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1.
Autoimmun Rev ; 18(11): 102396, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520794

RESUMO

Systemic Sclerosis (SSc) pathogenesis involves multiple immunological, vascular and fibroproliferative abnormalities that contribute to a severe and complex clinical picture. Vasculopathy and fibroproliferative alterations are two hallmark pathological processes in SSc that are responsible for the most severe clinical manifestations of the disease and determine its clinical outcome and mortality. However, the pathogenesis of SSc vasculopathy and of the uncontrolled SSc fibrotic process remain incompletely understood. Recent investigations into the molecular pathways involved in these processes have identified an important role for epigenetic processes that contribute to overall disease progression and have emphasized microRNAs (miRNAs) as crucial epigenetic regulators. MiRNAs hold unique potential for elucidating SSc pathogenesis, improving diagnosis and developing effective targeted therapies for the disease. This review examines the important role that miRNAs play in the development and regulation of vascular and fibroproliferative alterations associated with SSc pathogenesis and their possible participation in the establishment of pathogenetic connections between these two processes. This review also emphasizes that further understanding of the involvement of miRNA in SSc fibrosis and vasculopathy will very likely provide novel future research directions and allow for the identification of groundbreaking therapeutic interventions within these processes. MiR-21, miR- 31, and miR-155 are of particular interest owing to their important involvement in both SSc vasculopathy and fibroproliferative alterations.


Assuntos
MicroRNAs , Escleroderma Sistêmico/genética , Doenças Vasculares/genética , Animais , Fibrose , Humanos
2.
Ann Hematol ; 98(10): 2257-2265, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31440871

RESUMO

Vascular complications of sickle cell anemia (SCA) are influenced by many factors. Elevated plasma homocysteine (Hcy) is supposed to be an independent risk factor and is either genetic or nutritional origin. The present study evaluated the plasma Hcy level, MTHFR C677T gene polymorphism, effect of folic acid (FA) supplementation' and hemato-biochemical parameters in SCA and their effect on the vaso-occlusive crisis (VOC) in SCA patients of an Asian-Indian haplotype population. One hundred twenty cases of SCA (HbSS) and 50 controls with normal hemoglobin(HbAA) were studied. It was found that the plasma Hcy level is significantly higher (p < 0.0001) in patients with SCA (22.41 ± 7.8 µmol/L) compared to controls (13.2 ± 4.4 µmol/L). Moreover, patients without FA supplementation had a significantly (p < 0.001) higher Hcy level (27 ± 7 µmol/L) compared to those with supplementation (17.75 ± 5.7 µmol/L). Turkey-Kramer multiple comparison tests show that there is a significant difference (p < 0.05) in HbF percent, hemoglobin (Hb), platelet count, serum bilirubin (direct:Bil-D and total:Bil-T), aspartate transaminase (AST), lactate dehydrogenase (LDH), and plasma Hcy levels between mild and severe VOC. Between moderate VOC and severe VOC, there was a significant difference (p < 0.05) in HbF%, Bil-D, AST, Hcy. Pearson correlation revealed that plasma Hcy had a significantly (p < 0.05) positive correlation with AST, serum bilirubin (indirect and total), LDH, jaundice, stroke, VOC per year, and hospitalization per year whereas it was inversely correlated with HbF percentage, Hb level, and FA treatment. In the study population, increased plasma Hcy level, hemolysis, and platelet activation were found to influence VOC in SCA.


Assuntos
Anemia Falciforme , Homocisteína/sangue , Metilenotetra-Hidrofolato Redutase (NADPH2)/genética , Polimorfismo Genético , Doenças Vasculares , Adolescente , Adulto , Anemia Falciforme/sangue , Anemia Falciforme/complicações , Anemia Falciforme/genética , Anemia Falciforme/fisiopatologia , Aspartato Aminotransferases/sangue , Bilirrubina/sangue , Plaquetas/metabolismo , Feminino , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Hemólise , Homocisteína/genética , Humanos , L-Lactato Desidrogenase/sangue , Masculino , Metilenotetra-Hidrofolato Redutase (NADPH2)/sangue , Pessoa de Meia-Idade , Ativação Plaquetária , Contagem de Plaquetas , Doenças Vasculares/sangue , Doenças Vasculares/etiologia , Doenças Vasculares/genética , Doenças Vasculares/fisiopatologia
3.
J Agric Food Chem ; 67(22): 6169-6176, 2019 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-31117553

