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1.
Cell Death Dis ; 11(2): 97, 2020 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-32029701

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

2.
Cell Death Dis ; 11(1): 22, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924749

RESUMO

Accelerated atherosclerotic calcification is responsible for plaque burden, especially in diabetes. The regulatory mechanism for atherosclerotic calcification in diabetes is poorly characterized. Here we show that deletion of PARP-1, a main enzyme in diverse metabolic complications, attenuates diabetic atherosclerotic calcification and decreases vessel stiffening in mice through Runx2 suppression. Specifically, PARP-1 deficiency reduces diabetic arteriosclerotic calcification by regulating Stat1-mediated synthetic phenotype switching of vascular smooth muscle cells and macrophage polarization. Meanwhile, both vascular smooth muscle cells and macrophages manifested osteogenic differentiation in osteogenic media, which was attenuated by PARP-1/Stat1 inhibition. Notably, Stat1 acts as a positive transcription factor by directly binding to the promoter of Runx2 and promoting atherosclerotic calcification in diabetes. Our results identify a new function of PARP-1, in which metabolism disturbance-related stimuli activate the Runx2 expression mediated by Stat1 transcription to facilitate diabetic arteriosclerotic calcification. PARP-1 inhibition may therefore represent a useful therapy for this challenging complication.

3.
Hypertension ; 72(5): 1189-1199, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30354818

RESUMO

Abdominal aortic aneurysm (AAA) is a common vascular degenerative disease. PARP-1 (poly[ADP-ribose] polymerase 1) is a nuclear enzyme, which plays a critical role in vascular diseases. We hypothesized that PARP-1 inhibition might have protective effects on AAA. In vivo, Ang II (angiotensin II) was continuously infused by a micropump for 28 days to induce AAA in mice. In vitro, aortic endothelial cells and smooth muscle cells were stimulated by Ang II for 24 hours. Ang II infusion increased PARP-1 expression and activity and successfully induced AAA formation partly with a hemorrhage in ApoE-/- mice. Genetic deletion of PARP-1 markedly reduced the AAA incidence, abdominal aortic diameter, macrophage infiltration, ICAM-1 (intercellular adhesion molecule 1) and VCAM-1 (vascular adhesion molecule 1) expression, and MMP (matrix metalloproteinase) expression, as well as MMP activity; but increased smooth muscle cells content and collagens expression in AAA. PARP-1 inhibition by PJ-34 also exerted a protective effect on AAA in mice. In aortic endothelial cells, Ang II-induced oxidative stress and DNA damage, resulting in increased PARP-1 expression and activity. Compared with the control, Ang II increased TNF-α (tumor necrosis factor α) and IL-6 (interleukin-6) secretions, ICAM-1 expression and THP-1 (human acute monocytic leukemia cell line) cells adhesion, while PARP-1 inhibition by siRNA reduced the inflammatory response probably through inhibition of the phosphorylation of ERK (extracellular signal-regulated kinase), NF-κB (nuclear factor-κB), and Akt signaling pathways. In smooth muscle cells, Ang II promoted cell migration, proliferation, and apoptosis, reduced collagens expression, but increased MMPs expression, while PARP-1 deletion alleviated these effects partly by reducing NF-κB-targeted MMP-9 expression. PARP-1 inhibition might be a feasible strategy for the treatment of AAA.


Assuntos
Aneurisma da Aorta Abdominal/prevenção & controle , Pressão Sanguínea/fisiologia , Poli(ADP-Ribose) Polimerase-1/metabolismo , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Colágeno/metabolismo , Citocinas/metabolismo , Dano ao DNA/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Molécula 1 de Adesão Intercelular/metabolismo , Camundongos , Camundongos Knockout , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Poli(ADP-Ribose) Polimerase-1/genética , RNA Interferente Pequeno , Transdução de Sinais/efeitos dos fármacos
4.
J Cell Mol Med ; 22(2): 808-822, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29063670

