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1.
Nutrients ; 13(7)2021 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-34371816

RESUMO

(1) Background: Type-2-diabetes-mellitus (DM) is one the most important cardiovascular-risk-factors. Among many molecules regulating vascular tone, nitric oxide appears to be the most pivotal. Although micro- and macrovascular-abnormalities are extensively studied, the alterations in the nitric-oxide-metabolic-pathway require further investigations. Additionally, the role of erythrocytes in the vascular tone regulation has not been extensively explored. The aim of this study was to evaluate the endothelial-function and the nitric-oxide-metabolic-pathway in erythrocytes and plasma of diabetic individuals. (2) Methods: A total of 80 subjects were enrolled in this cross-sectional study, including 35 patients with DM and 45 healthy individuals. The endothelial-function was evaluated in response to different stimuli. (3) Results: In the DM group, decreased Arginine and citrulline concentrations in the plasma compartment with reduced Arginine/ADMA and ADMA/DMA-ratios were observed. Preserved nitric-oxide-metabolism in erythrocytes with reduced citrulline level and significantly higher NO-bioavailability were noted. Significant endothelial dysfunction in DM individuals was proved in response to the heat-stimulus. (4) Conclusions: DM patients at an early stage of disease show significant differences in the nitric-oxide-metabolic-pathway, which are more pronounced in the plasma compartment. Erythrocytes constitute a buffer with a higher nitric-oxide-bioavailability, less affected by the DM-related deviations. Patients at an early-stage of DM reveal endothelial-dysfunction, which could be diagnosed earlier using the laser-Doppler-flowmetry.


Assuntos
Arginina/análogos & derivados , Arginina/sangue , Diabetes Mellitus Tipo 2/sangue , Endotélio Vascular/metabolismo , Eritrócitos/metabolismo , Óxido Nítrico/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Citrulina/sangue , Estudos Transversais , Feminino , Humanos , Masculino , Redes e Vias Metabólicas , Pessoa de Meia-Idade
2.
Eur J Pharmacol ; 907: 174306, 2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34245744

RESUMO

The novel coronavirus disease 2019 (COVID-19) has led to a serious global pandemic. Although an oxidative stress imbalance occurs in COVID-19 patients, the contributions of thiol/disulphide homeostasis and nitric oxide (NO) generation to the pathogenesis of COVID-19 have been poorly identified. Therefore, the aim of this study was to evaluate the effects of antiviral drug therapy on the serum dynamics of thiol/disulphide homeostasis and NO levels in COVID-19 patients. A total of 50 adult patients with COVID-19 and 43 sex-matched healthy control subjects were enrolled in this prospective study. Venous blood samples were collected immediately on admission to the hospital within 24 h after the diagnosis (pre-treatment) and at the 15th day of drug therapy (post-treatment). Serum native thiol and total thiol levels were measured, and the amounts of dynamic disulphide bonds and related ratios were calculated. The average pre-treatment total and native thiol levels were significantly lower than the post-treatment values (P < 0.001 for all). We observed no significant changes in disulphide levels or disulphide/total thiol, disulphide/native thiol, or native thiol/total thiol ratios between pre- and post-treatments. There was also a significant increase in serum NO levels in the pre-treatment values when compared to control (P < 0.001) and post-treatment measurements (P < 0.01). Our results strongly suggest that thiol/disulphide homeostasis and nitrosative stress can contribute to the pathogenesis of COVID-19. This study was the first to show that antiviral drug therapy can prevent the depletion in serum thiol levels and decrease serum NO levels in COVID-19 patients.


Assuntos
Antivirais/farmacologia , COVID-19/sangue , COVID-19/tratamento farmacológico , Dissulfetos/sangue , Óxido Nítrico/sangue , SARS-CoV-2 , Compostos de Sulfidrila/sangue , Idoso , Antivirais/uso terapêutico , Feminino , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade
3.
Biomed Pharmacother ; 140: 111705, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34118598

RESUMO

PURPOSE: The purpose of this study was to explore the effects of a short-term high-calorie diet and the regulation mechanism of Raphanus sativus L. seeds (RSL seeds) on the intestinal motility of young rats. METHODS: We fed 20 Specific Pathogen Free (SPF) 4-week-old male Sprague-Dawley (SD) rats special high-calorie diet for 3 days and then randomized them to a high-calorie diet group (HCG, 10 rats) and an RSL seeds treatment group (TG, 10 rats). Ten rats of the same age served as the control group (CG). HCG and TG rats continued to be fed high-calorie feed. All of the rats were weighed every 2 days. After 3 days of treatment, the effects of RSL seeds on the regulation of intestinal motility in rats consuming a high-calorie diet were examined. RESULTS: After 3 days of consuming a high-calorie diet, body weight was significantly lower in the HCG group than in the control group, and body weight of the HCG group increased slowly with time. Serum substance P (SP) and ghrelin levels were significantly lower, while the nitric oxide (NO) level was significantly higher. There were no differences in hematoxylin-eosin (HE) staining of colon sections between the groups. The expression levels of Cx43 and BDNF protein and mRNA in colon tissue were significantly lower in the HCG group. There were no significant differences in body weight between the CG and TG groups. Serum SP and ghrelin indexes in TG group were higher than those in the HCG group, and the NO index was significantly decreased. The expression levels of Cx43 and BDNF proteins and mRNA in the colon tissue were also significantly greater. CONCLUSION: Consumption of a short-term high-calorie diet may result in intestinal motility dysfunction and reduced intestinal motility. RSL seeds may improve the intestinal motility by regulating the secretion of gastrointestinal motility hormones and the expression of intestinal motility-related proteins, such as Cx43 and BDNF.


