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Yuan L.,Harbin Medical University | Yuan L.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Zhao H.,Daqing Oilfield General Hospital | Zhang L.,Harbin Medical University | Liu X.,Harbin Medical University
Tumor Biology | Year: 2013

Multigene-based combination therapy is an effective practice in cancer gene therapy. Apoptin is a chicken anemia virus-derived, p53-independent, Bcl-2-insensitive apoptotic protein with the ability to specifically induce apoptosis in various human tumor cells. Interleukin-24 (IL-24) displays ubiquitous antitumor property and tumor-specific killing activity. Adeno-associated virus (AAV) is a promising gene delivery vehicle due to its advantage of low pathogenicity and long-term gene expression. In this study, we assessed the efficacy of combination therapy using AAV-mediated co-expression of apoptin and interleukin-24 on hepatocellular carcinoma in vitro and in vivo. Our results showed that AAV-mediated co-expression of IL-24 and apoptin significantly suppressed the growth and induced the apoptosis of HepG2 cells in vitro. Furthermore, AAV-mediated combined treatment of IL-24 and apoptin significantly suppressed tumor growth and induced apoptosis of tumor cells in xenograft nude mice. These data suggest that AAV vectors that co-express apoptin and IL-24 have great potential in cancer gene therapy. © 2013 International Society of Oncology and BioMarkers (ISOBM).

Liu L.,Harbin Medical University | Wang C.,Harbin Medical University | Lin Y.,Qiqihar Medical College | Xi Y.,Harbin Medical University | And 9 more authors.
Molecular Medicine Reports | Year: 2016

The calcium-sensing receptor (CaSR) releases intracellular calcium ([Ca2+]i) by accumulating inositol phosphate. Changes in [Ca2+]i initiate myocardial hypertrophy. Furthermore, autophagy associated with [Ca2+]i. Autophagy has previously been demonstrated to participate in the hypertrophic process. The current study investigated whether suppression of CaSR affects the hypertrophic response via modulating autophagy. Isoproterenol (ISO) was used to induce cardiac hypertrophy in Wistar rats. Hypertrophic status was determined by echocardiographic assessment, hematoxylin and eosin, and Masson's staining. The protein expression levels of CaSR and autophagy level were observed. Changes of hypertrophy and autophagy indicators were observed following intravenous injection of a CaSR inhibitor. An ISO-induced cardiomyocyte hypertrophy model was established and used determine the involvement of GdCl3. [Ca2+]i was determined using Fluo-4/AM dye followed by confocal microscopy. The expression levels of various active proteins were analyzed by western blotting. The size of the heart, expression levels of CaSR and autophagy level were markedly increased in hypertrophic myocardium. In addition, the present study demonstrated that the indicators of hypertrophy and autophagy were effectively suppressed by CaSR inhibitor. Furthermore, similar effects were demonstrated in neonatal rat hypertrophic cardiomyocytes treated with ISO. It was also observed that CaSR regulates the Ca2+/calmodulin-dependent protein kinase kinase β (CaMKKβ)-AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) signaling pathway induced by ISO in cardiomyocytes. Furthermore, the AMPK inhibition significantly reduced the autophagy level following CaSR stimulation (P<.05). The results of the present demonstrated that inhibition of CaSR may ameliorate cardiac hypertrophy induced by ISO and the effect may be associated with the inhibition of autophagy and suppression of the CaMKKβ-AMPK-mTOR signaling pathway.