RESUMO

Dietary choline and its containing foods are biotransformed to trimethylamine (TMA) via gut microbial metabolism. Subsequently, as an intermediate molecule, TMA is quickly transported and oxidized in the liver by hepatic flavin monooxygenases to form trimethylamine oxide (TMAO). TMAO was treated as a waste byproduct from choline metabolism, but recent convincing evidence demonstrated the association between the small molecule TMAO and inflammation-related diseases, including blood vessel inflammation and vascular diseases. The scope of this study is to investigate the preventive effect of nobiletin on TMAO-induced blood vessel inflammation. Our results from Western blot showed that the inhibition of TMAO-induced cardiovascular inflammation was correlated with nobiletin-mediated inhibitory effects on NF-κB and MAPK/ERK related pathways. More specifically, nobiletin prevented the oxidative damage of vascular sites (proximal aorta), inhibited the activity of MAPK/ERK, reduced the expression of NF-κB p65 and phospho-NF-κB p65, and consequently decreased the inflammatory response. Flow cytometry analyses showed that nobiletin decreased TMAO-induced apoptosis of HUVEC cells and counteracted TMAO-induced HUVEC cell proliferation. Results from HE staining and immunohistochemical results also showed that nobiletin reduced the degree of inflammation of the proximal aorta in Sprague-Dawley rats. In summary, nobiletin significantly reduced TMAO-induced vascular inflammation via inhibition of the NF-κB/MAPK pathways.


Assuntos
Flavonas/administração & dosagem , Quinases de Proteína Quinase Ativadas por Mitógeno/imunologia , Fator de Transcrição RelA/imunologia , Doenças Vasculares/prevenção & controle , Animais , Aorta/efeitos dos fármacos , Aorta/imunologia , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Masculino , Metilaminas/efeitos adversos , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Ratos , Ratos Sprague-Dawley , Fator de Transcrição RelA/genética , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/genética , Doenças Vasculares/imunologia
4.
Med Sci Monit ; 25: 1952-1959, 2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30873956

RESUMO

BACKGROUND MicroRNAs (miRNAs) have emerged as central regulators of many processes. MiRNA-34 (miR-34) functions as a well-known tumor suppressor. The aim of this study was to investigate the mechanisms underlying how miR-34 participates in vascular disorders. MATERIAL AND METHODS Three miR-34 family members (miR-34a, miR-34b, and miR-34c) were overexpressed or silenced in human vascular smooth muscle cells (VSMCs) and umbilical vein endothelial cells (UVECs), respectively, before the proliferation and apoptosis of cells were detected by using Cell Counting Kit-8 assay and Annexin V- fluorescein isothiocyanate/propidium iodide flow cytometry. The protein expression of apoptosis biomarkers was detected by western blot. Dual-luciferase reporter assay was performed to determine the candidate target of miR-34, and enzyme-linked immune sorbent assay was used to evaluate the effect of miR-34 on the expression of the target gene. RESULTS Overexpression of miR-34 family members repressed proliferation and promoted apoptosis of VSMCs and UVECs, whereas miR-34 knockdown led to the opposite results. In addition, miR-34a inhibited the expression of alpha-1 antitrypsin (AAT), a serine protease inhibitor that suppresses the degradation of extracellular matrix, through a miR-34-binding site within the 3'-UTR of AAT. CONCLUSIONS MiR-34 promoted apoptosis of VSMC and UVEC cells by inhibiting AAT expression. This finding provides an update on the understanding of the clinical value of miR-34, which might assist to uncover novel and effective therapeutic strategies for the treatment of vascular diseases.


Assuntos
MicroRNAs/genética , MicroRNAs/fisiologia , Doenças Vasculares/genética , Regiões 3' não Traduzidas/genética , Apoptose/genética , Movimento Celular/genética , Proliferação de Células/genética , China , Matriz Extracelular/genética , Regulação da Expressão Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/fisiologia , Neoplasias/genética
5.
Mediators Inflamm ; 2019: 7057303, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30733642