Assuntos
Dieta Hiperlipídica , Motilidade Gastrointestinal/efeitos dos fármacos , Preparações de Plantas/farmacologia , Raphanus , Sementes , Animais , Peso Corporal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/fisiologia , Conexina 43/genética , Conexina 43/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Grelina/sangue , Masculino , Óxido Nítrico/sangue , Ratos Sprague-Dawley , Substância P/sangue
4.
Int J Mol Sci ; 22(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802652

RESUMO

Red blood cells (RBCs) have been found to synthesize and release both nitric oxide (NO) and cyclic guanosine monophosphate (cGMP), contributing to systemic NO bioavailability. These RBC functions resulted impaired in chronic kidney disease (CKD). This study aimed to evaluate whether predialysis (conservative therapy, CT) and dialysis (peritoneal dialysis, PD; hemodialysis, HD) therapies used during CKD progression may differently affect NO-synthetic pathway in RBCs. Our data demonstrated that compared to PD, although endothelial-NO-synthase activation was similarly increased, HD and CT were associated to cGMP RBCs accumulation, caused by reduced activity of cGMP membrane transporter (MRP4). In parallel, plasma cGMP levels were increased by both CT and HD and they significantly decreased after hemodialysis, suggesting that this might be caused by reduced cGMP renal clearance. As conceivable, compared to healthy subjects, plasma nitrite levels were significantly reduced by HD and CT but not in patients on PD. Additionally, the increased carotid intima-media thickness (IMT) values did not reach the significance exclusively in patients on PD. Therefore, our results show that PD might better preserve the synthetic NO-pathway in CKD-erythrocytes. Whether this translates into a reduced development of uremic vascular complications requires further investigation.


Assuntos
Eritrócitos/metabolismo , Óxido Nítrico/biossíntese , Óxido Nítrico/sangue , Diálise Peritoneal , Diálise Renal , Uremia/sangue , Idoso , GMP Cíclico/sangue , GMP Cíclico/metabolismo , Feminino , Humanos , Falência Renal Crônica/sangue , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Óxido Nítrico Sintase/metabolismo , Nitritos/sangue , Nitrosação , Fosforilação
5.
Nutrients ; 13(5)2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33922621

RESUMO

Metabolic syndrome is a worldwide health problem, and obesity is closely related to type 2 diabetes, cardiovascular disease, hypertension, and cancer. According to WHO in 2018, the prevalence of obesity in 2016 tripled compared to 1975. D. morbifera reduces bad cholesterol and triglycerides levels in the blood and provides various antioxidant nutrients and germicidal sub-stances, as well as selenium, which helps to remove active oxygen. Moreover, D. morbifera is useful for treating cardiovascular diseases, hypertension, hyperlipidemia, and diabetes. Therefore, we study in vivo efficacy of D. morbifera to investigate the prevention effect of obesity and cholesterol. The weight and body fat were effectively reduced by D. morbifera water (DLW) extract administration to high-fat diet-fed C57BL/6 mice compared to those of control mice. The group treated with DLW 500 mg∙kg-1∙d-1 had significantly lower body weights compared to the control group. In addition, High-density lipoprotein (HDL) cholesterol increased in the group treated with DLW 500 mg∙kg-1∙d-1. The effect of DLW on the serum lipid profile could be helpful to prevent obesity. DLW suppresses lipid formation in adipocytes and decreases body fat. In conclusion, DLW can be applied to develop anti-obesity functional foods and other products to reduce body fat.


Assuntos
Fármacos Antiobesidade/farmacologia , Araliaceae/química , Hipolipemiantes/farmacologia , Extratos Vegetais/farmacologia , Folhas de Planta/química , Animais , Colesterol/sangue , Colesterol/urina , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Malondialdeído/sangue , Malondialdeído/urina , Camundongos Endogâmicos C57BL , Óxido Nítrico/sangue , Óxido Nítrico/urina , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/toxicidade , Proteínas/genética , Proteínas/metabolismo , Água/química
6.
Int J Mol Sci ; 22(8)2021 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-33919841

RESUMO

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (p < 0.01), blocking pathological increases in systemic extracellular water (p < 0.001) and prolonging median survival (15%, p < 0.01). The LSD activated the classical RAAS by increasing plasma renin activity, angiotensin II and aldosterone levels. However, the LSD also significantly up-elevated the counter-regulatory RAAS by boosting plasma angiotensin converting enzyme 2 (ACE2) and angiotensin (1-7) levels, promoting nitric oxide bioavailability and stimulating 3'-5'-cyclic guanosine monophosphate (cGMP) production. Plasma HF biomarkers associated with poor outcomes, such as B-type natriuretic peptide and neprilysin were decreased by a LSD. Cardiac systolic function, blood pressure and renal function were not affected. Although a LSD activates the classical RAAS system, we conclude that the LSD delayed HF progression and mortality in experimental DCM, in part through protective stimulation of the counter-regulatory RAAS to increase plasma ACE2 and angiotensin (1-7) levels, nitric oxide bioavailability and cGMP production.


