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1.
Signal Transduct Target Ther ; 6(1): 329, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471087

RESUMO

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

2.
Catheter Cardiovasc Interv ; 97 Suppl 2: 988-995, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33734575

RESUMO

OBJECTIVES: This study sought to compare the efficacy and clinical safety of the LONGTY drug-coated balloon (DCB) with those of SeQuent Please DCB in patients with in-stent restenosis (ISR). BACKGROUND: Although DCB technologies have evolved, little is known about the clinical efficacy of the new-generation LONGTY DCB. METHODS: This was a prospective, multicenter, randomized, noninferiority trial comparing LONGTY DCB with SeQuent Please DCB in patients with ISR. The primary endpoint was target lesion late lumen loss at 9 months' follow-up. RESULTS: A total of 211 patients with ISR from 13 Chinese sites were included (LONGTY DCB, n = 105; SeQuent Please DCB, n = 106). Device success was achieved in all patients. At the 9 month angiographic follow-up, target lesion late lumen loss was 0.35 ± 0.42 mm with LONGTY and 0.38 ± 0.45 mm with SeQuent Please (p for noninferiority <.001). The target lesion revascularization rates at 1 year were similar in both DCB groups (15.24 vs. 13.21%; p = .673). Over an extended follow-up of 2 years, the clinical endpoints, including cardiac death, myocardial infarction, and thrombus rate, were extremely low and similar in both groups. CONCLUSIONS: In this multicenter, head-to-head, randomized trial, the new-generation LONGTY DCB was noninferior to the SeQuent Please DCB for the primary endpoint of target lesion late lumen loss at 9 months.

3.
Med Sci Monit ; 27: e929626, 2021 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-33486501

RESUMO

BACKGROUND Angiopoietinlike protein 5 (ANGPTL5) is an adipocytokine and has an important role in metabolic processes including lipid metabolism, obesity, and type 2 diabetes mellitus. On the basis of these roles, the present study aimed to investigate the level and role of plasma ANGPTL5 in metabolic syndrome (MS) patients. MATERIAL AND METHODS A total of 139 participants was enrolled in this study; 69 of them were diagnosed with MS. Plasma ANGPTL5 levels were measured by enzyme-linked immunosorbent assay. Sex, age, and other laboratory tests were compared statistically. Correlations between ANGPTL5 and biochemical parameters such as lipid levels and insulin resistance were all evaluated statistically. RESULTS In patients with MS, plasma ANGPTL5 levels were higher than in those without MS (P<0.05). Moreover, after adjusting for the glucose profiles, positive correlations were found between plasma ANGPTL5 levels and body mass index (BMI), waist circumference, and waist-hip ratio (WHR); a weak negative correlation was found between ANGPTL5 concentration and high-density lipoprotein cholesterol. After controlling the lipid profiles, positive correlations were found between ANGPTL5 concentration and BMI, WHR, fasting plasma glucose, fasting insulin, glycated hemoglobin, and homeostatic model assessment (HOMA) of insulin resistance; a negative correlation was found between plasma ANGPTL5 concentration and HOMA of ß-cell function. The area under the curve was approximately 0.912 in receiver operating characteristic curve analysis. CONCLUSIONS The findings in the present study showed that plasma ANGPTL5 was more positively correlated with glucose metabolism disorders than with lipid metabolism disorders in patients with MS, which suggested that ANGPTL5 might serve as a potential and useful clinical predictor of MS.


Assuntos
Proteínas Semelhantes a Angiopoietina/sangue , Proteínas Semelhantes a Angiopoietina/genética , Transtornos do Metabolismo de Glucose/sangue , Transtornos do Metabolismo de Glucose/genética , Síndrome Metabólica/sangue , Síndrome Metabólica/genética , Feminino , Transtornos do Metabolismo de Glucose/complicações , Humanos , Masculino , Síndrome Metabólica/complicações , Pessoa de Meia-Idade
4.
Neurotox Res ; 39(3): 720-739, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32955723