RESUMO

The role of cytokines in the pathogenesis of chronic venous disease (CVD) remains obscure. It has been postulated that oscillatory flow present in incompetent veins causes proinflammatory changes. Our earlier study confirmed this hypothesis. This study is aimed at assessing chemokines and growth factors (GFs) released by lymphocytes in patients with great saphenous vein (GSV) incompetence. In 34 patients exhibiting reflux in GSV, blood was derived from the cubital vein and from the incompetent saphenofemoral junction. In 12 healthy controls, blood was derived from the cubital vein. Lymphocyte culture with and without stimulation by phytohemagglutinin (PHA) was performed. Eotaxin, interleukin 8 (IL-8), macrophage inflammatory protein 1 A and 1B (MIP-1A and MIP-1B), interferon gamma-induced protein (IP-10), monocyte chemoattractant protein-1 (MCP-1), interleukin 5 (IL-5), fibroblast growth factor (FGF), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), platelet-derived growth factor-BB (PDGF-BB), and vascular endothelial growth factor (VEGF) were assessed in culture supernatants by a Bio-Plex assay. Higher concentrations of eotaxin and G-CSF were revealed in the incompetent GSV, compared with the concentrations in the patients' upper limbs. The concentrations of MIP-1A and MIP-1B were higher in the CVD group while the concentration of VEGF was lower. In the stimulated cultures, the concentration of G-CSF proved higher in the incompetent GSV, as compared with the patients' upper limbs. Between the groups, the concentration of eotaxin was higher in the CVD group, while the IL-5 and MCP-1 concentrations were lower. IL-8, IP-10, FGF, GM-CSF, and PDGF-BB did not reveal any significant differences in concentrations between the samples. These observations suggest that the concentrations of chemokines and GFs are different in the blood of CVD patients. The oscillatory flow present in incompetent veins may play a role in these changes. However, the role of cytokines in CVD requires further study.


Assuntos
Quimiocinas/sangue , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Linfócitos/citologia , Veia Safena/metabolismo , Adulto , Idoso , Doenças Cardiovasculares/metabolismo , Feminino , Humanos , Sistema Imunitário , Inflamação , Masculino , Pessoa de Meia-Idade , Neovascularização Fisiológica , Oscilometria , Doenças Vasculares/genética , Doenças Vasculares/patologia , Adulto Jovem
7.
J Am Coll Cardiol ; 73(1): 58-66, 2019 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-30621952

RESUMO

BACKGROUND: Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndromes (ACS) afflicting predominantly younger to middle-aged women. Observational studies have reported a high prevalence of extracoronary vascular anomalies, especially fibromuscular dysplasia (FMD) and a low prevalence of coincidental cases of atherosclerosis. PHACTR1/EDN1 is a genetic risk locus for several vascular diseases, including FMD and coronary artery disease, with the putative causal noncoding variant at the rs9349379 locus acting as a potential enhancer for the endothelin-1 (EDN1) gene. OBJECTIVES: This study sought to test the association between the rs9349379 genotype and SCAD. METHODS: Results from case control studies from France, United Kingdom, United States, and Australia were analyzed to test the association with SCAD risk, including age at first event, pregnancy-associated SCAD (P-SCAD), and recurrent SCAD. RESULTS: The previously reported risk allele for FMD (rs9349379-A) was associated with a higher risk of SCAD in all studies. In a meta-analysis of 1,055 SCAD patients and 7,190 controls, the odds ratio (OR) was 1.67 (95% confidence interval [CI]: 1.50 to 1.86) per copy of rs9349379-A. In a subset of 491 SCAD patients, the OR estimate was found to be higher for the association with SCAD in patients without FMD (OR: 1.89; 95% CI: 1.53 to 2.33) than in SCAD cases with FMD (OR: 1.60; 95% CI: 1.28 to 1.99). There was no effect of genotype on age at first event, P-SCAD, or recurrence. CONCLUSIONS: The first genetic risk factor for SCAD was identified in the largest study conducted to date for this condition. This genetic link may contribute to the clinical overlap between SCAD and FMD.


Assuntos
Anomalias dos Vasos Coronários/epidemiologia , Anomalias dos Vasos Coronários/genética , Endotelina-1/genética , Displasia Fibromuscular/complicações , Loci Gênicos/genética , Proteínas dos Microfilamentos/genética , Doenças Vasculares/congênito , Adulto , Idoso , Austrália , Estudos de Casos e Controles , Anomalias dos Vasos Coronários/complicações , Feminino , Displasia Fibromuscular/genética , França , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Reino Unido , Estados Unidos , Doenças Vasculares/complicações , Doenças Vasculares/epidemiologia , Doenças Vasculares/genética
8.
Clin Hemorheol Microcirc ; 72(2): 201-210, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30689560

