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1.
Acute L-Citrulline Supplementation Increases Nitric Oxide Bioavailability but Not Inspiratory Muscle Oxygenation and Respiratory Performance.
Theodorou, AA, Zinelis, PT, Malliou, VJ, Chatzinikolaou, PN, Margaritelis, NV, Mandalidis, D, Geladas, ND, Paschalis, V
Nutrients. 2021;(10)
Abstract
The present study aimed to investigate whether acute L-citrulline supplementation would affect inspiratory muscle oxygenation and respiratory performance. Twelve healthy males received 6 g of L-citrulline or placebo in a double-blind crossover design. Pulmonary function (i.e., forced expired volume in 1 s, forced vital capacity and their ratio), maximal inspiratory pressure (MIP), fractional exhaled nitric oxide (NO•), and sternocleidomastoid muscle oxygenation were measured at baseline, one hour post supplementation, and after an incremental resistive breathing protocol to task failure of the respiratory muscles. The resistive breathing task consisted of 30 inspirations at 70% and 80% of MIP followed by continuous inspirations at 90% of MIP until task failure. Sternocleidomastoid muscle oxygenation was assessed using near-infrared spectroscopy. One-hour post-L-citrulline supplementation, exhaled NO• was significantly increased (19.2%; p < 0.05), and this increase was preserved until the end of the resistive breathing (16.4%; p < 0.05). In contrast, no difference was observed in the placebo condition. Pulmonary function and MIP were not affected by the L-citrulline supplementation. During resistive breathing, sternocleidomastoid muscle oxygenation was significantly reduced, with no difference noted between the two supplementation conditions. In conclusion, a single ingestion of 6 g L-citrulline increased NO• bioavailability but not the respiratory performance and inspiratory muscle oxygenation.
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Association Between Nitric Oxide, Oxidative Stress, Eryptosis, Red Blood Cell Microparticles, and Vascular Function in Sickle Cell Anemia.
Nader, E, Romana, M, Guillot, N, Fort, R, Stauffer, E, Lemonne, N, Garnier, Y, Skinner, SC, Etienne-Julan, M, Robert, M, et al
Frontiers in immunology. 2020;:551441
Abstract
Chronic hemolysis, enhanced oxidative stress, and decreased nitric oxide (NO) bioavailability promote vasculopathy in sickle cell anemia (SCA). Oxidative stress and NO are known to modulate eryptosis in healthy red blood cells (RBCs); however, their role in SCA eryptosis and their impact on the genesis of RBC-derived microparticles (RBC-MPs) remains poorly described. RBC-MPs could play a role in vascular dysfunction in SCA. The aims of this study were to evaluate the roles of oxidative stress and NO in eryptosis and RBC-MPs release, and to determine whether RBC-MPs could be involved in vascular dysfunction in SCA. Markers of eryptosis and oxidative stress, plasma RBC-MPs concentration and arterial stiffness were compared between SCA and healthy (AA) individuals. In-vitro experiments were performed to test: 1) the effects of oxidative stress (antioxidant: n-acetylcysteine (NAC); pro-oxidant: cumene hydroperoxide) and NO (NO donor: sodium nitroprusside (SNP); NO-synthase inhibitor (L-NIO)) on eryptosis, RBC deformability and RBC-MP genesis; 2) the effects of SCA/AA-RBC-MPs on human aortic endothelial cell (HAEC) inflammatory phenotype and TLR4 pathway. Eryptosis, RBC-MPs, oxidative stress and arterial stiffness were increased in SCA. NAC increased RBC deformability and decreased eryptosis and RBC-MPs release, while cumene did the opposite. SNP increased RBC deformability and limited eryptosis, but had no effect on RBC-MPs. L-NIO did not affect these parameters. Arterial stiffness was correlated with RBC-MPs concentration in SCA. RBC-MPs isolated directly from SCA blood increased adhesion molecules expression and the production of cytokines by HAEC compared to those isolated from AA blood. TLR4 inhibition alleviated these effects. Our data show that oxidative stress could promote eryptosis and the release of RBC-MPs that are potentially involved in macrovascular dysfunction in SCA.
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Hypertension is associated with blunted NO-mediated leg vasodilator responsiveness that is reversed by high-intensity training in postmenopausal women.
