Nitric Oxygen Research Articles

Functionalization of Zinc Oxide Nanoflowers with Palladium Nanoparticles via Microwave Absorption for Room Temperature-Operating Hydrogen Gas Sensors in the ppb Level.

Microwave-assisted functionalization of zinc oxide nanoflowers (ZnO NFs) with palladium nanoparticles (Pd NPs) is demonstrated to realize high-performance chemiresistive-type hydrogen (H2) gas sensors operating at room temperature (RT). The developed gas sensors exhibit a high response of up to 70% at 50 ppm and a theoretical detection limit of 10 ppb. The formation of ZnO NFs with an enhanced specific surface area and their functionalization with Pd NPs are investigated through various characterizations. Furthermore, the optimization of microwave absorption upon the structural incorporations between nanostructures (NF-NPs) is investigated for solution-based functionalization at low temperatures (below 120 °C) for short process times (within 1 min), compared to the conventional thermal annealing at 250 °C for 1 h. Highly sensitive and selective ZnO-based gas sensors enabling the detection of H2 gas molecules at 300 ppb concentration at RT exhibit a short response/recovery time of below 3 min and a good selectivity toward different gases including nitric oxide, carbon monoxide, and oxygen. The successful functionalization of nanostructured metal oxide semiconductors (MOSs) with metal NPs via effective and practical microwave absorption enhances the potential on highly sensitive and selective chemiresistive-type MOS-based gas sensors operating at RT without additional heaters or photogenerators.

On the photolysis branching ratio of methyl ethyl ketone

The methyl ethyl ketone (MEK) photolysis branching ratio (α) was re-evaluated by an end product analysis and box model simulations with the Master Chemical Mechanism (MCM). Using light emitting diodes centered at 285 nm or 315 nm, MEK was irradiated in the presence of nitric oxide and oxygen to produce peroxyacetic and peroxypropanoic nitric anhydride, CH3C(O)O2NO2 (PAN) and C2H5C(O)O2NO2 (PPN), which were quantified by gas chromatography. Box model simulations indicated that PPN is partially produced as a secondary product from chemistry initiated by reaction of the hydroxyl radical (OH) with MEK. Under NOx-limited experimental conditions or in the presence of ethane as an OH quencher, the product distribution observed required α = (7 ± 1)% + (1.1 ± 0.7) × 10−4 × (T-298) for 250K < T < 300K (2σ uncertainty), independent of pressure (at pressures > 266 hPa) and consistent with current IUPAC recommendations.

Deactivation, reactivation and super-activation of Fe-N/C oxygen reduction electrocatalysts: Gas sorption, physical and electrochemical investigation using NO and O2

We show that gaseous nitric oxide (NO) and oxygen (O2) are useful molecular probes to uncover complex surface processes in Fe-N/C catalysts. We unravel the difference between using gaseous NO in a temperature programmed desorption experiment and using NO (and progenitors) in an electrochemical experiment. Gas phase O2 adsorption is almost exclusively desorbed as CO2, and continued exposure to oxygen increases the amount of chemisorbed oxygen species on the surface. The oxidation state of the carbon surface is an important activity determining factor, and under normal “electrochemical” conditions many of the active sites are blocked. Only by treatment at 600 °C in Ar can we free those sites for oxygen adsorption, however under atmospheric storage, and especially during the oxygen reduction reaction (ORR), the surface quickly becomes deactivated with chemisorbed oxygen species and water. We demonstrate that the material can be super-activated by reductive electrochemical treatment, both in an electrochemical three electrode cell and in a fuel cell. The energy gained following the treatment is significantly larger than the energetic cost.

The effects of nitric oxide or oxygen on the stable products formed from the tyrosine phenoxyl radical