RESUMO

OBJECTIVE: To investigate the role and potential mechanism of Toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) signaling pathway in cognitive impairment induced by cerebral small vascular disease (CSVD), so as to provide a reference for the clinical treatment of CSVD-induced cognitive impairment. METHODS: Mice with TLR4 gene knockout (n = 20) and those with wild-type TLR4 gene (n = 40) aged 8-10 weeks old were divided into blank control group (Control group, n = 20), wild-type + CSVD group (WT + CSVD group, n = 20) and TLR4 gene knockout + CSVD group (TLR4 KO + CSVD group, n = 20). Allogeneic thrombosis (particle diameter: 50-70 mm) was injected to the mouse's external carotid artery to create a model of learning and memory dysfunction. Step-down test and Y-type maze test were utilized to examine the learning and memory abilities of the mice. Reverse transcription-polymerase chain reaction (RT-PCR) and immunoblotting techniques were adopted to measure the levels of apoptosis-related genes [B-cell lymphoma/leukemia-2 (Bcl-2), Bcl-2-associated X protein (Bax), C-caspase-3 and T-caspase-3] in the brain tissues of mice. Terminal dexynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) method was applied to detect the apoptosis of neuronal cells in the brain tissues. Meanwhile, the levels of oxidative stress markers, including superoxide dismutase (SOD), gp91 and malondialdehyde (MDA), were measured. Finally, the expression level of TLR4/NF-κB pathway was detected. RESULTS: The latency in the step-down test in the WT + CSVD group was remarkably longer than that in the Control group, and the number of errors was evidently larger than that in the Control group (p < 0.05). At the same time, in the WT + CSVD group, the expression levels of pro-apoptotic genes Bax and C-caspase-3 were up-regulated markedly, while the expression level of anti-apoptotic gene Bcl-2 declined notably (p < 0.05). TUNEL results showed that the number of apoptotic cells in the brain tissues in the WT + CSVD group was about 12 times that in the Control group (p < 0.05). Meanwhile, the SOD expression level was lowered, and the MDA expression level was elevated in the brain tissues in the WT + CSVD group. In addition, the TLR4/NF-κB pathway was prominently activated in the mice in the WT + CSVD group (p < 0.05). After TLR4 gene knockout, the cognitive functions of the mice were improved markedly, and the apoptosis of neuronal cells and oxidative stress in the brain tissues were suppressed significantly in the meantime. Moreover, the activation of the TLR4/NF-κB signaling pathway was also inhibited. CONCLUSION: The TLR4/NF-κB pathway is involved in the occurrence and development of CSVD-induced cognitive impairment through regulating oxidative stress and cell apoptosis.


Assuntos
Disfunção Cognitiva/genética , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Doenças Vasculares/genética , Animais , Masculino , Camundongos , Doenças Vasculares/patologia
9.
Int J Biochem Cell Biol ; 107: 27-31, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30543933

RESUMO

Cardiovascular diseases are a major cause of death and disability. Despite enormous progress in diagnosis, prevention, and treatment over the years, the incidence of this group of pathologies continues to increase worldwide. An important step in reversing this situation is filling in the gaps we have in our understanding of cardiovascular homeostasis and of the pathogenic processes leading to disease. On this point, the discovery of epigenetics - heritable chemical modifications of DNA bases and histone proteins, as well as non-coding RNA-based mechanisms regulating gene expression - has opened up new vistas. Here, we will review recent findings regarding the epigenetics of three main vascular diseases (atherosclerosis, restenosis, and aortic aneurysm), with a focus on DNA methylation and histone modification. The emerging fundamental nature of epigenetics for cardiovascular physiopathology and, importantly, the amenability to manipulation with pharmacological techniques are an indication that epigenetics-based prognostic and therapeutics procedures might be developed in the future.


Assuntos
Epigênese Genética , Doenças Vasculares/genética , Metilação de DNA , Histonas/metabolismo , Humanos , Doenças Vasculares/metabolismo , Doenças Vasculares/patologia
10.
Probl Radiac Med Radiobiol ; 23: 462-470, 2018 Dec.
Artigo em Inglês, Ucraniano | MEDLINE | ID: mdl-30582863

