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1.
Regen Med ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31829095

RESUMO

Aim: To determine the efficacy and safety of intracoronary infusion of autologous bone marrow mesenchymal stem cells (MSCINJ) in combination with intensive atorvastatin (ATV) treatment for patients with anterior ST-segment elevation myocardial infarction-elevation myocardial infarction. Patients & methods: The trial enrolls a total of 100 patients with anterior ST-elevation myocardial infarction. The subjects are randomly assigned (1:1:1:1) to receive routine ATV (20 mg/d) with placebo or MSCsINJ and intensive ATV (80 mg/d) with placebo or MSCsINJ. The primary end point is the absolute change of left ventricular ejection fraction within 12 months. The secondary end points include parameters in cardiac function, remodeling and regeneration, quality of life, biomarkers and clinical outcomes. Results & conclusion: The trial will implicate the essential of cardiac micro-environment improvement ('fertilizing') for cell-based therapy. Clinical Trial Registration: NCT03047772.

2.
Int J Ophthalmol ; 11(10): 1643-1648, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30364163

RESUMO

AIM: To evaluate the structural injure patterns in peripapillary retinal fiber layer (pRNFL), retinal ganglion cell layer (RGCL) and their correlations to visual function in various mitochondrial optic neuropathies (MON) to offer help to their differential diagnosis. METHODS: Totally 32 MON patients (60 eyes) were recruited within 6mo after clinical onsets, including 20 Leber hereditary optic neuropathy (LHON) patients (37 eyes), 12 ethambutol-induced optic neuropathy (EON) patients (23 eyes), and 41 age-gender matched healthy controls (HC, 82 eyes). All subjects had pRNFL and RGCL examinations with optic coherence tomography (OCT) and visual function tests. RESULTS: In the early stages of MON, the temporal pRNFL thickness decreased (66.09±22.57 µm), but increased in other quadrants, compared to HC (76.95±14.81 µm). The other quadrants remaining stable for LHON and EON patients besides the second hour sector of pRNFL thickness reduced and the temporal pRNFL decreased (56.78±15.87 µm) for EON. Total macular thickness in MON reduced remarkably (279.25±18.90 µm; P=0.015), which mainly occurring in the inner circle (3 mm diameter of circle) and the nasal temporal sectors in the outer circle (5.5 mm diameter of circle), in contrast to those in HC. RGCL thickness reduced in each sector of the macula (61.90±8.73 µm; P≤0.001). It strongly showed the correlationship of best corrected visual acuity (R=0.50, P=0.0003) and visual field injury (R=0.54, P=0.0002) in MON patients. CONCLUSION: OCT is a potential tool for detecting structural alterations in the optic nerves of various MON. Different types of MON may have different damage patterns.

3.
ChemMedChem ; 13(22): 2455-2463, 2018 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-30246417

RESUMO

Herein we describe the design and synthesis of a new series of heteroarylpyrimidine/heteroaryltriazine derivatives on the basis of quinazoline-2,4(1H,3H)-diones as CB2 R-selective ligands using a bioisosterism strategy. An acetamide group was explored to displace the enamine linker of the lead compound for the purpose of stereoisomerism elimination and hydrophilicity increase. As a result, some of the synthesized compounds showed high bioactivity and selectivity for CB2 R in calcium mobilization assays, and four displayed CB2 R agonist activity, with EC50 values below 30 nm. The compound exhibiting the highest agonist activity toward CB2 R (EC50 =7.53±3.15 nm) had a selectivity over CB1 R of more than 1328-fold. Moreover, structure-activity relationship (SAR) studies indicated that the substituents on the nucleus play key roles in the functionality of a ligand, with one such example demonstrating CB2 R antagonist activity. Additionally, molecular docking simulations were conducted with the aim of better understanding of these new derivatives in relation to the structural requirements for agonists/antagonists binding to CB2 R.