RESUMO

Emerging evidence indicates that irisin provides beneficial effects in diabetes. However, whether irisin influences the development of diabetic cardiomyopathy (DCM) remains unclear. Therefore, we investigated the potential role and mechanism of action of irisin in diabetes-induced myocardial dysfunction in mice. Type 1 diabetes was induced in mice by injecting streptozotocin, and the diabetic mice were administered recombinant r-irisin (low or high dose: 0.5 or 1.5 µg/g body weight/day, I.P.) or PBS for 16 weeks. Irisin treatment did not alter blood glucose levels in the diabetic mice. However, the results of echocardiographical and histopathological assays indicated that low-dose irisin treatment alleviated cardiac fibrosis and left ventricular function in the diabetic mice, whereas high-dose irisin failed to mitigate the ventricular function impairment and increased collagen deposition. The potential mechanism underlying the effect of low-dose irisin involved irisin-mediated inhibition of high glucose-induced endothelial-to-mesenchymal transition (EndMT); conversely, high-dose irisin treatment enhanced high glucose-induced MMP expression by stimulating MAPK (p38 and ERK) signalling and cardiac fibroblast proliferation and migration. Low-dose irisin alleviated DCM development by inhibiting high glucose-induced EndMT. By contrast, high-dose irisin disrupted normal MMP expression and induced cardiac fibroblast proliferation and migration, which results in excess collagen deposition. Thus, irisin can inhibit high glucose-induced EndMT and exert a dose-dependent bidirectional effect on DCM.


Assuntos
Cardiomiopatias Diabéticas/patologia , Fibronectinas/farmacologia , Glucose/toxicidade , Células Endoteliais da Veia Umbilical Humana/patologia , Mesoderma/patologia , Animais , Glicemia/metabolismo , Movimento Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Colágeno/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Experimental/fisiopatologia , Cardiomiopatias Diabéticas/sangue , Cardiomiopatias Diabéticas/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Mesoderma/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Miocárdio/patologia , Fosforilação/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Proteínas Smad/metabolismo , Estreptozocina , Fator de Crescimento Transformador beta/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
5.
J Mol Cell Cardiol ; 114: 334-344, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29269260

RESUMO

Peptidyl-prolyl isomerase Pin1 has been reported to be associated with endothelial dysfunction. However, the role of smooth muscle Pin1 in the vascular system remains unclear. Here, we examined the potential function of Pin1 in smooth muscle cells (SMCs) and its contribution to abdominal aortic aneurysm (AAA) pathogenesis. The level of Pin1 expression was found to be elevated in human AAA tissues and mainly localized to SMCs. We constructed smooth muscle-specific Pin1 knockout mice to explore the role of this protein in AAA formation and to elucidate the underlying mechanisms. AAA formation and elastin degradation were hindered by Pin1 depletion in the angiotensin II-induced mouse model. Pin1 depletion reversed the angiotensin II-induced pro-inflammatory and synthetic SMC phenotype switching via the nuclear factor (NF)-κB p65/Klf4 axis. Moreover, Pin1 depletion inhibited the angiotensin II-induced matrix metalloprotease activities. Mechanically, Pin1 deficiency destabilized NF-κB p65 by promoting its polyubiquitylation. Further, we found STAT1/3 bound to the Pin1 promoter, revealing that activation of STAT1/3 was responsible for the increased expression of Pin1 under angiotensin II stimulation. Thus, these results suggest that Pin1 regulates pro-inflammatory and synthetic SMC phenotype switching and could be a novel therapeutic target to limit AAA pathogenesis.