RESUMO

The activation of microglia is a hallmark of neuroinflammation and contributes to various neurodegenerative diseases. Chronic inorganic arsenic exposure is associated with impaired cognitive ability and increased risk of neurodegeneration. The present study aimed to investigate whether chronic inorganic arsenic-induced learning and memory impairment was associated with microglial activation, and how organic (DMAV 600 µM, MMAV 0.1 µM) and inorganic arsenic (NaAsO2 0.6 µM) affect the microglia. Male C57BL/6J mice were divided into two groups: a control group and a group exposed to arsenic in their drinking water (50 mg/L NaAsO2 for 24 weeks). The Morris water maze was performed to analyze neuro-behavior and transmission electron microscopy was used to assess alterations in cellular ultra-structures. Hematoxylin-eosin and Nissl staining were used to observe pathological changes in the cerebral cortex and hippocampus. Flow cytometry was used to reveal the polarization of the arsenic-treated microglia phenotype and GC-MS was used to assess metabolomic differences in the in vitro microglia BV-2 cell line model derived from mice. The results showed learning and memory impairments and activation of microglia in the cerebral cortex and dentate gyrus (DG) zone of the hippocampus, in mice chronically exposed to arsenic. Flow cytometry demonstrated that BV-2 cells were activated with the treatment of different arsenic species. The GC-MS data showed three important metabolites to be at different levels according to the different arsenic species used to treat the microglia. These included tyrosine, arachidonic acid, and citric acid. Metabolite pathway analysis showed that a metabolic pathways associated with tyrosine metabolism, the dopaminergic synapse, Parkinson's disease, and the citrate cycle were differentially affected when comparing exposure to organic arsenic and inorganic arsenic. Organic arsenic MMAV was predominantly pro-inflammatory, and inorganic arsenic exposure contributed to energy metabolism disruptions in BV-2 microglia. Our findings provide novel insight into understanding the neurotoxicity mechanisms of chronic arsenic exposure and reveal the changes of the metabolome in response to exposure to different arsenic species in the microglia.

5.
Cell Cycle ; 19(9): 1012-1021, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32233984

RESUMO

Numerous researches show that MicroRNAs (miRNAs) participate in tumorigenesis, progression, recurrence and drug resistance of malignant tumors, including laryngocarcinoma. miR-552 works as an oncogene in both colorectal cancer and liver cancer. However, the potential role of miR-552 in laryngocarcinoma is unknown. Herein, we for first found that miR-552 expression was upregulated in laryngocarcinoma tissues compared with their normal controls. Moreover, miR-552 expression was also increasing in the laryngocarcinoma cells. miR-552 interference inhibited the proliferation and metastasis of laryngocarcinoma cells in vitro and in vivo. Mechanically, bioinformatics and luciferase reporter analysis identified p53 as a direct target of miR-552. miR-552 knockdown upregulated the p53 mRNA and protein expression in laryngocarcinoma cells. miR-552 expression was negatively associated with p53 expression in laryngocarcinoma tissues. More importantly, the p53 siRNA or p53 overexpression virus abrogated the discrepancy of growth and metastasis capacity between miR-552 interference laryngocarcinoma cells and control cells.

6.
J Cardiovasc Transl Res ; 13(5): 677-685, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32020504

RESUMO

Whether intra-myocardial delivery of hydrogel can prevent post-infarct heart failure (HF) in a long follow-up period, especially after it is degraded, remains unclear. In this study, Dex-PCL-HEMA/PNIPAAm (DPHP) hydrogel was delivered into peri-infarct myocardium of rat when coronary artery was ligated, while PBS was employed as control. Twelve weeks later, compared with control, left ventricle remodeling was attenuated and cardiac function was preserved; serum brain natriuretic peptide, cardiac aldosterone, and pulmonary congestion were suppressed in hydrogel group. Pro-fibrogenic mRNA increased in infarct area while decreased in remote zone, as well as hypertrophic mRNA. These data proves DPHP hydrogel suppresses ventricular remodeling and HF by promoting fibrotic healing in infarct area and inhibiting reactive fibrosis and hypertrophy in remote zone. Timely intra-myocardial hydrogel implantation is an effective strategy to inhibit post-infarct cardiac remodeling and have a long-term beneficial effect even after it has been biodegraded.


