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Two adult patients with acute leukemia developed transplantation-associated microangiopathy (TAM) related to graft-versus-host disease (GVHD). Both patients were resistant to standard therapy for TAM and GVHD, which led to markedly elevated serum total bilirubin levels of 47.5 and 10.6 mg/dL, respectively. Transdermal isosorbide tape as a nitric oxide donor was applied to Patients 1 and 2 on post-transplantation days 60 and 66, respectively, which rapidly improved their jaundice after 1 day. This is the first report to describe the efficacy of transdermal isosorbide tape for adult patients with jaundice associated with TAM related to GVHD.

Asthma is a common and heterogeneous disease, characterised by lower airway inflammation and airflow limitation. Critical factors in asthma management include establishing an accurate diagnosis and ensuring appropriate selection and dosage of anti-inflammatory therapies. The majority of asthma patients exhibit type 2 (T2) inflammation, with increased interleukin (IL)-4, IL-5, and IL-13 signalling, often with associated eosinophilia. Identifying lower airway eosinophilia with sputum induction improves asthma outcomes, but is time consuming and costly. Increased T2-inflammation leads to upregulation of nitric oxide (NO) release into the airway, with increasing fractional exhaled NO (FeNO) reflecting greater T2-inflammation. FeNO can be easily and quickly measured in the clinic, offering a point of care surrogate measure of the degree of lower airway inflammation. FeNO testing can be used to help confirm an asthma diagnosis, to guide inhaled corticosteroid therapy, to assess adherence to treatment, and to aid selection of appropriate biologic therapy. However, FeNO levels may also be influenced by a variety of intrinsic and extrinsic factors other than asthma, including nasal polyposis and cigarette smoking, and must be interpreted in the broader clinical context rather than viewed in isolation. This review discusses the clinical application of FeNO measurement in asthma care, from diagnosis to treatment selection, and describes its place in current international expert guidelines.

Introduction Leg ulcers (LUs) are relatively common in patients with sickle cell anemia (SCA). The role of inflammation and nitric oxide (NO) pathways in the pathophysiology of the LU is not understood. Objective The aim of this study was to verify the association between inflammatory molecules and nitric oxide metabolites (NOx) and the occurrence of the LU in patients with SCA. Method It was a cross-sectional study on adult participants with SCA followed at Fundacao Hemominas, a public blood center in Brazil. Eligible participants were recruited and included in one of two groups: Group 1, comprised of cases with SCA (Hb SS) and at least one LU at the time of inclusion in the study and Group 2, comprised of controls with SCA without a history of LU, matched by sex and age to cases. Participants were interviewed to obtain sociodemographic data and blood samples were collected. Clinical and laboratory data were abstracted from medical records. Nitric oxide metabolites (NOx) and inflammatory molecules were quantified using an immunoassay and Multiplex xMAP® technology, respectively. Eighty-seven individuals were included, ranging in age from 17 to 61 years (mean 40 ± 10.7 years); 30 had LU and 57 were controls without LU. Results Participants with LU had significantly higher levels of interleukin 8 (IL-8), IL-10, IL-15, NOx and platelet and white blood cell (WBC) counts, when compared to those without LU. Participants with LU had a significantly higher risk of having a history of osteomyelitis and a higher use of antiseptic soap in bathing, when compared to those without LU. Conclusion In conclusion, our results showed that NOx, inflammatory molecules and hematological features were associated with LU in Brazilian adults with SCA.

Objectives: Based on the current state of knowledge, elevated levels of oxidative stress markers may be considered as risk factors for pregnancy complications. The aim of the research was to assess the correlation between selected oxidative stress biomarkers with the occurrence of foetal chromosomal aberration and congenital malformations. Material and methods : This retrospective research lasted for two years. The purpose was to determine serum levels of selected oxidative stress markers, including total protein (TP), glutathione (GSH), S-nitrosothiols (RSNO), nitric oxide (NO), trolox equivalent antioxidant capacity (TEAC) and glutathione S-transferase (GST) at 11–13 + 6 gestational weeks in 38 women with confirmed foetal developmental abnormalities and in 34 healthy pregnancies in order to assess their utility as predictors of abnormal foetal development. Results: Serum concentrations of TP (56.90 ± 5.30 vs 69.1 ± 15.30 mg/mL), TEAC (4.93 ± 0.82 vs 5.64 ± 0.74 μM/mL) and GST (15.94 ± 4.52 vs 21.72 ± 6.81 nM/min/mg) were statistically significantly (p < 0.05) lower in the group of patients with developmental abnormalities in the fetus, whereas GSH levels (6.43 ± 1.24 vs 4.98 ± 1.88 nM/mg) were significantly higher, compared to the group of healthy fetuses. There were no differences in the concentration of these markers between chromosomal aberrations and fetal dysmorphia in subjects. A significant difference in odds ratio obtained for GSH (OR = 0.57, 95% CL: 0.40–0.80) indicates that its higher concentration can relate to reduced risk of developmental abnormalities, whereas odds ratio for TP (OR=1.11, 95% CL: 1.04–1.17), TEAC (OR = 3.54, 95% CL: 1.56–8.05) and GST (OR = 1.18, 95% CL: 1.03–1.17) indicate that their elevation may increase the risk of developmental abnormalities Conclusions: Elevated levels of TP, GST, TEAC and low GSH level may be relevant to predict congenital defects.

An increase of glomerular filtration rate (GFR) is a common observation in early diabetes and is considered a key risk factor for subsequent kidney injury. However, the mechanisms underlying diabetic hyperfiltration have not been fully clarified. Here, we tested the hypothesis that macula densa neuronal nitric oxide synthase (NOS1) is upregulated via sodium glucose cotransporter type 1 (SGLT1) in diabetes, which then inhibits tubuloglomerular feedback (TGF) promoting glomerular hyperfiltration. Therefore, we examined changes in cortical NOS1 expression and phosphorylation, nitric oxide production in the macula densa, TGF response, and GFR during the early stage of insulin-deficient (Akita) diabetes in wild-type and macula densa-specific NOS1 knockout mice. A set of sophisticated techniques including microperfusion of juxtaglomerular apparatus in vitro, micropuncture of kidney tubules in vivo, and clearance kinetics of plasma fluorescent-sinistrin were employed. Complementary studies tested the role of SGLT1 in SGLT1 knockout mice and explored NOS1 expression and phosphorylation in kidney biopsies of cadaveric donors. Diabetic mice had upregulated macula densa NOS1, inhibited TGF and elevated GFR. Macula densa-selective NOS1 knockout attenuated the diabetes-induced TGF inhibition and GFR elevation. Additionally, deletion of SGLT1 prevented the upregulation of macula densa NOS1 and attenuated inhibition of TGF in diabetic mice. Furthermore, the expression and phosphorylation levels of NOS1 were increased in cadaveric kidneys of diabetics and positively correlated with blood glucose as well as estimated GFR in the donors. Thus, our findings demonstrate that the macula densa SGLT1-NOS1-TGF pathway plays a crucial role in the control of GFR in diabetes.

A 70-year-old man with severe interstitial pneumonia attributed to limited cutaneous systemic sclerosis was referred to our institution because of worsening dyspnea. High-resolution computed tomography did not show considerable progression compared with previous images, whereas transthoracic echocardiography showed severe right ventricular dysfunction. Oxygen saturation was decreased to 84% at room air. A blood test showed an increase in the plasma brain natriuretic peptide level (289.4 pg/mL). Right heart catheterization (RHC) showed a remarkably high mean pulmonary arterial pressure (mPAP) of 48 mmHg at room air. A vaso reactivity test using inhaled nitric oxide showed improvement of mPAP, pulmonary vascular resistance (PVR), and partial pressure of arterial oxygen. These findings suggested that the patient responded to pulmonary hypertension (PH)-targeted drugs. We then prescribed tadalafil 10 mg and inhaled iloprost 5 µg six times daily. Three weeks after initiating PH-targeted drugs, RHC indicated hemodynamic improvement similar to hemodynamic changes in the vaso reactivity test (mPAP: 28 mmHg; PVR: 4.2 W.U.). He was discharged with improved symptoms. Inhaled nitric oxide during RHC might be helpful to consider the treatment strategy when patients have PH comorbid systemic sclerosis and severe interstitial lung disease.

Pulmonary arterial hypertension is a rare disease characterized by pulmonary microvasculature remodeling leading to right ventricular failure and death. Medical management of pulmonary hypertension has grown increasingly complex as more therapeutic agents have been developed. Evolving treatment strategies leveraging the endothelin, nitric oxide, and prostacyclin pathways lead to improved exercise capacity and outcomes in patients; however, significant opportunities for advancement remain.