Assuntos
Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/enzimologia , Apolipoproteínas E/deficiência , Peptidilprolil Isomerase de Interação com NIMA/deficiência , Angiotensina II , Animais , Aneurisma da Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/prevenção & controle , Apolipoproteínas E/metabolismo , Movimento Celular , Proliferação de Células , Citocinas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Camundongos Knockout , Modelos Biológicos , Músculo Liso Vascular/patologia , Miócitos de Músculo Liso/metabolismo , NF-kappa B/metabolismo , Peptidilprolil Isomerase de Interação com NIMA/genética , Peptidilprolil Isomerase de Interação com NIMA/metabolismo , Fenótipo , Regiões Promotoras Genéticas/genética , Fatores de Transcrição STAT/metabolismo , Regulação para Cima
6.
Mol Med Rep ; 16(5): 7513-7519, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-28944890

RESUMO

Paeonol (Pae) is an herbal extract that has attracted extensive attention for its anti­cancer effects demonstrated by a number of studies, which have predominantly demonstrated inhibition of cell proliferation and induction of apoptosis. The influence of Pae on cancer cell metastasis has been less widely reported. The present study aimed to investigate the under­reported effects of Pae on the growth, invasion and migration of poorly differentiated BGC823 gastric cancer cells with strong invasive and metastatic abilities. The anti­proliferative and pro­apoptotic effects of Pae on BGC823 cells were verified by Cell Counting kit­8 and Annexin V­fluorescein isothiocyanate/propidium iodide assays. Cell scratch­wound healing and Transwell methods were applied, and it was demonstrated that Pae could exert inhibitory activities on the invasion and migration of BGC823 cells. Furthermore, it was indicated by western blot analysis that Pae could downregulate the protein expression levels of matrix metalloproteinase (MMP)­2 and ­9 in a concentration­dependent manner, which may support a novel potential mechanism accounting for its anti­cancer effects on gastric cancer.


Assuntos
Acetofenonas/toxicidade , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Humanos , Metaloproteinase 2 da Matriz/genética , Metaloproteinase 9 da Matriz/genética , Neoplasias Gástricas/metabolismo , Neoplasias Gástricas/patologia
7.
Exp Ther Med ; 14(2): 1722-1726, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28810641

RESUMO

Homocysteine (Hcy) is an important and independent risk factor for atherosclerotic diseases, such as coronary artery disease and ischemic cerebrovascular disease. Increased carotid artery intima-media thickness (IMT) is a non-invasive marker of systemic atherosclerosis. Allicin treatment may decrease serum Hcy levels and improve impaired endothelial function in rats with hyperhomocysteinemia (HHcy). The present study hypothesized that allicin has an anti-atherosclerotic effect in coronary heart disease and tested the effects of allicin treatment on carotid artery IMT and plasma Hcy levels in coronary heart disease patients with HHcy. Sixty-two coronary heart disease patients with HHcy were randomly divided into an allicin group and a control group. All patients underwent diagnostic assessment, plasma Hcy assay, blood lipid measurement and B-mode ultrasound of the carotid artery prior to and after treatment. Plasma Hcy levels were determined by high-performance liquid chromatography and fluorescence detection. Carotid artery IMT was calculated using an automated algorithm based on a validated edge-detection technique. After 12 weeks, significant decreases in carotid artery IMT, plasma Hcy levels, total cholesterol and triglycerides were observed in the allicin group (all P<0.05), and the decreases in the allicin group were significantly greater than those in the control group (all P<0.01). These findings suggested that reducing plasma Hcy levels may be useful for preventing the generation and development of atherosclerosis in patients with coronary heart disease. Allicin was able to decrease Hcy levels, total cholesterol and triglycerides as well as carotid artery IMT.