Assuntos
Insuficiência Cardíaca/prevenção & controle , Hipertrofia Ventricular Esquerda/prevenção & controle , Infarto do Miocárdio/tratamento farmacológico , Disfunção Ventricular Esquerda/prevenção & controle , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Implantes Absorvíveis , Animais , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca/etiologia , Insuficiência Cardíaca/fisiopatologia , Hidrogéis , Hipertrofia Ventricular Esquerda/etiologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , Ratos Sprague-Dawley , Fatores de Tempo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/fisiopatologia
7.
Front Pharmacol ; 11: 616813, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33574759

RESUMO

Arctigenin, one of the active ingredients extracted from Great Burdock (Arctium lappa) Achene, has been found to relieve myocardial infarction injury. However, the specific mechanism of Arctigenin against myocardial infarction remains largely unknown. Here, both acute myocardial ischemia-reperfusion injury (AMI/R) rat model and oxygen glucose deprivation (OGD)-induced myocardial cell injury model were constructed to explore the underlying role of AMPK/SIRT1 pathway in Arctigenin-mediated effects. The experimental data in our study demonstrated that Arctigenin ameliorated OGD-mediated cardiomyocytes apoptosis, inflammation and oxidative stress in a dose-dependent manner. Besides, Arctigenin activated AMPK/SIRT1 pathway and downregulated NF-κB phosphorylation in OGD-treated cardiomyocytes, while inhibiting AMPK or SIRT1 by the Compound C (an AMPK inhibitor) or SIRT1-IN-1 (a SIRT1 inhibitor) significantly attenuated Arctigenin-exerted protective effects on cardiomyocytes. In the animal experiments, Arctigenin improved the heart functions and decreased infarct size of the AMI/R-rats, accompanied with downregulated oxidative stress, inflammation and apoptotic levels in the heart tissues. What's more, Arctigenin enhanced the AMPK/SIRT1 pathway and repressed NF-κB pathway activation. Taken together, our data indicated that Arctigenin reduced cardiomyocytes apoptosis against AMI/R-induced oxidative stress and inflammation at least via AMPK/SIRT1 pathway.

8.
Kardiol Pol ; 77(10): 951-959, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31434864

RESUMO

BACKGROUND: Ischemic cardiomyopathy (ICM) resulting from coronary artery disease is a major cause of heart failure. The identification and quantification of differentially expressed proteins in patients with ICM may potentially lead to more effective diagnostic workup and treatment. AIMS: Liquid chromatography coupled to tandem mass spectrometry analysis was applied to identify differentially expressed proteins in individuals with ICM. METHODS: To identify proteins involved in the molecular mechanisms of ICM, we quantitatively analyzed the left ventricular proteome profiles of patients with ICM who had undergone heart transplantation. Liquid chromatography coupled to tandem mass spectrometry, which presents better comprehensiveness and accuracy of quantification than 2­dimensional electrophoresis, in combination with bioinformatics was applied to analyze cardiac samples and identify proteins that were differentially expressed in the left ventricles of 6 patients with ICM compared with 7 normal heart donors. RESULTS: A total of 1723 proteins was successfully quantified in 2 repeated experiments. Out of those, 104 proteins were upregulated and 63 proteins were downregulated in the left ventricles of individuals with ICM. For all these altered proteins, gene ontology (GO) analysis, the Kyoto Encyclopedia of Genes and Genomes pathway mapping, and protein interaction analysis were performed, which showed that most of the proteins were related to the extracellular matrix, metabolism, immune response, muscle contraction, cytoskeleton organization, transcription / translation, and signal transduction. Most importantly, in response to an ischemic stimulus, the C1 inhibitor SERPING1 helped to compensate for increases in complement activation through complement inhibition. CONCLUSIONS: Collectively, these differentially expressed proteins represent potential novel diagnostic and therapeutic targets for the treatment of patients with ICM.


Assuntos
Cardiomiopatias/genética , Ventrículos do Coração/metabolismo , Isquemia Miocárdica/genética , Proteoma , Cardiomiopatias/metabolismo , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/metabolismo
9.
Clin Epigenetics ; 11(1): 112, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31370883

RESUMO

SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein 2 (SMYD2) is a protein methyltransferase that methylates histone H3 at lysine 4 (H3K4) or lysine 36 (H3K36) and diverse nonhistone proteins. SMYD2 activity is required for normal organismal development and the regulation of a series of pathophysiological processes. Since aberrant SMYD2 expression and its dysfunction are often closely related to multiple diseases, SMYD2 is a promising candidate for the treatment of these diseases, such as cardiovascular disease and cancer. Here, we present an overview of the complex biology of SMYD2 and its family members and their context-dependent nature. Then, we discuss the discovery, structure, inhibitors, roles, and molecular mechanisms of SMYD2 in distinct diseases, with a focus on cardiovascular disease and cancer.


