Zhuoan Cheng

Shanghai University of Traditional Chinese Medicine, Shanghai, Shanghai Shi, China

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Publications (6)15.12 Total impact

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    ABSTRACT: Hypertension is one of the most frequent complications of solid organ transplantation, and cyclosporin A (CsA) plays a predominant role in the pathophysiology of post-transplant hypertension. However, the exact molecular mechanisms of CsA-induced hypertension remain obscure. We previously showed that CsA increased the mRNA expression and contractile function of endothelin B (ETB) receptor in vascular smooth muscle cells. The present study was designed to investigate the underlying mechanisms of CsA-induced upregulation of ETB receptor in vasculature. Rat mesenteric arteries were incubated with CsA in an organ culture system, and results showed that CsA enhanced ETB receptor mRNA in the time- and dose-dependent manner, and increased protein expression levels of ETB receptor after treatment with CsA 10(-5)M for 6h. Furthermore, CsA induced phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2), p38, and translocation of nuclear factor-kappaB (NF-κB) p65 in vasculature. Blocking ERK1/2, p38, or NF-κB activation with their specific inhibitors markedly attenuated CsA-induced upregulation of ETB receptor mRNA expression and protein levels, and ETB receptor-mediated contraction. In summary, this study showed that mitogen-activating protein kinases (ERK1/2 and p38) and the downstream transcriptional factor NF-κB pathways were involved in CsA-induced upregulation of ETB receptor in arterial smooth muscle cells. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Toxicology Letters 03/2015; DOI:10.1016/j.toxlet.2015.03.004 · 3.36 Impact Factor
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    ABSTRACT: Cyclosporin A (CsA) is a widely used immunosuppressive agent that also causes hypertension. However, the molecular basis for CsA-induced hypertension remains elusive. In this study, we established an in vitro model for CsA-induced pathological changes in vasculature. Rat mesenteric arteries were incubated with CsA for 24 hr in an organ culture system. Both vasocontraction and vasorelaxation in mesenteric artery were studied by using myograph technology, and mRNA expressions of the contractile receptors were determined by real-time PCR. The results showed that CsA increased the mRNA expression and contractile function of several G-protein coupled receptors (GPCRs), such as endothelin receptor type B (ETB ), 5-hydroxytryptamine type 1B (5-HT1B ) and 1D (5-HT1D ), in vascular smooth muscle cells. In addition, both nitric oxide (NO)-mediated vasorelaxation and endothelium-independent relaxation were impaired by CsA. In summary, this study showed the enhanced GPCRs-mediated contraction and reduced vasorelaxation in mesenteric artery after organ culture with CsA, which mimicked the CsA-induced pathological changes of the vascular system in vivo. Furthermore, this organ culture system would be an ideal in vitro tool to study the molecular mechanisms of CsA-induced hypertension. This article is protected by copyright. All rights reserved.
    Basic & Clinical Pharmacology & Toxicology 07/2013; DOI:10.1111/bcpt.12105 · 2.18 Impact Factor
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    ABSTRACT: Previous studies have reported that 8-c [6-(2-(2-(dimethylamino)ethylamino)ethylamino)-2-octyl-1H-benzo[de]isoquinoline-1,3(2H)-dione], a novel amonafide analogue, was generated as a new anticancer candidate. However, little is known about its activity in chemoresistant cells. In this study, the antitumor effects of 8-c on the multi-drug-resistant human colorectal carcinoma cancer cell lines HCT-116/L-OHP and HCT-8/VCR have been investigated for the first time. 8-c showed similar concentration-dependent inhibitory activities against multi-drug-resistant cells and corresponding parental cell lines by the MTT assay after 48 h of treatment. 8-c treatment resulted in the induction of apoptosis, as evidenced by fluorescent staining analysis, comet assay data, and the increase in the number of apoptotic cells as detected by flow cytometry. Western blot, qPCR, and siRNA techniques were used to elucidate the molecular mechanism. Our study suggested that the apoptotic effect of 8-c can be attributed to the upregulation of p53, caspase-3, and cleaved poly(ADP-ribose) polymerase (PARP) and the downregulation of Bcl-2. Furthermore, ERCC1 is essential for nucleotide excision repair. ERCC1 expression was correlated with sensitivity to chemotherapy in various colon cancer cell lines. It is intriguing that decreases in ERCC1 protein and mRNA levels were also observed in the HCT-116/L-OHP and HCT-8/VCR cells after exposure to 8-c. Further transient transfection of multi-drug-resistant cells with ERCC1 siRNA enhanced 8-c-induced cytotoxicity. In contrast, epidermal growth factor-induced increase in ERCC1 protein levels was shown to rescue cell viability upon 8-c treatment. These findings suggest that 8-c has a strong potential to be developed as a new antitumor agent for the treatment of multi-drug-resistant colon cancer cells, and is worthy of further studies.
