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1.
Zhongguo Zhong Yao Za Zhi ; 44(9): 1876-1881, 2019 May.
Artigo em Chinês | MEDLINE | ID: mdl-31342716

RESUMO

This study is aimed to investigate the intervention effect and possible mechanism of ophiopogonin D( OPD) in protecting cardiomyocytes against ophiopogonin D'( OPD')-induced injury,and provide reference for further research on toxicity difference of saponins from ophiopogonins. CCK-8 assay was used to evaluate the effect of OPD and OPD' on cell viability. The effect of OPD on OPD'-induced cell apoptosis was measured by flow cytometry. Morphologies of endoplasmic reticulum were observed by endoplasmic reticulum fluorescent probe. PERK,ATF-4,Bip and CHOP mRNA levels were detected by Real-time quantitative polymerase chain reaction( PCR) analysis. ATF-4,phosphorylated PERK and e IF2α protein levels were detected by Western blot assay. RESULTS:: showed that treatment with OPD'( 6 µmol·L-1) significantly increased the rate of apoptosis; expressions of endoplasmic reticulum stress related genes were increased. The morphology of the endoplasmic reticulum was changed. In addition,different concentrations of OPD could partially reverse the myocardial cell injury caused by OPD'. The experimental results showed that OPD'-induced myocardial toxicity may be associated with the endoplasmic reticulum stress,and OPD may modulate the expression of CYP2 J3 to relieve the endoplasmic reticulum stress caused by OPD'.


Assuntos
Estresse do Retículo Endoplasmático/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Saponinas/farmacologia , Espirostanos/farmacologia , Apoptose , Cardiotônicos/farmacologia , Células Cultivadas , Humanos
2.
Phytochemistry ; 166: 112065, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31362147

RESUMO

Ten undescribed neo-clerodane diterpenoids, named hispanins A-J, together with six known ones, were isolated from the aerial parts of Salvia hispanica L. Their structures were established by extensive spectroscopic analysis. The absolute configurations of the undescribed compounds were determined by the ECD data and single crystal X-ray diffraction analysis. Hispanins B and C represented the first neo-clerodane diterpenoids with a unique oxygen bridge between C-19 and C-20. All isolated compounds were evaluated for their protective effects against H2O2-induced cardiomyocyte injury. Five of these compounds showed significant cardioprotective effects.


Assuntos
Cardiotônicos/química , Cardiotônicos/farmacologia , Diterpenos Clerodânicos/química , Diterpenos Clerodânicos/farmacologia , Componentes Aéreos da Planta/química , Salvia/química , Animais , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Ratos
3.
Int J Nanomedicine ; 14: 3691-3703, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31190819

RESUMO

Background and aim: The extract of ginger, obtained from the rhizome of Zingiber officinale, contains 6-gingerol, 6-shogaol, 8-gingerol, and 10-gingerol. It has many therapeutic effects such as being chemopreventive against stroke and heart diseases, malabsorption, bacterial infections, indigestion, and nausea, which have been observed since ancient times. The main aim of this study is to evaluate the polyurethane (PU) as a proper material for the hollow nanoparticles' preparation. Methods: The PU nanoparticles were obtained by a spontaneous emulsification, in the presence of a nonionic surfactant, combined with an interfacial polyaddition process between an aliphatic diisocyanate and different mixtures of etheric and esteric polyols. The synthesis was done without any PU additives, such as catalysts, blowing agents, chains promoters, cross-linking agents, and stabilizers. Results: The particles present almost neutral pH values and low water solubility. They are heat resistant up to 280°C. Decreased irritation level was found in the assay of PU nanoparticles loaded with pure ginger extract (GE) on the murine skin tests than the irritation level recorded for pure GE. Conclusion: This research shows the reduced noxiousness of these PU nanoparticles and consequently the possibility of their use as a possible cardiovascular protector.


Assuntos
Cardiotônicos/farmacologia , Gengibre/química , Nanopartículas/química , Extratos Vegetais/farmacologia , Poliuretanos/química , Animais , Varredura Diferencial de Calorimetria , Eritema/patologia , Feminino , Concentração de Íons de Hidrogênio , Melaninas/metabolismo , Camundongos , Extratos Vegetais/química , Poliuretanos/síntese química , Solubilidade , Espectrofotometria Ultravioleta , Temperatura Ambiente
4.
Acta Cir Bras ; 34(5): e201900505, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31166461