Assuntos
Angiotensina I/biossíntese , GMP Cíclico/metabolismo , Dieta Hipossódica , Edema/prevenção & controle , Insuficiência Cardíaca/complicações , Óxido Nítrico/metabolismo , Fragmentos de Peptídeos/biossíntese , Animais , Disponibilidade Biológica , Biomarcadores/sangue , Pressão Sanguínea , Cardiomiopatia Dilatada/complicações , Cardiomiopatia Dilatada/fisiopatologia , Edema/sangue , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/fisiopatologia , Rim/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Peptídeo Natriurético Encefálico/metabolismo , Óxido Nítrico/sangue , Óxido Nítrico Sintase/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Derrame Pleural , Sistema Renina-Angiotensina , Análise de Sobrevida , Sístole
7.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808189

RESUMO

BACKGROUND: Calcific aortic valve disease (CAVD) is a rapidly growing global health problem with an estimated 12.6 million cases globally in 2017 and a 112% increase of deaths since 1990 due to aging and population growth. CAVD may develop into aortic stenosis (AS) by progressive narrowing of the aortic valve. AS is underdiagnosed, and if treatment by aortic valve replacement (AVR) is delayed, this leads to poor recovery of cardiac function, absence of symptomatic improvement and marked increase of mortality. Considering the current limitations to define the stage of AS-induced cardiac remodeling, there is need for a novel method to aid in the diagnosis of AS and timing of intervention, which may be found in metabolomics profiling of patients. METHODS: Serum samples of nine healthy controls and 10 AS patients before and after AVR were analyzed by untargeted mass spectrometry. Multivariate modeling was performed to determine a metabolic profile of 30 serum metabolites which distinguishes AS patients from controls. Human cardiac microvascular endothelial cells (CMECs) were incubated with serum of the AS patients and then stained for ICAM-1 with Western Blot to analyze the effect of AS patient serum on endothelial cell activation. RESULTS: The top 30 metabolic profile strongly distinguishes AS patients from healthy controls and includes 17 metabolites related to nitric oxide metabolism and 12 metabolites related to inflammation, in line with the known pathomechanism for calcific aortic valve disease. Nine metabolites correlate strongly with left ventricular mass, of which three show reversal back to control values after AVR. Western blot analysis of CMECs incubated with AS patient sera shows a significant reduction (14%) in ICAM-1 in AS samples taken after AVR compared to AS patient sera before AVR. CONCLUSION: Our study defined a top 30 metabolic profile with biological and clinical relevance, which may be used as blood biomarker to identify AS patients in need of cardiac surgery. Future studies are warranted in patients with mild-to-moderate AS to determine if these metabolites reflect disease severity and can be used to identify AS patients in need of cardiac surgery.


Assuntos
Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/cirurgia , Sangue/metabolismo , Óxido Nítrico/sangue , Idoso , Estenose da Valva Aórtica/diagnóstico por imagem , Biomarcadores/sangue , Estudos de Casos e Controles , Eicosanoides/sangue , Células Endoteliais , Ácidos Graxos/sangue , Feminino , Implante de Prótese de Valva Cardíaca , Humanos , Masculino , Metabolômica , Pessoa de Meia-Idade , Óxido Nítrico/genética , Óxido Nítrico/metabolismo , Tomografia por Emissão de Pósitrons , Transcriptoma
8.
Nitric Oxide ; 109-110: 20-25, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33676021

RESUMO

BACKGROUND AND AIMS: Preeclampsia is associated with reduced nitric oxide (NO) bioavailability. Arginase is related to NO synthesis, but relatively unexplored in preeclampsia. However, no previous study has examined whether variations in ARG1 and ARG2 genes affect NO bioavailability and the risk of preeclampsia. Here, we compared the alleles and genotypes of single nucleotide polymorphisms (SNPs) in ARG1 (rs2781659; rs2781667; rs2246012; rs17599586) and ARG2 (rs3742879; rs10483801) in healthy pregnant women and preeclampsia, and examined whether these SNPs affect plasma nitrite concentrations (a marker of NO formation) in these groups. METHODS: Genotypes for the ARG1 and ARG2 SNPs were determined by Taqman probe and plasma nitrite by an ozone-based chemiluminescence assay. RESULTS: Regarding ARG1 SNPs, the GG genotype and G allele frequencies for rs2781659, and the C allele frequencies for rs2246012 were higher in preeclampsia compared to healthy pregnant women. Moreover, the GG genotype for rs2781659 and the TT genotype for rs2781667 were associated with higher plasma nitrite in healthy pregnant. We found no association of ARG2 polymorphisms with preeclampsia or nitrite levels in the study groups. CONCLUSIONS: Our results suggest that SNPs of ARG1 increase the risk of preeclampsia and modulate plasma nitrite levels in healthy pregnant women.