    Anti-cancer drugs 04/2013; 24(4):355-65. DOI:10.1097/CAD.0b013e32835df8b5 · 2.23 Impact Factor
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    ABSTRACT: Myasthenia gravis (MG) are T-cell dependent antibody-mediated autoimmune disorders, microRNAs are important regulators of human autoimmune disease pathogenesis. Here, we investigated the miRNAs expression profiles in MG for the first time and found that miR-320a was significantly downregulated in MG patients compared to normal healthy people. Meanwhile, pro-inflammatory cytokins in MG patients were overexpressed. Furthermore, we identified MAPK1 as a direct target of miR-320a. Downregulation of miR-320a induced the overexpression of pro-inflammatory cytokins through promoting COX-2 expression. This process was modulated by ERK/ NF-κB pathways. Taken together, our findings suggested that miR-320a could play a role in modulation of inflammatory cytokins production.
    Journal of Clinical Immunology 11/2012; 33(3). DOI:10.1007/s10875-012-9834-5 · 2.65 Impact Factor
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    ABSTRACT: Photodynamic therapy (PDT) is a regulatory-approved modality for treating a variety of malignant tumors. It induces tumor tissue damage via photosensitizer-mediated oxidative cytotoxicity. The heat shock protein 70 (HSP70-1) is a stress protein encoded by the HSPA1A gene and is significantly induced by oxidative stress associated with PDT. The aim of this study was to identify the functional region of the HSPA1A promoter that responds to PDT-induced oxidative stress and uses the stress responsiveness of HSPA1A expression to establish a rapid and cost-effective photocytotoxic assessment bioassay to evaluate the photodynamic potential of photosensitizers. By constructing luciferase vectors with a variety of hspa1a promoter fractions and examining their relative luciferase activity, we demonstrated that the DNA sequence from -218 to +87 of the HSPA1A gene could be used as a functional promoter to detect the PDT-induced oxidative stress. The maximal relative luciferase activity level of HSPA1A (HSP70-1) induced by hypericin-PDT was nearly nine times that of the control. Our results suggest that the novel reporter gene assay using a functional region of the HSP70A1A promoter has significant advantages for the detection of photoactivity in terms of both speed and sensitivity, when compared with a cell viability test based on ATP quantification and ROS levels. Furthermore, phthalocyanine zinc and methylene blue both induced significantly elevated levels of relative luciferase activity in a dose-dependent manner.
    Cell Stress and Chaperones 11/2012; DOI:10.1007/s12192-012-0374-y · 2.48 Impact Factor
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    ABSTRACT: Myasthenia gravis (MG) is a T cell-dependent and B cell-mediated autoimmune disease of neuromuscular junctions and cytokines may play a crucial role in the pathogenesis and perpetuation of MG. MicroRNAs (miRNAs) have been implicated as fine-tuning regulators controlling diverse biological processes at the level of posttranscriptional repression. Dysregulation of miRNAs has been described in various disease states. In this study, miRNA microarrays identified let-7 family to be decreased in peripheral blood mononuclear cells (PBMCs) from MG patients compared to the healthy controls. We next demonstrated the differential expression of let-7 family in larger samples by quantitative real-time PCR. Using a combination of bioinformatics and molecular approaches, we confirmed IL-10 as a target for let-7c. IL-10 expression also showed a negative correlation with let-7c expression in PBMCs from MG patients. Further experiments revealed that induced levels of IL-10 were inversely related to let-7c levels. We also showed that let-7c could regulate IL-10 expression in Jurkat cells. In summary, our results suggest that abnormal expression/regulation of microRNAs may contribute to or be indicative of the initiation and progression of MG.
    International immunopharmacology 07/2012; 14(2):217-23. DOI:10.1016/j.intimp.2012.07.003 · 2.21 Impact Factor