RESUMO

PURPOSE: To evaluate the cardioprotective response of the pharmacological modulation of ß-adrenergic receptors (ß-AR) in animal model of cardiac ischemia and reperfusion (CIR), in spontaneously hypertensive (SHR) and normotensive (NWR) rats. METHODS: CIR was induced by the occlusion of left anterior descendent coronary artery (10 min) and reperfusion (75 min). The SHR was treated with ß-AR antagonist atenolol (AT, 10 mg/kg, IV) 5 min before CIR, and NWR were treated with ß-AR agonist isoproterenol (ISO, 0.5 mg/kg, IV) 5 min before CIR. RESULTS: The treatment with AT increased the incidence of VA, AVB and LET in SHR, suggesting that spontaneous cardioprotection in hypertensive animals was abolished by blockade of ß-AR. In contrast, the treatment with ISO significantly reduced the incidence of ventricular arrhythmia, atrioventricular blockade and lethality in NWR (30%, 20% and 20%, respectively), suggesting that the activation of ß-AR stimulate cardioprotection in normotensive animals. Serum CK-MB were higher in SHR/CIR and NWR/CIR compared to respective SHAM group (not altered by treatment with AT or ISO). CONCLUSION: The pharmacological modulation of ß-AR could be a new cardioprotective strategy for the therapy of myocardial dysfunctions induced by CIR related to cardiac surgery and cardiovascular diseases.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 1/farmacologia , Agonistas Adrenérgicos beta/farmacologia , Atenolol/farmacologia , Cardiotônicos/farmacologia , Isoproterenol/farmacologia , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Receptores Adrenérgicos beta/efeitos dos fármacos , Animais , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Creatina Quinase Forma MB/sangue , Testes de Função Cardíaca , Masculino , Traumatismo por Reperfusão Miocárdica/sangue , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Ratos Endogâmicos SHR , Reprodutibilidade dos Testes , Fatores de Tempo , Resultado do Tratamento
5.
J Toxicol Sci ; 44(6): 425-433, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31168029

RESUMO

Cardiac fibroblasts (CFs) could be activated after myocardial infarction (MI). Thus, it is necessary to explore effective drugs to suppress the activation of CFs following MI. This study was designed to investigate the impacts of ellagic acid on CFs and the underlying mechanisms. The expression of histone deacetylases (HDACs) and fibrosis-related genes was detected by qRT-PCR and western blot. The Masson's Trichrome Staining assay was used to evaluate the area of cardiac fibrosis. The proliferation and migration of CFs were measured by CCK8 Kit and Transwell assay, respectively. Our results showed that ellagic acid significantly reduced protein expression of HDAC1, mRNA expression of collagen I, collagen III, MMP-2 and MMP-9 and the area of cardiac fibrosis in MI rats. In Ang II-stimulated CFs, ellagic acid (60 µmol/L) decreased the protein expression of HDAC1, collagen I, collagen III, MMP-2 and MMP-9, and inhibited cell proliferation and migration. Further, HDAC1 over-expression reversed the inhibitor effects of ellagic acid on proteins expression (collagen I, collagen III, MMP-2 and MMP-9) and proliferation and migration of CFs. The present results suggested that ellagic acid suppressed proliferation and migration of CFs by down-regulating expression of HDAC1.


Assuntos
Cardiotônicos/farmacologia , Ácido Elágico/farmacologia , Fibroblastos/efeitos dos fármacos , Angiotensina II , Animais , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno Tipo I/genética , Colágeno Tipo III/genética , Regulação para Baixo , Fibroblastos/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Histona Desacetilase 1/genética , Masculino , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Miocárdio/citologia , Ratos Sprague-Dawley
6.
Oxid Med Cell Longev ; 2019: 1724194, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049126

RESUMO

Cardiovascular diseases (CVD) constitute one of the most prevalent health problems worldwide, being strongly associated with metabolic syndrome (MS). Oxidative stress (OS) is present in both CVD and MS. Infusions of Hibiscus sabdariffa Linnaeus (HSL) have antioxidant properties and could therefore decrease the presence of OS in these diseases. The aim of this study was to evaluate myocardial protection during ischemia/reperfusion due to the antioxidant effect of HSL infusion (3%) on a MS rat model induced by the administration of 30% sucrose in drinking water. We determined in control, MS, and MS + HSL rat hearts (n = 6 per group) cardiac mechanical performance (CMP), coronary vascular resistance (CVR), and activities of manganese and copper/zinc superoxide dismutases (Mn and Cu/Zn-SOD), peroxidases, glutathione peroxidase (GPx), catalase (CAT), glutathione s-transferase (GST), glutathione reductase (GR), and glutathione (GSH). We also determined lipoperoxidation (LPO), total antioxidant capacity (TAC), and the nitrate/nitrite ratio (NO3 -/NO2 -). The treatment with the HSL infusion restored the CMP (p = 0.01) and CVR (p = 0.04) and increased the Mn- (p = 0.02), Cu/Zn-SOD (p = 0.05), peroxidases (p = 0.04), GST (p = 0.02) activity, GHS (p = 0.02), TAC (p = 0.04), and NO3 -/NO2 - (p = 0.01) and decreased the LPO (p = 0.02) in the heart of MS rats undergoing ischemia/reperfusion. The results suggest that the treatment with an infusion from HSL calices protects the cardiac function from damage by ischemia and reperfusion through the antioxidant activities of the substances it possesses. It favors antioxidant enzymatic activities and nonenzymatic antioxidant capacity.