Previous studies have demonstrated that the levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthesis, are strongly associated with hypertension, diabetes, and cardiovascular diseases. Profilin‐1, an actin‐binding protein, has been documented to be involved in endothelial injury and in the proliferation of vascular smooth muscle cells resulting from hypertension. However, the role of profilin‐1 in ADMA‐induced vascular injury in hypertension remains largely unknown. Forty healthy subjects and forty‐two matched patients with essential hypertension were enrolled, and the related indexes of vascular injury in plasma were detected. Rat aortic smooth muscle cells (RASMCs) were treated with different concentrations of ADMA for different periods of time and transfected with profilin‐1 small hairpin RNA to interrupt the expression of profilin‐1. To determine the role of the Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway, RASMCs were pretreated with AG490 or rapamycin. The expression of profilin‐1 was tested using real‐time polymerase chain reaction (PCR) and western blot analysis. Cell proliferation was measured by flow cytometry and 3‐(4,5‐dimethylthiazol‐2yl)‐2,5‐diphenyltetrazoliumbromide assays. Compared with healthy subjects, the levels of ADMA and profilin‐1 were markedly elevated in hypertensive individuals, while the levels of NO were significantly decreased (p

Background The endothelium regulates vascular tonus by releasing nitric oxide (endothelium-derived nitric oxide, EDNO) and hyperpolarizing factor (endothelium-derived hyperpolarizing factor, EDHF). In vein grafts with poor runoff, lack of function of these factors causes severe intimal hyperplasia. This study evaluated how the functions of EDNO and EDHF are altered in artery grafts under poor runoff conditions. Materials and methods The right common carotid arteries of rabbits were excised and implanted in their original positions as autogenous grafts under normal runoff conditions ("nonoccluded grafts") or poor runoff conditions ("poor runoff grafts"). Histochemical changes, acetylcholine (ACh)-induced effects on endothelium-dependent relaxation and smooth muscle cell (SMC) hyperpolarization were examined. Results Both artery graft types displayed negligible intimal hyperplasia. In the absence and presence of an EDNO synthase inhibitor, ACh-induced relaxation was lower in grafts with poor runoff than in nonoccluded grafts. Furthermore, ACh-induced but not nonreceptor agonist A23187-induced SMC hyperpolarization was lower in the poor runoff graft group than in the nonoccluded graft group. Conclusions Unlike in those in vein grafts, the functions of EDNO and EDHF in autogenous carotid artery grafts under poor runoff conditions were reduced but partly maintained. In such artery grafts, intimal hyperplasia caused by surgical operation was not present. These results may explain some of the mechanisms underlying the improved patency of artery grafts compared with vein grafts.

Leptomeningeal anastomoses are small distal anastomotic vessels also known as pial collaterals in the brain. These vessels redirect blood flow during an occlusion and are important for stroke treatment and outcome. Pial collaterals have unique hemodynamic forces and experience significantly increased luminal flow and shear stress after the onset of ischemic stroke. However, there is limited knowledge of how pial collaterals respond to flow and shear stress, and whether this response is altered in chronic hypertension. Using an in vitro system, pial collaterals from normotensive and hypertensive rats (n=6–8/group) were isolated and luminal flow was induced with intravascular pressure maintained at 40 mm Hg. Collateral lumen diameter was measured following each flow rate in the absence or presence of pharmacological inhibitors and activators. Collaterals from male and female Wistar rats dilated similarly to increased flow (2 µL/minute: 58.4±18.7% versus 67.9±7.4%; P =0.275), and this response was prevented by inhibition of the transient receptor potential vanilloid type 4 channel, as well as inhibitors of nitric oxide and intermediate-conductance calcium-activated potassium channels, suggesting shear stress-induced activation of this pathway was involved. However, the vasodilation was significantly impaired in hypertensive rats (2 µL/minute: 17.7±7.7%), which was restored by inhibitors of reactive oxygen species and mimicked by angiotensin II. Thus, flow- and shear stress-induced vasodilation of pial collaterals appears to be an important stimulus for increasing collateral flow during large vessel occlusion. Impairment of this response during chronic hypertension may be related to poorly engaged pial collaterals during ischemic stroke in hypertensive subjects.

In this study, the survival capacity (acid and bile salt tolerance, and adhesion to gut epithelial cells) and probiotic properties (enzyme activity-inhibition and anti-inflammatory activities, inhibition of adipogenesis, and stress hormone level reduction) of Lactiplantibacillus plantarum LRCC5314, isolated from kimchi (Korean traditional fermented cabbage), were investigated. LRCC5314 exhibited very stable survival at pH 2 and in 0.2% bile acid with 89.9% adhesion to Caco-2 intestinal epithelial cells after treatment for 2 h. LRCC5314 also inhibited the activities of α-amylase and α-glucosidase, which are involved in elevating postprandial blood glucose levels, by approximately 72.9% and 51.2%, respectively. Treatment of lipopolysaccharide (LPS)-stimulated RAW 264.7 cells with the LRCC5314 lysate decreased the levels of the inflammatory factors nitric oxide, tumor necrosis factor (TNF-α), interleukin (IL)-1β, and interferon-γ by 88.5%, 49.3%, 97.2%, and 99.8%, respectively, relative to those of the cells treated with LPS alone. LRCC5314 also inhibited adipogenesis in differentiating preadipocytes (3T3-L1 cells), showing a 14.7% decrease in lipid droplet levels and a 74.0% decrease in triglyceride levels, as well as distinct reductions in the mRNA expression levels of adiponectin, FAS, PPAR, C/EBPα, TNF-α, and IL-6. Moreover, LRCC5314 reduced the level of cortisol, a hormone with important effect on stress, by approximately 35.6% in H295R cells. L. plantarum LRCC5314 is identified as a new probiotic with excellent in vitro multifunctional properties. Subsequent in vivo studies may further demonstrate its potential as a functional food or pharmabiotic.

The article presents a literature review on the application of such method of reflexotherapy acupuncture as myeloacupuncture used in the pathology of the peri­pheral joints and spine. It is theoretically grounded and associated with a positive clinical effect as a result of regenerating influence on the processes of free radical oxidation, imbalance of the cytokine network, growth factors, vascular endothelial function, the system of nitric oxide and pro-inflammatory enzymes (matrix metalloproteinases, cyclooxygenase-2, caspase-3). Achievement of the analgesic effect by acupuncture needle injection into the spinal cord is conducted due to the impact on peripheral, spinal and sub-spinal mechanisms, synthesis of neurotransmitters and neurohormones, neuroacid, that cause vanniloid-1 reception normalization, enhancement of production of endorphins, enkephalins and endomorphins, thyrotropin-releasing hormone and P substance.

Nitric oxide is a gas produced in the airways of asthmatic subjects and related to T2 inflammation. It can be measured as fractional nitric oxide (FeNO) in the exhaled air and used as a non-invasive, easy to evaluate, rapid marker. It is now widely used in many settings to determine airway inflammation. The aim of this narrative review is to report relationship between FeNO and the physiopathologic characteristics of asthmatic patients. Factors affecting FeNO levels have also been analysed as well as the impact of corticosteroid, target therapies and rehabilitation programs. Considering the availability of the test, spreading this method-ology to low income countries has also been considered as a possibility for evaluating airway inflammation and monitoring adherence to inhaled corticosteroid therapy. PubMed data search has been performed restricted to English language papers. Research was limited to studies in adults unless studies in children were the only ones reported for a particular issue. This revision could be useful to summarize the role of FeNO in relation to asthma charac-teristics and help in the use of FeNO in different clinical settings particularly in low income countries. (c) 2020 Sociedade Portuguesa de Pneumologia. Published by Elsevier Espana, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

AIMS Patients with type 2 diabetes mellitus (T2DM) have reduced vasodilatory responses during exercise partially attributable to low nitric oxide (NO) levels. Low NO contributes to greater α-adrenergic mediated vasoconstriction in contracting skeletal muscle. We hypothesized boosting NO bioavailability via 8wks of active beetroot juice (BRA, 4.03 mmol nitrate, 0.29 mmol nitrite, n = 19) improves hyperemia, via reduced α-mediated vasoconstriction, during handgrip exercise relative to nitrate/nitrite-depleted beetroot juice (BRP, n = 18) in patients with T2DM. METHODS Forearm blood flow (FBF) and vascular conductance (FVC) were calculated at rest and during handgrip exercise (20%max, 20contractions·min-1). Phenylephrine (α1-agonist) and dexmedetomidine (α2-agonist) were infused intra-arterially during independent trials to determine the influence of α-mediated vasoconstriction on exercise hyperemia. Vasoconstriction was quantified as the percent-reduction in FVC during α-agonist infusion, relative to pre-infusion, as well as the absolute change in %FVC during exercise relative to the respective rest trial (magnitude of sympatholysis). RESULTS ΔFBF (156 ± 69 to 175 ± 73 ml min-1) and ΔFVC (130 ± 54 to 156 ± 63 ml min-1·100 mmHg-1, both P