RESUMO

OBJECTIVE: To determine the features of the nitrogen oxide metabolism and risk of developing endothelial dysfunc-tion in children with e-NOS 4a/4b gene polymorphism, who live under prolonged enter 137Cs to the body. MATERIALS AND METHODS: There were examined 117 children-residents of radioactively contaminated territories and50 children of control group. The level of stable metabolites was defined in blood serum (NO2- and NO3-). The ther-mographic method was used to register the endothelium dependent reaction of the vascular bed to changes in theblood supply. The ventilation capacity of the lungs was evaluated using this method of pneumotachography.Polymorphism in intron 4 of the gene e-NOS was studied by the method of polymerase chain reaction. The contentof 137Cs in the body of children was determined using a human radiation counter Skrynner M-3. RESULTS AND CONCLUSIONS: In children-residents of radioactively contaminated territories with genotype 4a/4b com-paring to children who had genotype 4b/4b, the decrease in the nitric content of in the blood serum, the increase inthe thermographic index of the recovery period of blood circulation to the baseline level after occlusion test werenoted, that is indicative of the decreased NO-synthase active of vascular endothelium in the carriers of the minorallele a in the 4th intron of gene eNOS (genotype 4a/4b), and is a risk factor for development of endothelial dysfunc-tion. It was proved a decrease in the index of lung tissue elasticity and stretchability - FVC / NFVC of the lungs com-paring to children with genotype 4b/4b, there was a reduction of integral index of respiratory tract permeability -FEV1/NFEV1. The inverse correlation dependence between the presence of allele a in the genotype and the values ofFVC/NFVC of the lungs (r = -0.259; p <0.05) and FEV1/NFEV1 (r = -0.2267; p <0.05) was found. Signs of bron-chospasm were found in the carriers of the allele a in 1.5 times more often than in children-carriers of homozy-gotes from allele b.


Assuntos
Espasmo Brônquico/genética , Radioisótopos de Césio/sangue , Acidente Nuclear de Chernobyl , Óxido Nítrico Sintase Tipo III/genética , Polimorfismo Genético , Exposição à Radiação/efeitos adversos , Doenças Vasculares/genética , Alelos , Vasos Sanguíneos/enzimologia , Vasos Sanguíneos/fisiopatologia , Espasmo Brônquico/sangue , Espasmo Brônquico/etiologia , Espasmo Brônquico/fisiopatologia , Estudos de Casos e Controles , Criança , Exposição Ambiental/análise , Feminino , Expressão Gênica , Frequência do Gene , Genótipo , Humanos , Íntrons , Pulmão/enzimologia , Pulmão/fisiopatologia , Masculino , Óxido Nítrico Sintase Tipo III/metabolismo , Doses de Radiação , Exposição à Radiação/análise , Radiação Ionizante , Fatores de Risco , Ucrânia , Doenças Vasculares/sangue , Doenças Vasculares/etiologia , Doenças Vasculares/fisiopatologia
11.
Biomolecules ; 8(4)2018 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-30563176

RESUMO

Despite its substantial clinical importance, specific genetic variants associated with depression have not yet been identified. We sought to identify genetic variants associated with depression by (a) focusing on a more homogenous subsample (vascular depression) and (b) applying a three-stage approach. First, we contacted 730 participants with a confirmed atherosclerotic disease (coronary artery disease) from a population-based study population (German Myocardial Infarction Family Study IV) for psychiatric assessment with the Mini International Neuropsychiatric Interview. Second, we genotyped these patients using genome-wide single nucleotide polymorphism (SNP) arrays. Third, we characterized the SNP via in-silico analysis. The final sample consisted of 342 patients (78.3% male, age = 63.2 ± 9.9 years), 22.8% with a severe depressive disorder. Variant rs528732638 on chromosome 18q11.2 was a genome-wide significant variant and was associated with 3.6-fold increase in the odds of lifetime depression. The locus belongs to a linkage disequilibrium block showing expression quantitative trait loci effects on three putative cis-regulated genes, including the aquaporin 4 (AQP4) locus. AQP4 is already known to mediate the formation of ischemic edema in the brain and heart, increasing the size and extent of resulting lesions. Our findings indicate that AQP4 may also play a role in the etiopathology of vascular depression.


