Low Nitric Oxide Research Articles

Novel CYCLIN-O pathogenic variants in a patient presenting with bronchiectasis secondary to reduced generation of multiple motile cilia.

Reduced generation of multiple motile cilia (RGMC) represents a rare variant of Primary Ciliary Dyskinesia (PCD), associated with CYCLIN-O (CCNO) mutations. We report a novel compound mutation in the CCNO gene in an adult Chinese Singaporean exhibiting chronic productive cough since childhood and recurrent sino-pulmonary infections. Low nasal nitric oxide and bronchiectasis suggests PCD. Bronchoscopy for epithelial and nasal brushings for ciliary studies were repeated after adequate treatment of lower respiratory tract infections. Demonstration of oligo-cilia via transmission electron microscopy, and detection of CCNO mutation through genetic analysis were utilized to diagnose RGMC. Repeated courses of antibiotics including nebulised antibiotics were used to treat recurrent infections and exacerbations. Airway clearance techniques, immunizations and collaboration with otorhinolaryngologist form part of the long-term management. Heightened clinical suspicion and adherence to established diagnostic algorithms are essential for timely recognition of this entity.

Astodrimer sodium nasal spray forms a barrier to SARS-CoV-2 in vitro and preserves normal mucociliary function in human nasal epithelium

COVID-19 remains a severe condition for many including immunocompromised individuals. There remains a need for effective measures against this and other respiratory infections, which transmit via virus-laden droplets that reach the nasal or oral mucosae. Nasal sprays offer potential protection against viruses. Such formulations should preserve normal nasal mucociliary function. The antiviral barrier efficacy and effects on mucociliary function of astodrimer sodium nasal spray (AS-NS) were evaluated and compared with other available nasal sprays—low pH hydroxypropyl methylcellulose (HPMC-NS), iota-carrageenan (Carr-NS), nitric oxide (NO-NS), and povidone iodine (PI-NS). Assays simulated clinical conditions. Antiviral barrier function and cell viability were assessed in airway cell monolayers, while a model of fully differentiated human nasal epithelium (MucilAir™) was utilized to evaluate tissue integrity, cytotoxicity, cilia beating frequency, and mucociliary clearance. AS-NS reduced infectious virus in cell monolayers and demonstrated a benign cytotoxicity profile. In human nasal epithelium ex vivo, AS-NS had no impact on mucociliary function (cilia beating nor mucociliary clearance). Carr-NS, HPMC-NS, NO-NS and PI-NS demonstrated limited antiviral effects, while HPMC-NS caused inhibition of mucociliary function. Astodrimer sodium nasal spray demonstrates an acceptable nonclinical efficacy and safety profile as a barrier nasal spray against respiratory viral infection in the nasal cavity.

Low temperature conditioning and nitric oxide treatment reduced chilling injury and altered fatty acid metabolism of flat peaches

Low-temperature conditioning is a recognized method for alleviating chilling injuries in flat peaches. However, long-term low-temperature storage can mitigate volatile organic compounds, thereby limiting fruit availability. To improve the supply of flat peaches, we investigated the combined effects of low-temperature conditioning and nitric oxide treatment on various parameters including physiological quality, volatile organic compounds, fatty acids, associated enzymes, and genes involved in the fatty acid pathway with the transcriptome sequencing analysis. The results indicated that low-temperature conditioning coordinated with 10 µL L−1 nitric oxide treatment possessed higher firmness and vitamin C content and restricted the content of malonaldehyde and relative electrical conductivity, thus maintaining the overall quality of flat peaches. In the study, 10 µL L−1 nitric oxide was employed for subsequent experiments. Moreover, higher contents of volatile organic compounds were supported by increased contents of palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, alcohol dehydrogenase, hydroperoxide lyase, and up-regulated genes of LOX2, LOX3, LOX6, ADH2, and ADH3. In summary, nitric oxide treatment effectively facilitated the recovery of volatile organic compounds in flat peaches during cold storage. Therefore, low-temperature conditioning and nitric oxide treatment can be a promising strategy to prevent the loss of volatile organic compounds by modulating the fatty acid pathway and associated genes.

