Relationships between nitric oxide biomarkers and physiological outcomes following dietary nitrate supplementation.

Dietary nitrate (NO3-) supplementation can increase nitric oxide (NO) bioavailability, reduce blood pressure (BP) and improve muscle contractile function in humans. Plasma nitrite concentration (plasma [NO2-]) is the most oft-used biomarker of NO bioavailability. However, it is unclear which of several NO biomarkers (NO3-, NO2-, S-nitrosothiols (RSNOs)) in plasma, whole blood (WB), red blood cells (RBC) and skeletal muscle correlate with the physiological effects of acute and chronic dietary NO3- supplementation. Using a randomized, double-blind, crossover design, 12 participants (9 males) consumed NO3--rich beetroot juice (BR) (∼12.8 mmol NO3-) and NO3--depleted placebo beetroot juice (PL) acutely and then chronically (for two weeks). Biological samples were collected, resting BP was assessed, and 10 maximal voluntary isometric contractions of the knee extensors were performed at 2.5-3.5 h following supplement ingestion on day 1 and day 14. Diastolic BP was significantly lower in BR (-2 ± 3 mmHg, P = 0.03) compared to PL following acute supplementation, while the absolute rate of torque development (RTD) was significantly greater in BR at 0-30 ms (39 ± 57 N m s-1, P = 0.03) and 0-50 ms (79 ± 99 N m s-1, P = 0.02) compared to PL following two weeks supplementation. Greater WB [RSNOs] rather than plasma [NO2-] was correlated with lower diastolic BP (r = -0.68, P = 0.02) in BR compared to PL following acute supplementation, while greater skeletal muscle [NO3-] was correlated with greater RTD at 0-30 ms (r = 0.64, P=0.03) in BR compared to PL following chronic supplementation. We conclude that [RSNOs] in blood, and [NO3-] in skeletal muscle, are relevant biomarkers of NO bioavailability which are related to the reduction of BP and the enhanced muscle contractile function following dietary NO3- ingestion in humans.

Angiogenesis-associated pathways play critical roles in neonatal sepsis outcomes.

Neonatal sepsis is a major cause of childhood mortality. Limited diagnostic tools and mechanistic insights have hampered our abilities to develop prophylactic or therapeutic interventions. Biomarkers in human neonatal sepsis have been repeatedly identified as associated with dysregulation of angiopoietin signaling and altered arachidonic acid metabolism. We here provide the mechanistic evidence in support of the relevance for these observations. Angiopoetin-1 (Ang-1), which promotes vascular integrity, was decreased in blood plasma of human and murine septic newborns. In preclinical models, administration of Ang-1 provided prophylactic protection from septic death. Arachidonic acid metabolism appears to be functionally connected to Ang-1 via reactive oxygen species (ROS) with a direct role of nitric oxide (NO). Strengthening this intersection via oral administration of arachidonic acid and/or the NO donor L-arginine provided prophylactic as well as therapeutic protection from septic death while also increasing plasma Ang-1 levels among septic newborns. Our data highlight that targeting angiogenesis-associated pathways with interventions that increase Ang-1 activity directly or indirectly through ROS/eNOS provide promising avenues to prevent and/or treat severe neonatal sepsis.

Plasma Redox Balance in Advanced-Maternal-Age Pregnant Women and Effects of Plasma on Umbilical Cord Mesenchymal Stem Cells.