Gunnarsson, TP, Ehlers, TS, Baasch-Skytte, T, Lund, AP, Tamariz-Ellemann, A, Gliemann, L, Nyberg, M, Bangsbo, J
American journal of physiology. Regulatory, integrative and comparative physiology. 2020;(6):R712-R723
Abstract
The menopausal transition is associated with increased prevalence of hypertension, and in time, postmenopausal women (PMW) will exhibit a cardiovascular disease risk score similar to male counterparts. Hypertension is associated with vascular dysfunction, but whether hypertensive (HYP) PMW have blunted nitric oxide (NO)-mediated leg vasodilator responsiveness and whether this is reversible by high-intensity training (HIT) is unknown. To address these questions, we examined the leg vascular conductance (LVC) in response to femoral infusion of acetylcholine (ACh) and sodium nitroprusside (SNP) and skeletal muscle markers of oxidative stress and NO bioavailability before and after HIT in PMW [12.9 ± 6.0 (means ± SD) years since last menstrual cycle]. We hypothesized that ACh- and SNP-induced LVC responsiveness was reduced in hypertensive compared with normotensive (NORM) PMW and that 10 wk of HIT would reverse the blunted LVC response and decrease blood pressure (BP). Nine hypertensive (HYP (clinical systolic/diastolic BP, 149 ± 11/91 ± 83 mmHg) and eight normotensive (NORM (122 ± 13/75 ± 8 mmHg) PMW completed 10 wk of biweekly small-sided floorball training (4-5 × 3-5 min interspersed by 1-3-min rest periods). Before training, the SNP-induced change in LVC was lower (P < 0.05) in HYP compared with in NORM. With training, the ACh- and SNP-induced change in LVC at maximal infusion rates, i.e., 100 and 6 µg·min-1·kg leg mass-1, respectively, improved (P < 0.05) in HYP only. Furthermore, training decreased (P < 0.05) clinical systolic/diastolic BP (-15 ± 11/-9 ± 7 mmHg) in HYP and systolic BP (-10 ± 9 mmHg) in NORM. Thus, the SNP-mediated LVC responsiveness was blunted in HYP PMW and reversed by a period of HIT that was associated with a marked decrease in clinical BP.
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4.
FCER2 T2206C variant associated with FENO levels in asthmatic children using inhaled corticosteroids: The PACMAN study.
Karimi, L, Vijverberg, SJH, Farzan, N, Ghanbari, M, Verhamme, KMC, Maitland-van der Zee, AH
Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology. 2019;(11):1429-1436
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Abstract
BACKGROUND The FCER2 gene, via encoding of the CD23 receptor, plays an important role in the regulation of IgE responses. A genetic variant of the FCER2 gene (T2206C) was previously shown to be associated with IgE levels in asthmatic children. IgE sensitization has also been linked to increased levels of fractional exhaled nitric oxide (FENO). OBJECTIVE To investigate whether the FCER2 T2206C variant influences FENO levels in asthmatic children with a reported use of inhaled corticosteroids (ICS). METHODS This cross-sectional study involved 593 asthmatic children with a reported use of ICS, availability of FENO measurements and genotyping data on the FCER2 T2206C variant (rs28364072). An additive genetic model was assumed, and the association between the FCER2 T2206C variant and the log-transformed (ln) FENO levels was evaluated using linear regression analysis, adjusted for age, sex, adapted British Thoracic Society (BTS) treatment steps and atopy. RESULTS The mean age of the population was 9.1 ± 2.2 years, and the median of FENO levels was 13.0 ppb with an interquartile range (IQR) of (8.0-27.5 ppb). The minor allele (G) frequency of rs28364072 was 29.6%, and each extra copy of the G allele was significantly associated with a lower level of the geometric mean of FENO (log scale, β = -0.12, 95% CI: -0.23, -0.02). CONCLUSION AND CLINICAL RELEVANCE Our results showed that the FCER2 T2206C variant was significantly associated with lower FENO levels in carriers of the G allele. Nevertheless, this SNP contributed little to the variability in FENO levels in this patient population. Our findings contribute to the present knowledge on FENO in asthmatic children; however, future replication studies are required to establish the role of this gene in relation to FENO.
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Sex differences in the nitrate-nitrite-NO• pathway: Role of oral nitrate-reducing bacteria.
Kapil, V, Rathod, KS, Khambata, RS, Bahra, M, Velmurugan, S, Purba, A, S Watson, D, Barnes, MR, Wade, WG, Ahluwalia, A
Free radical biology & medicine. 2018;:113-121
Abstract
Oral reduction of nitrate to nitrite is dependent on the oral microbiome and is the first step of an alternative mammalian pathway to produce nitric oxide in humans. Preliminary evidence suggests important sex differences in this pathway. We prospectively investigated sex-differences following inorganic nitrate supplementation on nitrate/nitrite levels and vascular function, and separately examined sex differences in oral nitrate reduction, and oral microbiota by 16S rRNA profiling. At baseline, females exhibit higher nitrite levels in all biological matrices despite similar nitrate levels to males. Following inorganic nitrate supplementation, plasma nitrite was increased to a significantly greater extent in females than in males and pulse wave velocity was only reduced in females. Females exhibited higher oral bacterial nitrate-reducing activity at baseline and after nitrate supplementation. Despite these differences, there were no differences in the composition of either the total salivary microbiota or those oral taxa with nitrate reductase genes. Our results demonstrate that females have augmented oral nitrate reduction that contributes to higher nitrite levels at baseline and also after inorganic nitrate supplementation, however this was not associated with differences in microbial composition (clinicaltrials.gov: NCT01583803).