Central adiposity is associated with greater sympathetic support of blood pressure. β-adrenergic receptors (β-AR) buffer sympathetically mediated vasoconstriction and β-AR-mediated vasodilation is attenuated in preclinical models of obesity. With this information, we hypothesized β-AR vasodilation would be lower in obese compared with normal weight adults. Because β-AR vasodilation in normal weight adults is limited by cyclooxygenase (COX) restraint of nitric oxide synthase (NOS), we further explored the contributions of COX and NOS to β-AR vasodilation in this cohort. Forearm blood flow (FBF, Doppler ultrasound) and mean arterial blood pressure (MAP, brachial arterial catheter) were measured and forearm vascular conductance (FVC) was calculated (FVC = FBF/MAP). The rise in FVC from baseline (ΔFVC) was quantified during graded brachial artery infusion of isoproterenol (Iso, 1–12 ng/100 g/min) in normal weight (n = 36) and adults with obesity (n = 22) (18–40 yr old). In a subset of participants, Iso-mediated vasodilation was examined before and during inhibition of NOS [N(G)-monomethyl-l-arginine (l-NMMA)], COX (ketorolac), and NOS + COX (l-NMMA + ketorolac). Iso-mediated increases in FVC did not differ between groups (P = 0.57). l-NMMA attenuated Iso-mediated ΔFVC in normal weight (P = 0.03) but not adults with obesity (P = 0.27). In normal weight adults, ketorolac increased Iso-mediated ΔFVC (P < 0.01) and this response was lost with concurrent l-NMMA (P = 0.67). In contrast, neither ketorolac (P = 0.81) nor ketorolac + l-NMMA (P = 0.40) altered Iso-mediated ΔFVC in adults with obesity. Despite shifts in COX and NOS, β-AR vasodilation is preserved in young adults with obesity. These data highlight the presence of a compensatory shift in microvascular control mechanisms in younger humans with obesity. NEW & NOTEWORTHY We examined β-adrenergic receptor-mediated vasodilation in skeletal muscle of humans with obesity and normal weight. Results show that despite shifts in the contribution of cyclooxygenase and nitric oxide synthase, β-adrenergic-mediated vasodilation is relatively preserved in young, otherwise healthy adults with obesity. These data highlight the presence of subclinical changes in microvascular control mechanisms early in the obesity process and suggest duration of obesity and/or the addition of primary aging may be necessary for overt dysfunction.

Intestinal lymphangiectasia (IL) is a common complication in dogs. Since nitric oxide (NO) is known to relax the lymphatic vessel, we evaluated inducible NO synthase (iNOS) expression using immunohistochemistry in 13 dogs with lymphoplasmacytic enteritis (LPE) with or without IL. The duodenal iNOS expressing cells were significantly increased in dogs with IL-negative or IL-positive LPE dogs (P=0.025, P=0.007) compared with control dogs. However, there was no significant difference in iNOS expression between IL-positive and IL-negative tissues. Based on these results, there is no clear evidence for the NO overproduction in the pathogenesis of IL in dogs with LPE. Factors other than NO could, thus, contribute to IL in dogs with LPE.

Summary Background & aims Folic acid supplementation is widely accepted during pregnancy, as it exerts a protective effect on neural tube defects. However, the long-term underlying effects of folic acid supplementation during pregnancy (FASDP) on offspring remain unclear. Methods Thirty pregnant female rats were randomly divided into normal control group, folic acid appropriate supplementation group (2.5 × FA group) and folic acid oversupplementation group (5 × FA group) and fed with corresponding folic acid concentration AIN93G diet. UPLC-Q-TOF-MS, UPLC-TQ-MS and GC–MS were performed to detect the serum metabolites profiles in adult male offspring and explore the effects of FASDP. Moreover, molecular biology technologies were used to clarify the underlying mechanism. Results We demonstrate that 2.5-folds folic acid leads to dyslipidemic-diabetic slightly in male offspring, while 5-folds folic acid aggravates the disorder and prominent hepatic lipid accumulations. Using untargeted and targeted metabolomics, total 63 differential metabolites and 12 significantly differential KEGG pathways are identified. Of note, arginine biosynthesis, arginine and proline metabolism are the two most significant pathways. Mechanistic investigations reveal that the increased levels of arginase-1 (Arg1) causes the lipid metabolism disorder by regulating nitric oxide synthase-3 (NOS3)-adenosine monophosphate activated protein kinase-α (AMPKα) pathway, resulting in lipid accumulation in hepatocytes. Conclusions Our data suggest that maternal folic acid oversupplementation during pregnancy contributes to lipid metabolism disorder in male offspring by regulating Arg1-NOS3-AMPKα pathway.

Background: Age-dependent toxic effects of organophosphorus pesticides (OPs) have not been fully understood. The current study aimed to investigate the cardiotoxic damage of chlorpyrifos (CPF) by evaluating oxidative modifications in young (2-month old), middle-aged (10- month old), and aged (20-month old) rats. Objective: Five mg/kg of CPF was administered orally for 45 days to young, middle-aged, and aged male Wistar rats. In the end, animals were anesthetized and the heart of each rat was dissected for biochemical assay. Methods: Malondialdehyde (MDA), nitric oxide (NO), glutathione (GSH), total antioxidant capacity (TAC), and superoxide dismutase (SOD) were assessed in the cardiac tissue of rats. Results: The results indicated an increase in the levels of MDA and NO, and also a decline in the levels of GSH and TAC as well as a decrease in the SOD activity in the heart of aged rats compared with young rats. CPF administration deteriorated these changes in the heart of exposed rats compared with the age-matched controls. Additionally, these oxidative modifications were more severe in aged rats versus other age. Conclusion: In conclusion, advancing age may increase oxidative changes in the heart of animals exposed to CPF. It is suggested that aging can affect cardiac toxicity induced by OPs.

The pathogenesis of SARS-CoV-2 infection, causative pathogen of the known COVID-19 pandemic is not well clarified. In this regard oxidative stress is one of the topics that need to be investigated. Therefore, the present research was performed to explore the relationship between the oxidant/antioxidant system and COVID-19 exacerbation. Sera were collected from 120 patients with COVID-19 infection and 60 healthy volunteers as the control group. The patient group consisted of 60 cases with mild disease and 60 severely ill patients. Serum levels of total antioxidant capacity (TAC) and nitric oxide (NO) as well as serum activities of the two main antioxidant defense enzymes, superoxide dismutase (SOD) and catalase (CAT), were measured. TAC levels were considerably lower in patients compared with healthy individuals (p 0.05) and also between patients with mild and severe diseases (p 0.05). A rather decreasing trend was also found in NO concentration as well as SOD and CAT activity, though, the observed differences were not statistically significant (p 0.05). These findings suggest that COVID-19 patients may be susceptible to depleted total antioxidant capacity. Moreover, showing such variations in blood samples of infected individuals could be considered as a predictive marker of COVID-19 severity.

Patients with asthma-COPD overlap (ACO) account for 15–20% of chronic obstructive pulmonary disease (COPD), and the incidence increases with age. Patients with ACO have worse outcomes without proper treatment than those with COPD alone. However, the current diagnostic criteria of ACO are mainly based on symptom features and lack of objective indicators. Recently, several studies have demonstrated that fractional exhaled nitric oxide (FeNO) was higher in ACO than in COPD alone. Thus, this study aims to determine the diagnostic value of FeNO in differentiating ACO from COPD and assisting clinical decision-making. We conducted searches in the databases including PubMed, Web of Science, Cochrane Library, and Embase to extract original studies. In all, 10 studies involving 1335 participants were included in this meta-analysis. FeNO level was significantly higher in ACO patients than in patients with COPD alone (WMD = 11.15ppb, 95%CI = 9.01‒13.28; I2 = 18.0%, p = 0.000). The sensitivity and specificity of FeNO in distinguishing ACO from COPD were both 0.71, and the area under the receiver-operating characteristic curve (AUC) was 0.76, indicating that FeNO has moderate diagnostic accuracy in differentiating ACO from COPD. FeNO as an inflammatory biomarker is effective in differentiating ACO from COPD and assisting in clinical decision-making.