Assuntos
Doenças Cardiovasculares/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias/metabolismo , Doenças Cardiovasculares/tratamento farmacológico , Epigênese Genética , Regulação da Expressão Gênica , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Histona-Lisina N-Metiltransferase/química , Histonas/metabolismo , Humanos , Metilação , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico
10.
Int J Oncol ; 54(4): 1245-1255, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30720112

RESUMO

Hypopharyngeal carcinoma (HPC) is an aggressive malignancy with the worst prognosis among all head and neck cancers. MicroRNAs (miRNAs) are involved in the development of many human cancers, and may function as oncogenes or tumor suppressors. The present study aimed to evaluate the effects of miRNA (miR)­194­5p on the proliferation and invasion of HPC cells and to identify the potential regulatory mechanism. First, miR­194­5p and Smad ubiquitin regulatory factor 1 (SMURF1) expression levels were examined in HPC tissues. Subsequently, to explore the effects of miR­194­5p on SMURF1, a dual­luciferase reporter gene assay was performed to verify the target relationship. To define the role of miR­194­5p in HPC progression, miR­194­5p upregulation and depletion were used to evaluate its effects on cell viability, invasion and migration. SMURF1 silencing and rapamycin [an inhibitor of the mammalian target of rapamycin (mTOR) signaling pathway] treatment were also used to analyze the regulatory mechanism in HPC. Finally, tumor growth was assessed in xenografted tumors in nude mice. SMURF1 was demonstrated to be highly expressed, whereas miR­194­5p was poorly expressed in HPC tissues; SMURF1 was identified as a target gene of miR­194­5p. FaDu hypopharyngeal squamous cell carcinoma cells treated with miR­194­5p mimics exhibited decreased viability, invasion and migration. The results indicated that miR­194­5p may inactivate the mTOR signaling pathway by targeting SMURF1. In addition, the in vivo experiments further verified these regulatory effects. These data suggested that miR­194­5p­targeted SMURF1 inhibition may be involved in the disruption of HPC progression through the repression of the mTOR signaling pathway.


Assuntos
Carcinoma de Células Escamosas/patologia , Neoplasias Hipofaríngeas/patologia , MicroRNAs/genética , Ubiquitina-Proteína Ligases/genética , Regulação para Cima , Regiões 3' não Traduzidas , Idoso , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Invasividade Neoplásica , Transplante de Neoplasias , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/metabolismo
11.
Environ Toxicol ; 34(2): 103-111, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30375170

RESUMO

Intake of arsenic (As) via drinking water has been a serious threat to global public health. Though there are numerous reports of As neurotoxicity, its pathogenesis mechanisms remain vague especially its chronic effects on metabolic network. Hippocampus is a renowned area in relation to learning and memory, whilst recently, cerebellum is argued to be involved with process of cognition. Therefore, the study aimed to explore metabolomics alternations in these two areas after chronic As exposure, with the purpose of further illustrating details of As neurotoxicity. Twelve 3-week-old male C57BL/6J mice were divided into two groups, receiving deionized drinking water (control group) or 50 mg/L of sodium arsenite (via drinking water) for 24 weeks. Learning and memory abilities were tested by Morris water maze (MWM) test. Pathological and morphological changes of hippocampus and cerebellum were captured via transmission electron microscopy (TEM). Metabolic alterations were analyzed by gas chromatography-mass spectrometry (GC-MS). MWM test confirmed impairments of learning and memory abilities of mice after chronic As exposure. Metabolomics identifications indicated that tyrosine increased and aspartic acid (Asp) decreased simultaneously in both hippocampus and cerebellum. Intermediates (succinic acid) and indirect involved components of tricarboxylic acid cycle (proline, cysteine, and alanine) were found declined in cerebellum, indicating disordered energy metabolism. Our findings suggest that these metabolite alterations are related to As-induced disorders of amino acids and energy metabolism, which might therefore, play an important part in mechanisms of As neurotoxicity.