Pregnancy at advanced maternal age (AMA) is a condition of potential risk for the development of maternal-fetal complications with possible repercussions even in the long term. Here, we analyzed the changes in plasma redox balance and the effects of plasma on human umbilical cord mesenchymal cells (hUMSCs) in AMA pregnant women (patients) at various timings of pregnancy. One hundred patients and twenty pregnant women younger than 40 years (controls) were recruited and evaluated at various timings during pregnancy until after delivery. Plasma samples were used to measure the thiobarbituric acid reactive substances (TBARS), glutathione and nitric oxide (NO). In addition, plasma was used to stimulate the hUMSCs, which were tested for cell viability, reactive oxygen species (ROS) and NO release. The obtained results showed that, throughout pregnancy until after delivery in patients, the levels of plasma glutathione and NO were lower than those of controls, while those of TBARS were higher. Moreover, plasma of patients reduced cell viability and NO release, and increased ROS release in hUMSCs. Our results highlighted alterations in the redox balance and the presence of potentially harmful circulating factors in plasma of patients. They could have clinical relevance for the prevention of complications related to AMA pregnancy.

Blood Level of Nitric Oxide Metabolites and Expression of Genes Regulating NO Synthesis in Early Forms of Non-Alcoholic Fatty Liver Disease.

The levels of NO metabolites in the plasma and mRNA of the NOS3, ATG9B, and NOS2 genes in peripheral blood leukocytes of healthy people and patients with early forms of non-alcoholic fatty liver disease (steatosis and weak activity non-alcoholic steatohepatitis) were studied. In patients with steatohepatitis, the concentration of NO metabolites in the blood and the level of mRNA of the NOS2 gene were higher than in patients with steatosis and healthy people. These differences can be of diagnostic value for distinguishing between steatosis and weak activity steatohepatitis in non-alcoholic fatty liver disease. A correlation between the levels of NO metabolites and the expression of the NOS2 gene in weak activity steatohepatitis was established, which indicates activation of NO synthesis in non-alcoholic steatohepatitis due to the expression of the inducible NO synthase gene. The level of the NOS2 gene mRNA in peripheral blood leukocytes of patients with weak activity steatohepatitis correlated with the level of TNFα and IL-6 cytokines. An increase in the level of NO in the blood in weak activity steatohepatitis correlated with the level of MDA, an indicator of oxidative stress.

Correlation analysis between serum total IgE and FeNO and idiosyncratic reaction in bronchiolitis.

OBJECTIVE: This article focused on the correlation between the changes of serum total Immunoglobulin E (IgE) and Fractional exhaled Nitric Oxide (FeNO) and idiosyncratic reactions in children with bronchiolitis. METHODS: One hundred children with bronchiolitis and fifty healthy children were enrolled. Serum total IgE and FeNO were assessed, and the diagnostic value for bronchiolitis and the correlation with the severity of bronchiolitis were analyzed. Bronchiolitis children were divided into idiosyncratic + bronchiolitis and non-idiosyncratic + bronchiolitis groups, the relationship between serum total IgE and FeNO and idiosyncratic reaction was determined, and the diagnostic value of serum total IgE and FeNO for idiosyncratic bronchiolitis was examined. RESULTS: FeNO in bronchiolitis children was lower than that in healthy children but there was no significant difference in serum total IgE levels between the two populations. Serum total IgE increased while FeNO decreased with the aggravation of bronchiolitis in bronchiolitis children. The serum total IgE was positively correlated while FeNO was negatively correlated with the severity of bronchiolitis. Serum total IgE was higher in children with idiosyncratic bronchiolitis, but serum total IgE and FeNO were not the risk factors for idiosyncratic bronchiolitis; Area Under the Curve (AUC) of serum total IgE and FeNO for the diagnosis of idiosyncratic bronchiolitis was less than 0.7. CONCLUSION: Serum total IgE and FeNO in children with bronchiolitis are related to disease severity and idiosyncratic reaction. FeNO has a diagnostic value for bronchiolitis, but not for idiosyncratic bronchiolitis.

Significance of nitrosative stress and glycoxidation products in the diagnosis of COVID-19.