Synergistic approaches to NOx reduction: Fuel innovations and engine modifications in biomass waste-fueled CI engines

Achieving low nitric oxide emissions in biomass fuel combustion remains a challenge. This study aims at enhancement of NOx reduction by employing a sequence of strategies to arrive at the optimal combination of techniques. This work explores the role of nano particle emulsion, change in profile of combustion chamber geometry, exhaust gas recirculation rates and contribution of selective catalytic reduction (SCR) in the combustion and emission phenomena of CI engine. Cerium oxide and zinc oxide nanoparticles are added in emulsion form at 50 ppm and 100 ppm dosage to grapeseed oil biodiesel. Furthermore, combustion chamber geometry is modified to shallow depth and toroidal shape and tested with ZnO 100 nano blend of grapeseed oil biodiesel (GSBD). EGR at 5 %, 10 %, 15 % and 20 % rates are included in the toroidal shape after concluding that profile as the best performing geometry. A customized model of SCR is implemented to the above combination of ZnO fuel blend, toroidal combustion chamber geometry and 5 % EGR to further reduce NOx emission. SCR device is fabricated with suitable flow and injection parameters with dual type mixers to enhance its NOx conversion efficiency. Overall, this research work gives useful insights for development of NOx reduction strategies in biomass fuel combustion in CI engines. A comprehensive reduction of NOx from 9.3 g/kWh to 2.05 g/kWh is noticed at the end of cumulative set of experiments.

Dupilumab responder types and predicting factors in patients with type 2 severe asthma: A real-world cohort study

BackgroundSevere asthma (SA) presents a considerable healthcare challenge despite optimal standard treatment. Dupilumab, which is effective in type 2 (T2) SA patients, demonstrates variable responses, categorizing patients as non-responders, partial responders, or those achieving clinical remission. However, real-world response rates remain underexplored. Additionally, understanding the characteristics of patients achieving clinical remission is crucial for predicting favourable responses to dupilumab. ObjectiveTo investigate responder types and identify predictors of clinical remission and non-response induced by dupilumab in a real-world cohort of SA patients. MethodsWe analyzed retrospective data from SA patients undergoing dupilumab treatment in a study conducted at Franciscus Gasthuis & Vlietland hospital. Data were collected at baseline and at a 12 to 24-months follow-up (T = 12). Response rates were evaluated at T = 12. Predictors of non-response and clinical remission were investigated using multivariate logistic regression analysis with a stepwise forward variable selection approach. ResultsAmong the 175 patients screened, 136 met the inclusion criteria. At T = 12, 31.6 % achieved clinical remission, 47.1 % were partial responders and 21.3 % were non-responders. Predictors associated with clinical remission included high baseline blood eosinophil counts (BEC) and male sex. Conversely, younger age at baseline, low baseline total immunoglobin E (IgE) and low baseline fractional exhaled nitric oxide (FeNO) levels were identified as predictors of non-response. ConclusionsDupilumab results in clinical disease remission in one-third of the treated patients. Clinical remission is predicted by high BEC and male sex, whereas low total IgE, low FeNO and younger age indicate a lower likelihood of response.

Reciprocal Interactions of Human Monocytes and Cancer Cells in Co-Cultures In Vitro.

The tumor microenvironment (TME) includes immune and stromal cells and noncellular extracellular matrix (ECM) components. Tumor-associated macrophages (TAMs) are the most important immune cells in TME and are crucial for carcinomas' progression. The purpose was to analyze direct and indirect interactions in co-culture of tumor cells with monocytes/macrophages and, additionally, to indicate which interactions are more important for cancer development. Cytokines, reactive oxygen species, nitric oxide level, tumor cell cycle and changes in tumor cell morphology after human tumor cells (Hep-2 and RK33 cell lines) with human monocyte/macrophage (THP-1 cell line) interactions were tested. Morphology and cytoskeleton organization of tumor cells did not change after co-culture with macrophages. In co-culture of tumor cells with human monocyte, changes in the percentage of tumor cells in cell cycle phases was observed. No significant changes in reactive oxygen species (ROS) were found in the co-culture as compared to the tumor cell mono-culture. Monocytes produced about three times higher ROS than tumor cells. In co-cultures, a lower nitric oxide (NOx) level was found as compared to the sum of the production by both mono-cultures. Co-culture conditions limited the production of cytokines (IL-4, IL-10 and IL-13) as compared to the sum of their level in mono-cultures. In conclusion, macrophages influence tumor cell growth and functions. Mutual (direct and paracrine) interactions between tumor cells and macrophages changed cytokine production and tumor cell cycle profile. The data obtained may allow us to initially indicate which kind of interactions may have a greater impact on cancer development processes.

