with a better behavior score when completing pediatric restorative procedures.

Pillars and Gaps of S-Nitrosylation-Dependent Epigenetic Regulation in Physiology and Cancer.

Nitric oxide (NO) is a diffusible signaling molecule produced by three isoforms of nitric oxide synthase, which release NO during the metabolism of the amino acid arginine. NO participates in pathophysiological responses of many different tissues, inducing concentration-dependent effect. Indeed, while low NO levels generally have protective effects, higher NO concentrations induce cytotoxic/cytostatic actions. In recent years, evidences have been accumulated unveiling S-nitrosylation as a major NO-dependent post-translational mechanism ruling gene expression. S-nitrosylation is a reversible, highly regulated phenomenon in which NO reacts with one or few specific cysteine residues of target proteins generating S-nitrosothiols. By inducing this chemical modification, NO might exert epigenetic regulation through direct effects on both DNA and histones as well as through indirect actions affecting the functions of transcription factors and transcriptional co-regulators. In this light, S-nitrosylation may also impact on cancer cell gene expression programs. Indeed, it affects different cell pathways and functions ranging from the impairment of DNA damage repair to the modulation of the activity of signal transduction molecules, oncogenes, tumor suppressors, and chromatin remodelers. Nitrosylation is therefore a versatile tool by which NO might control gene expression programs in health and disease.

Neuronal nitric oxide synthase in dorsal raphe nucleus mediates PTSD-like behaviors induced by single-prolonged stress through inhibiting serotonergic neurons activity

The pathogenesis of post-traumatic stress disorder (PTSD) remains largely unclear. A large body of evidence suggests that the abnormal level of serotonin (5-HT) is closely related to the onset of PTSD. Several reports reveal that nitric oxide (NO) affects extracellular 5-HT levels in various brain regions, but no consistent direction of change was found and the underlying mechanisms remain unknown. The most of serotonergic neurons in dorsal raphe nucleus (DRN), a major source of serotonergic input to the forebrain, co-expresses neuronal nitric oxide synthase (nNOS), a synthase derived nitric oxide (NO) in the central nervous system. Here, we found that the excessive expression of nNOS and thereby the high concentration of NO followed by single-prolonged stress (SPS) caused suppression of the activity of DRN 5-HT neurons, inducing PTSD-like phenotype including increased anxiety-like behaviors, enhanced contextual fear memory, and fear generalization. Our study uncovered an important role of DRN nNOS-NO pathway in the pathology of PTSD, which may contribute to new understanding of the molecular mechanism of PTSD.

The role of reactive oxygen species and nitric oxide in the formation of root cortical aerenchyma under cadmium contamination.

The present study aimed to evaluate root cortical aerenchyma formation in response to Cd-driven hydrogen peroxide (H2 O2 ) production and the role of nitric oxide (NO) in the alleviation of Cd oxidative stress in maize roots and its effects on aerenchyma development. Maize plants were subjected to continuous flooding for 30 days, and the following treatments were applied weekly: Cd(NO3 )2 at 0, 10, and 50 μM and Na2 [Fe(CN)5 NO]·2H2 O (an NO donor) at 0.5, 0.1, and 0.2μM. The root biometrics; oxidative stress indicators H2 O2 and malondialdehyde (MDA); and activities of catalase (CAT), superoxide dismutase (SOD), and ascorbate peroxidase (APX) were analyzed. The root dry and fresh masses decreased at higher concentrations of NO and Cd. H2 O2 also decreased at higher NO concentrations; however, MDA increased only at higher Cd levels. SOD activity decreased at higher concentrations of NO, but CAT activity increased. Aerenchyma development decreased in response to NO. Consequently, NO acts as an antagonist to Cd, decreasing the concentration of H2 O2 by reducing SOD activity and increasing CAT activity. Although H2 O2 is directly linked to aerenchyma formation, increased H2 O2 concentrations are necessary for root cortical aerenchyma development.

Nitric oxide for the prevention and treatment ofviral, bacterial,protozoalandfungalinfections.