Nitrosative stress promotes protein glycoxidation, and both processes can occur during an infection with the SARS-CoV-2 virus. Therefore, the aim of this study was to assess selected nitrosative stress parameters and protein glycoxidation products in COVID-19 patients and convalescents relative to healthy subjects, including in reference to the severity of COVID-19 symptoms. The diagnostic utility of nitrosative stress and protein glycoxidation biomarkers was also evaluated in COVID-19 patients. The study involved 218 patients with COVID-19, 69 convalescents, and 48 healthy subjects. Nitrosative stress parameters (NO, S-nitrosothiols, nitrotyrosine) and protein glycoxidation products (tryptophan, kynurenine, N-formylkynurenine, dityrosine, AGEs) were measured in the blood plasma or serum with the use of colorimetric/fluorometric methods. The levels of NO (p = 0.0480), S-nitrosothiols (p = 0.0004), nitrotyrosine (p = 0.0175), kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan fluorescence was significantly (p < 0.0001) lower in COVID-19 patients than in the control group. Significant differences in the analyzed parameters were observed in different stages of COVID-19. In turn, the concentrations of kynurenine (p < 0.0001), N-formylkynurenine (p < 0.0001), dityrosine (p < 0.0001), and AGEs (p < 0.0001) were significantly higher, whereas tryptophan levels were significantly (p < 0.0001) lower in convalescents than in healthy controls. The ROC analysis revealed that protein glycoxidation products can be useful for diagnosing infections with the SARS-CoV-2 virus because they differentiate COVID-19 patients (KN: sensitivity-91.20%, specificity-92.00%; NFK: sensitivity-92.37%, specificity-92.00%; AGEs: sensitivity-99,02%, specificity-100%) and convalescents (KN: sensitivity-82.22%, specificity-84.00%; NFK: sensitivity-82,86%, specificity-86,00%; DT: sensitivity-100%, specificity-100%; AGE: sensitivity-100%, specificity-100%) from healthy subjects with high sensitivity and specificity. Nitrosative stress and protein glycoxidation are intensified both during and after an infection with the SARS-CoV-2 virus. The levels of redox biomarkers fluctuate in different stages of the disease. Circulating biomarkers of nitrosative stress/protein glycoxidation have potential diagnostic utility in both COVID-19 patients and convalescents.

Serum GAS6, sAXL, IL-10, NO, and BCL-2 levels are decreased in patients with Behçet's disease.

PURPOSE: Behçet's disease (BD) is an autoimmune chronic systemic inflammatory disease characterized by a versatile clinical spectrum. Growth arrest specific protein 6 (GAS6)/soluble AXL (sAXL) signaling pathway draws attention in the resolution of inflammation, and its deficiency is associated with chronic inflammatory, autoimmune diseases, as well as clearance of apoptotic cells by phagocytes - efferocytosis. In this study, it was aimed to investigate whether GAS6/sAXL, interleukin (IL)-10, nitric oxide (NO), and BCL-2 levels were associated with inflammation and efferocytosis contributes to the pathogenesis of BD. METHODS: A total of 37 Behçet patients with ocular involvement and 30 healthy control subjects were included in this study. GAS6, sAXL, IL-10, NO, and BCL-2 levels were quantified using enzyme-linked immunosorbent assay (ELISA) method. RESULTS: Serum GAS6, sAXL, IL-10, NO, and BCL-2 levels were significantly lower in patients with BD compared to the controls (P < 0.005, P < 0.001, P < 0.001, P < 0.001, and P < 0.001, respectively). In correlation analysis, research parameters decreased in patients with BD was significantly correlated with each other: GAS6-IL-10 (r = 0.585, P < 0.001), GAS6-BCL-2 (r = 0.541, P < 0.001), sAXL-BCL-2 (r = 0.696, P < 0.001), IL-10-NO (r = 0.717, P < 0.001), IL-10-BCL-2 (r = 0.759, P < 0.001), and NO-BCL-2 (r = 0.541, P < 0.001). CONCLUSION: In conclusion, decreased serum BCL-2 level may be an indicator of increased apoptosis in these patients and decreased levels of GAS6/sAXL, IL-10, and NO may indicate insufficient clearance of apoptotic bodies released as a result of increased apoptosis in BD patients.