Tyrosine is a critical component of many proteins and can be the subject of oxidative posttranslational modifications. Furthermore, the oxidation of tyrosine residues to phenoxyl radicals, sometimes quite stable, is essential for some enzymatic functions. The lifetime and fate of tyrosine phenoxyl radicals in biological systems are largely driven by the availability and proximity of oxidants and reductants. Tyrosine phenoxyl radicals have extremely low reactivity with molecular oxygen whereas reactions with nitric oxide are diffusion controlled. This is in contrast to equivalent reactions with tryptophanyl and cysteinyl radicals where reactions with oxygen are much faster. Despite, the quite disparate apparent reactivity of tyrosine phenoxyl radicals with oxygen and nitric oxide being known, the products of the reactions are not well established. Changes in the levels from expected basal concentrations of stable products resulting from tyrosine phenoxyl radicals, for example naturally occurring 3,3′-dityrosine, 3-nitrotyrosine, and 3-hydroxytyrosine, can be indicative of oxidative and/or nitrosative stress. Using the radiolytic generation of specific oxidizing radicals to form tyrosine phenoxyl radicals in an aqueous solution at a known rate, we have compared the products in the absence and presence of nitric oxide or oxygen. Possible reactions of the phenoxyl radicals with oxygen remain unclear although we show evidence for a small decrease in the yield of dityrosine and loss of tyrosine in the presence of 20% oxygen. Low concentrations of nitric oxide in anoxic conditions react with tyrosine phenoxyl radicals, by what is most probably through the formation of an unstable intermediate, regenerating tyrosine and forming nitrite.

Employing an Unnatural Amino Acid to Examine Local Environments in Multiple Protein Systems

Unnatural amino acids (UAAs) expand the landscape of protein biochemistry, providing new tools to examine and tune protein structure and function. Using the amber codon suppression technology these UAAs can be site-specifically incorporated into proteins. The UAA 4-cyano-L-phenylalanine (pCNF) contains the nitrile functional group whose nitrile stretching frequency is located both in a quiet region of protein IR spectra and is sensitive to local environment. Our work using pCNF site-specifically incorporated at various locations in both the gas-sensing Heme Nitric Oxide and/or Oxygen (H-NOX) binding protein from Caldanaerobacter subterraneus and the super folder Green Fluorescent Protein (sfGFP) will be discussed.

Lung toxicity and gene expression changes in response to whole-body inhalation exposure to cellulose nanocrystal in rats

Objective Human exposure to cellulose nanocrystal (CNC) is possible during the production and/or use of products containing CNC. The objectives of the current study were to determine the lung toxicity of CNC and the underlying molecular mechanisms of the toxicity. Methods Rats were exposed to air or CNC (20 mg/m3, six hours/day, 14 d) by whole-body inhalation and lung toxicity and global gene expression profile were determined. Results Significant increases in lactate dehydrogenase activity, pro-inflammatory cytokine levels, phagocyte oxidant production, and macrophage and neutrophil counts were detected in the bronchoalveolar lavage cells or fluid from the CNC exposed rats. Mild lung histological changes, such as the accumulation of macrophages and neutrophils, were detected in the CNC exposed rats. Gene expression profiling by next generation sequencing identified 531 genes whose expressions were significantly different in the lungs of the CNC exposed rats, compared with the controls. Bioinformatic analysis of the lung gene expression data identified significant enrichment in several biological functions and canonical pathways including those related to inflammation (cellular movement, immune cell trafficking, inflammatory diseases and response, respiratory disease, complement system, acute phase response, leukocyte extravasation signaling, granulocyte and agranulocyte adhesion and diapedesis, IL-10 signaling, and phagosome formation and maturation) and oxidative stress (NRF2-mediated oxidative stress response, production of nitric oxide and reactive oxygen species in macrophages, and free radical scavenging). Conclusion Our data demonstrated that inhalation exposure of rats to CNC resulted in lung toxicity mediated mainly through the induction of inflammation and oxidative stress.

Nitric Oxide Modulating Calcium Store for Ca2+‐Initiated Cancer Therapy

AbstractIons are essential to body, but sometimes can evolve into weapons to attack and destroy cells without systematic toxicity and drug resistance. Inspired by nitric oxygen as neurotransmitter in mediating Ca2+ release, NO nanodonors with high photoreactivity and stability are constructed with upconversion nanoparticles (UCNPs) coated by zeolitic nitro‐/nitrile‐imidazole framework‐82 (ZIF‐82), capable of near‐infrared light (NIR) triggered NO generation and berbamine (BER) release, to achieve cancer therapy with the stored Ca2+ in cells. The spatial confinement effect of 2‐nitroimidazole in ZIF‐82 enables NO‐releasing with tunable release kinetics. NO turns on the ryanodine receptors overexpressed in cancer cells for abrupt Ca2+ elevation; meanwhile, berbamine (BER) turns Ca2+‐excretion pumps off to inhibit calcium efflux, resulting in intracellular Ca2+ overload induced apoptosis. This work provides the first example of regulating endogenous ions for cell killing, which holds promise as an effective cancer therapeutics that is complementary to traditional chemotherapeutics.

