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Yang B.,Daqing Oilfield General Hospital | He K.,Key Laboratory of Cardiovascular Research | Zheng F.,Key Laboratory of Cardiovascular Research | Wan L.,Key Laboratory of Cardiovascular Research | And 7 more authors.
Journal of Cardiovascular Medicine | Year: 2014

OBJECTIVES: A great number of studies indicate that cardiac fibroblasts are essential for maintaining the structure and function of heart. Hypoxia-inducible factor-1 alpha (HIF-1α) is a central transcriptional regulator of hypoxic response. The present study examined whether over-expression of HIF-1α could prevent hypoxia-induced injury in neonatal rat cardiac fibroblasts and, if so, its possible molecular targets. METHODS: Western blotting was used to detect protein level. MTT, electron microscopy, TUNEL staining and confocal microscopy were used to identify cell viability, cell apoptosis and intracellular calcium ([Ca]i) in cardiac fibroblasts, respectively. RESULTS: When cardiac fibroblasts were exposed to hypoxia, HIF-1α protein in nuclei was transiently accumulated at 1h, and then gradually degraded within 24h of hypoxia exposure. Over-expression of HIF-1α enhanced nucleus expression of HIF-1α in cardiac fibroblasts, and significantly abolished the decrease of cell viability and cell apoptosis caused by 24-h hypoxia. Accordingly, hypoxia-induced Bax up-regulation, Bcl-2 down-regulation, caspase-3 activation and overload of [Ca]i in cardiac fibroblasts were reversed by HIF-1α over-expression, but were promoted by 30μmol/l SC205346, a specific HIF-1α blocker. CONCLUSIONS: Our results indicate that HIF-1α may act as a protective factor in the apoptotic process of cardiac fibroblasts and represent a potential therapeutic target for heart remodeling after hypoxia injury. © 2014 Italian Federation of Cardiology.

Sun Z.-J.,Harbin Engineering University | Sun B.,Key Laboratory of Cardiovascular Research | Sun C.-W.,Harbin Engineering University | Wang L.-B.,Harbin Medical University | And 4 more authors.
Journal of Bioactive and Compatible Polymers | Year: 2012

In this study, 5-fluorouracil-1-acetic acid was chemically conjugated with poly(glycerol-sebacate) (PGS) to form a unitary polymer poly(glycerol-sebacate- (5-fluorouracil-1-acetic acid)) (PGS-5-FU-CH 2COOH). The structure, the in vitro antitumor activity of 5-FU-CH 2COOH, the in vitro degradation, the drug release, and antitumor activity as well as the in vivo degradation and tissue biocompatibility of PGS-5-FU-CH 2COOH were investigated. The 5-FU-CH 2COOH inhibited HeLa (human cervical cancer cell line) and SGC-7901 (human gastric adenocarcinoma cell line) tumor cells with a half maximal inhibitory concentration (IC 50) of 0.196 and 0.267 μM, respectively, after a 3-day incubation. The in vitro drug release profiles of PGS-5-FU-CH 2COOH exhibited a biphasic release with an initial exponential phase in the first week and then the second constant linear phase. An in vitro antitumor assay of the PGS-5-FU-CH 2COOH polymer showed significant cytotoxicity against tumor cells. The implanted PGS-5-FU-CH 2COOH degraded completely in 1 month after implantation. The antitumor activity and improved drug release profile of PGS-5-FU-CH 2COOH indicate its potential as an implantable polymer for cancer therapy. © SAGE Publications 2011.

Cheng J.,Harbin Medical University | Sun X.,Harbin Medical University | Sun X.,Key Laboratory of Cardiovascular Research | Guo S.,Harbin Medical University | And 14 more authors.
International Journal of Nanomedicine | Year: 2013