Discovering the Potential Value of Coenzyme Q10 as an Adjuvant Treatment in Patients With Depression.

PURPOSE/BACKGROUND: Depressive disorder or mental cold is the most common mental disorder, and depression exists all over the world and in all countries and cultures. The results of several studies have shown that using compounds with antioxidant properties has been fruitful in patients with depression. Coenzyme Q10 (CoQ10) is a fat-soluble antioxidant and exerts its antioxidant effect by directly neutralizing free radicals or reducing tocopherol and preventing the inhibition of mitochondrial activity because of oxidative stress. This study aimed to investigate the effects of oral CoQ10 in patients with depression as an adjunctive treatment. METHODS/PROCEDURES: Sixty-nine patients with moderate and severe depression were randomly divided into 2 CoQ10 groups (36) and placebo (33). The first group of patients received CoQ10 supplements at a dose of 200 mg daily for 8 weeks along with standard interventions and treatments for depression, and the second group received standard treatments for depression along with a placebo. The change in the score of Montgomery-Åsberg Depression Rating Scale depression scale was evaluated 4 and 8 weeks after the intervention. Also, at baseline and 8 weeks later at the end of the study, serum levels of total antioxidant capacity, total thiol groups, nitric oxide, malondialdehyde, and interleukin 6 were assessed. FINDINGS/RESULTS: The changes in the depression score at the end of the study showed that, in the group receiving the CoQ10 supplement after 8 weeks, there was a reduction in depression symptoms, which was statistically significant compared with before the start of the study Meanwhile, no significant changes were observed in the patients of the placebo group in terms of symptom reduction. Compared with baseline and the placebo condition, serum levels of nitric oxide and total thiol groups significantly decreased and increased, respectively. Also, no statistically significant changes were observed for interleukin 6, malondialdehyde, and total antioxidant capacity. IMPLICATIONS/CONCLUSIONS: A dose of 200 mg of CoQ10 supplement daily for 8 weeks can reduce depression and fatigue, as well as improve the quality of life of patients with depression. In addition, CoQ10 can significantly improve inflammation and oxidative stress status in patients with depression.

Effects of Photobiomodulation Therapy on the Expression of Hypoxic Inducible Factor, Vascular Endothelial Growth Factor, and Its Specific Receptor: A Randomized Control Trial in Patients with Diabetic Foot Ulcer.

Background: Impaired angiogenesis is a significant factor contributing to delayed healing in diabetic foot ulcers (DFUs) due to inadequate oxygenation. Objective: This study aimed to investigate the impact of photobiomodulation (PBM) using a Ga-As laser on the release of serum hypoxia-inducible factor 1-α (HIF-1α), vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor-2, and nitric oxide (NO) in diabetic patients with DFUs. Materials and methods: In this double-blind RCT, a total of 30 patients with grade II DFUs were enrolled. The patients were randomly divided into two groups: the PBM (n = 15) and the placebo (n = 15). In the PBM group, a Ga-As laser (904 nm, 2 J/cm2, 90 W) was given for 3 days/week for 4 weeks (11 sessions). In the placebo group, the power was turned off. Both groups received similar standard wound care. Before and after interventions, the levels of serum HIF-1α, VEGF, NO, and sVEGFR-2 were measured. In addition, the percentage decrease in the wound surface area (%DWSA) was measured. Results: Following the intervention, the results revealed that the PBM group had significantly lower levels of VEGF than the placebo group (p = 0.005). The %DWSA was significantly higher in the PBM group compared to the placebo group (p = 0.003). Moreover, VEGF showed a significant negative correlation with %DWSA (p < 0.001). Conclusions: The observed decrease in serum levels of VEGF and an increase in %DWSA, compared to the placebo group, suggests that PBM effectively improves angiogenesis. Furthermore, the significant correlation found between VEGF levels and %DWSA emphasizes the importance of evaluating wound surface in patients as a dependable indicator of enhanced wound angiogenesis. Clinical Trial Registration: NCT02452086.