Assuntos
Agonistas de Receptores de Canabinoides/farmacologia , Pirimidinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Triazinas/farmacologia , Animais , Sítios de Ligação , Células CHO , Agonistas de Receptores de Canabinoides/síntese química , Agonistas de Receptores de Canabinoides/química , Cricetulus , Desenho de Drogas , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Receptor CB1 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/química , Relação Estrutura-Atividade , Triazinas/síntese química , Triazinas/química
4.
Eur J Med Chem ; 137: 598-611, 2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28651225

RESUMO

Herein, we described the design and synthesis of a series of pyridazine-3-carboxamides to be CB2-selective agonists via a combination of scaffold hopping and bioisosterism strategies. The compounds were subjected to assessment of their potential activities through calcium mobilization assays. Among the tested derivatives, more than half of these compounds exhibited moderate to potent CB2 agonist activity. Six compounds showed EC50 values below 35 nM, and several derivatives also exhibited significantly enhanced potency and high selectivity at the CB2 receptor over the CB1 receptor. Specifically, compound 26 showed the highest CB2 agonist activity (EC50 = 3.665 ± 0.553 nM) and remarkable selectivity (Selectivity Index > 2729) against CB1. In addition, logPs of some representative compounds were measured to display significantly decreased values in comparison with GW842166X. Furthermore, docking simulations were conducted to explain the interaction mode of this series.


Assuntos
Piridazinas/farmacologia , Receptor CB2 de Canabinoide/agonistas , Animais , Células CHO , Cricetulus , Relação Dose-Resposta a Droga , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piridazinas/síntese química , Piridazinas/química , Relação Estrutura-Atividade
5.
ACS Med Chem Lett ; 8(6): 678-681, 2017 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-28626532

RESUMO

Starting from a prototypical structure 1, we describe our efforts to design and obtain novel quinazoline/pyrimidine-2,4(1H,3H)-diones with high CB2 agonist potency and selectivity as well as improved physicochemical characteristics, mainly hydrophilicity. The most potent and selective CB2 agonists, 8 and 36, in this series were also endowed with lower logP values than that of GW842166X and lead compound 1. These derivatives appear to be promising lead compounds for the development of future CB2 agonists.

6.
Am J Med Sci ; 352(6): 557-562, 2016 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-27916210

RESUMO

OBJECTIVE: To explore the predictive value of heart-type fatty acid binding protein (H-FABP) in the stratification and prognosis of patients with acute pulmonary embolism (APE). METHODS: According to risk stratification, 69 patients with APE admitted into the emergency department within 24 hours after onset were divided into the following 3 groups: high-risk group, moderate-risk group and low-risk group. H-FABP- and cardiac troponin I (cTNI)-positive rates of all groups were analyzed and compared, and the correlation between major adverse events (death, endotracheal intubation and cardiopulmonary resuscitation) and the cardiac markers (heart rate, arterial partial pressure of oxygen, right ventricular dimension, pulmonary arterial pressure, etc.) during the in-hospital period were statistically analyzed. Then the prognosis (death, embolic pulmonary hypertension, right heart failure and recurrence of APE) at 6 months after onset of APE was followed-up on and compared between groups. RESULTS: The admission time of high-risk group patients was earlier than non-high-risk group (7.1 ± 2.9 versus 13.5 ± 6.7 versus 15.2 ± 10.7 hours, P = 0.001), had larger right ventricular dimension (33.1 ± 10.4 versus 26.7 ± 7.3 versus 20.5 ± 8.9mm, P = 0.002) and higher pulmonary arterial pressure (45.8 ± 14.6 versus 29.4 ± 13.9 versus 23.1 ± 12.6mmHg, P = 0.001). The major adverse events during in-hospital period, including death, endotracheal intubation and cardiopulmonary resuscitation, were more prevalent in the high-risk group than those in the other 2 risk groups. Further analysis indicated that the positive rate of H-FABP was remarkably higher than cTNI (52/69, 75.4% versus 28/69, 40.6%, P = 0.003). The H-FABP (r = 0.881, P = 0.020) was significantly correlated to the major adverse events; however, this was not so regarding cTNI (r = 0.115, P = 0.059). At 6 months after onset of APE, the follow-up data indicated that cTNI and H-FABP were both significantly correlated with the major adverse events. CONCLUSIONS: The positive rate of H-FABP was higher than cTNI during the 24 hours after the onset of APE. The H-FABP was significantly correlated to the major adverse events during hospitalization and to the primary prognosis at 6 months after onset of APE.