8.
Clin Exp Pharmacol Physiol ; 44(1): 114-122, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27757983

RESUMO

Poly (ADP-ribose) polymerase (PARP) plays an important role in endothelial dysfunction, leading to atherogenesis and vascular-related diseases. However, whether PARP regulates nitric oxide (NO), a key regulator of endothelial function, is unclear so far. We investigated whether inhibition of PARP-1, the most abundant PARP isoform, prevents atherogenesis by regulating NO production and tried to elucidate the possible mechanisms involved in this phenomenon. In apolipoprotein E-deficient (apoE-/- ) mice fed a high-cholesterol diet for 12 weeks, PARP-1 inhibition via treatment with 3,4-dihydro-54-(1-piperindinyl) butoxy-1(2H)-isoquinoline (DPQ) or PARP-1 gene knockout reduced aortic atherosclerotic plaque areas (49% and 46%, respectively). Both the groups showed restored NO production in mouse aortas with reduced arginase II (Arg II) expression compared to that in the controls. In mouse peritoneal macrophages and aortic endothelial cells (MAECs), PARP-1 knockout resulted in lowered Arg II expression. Moreover, phosphorylation of endothelial NO synthase (eNOS) was preserved in the aortas and MAECs when PARP-1 was inhibited. Reduced NO production in vitro due to PARP-1 deficiency could be restored by treating the MAECs with oxidized low-density lipoprotein treatment, but this effect could not be achieved with peritoneal macrophages, which was likely due to a reduction in the expression of induced NOS expression. Our findings indicate that PARP-1 inhibition may attenuate atherogenesis by restoring NO production in endothelial cells and thus by reducing Arg II expression and consequently arginase the activity.


Assuntos
Aorta/metabolismo , Arginase/metabolismo , Aterosclerose/metabolismo , Regulação para Baixo/fisiologia , Óxido Nítrico/biossíntese , Poli(ADP-Ribose) Polimerase-1/deficiência , Animais , Aterosclerose/induzido quimicamente , Aterosclerose/prevenção & controle , Células Cultivadas , Colesterol na Dieta/efeitos adversos , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
9.
Oncotarget ; 7(21): 31053-66, 2016 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-27105518

RESUMO

Cardiac fibrosis is an important pathological process of diabetic cardiomyopathy, the underlying mechanism remains elusive. This study sought to identify whether inhibition of Myocyte enhancer factor 2A (MEF2A) alleviates cardiac fibrosis by partially regulating Endothelial-to-mesenchymal transition (EndMT). We induced type 1 diabetes mellitus using the toxin streptozotocin (STZ) in mice and injected with lentivirus-mediated short-hairpin RNA (shRNA) in myocardium to inhibit MEF2A expression. Protein expression, histological and functional parameters were examined twenty-one weeks post-STZ injection. We found that Diabetes mellitus increased cardiac MEF2A expression, aggravated cardiac dysfunction and myocardial fibrosis through the accumulation of fibroblasts via EndMT. All of these features were abolished by MEF2A inhibition. MEF2A gene silencing by shRNA in cultured human umbilical vein endothelial cells (HUVECs) ameliorated high glucose-induced phenotypic transition and acquisition of mesenchymal markers through interaction with p38MAPK and Smad2. We conclude that inhibition of endothelial cell-derived MEF2A might be beneficial in the prevention of diabetes mellitus-induced cardiac fibrosis by partially inhibiting EndMT through interaction with p38MAPK and Smad2.


Assuntos
Diabetes Mellitus Experimental/terapia , Fibrose/terapia , Fatores de Transcrição MEF2/antagonistas & inibidores , Miocárdio/patologia , Animais , Células Cultivadas , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Transição Epitelial-Mesenquimal , Fibrose/genética , Fibrose/metabolismo , Fibrose/patologia , Células Endoteliais da Veia Umbilical Humana , Humanos , Fatores de Transcrição MEF2/biossíntese , Fatores de Transcrição MEF2/genética , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/metabolismo , Transdução de Sinais , Transfecção
10.
Oncotarget ; 7(1): 66-80, 2016 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-26623724