Background. C-reactive protein (CRP) is an independent biomarker of systemic inflammation and a predictor of future cardiovascular disease (CVD). More than just a pure bystander, CRP directly interacts with endothelial cells to decrease endothelial nitric oxide synthase (eNOS) expression and bioactivity, decrease nitric oxide (NO) production, and increase the release of vasoconstrictors and adhesion molecules. Race is significantly associated with CRP levels and CVD risks. With aerobic exercise, the vessel wall is exposed to chronic high laminar shear stress (HiLSS) that shifts the endothelium phenotype towards an anti-inflammatory, antioxidant, antiapoptotic, and antiproliferative environment. Thus, the purpose of this study was to assess the racial differences concerning the CRP-induced effects in endothelial cells and the potential role of HiLSS in mitigating these differences. Methods. Human umbilical vein endothelial cells (HUVECs) from four African American (AA) and four Caucasian (CA) donors were cultured and incubated under the following conditions: (1) static control, (2) CRP (10 μg/mL, 24 hours), (3) CRP receptor (FcγRIIB) inhibitor followed by CRP stimulation, (4) HiLSS (20 dyne/cm2, 24 hours), and (5) HiLSS followed by CRP stimulation. Results. AA HUVECs had significantly higher FcγRIIB receptor expression under both basal and CRP incubation conditions. Blocking FcγRIIB receptor significantly attenuated the CRP-induced decrements in eNOS expression only in AA HUVECs. Finally, HiLSS significantly counteracted CRP-induced effects. Conclusion. Understanding potential racial differences in endothelial function is important to improve CVD prevention. Our results shed light on FcγRIIB receptor as a potential contributor to racial differences in endothelial function in AA.

This study aimed to investigate the antidepressant effect and mechanism of catalpol on corticosterone (CORT)-induced depressive-like behavior in mice for the first time. As a result, CORT injection induced depressive-like behaviors of mice in behavioral tests, aggravated the serum CORT, adrenocorticotropic hormone, and corticotropin-releasing hormone levels, and conspicuously elevated the phosphorylations of nuclear factor kappa-B (NF-κB) in the hippocampus and frontal cortex, and down-regulated the expression levels of nuclear factor erythroid-2-related factor 2 (Nrf2). Furthermore, CORT exposure dramatically augmented the levels of inflammatory factors (interleukin-1β, tumor necrosis factor-α, nitric oxide synthase, and nitric oxide) and lipid peroxidation product malondialdehyde, and attenuated the levels of antioxidants including reduced glutathione, glutathione S-transferase, total superoxide dismutase, and heme oxygenase-1 in the mouse hippocampus and frontal cortex. On the contrary, catalpol administration markedly suppressed the abnormalities of the above indicators. From the overall results, this study displayed that catalpol exerted a beneficial effect on CORT-induced depressive-like behavior in mice possibly via the inhibition of hypothalamus-pituitary-adrenal (HPA) axis hyperactivity, central inflammation and oxidative damage at least partially through dual regulation of NF-κB and Nrf2.

The endothelium plays a pivotal role in the regulation of vascular tone by synthesizing and liberating endothelium-derived relaxing factors inclusive of vasodilator prostaglandins (eg, prostacyclin), nitric oxide (NO), and endothelium-dependent hyperpolarization factors in a distinct blood vessel size–dependent manner. Large conduit arteries are predominantly regulated by NO and small resistance arteries by endothelium-dependent hyperpolarization factors. Accumulating evidence over the past few decades has demonstrated that endothelial dysfunction and coronary vasomotion abnormalities play crucial roles in the pathogenesis of various cardiovascular diseases. Structural and functional alterations of the coronary microvasculature have been coined as coronary microvascular dysfunction (CMD), which is highly prevalent and associated with adverse clinical outcomes in many clinical settings. The major mechanisms of coronary vasomotion abnormalities include enhanced coronary vasoconstrictive reactivity at epicardial and microvascular levels, impaired endothelium-dependent and endothelium-independent coronary vasodilator capacities, and elevated coronary microvascular resistance caused by structural factors. Recent experimental and clinical research has highlighted CMD as the systemic small artery disease beyond the heart, emerging modulators of vascular functions, novel insights into the pathogenesis of cardiovascular diseases associated with CMD, and potential therapeutic interventions to CMD with major clinical implications. In this article, we will summarize the current knowledge on the endothelial modulation of vascular tone and the pathogenesis of coronary macrovascular and microvascular diseases from bench to bedside, with a special emphasis placed on the mechanisms and clinical implications of CMD.

Background Fractional exhaled nitric oxide (FeNO) can objectively guide clinical practice in the assessment, diagnosis, and treatment of eosinophilic airway inflammation. FeNO values may be affected by current smoking, but the role of tobacco smoke exposure (TSE) is understudied. Objective This study investigated the associations between biochemically validated and self-reported TSE and FeNO levels among U.S. nonsmoking adolescents without asthma. Methods National Health and Nutrition Examination Survey 2007–2012 data were used. TSE was assessed via serum cotinine and self-reported measures. We assessed FeNO continuously and using cutpoints of >35 ppb and >50 ppb to indicate likely eosinophilic inflammation in children and adults, respectively. We conducted linear and logistic regression adjusting for potential covariates. Results Overall, 34.0% of adolescents had low cotinine (0.05–2.99 ng/ml), 6.2% had high cotinine (≥3.00 ng/ml), and 11.9% had home TSE. Compared to adolescents with no/minimal cotinine, adolescents with high cotinine were at reduced odds to have FeNO >35 ppb (adjusted odds ratio [aOR] = 0.54, 95%CI = 0.43,0.69). Adolescents with low cotinine had lower FeNO values (β = −2.05, 95%CI = −3.61,-0.49), and were also at decreased odds to have FeNO >35 ppb (aOR = 0.74, 95%CI = 0.66,0.83) and FeNO >50 ppb (aOR = 0.62, 95%CI = 0.53,0.72). Adolescents with home TSE were at reduced odds to have FeNO >50 ppb (aOR = 0.72, 95%CI = 0.57,0.91) than adolescents without home TSE. Adolescents with a higher number of cigarettes/day smoked inside their home were at reduced odds to have FeNO >35 ppb (OR = 0.98, 95%CI = 0.97,0.99) and FeNO >50 ppb (OR = 0.98, 95%CI = 0.96,0.99). Conclusions TSE was associated with decreased FeNO levels. The addition of TSE may be clinically important when interpreting thresholds for FeNO.

Low doses of nitrite, close to physiological levels, increase blood flow in normal and ischemic tissues through a nitric oxide (NO) dependent mechanism. Given that nitrite therapy and dietary supplementation with vegetables high in nitrate (e.g. beets) are gaining popularity we decided to determine if low doses of nitrite impact the development of choroidal neovascularization (CNV), a key feature of wet age related macular degeneration (AMD). Sodium nitrite (at 50 mg/L, 150 mg/L, and 300 mg/L), nitrate (1 g/L) or water alone were provided in the drinking water of C57BL/6J mice aged 2 or 12 months. Mice were allowed to drink ad libitum for 1 week at which time laser-induced choroidal neovascularization (L-CNV) was induced. The mice continued to drink the supplemented water ad libitum for a further 14 days at which point optical coherence tomography (OCT) was performed to determine the volume of the CNV lesion. Blood was drawn to determine nitrite and nitrate levels and eyes taken for histology. CNV volume was 2.86 × 10(7) μm(3) (±0.4×10(7)) in young mice on water alone but CNV volume more than doubled to >6.9 × 10(7) μm(3) (±0.8×10(7)) in mice receiving 300 mg/L nitrite or 7.34 × 10(7) μm(3) (±1.4×10(7)) in 1 g/L nitrate (p