Cerebrospinal Fluid Nitric Oxide Synthase is a Potential Mediator Between Cigarette Smoke Exposure and Sleep Disorders.

Cigarette smoking and low peripheral nitric oxide synthase (NOS) levels are strongly associated with sleep disorders. However, whether cerebrospinal fluid (CSF) NOS relates to sleep disorders and whether CSF NOS mediates the relationship between cigarette smoking and sleep disorders is unclear. We measured CSF levels of total NOS (tNOS) and its isoforms (inducible NOS [iNOS] and constitutive NOS [cNOS]) in 191 Chinese male subjects. We applied the Pittsburgh Sleep Quality Index (PSQI). The PSQI scores of active smokers were significantly higher than those of non-smokers, while CSF tNOS, iNOS, and cNOS were significantly lower (all p < 0.001). CSF tNOS, iNOS, and cNOS were negatively associated with PSQI scores in the general population (all p < 0.001). Mediation analysis suggested that CSF tNOS, iNOS, and cNOS mediate the relationship between smoking and PSQI scores, and the indirect effect accounted for 78.93%, 66.29%, and 81.65% of the total effect, respectively. Cigarette smoking is associated with sleep disorders. Active smokers had significantly lower CSF levels of tNOS, iNOS, and cNOS. Furthermore, tNOS, iNOS, and cNOS mediate the relationship between cigarette smoking and sleep quality. This study provides insights into how cigarette smoke affects sleep disorders.

Phenolic and Metabolic Profiles, Antioxidant Activities, Glycemic Control, and Anti-Inflammatory Activity of Three Thai Papaya Cultivar Leaves.

This study thoroughly examined the proximate composition, bioactive composition, and in vitro biological activities of three different cultivars of papaya leaf extracts (PLEs) as potential functional ingredients and nutraceuticals. The dark green leaves of three papaya cultivars, Khaek Dam (KD), Holland (H), and Thai Local (L), were used in this study. The protein content of the leaves ranged from 25.96 to 32.18%, the fat content ranged from 7.34 to 11.66%, the carbohydrate content ranged from 5.80 to 17.91%, the moisture content ranged from 6.02 to 6.49%, the ash content ranged from 11.23 to 12.40%, and the fiber content ranged from 23.24 to 38.48%. The L cultivar possessed significantly higher protein and carbohydrate contents, whereas the H cultivar had the highest ash content (p < 0.05). The total phenolic content (TPC) ranged from 113.94 to 173.69 mg GAE/g extract, with the KD cultivar having the highest TPC (p < 0.05). Several metabolic compounds such as phenolic compounds (particularly kaempferol, isorhamnetin, quercetin, ferulic acid, isoferulic acid, salicylic acid, sinapic acid, syringic acid, and vanillin), terpenoids (such as eucalyptol), glycosides, and indole were identified. The PLE from the KD cultivar had the highest levels of DPPH• inhibition, metal chelation, reducing power, and antidiabetic activity (p < 0.05), suggesting superior biological activity. All three PLEs reduced the proliferation of RAW 264.7 cells in a dose-dependent manner with low nitric oxide formation. These results indicate that the papaya leaf, particularly from the KD cultivar, could be a promising source of functional food ingredients.

L-Citrulline Supplementation Improves Leg Endothelial Function and Blood Flow Responses to Plantarflexion Exercise in Hypertensive Postmenopausal Women

