State Province Key Laboratories of Biomedicine Pharmaceutics of China

of China, China

State Province Key Laboratories of Biomedicine Pharmaceutics of China

of China, China
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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.


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.


Wang D.,Harbin Medical University | Wang D.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Yang H.,Harbin Medical University | Yang H.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | And 25 more authors.
Journal of Alzheimer's Disease | Year: 2015

The stress protein heme oxygenase-1 (HO-1) is upregulated and co-localizes to pathological features, including tauopathies in the brains of individuals with Alzheimer's disease. However, the relationship between HO-1 and Alzheimer's disease remains unclear. In our previous research, the long-term overexpression of HO-1 was shown to promote tau aggregation by inducing tau phosphorylation in the mouse brain. In this study, we found that the long-term overexpression of HO-1 led to cognitive decline in transgenic mice, as determined by the water maze test, and that HO-1 can affect two pathways for tauopathy. Through one pathway, HO-1 promotes the expression of CDK5 by accumulating reactive oxygen species, which are produced by HO-1 downstream products of iron in neuro2a cell lines and mouse brain. Through the second pathway, HO-1 induces tau truncation at D421 in vivo and in vitro. Clearly, there is a HO-1-dependent mechanism responsible for tau protein phosphorylation and tau truncation in vivo and in vitro. Taken together, our results suggest that HO-1 plays an important role in the disease process of tauopathies in AD. © 2015 IOS Press and the authors. All rights reserved.


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).


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.


Zhang Y.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Zhang Y.,Harbin Medical University | Zhang L.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Chu W.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | And 14 more authors.
Cellular Physiology and Biochemistry | Year: 2010

Tanshinone IIA is a fat-soluble pharmacologically active ingredient of Danshen, a well-known traditional Chinese medicine used for cardiovascular diseases such as coronary heart disease. Tanshinone IIA has been confirmed to suppress miR-1 and reduce the arrhythmogenesis after myocardial infarction (MI). However, the modulation mechanism is not clear. Tanshinone IIA was administrated daily for 7 days before ligation of the left anterior descending artery (LAD) and lasted for 3 months after LAD. Neonatal cardiomyocytes were exposed to 2% O2+95% N2 condition for 24 h to simulate ischemia in vivo. Protein expression was examined with Western blot and miR-1 level was quantified by Real-time PCR. Our results showed that tanshinone IIA relieved ischemia-induced injury by improving the cardiac function. This beneficial effect may due to the depression of the elevated miR-1 level in ischemic and hypoxic cardiomyocytes, which subsequently restored its target Cx43 protein. Furthermore, tanshinone IIA could inhibit activated p38 MAPK and heart special transcription factors SRF and MEF2, in ischemic and hypoxic cardiomyocytes. Pretreatment with p38 MAPK inhibitor, SB203580 (10 uM), significantly relieved hypoxia-induced miR-1 increment and restored its downstream target Cx43 protein expression. These data suggest that tanshinone IIA play a role in protection cardiomyocytes from ischemic and hypoxic injury. The effect is based on inhibiting miR-1 expression through p38 MAPK signal pathway. This might provide us a new target to explore the novel strategy for ischemic cardioprotection. Copyright © 2010 S. Karger AG, Basel.


Wang H.,Harbin Medical University | Yang Y.,Harbin Medical University | Chen H.,Harbin Medical University | Dan J.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | And 19 more authors.
Cellular Physiology and Biochemistry | Year: 2014

Background: In advanced atherosclerosis, chronic endoplasmic reticulum (ER) stress induces foam cells apoptosis and generates inflammatory reactions. Methods: THP-1 macrophage-derived foam cells (FC) were incubated with 1 mM 5-Aminolevulinic acid (ALA). After ALA mediated sonodynamic therapy (ALA-SDT), apoptosis of FC was assayed by Annexin V-PI staining. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were detected by staining with CellROX® Green Reagent and jc-1. Pretreatment of FC with N-Acetylcysteine (NAC), Z-VAD-FMK or 4-phenylbutyrate (4-PBA), mitochondria apoptotic pathway associated proteins and C/EBP-homologous (CHOP) expressions were assayed by wertern blotting. Results: Burst of apoptosis of FC was observed at 5-hour after ALA-SDT with 6-hour incubation of ALA and 0.4 W/cm2 ultrasound. After ALA-SDT, intracellular ROS level increased and mitochondrial membrane potential collapsed. Translocations of cytochrome c from mitochondria into cytosol and Bax from cytosol into mitochondria, cleaved caspase 9, cleaved caspase 3, upregulation of CHOP, as well as downregulation of Bcl-2 after ALA-SDT were detected, which could be suppressed by NAC. Activation of mitochondria-caspase pathway could not be inhibited by 4-PBA. Cleaved caspase 9 and caspase 3 as well as apoptosis induced by ALA-SDT could be inhibited by Z-VAD-FMK. Conclusion: The mitochondria-caspase pathway is predominant in the apoptosis of FC induced by ALA-SDT though ER stress participates in. © 2014 S. Karger AG, Basel.