Changes in the Relative Nitric Oxide Content in the Cortex of a Rat Brain in the Acute Ischemia Model

This study uses the electron paramagnetic resonance (EPR) method to study changes in the relative nitric oxygen content in the cortex of a rat brain in conditions of acute ischemia. Laser-induced vascular thrombosis is used as the model of ischemia. Rose bengal is administered into the bloodstream beforehand. In response to laser beaming, it generates reactive oxygen species, which induces protein coagulation, vascular wall damage, and, as a consequence, the formation of thrombus. It is shown histologically that the acute ischemic process ends a day after the laser surgery, and active remission, with the corresponding morphological changes in the area of the lesion, starts within three days. The relative nitric oxide content is determined 1 and 3 days after the brain vascular photothrombosis using the NO–Fe–DETC paramagnetic complex as a spin trap. The nitric oxide content is estimated by the extreme lower field of the EPR spectrum of this complex. It is shown that a significant increase in the relative nitric oxide (NO) content occurs on the third day after laser surgery and coincides with the beginning of remission after the acute ischemia. A possible role of nitric oxide in the remission is discussed in the study.

Lanthanum: A novel inducer for enhancement of fungal laccase production by Shiraia bambusicola

Fungal laccases are industrially important inducible enzymes extensively used in the delignification of lignocellulosics, detoxification of environmental wastes and decolorization of textile dyes. The discovery of new inducers is crucial for laccase productivity by filamentous fungi. In this study, a novel laccase-producing strain S8 from a bambusicolous fungus Shiraia bambusicola was identified by using 2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonate) as laccase secretion indicator and native polyacrylamide gel electrophoresis. The corresponding full-length cDNA of laccase was cloned and characterized. The effect of lanthanum (LaCl3) on extracellular laccase activity was tested at the concentration from 0.2 to 2.0 g/L and at different addition time (day 1–4) in the mycelium culture. In the presence of 1.0 g/L La3+ at the beginning of the mycelium cultures, the highest laccase activity (2.7 × 104 U/L) is reached after 10 days of cultivation, about tenfold higher compared with non-induced cultures. La3+ is shown to be a very strong inducer for fungal laccase activity with no inhibitory effect on fungal growth at the optimized concentration. In vivo, La3+ added to the mycelium culture not only promotes a continuous and high expression of laccase gene (lcc1), but also induces a rapid generation of signaling molecules including reactive oxygen species (ROS) and nitric oxygen (NO). Both the NO donor sodium nitroprusside (SNP) and exogenous hydrogen peroxide (H2O2) potentiate La3+-induced laccase activity and increase membrane permeability of hyphal cells. Moreover, the scavengers such as 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (cPTIO) for NO and vitamin C for ROS suppress the induction. These results suggest that these signals can mediate La3+-induced laccase biosynthesis and its secretion. Our study provides a basis for understanding the induction mechanism of La3+ on laccase and a practical strategy for enhanced fungal laccase production.

1 + 1 &gt; 2: A critical review of MOF/bismuth-based semiconductor composites for boosted photocatalysis

• MOF/Bi-based semiconductor composites for boosted photocatalysis was reviewed. • The synthesis strategies of MOF/Bi-based semiconductor composites were summed up. • Photocatalytic mechanisms of MOF/Bi-based semiconductor composites were described. • The MOF/Bi-based semiconductor composites as photocatalysts were prospected. Photocatalysis is an effective procedure for environmental remediation and energy production. Considering that both the bismuth-based semiconductors and metal-organic frameworks (MOFs) are star photocatalysts, the combination of bismuth-based semiconductors with MOFs is beneficial to overcome their shortcomings like narrow sunlight absorption range, deficient active sites and rapid charges recombination rate. Recently, these composites displayed outstanding photocatalytic performances toward nitric oxide (NO) oxidation, Cr(VI) reduction, oxygen production, nitrogen (N 2 ) fixation and organic pollutants degradation. In this review, we focused to discuss the fabrication and synthesis methods, characterizations, photocatalytic applications as well as the corresponding mechanisms of some representative MOF/bismuth-based semiconductor composites (abbreviated as MBCs). Finally, new insights are proposed to meet the future challenges and development of the composites, which can provide better knowledge for the advancement of the related research areas.