Assuntos
Aquaporina 4/genética , Depressão/genética , Estudos de Associação Genética , Doenças Vasculares/genética , Depressão/fisiopatologia , Feminino , Predisposição Genética para Doença , Genótipo , Humanos , Desequilíbrio de Ligação , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Locos de Características Quantitativas/genética , Doenças Vasculares/fisiopatologia
12.
J Pharmacol Sci ; 137(3): 265-273, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30097377

RESUMO

Mangiferin (MAN), a naturally occurring polyphenol commonly found in mango and papaya. However, little is known its anti-vascular injury effects and the underlying mechanisms. This paper investigated the anti-vascular injury effect of MAN and the mechanisms in high-fat diet (HFD)-induced C57BL/6J mice and oxidized low-density lipoprotein (ox-LDL) induced human umbilical vein endothelial cells (HUVECs). The levels of plasma lipid, inflammatory factors and nitric oxide (NO) in mice were evaluated. The expression levels of PI3K, AKT, eNOS, PTEN and their phosphorylated proteins were measured by western blots. In addition, the PTEN-siRNA HUVECs were also used. The result showed that MAN markedly decreased the plasma lipid, inflammatory level in HFD-induced vascular injury mice respectively. Furthermore, MAN alleviate ox-LDL-stimulated dysfunction of HUVECs, restored the diminished NO release, decreased the ROS generation, significantly increased the expression of p-Akt, p-eNOS, and decreased the expression of PTEN, but have no effect on PI3K. However, the protective effects of MAN were significantly reduced by co-treatment with PI3K inhibitor or abolished by eNOS inhibitor. In addition, MAN has no protective effect on ox-LDL induced PTEN-siRNA HUVECs injury. Collectively, MAN appeared to alleviate ox-LDL-stimulated dysfunction of HUVECs via the PTEN/Akt/eNOS signaling pathway, thus decrease vascular injury in HFD-administrated mice.


Assuntos
Dieta Hiperlipídica/efeitos adversos , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/genética , Óxido Nítrico Sintase Tipo III/genética , Óxido Nítrico Sintase Tipo III/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , Fitoterapia , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Transdução de Sinais/efeitos dos fármacos , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/genética , Xantonas/farmacologia , Xantonas/uso terapêutico , Animais , Carica , Células Endoteliais da Veia Umbilical Humana , Humanos , Mediadores da Inflamação/sangue , Lipídeos/sangue , Lipoproteínas LDL/efeitos adversos , Masculino , Mangifera , Camundongos Endogâmicos C57BL , Terapia de Alvo Molecular , Óxido Nítrico/sangue , Doenças Vasculares/sangue , Doenças Vasculares/etiologia
13.
Physiol Res ; 67(Supplementum 1): S37-S54, 2018 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-29947527

RESUMO

During the last thirty years since the discovery of endothelin-1, the therapeutic strategy that has evolved in the clinic, mainly in the treatment of pulmonary arterial hypertension, is to block the action of the peptide either at the ET(A) subtype or both receptors using orally active small molecule antagonists. Recently, there has been a rapid expansion in research targeting ET receptors using chemical entities other than small molecules, particularly monoclonal antibody antagonists and selective peptide agonists and antagonists. While usually sacrificing oral bio-availability, these compounds have other therapeutic advantages with the potential to considerably expand drug targets in the endothelin pathway and extend treatment to other pathophysiological conditions. Where the small molecule approach has been retained, a novel strategy to combine two vasoconstrictor targets, the angiotensin AT(1) receptor as well as the ET(A) receptor in the dual antagonist sparsentan has been developed. A second emerging strategy is to combine drugs that have two different targets, the ET(A) antagonist ambrisentan with the phosphodiesterase inhibitor tadalafil, to improve the treatment of pulmonary arterial hypertension. The solving of the crystal structure of the ET(B) receptor has the potential to identify allosteric binding sites for novel ligands. A further key advance is the experimental validation of a single nucleotide polymorphism that has genome wide significance in five vascular diseases and that significantly increases the amount of big endothelin-1 precursor in the plasma. This observation provides a rationale for testing this single nucleotide polymorphism to stratify patients for allocation to treatment with endothelin agents and highlights the potential to use personalized precision medicine in the endothelin field.


Assuntos
Sistemas de Liberação de Medicamentos/tendências , Descoberta de Drogas/tendências , Endotelinas/metabolismo , Medicina de Precisão/tendências , Receptores de Endotelina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sequência de Aminoácidos , Animais , Sistemas de Liberação de Medicamentos/métodos , Descoberta de Drogas/métodos , Antagonistas dos Receptores de Endotelina/administração & dosagem , Antagonistas dos Receptores de Endotelina/metabolismo , Endotelinas/administração & dosagem , Endotelinas/agonistas , Endotelinas/antagonistas & inibidores , Humanos , Fragmentos de Peptídeos/administração & dosagem , Fragmentos de Peptídeos/metabolismo , Medicina de Precisão/métodos , Receptores de Endotelina/agonistas , Receptores de Endotelina/genética , Transdução de Sinais/fisiologia , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/genética , Doenças Vasculares/metabolismo
15.
Vascul Pharmacol ; 108: 1-7, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29778521