Assuntos
Proteínas de Ligação a Ácido Graxo/sangue , Embolia Pulmonar/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , China/epidemiologia , Proteína 3 Ligante de Ácido Graxo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/mortalidade , Medição de Risco , Troponina I/sangue , Adulto Jovem
7.
Mol Biosyst ; 12(4): 1250-68, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26883408

RESUMO

CDK2 is a promising target for the development of anti-cancer agents. It is not an easy task to design CDK2-selective inhibitors which do not exhibit activity for other CDK family members, particularly CDK4, due to a high degree of structural homology among CDK family members. In this study, 4-substituted N-phenylpyrimidin-2-amine derivatives as CDK2 inhibitors were examined to understand the selectivity mechanism against CDK4 using a combined approach of 3D-QSAR, molecular docking, MESP, MD simulations, and binding free energy calculations. 3D-QSAR models were developed to propose structural determinants for CDK2 and CDK4 inhibition. High q(2) and r(2) values for CoMFA and CoMSIA models based on both internal and external validations suggested that the generated 3D-QSAR models may exhibit good capability to predict bioactivities of inhibitors against CDK2 or CDK4. Electrostatic potentials on the molecular surface have been discussed in detail for determining the binding affinity of studied inhibitors by combining molecular docking with MESP and Mulliken charge analyses. Binding free energy calculations suggested that the residues Gln85, Asp86, and Lys89 of CDK2 would play a critical role in selective CDK2 inhibition. The electrostatic interactions of an inhibitor with Glu144 and Asn145 of CDK4 may predominately drive CDK4 inhibition. These findings may provide a better structural understanding of the mechanism of CDK2 selective inhibition. The results obtained in the current study may provide valuable guidelines for developing novel potent and selective CDK2 inhibitors.


Assuntos
Aminas/química , Quinase 2 Dependente de Ciclina/química , Quinase 4 Dependente de Ciclina/química , Modelos Moleculares , Inibidores de Proteínas Quinases/química , Relação Quantitativa Estrutura-Atividade , Algoritmos , Aminas/farmacologia , Aminoácidos/química , Sítios de Ligação , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Humanos , Ligações de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Eletricidade Estática
8.
Catheter Cardiovasc Interv ; 87 Suppl 1: 579-88, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26914391

RESUMO

OBJECTIVES: To evaluate the early and long-term outcomes of stent placement for left subclavian artery stenosis (LSAS) in patients scheduled for left internal mammary artery-coronary artery bypass grafting (LIMA-CABG). BACKGROUND: Few studies have demonstrated the safety and effectiveness of endovascular therapy for the treatment of LSAS before LIMA-CABG; therefore, use of this therapy requires further exploration and evaluation. METHODS: Between February 2000 and April 2014, the clinical data of 167 consecutive patients (mean age 64 ± 9 years, 141 males) scheduled for LIMA-CABG with LSAS who were treated by stenting at the Fuwai Hospital were collected and analyzed retrospectively. RESULTS: The technical success rate of the procedure was 97.6% (163/167). The mean stenosis of target lesions decreased from 86.5 ± 9.9% to 7.6 ± 4.6% (P < 0.001). The incidences of death, stroke, and myocardial infarction, as well as the combined incidence of death, stroke, and myocardial infarction from the time of stenting to 30 days after the stenting procedure were 0.6% (n = 1), 1.8% (n = 3), 0% (n = 0), and 1.8% (n = 3), respectively. The 10-year rate of follow-up was 94.6%. The overall survival rate was 98.8% at 1 year, 97.5% at 2 years, 93.9% at 5 years, and 86.2% at 10 years. A total of 14.1% (23/163) of patients developed in-stent restenosis. Stent restenosis-related angina and myocardial infarction were observed in 13 and 3 patients, respectively. The patency rates of the left subclavian artery were 95.7, 93.8, 86.5, and 75.2% at 1, 2, 5, and 10 years, respectively. The target vessel reconstruction rate was 8.0% (13/163). CONCLUSIONS: Stenting of LSAS at experienced medical centers for patients scheduled for LIMA-CABG was safe and effective with a low incidence of complication and in-stent restenosis.


Assuntos
Angioplastia com Balão/instrumentação , Doença da Artéria Coronariana/cirurgia , Anastomose de Artéria Torácica Interna-Coronária , Stents , Síndrome do Roubo Subclávio/terapia , Idoso , Angina Pectoris/etiologia , Angioplastia com Balão/efeitos adversos , Angioplastia com Balão/mortalidade , China , Angiografia Coronária , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/mortalidade , Síndrome do Roubo Coronário-Subclávio/etiologia , Feminino , Humanos , Anastomose de Artéria Torácica Interna-Coronária/efeitos adversos , Anastomose de Artéria Torácica Interna-Coronária/mortalidade , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/etiologia , Infarto do Miocárdio/mortalidade , Recidiva , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Acidente Vascular Cerebral/etiologia , Acidente Vascular Cerebral/mortalidade , Síndrome do Roubo Subclávio/complicações , Síndrome do Roubo Subclávio/diagnóstico por imagem , Síndrome do Roubo Subclávio/mortalidade , Fatores de Tempo , Resultado do Tratamento
9.
Mol Biosyst ; 12(1): 145-61, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26565382