Assuntos
Arginase/genética , Óxido Nítrico/metabolismo , Pré-Eclâmpsia/genética , Gravidez/genética , Adulto , Feminino , Frequência do Gene , Humanos , Óxido Nítrico/sangue , Nitritos/sangue , Nitritos/metabolismo , Polimorfismo de Nucleotídeo Único , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/metabolismo , Adulto Jovem
9.
Mol Med Rep ; 23(5)2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33760184

RESUMO

It has previously been shown that the number of endothelial progenitor cells (EPCs) is negatively correlated with Syntax score in patients with coronary artery disease (CAD). However, the association between alterations in EPC function and Syntax score is still unknown. The present study evaluated the association between the activity of EPCs as well as endothelial function and Syntax score in patients with CAD and investigated the underlying mechanisms. A total of 60 patients with CAD were enrolled in 3 groups according to Syntax score, and 20 healthy subjects were recruited as the control group. The number and migratory, proliferative and adhesive activities of circulating EPCs were studied. The endothelial function was measured by flow­mediated dilatation (FMD) and the levels of nitric oxide (NO) in plasma or secreted by EPCs were detected. The number and activity of circulating EPCs were lower in patients with a high Syntax score, which was similar to the alteration in FMD. The level of NO in plasma or secreted by EPCs also decreased as Syntax score increased. There was a negative association between FMD or circulating EPCs and Syntax score. A similar association was observed between the levels of NO in plasma or secreted by EPCs and Syntax score. Patients with CAD who had a higher Syntax score exhibited lower EPC numbers or activity and weaker endothelial function, which may be associated with attenuated NO production. These findings provide novel surrogate parameters for evaluation of the severity and complexity of CAD.


Assuntos
Doença da Artéria Coronariana/sangue , Células Progenitoras Endoteliais/metabolismo , Óxido Nítrico/sangue , Idoso , Movimento Celular/genética , Proliferação de Células/genética , Doença da Artéria Coronariana/genética , Doença da Artéria Coronariana/patologia , Endotélio Vascular/crescimento & desenvolvimento , Endotélio Vascular/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Vasodilatação/genética
10.
Medicine (Baltimore) ; 100(11): e25104, 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33725987

RESUMO

ABSTRACT: Our aim in this study was to investigate the relationship between serum ischemia modified albumin (IMA) levels with oxidative stress parameters [protein carbonyl (PCO), advanced protein oxidation products (AOPPs), malondialdehyde (MDA), total nitric oxide (NOx), prooxidant-antioxidant balance (PAB), and ferric reducing of antioxidant power (FRAP)] in breast cancer (BC) and colon cancer (CC).In total, 90 patients undergoing surgical treatment for BC (n = 45) or CC (n = 45) and 35 healthy controls were included in this cross-sectional study.The serum PCO, AOPPs, MDA, NOx, PAB, and IMA levels were all statistically significantly higher in the cancer patients than in the control group. MDA, NOx, and PAB levels were significantly lower in the BC group than in the CC group. FRAP values were statistically significantly lower in both the CC group and the BC group compared to the control. IMA showed a weak positive correlation with CA-19.9 (r = 0.423 P = .007) but a moderate positive correlation with tumor size in the CC group. IMA showed a positive correlation with metastasis, grade, and HER2 and a negative correlation with ER and PR in the BC group.Oxidative stress is a key player in the development of solid malignancies. Cancer development is a multistage process, and oxidative stress caused by the production of ROS/RNS in the breast and colon may predispose individuals to BC and CC. Patients with BC and CC had an impaired oxidative/antioxidant condition that favored oxidative stress. The ROC analysis indicated that IMA sensitivity above 80% could be used as a secondary biomarker in diagnosis.


Assuntos
Neoplasias da Mama/sangue , Neoplasias do Colo/sangue , Estresse Oxidativo , Espécies Reativas de Nitrogênio/sangue , Espécies Reativas de Oxigênio/sangue , Produtos da Oxidação Avançada de Proteínas/sangue , Antioxidantes/metabolismo , Biomarcadores Tumorais/sangue , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Neoplasias do Colo/patologia , Estudos Transversais , Feminino , Compostos Férricos/sangue , Humanos , Masculino , Malondialdeído/sangue , Pessoa de Meia-Idade , Gradação de Tumores/métodos , Estadiamento de Neoplasias/métodos , Óxido Nítrico/sangue , Oxirredução , Carbonilação Proteica , Curva ROC , Albumina Sérica/análise
11.
Lab Invest ; 101(7): 808-823, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33574439