Association between endotoxemia and blood no in the portal circulation of cirrhotic patients: results of a pilot study.

Pathophysiology of portal vein thrombosis (PVT) in cirrhosis is still not entirely understood. Elevated levels of lipopolysaccharides (LPS) in portal circulation are significantly associated with hypercoagulation, increased platelet activation and endothelial dysfunction. The aim of the study was to investigate if LPS was associated with reduced portal venous flow, the third component of Virchow's triad, and the underlying mechanism. Serum nitrite/nitrate, as a marker of nitric oxide (NO) generation, and LPS were measured in the portal and systemic circulation of 20 patients with cirrhosis undergoing transjugular intrahepatic portosystemic shunt (TIPS) procedure; portal venous flow velocity (PVV) was also measured in each patient and correlated with NO and LPS levels. Serum nitrite/nitrate and LPS were significantly higher in the portal compared to systemic circulation; a significant correlation was found between LPS and serum nitrite/nitrate (R = 0.421; p < 0.01). Median PVV before and after TIPS was 15 cm/s (6-40) and 31 cm/s (14-79), respectively. Correlation analysis of PVV with NO and LPS showed a statistically significant negative correlation of PVV with portal venous NO concentration (R = - 0.576; p = 0.020), but not with LPS. In vitro study with endothelial cells showed that LPS enhanced endothelial NO biosynthesis, which was inhibited by L-NAME, an inhibitor of NO synthase, or TAK-242, an inhibitor of TLR4, the LPS receptor; this effect was accomplished by up-regulation of eNOS and iNOS. The study shows that in cirrhosis, endotoxemia may be responsible for reduced portal venous flow via overgeneration of NO and, therefore, contribute to the development of PVT.

Asymmetric Dimethylarginine Is Associated with the Phenomenon of Coronary Slow Flow in Patients with Nonvalvular Atrial Fibrillation.

INTRODUCTION: Coronary slow flow phenomena (CSFP) are associated with endothelial and blood component abnormalities in coronary arteries. Asymmetric dimethylarginine (ADMA) can damage the endothelium of the heart or blood vessels in patients with non-valvular atrial fibrillation (NVAF), causing changes in levels of biological indicators. Our aim was to analyze the relationship between ADMA and CSFP in NVAF patients. METHODS: We consecutively enrolled 134 patients diagnosed with NVAF and underwent coronary angiography, 50 control patients without a history of atrial fibrillation and with normal coronary angiographic flow were included at the same time. Based on the corrected TIMI frame count (CTFC), the NVAF patients were categorized into two groups, CTFC ≤27 frames and CTFC >27 frames. Plasma ADMA, P-selectin (p-sel), von Willebrand factor (vWF), D-dimer (D-Di), plasminogen activator inhibitor 1 (PAI-1), and nitric oxide (NO) were detected by ELISA in the different groups. RESULTS: We found that plasma ADMA levels were significantly higher among NVAF patients in the CTFC >27 grade group compared with the control or CTFC ≤27 group. In addition, the levels of blood cells and endothelium-related biomarkers (NO, P-selectin, vWF, D-Di, and PAI-1) were significantly altered and correlated with ADMA levels. Multifactorial analysis showed that plasma ADMA (odd ratio [OR; 95% CI]: 1.65 [1.21-2.43], p < 0.001) and left atrial internal diameter (OR [95% CI]: 1.04 [1.02, 1.1], p < 0.001) could be used as independent risk factors for the development of CSFP in patients with NVAF. The ROC curves of ADMA can predict the development of CSFP in NVAF patients. The minimum diagnostic concentration for the development of CSFP in patients was 2.31 µmol/L. CONCLUSION: Our study demonstrated that CSFP in NVAF patients was associated with high levels of ADMA and left atrial internal diameter. Therefore, aggressive preoperative detection and evaluation of ADMA and left atrial internal diameter can help deal with the intraoperative presence of CSFP.