Assuntos
Antioxidantes/farmacologia , Cardiotônicos/farmacologia , Hibiscus/química , Síndrome Metabólica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Antioxidantes/química , Cardiotônicos/química , Masculino , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Proteínas Musculares/metabolismo , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Miocárdio/patologia , Ratos
7.
Chem Commun (Camb) ; 55(44): 6193-6196, 2019 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-31070620

RESUMO

Hydrogen sulfide (H2S) is an important signaling molecule with promising protective effects in many physiological and pathological processes. However, the study of H2S has been impeded by the lack of appropriate H2S donors that could mimic its slow-releasing process in vivo. Herein, we report the rational design, synthesis, and biological evaluation of a series of thioester-based H2S donors. These cysteine-activated H2S donors release H2S in a slow and controllable manner. Most of the donors comprising an allyl moiety showed significant cytoprotective effects in H9c2 cellular models of oxidative damage. The most potent donor 5e decreased the mitochondrial membrane potential (MMP) loss and lactate dehydrogenase (LDH) release in H2O2-stimulated H9c2 cells. More importantly, donor 5e exhibited a potent cardioprotective effect in an in vivo myocardial infarction (MI) mouse model by reducing myocardial infarct size and cardiomyocyte apoptosis. Taken together, our studies demonstrated that these new allyl thioesters are potential cardioprotective agents by releasing H2S.


Assuntos
Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Ésteres/química , Sulfeto de Hidrogênio/química , Compostos de Sulfidrila/química , Animais , Linhagem Celular , Modelos Animais de Doenças , Peróxido de Hidrogênio/farmacologia , L-Lactato Desidrogenase/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/metabolismo , Estresse Oxidativo
8.
Chem Biol Interact ; 308: 20-44, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31067438

RESUMO

Ischemic heart disease (IHD) is a major cause of cardiovascular morbidity and mortality worldwide, which is characterized by an imbalance between cardiac oxygen supply and demand predominantly due to obstruction of coronary arteries. Activation of the innate immune system and the consequent inflammatory response plays a role in the pathogenesis of IHD. Where an excessive inflammatory response may contribute to adverse cardiac remodeling and fibrosis, making inflammation an important therapeutic target for improving outcomes of IHD. While there are many discrepancies in the literature, evidence from both bench and clinical research demonstrate important effects of n-3 polyunsaturated fatty acids (n-3 PUFA), eicosapentaenoic acid (EPA) and/or docosahexaenoic acid (DHA), toward IHD. N-3 PUFAs, and their metabolites, have been demonstrated to modulate various components of the immune system, including regulation of chemokines and cytokines, leukocyte chemotaxis and inflammasome formation. In this article, we provide an overview of the role the innate immune system has in IHD and focus on the immunomodulatory effects of n-3 PUFAs and their biologically active metabolites.


Assuntos
Cardiotônicos/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Imunidade Inata , Isquemia Miocárdica/tratamento farmacológico , Alarminas/metabolismo , Cardiotônicos/farmacologia , Membrana Celular/química , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Ciclo-Oxigenase 1/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Humanos , Imunidade Inata/efeitos dos fármacos , Leucócitos/citologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Isquemia Miocárdica/imunologia , Isquemia Miocárdica/patologia , Proteína-Lisina 6-Oxidase/metabolismo
9.
Phytomedicine ; 55: 320-329, 2019 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-30940361

RESUMO

BACKGROUND: It has been reported that n-butanol extract of Potentilla anserina L (NP) had protective effect against acute myocardial ischemia/reperfusion (I/R) injury in mice. Because of limited phytochemical study on NP, its bioactive compounds and underlying protective mechanisms are largely unclear. PURPOSE: The purpose of this study was to investigate the major bioactive compounds and possible mechanism for the cardioprotective effect of NP on rat with I/R injury. METHODS: We analyzed the phytochemical isolation of NP and identified the structure of compounds, which was elucidated by a combination of spectroscopic analyses. An I/R model was established by I-30 min/R-2 h in Sprage-Dawley rats. The rats were given intragastric administration of NP (49.3, 98.6, and 197.2 mg•kg-1) continuously for 10 days before I/R operation. The morphological changes and apoptosis of cardiomyocytes were observed by H&E staining, Transmission electron microscope and TUNEL staining respectively. The activities or contents of catalase (CAT), superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) in plasma were detected. Apoptosis related factors were also measured by RT-PCR and western blot. In order to discover the underlying mechanism of NP on I/R, we performed proteomic analysis using two-dimensional gel electrophoresis (2D-DIGE) and matrix assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/MS) to describe differential proteins expression. Potential target protein resulted from 2D-DIGE coupled to MALDI-TOF/MS analysis were further confirmed by immunohistochemical staining, RT-PCR, and western blot. RESULTS: We isolated and identified 14 compounds, of which 7 compounds belong to triterpenes. Rats pretreated with NP showed a significant increase on the activities of GSH, SOD and CAT, and remarkable decrease on the content of MDA. NP significantly inhibited the apoptosis of cardiomyocyte and decreased the expression of Cyt C and cleaved-caspase-3. Proteomic analysis revealed that alpha B-crystallin (CryAB) might participate in the NP protective effect against I/R. NP enhanced the level of pCryAB Ser59, whereas the expression of CryAB was decreased. CONCLUSION: NP was showed to alleviate I/R injury and inhibit myocardial apoptosis, which might be associated with reduction on oxidative stress and apoptosis. CryAB as a possible target involved in the NP protective effect. This study supplied valuable information to develop novel cardioprotective agents from NP extract.