RESUMO

Prohibitin (PHB) is a highly conserved protein implicated in various cellular functions including proliferation, apoptosis, tumor suppression, transcription, and mitochondrial protein folding. However, its function in diabetic cardiomyopathy (DCM) is still unclear. In vivo, type 2 diabetic rat model was induced by using a high-fat diet and low-dose streptozotocin. Overexpression of the PHB protein in the model rats was achieved by injecting lentivirus carrying PHB cDNA via the jugular vein. Characteristics of type 2 DCM were evaluated by metabolic tests, echocardiography and histopathology. Rats with DCM showed severe insulin resistance, left ventricular dysfunction, fibrosis and apoptosis. PHB overexpression ameliorated the disease. Cardiofibroblasts (CFs) and H9c2 cardiomyoblasts were used in vitro to investigate the mechanism of PHB in altered function. In CFs treated with HG, PHB overexpression decreased expression of collagen, matrix metalloproteinase activity, and proliferation. In H9c2 cardiomyoblasts, PHB overexpression inhibited apoptosis induced by HG. Furthermore, the increased phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 was significantly decreased and the inhibited phosphorylation of Akt was restored in DCM. Therefore, PHB may be a new therapeutic target for human DCM.


Assuntos
Cardiomiopatias/fisiopatologia , Diabetes Mellitus Experimental/fisiopatologia , Diabetes Mellitus Tipo 2/fisiopatologia , Miocárdio/metabolismo , Proteínas Repressoras/metabolismo , Animais , Animais Recém-Nascidos , Apoptose/genética , Western Blotting , Cardiomiopatias/etiologia , Cardiomiopatias/genética , Linhagem Celular , Células Cultivadas , Diabetes Mellitus Experimental/etiologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/genética , Dieta Hiperlipídica/efeitos adversos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Fibrose/genética , Expressão Gênica , Testes de Função Cardíaca , Humanos , Resistência à Insulina/genética , Masculino , Microscopia de Fluorescência , Miocárdio/patologia , Fosforilação , Ratos Sprague-Dawley , Proteínas Repressoras/genética , Disfunção Ventricular Esquerda/genética
11.
Exp Ther Med ; 10(4): 1394-1400, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26622496

RESUMO

This study was designed to explore the protective effect of allicin on aortic endothelial cell injury induced by high glucose/hypoxia and to investigate the corresponding mechanisms. The primary-cultured murine aortic endothelial cells were subcultured. The third passage of cells was adopted and randomly divided into five groups: The normal group (NG), the mannitol group (MG), the high-glucose/hypoxia group (HG), the allicin group (AG) and the protein kinase C (PKC) inhibitor group (GG). The general morphology was observed under an inverted phase-contrast microscope and cell viability was assessed using the MTT assay. Intracellular reactive oxygen species (ROS) levels in the endothelial cells were quantified using dihydroethidium staining. The levels of 8-hydroxydeoxyguanosine (8-OHdG), nuclear factor-κB (NF-κB), NADPH oxidase 4 (Nox4) and hypoxia-inducible factor-1α (HIF-1α) and the activity of PKC were measured using ELISA. A quantitative polymerase chain reaction (qPCR) was adopted to evaluate the mRNA expression of Nox4, HIF-1α and NF-κB. The altered cell morphology observed in HG was notably ameliorated in the AG and GG. The protein levels of 8-OHdG, NF-κB, Nox4, HIF-1α and PKC in the HG were higher than those in the other groups. Furthermore, the cell viability in the AG was significantly increased and the protein levels of 8-OHdG, NF-κB, Nox4, HIF-1α and PKC were significantly decreased compared with those in the HG. The ROS production was found to be increased in the HG cells, while there was a significant decrease in the AG cells. These data indicate that allicin exerts a protective effect against high glucose/hypoxia-induced injury in aortic endothelial cells through its antioxidative action, which may involve the inhibition of the PKC pathway and regulation of HIF-1α.