Menopause and hypertension are associated with macro- and microvascular endothelial dysfunction at rest. Arginine deficiency and low nitric oxide (NO) synthesis may contribute to reduced muscle blood flow (BF) and oxygen delivery to exercising muscles. Improving BF to calf muscles may enhance physical activity. L-Citrulline supplementation (CIT) has improved resting macrovascular endothelial function via increased arginine availability for NO synthesis. Thus, the purpose of this study was to examine the effects of CIT on resting microvascular endothelial function and BF responses to plantarflexion exercise (PFE) in hypertensive postmenopausal women. We hypothesized that CIT would improve microvascular function and BF responses to PFE compared to placebo (PL). Twenty-one hypertensive postmenopausal women were randomized to 4 weeks of CIT (10g/day, n=10) or PL ( n=11). Superficial femoral macro- (flow-mediated dilation; FMD) and microvascular function (5s average peak blood velocity and flow during reperfusion) were assessed by ultrasound at 0 and 4 weeks. Femoral artery BF and vascular conductance (VC) were measured via ultrasound at rest and during 3-minute stages of rhythmic PFE at 5%, 15%, and 30% of 1-repetition maximum (1RM) at 0 and 4 weeks. BF and VC responses to PFE were analyzed as the change from rest to the last minute of each stage. There were no differences between groups in FMD, 5s peak velocity and flow during reperfusion, and vascular responses to PFE at 0 weeks. CIT significantly increased FMD (CIT:Δ1.28 ± 0.42 vs PL:Δ0.01 ± 0.40%, p = 0.04) and 5s peak velocity (CIT:Δ17.44 ± 4.21 vs PL:Δ0.09 ± 4.01 cm/s, p = 0.01) and flow (CIT:Δ220 ± 54 vs PL:Δ35 ± 51 mL/min, p = 0.02) during reperfusion compared to PL. CIT had no effect on BF and VC responses to 5% PFE ( p &gt; 0.05). CIT significantly augmented BF responses to 15% PFE (CIT:Δ82 ± 16 vs PL:Δ22 ± 15 mL/min, p &lt; 0.01) and 30% PFE (CIT:Δ156 ± 33 vs PL:Δ38 ± 32 mL/min, p &lt; 0.01) and VC responses to 15% PFE (CIT:Δ0.80 ± 0.16 vs PL:Δ0.11 ± 0.15 mL*100mmHg/min, p &lt; 0.01) and 30% PFE (CIT:Δ1.49 ± 0.29 vs PL:Δ0.24 ± 0.27 mL*100mmHg/min, p &lt; 0.01) compared to PL. Improvements in FMD were not correlated with BF or VC responses to PFE ( p &gt; 0.05). Improvements in 5s peak velocity were positively correlated with BF responses to 15% PFE ( r = 0.498, p = 0.02) and 30% PFE ( r = 0.532, p = 0.01), and with VC responses to 15% PFE ( r = 0.542, p = 0.01) and 30% PFE ( r = 0.633, p &lt; 0.01). Similarly, augmented 5s flow was positively correlated with BF ( r = 0.461, p = 0.04) and VC ( r = 0.558, p = 0.01) responses to 30% PFE. These findings indicate that CIT improved superficial femoral artery macro- and microvascular endothelial function at rest. However, only improvements in microvascular endothelial function influenced vascular function during leg exercise in hypertensive postmenopausal women. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Bifunctional Sildenafil Diazeniumdiolates Acting as Phosphodiesterase 5 Inhibitors and Nitric Oxide Donors- Towards Wound Healing.

Inefficient wound healing poses a global health challenge with a lack of efficient treatments. Wound healing issues often correlate with low endogenous nitric oxide (NO) levels. While exogenous delivery with NO-releasing compounds represents a promising therapeutic strategy, controlling the release of the highly reactive NO remains challenging. Phosphodiesterase 5 (PDE5) inhibitors, like sildenafil, have also been shown to promote wound healing. This study explores hybrid compounds, combining NO-releasing diazeniumdiolates with a sildenafil-derived PDE5 inhibitor. One compound demonstrated a favorable NO-release profile, triggered by an esterase (prodrug), and displayed in vitro nanomolar inhibition potency against PDE5 and thrombin-induced platelet aggregation. Both factors are known to promote blood flow and oxygenation. Thus, our findings unveil promising prospects for effective wound healing treatments.

