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1.
BMC Complement Altern Med ; 19(1): 316, 2019 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-31744482

RESUMO

BACKGROUND: Icariin (ICA) is the major active ingredient extracted from Chinese herbal medicine Epimedium, which has the effects of improving cardiovascular function, inducing tumor cell differentiation and increasing bone formation. It is still rarely reported that ICA can exert its therapeutic potential in asthma via anti-airway remodeling. The point of the study was to estimate the role of ICA in anti-. airway remodeling and its possible mechanism of action in a mouse ovalbumin. (OVA)-induced asthma model. METHODS: Hematoxylin and Eosin Staining were performed for measuring airway remodeling related indicators. ELISA, Western blot and Immunohistochemistr-. y (IHC) were used for analyzing the level of protein. RT-PCR was used for analyzing the level of mRNA. RESULTS: On days 1 and 8, mice were sensitized to OVA by intraperitoneal injection. From day 16 to day 43, previously sensitized mice were exposed to OVA once daily by nebulizer. Interventions were performed orally with ICA (ICA low, medium and high dose groups) or dexamethasone 1 h prior to each OVA exposure. ICA improves pulmonary function, attenuates pulmonary inflammation and airway remodeling in mice exposed to OVA. Histological and Western blot analysis of the lungs show that ICA suppressed transforming growth factor beta 1 and vascular endothelial growth factor expression. Increase in interleukin 13 and endothelin-1 in serum and bronchoalveolar lavage fluid in OVA-induced asthmatic mice are also decreased by ICA. ICA attenuates airway smooth muscle cell proliferation, as well as key factors in the MAPK/Erk pathway. CONCLUSIONS: The fact that ICA can alleviate OVA-induced asthma at least partly through inhibition of ASMC proliferation via MAPK/Erk pathway provides a solid theoretical basis for ICA as a replacement therapy for asthma. These data reveal the underlying reasons of the use of ICA-rich herbs in Traditional Chinese Medicine to achieve good results in treating asthma.


Assuntos
Remodelação das Vias Aéreas/efeitos dos fármacos , Asma/tratamento farmacológico , Medicamentos de Ervas Chinesas/administração & dosagem , Epimedium/química , Flavonoides/administração & dosagem , Animais , Asma/genética , Asma/metabolismo , Asma/fisiopatologia , Endotelina-1/genética , Endotelina-1/metabolismo , Feminino , Humanos , Interleucina-13/genética , Interleucina-13/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo
2.
Nat Commun ; 10(1): 3196, 2019 07 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324767

RESUMO

The limited clinical response observed in high-grade serous ovarian cancer (HG-SOC) with high frequency of TP53 mutations (mutp53) might be related to mutp53-driven oncogenic pathway network. Here we show that ß-arrestin1 (ß-arr1), interacts with YAP, triggering its cytoplasmic-nuclear shuttling. This interaction allows ß-arr1 to recruit mutp53 to the YAP-TEAD transcriptional complex upon activation of endothelin-1 receptors (ET-1R) in patient-derived HG-SOC cells and in cell lines bearing mutp53. In parallel, ß-arr1 mediates the ET-1R-induced Trio/RhoA-dependent YAP nuclear accumulation. In the nucleus, ET-1 through ß-arr1 orchestrates the tethering of YAP and mutp53 to YAP/mutp53 target gene promoters, including EDN1 that ensures persistent signals. Treatment of patient-derived xenografts reveals synergistic antitumoral and antimetastatic effects of the dual ET-1R antagonist macitentan in combination with cisplatinum, shutting-down the ß-arr1-mediated YAP/mutp53 transcriptional programme. Furthermore, ETAR/ß-arr1/YAP gene signature correlates with a worst prognosis in HG-SOC. These findings support effective combinatorial treatment for repurposing the ET-1R antagonists in HG-SOC.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cistadenocarcinoma Seroso/metabolismo , Neoplasias Ovarianas/metabolismo , Receptor de Endotelina A/metabolismo , Transdução de Sinais , Fatores de Transcrição/metabolismo , Proteína Supressora de Tumor p53/metabolismo , beta-Arrestina 1/metabolismo , Animais , Antineoplásicos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cistadenocarcinoma Seroso/tratamento farmacológico , Cistadenocarcinoma Seroso/genética , Modelos Animais de Doenças , Endotelina-1/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Humanos , Camundongos Nus , Mutação , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/farmacologia , Receptor de Endotelina A/efeitos dos fármacos , Sulfonamidas/farmacologia , Proteína Supressora de Tumor p53/genética , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Arrestina 1/efeitos dos fármacos , Proteínas rho de Ligação ao GTP/metabolismo , Proteína rhoA de Ligação ao GTP/metabolismo
3.
J Toxicol Sci ; 44(7): 505-513, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31270306