RESUMO

Dimethylarginine dimethylamino hydrolase-1 (DDAH-1) is an important regulator of nitric oxide (NO) metabolism that has been implicated in the pathogenesis of cardiovascular diseases. Nevertheless, its role in cerebral ischemia still needs to be elucidated. Herein, we examined the expression of DDAH-1 in the brain of rat by double-label immunofluorescence staining. DDAH-1 knock-out (DDAH-1-/-) and wild-type rats underwent middle cerebral artery occlusion/reperfusion (MCAO/R). After 24 h, neurological scores, TTC staining and TUNEL assay were used to evaluate neurological damages. 3 and 7-days infarct outcomes were also shown. Blood-brain-barrier (BBB) permeability was examined via Evans blue extravasation and tight junction (TJ) proteins expression and mRNA levels by western blot and RT-qPCR. The levels of plasma asymmetric dimethylarginine (ADMA), NO and ADMA in brain tissue were also assessed. In addition, supplementation of L-arginine to DDAH-1-/- rats was used to explore its role in regulating NO. DDAH-1 was abundantly distributed in cerebral cortex and basal nuclei, and mainly expressed in neurons and endothelial cells. DDAH-1-/- rats showed aggravated neurological damage and BBB disruption, including decrease of TJ proteins expression but indistinguishable mRNA levels after MCAO/R. DDAH-1 depletion and neurological damages were accompanied with increased ADMA levels and decreased NO concentrations. The supplementation with L-arginine partly restored the neurological damages and BBB disruption. To sum up, DDAH-1 revealed to have a protective role in ischemia stroke (IS) and IS-induced leakage of BBB via decreasing ADMA level and possibly via preventing TJ proteins degradation.


Assuntos
Amidoidrolases , Arginina/análogos & derivados , Barreira Hematoencefálica/fisiopatologia , Isquemia Encefálica/fisiopatologia , Amidoidrolases/genética , Amidoidrolases/metabolismo , Animais , Arginina/sangue , Arginina/metabolismo , Barreira Hematoencefálica/metabolismo , Barreira Hematoencefálica/patologia , Encéfalo/patologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Masculino , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
12.
PLoS One ; 16(2): e0246067, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33539452

RESUMO

Priapism is a urologic emergency characterized by an uncontrolled, persistent and painful erection in the absence of sexual stimulation, which can lead to penile fibrosis and impotence. It is highly frequent in sickle cell disease (SCD) associated with hemolytic episodes. Our aim was to investigate molecules that may participate in the regulation of vascular tone. Eighty eight individuals with SCD were included, of whom thirty-seven reported a history of priapism. Priapism was found to be associated with alterations in laboratory biomarkers, as well as lower levels of HbF. Patients with sickle cell anemia using hydroxyurea and those who received blood products seemed to be less affected by priapism. Multivariate analysis suggested that low HbF and NOm were independently associated with priapism. The frequency of polymorphisms in genes NOS3 and EDN1 was not statistically significant between the studied groups, and the presence of the variant allele was not associated with alterations in NOm and ET-1 levels in patients with SCD. The presence of the variant allele in the polymorphisms investigated did not reveal any influence on the occurrence priapism. Future studies involving larger samples, as well as investigations including patients in priapism crisis, could contribute to an enhanced understanding of the development of priapism in SCD.


Assuntos
Anemia Falciforme/complicações , Endotelina-1/genética , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo de Nucleotídeo Único , Priapismo/genética , Adolescente , Anemia Falciforme/sangue , Anemia Falciforme/genética , Estudos de Casos e Controles , Criança , Endotelina-1/sangue , Hemoglobina Fetal/metabolismo , Estudos de Associação Genética , Humanos , Masculino , Análise Multivariada , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo III/sangue , Priapismo/sangue , Priapismo/etiologia
13.
Nurs Res ; 70(2): E11-E20, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33630539

RESUMO

BACKGROUND: Fibromyalgia (FM) is a complex syndrome of uncertain etiology, characterized by the presence of widespread pain. Both nitric oxide and enkephalinases modulate pain perception. OBJECTIVES: The aim of this study was to evaluate the relationships among serum nitric oxide levels, oxytocinase activity, and enkephalin-degrading aminopeptidase (EDA) activity with pain-related clinical manifestations in women with FM. METHODS: We performed an observational case study in a population of 58 women diagnosed with FM. Serum nitric oxide levels were analyzed by an ozone chemiluminescence-based assay. Both serum oxytocinase and EDA activities were fluorometrically determined. Pain threshold and pain magnitude were evaluated using the PainMatcher. The pressure pain thresholds were measured using a digital pressure algometer. We used a visual analog scale, the Central Sensitization Inventory, the Revised Fibromyalgia Impact Questionnaire, and the Beck Anxiety Inventory to assess the global level of pain, the symptoms associated with the central sensitization syndrome, the severity of FM, and the anxiety level, respectively. RESULTS: Multiple linear regression analysis adjusted by age, body mass index, and menopause status revealed significant associations between nitric oxide levels and dominant occiput pressure pain thresholds, nondominant occiput pressure pain thresholds, and FM effects. Significant associations of oxytocinase activity with the visual analog scale and dominant knee pressure pain thresholds were also found. Moreover, results showed a significant association between high EDA activity levels and dominant second-rib pressure pain thresholds. DISCUSSION: Our data have shown significant relationships of serum nitric oxide levels and oxytocinase and EDA activities with some body pressure pain thresholds, the daily activity level, and the global intensity of pain in women with FM. These results suggest that pain, which is the main symptom of this syndrome, may be related to alterations in nitric oxide levels and in oxytocinase and EDA activities in patients with FM.