Study of the relationship between ghrel in hormone and nitric oxide in patients with chronic kidney disease in thi-qar governorate – IRAQ

Objective: When abnormalities in kidney structure or function are evident for more than three months, it is referred to as chronic kidney disease (CKD), a complicated and progressive chronic disorder that can have devastating health effects. Either reduced glomerular filtration rate or indicators of renal injury could be evident. End-stage renal disease (ESRD) patients are increasingly choosing PD, HD, and kidney transplantation as treatments to extend their lives because of the development of renal replacement therapies, such as kidney transplantation, hemodialysis (HD), peritoneal dialysis (PD), and continuous renal replacement therapy (which is frequently used for acute renal failure). Loss of muscle mass may result from dialysis treatments that increase protein breakdown and decrease protein synthesis. These reactions continue after dialysis. The purpose of this research is to look into the connection between the ghrelin. Materials and Method: In order to determine the blood lipid profile and Ghrelin hormone levels, 90 individuals with Chronic Kidney Disease (CKD) on dialysis were divided into 45 males, 45 females, and 90 healthy subjects. The Ghrelin hormone concentration was compared with the other biochemical parameters, and the relationship between the hormones Ghrelin and Nitric Oxide was also found. Results: Ninety healthy subjects and ninety chronic kidney disease (CKD) patients with dialysis had their blood lipid profiles and Ghrelin hormone and nitric oxide levels measured. The results included a comparison of the hormone's concentration with other biochemical parameters and the identification of the hormone's relationship with nitric oxide. Results: When compared to the control group, dialysis patients' nitric oxide levels significantly decreased (p≤0.05). There were no discernible variations in the levels of serum nitric oxide between the sexes. (p &lt; 0.05).Ghrelin levels in the blood serum of dialysis patients were significantly lower than those in the control group (p≤0.05). Additionally, it was demonstrated that the level of the hormone Ghrelin was significantly lower in females than in males (p≤0.05). Conclusion: When comparing dialysis patients to the control group, we detect a significant drop in the levels of Ghrelin Hormone and Nitric Oxide in patients with chronic kidney disease.It follows that low nitric oxide and ghrelin levels in chronic renal disease patients can cause kidney failure to progress to an advanced degree and eventually require dialysis.

Effect of excitation Strouhal number on a backward-inclined jet flame in crossflow

Combustion is often accompanied by environmental pollution due to incomplete reaction. A non-excited flame usually exhibits poor combustion performance with features of diffusion flame such as dual-peak temperature distributions and large combustion product concentrations. Efficient fuel-air mixing has been identified as a key factor in mitigating this issue. The present study investigated the effects of the acoustic excitation Strouhal number on the combustion performance of a backward-inclined jet flame in crossflow. A loudspeaker was used to induce jet pulsations with excitation Strouhal numbers ranging from 0.47 to 1.54 at a pulsation intensity of 0.90. Time-averaged and instantaneous flame images were captured using digital cameras. A customized R-type thermocouple and a commercial gas analyzer were employed to analyze the thermochemical structures. A critical excitation Strouhal number of approximately 0.9, distinguishing two characteristic flame modes: strongly affected flame (SA flame) and weakly affected flame (WA flame), was found. At excitation Strouhal numbers lower than the critical value, the SA flame featured single-peak temperature profiles and low unburned hydrocarbon, carbon monoxide, and nitric oxide emissions. The combustion performance was significantly improved due to the strong mixing effect induced by the acoustic excitation. The WA flame appeared at excitation Strouhal numbers higher than the critical value. It exhibited dual-peak temperature distributions and slightly improved combustion performance. The dynamic behavior and emissions of acoustically excited jet flames offered a fascinating insight into the influence of excitation Strouhal numbers on combustion characteristics. More excitation conditions were expected for future research.

Functional, Structural and Proteomic Effects of Ageing in Resistance Arteries.

The normal ageing process affects resistance arteries, leading to various functional and structural changes. Systolic hypertension is a common occurrence in human ageing, and it is associated with large artery stiffening, heightened pulsatility, small artery remodeling, and damage to critical microvascular structures. Starting from young adulthood, a progressive elevation in the mean arterial pressure is evidenced by clinical and epidemiological data as well as findings from animal models. The myogenic response, a protective mechanism for the microcirculation, may face disruptions during ageing. The dysregulation of calcium entry channels (L-type, T-type, and TRP channels), dysfunction in intracellular calcium storage and extrusion mechanisms, altered expression of potassium channels, and a change in smooth muscle calcium sensitization may contribute to the age-related dysregulation of myogenic tone. Flow-mediated vasodilation, a hallmark of endothelial function, is compromised in ageing. This endothelial dysfunction is related to increased oxidative stress, lower nitric oxide bioavailability, and a low-grade inflammatory response, further exacerbating vascular dysfunction. Resistance artery remodeling in ageing emerges as a hypertrophic response of the vessel wall that is typically observed in conjunction with outward remodeling (in normotension), or as inward hypertrophic remodeling (in hypertension). The remodeling process involves oxidative stress, inflammation, reorganization of actin cytoskeletal components, and extracellular matrix fiber proteins. Reactive oxygen species (ROS) signaling and chronic low-grade inflammation play substantial roles in age-related vascular dysfunction. Due to its role in the regulation of vascular tone and structural proteins, the RhoA/Rho-kinase pathway is an important target in age-related vascular dysfunction and diseases. Understanding the intricate interplay of these factors is crucial for developing targeted interventions to mitigate the consequences of ageing on resistance arteries and enhance the overall vascular health.