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).


Xu H.,Harbin Medical University | Xu H.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Sun Y.,Harbin Medical University | Sun Y.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | And 12 more authors.
Cellular Physiology and Biochemistry | Year: 2014

Background: Protoporphyrin IX (PpIX) and its derivatives are widely used in photodynamic therapy (PDT) to kill cancer cells. Studies showed that the application of these drugs could cause systemic toxic effects in human. However, the molecular pathways involved in PpIX-induced cytotoxicity are not well-defined. Macrophages represent the primary system for protecting tissues from toxicants and initiating the resolution of inflammation. Thus, this study aims to investigate the toxicity of PpIX on macrophages and provide strategies to prevent the toxic effects. Methods: THP-1 macrophages were incubated with PpIX and cell death was measured by MTT assay and Annexin V-PI staining. Intracellular reactive oxygen species (ROS) were evaluated by 2', 7'-Dichlorodihydrofluorescin diacetate (DCFH-DA) and MitoSOX® Red staining and mitochondrial membrane potential (ΔΨm) was detected by tetramethylrhodamine methyl ester (TMRM) staining. Mitogen-activated protein (MAP) kinase activation was assayed by western blotting. Mitochondrial permeability transition pore (mPTP) opening was measured by calcein loading/Co2+ quenching technique and evaluating the release of mitochondrial content. Results: PpIX reduced cell viability in a dose- and time-dependent manner. The cell death was characterized by increasing PI-positive cells, ATP depletion, LDH releasing and rapid ΔΨm loss favoring necrotic features. In addition, PpIX successively induced ROS production, c-Jun N-terminal protein kinase (JNK) activation and mPTP opening. ROS scavengers, N-acetylcysteine (NAC) and deferoxamine (DFX), JNK inhibitor, SP600125, and mPTP inhibitor, cyclosporin A (CsA), all significantly rescued this cell death. Furthermore, mPTP opening was directly regulated by ROS/JNK pathway. Conclusion: PpIX induces a necrotic cell death in THP-1 macrophages through ROS production, JNK activation, and mPTP opening. It is tempting to speculate that blocking the pathways involved in the cytotoxic effects of PpIX will alleviate its side effects. © 2015 S. Karger AG, Basel.


Li L.,Harbin Medical University | Li L.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | Peng Y.,Harbin Medical University | Peng Y.,State Province Key Laboratories of Biomedicine Pharmaceutics of China | And 15 more authors.
Journal of Alzheimer's Disease | Year: 2015

The expression of heme oxygenase 1 (HO-1) in the cortex and hippocampus is higher in Alzheimer's disease (AD) and mild cognitive impairment patients than healthy individuals, and epidemiological studies suggest that HO-1 is an important factor for AD. However, its influence on nerve function is poorly understood. Here, we studied the effect of the overexpression of HO-1 on the cognitive and synaptic plasticity in 3-month-old mice.We found that the overexpression of HO-1 induced spatial learning and memory deficits with an apparent decrease of AMPKR, NMDAR, postsynaptic density protein 95, synapsin I, synaptophysin, and microtubule-Associated protein 2, all of which are memory-related synaptic proteins. Concurrently, HO-1 could co-express and induce the aggregation of Aβ42 and Aβ oligomer in the hippocampus area. Additionally, our research is the first to demonstrate that HO-1 changes the morphology of the synapse to impair the neural circuit.Tthese results indicate that the overexpression of HO-1 can damage synaptic plasticity in early stages to induce AD-like pathology and cognitive abnormality in mice. © 2015 - IOS Press and the authors. All rights reserved.

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