RESUMO

Dioxins are a group of structurally related chemicals that persist in the environment. Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener, is a suspected risk factor for cardiac diseases in humans. TCDD induces signs of cardiotoxicity in various animals. Mouse models of TCDD exposure suggest cardiotoxicity phenotypes develop differently depending on the timing and time-course of exposure. In order to clarify and characterize the TCDD-induced cardiotoxicity in the developing period, we utilized mouse pups exposed to TCDD. One day after delivery, groups of nursing C57BL/6J dams were orally administered TCDD at a dose of 0 (Control), 20 (TCDD-20), or 80 µg/kg (TCDD-80) body weight (BW). On postnatal days (PNDs) 7 and 21, pups' hearts were examined by histological and gene expression analyses. The TCDD-80 group was found to have a left ventricular remodeling on PND 7, and to develop heart hypertrophy on PND 21. It was accompanied by fibrosis and increased expression of associated genes, such as those for atrial natriuretic peptide (ANP), ß-myosin heavy chain (ß-MHC), and endothelin-1 (ET-1). These results revealed that TCDD directly induces cardiotoxicity in the postnatal period represented by progressive hypertrophy in which ANP, ß-MHC, and ET-1 have potentials to mediate the cardiac hypertrophy and heart failure.


Assuntos
Cardiomegalia/induzido quimicamente , Cardiomegalia/genética , Cardiotoxicidade , Poluentes Ambientais/metabolismo , Poluentes Ambientais/toxicidade , Insuficiência Cardíaca/induzido quimicamente , Insuficiência Cardíaca/genética , Lactação/metabolismo , Dibenzodioxinas Policloradas/metabolismo , Dibenzodioxinas Policloradas/toxicidade , Administração Oral , Animais , Animais Recém-Nascidos , Fator Natriurético Atrial/genética , Fator Natriurético Atrial/metabolismo , Endotelina-1/genética , Endotelina-1/metabolismo , Poluentes Ambientais/administração & dosagem , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos Endogâmicos C57BL , Modelos Animais , Cadeias Pesadas de Miosina/genética , Cadeias Pesadas de Miosina/metabolismo , Dibenzodioxinas Policloradas/administração & dosagem , Gravidez
4.
Life Sci ; 231: 116580, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31216440

RESUMO

AIMS: Chemerin has been recently identified as a vasoactive adipokine implicated in blood pressure regulation. In this context, we evaluated whether chemerin could influence pulmonary vasoreactive response. MATERIALS AND METHODS: Vascular reactivity to chemerin and to phenylephrine, serotonin and endothelin-1 after chemerin pretreatment was evaluated in rat isolated pulmonary artery versus thoracic aorta with and without endothelium. Vasoreactivity to acetylcholine in presence of nitric oxide (NO)-synthase inhibitor (L-NAME) and to NO donor sodium nitroprusside (SNP) was evaluated in chemerin-pretreated pulmonary artery versus thoracic aorta with endothelium. Pretreatment with ODQ, a soluble guanylate cyclase inhibitor and apocynin, a ROS production inhibitor, were also tested. Arteries and lung tissue were harvested for pathobiological evaluation. KEY FINDINGS: Chemerin contracted endothelium-denuded pulmonary artery, while no response was observed in arteries with endothelium. Chemerin potentiated phenylephrine-, endothelin-1- and serotonin-induced vasoconstriction, which was further enhanced by endothelium removal. Chemerin decreased acetylcholine-induced vasorelaxation in arteries with endothelium, while it did not affect SNP-induced relaxation. In presence of L-NAME, there remained a vasorelaxation in chemerin-pretreated arteries. Chemerin or ODQ alone partly decreased acetylcholine-induced vasorelaxation in pulmonary artery and thoracic aorta, while combined chemerin and ODQ incubation abolished it. Treatment with apocynin partly or totally reversed chemerin effects. In both types of arteries, chemerin reduced acetylcholine-induced NO production, as well as endothelial and inducible NO-synthase expression. SIGNIFICANCE: Chemerin potentiates vascular responses to vasoconstrictors in pulmonary artery and thoracic aorta and, impairs acetylcholine-induced pulmonary artery vasodilatation, by mechanisms involving at least partly NO signaling and oxidative stress.


Assuntos
Quimiocinas/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Artéria Pulmonar/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Acetilcolina/farmacologia , Adipocinas/metabolismo , Animais , Quimiocinas/metabolismo , Endotelina-1/metabolismo , Endotelinas/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Masculino , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Nitroprussiato/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fenilefrina/farmacologia , Artéria Pulmonar/metabolismo , Ratos , Ratos Wistar , Serotonina/metabolismo , Artérias Torácicas/efeitos dos fármacos , Artérias Torácicas/metabolismo , Vasoconstritores/farmacologia , Vasodilatação/efeitos dos fármacos
5.
Bull Exp Biol Med ; 167(2): 287-292, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31243673

RESUMO

Two models of retinal ischemia/reperfusion were developed in an experiment on rats and structural changes in eye tissues in the early and late postischemic periods were studied. Ischemia/reperfusion was modeled by elevation of intraocular pressure to 110 mm Hg for 30 min with air injection into the anterior chamber of the eye with a special device or subconjunctival administration of 0.2 ml 4×10-6 M endothelin-1. Morphological studies of the retina of enucleated eyes were performed in 3, 7, and 30 days after ischemia/reperfusion. In 3 days, signs of retinal ischemia were seen (retinal edema and ganglion cell damage). In the late post-ischemic period (30 days), atrophy of the outer nuclear and outer plexiform layer of the retina was observed in animals with retinal ischemia/reperfusion caused by intraocular pressure elevation and complete destruction of neuronal cells was found after administration of endothelin-1.