This study investigated the impact of dietary nitrate supplementation on peripheral hemodynamics, the development of neuromuscular fatigue, and time to task failure during cycling exercise. Eleven recreationally active male participants (27 ± 5 yr, V̇o(2max): 42 ± 2 mL/kg/min) performed two experimental trials following 3 days of either dietary nitrate-rich beetroot juice (4.1 mmol NO(3)(−)/day; DNS) or placebo (PLA) supplementation in a blinded, counterbalanced order. Exercise consisted of constant-load cycling at 50, 75, and 100 W (4 min each) and, at ∼80% of peak power output (218 ± 12 W), to task-failure. All participants returned to repeat the shorter of the two trials performed to task failure, but with the opposite supplementation regime (iso-time comparison; ISO). Mean arterial pressure (MAP), leg blood flow (Q(L); Doppler ultrasound), leg vascular conductance (LVC), and pulmonary gas exchange were continuously assessed during exercise. Locomotor muscle fatigue was determined by the change in pre to postexercise quadriceps twitch-torque (ΔQ(tw)) and voluntary activation (ΔVA; electrical femoral nerve stimulation). Following DNS, plasma [nitrite] (∼670 vs. ∼180 nmol) and [nitrate] (∼775 vs. ∼11 μmol) were significantly elevated compared with PLA. Unlike PLA, DNS lowered both Q(L) and MAP by ∼8% (P < 0.05), but did not alter LVC (P = 0.31). V̇O(2) across work rates, as well as cycling time to task-failure (∼7 min) and locomotor muscle fatigue following the ISO-time comparison were not different between the two conditions (ΔQ(tw) ∼42%, ΔVA ∼4%). Thus, despite significant hemodynamic changes, DNS did not alter the development of locomotor muscle fatigue and, ultimately, cycling time to task failure. NEW & NOTEWORTHY This study sought to characterize the impact of dietary nitrate supplementation on the hemodynamic response, locomotor muscle fatigue, and time to task failure during cycling exercise. Although nitrate supplementation lowered mean arterial pressure and exercising leg blood flow, leg vascular conductance and oxygen utilization were unaffected. Despite significant hemodynamic changes, there was no effect of dietary nitrate on neuromuscular fatigue development and, ultimately, cycling time to task failure.

Endotoxin shock is associated with severe impairments in cardiovascular and respiratory functions. We showed previously that choline or cytidine-5′-diphosphocholine (CDP-choline) provides beneficial effects in experimental endotoxin shock in dogs. The objective of the present study was to determine the effects of choline or CDP-choline on endotoxin-induced cardiovascular and respiratory dysfunctions. Dogs were treated intravenously (i.v.) with saline or endotoxin (LPS, 0.1 mg/kg) 5 min before i.v. infusion of saline, choline (20 mg/kg) or CDP-choline (70 mg/kg). Blood pressure, cardiac rate, myocardial and left ventricular functions, respiratory rate, blood gases, serum electrolytes and cardiac injury markers were determined before and at 0.5-48 h after endotoxin. Plasma tumor necrosis factor alpha (TNF-α), high mobility group box-1 (HMGB1), catecholamine and nitric oxide (NO) levels were measured 2 h and 24 h after the treatments. Endotoxin caused immediate and sustained reductions in blood pressure, cardiac output, pO2 and pH; changes in left ventricular functions, structure and volume parameters; and elevations in heart rate, respiratory rate, pCO2 and serum electrolytes (Na, K, Cl, Ca and P). Endotoxin also resulted in elevations in blood levels of cardiac injury markers, TNF-α, HMGB1, catecholamine and NO. In choline- or CDP-choline-treated dogs, all endotoxin effects were much smaller in magnitude and shorter in duration than observed values in controls. These data show that treatment with choline or CDP-choline improves functions of cardiovascular and respiratory systems in experimental endotoxemia and suggest that they may be useful in treatment of endotoxin shock in clinical setting.

Hypertension is a common comorbid condition in patients with diabetes. The pathogenesis of hypertension in diabetes has not been fully clarified. Primary tubular hyperreabsorption may contribute, which may be counteracted by glomerular hyperfiltration in the early diabetic kidney. In this study, we hypothesize that in early diabetes, the macula densa neuronal nitric oxide synthase (NOS1)-derived nitric oxide (NO) production is enhanced, which blunts tubuloglomerular feedback (TGF) response, promotes glomerular hyperfiltration, and maintains normal blood pressure; conversely, insufficient NO generation by the macula densa induces hypertension by lowering glomerular filtration rate and thus inhibiting natriuresis. To test this hypothesis, we examined the changes of macula densa NOS1 expression and phosphorylation as well as NO production, TGF response, glomerular filtration rate, sodium excretion, and blood pressure in a murine model of leptin receptor-deficient (db/db) diabetes with or without macula densa-specific NOS1 deletion. We found that db/db mice presented reduced fractional renal sodium excretion and only a small increase in blood pressure, associated with upregulated expression and activity of macula densa NOS1, inhibited TGF response, and glomerular hyperfiltration. Genetic knockout of macula densa NOS1 restored the TGF response and attenuated glomerular hyperfiltration in db/db mice but also further reduced fractional renal sodium excretion and substantially increased blood pressure. In conclusion, the present study demonstrates that in the early stage of leptin receptor-deficient diabetes, the upregulation of macula densa NOS1 inhibits TGF and increases glomerular filtration rate, which counteracts renal sodium retention and limits the rise in blood pressure.

OBJECTIVE To evaluate the effect of inhaled nitric oxide (iNO) combined with high-frequency oscillatory ventilation (HFOV) in the treatment of infants with acute hypoxemic respiratory failure (AHRF) and pulmonary hypertension (PH) after congenital heart surgery. METHODS A retrospective study was conducted on 63 infants with AHRF and PH after congenital heart surgery in our cardiac intensive care unit (CICU) from January 2020 to March 2021. A total of 24 infants in the A group were treated with HFOV combined with iNO, and 39 infants in the B group were treated with HFOV. Relevant clinical data were collected. RESULTS Comparing the two groups, the improvement of the oxygenation index, PaO2 and PaO2 /FiO2 was more obvious for patients in the A group than for those in the B group after intervention (p

The human Dietary Approaches to Stop Hypertension-Sodium Trial has shown that β-aminoisobutyric acid (BAIBA) may prevent the development of salt-sensitive hypertension (SSHT). However, the specific antihypertensive mechanism remains unclear in the renal tissues of salt-sensitive (SS) rats. In this study, BAIBA (100 mg/kg/day) significantly attenuated SSHT via increased nitric oxide (NO) content in the renal medulla, and it induced a significant increase in NO synthesis substrates (L-arginine and malic acid) in the renal medulla. BAIBA enhanced the activity levels of total NO synthase (NOS), inducible NOS, and constitutive NOS. BAIBA resulted in increased fumarase activity and decreased fumaric acid content in the renal medulla. The high-salt diet (HSD) decreased fumarase expression in the renal cortex, and BAIBA increased fumarase expression in the renal medulla and renal cortex. Furthermore, in the renal medulla, BAIBA increased the levels of ATP, ADP, AMP, and ADP/ATP ratio, thus further activating AMPK phosphorylation. BAIBA prevented the decrease in renal medullary antioxidative defenses induced by the HSD. In conclusion, BAIBA's antihypertensive effect was underlined by the phosphorylation of AMPK, the prevention of fumarase's activity reduction caused by the HSD, and the enhancement of NO content, which in concert attenuated SSHT in SS rats.

Insulin, which is released by pancreatic islet β-cells in response to elevated levels of glucose in the blood, is a critical regulator of metabolism. Insulin triggers the uptake of glucose and fatty acids into the liver, adipose tissue and muscle, and promotes the storage of these nutrients in the form of glycogen and lipids. Dysregulation of insulin synthesis, secretion, transport, degradation or signal transduction all cause failure to take up and store nutrients, resulting in type 1 diabetes mellitus, type 2 diabetes mellitus and metabolic dysfunction. In this Review, we make the case that insulin signalling is intimately coupled to protein S-nitrosylation, in which nitric oxide groups are conjugated to cysteine thiols to form S-nitrosothiols, within effectors of insulin action. We discuss the role of S-nitrosylation in the life cycle of insulin, from its synthesis and secretion in pancreatic β-cells, to its signalling and degradation in target tissues. Finally, we consider how aberrant S-nitrosylation contributes to metabolic diseases, including the roles of human genetic mutations and cellular events that alter S-nitrosylation of insulin-regulating proteins. Given the growing influence of S-nitrosylation in cellular metabolism, the field of metabolic signalling could benefit from renewed focus on S-nitrosylation in type 2 diabetes mellitus and insulin-related disorders.