Assuntos
Aminopeptidases/sangue , Fibromialgia/sangue , Óxido Nítrico/sangue , Dor/diagnóstico , Adulto , Feminino , Fibromialgia/complicações , Fibromialgia/fisiopatologia , Humanos , Pessoa de Meia-Idade , Dor/sangue , Dor/etiologia , Medição da Dor , Limiar da Dor , Índice de Gravidade de Doença
14.
Reprod Domest Anim ; 56(3): 498-510, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33403762

RESUMO

This study hypothesizes that melatonin with exogenous progesterone (CIDR) can improve follicular, luteal, ovarian and uterine haemodynamic of heat-stressed cows. Holstein cows (N = 12) studied for two spontaneous oestrous cycles during winter then divided equally during summer into the CIDR group received CIDR for 7 days and the melatonin group (Mel) received three injections of melatonin (75 mg/head) at the CIDR insertion, removal and ovulation days. Blood samples were collected to assay oestradiol (E2), progesterone (P4) and nitric oxide (NO). On day 0 (Ovulation), Mel had more small follicles (p < .05), higher ipsilateral and contralateral ovarian arteries (Ov.A.) peak systolic velocity (PSV), higher ipsilateral uterine artery (Ut.A.) PSV (p = .031) and blood flow volume (BFV), also Mel elevated contralateral Ut.A. PSV and BFV (p < .0001) but lowered contra Ut.A. pulsatility index (PI, p < .0001), E2 (p < .01) and NO (p < .0001). Mel increased the corpus luteum diameter (CL, p < .001), coloured area (p < .007) and P4 (p < .0001) on day 5 and reduced them (p < .05; p < .01) on Day 14. On day 10, Mel obtained CL diameter (p < .03) and coloured area (p < .002) of spontaneous that was higher than CIDR and decreased P4 (p < .003). Mel increased CL diameter, area and coloured area and decreased them thereafter. Mel increased the ipsilateral ovarian and uterine arteries PSV and BFV before ovulation and until day 8. Mel increased P4 and decreased NO until days 6 and 14. In conclusion, the improvement in follicular, luteal, ovarian and uterine haemodynamic and the decrease of NO production proved our hypothesis Melatonin doses higher than 75 mg/head is recommended to improve the heat-stressed cow's fertility.


Assuntos
Corpo Lúteo/efeitos dos fármacos , Melatonina/administração & dosagem , Folículo Ovariano/efeitos dos fármacos , Progesterona/administração & dosagem , Animais , Bovinos , Corpo Lúteo/irrigação sanguínea , Sistemas de Liberação de Medicamentos/veterinária , Estradiol/sangue , Feminino , Hemodinâmica , Óxido Nítrico/sangue , Folículo Ovariano/irrigação sanguínea , Ovário/irrigação sanguínea , Ovário/efeitos dos fármacos , Progesterona/sangue , Útero/irrigação sanguínea , Útero/efeitos dos fármacos
15.
Life Sci ; 269: 119001, 2021 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-33421527

RESUMO

AIMS: Osteoarthritis (OA) is a common joint disease and the main cause of disability. We sought to determine the effective concentration of emodin on chondrocytes and to identify the dosage of emodin that induces a comparable therapeutic effect with the COX-2 inhibitor drug, celecoxib that is currently used to treat OA. MATERIAL AND METHODS: In vitro experiments induced inflammation of chondrocytes by IL-1ß, and an osteoarthritis model was established in vivo by cutting rat anterior cruciate ligament. Western Blot, Real-time PCR, HE staining, Safranin O-green staining and immunohistochemistry were performed to detect MMP-3, MMP-13, ADAMTS-4, iNOS and COL2A1 on the chondrocytes or the tibial plateau. The cytokine activity and content in serum of six groups of rats were measured by kit. RESULTS: It was found that the surface layer of the cartilage was thicker and smoother after the administration of emodin. Tissue expression of MMP-3, MMP-13, ADAMTS-4 and iNOS were significantly (p < 0.05) decreased in chondrocytes and cartilage treated with different doses of emodin, and the content of COL2A1 was reversed. Emodin also significantly decreased the blood levels of COX-2 and PGE2. The effective emodin in vitro was 5 µmol/L, whereas emodin at 80 mg/kg was equivalent to celecoxib in vivo. CONCLUSION: Emodin reduces the expression of cartilage matrix degradation biomarkers, thereby reducing the degradation of cartilage matrix and protecting the knee joint cartilage. Emodin at 5 µmol/L shows the best concentration to treat chondrocytes, and the protective effect of emodin at 80 mg/kg is comparable to that of celecoxib.


Assuntos
Cartilagem Articular/patologia , Emodina/farmacologia , Matriz Extracelular/metabolismo , Articulação do Joelho/patologia , Substâncias Protetoras/farmacologia , Proteína ADAMTS4/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Condrócitos/efeitos dos fármacos , Condrócitos/metabolismo , Condrócitos/patologia , Ciclo-Oxigenase 2/sangue , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Emodina/administração & dosagem , Matriz Extracelular/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Metaloproteinases da Matriz/metabolismo , Óxido Nítrico/sangue , Óxido Nítrico Sintase Tipo II/sangue , Óxido Nítrico Sintase Tipo II/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia
16.
Nitric Oxide ; 107: 58-65, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33340674