RESUMO

Cyclin dependent kinase 2 (CDK2) was regarded as a potentially therapeutic target for cancer therapy. Since the CDK family includes couples of high homology members, designing CDK2-selective inhibitors would provide valuable opportunities for the development of anticancer drugs with optimal efficacy. In this study, three thiazo-5-yl-pyrimidines as CDK2 inhibitors with different selectivity over cyclin dependent kinase 7 (CDK7) were examined to study the selectivity mechanism using a combined approach of computational techniques of flexible docking, EasyMIFs, molecular electrostatic potential (MESP), natural bond orbital (NBO), molecular dynamics (MD) simulations, and binding free energy calculations. Molecular simulations elicited new chemical insights into steric and electronic complementarities of these molecules to the binding sites of CDK2 and CDK7. The computed binding free energies were consistent with the ranking of their experimental binding affinities on CDK2 and CDK7. We also conducted in silico mutations of three key amino acids (CDK2: Gln85, Lys89, Asp145) to examine their impact on ligand binding with MD simulations and binding free energy calculations. The results indicated that these residues exhibited a strong tendency to mediate ligand-protein interactions through the H-bond and vdW interaction with CDK2-selective inhibitor. The present work may provide a better structural understanding of the molecular mechanism of CDK2 selective inhibition. The new computational insights presented in this study are expected to be valuable for the guidelines and development of new potent CDK2 inhibitors.


Assuntos
Quinase 2 Dependente de Ciclina/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Sítios de Ligação , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Conformação Molecular , Ligação Proteica , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/metabolismo , Pirimidinas/farmacologia , Pironas/química , Pironas/metabolismo , Pironas/farmacologia , Relação Quantitativa Estrutura-Atividade
10.
Cell Physiol Biochem ; 37(5): 1914-26, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26584290

RESUMO

BACKGROUND/AIMS: Dipeptidyl peptidase-4 (DPP-4) inhibitors have pleiotropic effects on cardiovascular protection beyond the antidiabetic property. However, it remains unknown that the impact of one DPP-4 inhibitor sitagliptin on the survival of mesenchymal stem cells (MSCs) in hypoxia and serum deprivation (H/SD) environment. METHODS: The apoptosis and autophagy of MSCs were analyzed in different concentrations of sitagliptin under H/SD condition. For later studies, we tested the relationship between anti-apoptotic and anti-autophagic effects of sitagliptin. The level of cell apoptosis was analyzed by Annexin V-FITC/PI staining, western blot of Bcl-2 and Bax proteins. Autophagy flux was assessed by multiple autophagy related proteins and substrates. Cell autophagy was identified by acridine orange staining, western blot of Beclin 1 and light chain 3 protein, and transmission electron microscopy. RESULTS: We demonstrated that sitagliptin attenuated hypoxia-induced apoptosis and autophagy of MSCs. Furthermore, sitagliptin regulated cell autophagy by Bcl-2/ Beclin 1 pathway in H/SD condition. CONCLUSIONS: This study provides insight into the utility of the DPP-4 inhibitor sitagliptin for MSCs transplantation in the ischemic microenvironment that extends its antidiabetic property.


Assuntos
Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Hipóxia Celular , Inibidores da Dipeptidil Peptidase IV/farmacologia , Fosfato de Sitagliptina/farmacologia , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Proteína Beclina-1 , Meios de Cultura Livres de Soro/farmacologia , Humanos , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Proteína X Associada a bcl-2/metabolismo
11.
Am J Transl Res ; 7(6): 1058-70, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26279750