Oxygen-binding properties of blood in insulin resistance with different asprosin content.

The oxygen-binding properties of blood were studied in male patients with insulin resistance (IR) with different levels of asprosin. The content of asprosin, parameters of blood oxygen transport function, as well as gas transmitters, nitrogen monoxide and hydrogen sulfide, were determined in the venous blood plasma. In the studied IR patients with increased blood asprosin content, impaired blood oxygenation was noted; IR patients with normal body weight had increased hemoglobin affinity for oxygen, while in IR patients with overweight and the 1st degree obesity, this parameter decreased. The detected increase in the concentration of nitrogen monoxide and the decrease in hydrogen sulfide may be important for the oxygen-binding properties of the blood and the development of metabolic imbalance.

Clinical Significance and Correlation Decomposition of Cord Blood NO, Activin A Levels, and MCA/UA with Fetal Distress.

The clinical significance and correlation of cord blood NO, activin A levels, and middle cerebral artery (MCA)/umbilical artery (UA) with fetal distress are explored. 120 puerperae who delivered in the obstetrics department of our hospital from January 2021 to January 2022 are selected as the examination subjects. According to the diagnostic criteria of fetal distress, they are divided into 70 cases of fetal distress and 50 cases of normal delivery. The parameters of umbilical cord blood NO, activin A, UA, and MCA are contrast between the two sets, then the diagnostic value of umbilical cord blood NO and activin A combined with UA and MCA in fetal distress is analyzed. The experimental results show cord blood NO and activin A combined with UA and MCA have a high diagnostic value for fetal distress, and there is an extensive correlation with the occurrence of fetal distress, which provides a reliable clinical diagnosis of fetal distress in a timely manner.

Predictive Analysis of Serum NO, PGI2, and Ox-LDL Levels on Disease Progression in Patients with Lacunar Cerebral Infarction.

Objective: To analyze and predict the progress of patients with lacunar infarction by analyzing the levels of serum NO, PGI2, and Ox-LDL produced by endothelial cells. Methods: 138 patients with lacunar infarction and 34 healthy people were selected. The selected samples were divided into progressive group, nonprogressive group, and control group for biochemical test and endothelial function test. The levels of serum NO, PGI2, and Ox-LDL were obtained. The observation indexes of different groups were compared for statistical analysis and multivariate logistic regression analysis. Results: The indexes of LI patients in the nonprogression group were different from those in the control group. The content of Ox-LDL in the nonprogression group was higher than that in the control group, while the indexes of serum NO and PGI2 were lower than that in the control group. The level of Ox-LDL in LI patients in the progressive group was much higher than that in healthy people in the control group seven days after admission, while the levels of serum NO and PGI2 were lower, and the difference of serum on was more obvious. The level of Ox-LDL in the progressive group was much higher than that in the nonprogressive group, while the levels of serum NO and PGI2 in the progressive group were lower, and the level of serum NO was significantly different from that in the nonprogressive group. Ox - LDL > 76.48 U/L, NO > 55.24 ummol/L, and PGI2 > 29.78 ng/L were independent risk factors for the progression of lacunar infarction. Conclusion: Because the patients with lacunar infarction have endothelium-dependent relaxation disorder, the changes of serum NO, PGI2, and Ox-LDL can be used as the evaluation index of the disease progress of patients with lacunar infarction and can be widely used in clinical detection.

Associations between potential inflammatory properties of the diet and frequency, duration, and severity of migraine headaches: a cross-sectional study.