RESUMO

The master mammalian circadian clock (i.e. central clock), located in the suprachiasmatic nucleus of the hypothalamus, orchestrates the synchronization of the daily behavioural and physiological rhythms to better adapt the organism to the external environment in an anticipatory manner. This central clock is entrained by a variety of signals, the best established being light and food. However, circadian cycles are not simply the consequences of these two cues but are generated by endogenous circadian clocks. Indeed, clock machinery is found in mainly all tissues and cell types, including cells of the vascular system such as endothelial cells, fibroblasts, smooth muscle cells and stem cells. This machinery physiologically contributes to modulate the daily vascular function, and its disturbance therefore plays a major role in the pathophysiology of vascular dysfunction. Therapies targeting the circadian rhythm may therefore be of benefit against vascular disease.


Assuntos
Vasos Sanguíneos/metabolismo , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/metabolismo , Ritmo Circadiano , Hemodinâmica , Núcleo Supraquiasmático/metabolismo , Doenças Vasculares/metabolismo , Vasos Sanguíneos/efeitos dos fármacos , Vasos Sanguíneos/fisiopatologia , Fármacos Cardiovasculares/administração & dosagem , Peptídeos e Proteínas de Sinalização do Ritmo Circadiano/genética , Cronoterapia Farmacológica , Regulação da Expressão Gênica , Hemodinâmica/efeitos dos fármacos , Humanos , Transdução de Sinais , Núcleo Supraquiasmático/efeitos dos fármacos , Núcleo Supraquiasmático/fisiopatologia , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/genética , Doenças Vasculares/fisiopatologia
16.
Rev Invest Clin ; 70(2): 68-75, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29718010

RESUMO

Background: Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult-onset, autosomal dominant disease involving microvessels of the brain and eye resulting in central nervous system degeneration with visual disturbances, stroke, motor impairment, and cognitive decline. Frameshift mutations at the C-terminus of TREX1 gene are the molecular cause of this disorder. Objectives: The objective of this study is to present the different clinical manifestations of RVCL in three-related patients and to investigate the presence of TREX1 mutation in the extended genealogy. Methods: Multidisciplinary testing was performed in three related patients. Based on their family history, the study was extended to 34 relatives from the same small community. Neurological evaluation, sequencing of TREX1, and presymptomatic diagnosis were offered to all participants. Results: The patients exhibited the heterozygous TREX1 mutation p.V235Gfs*6, but with phenotypic variability. In addition, 15 relatives were identified as pre-manifest mutation carriers. The remaining participants did not carry the mutation. Conclusions: This is the figrst report of a large Mexican genealogy with RVCL, where the same TREX1 mutation causes a variation in organ involvement and clinical progression. The early identification and follow-up of individuals at risk may help provide insights into the basis for this variability in presentation.


Assuntos
Variação Biológica da População , Exodesoxirribonucleases/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/fisiopatologia , Fosfoproteínas/genética , Doenças Retinianas/fisiopatologia , Doenças Vasculares/fisiopatologia , Feminino , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/diagnóstico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Heterozigoto , Humanos , Masculino , México , Pessoa de Meia-Idade , Mutação , Doenças Retinianas/diagnóstico , Doenças Retinianas/genética , Doenças Vasculares/diagnóstico , Doenças Vasculares/genética
17.
Int J Mol Sci ; 19(4)2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29596344