Cytoglobin regulates NO-dependent cilia motility and organ laterality during development

Cytoglobin is a heme protein with unresolved physiological function. Genetic deletion of zebrafish cytoglobin (cygb2) causes developmental defects in left-right cardiac determination, which in humans is associated with defects in ciliary function and low airway epithelial nitric oxide production. Here we show that Cygb2 co-localizes with cilia and with the nitric oxide synthase Nos2b in the zebrafish Kupffer’s vesicle, and that cilia structure and function are disrupted in cygb2 mutants. Abnormal ciliary function and organ laterality defects are phenocopied by depletion of nos2b and of gucy1a, the soluble guanylate cyclase homolog in fish. The defects are rescued by exposing cygb2 mutant embryos to a nitric oxide donor or a soluble guanylate cyclase stimulator, or with over-expression of nos2b. Cytoglobin knockout mice also show impaired airway epithelial cilia structure and reduced nitric oxide levels. Altogether, our data suggest that cytoglobin is a positive regulator of a signaling axis composed of nitric oxide synthase–soluble guanylate cyclase–cyclic GMP that is necessary for normal cilia motility and left-right patterning.

FRI141 Dietary Salt Regulates mTORC1 Signaling In Humans And Mice With Hypertension

Abstract Disclosure: H. Aljaibeji: None. D.L. Brooks: None. A.E. Garza: None. P. Gerges: None. M. Heydarpour: None. P. Luminita: None. J.S. Williams: None. G. Williams: None. J.R. Romero: None. Raptor and the mammalian target of rapamycin (mTOR) form a complex (mTORC1) that has been proposed to play a role in aldosterone (ALDO) production. Pharmacological inhibition of mTORC1 reduces blood pressure (BP) and ALDO levels. However, the effects of environmental factors such as dietary salt on mTORC1 in humans are unclear. We studied the impact of one-week liberal Na+ (LIB, 200 mmol/day) and restricted (RES, 10 mmol/day) Na+ diets on Raptor and mTOR expression in human peripheral blood mononuclear cells (PBMC) from hypertensive subjects. Raptor and mTOR expression were higher on PBMCs from subjects on a LIB than on RES Na+ diet (n=13; P=0.036 and P=0.0008, respectively). We also studied Caucasian subjects (n=792) from the Hypertensive Pathotype (HyperPATH) cohort using the Multi-Ethnic Genotyping Array on the Illumina platform. Candidate gene association analyses showed that the single nucleotide polymorphic (SNP) Raptor gene variant, rs99001846, was associated with BP and ALDO levels. Multivariate linear regression analyses performed on hypertensive and normotensive participants showed that in hypertensives, rs99001846 risk allele carriers (AA/GA), as compared to non-risk carriers (GG), were associated with increased systolic BP levels on bothLIB and RES Na+ diets (P=0.02, P=0.01 respectively). In addition, risk allele carriers, as compared to non-risk carriers, showed increased ALDO and reduced Na+ excretion on a LIB Na+ diet (P=0.009, P=0.025, respectively). We also studied a mouse model of low nitric oxide and high AngII-mediated hypertension and observed increased cardiac Raptor and mTOR expression (n=4, P=0.0008 and P=0.03 respectively). We then performed in silico bioinformatic analyses of rat zona glomerulosa cells following 2 hr treatment with 100 nM angiotensin II (AngII) using the Gene Expression Omnibus (GEO). AngII treatment led to the activation of mTOR signaling pathways as shown by increased expression of insulin receptor substrate type 2 (P=0.00001) and Low-density lipoprotein-related receptor 5 (P=0.03). Also, AngII reduced the expression of Eukaryotic Translation Initiation Factor 4E Binding Protein 1 by 43% (P= 0.001) and increased expression of CAP-Gly Domain Containing Linker Protein 1 by 70% (P= 0.00003) - important signaling molecules that are downstream of mTOR activation. Our results suggest that in hypertension, Na+ intake and Raptor gene variants modify mTORC1. Thus, mTOR/Raptor expression are a potential biomarker of ALDO-mediated cardiovascular injury. Presentation: Friday, June 16, 2023