RESUMO

BACKGROUND: The interaction between stromal cell-derived factor 1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) plays an important role in mesenchymal stem cells (MSCs) migration and engraftment. Statins can increase the survival of MSCs. However, whether statins could enhance MSCs migration and engraftment is still unknown. Therefore, we designed the study to investigate whether atorvastatin (ATV) could enhance CXCR4 expression of MSCs and promote them homing toward the injured myocardium. METHODS AND RESULTS: Expression of CXCR4 was evaluated by flow cytometry and real time PCR. A transwell system was used to assess MSCs migration ability. Recruitment of systematically delivered MSCs to the infarcted heart was evaluated in Sprague-Dawley rats with acute myocardial infarction (AMI). ATV pretreatment enhanced the expression of CXCR4 and stimulated MSCs migration in vitro. However, the effect was largely abolished by CXCR4 neutralizing antibody. In AMI models, we found much more ATV-pretreated MSCs homing toward the infarcted myocardium than non-treated cells and this was accompanied by improved cardiac performance. CONCLUSIONS: ATV increases the migration ability of MSCs and improves cardiac performance due to up-regulated expression of CXCR4. These results suggest that ATV pretreatment of donor MSCs is an effective way to promote cell therapeutic potential for AMI.

12.
J Med Chem ; 58(15): 5751-69, 2015 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-26151231

RESUMO

The cannabinoid type 2 receptors (CB2Rs) play crucial roles in inflammatory diseases. There has been considerable interest in developing potent and selective ligands for CB2R. In this study, quinoline-2,4(1H,3H)-dione analogs have been designed, synthesized, and evaluated for their potencies and binding properties toward the cannabinoid type 1 receptor (CB1R) and CB2R. C5- or C8-substituted quinoline-2,4(1H,3H)-diones demonstrate CB2R agonist activity, while the C6- or C7-substituted analogs are antagonists of CB2R. In addition, oral administration of 21 dose-dependently alleviates the clinical symptoms of experimental autoimmune encephalomyelitis in a mouse model of multiple sclerosis and protects the central nervous system from immune damage. Furthermore, the interaction modes predicted by docking simulations and the 3D-QSAR model generated with CoMFA may offer guidance for further design and modification of CB2R modulators.


Assuntos
Quinolinas/química , Quinolinas/farmacologia , Receptor CB2 de Canabinoide/efeitos dos fármacos , Animais , Células CHO , Cricetinae , Cricetulus , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Feminino , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Esclerose Múltipla/tratamento farmacológico , Relação Quantitativa Estrutura-Atividade , Quinolinas/uso terapêutico
13.
Chin Med J (Engl) ; 128(9): 1171-6, 2015 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-25947399

RESUMO

BACKGROUND: The aim of this research was to investigate the changes in the vision-related resting-state network (V-RSN) in pituitary adenoma (PA) patients after vision improvement, which was induced by operative treatment. METHODS: Ten PA patients with an improved visual acuity or/and visual field after transsphenoidal pituitary tumor resection were recruited and underwent a complete neuro-ophthalmologic evaluation, as well as an magnetic resonance imaging (MRI) protocol, including structural and resting-state functional MRI sequences before and after the operation. The regional homogeneity (ReHo) of the V-RSN was evaluated. Two sample t-test was performed to identify the significant differences in the V-RSN in the PA patients before and after transsphenoidal pituitary tumor resection. RESULTS: Compared with the preoperation counterparts, the PA patients with improved vision after the operation exhibited reduced ReHo in the bilateral thalamus, globus pallidus, caudate nucleus, putamen nucleus, supplementary motor area, and left hippocampal formation, and increased ReHo in the bilateral cuneus gyrus, calcarine gyrus, right lingual gyrus, and fusiform gyrus. CONCLUSIONS: PA patients with improved vision exhibit increased neural activity within the visual cortex, but decreased neural activity in subareas of the multisensory and multimodal systems beyond the vision cortex.


Assuntos
Adenoma/patologia , Neoplasias Hipofisárias/patologia , Adolescente , Adulto , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Eur J Med Chem ; 93: 16-32, 2015 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-25644673

RESUMO

The CB2 receptor has been considered as an inspiring drug target for the treatment of pain and immune-related diseases. In the current manuscript, a novel series of coumarin derivatives is reported to be designed and synthesized by combining the structural features of some known ligands for the cannabinoid receptors based on the CoMFA model of the lead compounds. The compounds were evaluated to be highly selective ligands for the CB2 receptor over the CB1 receptor by calcium mobilization assays. Furthermore, SAR results indicate that the functionality of a ligand is controlled by the substituent on the nucleus. Therefore, molecular docking simulations were performed to calculate the receptor-ligand interactions of our synthesized compounds binding to the CB2 receptor. The understanding of the binding modes could be advantageous for further development of selective ligands for the CB2 receptor.