Background: Inflammatory cells exhibit an elevated level of protoporphyrin IX (PpIX) after the administration of 5-aminolevulinic acid (ALA). Here, we investigate the sonodynamic effects of ALA-derived PpIX (ALA-PpIX) on macrophages, which are the pivotal inflammatory cells in atherosclerosis. Methods and results: Cultured THP-1 macrophages were incubated with ALA. Fluorescence microscope and fluorescence spectrometer detection showed that intracellular PpIX increased with the concentration of ALA in the incubation solution in a time dependent manner; the highest level of intracellular PpIX was observed after 3-hour incubation. 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays demonstrated that lower concentrations (less than 2 mM) of ALA have no influence on cell viability (more than 90% of cells survived), but sonodynamic therapy (SDT) with a low concentration of ALA significantly decreased the survival rate of cells, and the effect was increased with both ALA concentration and ultrasound exposure time. Cell apoptosis and necrosis induced by ALA-mediated SDT (ALA-SDT) were measured using Hoechst 33258 and propidium iodide assay. ALA-SDT induced both cell apoptosis and necrosis, and the maximum apoptosis/necrosis ratio was observed at 6 hours after SDT with 1 mM of ALA and 5 minutes of ultrasound exposure. Flow cytometry analysis showed that ALA-SDT significantly increased late stage apoptotic cells (about 10-fold control). Furthermore, ALA-SDT induced reactive oxygen species generation in THP-1 macrophages immediately after the treatment and a conspicuous loss of mitochondrial membrane potential (MMP) at 6 hours compared with that of the control, ALA alone, and ultrasound alone groups. Conclusion: ALA-SDT exhibited synergistic apoptotic effects on THP-1 macrophages, involving excessive intracellular reactive oxygen species generation and MMP loss. Therefore, ALA-SDT is a potential treatment for atherosclerosis. © 2013 Cheng et al, publisher and licensee Dove Medical Press Ltd.

Chen C.,Key Laboratory of Cardiovascular Research | Huo R.,Key Laboratory of Cardiovascular Research | Tong Y.,Key Laboratory of Cardiovascular Research | Sheng Y.,Key Laboratory of Cardiovascular Research | And 6 more authors.
Cellular Physiology and Biochemistry | Year: 2011

Background/Aims: Heme oxygenase-1(HO-1) has been reported to protect against cardiac hypertrophy in cultured neonatal cardiomyocytes treated with HO-1 inducer, cardiac specific HO-1 transgenic mice, or animals treated with HO-1 inducer. The aim of the present study is to examine the effects of systemic HO-1 transgenic overexpression on pressure overload-induced cardiac hypertrophy in mice. Methods: Pressure-overload cardiac hypertrophy was induced by transverse aortic constriction (TAC) in WT (wild type) and systemic HO-1 transgenic overexpression (TG) mice. Results: We found that systemic HO-1 transgenic overexpression aggravated pressure overload-induced cardiac hypertrophy. Pressure-overload induced the more increases of heart weight/body weigh index, left ventricular weight/body weight index, β-MHC protein expression, cardiac interstitial fibrosis in TG mice than in WT mice. Pressure-overload increased cardiac HO-1 protein expression in WT but not TG mice, but the cardiac HO-1 protein level was still higher in TAC-treated TG mice than in TAC-treated WT mice. The basal cardiac calcineurin protein level in TG mice was lower than that in WT mice. Pressure-overload increased calcineurin protein expression in both WT and TG mice; however, pressure-overload induced more calcineurin protein expression in TG mice than in WT mice. Conclusion: This study shows for the first time that systemic HO-1 transgenic overexpression aggravates pressure overload-induced cardiac hypertrophy. © 2011 S. Karger AG, Basel.

Sun X.,Harbin Medical University | Sun X.,Key Laboratory of Cardiovascular Research | Tian Y.,Harbin Medical University | Tian Y.,Key Laboratory of Cardiovascular Research | And 6 more authors.
Ultrasonics Sonochemistry | Year: 2015

Reactive oxygen species (ROS) elevation and mitochondrial membrane potential (MMP) loss have been proven recently to be involved in sonodynamic therapy (SDT)-induced macrophage apoptosis and necrosis. This study aims to develop an experimental system to monitor intracellular ROS and MMP in real-time during ultrasonic irradiation in order to achieve optimal effect in SDT. Cultured THP-1 derived macrophages were incubated with 5-aminolevulinic acid (ALA), and then sonicated at different intensities. Intracellular ROS elevation and MMP loss were detected in real-time by fluorospectrophotometer using fluorescence probe DCFH-DA and jc-1, respectively. Ultrasound at low intensities (less than 0.48 W/cm2) had no influence on ROS and MMP in macrophages, whereas at an intensity of 0.48 W/cm2, ROS elevation and MMP loss were observed during ultrasonic irradiation. These effects were strongly enhanced in the presence of ALA. Quantitative analysis showed that ROS elevation and MMP loss monotonically increased with the rise of ultrasonic intensity between 0.48 and 1.16 W/cm2. SDT at 0.48 and 0.84 W/cm 2 induced mainly apoptosis in THP-1 macrophages while SDT at 1.16 W/cm2 mainly cell necrosis. This study supports the validity and potential utility of real-time ROS and MMP detection as a dosimetric tool for the determination of optimal SDT. © 2014 Elsevier B.V. All rights reserved.

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