Assuntos
Retina/patologia , Doenças Retinianas/patologia , Animais , Apoptose , Modelos Animais de Doenças , Endotelina-1/metabolismo , Pressão Intraocular/fisiologia , Isquemia/metabolismo , Isquemia/patologia , Masculino , Ratos , Ratos Wistar , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Retina/metabolismo , Doenças Retinianas/metabolismo
6.
Biochim Biophys Acta Mol Cell Res ; 1866(10): 1663-1675, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31233801

RESUMO

Liver sinusoidal endothelial cells (LSECs) undergo capillarization, or loss of fenestrae, and produce basement membrane during liver fibrotic progression. DLL4, a ligand of the Notch signaling pathway, is predominantly expressed in endothelial cells and maintains liver sinusoidal homeostasis. The aim of this study was to explore the role of DLL4 in LSEC capillarization. The expression levels of DLL4 and the related genes, capillarization markers and basement membrane proteins were assessed by immunohistochemistry, immunofluorescence, RT-PCR and immunoblotting as appropriate. Fenestrae and basement membrane formation were examined by electron microscopy. We found DLL4 was up-regulated in the LSECs of human and CCl4-induced murine fibrotic liver, consistent with LSEC capillarization and liver fibrosis. Primary murine LSECs also underwent capillarization in vitro, with concomitant DLL4 overexpression. Bioinformatics analysis confirmed that DLL4 induced the production of basement membrane proteins in LSECs, which were also increased in the LSECs from 4 and 6-week CCl4-treated mice. DLL4 overexpression also increased the coverage of liver sinusoids by hepatic stellate cells (HSCs) through endothelin-1 (ET-1) synthesis. The hypoxic conditions that was instrumental in driving DLL4 overexpression in the LSECs. Consistent with the above findings, DLL4 silencing in vivo alleviated LSEC capillarization and CCl4-induced liver fibrosis. In conclusion, DLL4 mediates LSEC capillarization and the vicious circle between fibrosis and pathological sinusoidal remodeling.


Assuntos
Células Endoteliais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Cirrose Hepática/metabolismo , Fígado/metabolismo , Proteínas de Membrana/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Proteínas de Ligação ao Cálcio/metabolismo , Linhagem Celular , Técnicas de Cocultura , Células Endoteliais/patologia , Endotelina-1/metabolismo , Regulação da Expressão Gênica , Técnicas de Silenciamento de Genes , Hepatócitos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Fígado/patologia , Proteínas de Membrana/genética , Camundongos , RNA Mensageiro/metabolismo , Transdução de Sinais
7.
Oxid Med Cell Longev ; 2019: 6508328, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31214281

RESUMO

Endothelin-1 (ET-1) is synthesized primarily by endothelial cells. ET-1 administration in vivo enhances the cardiac sympathetic afferent reflex and sympathetic activity. Previous studies have shown that sympathetic hyperactivity promotes malignant ventricular arrhythmia (VA). The aim of this study was to investigate whether ET-1 could activate the left stellate ganglion (LSG) and promote malignant VA. Twelve male beagle dogs who received local microinjections of saline (control, n = 6) and ET-1 into the LSG (n = 6) were included. The ventricular effective refractory period (ERP), LSG function, and LSG activity were measured at different time points. VA was continuously recorded for 1 h after left anterior descending occlusion (LADO), and LSG tissues were then collected for molecular detection. Compared to that of the control group, local ET-1 microinjection significantly decreased the ERP and increased the occurrence of VA. In addition, local microinjection of ET-1 increased the function and activity of the LSG in the normal and ischemic hearts. The expression levels of proinflammatory cytokines and the protein expression of c-fos and nerve growth factor (NGF) in the LSG were also increased. More importantly, endothelin A receptor (ETA-R) expression was found in the LSG, and its signaling was significantly activated in the ET-1 group. LSG activation induced by local ET-1 microinjection aggravates LADO-induced VA. Activated ETA-R signaling and the upregulation of proinflammatory cytokines in the LSG may be responsible for these effects.


Assuntos
Arritmias Cardíacas/fisiopatologia , Células Endoteliais/metabolismo , Endotelina-1/metabolismo , Isquemia Miocárdica/fisiopatologia , Gânglio Estrelado/metabolismo , Animais , Células Cultivadas , Citocinas/metabolismo , Modelos Animais de Doenças , Cães , Eletrocardiografia , Células Endoteliais/patologia , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Fatores de Crescimento Neural/metabolismo , Receptor de Endotelina A/metabolismo , Transdução de Sinais , Sistema Nervoso Simpático
8.
Inhal Toxicol ; 31(3): 99-106, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31050300