Assuntos
Cumarínicos/síntese química , Desenho de Drogas , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/antagonistas & inibidores , Animais , Células CHO , Cálcio/metabolismo , Cumarínicos/química , Cumarínicos/farmacologia , Cricetulus , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Receptor CB1 de Canabinoide/agonistas , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB1 de Canabinoide/genética , Receptor CB2 de Canabinoide/genética , Relação Estrutura-Atividade , Transfecção
15.
Int J Cardiol ; 176(3): 670-9, 2014 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-25139321

RESUMO

BACKGROUND: Statins protect mesenchymal stem cells (MSCs) against the harsh microenvironment and improve the efficacy of MSC transplantation after acute myocardial infarction (AMI); however, the mechanism remains uncertain. Furthermore, the transdifferentiation potential of MSCs in the post-infarct heart remains highly controversial. The RhoA/Rho-associated coiled-coil-forming kinase (ROCK) pathway participates in many aspects of the damaged heart after AMI and related to the "pleiotropic" effects of statins. This study aimed to explore whether atorvastatin (ATV) facilitates the survival and therapeutic efficacy of MSCs via the inhibition of RhoA/ROCK pathway and subsequently its downstream molecular extracellular regulated protein kinase (ERK1/2), and to investigate the transdifferentiation potential of MSCs in vivo. METHODS AND RESULTS: Female rats received myocardial injections of male rat MSCs 30 min after AMI. Four weeks after AMI, ATV combined with MSC treatment resulted in improved cardiac function and reduced infarct area. ATV facilitated the MSC survival, as revealed by the increased expression of Y chromosomal genes and the increased number of Y chromosome-positive cells; however, no transdifferentiation markers were observed. ATV inhibited the production of inflammatory cytokines both in vitro and vivo, accompanied by suppression of ROCK and ERK activities. Geranylgeranyl pyrophosphate (GGPP) abrogated the effects of ATV in the H9c2 cells under hypoxia/serum deprivation (H/SD), while the ROCK inhibitor fasudil mimicked the benefits of ATV after AMI. CONCLUSIONS: ATV improves the post-infarct microenvironment via RhoA/ROCK/ERK inhibition and thus facilitates the survival and efficacy of implanted MSCs. Transdifferentiation may be not responsible for the cardiac benefits that follow MSC transplantation.


Assuntos
Ácidos Heptanoicos/uso terapêutico , Sistema de Sinalização das MAP Quinases/fisiologia , Transplante de Células-Tronco Mesenquimais , Infarto do Miocárdio/terapia , Pirróis/uso terapêutico , Quinases Associadas a rho/fisiologia , Proteína rhoA de Ligação ao GTP/fisiologia , Animais , Atorvastatina , Células Cultivadas , Feminino , Ácidos Heptanoicos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Transplante de Células-Tronco Mesenquimais/métodos , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/enzimologia , Pirróis/farmacologia , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Ultrassonografia , Quinases Associadas a rho/antagonistas & inibidores , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores
16.
Am J Cardiovasc Drugs ; 14(5): 367-76, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25027352

RESUMO

INTRODUCTION: By inhibiting apolipoprotein B (ApoB) synthesis, mipomersen can significantly reduce ApoB-containing lipoproteins in hypercholesterolemic patients. OBJECTIVE: This study sought to ascertain both the extent to which mipomersen can decrease ApoB-containing lipoproteins and the safety of mipomersen therapy. METHODS: Studies were identified through PubMed, CENTRAL, Embase, Clinical Trials, reviews, and reference lists of relevant papers. The efficacy endpoints were the changes in low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), ApoB, and lipoprotein (a) [Lp(a)]. The safety endpoints were the incidence of injection-site reactions, flu-like symptoms, and elevated transaminases. RESULTS: Six randomized controlled trials with 444 patients were included in the analysis. Compared with the placebo group, patients who received mipomersen therapy had a significant reduction in LDL-C (33.13%), as well as a reduction in non-HDL-C (31.70%), ApoB (33.27%), and LP(a) (26.34%). Mipomersen therapy was also associated with an obvious increase in injection-site reactions with an odds ratio (OR) of 14.15, flu-like symptoms with an OR of 2.07, and alanine aminotransferase levels ≥ 3 × the upper limit of normal with an OR of 11.21. CONCLUSIONS: Mipomersen therapy is effective for lowering ApoB-containing lipoproteins in patients with severe hypercholesterolemia. Future studies exploring how to minimize side effects of mipomersen therapy are needed.