Despite a large body of literature on the association between the dietary inflammatory index (DII) and various chronic diseases, limited knowledge is available regarding the association between DII and migraine. Therefore, we assessed the relationship between the DII and migraine characteristics, including duration, frequency, and severity of migraine headaches, Headache Impact Test-6 (HIT-6), and serum levels of nitric oxide (NO). This population-based cross-sectional study was conducted from August 2019 to June 2020 among 262 patients (38 men and 224 women; 20-50 years). A 168-item semiquantitative food frequency questionnaire (FFQ) was gathered to evaluate dietary intake, and subsequently, an energy-adjusted DII score was calculated. After controlling for potential confounders, an increase of 3.48 in headache frequency was observed when the DII score increased from - 4.04 to - 1.83 (ß = 3.48; 95% CI 1.43, 5.54). In the crude model, headache duration tended to be inversely associated with DII in the subjects with the pro-inflammatory diet compared to those with the anti-inflammatory diet (ß = - 0.22; 95% CI - 0.46, 0.02). After adjustment for confounders, those with the highest DII values were at a higher risk of severe headaches than those with the lowest values (OR = 2.25; 95% CI 1.17, 4.32). No other significant results were found in terms of the association between DII and HIT-6 or serum NO levels. We found evidence suggesting that higher adherence to a diet with anti-inflammatory properties was significantly and inversely related to headache frequency. Furthermore, our results suggest that the DII score is substantially related to migraine severity.

Association between dietary acid load and clinical features of migraine headaches among Iranian individuals.

There is limited evidence regarding the possible role of dietary acid load (DAL) in the pathophysiology of migraine headaches. Therefore, we sought to examine DAL in relation to the clinical features of migraine including headache frequency, severity and duration, headache impact test-6 (HIT-6), and serum levels of nitric oxide (NO). In the present cross-sectional study, 262 patients (38 men and 224 women aged 20-50 years) were recruited through a simple random sampling method. Dietary intakes were obtained by using a validated 168-item semi-quantitative food frequency questionnaire (FFQ). DAL was then calculated by two different methods; potential renal acid load (PRAL) and net endogenous acid production (NEAP). In total, 262 patients with a mean (SE) age of 36.1 (0.53) and a BMI of 25.55 (0.21) were included in the current study. After controlling for potential confounders, a higher DAL was positively associated with headache frequency in those with the highest DAL score compared to the lowest (PRAL; ß = 2.33; 95% CI 0.78, 3.88; NEAP; ß = 1.74; 95% CI 0.13, 3.34). Increasing NEAP from 28.96 to 35.89 resulted in a 3.43 and 2.74 increment in HIT-6 scores in the crude (95% CI 1.35, 5.52) and fully-adjusted models (95% CI 0.40, 5.07), respectively. Moreover, a higher dietary PRAL was significantly associated with migraine-related disability, as shown by HIT-6, in subjects of the third tertile compared to those in the first tertile after controlling for confounders (ß = 2.42; 95% CI 0.13, 4.70). In conclusion, our study highlighted the importance of the acid-base properties of a diet in the pathophysiology of migraine headaches. However, further well-designed studies are needed to confirm our findings.

An Optimized MRM-Based Workflow of the l-Arginine/Nitric Oxide Pathway Metabolites Revealed Disease- and Sex-Related Differences in the Cardiovascular Field.

Clinical data indicate that low circulating l-homoarginine (HArg) concentrations are associated with cardiovascular (CV) disease, CV mortality, and all-cause mortality. A high number of LC-based analytical methods for the quantification of HArg, in combination with the l-arginine (Arg)-related pathway metabolites, have been reported. However, these methods usually consider a limited panel of analytes. Thus, in order to achieve a comprehensive picture of the Arg metabolism, we described an improved targeted metabolomic approach based on a multiple reaction monitoring (MRM) mass spectrometry method for the simultaneous quantification of the Arg/nitric oxide (NO) pathway metabolites. This methodology was then employed to quantify the plasma concentrations of these analytes in a cohort of individuals with different grades/types of coronary artery disease (CAD) in order to increase knowledge about the role of HArg and its associated metabolites in the CV field. Our results showed that the MRM method here implemented is suitable for the simultaneous assessment of a wide panel of amino acids involved in the Arg/NO metabolic pathway in plasma samples from patients with CV disease. Further, our findings highlighted an impairment of the Arg/NO metabolic pathway, and suggest a sex-dependent regulation of this metabolic route.