RESUMO

Introduction: Tobacco use is a major risk factor of cardiovascular diseases (CVD) and atherosclerosis in particular. The use of waterpipe smoking (WPS) is increasing due to the misperception that it is less harmful than cigarette smoking due to its flavor and the use of water as a filter. Thus, research that investigates toxic effects of WPS is essential. The aim of this study was to investigate the effect of WPS on major cardiovascular biomarkers that may develop atherosclerosis in mice. Methods: BALB/c mice were exposed to WPS for either two weeks (acute exposure) or eight weeks (chronic exposure). Then, the heart tissue homogenates were analyzed to elucidate the effects of WPS on matrix metalloproteinase (MMPs: isoforms 1, 3, and 9), metallopeptidase inhibitor (TIMP1), endothelin-1 (ET-1) and myeloperoxidase (MPO) using ELISA technique. Results: Current data showed that acute exposure to WPS significantly enhanced the levels of MMP-3, MMP-9, and MPO (p < 0.05) compared to their corresponding control. However, the body was capable to restore the increased levels of these parameters following chronic exposure to WPS for 8 weeks (p > 0.05). Additionally, the levels of ET-1 were significantly higher upon chronic exposure to WPS compared to both control and acute exposure groups (p < 0.05). Conclusions: Waterpipe exposure has a significant negative effect on the cardiovascular system. The enhancement of the atherosclerotic biomarkers (MMP-3, MMP-9, MPO, and ET-1) might represent an early scavenger of compensatory efforts to maintain cardiovascular function after WPS exposure.


Assuntos
Miocárdio/metabolismo , Fumaça/efeitos adversos , Tabaco para Cachimbos de Água , Animais , Biomarcadores/metabolismo , Endotelina-1/metabolismo , Masculino , Metaloproteases/metabolismo , Camundongos Endogâmicos BALB C , Peroxidase/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo
9.
J Ovarian Res ; 12(1): 39, 2019 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-31064393

RESUMO

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive endocrine disorder characterized by obesity, hyperandrogenism, and insulin resistance (IR). MicroRNAs (miRNAs) are small noncoding RNA associated with ovarian follicle development and female fertility. The objective of this study was to investigate the role of miRNA- 320 and its target gene endothelin-1 (ET-1) as a noninvasive biomarker of PCOS and to evaluate its possible relationship with IR as well as clinic-morphological features of PCOS. METHODS: Case-control study enrolled 60 patients with PCOS and 40 control group. We subdivided our PCOS women according to homeostasis model assessments of insulin resistance (HOMA-IR) to PCOS women with and without IR.ET-1 levels were measured by ELISA. We estimated the serum expression level of miRNA- 320 by real-time polymerase chain reaction. RESULTS: Our results revealed that serum miR-320 expression level was lower in PCOS patients compared to controls, in particular, PCOS women with IR. Moreover, it was negatively correlated to its target gene; ET-I as well as fasting serum insulin (FSI), HOMA-IR, PCOS phenotype; hirsutism score, ovarian volume and antral follicle count (AFC). In the PCOS group, linear regression analysis revealed that only hirsutism and HOMA-IR was the main predictor of expression levels of miRNA - 320 among other clinical and laboratory biomarkers of PCOS. The sensitivity and specificity of serum miR-320 expression levels in diagnosis PCOS was 80, and 97.5% respectively. CONCLUSION: The Expression serum levels of miR-320 were lower in PCOS compared to control and it could be a noninvasive diagnostic biomarker of PCOS.


Assuntos
Endotelina-1/metabolismo , MicroRNAs/genética , Síndrome do Ovário Policístico/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos
10.
Wiad Lek ; 72(4): 523-526, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31055525

RESUMO

OBJECTIVE: Introduction: The study increase in the incidence of non-alcoholic steatohepatitis (NASH) on the background of obesity and chronic kidney disease (CKD) in people of working age in Ukraine and in the world necessitates the research into mechanisms of mutual burden and the search for new factors in the pathogenesis of this comorbidity progression . The aim: To establish the role of endothelial dysfunction in the mechanisms of mutual burden and progression of non-alcoholic steatohepatitis and chronic kidney disease in patients with obesity. PATIENTS AND METHODS: Materials and methods: 135 patients were examined: of which 52 patients with non-alcoholic steatohepatitis with obesity I degree (1 group), 53 patients with nonalcoholic steatohepatitis with comorbid obesity of the I degree and chronic kidney disease of the І-ІІ stage (group 2). The control group consisted of 30 practically healthy persons of the corresponding age and sex. The average age of patients was (45.8 ± 3.81) years. RESULTS: Results: The results of the study showed that in patients with NASH, a significant increase in the content of NO in the blood was detected in comparison with the index in PHP (p <0,05) in group 1 - in 2,1 times, in the 2nd group - in 2,6 times (p <0,05). The role of nitrosative stress in the pathogenesis of NASH was proved, the confirmation of which is the increase in the concentration of nitrosothiols, peroxynitrite and other metabolites NO in the blood. Increased peroxynitrite formation due to the generation of NO by leukocytes is an important aspect of the damaging effect and inflammation process in NASH. Pathological hyperproduction of NO by endothelial cells and leukocytes from inflammatory infiltrates in the liver contributes to the development of nitrosative stress in NASH. The established hypernitrate in blood may also be considered compensatory in response to hyperproduction of ET-1 in all observational groups. CONCLUSION: Conclusions: Confirmation of the presence of endothelial dysfunction (ED) in patients with NASH with CKD resulted in a probable growth of the number of desquamated endothelial cells (DEC) in the 2nd group of patients in 1.9 times (p2 <0.05). Generation by neutrophils during the exacerbation of NASH of a significant number of active forms of oxygen and nitrogen and hyperproduction of endothelial cells and endometrial lymphocytes with progressive damage to the endothelium (growth of DEC) leads to significant ED, accompanied by mosaic angiospasm of the arteries due to hyperproduction of ET-1 and parectic vasodilatation of the veins of the portal vein system because of the hyperproduction of NO.