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A Phase 2, Controlled, Dose-Ranging Study of SB208, an Investigational Topical Nitric Oxide-Releasing Drug, for the Treatment of Tinea Pedis.
Elewski, BE, Kircik, LH, Stasko, N, De Leon, E, Enloe, C, Durham, T, Maeda-Chubachi, T
Journal of drugs in dermatology : JDD. 2018;(8):888-893
Abstract
BACKGROUND Tinea pedis, or athlete's foot, is a superficial, skin infection caused by dermatophytes. It is usually topically treated. Nitric oxide is endogenously produced in humans and has a variety of physiologic and antimicrobial properties. SB208 is a novel topical treatment comprising berdazimer sodium (a nitric oxide-storing macromolecule) and a hydrogel. Admixing these two components releases nitric oxide to the application site. METHODS A phase 2, double-blind, randomized trial evaluated the safety and efficacy of 3 doses of SB208 (2%, 4%, and 16%) vs matching vehicle, administered once daily for 14 days, in subjects with culture-confirmed interdigital tinea pedis. The primary efficacy outcome was the proportion of subjects with negative fungal cultures at end of treatment (day 14). Secondary outcomes at days 14 and 42 were the proportion of subjects with mycological cure (negative potassium hydroxide wet mount skin test and culture), clinical cure (reduced signs and symptoms from baseline graded on a 4-point scale). Safety was monitored through physical examinations, adverse events, and hemoglobin and methemoglobin levels. Efficacy outcomes were analyzed using a two-sided Cochran-Mantel-Haenszel test for general association, stratified by site. RESULTS At day 14, a higher proportion of patients had negative fungal cultures in the pooled SB208-treated group (62%; P=0.04) than the vehicle-treated group (43%). Of SB208 groups, the 4% group had higher incidence of negative fungal cultures vs the vehicle group (67.6% vs 42.9%; P=0.03). At day 42, pooled SB208-treated groups had significantly more mycological cure vs vehicle group (47% vs 31%, respectively; P=0.08), and clinical cure was maintained in 23% of pooled SB208-treated patients vs 14% of vehicle-treated patients. No safety concerns were reported. Adverse events were mild, not serious, and considered unrelated to study medications. CONCLUSIONS Topical SB208 was effective and well tolerated in the treatment of tinea pedis. J Drugs Dermatol. 2018;17(8):888-893.
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Reduction of FENO by tap water and carbonated water mouthwashes: magnitude and time course.
Lassmann-Klee, PG, Lindholm, T, Metsälä, M, Halonen, L, Sovijärvi, ARA, Piirilä, P
Scandinavian journal of clinical and laboratory investigation. 2018;(1-2):153-156
Abstract
Fractional exhaled nitric oxide (FENO) assesses eosinophilic inflammation of the airways, but FENO values are also influenced by oral nitric oxide (NO). The aim of this pilot study was to measure FENO and compare the effect of two different mouthwashes on FENO and analyse the duration of the effect. FENO was measured in 12 randomized volunteers (healthy or asthmatic subjects) with a NIOX VERO® analyser at an expiratory flow rate of 50 mL/s. After a baseline measurement, a mouthwash was performed either with tap water or carbonated water and was measured during 20 min in 2 min intervals. The procedure was repeated with the other mouthwash. We found that both mouthwashes reduced FENO immediately at the beginning compared to the baseline (p < .001). The carbonated water mouthwash effect lasted 12 min (p ranging from <0.001 to <0.05). The tap water mouthwash reduced FENO statistically significantly only for 2 min compared with the baseline. We conclude that a single carbonated water mouthwash can significantly reduce the oropharyngeal NO contribution during a 12 min time interval.
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Deferiprone increases endothelial nitric oxide synthase phosphorylation and nitric oxide production.