Characterization of the L-Arginine/Nitric Oxide Pathway and Oxidative Stress in Pediatric Patients with Atopic Diseases.

INTRODUCTION: L-Arginine (Arg) is a semi-essential amino acid. Constitutive and inducible nitric oxide synthase (NOS) isoforms convert Arg to nitric oxide (NO), a potent vaso- and bronchodilator with multiple biological functions. Atopic dermatitis (AD) and bronchial asthma (BA) are atopic diseases affecting many children globally. Several studies analyzed NO in airways, yet the systemic synthesis of NO in AD and BA in children with BA, AD or both is elusive. METHODS: In a multicenter study, blood and urine were obtained from 130 of 302 participating children for the measurement of metabolites of the Arg/NO pathway (BA 31.5%; AD 5.4%; AD + BA 36.1%; attention deficit hyperactivity disorder (ADHD) 12.3%). In plasma and urine amino acids Arg and homoarginine (hArg), both substrates of NOS, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), both inhibitors of NOS, dimethylamine (DMA), and nitrite and nitrate, were measured by gas chromatography-mass spectrometry. Malondialdehyde (MDA) was measured in plasma and urine samples to evaluate possible effects of oxidative stress. RESULTS: There were no differences in the Arg/NO pathway between the groups of children with different atopic diseases. In comparison to children with ADHD, children with AD, BA or AD and BA had higher plasma nitrite (p < 0.001) and nitrate (p < 0.001) concentrations, suggesting higher systemic NO synthesis in AD and BA. Urinary excretion of DMA was also higher (p = 0.028) in AD and BA compared to patients with ADHD, suggesting elevated ADMA metabolization. DISCUSSION/CONCLUSION: The Arg/NO pathway is activated in atopic diseases independent of severity. Systemic NO synthesis is increased in children with an atopic disease. Plasma and urinary MDA levels did not differ between the groups, suggesting no effect of oxidative stress on the Arg/NO pathway in atopic diseases.

The beneficial effect of Alpha-lipoic acid supplementation as a potential adjunct treatment in episodic migraines.

The current study was performed to evaluate the effects of alpha-lipoic acid (ALA) supplementation on lactate, nitric oxide (NO), vascular cell adhesion molecule-1 (VCAM-1) levels, and clinical symptoms in women with episodic migraines. Considering the inclusion and exclusion criteria, ninety-two women with episodic migraines participated in this randomized, double-blind, placebo-controlled, parallel-design trial. The participants were randomly assigned to receive either 300 mg/day ALA or placebo, twice per day for 12 weeks. The primary outcomes included headache severity, headache frequency per month, and duration of attacks and the secondary outcomes included lactate (a marker of mitochondrial function), NO, and VCAM-1 serum levels were measured at baseline and the end of the intervention. At the end of the study, there was a significant decrease in lactate serum levels (- 6.45 ± 0.82 mg/dl vs - 2.27 ± 1.17 mg/dl; P = 0.039) and VCAM-1 (- 2.02 ± 0.30 ng/ml vs - 1.21 ± 0.36 ng/ml; P = 0.025) in the ALA as compared to the placebo group. In addition, the severity (P < 0.001), frequency (P = 0.001), headache impact test (HIT-6) (P < 0.001), headache dairy results (HDR) (P = 0.003), and migraine headache index score (MHIS) (P < 0.001) had significantly decreased in the intervention as compared to the control group. No significant changes were observed for NO levels and duration of migraine pains. ALA supplementation can be considered a potential adjunct treatment in patients with migraine due to its improving mitochondrial and endothelial functions and clinical symptoms.