Assuntos
Endotélio Vascular/fisiopatologia , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Obesidade/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Adulto , Estudos de Casos e Controles , Progressão da Doença , Endotelina-1/metabolismo , Humanos , Pessoa de Meia-Idade , Óxido Nítrico/sangue , Ucrânia
11.
Cell Mol Neurobiol ; 39(5): 671-686, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31025223

RESUMO

The present study explored the role of endothelin-1, H2S, and Nrf2 in remote preconditioning (RIPC)-induced beneficial effects in ischemia-reperfusion (I/R)-induced vascular dementia. Mice were subjected to 20 min of global ischemia by occluding both carotid arteries to develop vascular dementia, which was assessed using Morris water maze test on 7th day. RIPC was given by subjecting hind limb to four cycles of ischemia (5 min) and reperfusion (5 min) and it significantly restored I/R-induced locomotor impairment, neurological severity score, cerebral infarction, apoptosis markers along with deficits in learning and memory. Biochemically, there was increase in the plasma levels of endothelin-1 along with increase in the brain levels of H2S and its biosynthetic enzymes viz., cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CLS). There was also an increase in the expression of Nrf2 and glutathione reductase in the brain in response to RIPC. Pretreatment with bosentan (dual blocker of ETA and ETB receptors), amino-oxyacetic acid (CBS synthase inhibitor), and DL-propargylglycine (CLS inhibitor) significantly attenuated RIPC-mediated beneficial effects and biochemical alterations. The effects of bosentan on behavioral and biochemical parameters were more significant than individual treatments with CBS or CLS inhibitors. Moreover, CBS and CLS inhibitors did not alter the endothelin-1 levels possibly suggesting that endothelin-1 may act as upstream mediator of H2S. It is concluded that RIPC may stimulate the release endothelin-1, which may activate CBS and CLS to increase the levels of H2S and latter may increase the expression of Nrf2 to decrease oxidative stress and prevent vascular dementia.


Assuntos
Isquemia Encefálica/metabolismo , Demência Vascular/metabolismo , Endotelina-1/metabolismo , Sulfeto de Hidrogênio/metabolismo , Precondicionamento Isquêmico , Fator 2 Relacionado a NF-E2/metabolismo , Animais , Apoptose , Comportamento Animal , Encéfalo/enzimologia , Encéfalo/patologia , Isquemia Encefálica/complicações , Cistationina beta-Sintase/metabolismo , Cistationina gama-Liase/metabolismo , Demência Vascular/etiologia , Masculino , Aprendizagem em Labirinto , Camundongos , Traumatismo por Reperfusão/patologia
12.
J Physiol Pharmacol ; 70(1)2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-31019122

RESUMO

The influence of low-energy defibrillation on changes in the ET-1 levels in the myocardium and on disruptions in coronary blood flow and microcirculation being their consequence still remains unclear. Myocardial microcirculatory dysfunction is considered as a significant cause underlying myocardial dysfunction in post-cardiac arrest syndrome. This study is aimed at evaluating time-dependent changes in ET-1 levels in serum and the heart of a healthy rabbit following the application of a low-energy two-phase shock impulse. The research was conducted in 35 healthy rabbits at the age of 36 - 42 weeks and with body mass from 3200 to 4150 grams. The animals were divided in a randomized way into four groups depending on the dose of the electrical energy planned for the application during the experiment. The life parameters of the animals were monitored with the application of BeneView T5 patient monitor. The concentration of endothelin-1 in the groups was measured before, 15 and 360 minutes after the application of the low-energy double-phase straight-lined electrical impulse. A transthoracic low-energy defibrillation shock impulse causes a long-term increase in the endothelin-1 levels in the heart muscle and blood serum in a healthy rabbit. The increase in ET-1 levels results from the effect of electrical energy, independently of consequences of the ischemia/reperfusion injury. The increase in the endothelin-1 levels may lead to capillary blood flow abnormalities in the heart, contributing to the development of its dysfunction in the course of postresuscitation disease.