Assuntos
Arsênio/toxicidade , Cerebelo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Poluentes Químicos da Água/toxicidade , Animais , Arsênio/metabolismo , Cerebelo/metabolismo , Cerebelo/ultraestrutura , Cromatografia Gasosa-Espectrometria de Massas , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Metabolômica/métodos , Camundongos , Camundongos Endogâmicos C57BL , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos , Poluentes Químicos da Água/metabolismo
12.
Toxicol Sci ; 166(1): 65-81, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085273

RESUMO

Benzo[a]pyrene (B[a]P) is a common environmental pollutant that is neurotoxic to mammals, which can cause changes to hippocampal function and result in cognitive disorders. The mechanisms of B[a]P-induced impairments are complex .To date there have been no studies on the association of epigenetic, transcriptomic, and metabolomic changes with neurotoxicity after B[a]P exposure. In the present study, we investigated the global effect of B[a]P on DNA methylation patterns, noncoding RNAs (ncRNAs) expression, coding RNAs expression, and metabolites in the rat hippocampus. Male Sprague Dawley rats (SD rats) received daily gavage of B[a]P (2.0 mg/kg body weight [BW]) or corn oil for 7 weeks. Learning and memory ability was analyzed using the Morris water maze (MWM) test and change to cellular ultrastructure in the hippocampus was analyzed using electron microscope observation. Integrated analysis of epigenetics, transcriptomics, and metabolomics was conducted to investigate the effect of B[a]P exposure on the signaling and metabolic pathways. Our results suggest that B[a]P could lead to learning and memory deficits, likely as a result of epigenetic and transcriptomic changes that further affected the expression of CACNA1C, Tpo, etc. The changes in expression ultimately affecting LTP, tyrosine metabolism, and other important metabolic pathways.


Assuntos
Benzo(a)pireno/toxicidade , Metilação de DNA/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Redes e Vias Metabólicas/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Relação Dose-Resposta a Droga , Epigenômica , Perfilação da Expressão Gênica , Hipocampo/metabolismo , Hipocampo/ultraestrutura , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Redes e Vias Metabólicas/genética , Metabolômica , Síndromes Neurotóxicas/metabolismo , Síndromes Neurotóxicas/patologia , Ratos , Ratos Sprague-Dawley , Transdução de Sinais
13.
Pak J Pharm Sci ; 29(5): 1513-1517, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27731805

RESUMO

This research is to explore the effects of traditional Chinese medicine Ginseng-spikenard heart-nourishing capsule on the inactivation of c-type Kv1.4 channels (Kv1.4∆N) in Xenopus laevis oocytes with two-electrode voltageclamp technique. Defolliculated oocytes (stage V-VI) were injected with transcribed cRNAs of ferret Kv1.4δN channels. During recording, oocytes were continuously perfused with ND96 solution (control group) and solution prepared from Ginseng-spikenard heart-nourishing capsule (experimental group). Results found that, at the command potential of +50 mV, the current of experimental group was reduced to 48.33±4.0% of that in control group. The inactivation time constants in control and experimental groups were 2962.56±175.35 ms and 304.13±36.22ms, respectively (P<0.05, n=7). The recovery time of fKv1.4∆N channel after inactivation in control group and experimental groups was 987±68.39 ms and 1734.15±98.45 ms, respectively (P<0.05, n=5). Ginseng-spikenard heart-nourishing capsule can inhibit the Kv1.4δN channel, which may be one of the mechanisms of underlying antiarrhythmia.


Assuntos
Antiarrítmicos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Canal de Potássio Kv1.4/antagonistas & inibidores , Bloqueadores dos Canais de Potássio/farmacologia , Animais , Feminino , Furões , Técnicas de Transferência de Genes , Cinética , Canal de Potássio Kv1.4/genética , Canal de Potássio Kv1.4/metabolismo , Potenciais da Membrana , Oócitos , Xenopus laevis
14.
Oncol Rep ; 35(3): 1385-94, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26707908