Assuntos
Cardiotônicos/farmacologia , Isquemia/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Miocárdio/metabolismo , Extratos Vegetais/farmacologia , Potentilla/química , Cadeia B de alfa-Cristalina/uso terapêutico , Animais , Cardiotônicos/uso terapêutico , Masculino , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-Dawley
10.
Oxid Med Cell Longev ; 2019: 7973098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31015891

RESUMO

Apigenin (Api), a natural flavone found in high amounts in several herbs, has shown potent cardioprotective effects in clinical studies, although the underlying mechanisms are not clear. We hypothesized that Api protects the myocardium from simulated ischemia/reperfusion (SI/R) injury via nutritional preconditioning (NPC). Rats fed with Api-containing food showed improvement in cardiac functions; lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) activities; infarct size; apoptosis rates; malondialdehyde (MDA) levels; caspase-3, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities; and ferric reducing antioxidant power (FRAP) compared to those fed standard chow following SI/R injury. In addition, Api pretreatment significantly improved the viability, decreased the LDH activity and intracellular reactive oxygen species (ROS) generation, alleviated the loss of mitochondrial membrane potential (MMP), prevented the opening of the mitochondrial permeability transition pore (mPTP), and decreased the caspase-3 activity, cytochrome c (Cyt C) release, and apoptosis induced by SI/R in primary cardiomyocytes. Mechanistically, Api upregulated Hes1 expression and was functionally neutralized by the Notch1 γ-secretase inhibitor GSI, as well as the mPTP opener atractyloside (Atr). Taken together, Api protected the myocardium against SI/R injury via the mitochondrial pathway mediated by the Notch1/Hes1 signaling pathway.


Assuntos
Apigenina/uso terapêutico , Mitocôndrias/metabolismo , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Receptor Notch1/metabolismo , Fatores de Transcrição HES-1/metabolismo , Animais , Animais Recém-Nascidos , Apigenina/farmacologia , Apoptose/efeitos dos fármacos , Atractilosídeo/farmacologia , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Sobrevivência Celular/efeitos dos fármacos , Peroxidação de Lipídeos/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Regulação para Cima/efeitos dos fármacos
11.
Cell Commun Signal ; 17(1): 34, 2019 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-30987657

RESUMO

BACKGROUNDS/AIM: Male and female hearts have many structural and functional differences. Here, we investigated the role of estrogen (E2) in the mechanisms of sex differences in contraction through the cAMP-L-type Ca2+channel pathway in adult mice left ventricular (LV) apical myocytes at basal and stress state. METHODS: Isolated LV apical myocytes from male, female (Sham) and ovariectomised mice (OVX) were used to investigate contractility, Ca2+ transients and L-type Ca2+ channel (LTCC) function. The levels of ß2AR, intracellular cAMP, phosphodiesterase (PDE 3 and PDE 4), RyR2, PLB, SLN, and SERCA2a were compared among the experimental groups. RESULTS: We found that (1) intracellular cAMP, ICaL density, contraction and Ca2+ transient amplitudes were larger in Sham and OVX + E2 myocytes compared to male and OVX. (2) The mRNA expression of PDE 3 and 4 were lower in Sham and OVX + E2 groups compared with male and OVX groups. Treatment of myocytes with IBMX (100 µM) increased contraction and Ca2+ transient amplitude in both sexes and canceled differences between them. (3) ß2AR-mediated stress decreased cAMP concentration and peak contraction and Ca2+ transient amplitude only in male and OVX groups but not in Sham or OVX + E2 groups suggesting a cardioprotective role of E2 in female mice. (4) Pretreatment of OVX myocytes with GPR30 antagonist G15 (100 nM) abolished the effects of E2, but ERα and ERß antagonist ICI 182,780 (1 µM) did not. Moreover, activation of GPR30 with G1 (100 nM) replicated the effects of E2 on cAMP, contraction and Ca2+ transient amplitudes suggesting that the acute effects of E2 were mediated by GPR30 via non-genomic signaling. (5) mRNA expression of RyR2 was higher in myocytes from Sham than those of male while PLB and SLN were higher in male than Sham but no sex differences were observed in the mRNA of SERCA2a. CONCLUSION: Collectively, these results demonstrate that E2 modulates the expression of genes related to the cAMP-LTCC pathway and contributes to sex differences in cardiac contraction and responses to stress. We also show that estrogen confers cardioprotection against cardiac stress by non-genomic acute signaling via GPR30.