Assuntos
Estimulação Elétrica , Endotelina-1/metabolismo , Ventrículos do Coração/metabolismo , Miocárdio/metabolismo , Animais , Pressão Sanguínea , Proteínas de Ligação a Ácido Graxo/sangue , Feminino , Ventrículos do Coração/ultraestrutura , Masculino , Miocárdio/ultraestrutura , Coelhos , Tirosina/análogos & derivados , Tirosina/metabolismo , Função Ventricular
13.
Mol Med Rep ; 19(6): 4569-4578, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30942413

RESUMO

Previous studies suggest that granulocyte colony­stimulating factor (G­CSF) can promote bone marrow derived progenitor cells to mediate cardiovascular repair, potentially reversing mechanical dysfunction in chronic ischaemic heart disease and post myocardial infarction. Two models were used in the present study both using a surgical ameroid constrictor to induce arterial stenosis. The first model used the carotid artery of rabbits. They were divided into high fat diet (inducing atherosclerosis) or normal fat diet (control) groups. Each was subdivided into surgical exposure group without constrictor, ameroid constrictor receiving normal saline or receiving G­CSF 15 µg/kg/day. Endothelial markers of endothelial nitric oxide synthase and endothelin 1 were increased by the use of ameroid constrictor in both atherosclerotic and non­atherosclerotic mice, however were not further altered by G­CSF. Scanning electron microscopy indicated that ameroid constrictor application altered endothelial morphology from an oval shape to a round shape and this was more prominent in the atherosclerotic compared with the non­atherosclerotic group. G­CSF injection increased the number of endothelial cells in all groups. The second model used the left coronary artery of pigs. They were equally divided into following groups, receiving normal saline (control), G­CSF 2.5 µg/kg/day (low dose), 5 µg/kg/day (medium dose) and 10 µg/kg/day (high dose) for 5 days. G­CSF at a low or high dose worsened intimal hyperplasia however at a medium dose improved it. In conclusion, G­CSF had no effect in a rabbit carotid artery model of atherosclerosis. Its effects on the porcine heart were dose­dependent; arterial disease worsened at a low or high dose, but improved at a medium dose.


Assuntos
Fator Estimulador de Colônias de Granulócitos/farmacologia , Animais , Artérias Carótidas/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Endotelina-1/metabolismo , Coração/efeitos dos fármacos , Masculino , Infarto do Miocárdio/tratamento farmacológico , Isquemia Miocárdica/tratamento farmacológico , Óxido Nítrico Sintase Tipo III/metabolismo , Coelhos , Suínos , Fator de Necrose Tumoral alfa/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo
14.
Biochim Biophys Acta Gen Subj ; 1863(5): 917-924, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30851407

RESUMO

The angiotensin II AT1 and the endothelin 1 ETA receptors play a crucial role in the pathogenesis of cardiovascular diseases like hypertension, heart failure, stroke, pulmonary hypertension, and cardiac hypertrophy. Both receptors are members of the rhodopsion-like superfamily of G protein-coupled receptors which can exist as monomers, dimers, and higher order aggregates. Recently, oligomerization of these two receptors have been described by several biophysical methods based mainly on luminescence and fluorescence energy transfer. Since this oligomerization can occur either spontaneously or it can be induced by ligand-binding, the aim of this work was to address whether the oligomerization of these receptors occurs upon ligand-binding. For this purpose the Number and Brightness analysis, a method that allows the identification, localization, and quantification of protein aggregates in the plasma membrane of a single cell, was used. An advantage of this method is that it is not limited to certain dyes specially required for Fluorescence Resonance Energy Transfer measurements. Our results showed that stably transfected angiotensin II AT1 receptors and transiently transfected endothelin 1 ETA receptors, were found as monomeric, dimeric, and tetrameric receptor aggregates. Interestingly, the binding of antihypertensive agents like losartan and BQ123, earlier suggested to be inverse agonists, significantly increased the proportion of monomers and reduced the occurrence of dimers on the cell membrane; while the kown endothelin 1 ETA antagonist sitaxentan did not influence the aggregation state of these receptors.


Assuntos
Angiotensina II/metabolismo , Endotelina-1/agonistas , Receptor de Endotelina A/metabolismo , Animais , Sítios de Ligação/efeitos dos fármacos , Células CHO , Cricetulus , Endotelina-1/metabolismo , Transferência Ressonante de Energia de Fluorescência , Humanos , Isoxazóis/farmacologia , Ligantes , Losartan/farmacologia , Peptídeos Cíclicos/farmacologia , Agregados Proteicos/efeitos dos fármacos , Tiofenos/farmacologia
15.
Int J Med Sci ; 16(3): 443-449, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911278

RESUMO

Background: Hypoxia plays an important role in the vascular tone of pulmonary circulation via the vasculature and parenchymal tissue. Endothelin-1 (ET-1), a potent vasoconstrictive peptide, plays a role in inflammation in mononuclear cells. Nitric oxide synthase (NOS), which generates nitric oxide (NO)/cyclic 3', 5'-monophosphate (cGMP), is coexpressed with ET-1 in many cell types. The aim of this study was to assess whether hypoxia induces the production of ET-1 and associated expression of NOS, NO/cGMP and chemokines in rat alveolar macrophages (AMs). Methods: NR8383 cells were cultured under hypoxic (1% oxygen) conditions for 0, 2, 4, 8 and 12 hours. Levels of ET-1, inducible NOS (iNOS), phosphorylated iNOS (p-iNOS), nitrite/nitrate (NOx), cGMP and monocyte chemoattractant protein-1 (MCP-1) were measured. Results: ET-1, p-iNOS, NOx, and cGMP increased significantly in AMs after 4 hours of hypoxia (p < 0.05). ET-1 and MCP-1 mRNA increased after 8 hours (p < 0.05). The protein expression of ET-1, MCP-1, and p-iNOS increased in a time-dependent manner, while iNOS expression decreased with time. Conclusions: The changes in ET-1, p-iNOS, and the NO/cGMP pathway in AMs may help elucidate the mechanisms in the hypoxic lung. Understanding changes in the endothelin axis in hypoxic AMs is a crucial first step to unravel its role in pulmonary circulation.