12.
Eur J Pharmacol ; 714(1-3): 163-9, 2013 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-23792140

RESUMO

This study was designed to investigate the effect and mechanism of allicin on hyperhomocysteinemia-induced experimental vascular endothelial dysfunction in rats. Fifty male Wistar rats were randomly divided into five groups: the normal control rats (NC), the high-methionine-diet rats (Met), the high-methionine-diet rats treated with folic acid, vitaminB6 and vitaminB12 (Met+F), or with low-dose allicin (Met+L), or with high-dose allicin (Met+H). After 6 weeks, we collected blood samples of all groups to determine plasma endothelin (ET), serum homocysteine (Hcy), nitric oxide (NO), superoxide dismutase (SOD), malondialdehyde (MDA), and detected the expression of basic fibroblast growth factors (bFGF), transforming growth factor beta (TGF-ß), tumor necrosis factor-alpha (TNF-α), and intercellular adhesion molecule-1 (ICAM-1) in the aorta. The Hcy and the expression of TGF-ß in both the Met+L and Met+H groups were significantly lower than the Met and Met+F groups. The ET, ET/NO ratio and the MDA levels of the Met+L and Met+H groups were significantly lower than the Met group. The SOD and NO levels and the expression of bFGF, TNF-α and ICAM-1 of the Met+L and Met+H groups were significantly higher than the Met group. Our data indicate that allicin inhibits lipid peroxidation induced by hyperhomocysteinemia and regulates the excretion and equilibrium of ET and NO, and suggest that allicin might be useful in the prevention of endothelial dysfunction caused by hyperhomocysteinemia.


Assuntos
Endotélio Vascular/efeitos dos fármacos , Hiper-Homocisteinemia/metabolismo , Hiper-Homocisteinemia/patologia , Ácidos Sulfínicos/farmacologia , Animais , Aorta/efeitos dos fármacos , Aorta/metabolismo , Endotelinas/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Fator 2 de Crescimento de Fibroblastos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Homocisteína/sangue , Hiper-Homocisteinemia/sangue , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Malondialdeído/sangue , Óxido Nítrico/metabolismo , Ratos , Ratos Wistar , Superóxido Dismutase/sangue , Fator de Crescimento Transformador beta/metabolismo , Fator de Necrose Tumoral alfa/metabolismo
13.
J Ethnopharmacol ; 145(1): 168-74, 2013 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-23127652

RESUMO

OBJECTIVE: To explore the protective effects of the Chinese Yi-Qi-Bu-Shen recipe (YB) against neuronal injury induced by hypoxia-reoxygenation, which has shown beneficial effect in improving the brain function of type 2 diabetics likely through its antihyperglycemic, antioxidant activity, and investigate its mechanisms. METHODS: The bilateral hippocampus was collected from newborn rats to establish single cell suspension. On the 10th day, the primarily cultured hippocampal neurons were randomly divided into five groups: the normal group (NG), the hypoxia/reoxygenation group (HG), and groups protected with small, medium and large dosages of YB (SG, MG and LG, respectively). The YB-protected groups were treated with different concentrations of YB containing serum before reoxygenation. The metabolic rate of MTT, the malondialdehyde (MDA) content, and the activity of superoxide dismutase (SOD) and lactate dehydrogenase (LDH) were measured with assay kits. The apoptosis rate of hippocampal neurons were tested using flow cytometry analysis. RT-PCR was used to evaluate the mRNA expressions of bcl-2 and bax genes. RESULTS: The SOD activity, the cell survival rate, the bcl-2/bax ratio, and the bcl-2mRNA expression in the HG group were significantly lower (all P<0.01), but the levels of MDA and LDH, the apoptosis rate, and the bax mRNA expression were higher (all P<0.01) than those in the NG group. The SOD activity, the cell survival, the bcl-2mRNA expression, and the bcl-2/bax ratio were significantly higher in all of the YB-protected groups (all P<0.01), but the level of MDA and LDH, the apoptosis rate, and the bax mRNA expression were lower (P<0.01, P<0.05) than those in the HG group in a dose dependent manner. CONCLUSION: The YB extract has a protective effect on hippocampal neurons against injury induced by hypoxia/reoxygenation, through its antioxidant activity and the regulation of apoptosis.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Hipocampo/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Animais , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Feminino , Hipóxia/tratamento farmacológico , Hipóxia/metabolismo , L-Lactato Desidrogenase/metabolismo , Masculino , Malondialdeído/metabolismo , Neurônios/fisiologia , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-bcl-2/biossíntese , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Proteína X Associada a bcl-2/biossíntese
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