RESUMO

AIM: In this randomized placebo-controlled clinical trial, effect of oral inorganic nitrate (NO3-) on metabolic parameters was assessed in patients with type 2 diabetes mellitus (T2DM). METHODS: Seventy-four eligible patients with T2DM were randomly assigned to NO3--rich beetroot powder (5 g/d contains ~250 mg NO3-) and placebo groups to complete intervention over a 24-week period. Blood HbA1c, fasting serum glucose, insulin, C-peptide, as well as lipid profile were assessed at baseline and again at weeks 4, 12, and 24; indices of insulin resistance were also calculated. To assess safety of long-term oral NO3-, liver and renal function tests were measured. An intention-to-treat approach was used for data analysis. To compare effect of intervention over time between the groups (time×group), repeated measures generalized estimating equation (GEE) linear regression models were used. RESULTS: Mean age of the participants was 54.0 ± 8.5 (47.9% were male) and mean duration of diabetes was 8.5 ± 6.1 years. A total of 64 patients (n = 35 in beetroot group and n = 29 in placebo group) completed at least two visits and were included in the analyses. No significant difference was observed between the groups for glycemic and lipid parameters over time. Liver and renal function tests, as safety outcome measures, showed no undesirable changes during the study follow-up. CONCLUSION: Supplementation with inorganic NO3- had no effect on metabolic parameters in patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Nitratos/farmacologia , Administração Oral , Beta vulgaris/química , Glicemia/análise , Peptídeo C/sangue , Peptídeo C/metabolismo , Diabetes Mellitus Tipo 2/sangue , Método Duplo-Cego , Feminino , Sucos de Frutas e Vegetais , Hemoglobina A Glicada/análise , Hemoglobina A Glicada/metabolismo , Humanos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Nitratos/administração & dosagem , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Raízes de Plantas/química
17.
Nitric Oxide ; 107: 66-72, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33346127

RESUMO

Nitric oxide seems to be involved in the altitude acclimatization process due to its ability to regulate pulmonary, cardiovascular and muscular responses to hypoxia. In this study, we investigated the plasma nitrate (NO3-) and nitrite (NO2-) response to hypobaric hypoxia in two groups of lowlanders exposed at different altitudes. For seven days, fourteen subjects were evaluated at Casati Hut (3269 m a.s.l. M.CEVEDALE) and eleven individuals were studied at Capanna Regina Margherita (4554 m a.s.l. M.ROSA). Before expeditions and at different time points during high-altitude sojourn, plasma NO3- and NO2- concentrations were measured by chemiluminescence. Resting peripheral arterial oxygen saturation (SpO2), heart rate (HR) and mean arterial blood pressure (MAP) were monitored during the experimental period. Possible confounding factors such as dietary NO3- intake, physical activity and altitude changes were controlled. Sea level plasma NO3- and NO2- concentrations significantly increased at altitude in both M.CEVEDALE group (+26.2 µM, p ≤ 0.0001, 95% CI [+17.6, +34.8] and +559.2 nM, p ≤ 0.0001, [+332.8, +785.6]) and M.ROSA group (+18.7 µM, p ≤ 0.0001, [+10.8, +26.5] and +463.7 nM, p ≤ 0.0001, [+314.3, +613.0]). Average peak value in NO metabolites concentration occurred earlier in M.CEVEDALE group vs M.ROSA group (NO3-, day 3 vs day 5, p = 0.007; NO2-, day 3 vs day 5, p = 0.019). In both groups, resting SpO2, HR and MAP values changed according to altitude levels. This study shows that exposure to hypobaric hypoxia affects nitric oxide metabolites, resulting in a significant increase in plasma NO3- and NO2- concentrations from sea level values. Interestingly, the higher the altitude reached, the longer the time taken to reach a peak in plasma concentrations of nitric oxide metabolites.


Assuntos
Aclimatação/fisiologia , Doença da Altitude/fisiopatologia , Hipóxia/fisiopatologia , Nitratos/metabolismo , Nitritos/metabolismo , Adulto , Altitude , Doença da Altitude/sangue , Feminino , Humanos , Hipóxia/sangue , Masculino , Pessoa de Meia-Idade , Nitratos/sangue , Óxido Nítrico/sangue , Óxido Nítrico/metabolismo , Nitritos/sangue
18.
Free Radic Biol Med ; 163: 153-162, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33347987

RESUMO

Nitric oxide (NO) is a free radical playing an important pathophysiological role in cardiovascular and immune systems. Recent studies reported that NO levels were significantly lower in patients with COVID-19, which was suggested to be closely related to vascular dysfunction and immune inflammation among them. In this review, we examine the potential role of NO during SARS-CoV-2 infection from the perspective of the unique physical, chemical and biological properties and potential mechanisms of NO in COVID-19, as well as possible therapeutic strategies using inhaled NO. We also discuss the limits of NO treatment, and the future application of this approach in prevention and therapy of COVID-19.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , COVID-19/tratamento farmacológico , Pulmão/efeitos dos fármacos , Óxido Nítrico/uso terapêutico , Administração por Inalação , Anti-Inflamatórios/sangue , Anticoagulantes/sangue , Antivirais/sangue , COVID-19/sangue , COVID-19/patologia , COVID-19/virologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Células Endoteliais/virologia , Humanos , Inflamação , Pulmão/irrigação sanguínea , Pulmão/virologia , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/virologia , Óxido Nítrico/sangue , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/patogenicidade , Índice de Gravidade de Doença , Vasodilatação/efeitos dos fármacos
19.
Microvasc Res ; 133: 104075, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32950484