Although the antimicrobial potential of nitric oxide(NO)is widelypublished, it is little used clinically. NO is a key signalling molecule modulating vascular, neuronal, inflammatory and immune responses.Endogenous antimicrobial activity is largely mediated by high local NO concentrations produced by cellular inducible nitric oxide synthase, and by derivative reactive nitrogen oxide species including peroxynitrite andS-nitrosothiols. NO may be taken as dietary substrate (inorganic nitrate, L-arginine), and therapeutically as gaseous NO, and transdermal, sublingual, oral, intranasal and intravenous nitrite or nitrate. Numerous preclinical studies have demonstrated that NO has generic static and cidal activities against viruses (includingβ-coronaviruses such as SARS-CoV-2), bacteria, protozoa and fungi/yeasts in vitro. Therapeutic effects have been seen in animal models in vivo, and phase II trials have demonstrated that NO donors can reduce microbial infection. Nevertheless, excess NO, as occurs in septic shock, is associated with increased morbidity and mortality. In view of the dose-dependent positive and negative effects of NO, safety and efficacy trials of NO and its donors are needed for assessing their role in the prevention and treatment of infections. Trialsshould test dietary inorganic nitrate forpre- or post-exposureprophylaxis and gaseous NO or oral, topical or intravenous nitrite and nitrate for treatment ofmild-to-severe infections, including due to SARS-CoV-2(COVID-19). This review summarises the evidence base from in vitro, in vivoand early phase clinical studies of NO activity inviral, bacterial,protozoalandfungalinfections.

Monitoring Nitric Oxide-Induced Hypoxic Tumor Radiosensitization by Radiation-Activated Nanoagents under BOLD/DWI Imaging.

Tumor heterogeneity leads to unpredictable radiotherapeutic outcomes although multiple sensitization strategies have been developed. Real-time monitoring of treatment response through noninvasive imaging methods is critical and a great challenge in optimizing radiotherapy. Herein, we propose a combined functional magnetic resonance imaging approach (blood-oxygen-level-dependent/diffusion-weighted (BOLD/DWI) imaging) for monitoring tumor response to nitric oxide (NO)-induced hypoxic radiosensitization achieved by radiation-activated nanoagents (NSC@SiO2-SNO NPs). This nanoagent carrying NO donors can efficiently concentrate in tumors and specifically produce high concentrations of NO under radiation. In vitro and in vivo studies show that this nanoagent can effectively reduce tumor hypoxia, promote radiation-induced apoptosis and DNA damage under hypoxia, and ultimately inhibit tumor growth. In vivo BOLD/DWI imaging enables noninvasive monitoring of improvements in tumor oxygen levels and radiosensitivity during treatment with this nanostrategy by quantifying functional parameters. This work demonstrates that BOLD/DWI imaging is a useful tool for evaluating tumor response and monitoring the effectiveness of radiotherapeutic strategies aimed at improving hypoxia, with great clinical potential.

Исследование влияния адемола на обмен оксида азота в головном мозге крыс с черепно-мозговой травмой

Актуальность. Высокие концентрации оксида азота (NO) приводят к прогрессированию нарушений мозгового кровообращения на фоне черепно-мозговой травмы (ЧМТ). Одним из ведущих молекулярных механизмов нейроцитопротекторного действия современных фармакологических препаратов является их корректирующее воздействие на обмен NO. Цель: оценить влияние адемола по сравнению с амантадином сульфатом на состояние L-аргинин/NO в головном мозге крыс с ЧМТ. Материалы и методы. Опыты проведены на крысах-самцах. Экспериментальную модель тяжелой ЧМТ создавали с использованием пневматического пистолета. Терапевтическое действие адемола при ЧМТ оценивали в дозе 2 мг/кг с интервалом 2 р/сутки в течение 8 суток. В качестве лекарственного средства для контрольной группы применяли 0,9% NаСl в дозе 2 мл/кг, а препарата сравнения — амантадина сульфат в дозе 5 мг/кг. Для определения эффективности исследуемых препаратов использовали уровень L-аргинина и суммарную активность NO-синтазы. Результаты. Сравнительный анализ эффективности адемола и амантадина сульфата на 8-е сутки наблюдения показал, что в группе животных с ЧМТ, которым применяли адемол, содержание L-аргинина в мозге было больше на 112 % (р < 0,05), чем в группе контроля. В этих условиях суммарная активность NO-синтазы в головном мозге была меньше на 26,6 % (р < 0,05) относительно нелеченых животных с ЧМТ. Зато у животных, леченных амантадином сульфатом, уровень L-аргинина в головном мозге был больше на 72 % (р < 0,05), чем в группе контрольной патологии. При этом суммарная активность NO-синтазы в головном мозге была меньше на 15,4 % (р < 0,05). Выводы. Экспериментальное моделирование травматического поражения головного мозга сопровождалось развитием в его структурах пертурбаций в системе L-аргинин/NO-синтаза. Одним из патогенетических механизмов защитного действия на головной мозг при ЧМТ является способность адемола предупреждать истощение в поврежденном мозге запасов аминокислоты L-аргинина и гиперактивацию NO-синтазы, причем по указанному эффекту адемол превосходил амантадина сульфат (р < 0,05).