RESUMO

The present study investigated the effects of microRNA-124-3p (miR-124-3p) expression on nasopharyngeal carcinoma (NPC) cells and its relevant mechanism. A total of 90 NPC tissues and 85 postnasal catarrh tissues were collected. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect tissue samples and expression of miR-124-3p in CNE1, CNE2, SUNE1, H0NE1, 5-8F, 6-10B and C666-1 NPC cell line and immortalized nasopharyngeal epithelial cells line (NP69). Overexpressed miRNA-124-3p in CNE-2 was downregulated, and low-expressed miRNA­124-3p in C666-1 was upregulated by liposome-mediated transfection. Cell Counting Kit-8 (CCK-8), flow cytometry, the scratch test, Transwell migration assay and Boyden chamber assays were used to detect cell proliferation, apoptosis, migration and invasion. The target gene of miRNA-124-3 calculated by bioinformatics was further determined using dual-luciferase system. Protein levels of the signal transducers and activators of transcription 3 (STAT3), phospho-STAT3 (p-STAT3), mouse anti-human cyclin D2 (CCND2) and matrix metalloproteinase-2 (MMP-2) were tested by western blotting. miRNA-124-3p expression in NPC was markedly downregulated compared to postnasal catarrh tissues (P<0.001); miRNA-124-3p expression showed close linkage with clinical stages, regional lymph node involvement and T stages (all P<0.001). miRNA-124-3p expression was lower in the 7 NPC cell lines than NP69 cells (all P<0.05). After upregulation of miR-124-3p, proliferation, apoptosis, migration and invasion of C666-1 cells were suppressed; while after downregulation of miR-124-3p, CNE2 cells were increased (all P<0.05). Expression of STAT3, p-STAT3, CCND2 and MMP-2 in C666-1 cells was decreased after transfection with miRNA-124-3p, and the above protein expression in CNE-2 cells was increased after inhibition of miRNA-124-3p (all P<0.05). To sum up, this study shows that miR-124-3p may negatively regulate the transcription of the STAT3 by interfering with its 3'UTR, and the degradation of STAT3 affects its downstream expression of such as p-STAT3, CCND2 and MMP-2, thereby promoting NPC cells apoptosis and inhibiting proliferation, migration and invasion of NPC cells.


Assuntos
Ciclina D2/biossíntese , Metaloproteinase 2 da Matriz/biossíntese , MicroRNAs/genética , Neoplasias Nasofaríngeas/genética , Fator de Transcrição STAT3/biossíntese , Regiões 3' não Traduzidas , Animais , Apoptose/genética , Carcinoma , Linhagem Celular Tumoral , Proliferação de Células/genética , Ciclina D2/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Metaloproteinase 2 da Matriz/genética , Camundongos , MicroRNAs/metabolismo , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/patologia , Metástase Neoplásica , Fator de Transcrição STAT3/genética
15.
Exp Physiol ; 101(2): 260-71, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26556551

RESUMO

NEW FINDINGS: What is the central question of this study? The enzyme system that is responsible for extracellular matrix (ECM) turnover is the matrix metalloproteinases (MMPs), which can be blocked by the tissue inhibitors of MMPs (TIMPs). Whether renal sympathetic denervation (RSD) is able to ameliorate post-myocardial infarction left ventricular remodelling through attenuation of ECM via regulation of MMP activity and/or the MMP-TIMP complex remains unknown. What is the main finding and its importance? Renal sympathetic denervation has therapeutic effects on post-myocardial infarction left ventricular remodelling, probably by attenuating the ECM through regulation of the MMP9-TIMP1 complex in the transforming growth factor-ß1 (a profibrotic cytokine that accelerates ECM remodelling after ischaemia) signalling pathway. Whether renal sympathetic denervation (RSD) is able to ameliorate post-myocardial infarction (post-MI) left ventricular (LV) remodelling by attenuation of the extracellular matrix via regulation of matrix metalloproteinase (MMP) activity and/or the MMP-tissue inhibitor of matrix metalloproteinase (TIMP) complex remains unknown. Sixty-five Sprague-Dawley rats were randomly divided into the following four groups: normal (N, n = 15), RSD (RSD, n = 15), myocardial infarction (MI, n = 15) and RSD 3 days after MI (MI3d+RSD, n = 20). The bilateral renal nerves were surgically denervated 3 days after MI had been induced by coronary artery ligation. Left ventricular function was assessed using echocardiography and a Millar catheter at 6 weeks post-MI. Plasma noradrenaline, angiotensin II and aldosterone, collagen volume fraction, transforming growth factor-ß1 (TGF-ß1), MMP2, MMP9 and TIMP1 in heart tissue were measured 6 weeks after MI. In rats with MI3d+RSD compared with MI rats, RSD improved systolic and diastolic function, resulting in an improvement in ejection fraction (P < 0.05), fractional shortening (P < 0.05) and LV internal dimension in systole (P < 0.05) and diastole (P < 0.05). Additionally, RSD treatment decreased left ventricular end-diastolic pressure (P < 0.05) and increased LV systolic pressure (P < 0.05) and maximal and minimal rate of LV pressure (both P < 0.05). Meanwhile, RSD reduced collagen content (P < 0.01). TIMP1 was upregulated (P < 0.05), whereas MMP2, MMP9 and TGF-ß1 were downregulated in the LV of RSD-treated animals (P < 0.05). Renal sympathetic denervation has therapeutic effects on post-MI LV remodelling, probably owing to effects on the extracellular matrix by regulation of the MMP9-TIMP1 balance in the TGF-ß1 signalling pathway. Renal sympathetic denervation may be considered as a non-pharmacological approach for the improvement of post-MI cardiac dysfunction.