RESUMO

OBJECTIVE: Phosphorylation plays an essential role in the regulation of endothelial nitric oxide synthase (eNOS) activity. However, the phosphorylation of eNOS under hypoglycemia and whether hypoglycemia changes eNOS activity is unknown. This paper aims to clarify the regulation of eNOS phosphorylation and its activity change under hypoglycemia. METHODS: Bovine aortic endothelial cells (BAECs) and Sprague-Dawley rats were treated with hypoglycemia, and the phosphorylation of eNOS was subjected to western blot. Blood nitric oxide (NO) concentration was determined by NO kit and endothelial-dependent vasodilation was detected by multi-wire myograph. RESULTS: In both BAECs and rats' thoracic aorta, hypoglycemia induced eNOS phosphorylation decrease specifically on Threonine (Thr) 497. Inhibition of ubiquitination of protein kinase C α subunit (PKCα) reverses the decrease of eNOS phosphorylation in hypoglycemia. Ubiquitinated PKCα can be reversed by AMPK knockdown. In rats, insulin induced hypoglycemia increased the concentration of NO in arterial blood, and progressively enhanced the endothelium-dependent vasodilation of the thoracic and mesenteric aorta. CONCLUSIONS: In vitro, the activation of AMPK may lead to the expression of PKCα by regulating ubiquitination, resulting in a decrease in the level of P-eNOS Thr497 phosphorylation under hypoglycemia. In vivo, insulin-induced hypoglycemia produces a beneficial cardiovascular effect on rats.


Assuntos
Aorta Torácica/enzimologia , Células Endoteliais/enzimologia , Hipoglicemia/enzimologia , Artérias Mesentéricas/enzimologia , Óxido Nítrico Sintase Tipo III/metabolismo , Vasodilatação , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Animais , Aorta Torácica/fisiopatologia , Glicemia/metabolismo , Bovinos , Células Cultivadas , Modelos Animais de Doenças , Feminino , Hipoglicemia/fisiopatologia , Masculino , Artérias Mesentéricas/fisiopatologia , Óxido Nítrico/sangue , Fosforilação , Proteína Quinase C-alfa/genética , Proteína Quinase C-alfa/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais
20.
Biomed Res Int ; 2020: 3251956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33145345

RESUMO

Background: Preeclampsia is a major cause of maternal and neonatal morbidity and mortality in sub-Saharan Africa. Evidence indicates that endothelial dysfunction is central to the pathogenesis of preeclampsia. This study assessed the level of the components of the arginine-nitric oxide pathway to evaluate endothelial dysfunction in normotensive pregnancies and pregnancies complicated with preeclampsia. Methods: This case-control study was conducted among pregnant women who visited Comboni Hospital from January 2017 to May 2018. A total of 180 pregnant women comprising 88 preeclamptic women (PE) and 92 healthy normotensive pregnant women (NP) were recruited. Sociodemographic, clinical, and obstetric data were obtained using validated questionnaires. Blood pressure and anthropometrics were measured, and blood samples were collected for the estimation of nitric oxide (NO∙), L-arginine, asymmetric dimethylarginine (ADMA), and 3-nitrotyrosine using an enzyme-linked immunosorbent assay technique. Results: The mean NO∙ (p = 0.010) and L-arginine/ADMA ratio (p < 0.0001) was significantly lower in PE compared to NP while mean L-arginine (p = 0.034), ADMA (p < 0.0001), and 3-nitrotyrosine (p < 0.0001) were significantly higher in PE than NP. ADMA showed a significant positive association with systolic blood pressure (ß = 0.454, p = 0.036) in severe PE. Women with PE had significant intrauterine growth restriction (p < 0.0001) and low birth weight infants (p < 0.0001) when compared to NP. Conclusion: Preeclampsia is associated with reduced NO∙ bioavailability, L-arginine/ADMA ratio, and elevated levels of ADMA and 3-nitrotyrosine. Measurements of the levels of these parameters can help in the early prediction of endothelial dysfunction in preeclampsia. Exogenous therapeutic supplementation with L-arginine during pregnancy to increase the L-arginine/ADMA ratio should be considered to improve endothelial function in preeclampsia and pregnant women at risk of developing preeclampsia.


Assuntos
Arginina/análogos & derivados , Arginina/sangue , Endotélio Vascular/metabolismo , Retardo do Crescimento Fetal/sangue , Óxido Nítrico/sangue , Pré-Eclâmpsia/sangue , Tirosina/análogos & derivados , Adolescente , Adulto , Biomarcadores/sangue , Pressão Sanguínea , Estudos de Casos e Controles , Endotélio Vascular/fisiopatologia , Feminino , Retardo do Crescimento Fetal/diagnóstico , Retardo do Crescimento Fetal/fisiopatologia , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Pré-Eclâmpsia/diagnóstico , Pré-Eclâmpsia/fisiopatologia , Gravidez , Tirosina/sangue
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