Sriwantana, T, Vivithanaporn, P, Paiboonsukwong, K, Rattanawonsakul, K, Srihirun, S, Sibmooh, N
Canadian journal of physiology and pharmacology. 2018;(9):879-885
Abstract
Iron chelation can improve endothelial function. However, effect on endothelial function of deferiprone has not been reported. We hypothesized deferiprone could promote nitric oxide (NO) production in endothelial cells. We studied effects of deferiprone on blood nitrite and blood pressure after single oral dose (25 mg/kg) in healthy subjects and hemoglobin E/β-thalassemia patients. Further, effects of deferiprone on NO production and endothelial NO synthase (eNOS) phosphorylation in primary human pulmonary artery endothelial cells (HPAEC) were investigated in vitro. Blood nitrite levels were higher in patients with deferiprone therapy than those without deferiprone (P = 0.023, n = 16 each). Deferiprone increased nitrite in plasma and whole blood of healthy subjects (P = 0.002 and 0.044) and thalassemia patients (P = 0.003 and 0.046) at time 180 min (n = 20 each). Asymptomatic reduction in diastolic blood pressure (P = 0.005) and increase in heart rate (P = 0.009) were observed in healthy subjects, but not in thalassemia patients. In HPAEC, deferiprone increased cellular nitrite and phospho-eNOS (Ser1177) (P = 0.012 and 0.035, n = 6) without alteration in total eNOS protein and mRNA. We conclude that deferiprone can induce NO production by enhancing eNOS phosphorylation in endothelial cells.
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Exhaled breath NOx levels in a middle-aged adults population-based study: reference values and association with the smoking status.
Chérot-Kornobis, N, Hulo, S, Giovannelli, J, de Broucker, V, Matran, R, Amouyel, P, Sobaszek, A, Dauchet, L, Edmé, JL
Respiratory medicine. 2018;:134-140
Abstract
BACKGROUND Biomarkers in exhaled breath condensate (EBC) are potentially sensitive indicators of early biochemical changes in airways following exposure to pneumotoxic substances, particularly in susceptible subjects. NOx are the stable end products of the nitrite-nitrate-NO oxidative stress pathway and can be used to monitor airway inflammatory diseases, especially in asthma. Nevertheless, population-based surveys are needed to better interpret EBC NOx levels in clinical studies. The aim of this study was to establish reference values of EBC NOx in a large group of middle-aged, healthy adults of a sample of the general population with particular focus on the smoking status. METHODS The EBC NOx levels were analysed from 2872 subjects among the ELISABET population-based cross sectional study including a representative sample of men and women aged from 40 to 66 years olds conducted in northern France, which included comprehensive questionnaires by interview and spirometry data. Healthy participants were defined as participants with no self-reported respiratory disease. RESULTS For the healthy subjects (n = 1251), the median NOx concentration (IQR) was equal to 7.2 μM (3.12) and concentrations of NOx in EBC did not differ significantly according to smoking status. The upper fifth percentile (95%) (ULN) of NOx concentrations among healthy subjects was equal to 13.6 μM, ranging from 12.7 μM (smokers) to 14.4 μM (ex smokers). Among subjects with EBC NOx values higher than the ULN and compared with subjects that had EBC NOx values lower than the ULN, we found a significant higher proportion of subjects with current asthma (10.5% vs 6.5%) or with chronic bronchitis symptoms (7.6% vs 3.3%). CONCLUSION This population-based study has provided the distribution and the upper limit reference value of a nitrosative stress biomarker (NOx) in EBC of middle aged, healthy adults. EBC NOx levels were not associated with smoking status.
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Spirometry-adjusted fraction of exhaled nitric oxide increases accuracy for assessment of asthma control in children.
Martins, C, Silva, D, Severo, M, Rufo, J, Paciência, I, Madureira, J, Padrão, P, Moreira, P, Delgado, L, Oliveira Fernandes, E, et al
Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 2017;(8):754-762
Abstract
Spirometry and exhaled nitric oxide are two important complimentary tools to identify and assess asthma control in children. We aimed to determine the ability of a new suggested spirometry-adjusted fraction of exhaled nitric oxide (NO) index in doing that. A random sample of 1602 schoolchildren were screened by a health questionnaire, skin prick tests, spirometry with bronchodilation and exhaled NO. A total of 662 children were included with median (IQR) exhaled NO 11(14) ppb. Receiver operating characteristic (ROC) curves using exhaled NO equations from Malmberg, Kovesi and Buchvald, and spirometry-adjusted fraction of exhaled NO values were applied to identify asthmatic children and uncontrolled asthma. Receiver operating characteristic (ROC) curves failed to identify asthmatic children (all AUC < 0.700). Spirometry-adjusted fraction of exhaled NO/FEV1 (AUC = 0.712; P = .010) and NO/FEF25%-75% (AUC = 0.735 P = .004) had a fair and increased ability to identify uncontrolled disease compared with exhaled NO (AUC = 0.707; P = .011) or the Malmberg equation (AUC = 0.701; P = .014). Sensitivity and specificity identifying non-controlled asthma were 59% and 81%, respectively, for the cut-off value of 9.7 ppb/L for exhaled NO/FEV1 , and 40% and 100% for 15.7 ppb/L/s for exhaled NO/FEF25%-75% . Exhaled NO did not allow to identify childhood asthma. Spirometry-adjusted fraction of exhaled NO performed better-assessing asthma control in children. Thus, although more validation studies are needed, we suggest its use in epidemiological studies to assess asthma control.