Beneficial Effects of Spirulina Aqueous Extract on Vasodilator Function of Arteries from Hypertensive Rats.

Hypertension is a multifactorial disorder considered one of the major causes of premature death worldwide. This pathology is associated with vascular functional/structural alterations in which nitric oxide (NO) and oxygen reactive species participate. On the other hand, the use of microalgae extracts in the treatment of cardiovascular diseases is increasing. Based on the antioxidant and antihypertensive properties of Spirulina, this study aims to investigate the effect of an aqueous extract of Spirulina on the vasodilator function of the aorta from spontaneously hypertensive rats (SHR), analyzing the functional role of NO. For this, aortic segments from male SHR were divided into two groups, one control and the other exposed to an Spirulina aqueous extract (0.1% w/v, for 3 hours), to analyze (i) the production of NO, superoxide anion, and hydrogen peroxide; (ii) the vasodilator response induced by acetylcholine (ACh), by the NO donor and sodium nitroprusside (SNP), and by the KATP channel opener and pinacidil; and (iii) the expression of the p-Akt, p-eNOS, and HO-1 proteins. The results showed that the aqueous Spirulina extract (i) increased the production of NO, did not significantly modify that of superoxide, while decreased that of hydrogen peroxide; (ii) increased the vasodilatory responses induced by ACh, NPS, and pinacidil; and (iii) increased the expression of p-Akt and HO-1. These results suggest that incubation with the aqueous Spirulina extract improves the vascular function of arteries from SHR by increasing the release/bioavailability/function of NO. Increased KATP channel activation and expression of pAkt and HO-1 appear to be participating in these actions.

INOS Expression by Tumor-Infiltrating Lymphocytes, PD-L1 and Prognosis in Non-Small-Cell Lung Cancer.

Simple SummaryThe role of Inducible Nitric Oxygen Synthase (iNOS) in the progression of human malignancies is obscure. We studied the expression patterns of iNOS in non-small-cell lung cancer. iNOS was expressed by cancer cells and cancer-associated fibroblasts. None of these patterns, however, are related to stage or prognosis. Extensive infiltration of the tumor stroma by iNOS-expressing tumor-infiltrating lymphocytes (iNOS+TILs) occurred in 48% of cases. This was related to low Hypoxia-Inducible Factor 1α (HIF1α) and better overall survival. Expression of Programmed death-ligand 1 PD-L1, however, mitigates the beneficial effect of the presence of iNOS+TIL. An important role of iNOS in anti-neoplastic lymphocyte biology has been brought forward, supporting iNOS+TILs as putative immune response markers.Background: Inducible Nitric Oxygen Synthase (iNOS) promotes the generation of NO in tissues. Its role in tumor progression and immune response is unclear. Methods: The immunohistochemical expression patterns of iNOS were studied in a series of 98 tissue samples of non-small-cell lung carcinoma (NSCLC), in parallel with the expression of hypoxia and anaerobic metabolism markers, PD-L1 and tumor-infiltrating lymphocytes (TILs). Results: iNOS is expressed by cancer cells in 19/98 (19.4%), while extensive expression by cancer-associated fibroblasts occurs in 8/98 (8.2%) cases. None of these patterns relate to stage or prognosis. Extensive infiltration of the tumor stroma by iNOS-expressing TILs (iNOS+TILs) occurs in 47/98 (48%) cases. This is related to low Hypoxia-Inducible Factor 1α (HIF1α), high PD-L1 expression and a better overall survival (p = 0.002). Expression of PD-L1, however, mitigates the beneficial effect of the presence of iNOS+TIL. Conclusions: Extensive expression of iNOS by TILs occurs in approximately 50% of NSCLCs, and this is significantly related to an improved overall survival. This brings forward the role of iNOS in anti-neoplastic lymphocyte biology, supporting iNOS+TILs as a putative marker of immune response. The value of this biomarker as a predictive and treatment-guiding tool for tumor immunotherapy demands further investigation.

Identifying Thermal Decomposition Products of Nitrate Ester Explosives Using Gas Chromatography-Vacuum Ultraviolet Spectroscopy: An Experimental and Computational Study.