Iron [Fe(II)] and copper [Cu(II)] ions produced liver oxidative stress and damage, and as a consequence, changes in the antioxidant protection. The objective of this work is to evaluate whether control of redox homeostasis in chronic overload of Fe(II) and Cu(II) is associated with nitric oxide (NO) and antioxidant enzymes protection in liver. Male Sprague–Dawley rats of 80–90 g received the standard diet ad libitum and drinking water supplemented with either 1.0 g/L of ferrous chloride (0.1% w/v, n = 24) or 0.5 g/L cupric sulfate (0.05% w/v, n = 24) for 42 days. The activities of the enzymes involved in the control of cellular redox homeostasis, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, superoxide dismutase (SOD), catalase and glutathione peroxidase (GPx), were determined by spectrophotometric methods, and NO production was determined by the determination of nitrite levels in liver. Chronic overload with Fe(II) and Cu(II) led to a significant increase of NO production while hampering the activity of NADPH oxidase. Meanwhile, the animals supplemented with Fe(II) showed a decrease in SOD and Gpx activities in liver homogenates with respect to baseline activity after 7 days of treatment, whereas the rats which received Cu(II) showed an increased SOD and catalase activity after 28 and 7 days of chronic overload. Further research is required to understand whether the modulation of the activity of these enzymes upon Cu and Fe overload is involved in a common toxic pathway or may serve to control the steady state of oxidant species related to redox signaling pathways.

Background: The fractional exhaled nitric oxide (FENO) test is a point-of-care test that is used in the assessment of asthma.Objective: To provide evidence-based clinical guidance on whether FENO testing is indicated to optimize asthma treatment in patients with asthma in whom treatment is being considered.Methods: An international, multidisciplinary panel of experts was convened to form a consensus document regarding a single question relevant to the use of FENO. The question was selected from three potential questions based on the greatest perceived impact on clinical practice and the unmet need for evidencebased answers related to this question. The panel performed systematic reviews of published randomized controlled trials between 2004 and 2019 and followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) evidence-to-decision framework to develop recommendations. All panel members evaluated and approved the recommendations.Main Results: After considering the overall low quality of the evidence, the panel made a conditional recommendation for FENO-based care. In patients with asthma in whom treatment is being considered, we suggest that FENO is beneficial and should be used in addition to usual care. This judgment is based on a balance of effects that probably favors the intervention; the moderate costs and availability of resources, which probably favors the intervention; and the perceived acceptability and feasibility of the intervention in daily practice.Conclusions: Clinicians should consider this recommendation to measure FENO in patients with asthma in whom treatment is being considered based on current best available evidence.

OBJECTIVE: The study aims at assessing the relationship between blood pressure, heart geometry parameters, and the erythrocyte content of sulfur, potassium, chlorine and phosphorus, in a group of patients with ambulatory systolic and diastolic blood pressure (SBP, DBP) below 140 or 90 mm Hg, respectively, who were otherwise healthy and untreated. METHODS: The study group consisted of 42 adults recruited in a primary care setting. The individuals were healthy, not undergoing any therapy and free from smoking. For each individual, data were obtained on: average 24-hour SBP and DBP, left ventricle geometry, complete blood count, lipids profile, fibrinogen, hs-CRP and the erythrocyte concentration of sulfur (S), potassium (K), chlorine (Cl) and phosphorus (P). RESULTS: Multivariate regression analysis showed statistically significant relationships of diastolic posterior wall thickness (PWTd) and relative wall thickness (RWT) with the concentration ratio of sulfur and potassium (S/K) in erythrocytes: PWTd and RWT increase as the S/K ratio increases. Also, SBP was found to be positively correlated with the S/K ratio. CONCLUSIONS: The increase in sulfur content in RBCs could be an indicator of the downregulation of nitric oxide (NO) erythrocyte bioavailability exerted by endogenously produced hydrogen sulfide (H2S), and, in consequence, a marker of the development of hypertension and/or adverse changes in heart geometry.

This work explored the mechanism of augmented stress-induced vascular reactivity of senescent murine femoral arteries (FAs). Mechanical and pharmacological reactivity of young (12-25 weeks, y-FA) and senescent (>104 weeks, s-FAs) femoral arteries was measured by wire myography. Expression and protein phosphorylation of selected regulatory proteins were studied by western blotting. Expression ratio of the Exon24 in/out splice isoforms of the regulatory subunit of myosin phosphatase, MYPT1 (MYPT1-Exon24 in/out), was determined by polymerase chain reaction (PCR). While the resting length-tension relationship showed no alteration, the stretch-induced-tone increased to 8.3 ± 0.9 mN in s-FA versus only 4.6 ± 0.3 mN in y-FAs. Under basal conditions, phosphorylation of the regulatory light chain of myosin at S19 was 19.2 ± 5.8% in y-FA versus 49.2 ± 12.6% in s-FA. Inhibition of endogenous NO release raised tone additionally to 10.4 ± 1.2 mN in s-FA, whereas this treatment had a negligible effect in y-FAs (4.8 ± 0.3 mN). In s-FAs, reactivity to NO donor was augmented (pD2 = -4.5 ± 0.3 in y-FA vs. -5.2 ± 0.1 in senescent). Accordingly, in s-FAs, MYPT1-Exon24-out-mRNA, which is responsible for expression of the more sensitive to protein-kinase G, leucine-zipper-positive MYPT1 isoform, was increased. The present work provides evidence that senescent murine s-FA undergoes vascular remodelling associated with increases in stretch-activated contractility and sensitivity to NO/cGMP/PKG system.

Head and neck cancers commonly require radiation as part of treatment. Irradiated patients suffer from severe salivary gland impairment. In this study, we investigated the role of silver nanoparticles (AgNPs) in preventing radiation-induced changes in Albino rats’ submandibular glands (SMG). Thirty adult male Albino rats were divided into three groups ten rats each; group I (control) and group II (irradiated group (IR)) received a single dose of 15 Gray (Gy), and group III (AgNPs + IR) received 150 µg/kg of AgNPs and a single dose of 15 Gy. Sialochemical analysis of salivary function has been evaluated. Salivary levels of 8 hydroxydeoxyguanosine (8-OHdG), nitric oxide (NO), and total antioxidant capacity (TAC) have been measured. Histological and ultrastructural examinations of the salivary gland have been assessed. Immunohistochemical expression of malondialdehyde (MDA), superoxide dismutase (SOD), and inducible nitric oxide synthetase (iNOS) were detected. The results showed a significant decrease in salivary gland function and total protein levels in the IR group, contrary to group III. The 8-OHdG and NO levels and the immunohistochemical expression of MDA and iNOS were significantly increased in the IR group. However, the levels of TAC and SOD were significantly decreased. IR group showed atrophy of acinar cells with signs of degeneration, wide intercellular spaces, and cytoplasmic vacuolizations in addition to apoptotic cells. The results of group III showed protection of the submandibular salivary gland from radiation. We concluded that silver nanoparticles could have a protective role against radiotherapy through their antioxidant activity and scavenging of reactive oxygen species (ROS).

The imbalance of vasoconstrictor and vasodilator axes of the renin-angiotensin system (RAS) is observed in hypertension. Exercise regulates RAS level and improves vascular function. This study focused on the contribution of RAS axes in vascular function of mesenteric arteries and exercise-induced DNA methylation of the Agtr1a (AT1aR) and Mas1 (MasR) genes in hypertension. Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto rats were randomized into exercise or sedentary group. Levels of plasma RAS components, vascular tone, and DNA methylation markers were measured. Blood pressure of SHR was markedly reduced after 12 weeks of aerobic exercise. RAS peptides in plasma were all increased with an imbalanced upregulation of Ang II and Ang-(1–7) in SHR, exercise revised the level of RAS and increased Ang-(1–7)/Ang II. The vasoconstriction response induced by Ang II was mainly via type 1 receptors (AT1R), while this contraction was inhibited by Mas receptor (MasR). mRNA and protein of AT1R and MasR were both upregulated in SHR, whereas exercise significantly suppressed this imbalanced increase and increased MasR/AT1R ratio. Exercise hypermethylated Agtr1a and Mas1 genes, associating with increased DNMT1 and DNMT3b and SAM/SAH. Aerobic exercise ameliorates vascular function via hypermethylation of the Agtr1a and Mas1 genes and restores the vasoconstrictor and vasodilator axes balance.