Assuntos
Anticolesterolemiantes/uso terapêutico , Hipercolesterolemia/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Adulto , Anticolesterolemiantes/efeitos adversos , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oligonucleotídeos/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Resultado do Tratamento
17.
J Cardiovasc Pharmacol ; 63(3): 265-73, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24220313

RESUMO

Tongxinluo (TXL), a traditional Chinese medicine, is widely used to treat cardiovascular diseases in China. Our previous study has demonstrated the pro-survival role of TXL on mesenchymal stem cells (MSCs) in vivo. But whether TXL could decrease apoptosis of MSCs in vitro, and the underlying mechanism are still unknown. Moreover, AMPK/eNOS pathway is crucial in regulating cell apoptosis. Therefore, we designed the study to investigate whether TXL could decrease MSCs apoptosis under hypoxia and serum deprivation (H/SD) conditions and to determine the role of AMPK/eNOS pathway. To test the hypothesis, MSCs were treated with TXL (50-400 µg/mL) under H/SD for 6 hours. For inhibitor studies, the cells were preincubated with AMPK inhibitor compound C. Results indicated that TXL decreased MSCs apoptosis concentration-dependently evidenced by reduced Annexin V+/PI- cells and increased red/green ratio of JC-1. Further, TXL enhanced the phosphorylation of AMPK and eNOS. Whereas, treatment with compound C decreased the phosphorylation of AMPK and eNOS and was accompanied by attenuated anti-apoptotic effect of TXL. In conclusion, TXL protected MSCs against H/SD-induced injury at least in part through the AMPK/eNOS pathway, which provides a novel explanation for the multi-effect of TXL on cardiovascular system.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Células-Tronco Mesenquimais/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Animais , Hipóxia Celular , Relação Dose-Resposta a Droga , Medicamentos de Ervas Chinesas/administração & dosagem , Masculino , Células-Tronco Mesenquimais/patologia , Fosforilação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
Fundam Clin Pharmacol ; 28(5): 501-11, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24188213

RESUMO

Telmisartan with partial activation of peroxisome proliferator-activated receptor γ (PPARγ) powerfully reduces blood pressure, improves endothelial function and lipid metabolism. Hepatocyte growth factor/mesenchymal-epithelial transition factor (HGF/Met) system in the local vasculature plays a pivotal role in maintaining normal endothelial function. This study is aimed to evaluate whether telmisartan directly prevents angiotensin II (Ang II)-induced endothelial dysfunction (ED) via activating HGF/Met system and/or PPARγ pathway. The isolated aortic rings of rabbits were incubated with Ang II (0.01-1 µM), telmisartan (0.1-10 µM), SU11274 (5 µM) as a specific Met inhibitor, GW9662 (10 µM) as a PPARγ antagonist alone or a combination for 6 h. Ang II obviously inhibited the mRNA and protein expression of HGF, Met and PPARγ, and the accumulative concentration-relaxation of the aortic rings to acetylcholine, among which the inhibitory effect of 1 µM Ang II was most significant. By contrast, telmisartan significantly increased the mRNA and protein expression of HGF, Met, and PPARγ, thus preventing Ang II-induced ED in a dose-dependent pattern. However, SU11274, GW9662 or a combination of both partially abolished the protective effects derived from telmisartan, with the effect of SU11274 exceeding that of GW9662. These results demonstrate that Ang II-induced ED in rabbit aortic rings in vitro can be prevented by telmisartan through selective PPARγ-modulating pathway. Moreover, this study indicates for the first time that activating HGF/Met system in the local vasculature is involved in the protective mechanism of telmisartan.


Assuntos
Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Aorta/efeitos dos fármacos , Benzimidazóis/farmacologia , Benzoatos/farmacologia , Anilidas/farmacologia , Animais , Aorta/metabolismo , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Indóis/farmacologia , Masculino , PPAR gama/antagonistas & inibidores , PPAR gama/metabolismo , Piperazinas/farmacologia , Reação em Cadeia da Polimerase , Coelhos , Serina Endopeptidases/metabolismo , Sulfonamidas/farmacologia , Telmisartan
19.
J Pineal Res ; 55(4): 388-98, 2013 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-24006943