Analysis of nitrate ester explosives (e.g., nitroglycerine) using gas chromatography-vacuum ultraviolet spectroscopy (GC-VUV) results in their thermal decomposition into nitric oxide, water, carbon monoxide, oxygen, and formaldehyde. These decomposition products exhibit highly structured spectra in the VUV that is not seen in larger molecules. Computational analysis using time-dependent density functional theory (TDDFT) was utilized to investigate the excited states and vibronic transitions of these decomposition products. The experimental and computational results are compared with those in previous literature using synchrotron spectroscopy, electron energy loss spectroscopy (EELS), photoabsorption spectroscopy, and other computational excited state methods. It was determined that a benchtop GC-VUV detector gives comparable results to those previously reported, and TDDFT could predict vibronic spacing and model molecular orbital diagrams.

Application of Laser Blue Light With a Wavelength of 405 nm in the Treatment of Patients With the Virus COVID-19.

Dear Editor, Scientists are concerned about a new virus that has infected tens of thousands of people and killed more than 2,000. The virus, which emerged in the Chinese city of Wuhan in December, is a coronavirus and belongs to the same family as the pathogen that causes severe acute respiratory syndrome, or SARS. It causes a respiratory illness called COVID-19, which can spread from person to person.[1] Laser and Virus Fatma Vatansever Together with their research team in the year 2013 they came to this conclusion by testing on viruses and pathogens UVC, blue light, PDI have been shown to be effective in inactivating pathogens without harm [2].Research on the use of lasers in viral mortality is not widespread, but with a few studies, the effectiveness of laser blue light and LEDs in eliminating the virus can now be studied. Diem ThoHo, with his research team studying 400 nm blue light, concluded thatThe results of this study provide the first evidence that 405-nm LED light has antiviral activity [3]. there are some wavelengths that can decrease microorganisms directly, such as blue, ultraviolet, or violet wavelengths. We can increase these effects by possibly combining this method with another method known as antimicrobial photodynamic therapy (aPDT).&nbsp; According to mechanisms mentioned earlier, we are referring to the capabilities of PBM and photodynamic therapy. The best use is a combination of both methods, as mentioned earlier. The present treatments are focused on virus removal, tissue oxygenation, and reduction or inhibition of cytokine storm caused by severe inflammation. With a combination of these two methods, we can achieve these goals with minimal interference with pharmaceutical methods and battle this disease with biophysical agen [4]. The Blue Laser: Blue laser light of different wavelengths has been reported to have positive effects on our immune system. Can be used for anti-microbial photodynamic therapy&nbsp; (for bacterial, viral and parasitic diseases) [5]. Based on past studies and the effectiveness of low-power laser light, we can use venous laser light in this method intravenously, but it should be noted that using blue light in a venous form is more cautious. Therefore, the use of this method should be all factors such as: Age, gender, weight, specific disease, and laser duration were considered so that we could do this properly.The wavelength used will be 405 nanometers with a power of 1.5 to 2 milliwatts, which due to the high energy of this wavelength should not exceed the mentioned power, and the duration of laser radiation according to the factors from 10 to 20 minutes in 10 sessions. There will be a day in between The goal is to reduce inflammation of the lungs and increase the amount of nitric oxygen that will increase the body's immunity and improve oxygen delivery to the blood and tissues.

The future of Cochrane Neonatal

The future of Cochrane Neonatal

The leaves of Bougainvillea spectabilis suppressed inflammation and nociception in vivo through the modulation of glutamatergic, cGMP, and ATP-sensitive K+ channel pathways