Assuntos
Canais de Cálcio Tipo L/metabolismo , AMP Cíclico/metabolismo , Estradiol/fisiologia , Contração Miocárdica/fisiologia , Miócitos Cardíacos/fisiologia , Receptores Adrenérgicos beta 2/metabolismo , Caracteres Sexuais , Função Ventricular Esquerda/fisiologia , Animais , Canais de Cálcio Tipo T/metabolismo , Sinalização do Cálcio , Cardiotônicos/farmacologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 3/metabolismo , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Estradiol/farmacologia , Feminino , Regulação da Expressão Gênica , Masculino , Camundongos , Contração Miocárdica/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Receptores Adrenérgicos beta 1/metabolismo , Receptores Estrogênicos/metabolismo , Receptores Acoplados a Proteínas-G/agonistas , Receptores Acoplados a Proteínas-G/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos
12.
Int J Mol Sci ; 20(8)2019 Apr 17.
Artigo em Inglês | MEDLINE | ID: mdl-30999666

RESUMO

Autophagy is an evolutionarily conserved 'self-eating' process that maintains cellular, tissue, and organismal homeostasis. New studies on autophagy, mediated by subsets of autophagy proteins, are emerging in many physiological and pathological processes. Astragalus membranaceus (AM), also named Huangqi, is one of the fundamental herbs in traditional Chinese medicine and its extracts have been proved to possess many biological activities related to autophagy, including anti-oxidation, anti-inflammation, anticancer, anti-photoaging, and improvement of cardiomyocyte function. Evidence suggests that AM extracts can have therapeutic potential in autophagy dysregulation-associated diseases because of their biological positive effects. Here we will review the literature concerning the effects of AM extracts on autophagy dysregulation-associated diseases.


Assuntos
Astragalus propinquus , Autofagia/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Extratos Vegetais/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antioxidantes/química , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Astragalus propinquus/química , Cardiotônicos/química , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/uso terapêutico , Humanos , Neoplasias/tratamento farmacológico , Doenças Neurodegenerativas/tratamento farmacológico , Extratos Vegetais/química , Extratos Vegetais/uso terapêutico , Envelhecimento da Pele/efeitos dos fármacos
13.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010001

RESUMO

Dipeptidyl peptidase IV (DPPIV) inhibitors are antidiabetic agents that exert renoprotective actions independently of glucose lowering. Cardiac dysfunction is one of the main outcomes of chronic kidney disease (CKD); however, the effects of DPPIV inhibition on cardiac impairment during CKD progression remain elusive. This study investigated whether DPPIV inhibition mitigates cardiac dysfunction and remodeling in rats with a 5/6 renal ablation and evaluated if these effects are associated with changes in the cardiac renin-angiotensin system (RAS). To this end, male Wistar rats underwent a 5/6 nephrectomy (Nx) or sham operation, followed by an 8-week treatment period with the DPPIV inhibitor sitagliptin (IDPPIV) or vehicle. Nx rats had lower glomerular filtration rate, overt albuminuria and higher blood pressure compared to sham rats, whereas CKD progression was attenuated in Nx + IDPPIV rats. Additionally, Nx rats exhibited cardiac hypertrophy and fibrosis, which were associated with higher cardiac DPPIV activity and expression. The sitagliptin treatment prevented cardiac fibrosis and mitigated cardiac hypertrophy. The isovolumic relaxation time (IRVT) was higher in Nx than in sham rats, which was suggestive of CKD-associated-diastolic dysfunction. Sitagliptin significantly attenuated the increase in IRVT. Levels of angiotensin II (Ang II) in the heart tissue from Nx rats were higher while those of angiotensin-(1-7) Ang-(1-7) were lower than that in sham rats. This cardiac hormonal imbalance was completely prevented by sitagliptin. Collectively, these results suggest that DPPIV inhibition may delay the onset of cardiovascular impairment in CKD. Furthermore, these findings strengthen the hypothesis that a crosstalk between DPPIV and the renin-angiotensin system plays a role in the pathophysiology of cardiorenal syndromes.