Assuntos
Ventrículos do Coração/fisiopatologia , Rim/inervação , Infarto do Miocárdio/fisiopatologia , Função Ventricular Esquerda/fisiologia , Remodelação Ventricular/fisiologia , Animais , Pressão Sanguínea/fisiologia , Colágeno/metabolismo , Diástole/fisiologia , Ventrículos do Coração/metabolismo , Masculino , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Infarto do Miocárdio/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Simpatectomia/métodos , Sístole/fisiologia , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
16.
Exp Ther Med ; 9(6): 2285-2292, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26136975

RESUMO

Paclitaxel-coated balloons (PCBs) have become attractive alternative treatment options for patients with in-stent restenosis (ISR); however, the safety and efficacy of PCBs in comparison with those of conventional therapies are less well defined. The aim of this meta-analysis was to systematically review the efficacy and safety of PCBs for patients with ISR using comparisons with control groups. Electronic databases, such as MEDLINE, Embase and the Cochrane Central Register of Controlled Trials, were searched, and eligible studies that compared PCBs with uncoated balloons (UCBs) or drug-eluting stents (DESs) in patients with ISR were considered. Subgroup analyses were performed with different control groups. Nine studies (1,488 patients, 1,608 lesions) were included in the meta-analysis. Compared with patients who underwent UCB angioplasty, those who underwent PCB angioplasty exhibited a clear superiority in late lumen loss (LLL) [weighted mean difference (WMD), -0.46; 95% confidence interval (CI), (-0.59)-(-0.34); P<0.00001] and major adverse cardiac events (MACEs) [odds ratio (OR), 0.21; 95% CI, 0.13-0.33; P<0.00001]. The OR for myocardial infarction (MI) (OR, 0.46; 95% CI, 0.15-1.47; P=0.19) did not reach statistical significance. PCBs were associated with similar outcomes when compared with DESs with regard to LLL (WMD, -0.04; 95% CI, -0.18-0.10; P=0.57), MACEs (OR, 0.74; 95% CI, 0.36-1.53; P=0.42) and the ORs for all endpoints, including total mortality, target lesion revascularization, MI, stent thrombosis and binary restenosis, and no statistically significant differences were found. This meta-analysis showed that PCBs are associated with superior outcomes when compared with UCBs in the management of ISR, and are at least as efficacious and as well tolerated as DESs.

17.
Int Heart J ; 56(2): 163-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25740578

RESUMO

To determine the number and function of naturally occurring CD4(+)CD25(+)FOXP3(+) regulatory T cells (nTregs) in patients with acute coronary syndrome (ACS) and to determine the effects of a low dose of atorvastatin treatment (20 mg/day) on nTregs.Patients with ACS were randomly divided into a group receiving conventional therapy (n = 60) or conventional therapy supplemented with atorvastatin (20 mg/day) (n = 60). A group of healthy volunteers that did not suffer from ACS was used as controls (n = 60). T lymphocytes were isolated from ACS patients, both before and 4 weeks after treatment, or control patients and the percentage of nTregs was determined by flow cytometry. Serum levels of cytokines were determined by enzyme-linked immunosorbent assays. A mixed lymphocyte reaction was used to determine the ability of nTregs to inhibit proliferation of effector T cells. Quantitative PCR and Western blot were used to analyze (forkhead box P3) FOXP3 mRNA transcript levels and the expression of FOXP3 protein.In ACS patients, the percentage and inhibitory properties of nTregs were reduced, IFN-γ and hsCRP levels were increased, and IL-10 and TGF-ß1 levels were lowered. Atorvastatin treatment increased the percentage and inhibitory ability of nTregs, decreased serum IFN-γ and hsCRP levels, and decreased IL-10 and TGF-ß1 levels, as compared with the non-atorvastatin group.Our findings suggest that nTregs play an atheroprotective role in atherosclerosis. The inhibitory effects of atorvastatin on inflammation in ACS may be due to its beneficial effects on nTregs and restoration of immune homeostasis.