Assuntos
GMP Cíclico/metabolismo , Endotelina-1/metabolismo , Macrófagos Alveolares/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Animais , Hipóxia Celular , Células Cultivadas , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Endotelina-1/genética , Regulação da Expressão Gênica , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Ratos Sprague-Dawley
16.
Biomed Res Int ; 2019: 2075968, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911541

RESUMO

Purpose: Blood vessels and skeleton interact together. Endothelin-1 is a potent vasoconstrictor and also has an effect on bone metabolism. The dual antagonist to both endothelin-1 type A and B receptors, Macitentan, has been approved for clinical management of pulmonary arterial hypertension while little is known about the secondary effect of the drug on spine. We aimed to answer how vertebral bone mass responded to Macitentan treatment in mice. Methods: Sixteen male balb/c mice at 6 months were randomly assigned into 2 groups. Vehicle and Macitentan were administrated via intraperitoneal injection to Control group and Treatment group, respectively, for 4 months. At sacrifice, plasma endothelin-1 was evaluated with ELISA and vertebral bone mass was evaluated with Microcomputed Tomography and histological analysis. Results: We found higher plasma endothelin-1 level (p<0.01) and less vertebral bone mass (p<0.05) in Treatment group compared to controls. Moreover, less osteoblasts and more osteoclasts were observed in the vertebral trabecular bone in the Treatment group compared to controls, by immunohistochemistry of the cell-specific markers. Conclusions: Treatment with Macitentan is associated with significant lower vertebral bone mass and therefore the secondary effect of dual antagonists to endothelin-1 receptors on the skeleton should be monitored and investigated in clinical practice. Both osteoblasts and osteoclasts may be involved while the molecular mechanism needs to be further explored.


Assuntos
Densidade Óssea/efeitos dos fármacos , Osso Esponjoso , Osteoblastos , Pirimidinas/efeitos adversos , Coluna Vertebral , Sulfonamidas/efeitos adversos , Animais , Osso Esponjoso/diagnóstico por imagem , Osso Esponjoso/metabolismo , Endotelina-1/metabolismo , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Hipertensão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Osteoblastos/metabolismo , Osteoblastos/patologia , Projetos Piloto , Pirimidinas/farmacologia , Coluna Vertebral/diagnóstico por imagem , Coluna Vertebral/metabolismo , Sulfonamidas/farmacologia
17.
Spine (Phila Pa 1976) ; 44(17): E1000-E1009, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30921293

RESUMO

STUDY DESIGN: Experimental study. OBJECTIVE: To examine the role of endothelin-1 (ET-1) and the Notch signaling pathway in giant cell tumor (GCT) of the spine. SUMMARY OF BACKGROUND DATA: Previously published studies have shown that the Notch signaling pathway has a role in tumor invasion and that ET-1 is involved in tumor invasion and angiogenesis. However, the roles of both Notch signaling and ET-1 in GCT of the spine remain unknown. METHODS: Expression of ET-1 in tissue samples from patients with spinal GCT, and adjacent normal tissue, were analyzed by immunohistochemistry and western blot. GCT stromal cells (GCTSCs) were isolated and ET-1 expression was demonstrated by immunofluorescence. Cell viability and cell migration of GCTSCs and human vascular endothelial cells following ET-1 treatment were assessed using the cell counting kit-8 assay and a transwell assay. Receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoprotegerin (OPG) mRNA expression was determined following ET-1 treatment of GCTSCs using quantitative real-time polymerase chain reaction. In GCTSCs treated with ET-1 and the ET-1 signaling antagonist, BQ-123, levels of cyclin D1, vascular endothelial growth factor, matrix metalloproteinase-2 and -9 (MMP-2 and MMP-9), Jagged1, Hes1, Hey2, and Notch intracellular domain were examined by western blot. RESULTS: Compared with normal adjacent tissue, ET-1 was highly expressed in GCT tissue. In GCTSCs studied in vitro, treatment with ET-1 significantly increased GCTSC and human vascular endothelial cells growth and migration and increased the expression of RANKL and OPG, meanwhile the ratio of RANKL/OPG was increased, in GCTSCs, it upregulated the production of cyclin D1, vascular endothelial growth factor, MMP-2, MMP-9, Jagged1, Hes1, Hey2, and Notch intracellular domain expression in a dose-dependent manner. Treatment with BQ-123 reversed these effects. CONCLUSION: In GCT of the spine, ET-1 showed increased expression. In cultured GCTSCs, ET-1 treatment activated the Notch signaling pathway. LEVEL OF EVIDENCE: 2.