Assuntos
Angiotensina II/metabolismo , Angiotensina I/metabolismo , Cardiotônicos/uso terapêutico , Miocárdio/metabolismo , Fragmentos de Peptídeos/metabolismo , Insuficiência Renal Crônica/tratamento farmacológico , Insuficiência Renal Crônica/metabolismo , Fosfato de Sitagliptina/uso terapêutico , Angiotensina I/sangue , Angiotensina II/sangue , Animais , Anti-Inflamatórios/farmacologia , Anti-Inflamatórios/uso terapêutico , Antioxidantes/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cardiotônicos/farmacologia , Diástole/efeitos dos fármacos , Dipeptidil Peptidase 4/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Rim/efeitos dos fármacos , Rim/fisiopatologia , Testes de Função Renal , Masculino , Miocárdio/patologia , Fragmentos de Peptídeos/sangue , Peptidil Dipeptidase A/metabolismo , Ratos Wistar , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Sistema Renina-Angiotensina/efeitos dos fármacos , Fosfato de Sitagliptina/farmacologia , Regulação para Cima/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos
14.
Int J Mol Sci ; 20(6)2019 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-30934608

RESUMO

Despite the availability of several therapies for the management of blood glucose in diabetic patients, most of the treatments do not show benefits on diabetic cardiomyopathy, while others even favor the progression of the disease. New pharmacological targets are needed that might help the management of diabetes and its cardiovascular complications at the same time. GRK2 appears a promising target, given its established role in insulin resistance and in systolic heart failure. Using a custom peptide inhibitor of GRK2, we assessed in vitro in L6 myoblasts the effects of GRK2 inhibition on glucose extraction and insulin signaling. Afterwards, we treated diabetic male mice (db/db) for 2 weeks. Glucose tolerance (IGTT) and insulin sensitivity (ITT) were ameliorated, as was skeletal muscle glucose uptake and insulin signaling. In the heart, at the same time, the GRK2 inhibitor ameliorated inflammatory and cytokine responses, reduced oxidative stress, and corrected patterns of fetal gene expression, typical of diabetic cardiomyopathy. GRK2 inhibition represents a promising therapeutic target for diabetes and its cardiovascular complications.


Assuntos
Cardiotônicos/uso terapêutico , Diabetes Mellitus Experimental/tratamento farmacológico , Quinase 2 de Receptor Acoplado a Proteína G/antagonistas & inibidores , Hipoglicemiantes/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Animais , Transporte Biológico/efeitos dos fármacos , Cardiomegalia/complicações , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Cardiotônicos/farmacologia , Linhagem Celular , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Quinase 2 de Receptor Acoplado a Proteína G/metabolismo , Glucose/metabolismo , Hipoglicemiantes/farmacologia , Inflamação/patologia , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos
15.
Eur J Med Res ; 24(1): 20, 2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027517

RESUMO

BACKGROUND: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a crucial mediator in response to inflammation. Myricetin protects cardiomyocytes against inflammatory injury. However, it's still unexplored whether myricetin exerted anti-inflammatory properties via MALAT1. The purpose of our study was to validate the cardio-protective function of myricetin against myocarditis and its underlying mechanism in vitro. METHODS: H9c2 cells were pre-incubated with myricetin before stimulation with lipopolysaccharide (LPS). Enforced silence of MALAT1 was achieved by transducing short hairpin (sh)-MALAT1 into H9c2 cells. Next, cell viability and apoptotic cells were detected with cell counting kit-8 (CCK-8) and Annexin V-fluorescein isothiocyanate/propidium iodide (Annexin V-FITC/PI) apoptosis detection kit, respectively. Western blot assay was conducted to examine apoptosis-relative proteins, pro-inflammatory factors, and signaling regulators. Quantitative real-time PCR (qRT-PCR) was performed to quantify pro-inflammatory factors and MALAT1 at mRNA levels. Enzyme-linked immune sorbent assay (ELISA) was employed to determine protein concentration of pro-inflammatory factors. RESULTS: Myricetin ameliorated LPS-elicited reduction of cell viability, augment of apoptosis, and overexpression of monocyte chemo-attractant protein-1 (MCP-1) and interleukin-6 (IL-6) in H9c2 cells. Meanwhile, phosphorylation of p65 and inhibitor of nuclear factor kappa B alpha (IκBα) were suppressed. Besides, myricetin enhanced the expression of MALAT1 which was originally down-regulated by LPS. However, the protective effects of myricetin against LPS-caused inflammatory lesions were abrogated in MALAT1-deficiency cells, with the restored phosphorylation of p65 and IκBα. CONCLUSION: Myricetin possessed an anti-inflammatory function against LPS-induced lesions in cardiomyocytes. Mechanically, myricetin up-regulated MALAT1, blocked LPS-evoked activation of nuclear factor-κB (NF-κB) inflammatory pathway, and, finally, exerted cardio-protective effects.