Assuntos
Síndrome Coronariana Aguda/metabolismo , Síndrome Coronariana Aguda/terapia , Ácidos Heptanoicos/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pirróis/uso terapêutico , Linfócitos T Reguladores/fisiologia , Síndrome Coronariana Aguda/imunologia , Adulto , Idoso , Atorvastatina , Antígenos CD4/metabolismo , Citocinas/metabolismo , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo
18.
J Mater Chem B ; 3(27): 5389-5410, 2015 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-32262511

RESUMO

In order to design scaffolds for tissue engineering with proper architectures, organization and properties, a variety of materials and technologies are being developed. In addition to being biocompatible both in their bulk and degraded forms, scaffolds should not only possess appropriate mechanical properties to provide a suitable stress environment, but also be porous and permeable to permit the ingress of cells and nutrients. In this review, we aim to summarize recent advances in electrospun anisotropic architectures such as aligned fibrous arrays, fibrous yarns and bundles, fibrous tubular structures, and porous structures, as well as their formation mechanisms and mechanical properties. In particular, the potential applications of these structure-controlled fibrous constructs in neural regeneration, vascular grafts, cardiac tissue, skeletal muscle regeneration, tendon repair, and cornea repair are presented. Moreover, the current challenges and future opportunities for the use of these scaffolds in research and clinical practice are proposed.

19.
Am J Transl Res ; 7(11): 2159-75, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26807165

RESUMO

Histone lysine methylation plays a critical role in epigenetic regulation of eukaryotes. To date, studies have shown that lysine residues of K4, K9, K27, K36 and K79 in histone H3 and K20 in histone H4 can be modified by histone methyltransferases (HMTs). Such histone methylation can specifically activate or repress the transcriptional activity to play a key role in gene expression/regulation and biological genetics. Importantly, abnormities of patterns or levels of histone methylation in higher eukaryotes may result in tumorigenesis and developmental defects, suggesting histone methylation will be one of the important targets or markers for treating these diseases. This review will outline the structural characteristics, active sites and specificity of HMTs, correlation between histone methylation and human diseases and lay special emphasis on the progress of the research on H3K36 methylation.

20.
Mol Cell Biochem ; 400(1-2): 163-72, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25389006

RESUMO

Atherosclerosis is a chronic inflammatory disease characterized by the formation of plaques inside arteries, leading to narrowing and blockage. Potential therapeutic strategies include expanding the population of regulatory T-cells (Tregs) to enhance atheroprotective immunity, and inhibiting the formation of macrophage foam cells. Here, we studied the effect of bone marrow-derived mesenchymal stem cells (BM-MSCs) on atherosclerotic plaque formation in Apolipoprotein E(-/-) (ApoE-KO) mice, and elucidated the underlying mechanism. BM-MSCs isolated from 4 week-old ApoE-KO mice were evaluated by flow cytometry for expression of MSC-specific markers. Thirty eight week-old ApoE-KO mice were randomly divided into three experimental groups (n = 10 per group): 1. MSC group-received BM-MSCs intravenously; 2. Vehicle group-received DMEM; 3. Control group-did not receive any treatment. Administration of MSCs resulted in a marked decrease in the size of atherosclerotic plaques 3 months after treatment. In addition, the number and function of CD4(+)CD25(+)FOXP3(+) regulatory T-cells (Tregs) in cultured splenocytes, and the expression of FOXP3 at both mRNA and protein levels, was significantly increased in the MSC group. In vitro experiments further indicated that the formation of macrophage foam cells was inhibited by treatment with MSCs, accompanied by a significant downregulation in CD36 and scavenger receptor A (SRA). Our findings suggest that MSCs play an atheroprotective role by enhancing the number and function of Tregs and inhibiting the formation of macrophage foam cells. Hence, administration of MSCs to atherosclerotic patients might have significant clinical benefits.


Assuntos
Aterosclerose/terapia , Macrófagos/patologia , Transplante de Células-Tronco Mesenquimais , Linfócitos T Reguladores/imunologia , Animais , Aterosclerose/imunologia , Aterosclerose/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Células Cultivadas , Citometria de Fluxo , Células Espumosas/imunologia , Células Espumosas/patologia , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Humanos , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Macrófagos/imunologia , Camundongos , Baço/imunologia , Baço/metabolismo , Linfócitos T Reguladores/metabolismo
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