Ethnopharmacological relevanceBougainvillea spectabilis is an ornamental shrub from Nyctaginaceae family, widely used in the traditional medicine in the treatment of pain, inflammation, and ulcer. Some research investigated the analgesic potential of this plant, however, the in-depth analysis of its antinociceptive properties and molecular mechanism(s) are yet to be revealed. Purpose of the studyThis study, therefore, investigated the antinociceptive potential of methanol extract of the leaves of B. spectabilis (MEBS) with possible molecular mechanism(s) of action using several pre-clinical models of acute and chronic pain in mice. Materials and methodsThe dry leaf powder of B. spectabilis was macerated with 100% methanol, and then dried crude extract was used for in vivo experiments. Following the acute toxicity test with 500, 1000, and 2000 mg/kg b.w. doses of MEBS, the central antinociceptive activities of the extract (50, 100, and 200 mg/kg b.w.) were evaluated using hot plate and tail immersion tests, whereas the peripheral activities were investigated using acetic acid-induced writhing, formalin-induced licking and oedema, and glutamate-induced licking tests. Moreover, the possible involvements of cGMP and ATP-sensitive K+ channel pathways in the observed antinociceptive activities were also investigated using methylene blue (20 mg/kg b.w.) and glibenclamide (10 mg/kg b.w.), respectively. We also performed GC/MS-MS analysis of MEBS to identify the phyto-constituents and in silico modelling of the major compounds for potential molecular targets. ResultsOur results demonstrated that MEBS at 50, 100, and 200 mg/kg b.w. doses were not effective enough to suppress centrally mediated pain in the hot plate and tail immersion models. However, the extract was potent (at 100 and 200 mg/kg b.w. doses) in reducing peripheral nociception in the acetic acid-induced writhing and inflammatory phase of the formalin tests. Further analyses revealed that MEBS could interfere with glutamatergic system, cGMP and ATP-sensitive K+ channel pathways to show its antinociceptive properties. GC/MS-MS analysis revealed 35 different phytochemicals with potent anti-inflammatory and antinociceptive properties including phytol, neophytadiene, 2,4-Di-tert-butylphenol, fucoxanthin, and Vit-E. Prediction analysis showed high intestinal absorptivity and low toxicity profiles of these compounds with capability to interact with glutamatergic system, inhibit JAK/STAT pathway, scavenge nitric oxide and oxygen radicals, and inhibit expression of COX3, tumor necrosis factor, and histamine. ConclusionTaken together, these results suggested the antinociceptive potentials of MEBS which were mediated through the modulation of glutamatergic, cGMP, and ATP-sensitive K+ channel pathways. These also suggested that MEBS could be beneficial in the treatment of complications associated with nociceptive pain.

Low androgen status inhibits erectile function by inducing eNOS uncoupling in rat corpus cavernosum.

The number of erectile dysfunction (ED) patients is increasing annually. How to improve the effectiveness of ED treatment is an important issue for the field of andrology. To investigate whether low androgen status impairs the erectile function of rats by regulated endothelial nitric oxide synthase (eNOS) uncoupling. Thirty-six 8-week-old male Sprague Dawley (SD) rats were randomly divided into six groups as follows: 4-week sham-operated group (4w-sham), 4-week castration group (4w-cast), 4-week castration+testosterone (T) group (4w-cast+T), 8-week sham-operated group (8w-sham), 8-week castration group (8w-cast), and 8-week castration+T group (8w-cast+T). Three mg/kg of T was subcutaneously injected every other day in castration+T groups. The ratio of the maximum intracavernous pressure/the mean arterial pressure (ICPmax/MAP), the level of serum T, dihydrobiopterin(BH2 ), tetrahydrobiopterin (BH4 ), nitric oxygen(NO), 3-nitrotyrosine(3NT), dihydrofolate reductase (DHFR), guanosine triphosphate cyclohydrolase 1 (GTPCH1), nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2), and eNOS monomers/dimers in the corpus cavernosum were detected. The ratio of ICPmax/MAP and BH4 /BH2 , the level of serum T, NO, and GTPCH1 decreased significantly in castration groups compared with sham-operated groups and castration+T groups (P<.05) and decreased significantly in 8w-cast group compared with 4w-cast group (P<.05). The expression of 3NT and NOX2 and the ratio of eNOS monomers/dimers increased significantly in castration groups compared with sham-operated groups and castration+T groups (P<.01) and increased significantly in 8w-cast group compared with 4w-cast group (P<.01). The expression of DHFR in 4w-cast group was significantly higher than that in 4w-sham group and 4w-cast+T group (P<.01) and in 8w-cast group was significantly lower than that in 8w-sham group and 8w-cast+T group (P<.01). Low androgen status induces eNOS uncoupling by reducing BH4 /BH2 and increasing 3NT. Due to the decreased NO production, the erectile function of the rats was impaired.

Effects of Different Types of Exercise Training on Pulmonary Arterial Hypertension: A Systematic Review.

Pulmonary arterial hypertension (PAH) represents a chronic progressive disease characterized by high blood pressure in the pulmonary arteries leading to right heart failure. The disease has been a focus of medical research for many years due to its worse prognosis and limited treatment options. The aim of this study was to systematically assess the effects of different types of exercise interventions on PAH. Electronic databases were searched until July 2019. MEDLINE database was used as the predominant source for this paper. Studies with regards to chronic physical activity in adult PAH patients are compared on retrieving evidence on cellular, physiological, and psychological alterations in the PAH setting. Twenty human studies and 12 rat trials were identified. Amongst all studies, a total of 628 human subjects and 614 rats were examined. Regular physical activity affects the production of nitric oxygen and attenuates right ventricular hypertrophy. A combination of aerobic, anaerobic, and respiratory muscle training induces the strongest improvement in functional capacity indicated by an increase of 6 MWD and VO2 peak. In human studies, an increase of quality of life was found. Exercise training has an overall positive effect on the physiological and psychological components of PAH. Consequently, PAH patients should be encouraged to take part in regular exercise training programs.