Investigation on 1-Propanol Electronic mode of fumigation on diesel engine performance and emission Fueled with diesel and lemongrass biodiesel blend using AHP- COPRAS

The current experimental work investigated the engine performance and emissions when a compression ignition engine was powered by 1-propanol Electronic Mode (EM) fumigation with biodiesel and diesel fuel.The biodiesel (20 %) was blended with the reference diesel (80 %). The reference diesel and biodiesel blend values were notified to compare different timings of 1-propanol EM fumigation. 1 ms, 3 ms, and 5 ms injected fuel into the inlet manifold with varying loads. The test engine was powered by the mentioned biodiesel mixture with different timing of 1-propanol EM fumigation and reported the engine operating parameters. The test engine was subjected to additional brake power and fumigation timings. Initially, the experiments were conducted at extra engine brake power to identify the engine performance and emission characteristics, and later on, this investigation deals with the use of multi-criteria decision-making (MCDM) based Analytic Hierarchy Process (AHP) and Complex proportional assessment method (COPRAS) to identify the weights and Rank of the various tested blends. The experiment results were compared to the effects of reference diesel and biodiesel. The 5 ms 1-propanol EM fumigation produced good results in all engine parameters. The 3 ms EM fumigation produced intermediate results in all engine parameters.In comparison to 1-propanol EM fumigation timings, 5 ms produced maximum efficiency in peak load conditions and produced low carbon dioxide (CO2), nitric oxide (NO), and smoke at all load conditions.

Impaired Nitric Oxide Synthetase Activity in Primary Ciliary Dyskinesia-Data-Driven Hypothesis.

Low nasal nitric oxide (nNO) is a typical feature of Primary Ciliary Dyskinesia (PCD). nNO is part of the PCD diagnostic algorithm due to its discriminative power against other lung diseases, such as cystic fibrosis (CF). However, the underlying pathomechanisms are elusive. To better understand NO dysregulation in PCD, the L-arginine/NO (Arg/NO) pathway in patients with PCD (pwPCD) and CF (pwCF) and in healthy control (HC) subjects was investigated. In a prospective, controlled study, we measured in 24 pwPCD, 25 age-matched pwCF, and 14 HC the concentrations of the NO precursors Arg and homoarginine (hArg), the arginase metabolite ornithine (Orn), the NO inhibitor asymmetric dimethylarginine (ADMA), and the major NO metabolites (nitrate, nitrite) in sputum, plasma, and urine using validated methods. In comparison to HC, the sputum contents (in µmol/mg) of L-Arg (PCD 18.43 vs. CF 329.46 vs. HC 9.86, p < 0.001) and of ADMA (PCD 0.055 vs. CF 0.015 vs. HC 0.010, p < 0.001) were higher. In contrast, the sputum contents (in µmol/mg) of nitrate and nitrite were lower in PCD compared to HC (nitrite 4.54 vs. 9.26, p = 0.023; nitrate 12.86 vs. 40.33, p = 0.008), but higher in CF (nitrite 16.28, p < 0.001; nitrate 56.83, p = 0.002). The metabolite concentrations in urine and plasma were similar in all groups. The results of our study indicate that PCD, unlike CF, is associated with impaired NO synthesis in the lung, presumably due to mechano-chemical uncoupling.