RESUMO

Arsenite (As), a notorious toxic metal, is ubiquitously distributed in the earth and poses a serious threat to human health. Histopathological lesions of As intoxication are known as thromboangiitis obliterans, which are resistant to current treatment and often lead to lower limb amputation. In this study, we attempt to find that treatment with mesenchymal stem cells (MSCs) may be effective for As-induced vasculopathy. We first conducted an in vitro study with a co-culture system containing human MSCs and human umbilical vein endothelial cells (HUVECs) and treated individual and co-cultured cells with various concentrations of arsenite. We also designed an in vivo study in which Sprague Dawley (SD) rats received periodic intraperitoneal (IP) injections of 16 ppm arsenite for 12 weeks. MSCs were harvested from BALB/c mice that were transplanted via tail vein injection. We found that there was significantly higher cellular viability in human mesenchymal stem cells (hMSCs) than in HUVECs under concentrations of arsenite between 15 and 25 µM. The Annexin V apoptosis assay further confirmed this finding. Cytokine array assay for As-conditioned media revealed an elevated vascular endothelial growth factor (VEGF) level secreted by MSCs, which is crucial for HUVEC survival and was evaluated by an siRNA VEGF knockdown test. In the in vivo study, we demonstrated early apoptotic changes in the anterior tibial vessels of As-injected SD rats with a Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, but these apoptotic changes were less frequently observed upon MSCs transplantation, indicating that the cytoprotective effect of MSCs successfully protected against As-induced peripheral vasculopathy. The feasibility of MSCs to treat and /or prevent the progression of As-induced vasculopathy is justified. Further clinical studies are required to demonstrate the therapeutic efficacy of MSCs in patients suffering from As intoxication with vasculopathy.


Assuntos
Arsenitos/toxicidade , Células Endoteliais da Veia Umbilical Humana/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Doenças Vasculares , Animais , Sobrevivência Celular , Técnicas de Silenciamento de Genes , Xenoenxertos , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Ratos , Ratos Sprague-Dawley , Doenças Vasculares/induzido quimicamente , Doenças Vasculares/genética , Doenças Vasculares/metabolismo , Doenças Vasculares/terapia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
18.
Zhonghua Er Ke Za Zhi ; 56(3): 179-185, 2018 Mar 02.
Artigo em Chinês | MEDLINE | ID: mdl-29518827

RESUMO

Objective: To summarize the clinical characteristics and treatment efficacy of the first reported case of a Chinese boy with stimulator of interferon genes (STING) associated vasculopathy with onset in infancy (SAVI). Methods: Sanger sequencing of the gene TMEM173 was performed based on systemic evaluation and clinical analysis of a highly suspected SAVI child admitted to Peking Union Medical College Hospital. A literature search (search terms included 'STING''SAVI''autoinflammatory diseases' and 'interferonopathy') was conducted using Chinese literature database, EMBASE and PubMed to include recently published SAVI studies (searched from January 2010 to December 2017). Results: A 14-year-old boy who had a history of chronic dry cough along with decreased activity tolerance after birth presented with growth retardation, chilblain lesions on the ear, telangiectasia of multiple skin areas and long clubbed fingers. His C-reactive protein was 21 mg/L, erythrocyte sedimentation rate was 78 mm/1h, and IgG was 22.16 g/L. The high-resolution computed tomography (HRCT) revealed interstitial lung diseases and echocardiography showed pulmonary artery hypertension, with a level of 61 mmHg (1 mmHg=0.133 kPa). Genetic mutation of TMEM173 (c.463G>A, p.V155M) was confirmed by Sanger sequencing. His activity tolerance increased to some extent after treatment with tofacitinib at a dose of 5 mg twice a day. Our review yielded 8 publications (8 English and 0 Chinese) . To date 20 cases have been reported worldwide, who mostly presented with skin and lung involvement as well as growth retardation. Conclusions: SAVI has been included within the spectrum of interferonopathy, which is a kind of autoinflammatory diseases as well. Typical clinical features include chilblain skin lesions, interstitial lung disease, growth retardation, elevated IgG levels, and increased inflammation markers. Janus kinase (JAK) inhibitors may offer benefit for SAVI patients.


Assuntos
Interferons/genética , Doenças Pulmonares Intersticiais/genética , Proteínas de Membrana/genética , Mutação , Doenças Vasculares/genética , Adolescente , Antivirais , Proteína C-Reativa , China , Humanos , Inflamação , Masculino , Pele
19.
Mol Genet Genomic Med ; 6(3): 446-451, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29500860

RESUMO

BACKGROUND: Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi-allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far. METHODS: We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment. RESULTS: The present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease's mechanism due to the stabilization of the occluded conformation or a protein misfolding. CONCLUSION: Our data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome.


Assuntos
Hidranencefalia/genética , Proteínas de Membrana Transportadoras/genética , Receptores Virais/genética , Alelos , Sequência de Aminoácidos/genética , Feto/patologia , Heme/genética , Heme/metabolismo , Humanos , Hidranencefalia/fisiopatologia , Hidrocefalia/genética , Proteínas de Membrana Transportadoras/fisiologia , Mutação , Receptores Virais/fisiologia , Doenças Vasculares/genética
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