Reproductive toxicity is a major challenge associated with aluminum (Al) exposure. Therefore, this study aimed to investigate the effects of zinc oxide nanoparticle (ZnONP) treatment on Al-induced reproductive toxicity in rats. Thirty-two adult male albino rats were allocated into four equal groups as follows: control, AlCl3 orally administered group (100 mg/kg bwt), ZnONPs injected intraperitoneally (i.p.) group (4 mg/kg bwt), and ZnONPs + AlCl3–treated group. The treatment was daily extended for 42 consecutive days. Oral administration of AlCl3 showed an oxidative damage confirmed by an increase in malondialdehyde and nitric oxide levels and superoxide dismutase activity and accompanied by a decrease in glutathione content and catalase activity. Also, AlCl3 administration increased the pro-inflammatory mediator tumor necrosis factor-alpha. Furthermore, significant declines in the levels of serum male reproductive hormones testosterone, luteinizing hormone, and follicle-stimulating hormone in AlCl3-intoxicated rats were noticed. In parallel, severe histopathological alterations were observed in testis tissues. Additionally, the immunohistochemical analysis showed that AlCl3 administration potentiates cell death in the testicular tissue by elevating the immunostaining intensity signal for the pro-apoptotic protein, cysteinyl aspartate specific protease-3 (caspase-3) and a marked depletion in the cell proliferation expression marker, Ki-67, in germinal cells of AlCl3-treated group. On the other hand, the daily i.p. injection to rats with ZnONPs before AlCl3 was found to ameliorate the reproductive toxicity induced by Al administration through reducing the testicular oxidative stress and improving the inflammatory, apoptotic, and reproductive markers as well as histopathological alterations in the testis. These results suggest that ZnONPs could be used as an alternative agent to minimize the reproductive toxicity associated with Al exposure through its antioxidant, anti-inflammatory, anti-apoptotic, and reproductive modulatory activities.

Background and aim Hind limb ischemia is one of the peripheral arterial diseases affecting majority of the people with atherosclerosis, diabetes and chronic cigarette smokers. Hind limb ischemic-reperfusion injury is also one of the exacerbating events in these peoples, resulting in hind limb dysfunction. The aim of this study was to identify the effects of ethanolic extracts of mangifera indica (EEMI) on reversing hind limb dysfunction in diabetic rats with acute hind limb ischemia-reperfusion injury. Experimental procedure Unilateral femoral artery ligated diabetic rats were orally fed with EEMI (0.2 and 0.4 g/kg) for 14 days. At the end of the study, plasma levels of pro-inflammatory cytokines and relevant biochemical parameters were measured. The isolated gastrocnemius muscles were used for gene expression and histopathological studies. Results There was a significant reduction (p < 0.05) in the plasma levels of pro-inflammatory cytokines, nitric oxide, malondialdehyde; and the expression levels of mRNA of induced nitric oxide synthase and intercellular adhesion molecule −1; and increase in anti-inflammatory cytokine, in isolated gastrocnemius muscles of animals treated with 0.2 and 0.4 g/kg of EEMI in comparison to disease control. In addition, histopathological study of gastrocnemius muscle and hind limb function test indicated the recovery of tissue damage from ischemic reperfusion at 0.2 and 0.4 g/kg of EEMI in comparison to disease control. Conclusion We conclude that 14-day EEMI treatment of rats with acute hind limb ischemia/reperfusion in diabetic rats recovered from ischemic/reperfusion injury by modulating (decreasing) oxidative stress and inflammation., Graphical abstract Image 1, Highlights • Ethanolic extracts of M.indica (EEMI) was effective in diabetic rats with acute hind limb ischemia-reperfusion (AHLI-R) injury. • EEMI attenuated plasma levels of pro-inflammatory cytokines and augmented IL-10 in diabetic rats with AHLI-R injury. • EEMI augmented cell-cell adhesion molecule, ICAM-1 in gastrocnemius muscle of diabetic rats with AHLI-R injury. • EEMI reversed I/R injury and hind limb dysfunction by modulating mechanisms of oxidative stress and inflammation.

Introduction Endothelial dysfunction occurs at the very beginning of hypertension. The primary goal of our study was to determine plasmatic levels of multiple endothelial substances in otherwise healthy patients with primary hypertension and compare them to healthy individuals. Secondary goals were to determine the change in NOx levels after initiation of treatment and to compare the NOx levels in patients with established resistant hypertension. Materials and methods 87 consecutive patients were enrolled. In the exploratory cohort of 22 healthy and 28 hypertensive individuals, plasmatic levels of big endotelin-1, asymmetric dimethylarginin, osteopontin, oxidized LDL, 3-nitro-L-tyrosine, growth/differentiation factor 15, intercellular adhesion molecule, vascular cell adhesion molecule, tumor necrosis factor-α, vascular endothelial growth factor, interleukins -1β, -6 and nitric oxide levels (NO, expressed as NOx) were determined. The remaining 27 individuals were used as a validation cohort. Ten patients with established resistant hypertension were enrolled from our Hypertension Clinic. Results There was a statistically significant difference in NOx levels between healthy controls and hypertensive patients/resistant hypertensive patients: 45.164 µmol/L ± 48.627 vs 17.763 µmol/L ± 10.333 (P=0.00004)/14.36 µmol/L ± 7.194 (P=0.00007). Conclusion We identified a decrease in total NOx plasmatic levels in otherwise healthy patients with primary hypertension that was more profound in patients with resistant hypertension. Plasmatic levels of other determined endothelial substances did not differ among the groups. However, due to the significant variability of plasmatic NOx levels even in healthy controls and many factors that affect it, we cannot recommend it to be used to assess endothelial function routinely.

Diabetes pulmonary and microvascular consequences are well recognized but have not been characterized. We assessed lung microvascular changes in a live anesthetized mouse model of type 1 diabetes, using a novel intravital microscopy technique. Our results show new evidence that a diabetes-induced decrease in lung nitric oxide bioavailability underlies oxidative damage, enhanced platelet activation, and endothelial injury causing pulmonary microvascular dysfunction and altered vasoreactivity. These findings could provide novel strategies to prevent or reverse diabetes systemic consequences.

Age-related cerebral small-vessel disease (CSVD) is a major cause of stroke and dementia. Despite a widespread acceptance of small-vessel arteriopathy, lacunar infarction, diffuse white matter injury, and cognitive impairment as four cardinal features of CSVD, a unifying pathologic mechanism of CSVD remains elusive. Herein, we introduce partial endothelial nitric oxide synthase (eNOS)-deficient mice as a model of age-dependent, spontaneous CSVD. These mice developed cerebral hypoperfusion and blood-brain barrier leakage at a young age, which progressively worsened with advanced age. Their brains exhibited elevated oxidative stress, astrogliosis, cerebral amyloid angiopathy, microbleeds, microinfarction, and white matter pathology. Partial eNOS-deficient mice developed gait disturbances at middle age, and hippocampus-dependent memory deficits at older ages. These mice also showed enhanced expression of bone morphogenetic protein 4 (BMP4) in brain pericytes before myelin loss and white matter pathology. Because BMP4 signaling not only promotes astrogliogenesis but also blocks oligodendrocyte differentiation, we posit that paracrine actions of BMP4, localized within the neurovascular unit, promote white matter disorganization and neurodegeneration. These observations point to BMP4 signaling pathway in the aging brain vasculature as a potential therapeutic target. Finally, because studies in partial eNOS-deficient mice corroborated recent clinical evidence that blood-brain barrier disruption is a primary cause of white matter pathology, the mechanism of impaired nitric oxide signaling-mediated CSVD warrants further investigation.

Background Preventing pulmonary vascular remodeling is a key strategy for pulmonary hypertension (PH). Causes of PH include pulmonary vasoconstriction and inflammation. This study aimed to determine whether cilostazol (CLZ), a phosphodiesterase-3 inhibitor, prevents monocrotaline (MCT)- and chronic hypoxia (CH)-induced PH development in rats. Methods Fifty-one male Sprague–Dawley rats were fed rat chow with (0.3% CLZ) or without CLZ for 21 days after a single injection of MCT (60 mg/kg) or saline. Forty-eight rats were fed rat chow with and without CLZ for 14 days under ambient or hypobaric (air at 380 mmHg) CH exposure. The mean pulmonary artery pressure (mPAP), the right ventricle weight-to-left ventricle + septum weight ratio (RV/LV + S), percentages of muscularized peripheral pulmonary arteries (%Muscularization) and medial wall thickness of small muscular arteries (%MWT) were assessed. Levels of the endothelial nitric oxide synthase (eNOS), phosphorylated eNOS (peNOS), AKT, pAKT and IκB proteins in lung tissue were measured using Western blotting. Monocyte chemotactic protein (MCP)-1 mRNA in lung tissue was also assessed. Results mPAP [35.1 ± 1.7 mmHg (MCT) (n = 9) vs. 16.6 ± 0.7 (control) (n = 9) (P P P P P P Conclusions We found model differences in the effect of CLZ on PH development. CLZ might exert a preventive effect on PH development in an inflammatory PH model but not in a vascular structural change model of PH preceded by vasoconstriction. Thus, the preventive effect of CLZ on PH development might depend on the PH etiology.