Hui Y.,Harbin Medical University | Hui Y.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Zhao Y.,Harbin Medical University | Zhao Y.,Qinghai University | And 8 more authors.
Journal of Cardiovascular Pharmacology | Year: 2012

Background: The protective role of M3-mAChR against apoptosis has been identified previously. However, the underlying mechanisms remain unclear. This study was performed to clarify the signaling pathways of the anti-apoptotic effect mediated by activation of M3-mAChR in cultured cardiac H9c2 cells. Methods: Both H9c2 rat ventricular cells and H9c2 cells with stable expression of M3-mAChR were used. Results: Activation of M3-mAChR by cabarchol produced protective effect on etoposide-induced apoptosis in H9c2 cells. Forced overexpression of M3-mAChR in H9c2 cells further enhanced this effect. Application of 4-diphenyl-acetoxy-N-methyl- piperidine methiodide (inhibitor of M3-mAChR), YC-1 [inhibitor of hypoxia-inducible factor 1, (HIF-1], or ZnPP (inhibitor of heme oxygenase-1)abrogated carbacol-induced cardioprotection, respectively. Moreover, the expression of HIF-1α, HO-1, and vascular endothelial growth factor (VEGF) were enhanced after the activation of M3-mAChR, and the induction of HO-1 and VEGF was reversed by HIF-1α inhibitor YC-1. Conclusions: These findings indicated that M3-mAChR upregulates HO-1 and VEGF expression likely through induction of HIF-1α, which at least partly underlies the cytoprotection of M3-mAChR activation in H9c2 cells. Copyright © 2012 by Lippincott Williams & Wilkins.

Yuan L.,Harbin Medical University | Yuan L.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Zhang L.,Harbin Medical University | Dong X.,Harbin Medical University | And 7 more authors.
Tumor Biology | Year: 2013

Apoptin is a nonstructural viral protein encoded by VP3 gene of chicken anemia virus, which could specially induce apoptosis of tumor cells. However, the mechanism of apoptin-induced apoptosis in tumor cells without any side effects in normal cells has not yet been well characterized. This study aimed to investigate the molecular mechanism underlying the selective antitumor effects of apoptin. HepG2 cells were treated with apoptin or transfected with apoptin expression vector. Heat shock protein 70 (HSP70) expression was examined by Western blot. The binding of apoptin to HSP70 promoter was detected by electrophoretic mobility shift assay, chromatin immunoprecipitation, and luciferase assay. The results showed that apoptin inhibited HSP70 expression in HepG2 cells and apoptin-induced apoptosis of HepG2 cells was dependent on the expression level of HSP70. Furthermore, apoptin promoted HSF1 trimer depolymerization and inhibited HSF1-mediated HSP70 transcription. In addition, apoptin competed with HSF1 to bind heat shock element in HSP70 promoter, leading to reduced HSP70 transcription. Both these mechanisms contribute to the suppression of HSP70 transcription and expression. Our findings provide the first evidence that apoptin induces tumor cell apoptosis by specifically downregulating the expression of HSP70, which helps explain the specific antitumor effects of apoptin. © 2012 International Society of Oncology and BioMarkers (ISOBM).

Li Y.,Key Laboratory of Pathogenic Biology Heilongjiang Higher Education Institutions | Li Y.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Song W.,Key Laboratory of Pathogenic Biology Heilongjiang Higher Education Institutions | Song W.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | And 12 more authors.
International Journal of Biochemistry and Cell Biology | Year: 2013

Viruses often have strategies for preventing host cell apoptosis, which antagonizes viral replication.Borna disease virus (BDV) is a neurotropic RNA virus that establishes a non-cytolytic persistent infection. Although BDV suppresses type I Interferon (IFN) through (TANK)-binding kinase 1 (TBK-1) associated BDV P protein, it is still unclear how BDV can survive in the host cell and establish a persistent infec-tion. Recently, it has been recognized that mitochondria-mediated apoptosis through the mitochondrial antiviral signaling protein (MAVS) and the RIG-I-like receptor (RLR) signaling pathway is a crucial com-ponent of the innate immune response. In this work we show that BDV X protein colocalizes and interacts with MAVS in the mitochondria to block programmed cell death. BDV X protein-mediated inhibition of apoptosis was independent of type I IFN production and NF- κB activity. The reduction of BDV X expression with RNA interference (RNAi) or the mutation of BDV X enhanced MAVS-induced cell death. Collectively,our data provide novel insights into how BDV X protein inhibits antiviral-associated programmed cell death, through its action of MAVS function. Crown Copyright © 2013 Published by Elsevier Ltd. All rights reserved.

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