Assuntos
Cardiotônicos/farmacologia , Flavonoides/farmacologia , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , RNA Longo não Codificante/metabolismo , Animais , Linhagem Celular , Flavonoides/química , Inflamação/patologia , Mediadores da Inflamação/metabolismo , Lipopolissacarídeos , Miócitos Cardíacos/efeitos dos fármacos , NF-kappa B/metabolismo , RNA Longo não Codificante/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Regulação para Cima/efeitos dos fármacos , Regulação para Cima/genética
16.
Phytomedicine ; 58: 152765, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31005720

RESUMO

BACKGROUND: Cardiac hypertrophy is an adaptive response of the myocardium to pressure or volume overload. Recent evidences indicate that allicin can prevent cardiac hypertrophy. However, it is not clear whether allicin alleviates cardiac hypertrophy by inhibiting autophagy. PURPOSE: We aimed to investigate the effects of allicin on pressure overload-induced cardiac hypertrophy, and further to clarify the related mechanism. STUDY DESIGN/METHODS: Cardiac hypertrophy was successfully established by abdominal aortic constriction (AAC) in rats, and cardiomyocytes hypertrophy was simulated by angiotensin II (Ang II) in vitro. Hemodynamic parameters were monitored by organism function experiment system in vivo. The changes of cell surface area were observed using HE and immunofluorescence staining in vivoand in vitro, respectively. The expressions of cardiac hypertrophy relative protein (BNP and ß-MHC), autophagy marker protein (LC3-II and Beclin-1), Akt, PI3K and ERK were detected by western blot. RESULTS: Allicin could improve cardiac function, and reduce cardiomyocytes size, and decrease BNP and ß-MHC protein expressions. Further results showed that allicin could lower LC3-II and Beclin-1 protein expressions both in vivo and in vitro experiments. And pharmacological inhibitor of mTOR, rapamycin could antagonize the effects of allicin on Ang II-induced cardiac hypertrophy and autophagy. Simultaneously, allicin could promote the expressions of p-Akt, p-PI3K and p-ERK protein. CONCLUSION: These findings reveal a novel mechanism of allicin attenuating cardiac hypertrophy which allicin could inhibit excessive autophagy via activating PI3K/Akt/mTOR and MAPK/ERK/mTOR signaling pathways.


Assuntos
Autofagia/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiotônicos/farmacologia , Ácidos Sulfínicos/farmacologia , Angiotensina II/farmacologia , Animais , Cardiomegalia/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo
17.
Eur J Pharmacol ; 853: 336-344, 2019 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-30978321

RESUMO

Despite the success which was achieved in the treatment of arterial hypertension, the problem remains actual. At the departments of pharmaceutical chemistry and pharmacology of the Zaporozhye State Medical Institute (Ukraine), our research team isolated the compound 1-(ß-phenylethyl)-4-amino-1,2,4-triazolium bromide (Hypertril) as derivative of 4-amino-1,2,4-triazole. The objectives of this investigation were the study of cardioprotective and antihypertensive activities of this new compound Hypertril and we used the Spontaneously hypertensive rats (SHR) as an experimental model. We discovered that Hypertril has a reliable dose-dependent antihypertensive effect in the dose range 5-20 mg/kg after 30-day administration and this antihypertensive effect of Hypetril competes or significantly exceeds Metoprolol (20 mg/kg). Our studies obtained evidence of a dose-dependent improvement of myocardial energy metabolism. Hypertril reduces the manifestations of secondary mitochondrial dysfunction due to arterial hypertension. Hypertril can prevent oxidative modification of the protein; also Hypertril reduces the insufficiency of mitochondrial pores. As a result, Hypertril increases the content of ATP in the myocardium of SHR, normalizes the activity of mitochondrial enzymes, decreases lactate production and increases pyruvate. Hypertril enhances the cardioprotective effects of NO and increases the resistance of the cardiomyocytes to ischemia. The use of Hypertril leads to a dose-dependent increase of the density of cardiomyocyte nuclei, significant increase RNA content in nuclei and the cytoplasm of cardiomyocytes, and an increase of the nuclear-cytoplasmic index. These changes indicate a decrease of myocardial hypertrophy.


Assuntos
Anti-Hipertensivos/farmacologia , Cardiotônicos/farmacologia , Triazóis/farmacologia , Animais , Relação Dose-Resposta a Droga , Masculino , Ratos , Ratos Endogâmicos SHR
18.
Int J Mol Sci ; 20(7)2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30939728

RESUMO

Dexmedetomidine (DEX), a highly selective alpha2 adrenergic receptor agonist, directly protects hearts against ischemia/reperfusion (I/R) injury. However, the detailed mechanism has not been fully elucidated. We studied differentially expressed mRNAs and miRNAs after DEX administration in rat hearts by comprehensive analysis. Additionally, bioinformatics analysis was applied to explore candidate genes and pathways that might play important roles in DEX-induced cardioprotection. The results of microarray analysis showed that 165 mRNAs and 6 miRNAs were differentially expressed after DEX administration. Through bioinformatics analysis using differentially expressed mRNAs, gene ontology (GO) terms including MAP kinase tyrosine/serine/threonine phosphatase activity and pathways including the p53 pathway were significantly enriched in the down-regulated mRNAs. Dusp1 and Atm were associated with the GO term of MAP kinase tyrosine/serine/threonine phosphatase activity and the p53 pathway, respectively. On the other hand, no significant pathway was found in the target mRNAs of deregulated miRNAs. The results indicated some possible key genes and pathways that seem to be of significance in DEX-induced cardioprotection, although miRNAs seem to be unlikely to contribute to cardioprotection induced by DEX.