NAD+-boosting compounds enhance nitric oxide production and prevent oxidative stress in endothelial cells exposed to plasma from patients with COVID-19

SARS-CoV-2, the virus that causes coronavirus disease 2019 (COVID-19), induces vascular endothelial dysfunction, but the mechanisms are unknown. We tested the hypothesis that the “circulating milieu” (plasma) of patients with COVID-19 would cause endothelial cell dysfunction (characterized by lower nitric oxide (NO) production), which would be linked to greater reactive oxygen species (ROS) bioactivity and depletion of the critical metabolic co-substrate, nicotinamide adenine dinucleotide (NAD+). We also investigated if treatment with NAD+-boosting compounds would prevent COVID-19-induced reductions in endothelial cell NO bioavailability and oxidative stress. Human aortic endothelial cells (HAECs) were exposed to plasma from men and women (age 18–85 years) who were hospitalized and tested positive (n = 34; 20 M) or negative (n = 13; 10 M) for COVID-19. HAECs exposed to plasma from patients with COVID-19 also were co-incubated with NAD+ precursors nicotinamide riboside (NR) or nicotinamide mononucleotide (NMN). Acetylcholine-stimulated NO production was 27% lower and ROS bioactivity was 54% higher in HAECs exposed to plasma from patients with COVID-19 (both p < 0.001 vs. control); these responses were independent of age and sex. NAD+ concentrations were 30% lower in HAECs exposed to plasma from patients with COVID-19 (p = 0.001 vs. control). Co-incubation with NR abolished COVID-19-induced reductions in NO production and oxidative stress (both p > 0.05 vs. control). Co-treatment with NMN produced similar results. Our findings suggest the circulating milieu of patients with COVID-19 promotes endothelial cell dysfunction, characterized by lower NO bioavailability, greater ROS bioactivity, and NAD+ depletion. Supplementation with NAD+ precursors may exert a protective effect against COVID-19-evoked endothelial cell dysfunction and oxidative stress.

EXPERIMENTAL STUDY OF ERYTHROCYTE ENERGY METABOLISM UNDER INHALATIONS OF NITRIC OXIDE

Abstract Biological effects of nitric oxide are multiply, including vasoactive activity, participation in neurotransmission and intercellular communication etc. These effects are associated with endogenous releasing of nitric oxide, but influence of exogenous administration of this substance does not study in details. In particular, systemic action of nitric oxide inhalations is not so clear. The aim of this work was the investigation of nitric oxide inhalations action on some parameters of energy and oxidative metabolism of healthy rat blood. Wistar rats were randomly divided into two groups: control group (without any manipulations; n=10) and main group (n=10) with inhalations by nitric oxide-containing gas flow (20 ppm). Lactate dehydrogenase and lactate level were estimated in rat blood samples. In addition, we calculated a number of integral coefficients of energy metabolism, such as substrate provision coefficient and coefficient of energy reactions balance. Our experiments demonstrate that 10-days course of inhalations of low nitric oxide doses (20 ppm) increases the adaptive potential of healthy rats’ organism. One of these positive effects is associated with activation of some components of energy metabolism. First of all, it realized through stimulation of catalytic activity of lactate dehydrogenase, including its erythrocyte pool. Observed metabolic effect provides the basis for pathogenic correction of diseases, associated with hypoxia, oxidative stress and energy deficiency.

Molecular Study on Twin Cohort with Discordant Birth Weight.

The increased rate of twinning has pointed out newer challenges in clinical practices related to gestational complications, intrauterine growth restriction, perinatal mortality, and comorbidities. As a twin pregnancy progresses, the increased demand for oxygen supply can easily disrupt the redox homeostasis balance and further impose a greater challenge for the developing fetuses. A substantial birth-weight difference acts as an indicator of a deficit in oxygenation or blood flow to one of the fetuses, which might be related to a low bioavailable nitric oxide level. Therefore, in this study, we focused on networks involved in the adjustment of oxygen supply, like the activation of inducible and endothelial nitric oxide synthase (NOS3) along with free radical and lipid peroxide formation in mature twin pairs with high birth-weight differences. The selected parameters were followed by immunofluorescence staining, fluorescence-activated cell sorting analysis, and biochemical measurements in the umbilical cord vessels and fetal red blood cells. Based on our data set, it is clear that the lower-weight siblings are markedly exposed to persistent intrauterine hypoxic conditions, which are connected to a decreased level in NOS3 activation. Furthermore, the increased level of peroxynitrite aggravates lipid peroxidation and induces morphological and functional damage and loss in redox homeostasis.