Impaired angiogenesis function in pulmonary artery endothelial cells (PAEC) contributes to persistent pulmonary hypertension of the newborn (PPHN). Decreased nitric oxide (NO) amounts in PPHN lead to impaired mitochondrial biogenesis and angiogenesis in the lung; the mechanisms remain unclear. We hypothesized that decreased cyclic guanosine monophosphate (cGMP)–PKG (protein kinase G) signaling downstream of NO leads to decreased mitochondrial biogenesis and angiogenesis in PPHN. PPHN was induced by ductus arteriosus constriction from 128–136 days’ gestation in fetal lambs. Control animals were gestation-matched lambs that did not undergo ductal constriction. PAEC isolated from PPHN lambs were treated with the sGC (soluble guanylate cyclase) activator cinaciguat, the PKG activator 8-bromo-cGMP, or the PDE-V (PDE type V) inhibitor sildenafil. Lysates were immunoblotted for mitochondrial transcription factors and electron transport chain C-I (complex I), C-II, C-III, C-IV, and C-V proteins. The in vitro angiogenesis of PAEC was evaluated by using tube-formation and scratch-recovery assays. cGMP concentrations were measured by using an enzyme immunoassay. Fetal lambs with ductal constriction were given sildenafil or control saline through continuous infusion in utero, and the lung histology, capillary counts, vessel density, and right ventricular pressure were assessed at birth. PPHN PAEC showed decreased mitochondrial transcription factor levels, electron transport chain protein levels, and in vitro tube formation and cell migration; these were restored by cinaciguat, 8-bromo-cGMP, and sildenafil. Cinaciguat and sildenafil increased cGMP concentrations in PPHN PAEC. Radial alveolar and capillary counts and vessel density were lower in PPHN lungs, and the right ventricular pressure and Fulton Index were higher in PPHN lungs; these were improved by in utero sildenafil infusion. cGMP–PKG signaling is a potential therapeutic target to restore decreased mitochondrial biogenesis and angiogenesis in PPHN.

BACKGROUND AND AIM The pathogenesis of the pain that occurs in episodic migraine attack is due to the activation of the trigeminal system's first neuron receptors located on vessel wall. The release from the endothelium of nitric oxide, a product of arginine metabolism, causes vasodilation and stretching of the vascular trigeminal system and promotes pain. It is unknown whether this same metabolic event is involved in the pain accompanying chronic migraine. To understand the possible role of arginine in the pathogenesis of chronic migraine patients, we evaluated the metabolism of arginine in plasma of chronic migraine and control subjects. METHODS We evaluated the metabolism of arginine in a group of patients affected by chronic migraine. Quantification of arginine, ornithine, citrulline, monomethyl arginine (NMMA), dimethylarginines (ADMA, SDMA), and tyramine was performed by ultra-performance liquid chromatography coupled with a triple quadrupole mass spectrometer. RESULTS Chronic migraine patients showed low plasma levels of arginine, significantly elevated levels of ornithine, ADMA, and NMMA whereas the levels of citrulline and SDMA were in the range of controls. CONCLUSIONS The elevated levels of ADMA and NMMA, inhibitors of nitric oxide synthase, suggest that the metabolism of arginine may be inhibited with a possible reduction of NO release in the circulation of chronic patients. This suggests that the origin of pain may not be related to the vasodilation of trigeminal vascular system that occurs in episodic migraine patients.

To explore the relationship between the severity of hypertension and the imbalanced intestinal flora, inflammatory factors, adiponectin (ADPN) and vascular endothelial function in primary hypertension patients. According to the grading criteria for hypertension, in total of 60 patients with primary hypertension in our hospital from April to July, 2020 were divided into Grade 1 group (n = 20), Grade 2 group (n = 20), and Grade 3 group (n = 20). The feces of the research subjects were collected to extract the deoxyribonucleic acid (DNA) and detect its composition of intestinal flora. Subsequently, the peripheral blood was collected to determine the changes in inflammatory factors interleukin‐2 (IL‐2), IL‐4, tumor necrosis factor‐α (TNF‐α) and IL‐1β, serum immunoglobulin G (IgG) and IgM, ADPN and vascular endothelial function‐related endothelin‐1 (ET‐1), nitric oxide (NO), vascular endothelial growth factor (VEGF), and intercellular adhesion molecule‐1 (ICAM‐1). There were no significant differences in the gender, age, and body mass index (BMI), the proportion of smokers, diet habit, probiotics and antihypertensive medication use, and number of diabetic cases among groups (p > 0.05). We found an inverse association between blood pressure measures and microbial diversity, in particular microbial richness (p < 0.05). Among the four major kinds of intestinal flora, the composition of firmicutes (p < 0.05) and bacteroidetes (p < 0.05) showed obvious differences among the three groups, and they had consistent trends with the changes in the abundance of firmicutes and bacteroidetes. Intestinal flora imbalance is closely related to the severity of hypertension, inflammatory factors, ADPN, and vascular endothelial function.

The study aimed to develop a personalized pharmacological correction of immune, metabolic and neuropsychiatric disorders in chronic cerebral ischemia (CCI) stages I and II. The study included 104 patients, of which 76 were female and 28 were male, with CCI on the background of grade II hypertension, of which 52 patients were with stage I and 52 with stage II at the age of 50±5 years. Clinical and laboratory parameters were studied in 22 healthy donors of the same age who formed a control group. Patients with CCI were randomized according to gender, age, treatment method, concomitant pathology, and duration of the disease. Evaluation of clinical and laboratory data was carried out at the beginning of treatment and 2 weeks after its end. The sorption capacity of erythrocytes and the sorption capacity of the glycocalyx (SEG), the activity of lipid peroxidation processes, the state of the antioxidant system were determined in blood plasma and erythrocytes, the level of stable metabolites of nitric oxide (SMNO), neopterin, C-reactive protein, cytokines (TNFα, IL-1β, IL-8, IFNγ, IL-18, G-CSF, IL-4, IL-10), immunoglobulins (IgM, IgG, IgA), complement system components (C3, C4, C5, C5A), phagocytic and oxygen-dependent activity of polymorphonuclear blood leukocytes. It has been established that for patients with CCI I with high concentrations of IL-8, IL-10, SMNO and a low SEG index, the intake of Cereton and Actovegin or Ceraxon and Mexicor will be insufficient for effective correction of immunometabolic disorders, which requires additional administration of an immunomodulator. Patients with CCI II, who have a higher plasma level of TNFα, IL-10 and low SEG values, need to prescribe Ceraxon, Mexicor and Glutoxim or Ceraxon, Mexicor and Polyoxidonium in order to obtain the maximum clinical and laboratory positive effect.

Non-enzymatic nitric oxide (NO) generation via the reduction of nitrate and nitrite ions, along with remarkably high levels of nitrate ions in skeletal muscle, have been recently described. Skeletal muscle nitrate storage may be critical for maintenance of NO homeostasis in healthy ageing and nitrate supplementation may be useful for treatment of specific pathophysiologies as well as enhancing normal functions.

The study aimed to compare the effectiveness of various pharmacotherapy regimens for infertility of tubo-peritoneal genesis. Under constant supervision were 96 patients referred to the hospital for diagnostic laparoscopy for infertility of tubo-peritoneal genesis, divided equally into 4 groups depending on the pharmacological treatment methods: the 1st group received basic pharmacotherapy (BPT) after endoscopic surgery (antibacterial, antifungal, vitamin therapy). Patients of groups 2-4, in addition to BPT, received Hepon, Cycloferon or Lavomax, respectively. The control group consisted of 38 gynecologically healthy women. Laboratory examination was performed within 24 hours after the operation and on the 30th day after BPT. Vaginocervical lavage and plasma were assayed for the activity of lipid peroxidation processes, the state of the antioxidant system, the level of stable nitric oxide metabolites, neopterin, C-reactive protein, cytokines (TNFα, IL-1β, IL-8, IFNγ, IL-18, G-CSF, IL-4, IL-10), immunoglobulins (IgM, IgG, IgA, sIgA), components of the complement system (C3, C4, C5, C5А), phagocytic and oxygen-dependent activity of polymorphonuclear leukocytes. It was established that the use of immunomodulatory and antiviral activity medication with BPT according to the degree of increasing efficiency in the correction of immunometabolic laboratory parameters at the systemic and local level in infertility of tuboperitoneal genesis is as the following sequence: basic pharmacotherapy < basic pharmacotherapy + Hepon < basic pharmacotherapy + Cycloferon < basic pharmacotherapy + Lavomax.