Assuntos
Cardiotônicos/farmacologia , Dexmedetomidina/farmacologia , Coração/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/genética , Transcriptoma , Animais , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismo , Cardiotônicos/uso terapêutico , Dexmedetomidina/uso terapêutico , Fosfatase 1 de Especificidade Dupla/genética , Fosfatase 1 de Especificidade Dupla/metabolismo , Perfilação da Expressão Gênica , Sistema de Sinalização das MAP Quinases , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/metabolismo , Ratos , Ratos Wistar , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo
19.
Int J Mol Sci ; 20(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934670

RESUMO

Resveratrol, the phenolic substance isolated initially from Veratrum grandiflorum and richly present in grapes, wine, peanuts, soy, and berries, has been attracting attention of scientists and medical doctors for many decades. Herein, we review its effects on the vascular system. Studies utilizing cell cultures and pre-clinical models showed that resveratrol alleviates oxidative stress and inflammation. Furthermore, resveratrol suppresses vascular smooth muscle cell proliferation, promotes autophagy, and has been investigated in the context of vascular senescence. Pre-clinical models unambiguously demonstrated numerous vasculoprotective effects of resveratrol. In clinical trials, resveratrol moderately diminished systolic blood pressure in hypertensive patients, as well as blood glucose in patients with diabetes mellitus. Yet, open questions remain, as exemplified by a recent report which states that the intake of resveratrol might blunt certain positive effects of exercise in older persons, and further research addressing the framework for long-term use of resveratrol as a food supplement, will stay in demand.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Resveratrol/farmacologia , Animais , Cardiotônicos/farmacologia , Cardiotônicos/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Doenças Cardiovasculares/patologia , Ensaios Clínicos como Assunto , Modelos Animais de Doenças , Humanos , Resveratrol/uso terapêutico
20.
Pharm Biol ; 57(1): 176-183, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30860934

RESUMO

CONTEXT: Ophiopogonis Radix, the root of Ophiopogon japonicus (Thunb.) Ker-Gawl (Liliaceae), is a Traditional Chinese Medicine, which has been investigated to possess effective treatment of cardiovascular diseases. OBJECTIVE: This study evaluates the cardioprotective effects of steroidal saponins extract from Ophiopogon japonicus (SOJ) root against doxorubicin-induced chronic heart failure (CHF) through the amelioration of oxidative stress and inflammation. MATERIALS AND METHODS: A Sprague-Dawley rat model of CHF was established by intraperitoneally injected with DOX. All rats were randomly divided into four groups: Control group, CHF group, CHF + SOJ (100 mg/kg) treatment group, SOJ (100 mg/kg) treatment group (n = 8/group). After six weeks administration, biometric and echocardiography were measured. The levels of biochemical parameters were measured using commercial kits. RESULTS: The values of LVESP, +dP/dtmax, -dP/dtmax, EF and FS increased to 116.20 ± 1.68 mmHg, 2978.71 ± 168.26 mmHg/s, 3452.61 ± 286.09 mmHg/s, 68.26 ± 5.28% and 31.97 ± 3.79%, respectively; the values of LVEDP, LVESD and LVEDD decreased to 8.85 ± 0.84 mmHg, 8.39 ± 0.45 mm and 12.36 ± 0.87 mm in CHF + SOJ group. In addition, the levels of IL-6, TNF-α and IL-1ß decreased to 154.41 ± 7.72 pg/mg protein, 110.02 ± 6.96 pg/mg protein and 39.39 ± 5.27 pg/mg protein, respectively; the relative activity of p38 MAPK decreased to 2.60 ± 0.40 in CHF + SOJ group. Furthermore, the activities of SOD, CAT and GSH-Px increased to 268.77 ± 6.20 U/mg protein, 13.68 ± 0.68 U/mg protein and 316.90 ± 8.08 µmol/mg protein, and the content of MDA decreased to 4.03 ± 0.43 nmol/mg protein in CHF + SOJ group. CONCLUSIONS: SOJ exerts the cardioprotective effect against DOX-induced CHF through suppressing inflammatory and oxidative stress. These results provide evidence that SOJ might be an effective treatment for CHF.


Assuntos
Cardiotônicos/farmacologia , Insuficiência Cardíaca/prevenção & controle , Ophiopogon/química , Saponinas/farmacologia , Animais , Cardiotônicos/isolamento & purificação , Doença Crônica , Doxorrubicina/toxicidade , Ecocardiografia , Insuficiência Cardíaca/induzido quimicamente , Inflamação/induzido quimicamente , Inflamação/prevenção & controle , Masculino , Medicina Tradicional Chinesa/métodos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Ratos , Ratos Sprague-Dawley , Saponinas/isolamento & purificação , Esteroides/isolamento & purificação , Esteroides/farmacologia
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