RESUMO

Vascular endothelial dysfunction (VED) and inflammation contribute to the initiation and progression of atherosclerosis. Melatonin (MLT) normalizes lipid profile, improves endothelial function, and possesses anti-inflammatory properties. However, the precise mechanisms are still unclear. This study investigated whether MLT could ameliorate VED, inflammation, and atherosclerosis by suppressing the Toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) system in high-fat-fed rabbits. Rabbits were randomly divided into three groups that received a standard diet (control group), high-cholesterol diet (atherosclerosis group), or high-cholesterol diet plus 10 mg/kg/day MLT (MLT group) for 12 wk. After treatment, high-fat diet significantly increased serum lipid and inflammatory markers in rabbits in atherosclerosis group compared with that in control group. In addition, high-fat diet also induced VED and typical atherosclerotic plaque formation and increased intima/media thickness ratio, which were significantly improved by MLT therapy as demonstrated in MLT group. Histological and immunoblot analysis further showed that high-fat diet enhanced the expressions of TLR4, myeloid differentiation primary response protein (MyD88), and NF-κB p65, but decreased inhibitor of NF-κB (IκB) expression. By contrast, MLT therapy decreased the expressions of TLR4, MyD88, and NF-κB p65 and increased IκB expression. This study has demonstrated that MLT ameliorates lipid metabolism, VED, and inflammation and inhibits the progression of atherosclerosis in high-fat-fed rabbits. Moreover, our study indicates for the first time that suppression of the TLR4/NF-κB system in local vasculature with atherosclerotic damage is important for the protective effects of MLT.


Assuntos
Aterosclerose/tratamento farmacológico , Inflamação/tratamento farmacológico , Melatonina/uso terapêutico , NF-kappa B/metabolismo , Receptor 4 Toll-Like/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Masculino , Coelhos
20.
PLoS One ; 8(5): e65702, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23741509

RESUMO

BACKGROUND: In a swine model of acute myocardial infarction (AMI), Statins can enhance the therapeutic efficacy of mesenchymal stem cell (MSCs) transplantation. However, the mechanisms remain unclear. This study aims at assessing whether atorvastatin (Ator) facilitates the effects of MSCs through activation of nitric oxide synthase (NOS), especially endothelial nitric oxide synthase (eNOS), which is known to protect against ischemic injury. METHODS AND RESULTS: 42 miniswines were randomized into six groups (n = 7/group): Sham operation; AMI control; Ator only; MSC only, Ator+MSCs and Ator+MSCs+NG-nitrol-L-arginine (L-NNA), an inhibitor of NOS. In an open-heart surgery, swine coronary artery ligation and reperfusion model were established, and autologous bone-marrow MSCs were injected intramyocardium. Four weeks after transplantation, compared with the control group, Ator+MSCs animals exhibited decreased defect areas of both "perfusion" defined by Single-Photon Emission Computed Tomography (-6.2±1.8% vs. 2.0±5.1%, P = 0.0001) and "metabolism" defined by Positron Emission Tomography (-3.00±1.41% vs. 4.20±4.09%, P = 0.0004); Ejection fraction by Magnetic Resonance Imaging increased substantially (14.22±12.8% vs. 1.64±2.64%, P = 0.019). In addition, indices of inflammation, fibrosis, and apoptosis were reduced and survivals of MSCs or MSC-derived cells were increased in Ator+MSCs animals. In Ator or MSCs alone group, perfusion, metabolism, inflammation, fibrosis or apoptosis were reduced but there were no benefits in terms of heart function and cell survival. Furthermore, the above benefits of Ator+MSCs treatment could be partially blocked by L-NNA. CONCLUSIONS: Atorvastatin facilitates survival of implanted MSCs, improves function and morphology of infarcted hearts, mediated by activation of eNOS and alleviated by NOS inhibitor. The data reveal the cellular and molecular mechanism for anti-AMI therapy with a combination of statin and stem cells.


Assuntos
Ácidos Heptanoicos/farmacologia , Transplante de Células-Tronco Mesenquimais , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Óxido Nítrico Sintase/metabolismo , Pirróis/farmacologia , Animais , Apoptose/efeitos dos fármacos , Atorvastatina , Proteína C-Reativa/metabolismo , Modelos Animais de Doenças , Ativação Enzimática/efeitos dos fármacos , Fibrose , Ácidos Heptanoicos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Inflamação/metabolismo , Inflamação/patologia , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Pirróis/administração & dosagem , Suínos , Tomografia Computadorizada de Emissão de Fóton Único , Função Ventricular Esquerda/efeitos dos fármacos
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