245-LB: Aberrant DNA Methylation as a Contributor to Obesity-Associated Vascular Dysfunction

Obesity is a major risk factor for cardiovascular disease. We previously demonstrated an impaired vascular function in obese adults (OB). We now hypothesize a role of obesity-associated hypoxia in disturbing the methylation of genes involved in inflammation and vascular dysfunction and propose a mediating role of the hypoxia-inducible factor, HIF1α and the DNA hydroxymethylase, TET1. Methods: We obtained subcutaneous and visceral adipose tissue (AT) biopsies from bariatric patients (n=60; age: 36±7 yrs; BMI: 50.7±8.7 kg/m2) and non-obese (NOB) adults having elective surgeries (n=36; age: 36±2 yrs; BMI: 25.8±1 kg/m2). AT-isolated arterioles were tested for vasoreactivity in response to increasing pressure gradients. Arteriolar nitric oxide (NO) and reactive oxygen species (ROS) were measured. Protein expression of HIF1α and TET1 and promoter methylation/gene expression of leptin, IL1β, IL6, IL8, IL17, CXCL5, TNF-α, and IFNɣ were measured in the AT biopsy. Brachial artery flow-mediated dilation (FMD) was measured via doppler ultrasound. Results: Flow-induced dilation (FID) was 40-50% higher in NOB than OB adults across all pressure gradients (p&amp;lt;0.05). NO production was higher, and ROS generation was lower in the OB arterioles compared to NOB. HIF1α and TET1 proteins were 2 to 4-fold higher in OB compared to NOB adults and correlated negatively with arteriolar FID and NO and brachial artery FMD (r=0.82, 0.64, 0.91, respectively; p&amp;lt;0.001) and positively with arteriolar ROS production (r=-0.71, p&amp;lt;0.01). Global hydroxymethylation was observed in OB compared to NOB as well as DNA promoter hypomethylation and increased gene expression of the targeted adipocytokines. Conclusion: Our results suggest that vascular dysfunction in OB adults may be attributed to aberrant DNA methylation and increased expression of adipocytokines in the hypoxic AT. A downstream target for this pathway could reside in endothelial cells of nearby arterioles and remote arteries resulting in vascular dysfunction. Disclosure M.M. Ali: None. C. Hassan: None. M. Masrur: None. F. Bianco: Consultant; Self; Intuitive, Medtronic. S.A. Phillips: None. A.M. Mahmoud: None. Funding National Institutes of Health (4R00HL140049, 031K99, HL14004901)

Tyrosine 135 of the β1 subunit as binding site of BAY-543: Importance of the Y-x-S-x-R motif for binding and activation by sGC activator drugs

Soluble guanylyl cyclase (sGC), the major receptor for nitric oxide (NO), is a heterodimer consisting of two subunits, the α and the β subunit. The NO/sGC/cGMP signaling pathway is protective in different disease pathomechanisms including angina pectoris, pulmonary hypertension and fibrotic diseases. The natural ligand heme has two carboxylic acids which interact in the β1 heme nitric oxide oxygen binding (HNOX) domain with the amino acids of the highly conserved Y-x-S-x-R motif. The Y-x-S-x-R motif is also involved in binding of the dicarboxylic activators cinaciguat and BAY 60–2770 as indicated by crystallization studies of sGC activator and bacterial HNOX homologs. To what extent the Y-x-S-x-R motif hydrogen bond network contributes to binding of monocarboxylic acids has not been examined so far. In the current paper, the chemical structural formula of the novel monocarboxylic drug BAY-543 is described for the first time. Using this novel drug, we evaluate the importance of the amino acids Y135 and R139 for thermostabilization and activation in comparison to the dicarboxylic acid BAY 60–2770. Measurements with point mutated sGC variants demonstrate tyrosine 135 as exclusive binding site of the monocarboxylic acid BAY-543 but not the dicarboxylic BAY 60–2770.