Assuntos
Carcinogênese/metabolismo , Endotelina-1/metabolismo , Tumores de Células Gigantes/metabolismo , Receptores Notch/metabolismo , Neoplasias da Coluna Vertebral/metabolismo , Humanos , Transdução de Sinais/fisiologia
18.
Biol Cell ; 111(7): 169-186, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30866090

RESUMO

This review highlights new developments in miRNA as diagnostic and surveillance tools in diseases damaging the renal proximal tubule mediated by endothelin in the field of renal carcinoma, proteinuric kidney disease and tubulotoxicity. A new mechanism in the miRNA regulation of proteins leads to the binding of the miRNA directly to the DNA with premature transcriptional termination and hence the formation of truncated protein isoforms (Mxi2, Vim3). These isoforms are mediated through miRNA15a or miRNA 498, respectively. ET-1 can activate a cytoplasmic complex consisting of NF-κB p65, MAPK p38α, and PKCα. Consequently, PKCα does not transmigrate into the nucleus, which leads to the loss of suppression of a primiRNA15a, maturation of this miRNA in the cytoplasm, tubular secretion and detectability in the urine. This mechanism has been shown in renal cell carcinoma and in proteinuric disease as a biomarker for the activation of the signalling pathway. Similarly, ET-1 induced miRNA 498 transmigrates into the nucleus to form the truncated protein Vim3, which is a biomarker for the benign renal cell tumour, oncocytoma. In tubulotoxicity, ET-1 induced miRNa133a down-regulating multiple-drug-resistant related protein-2, relevant for proteinuric and cisplatin/cyclosporine A toxicity. Current advantages and limitations of miRNAs as urinary biomarkers are discussed.


Assuntos
Carcinoma de Células Renais/diagnóstico , Endotelina-1/metabolismo , Neoplasias Renais/diagnóstico , Túbulos Renais Proximais/patologia , MicroRNAs/urina , Proteinúria/diagnóstico , Animais , Biomarcadores/urina , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/urina , Perfilação da Expressão Gênica , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/urina , Camundongos , Proteinúria/tratamento farmacológico , Proteinúria/urina , Ratos , Transdução de Sinais
19.
Lupus ; 28(3): 347-358, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30755145

RESUMO

Our study aims to evaluate the endothelial cell-podocyte crosstalk in proliferative lupus nephritis (LN). The semi-quantification scores of glomerular endothelial cell injury and the foot process width (FPW) were processed in 110 proliferative LN patients. Podocytes were stimulated with LN-derived IgG. Glomerular endothelial cells were treated with podocyte-conditioned medium (PCM), and then podocytes were incubated with endothelial cell-conditioned medium (ECM). The levels of vascular endothelial growth factor-A (VEGF-A) in PCM and endothelin-1 in ECM were analyzed, and the injury of podocyte and glomerular endothelial cells were further evaluated. The pathological score of glomerular endothelial cell injury was correlated with FPW in LN complicated with thrombotic microangiopathy. In vitro study showed the following: 1. Stimulation of podocytes by IgG from LN led to decline in the expression of nephrin with cytoskeleton rearrangement, and reduction of VEGF-A levels. 2. Exposure of glomerular endothelial cells to PCM incubated with LN-derived IgG (PCM-LN) induced more endothelin-1 secretion and disruption of intercellular tight junction. 3. Exposure of podocytes to ECM stimulated with PCM-LN could induce cytoskeleton redistribution with decrease of nephrin. In conclusion, the pathological glomerular endothelial cell lesions were associated with FPW and the VEGF-endothelin-1 system might play a critical role in the endothelial cell-podocyte crosstalk in LN.


Assuntos
Células Endoteliais/metabolismo , Glomérulos Renais/metabolismo , Nefrite Lúpica/metabolismo , Nefrite Lúpica/patologia , Podócitos/metabolismo , Receptor Cross-Talk/fisiologia , Adulto , Biópsia , Estudos de Casos e Controles , Células Cultivadas , Células Endoteliais/patologia , Endotelina-1/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Rim/metabolismo , Rim/patologia , Glomérulos Renais/lesões , Glomérulos Renais/patologia , Nefrite Lúpica/sangue , Masculino , Podócitos/patologia , Fator A de Crescimento do Endotélio Vascular/metabolismo , Adulto Jovem
20.
Biochem Biophys Res Commun ; 511(1): 69-72, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30771901

RESUMO

The overexpression of endothelin (ET)-1 or ET receptors (ETRs) is related to initiation and progression of tumor. In cancer cells, ET-1 activates various signaling pathways, including mitogen-activated protein kinase, phosphatidylinositol 3-kinase, protein kinase C through ETRs, although the mechanisms by which ET-1 activates these signaling pathways remain uncertain. Here, we found that ETRs interacted with annexin A2, which is overexpressed in various cancers. Annexin A2 bound to ET type A receptor and ET type B receptor. Upon ET-1 stimulation, serine phosphorylation of annexin A2 increased, while there is no change in tyrosine phosphorylation of annexin A2. On the other hand, annexin A2 silencing suppressed activation of ERK upon ET-1 stimulation. These results suggest that interaction of ETRs and annexin A2 may play important roles in activation of extracellular signal-regulated kinase upon ET-1 stimulation.


Assuntos
Anexina A2/metabolismo , Endotelina-1/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Sistema de Sinalização das MAP Quinases , Linhagem Celular Tumoral , Ativação Enzimática , Células HeLa , Humanos , Neoplasias/metabolismo , Fosforilação
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