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The Function and Regulatory Mechanism of TBK1 in Antiviral Innate Immunity

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):1-6.

TANK- binding kinase 1（TBK1）acts as the hub of antiviral innate immune signal transduction. On the one hand，TBK1 could be activated by a variety of pattern recognition receptors（PRR）. On the other hand，as a critical kinase，activated TBK1 phosphorylates varieties of substrates，such as transcription factors interferon regulatory factor 3（IRF3）and IRF7 ，resulting in the initiation of antiviral innate immune responses. In this review ，we put emphasis on the TBK1 associated antiviral innate immune signaling ，as well as the regulation mechanisms of TBK1 expression and activation.

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Study on Anti-tumor Targets and Associated Therapeutics

Zhen-you JIANG

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):7-15.

Anti-cancer targeted therapy “(targeted” cancer therapy) is the use of small molecule drugs or antibodies themselves, guided by specific targeting tools, to attack tumor cells and their microenvironment or activate the body’s immune response. The rapid development of targeted therapy has enabled specific anti- tumor therapies to be achieved, which has taken us another step closer to our ultimate goal of treating tumors, that is, to effectively kill tumors without harming normal tissues. This article reviews the related contents of tumor targeted therapy, such as tumor-associated antigens, antibodies, and targeting strategies and also elaborates on the research in this field in combination with the study of our team.

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Host Cell Responses to Dengue Virus

Ping ZHANG

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):16-23.

Recent outbreak of dengue virus （DENV） in subtropics and tropics and the increasing incidence of DENV infection have seriously threatened the public health. Upon virus infection，the host cells rapidly elicit various responses through activating different signaling pathways，to fight against the invasion of DENV. On the other hand，dengue virus has evolved many strategies of escaping，antagonizing or even utilizing these host responses. This review summarizes the progress of molecular biology of DENV and the cellular responses against DENV infection，including innate immune response，adaptive immune response，cell death，autophagy，unfolded protein response，and stress granule formation.

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Research Progress of Glioma Immunotherapy

Yong-gao MOU

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):24-29.

Gliomas are the most common primary malignant tumors in the central nervous system，and more than half of them are WHO grade IV glioblastomas. Even if surgery，concurrent chemoradiotherapy and adjuvant chemotherapy were applied，median survival of GBM patients is still only 14.2 months. Immunosuppression is an important feature of malignant glioma. Immunotherapy which reverse immunosuppression may be the most promising way to improve the treatment effect of glioma patients in recent years. This article reviews the recent progress of glioma immunotherapy and the research progress of regulatory T cells（Treg）and glucocorticoid-induced tumor necrosis factor receptor（GITR）in the glioma microenvironment. We hope this article will provides new research ideas for glioma immunotherapy.

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Advance in the Monitoring and Treatment of Sepsis-Induced Immunosuppression

Jian-feng WU

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):30-36.

Sepsis is defined as a life- threatening organ dysfunction caused by a deregulated host response to infection and is the leading cause of mortality in intensive care units. Although the exact pathogenesis of sepsis remains unclear，immunosuppression is considered to play a key role. Sepsis-induced immunosuppression is characterized by a failure to eradicate the primary infection and by development of secondary nosocomial infections， resulting in a prolonged hospitalization and increased death rate in sepsis patients. Early recognition of immunosuppression and appropriate intervention will benefit these patients. This review helps clinicians identify patients with immunosuppression through high-risk population screening and biomarkers detection，and introduces immunostimulants that have been used in clinics and clinical trials.

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LncRNA Xist Promotes Proliferation and Migration of Rat BMSC by Regulating CXCR4 Expression

Ya-ni DUAN ; A-bi-lai-lie-ti2 MU-LA-TI ; Yan-qiu ZHU ; Lei-lei TANG ; Jun-ying ZHU ; Jie QIN

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):37-43.

【Objective】To explore the role of lncRNA Xist in proliferation and migration of rat bone marrow mesenchymal stem cells（BMSC）and its possible mechanism.【Methods】BMSC were isolated，cultured and identified from the femur and tibia of 3 weeks old SD female rats in vitro. SiRNAs was designed and screened to acquire a high silencing efficiency siRNA. Lipo2000 was used to transfected si- Xist and si- NC into BMSC of the experimental group（si- Xist group）and the control group（si-NC group）. BMSC proliferation capacity was determined by CCK-8 assay. The transverse and longitudinal mobility of BMSC were measured by wound healing assay and transwell migration assays. QPCR was performed to verify the silencing efficiency of lncRNA Xist and detect the expression levels of SDF- 1 and CXCR4 mRNA. Western blot was used to quantify the expression of CXCR4 protein.【Results】The P3 generation BMSC shows shuttle- like or whirlpool-like，and flow cytometry showed CD11b（-），CD34（-），CD45（-），CD44（+），CD90（+），CD105（+）. When siRNAs were used to interfere with the expression of lncRNA Xist in BMSC ，the silencing efficiency of three siRNAs was 67.92% ，68.72% and 98.32% ，respectively. CCK- 8 assay showed that the OD450 value of si- Xist group decreased compared with si-NC group at 24 h and 48 h（P < 0.001，P < 0.01，respectively）and had no statistical difference at 12 h（P > 0.05）. Wound healing assay showed that the wound healing percentage of si-Xist group was lower than that of si-NC group（P < 0.05）；and the transwell migration assay showed that，compared with si- NC group，the cells that migrated through the polycarbonate membrane were obviously decreased at 6 h（P < 0.001）. QPCR experiment showed that CXCR4 expression in si-Xist group was lower than that in si-NC group at mRNA level（P < 0.05），while SDF-1 expression showed no significant statistical difference（P > 0.05）. Western blotting confirmed that CXCR4 expression in si- Xist group was lower than that in si-NC group（P < 0.05）.【Conclusions】LncRNA Xist promotes proliferation and migration of rat BMSC by regulating CXCR4 expression.

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Berberine Inhibits Mechanical Stretch Stress induced MAPK Phosphorylation，Proliferation and Migration of Vascular Smooth Muscle Cells

Lie DENG ; Lin-li WANG ; Shu-ying LIU ; Chao-hong LI

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):44-52.

【Objective】To observe whether berberine can inhibit vascular smooth muscle cells（VSMC）proliferation induced by mechanical strength stress and to investigate the role of MAPK pathway in it.【Methods】The cultured VSMC were divided into 4 groups：negative control group（NC group），stretch stress group（SS group），berberine pretreated and stretch stress stimulation group（BBR+SS group），and berberine group. In NC group，phosphate buffer saline was used as a negative control；in SS group，stretch stress was given to VSMC；in BBR+SS group，VSMC were pretreated with berberine for 1 hour and then exposed to stretch stress；in BBR group，VSMC were treated only with berberine for 1 hour and cultured in serum- free DMEM afterwards. We collected VSMC in each group ，detected and analyzed their MAPK phosphorylation，proliferation and migration by using Western blotting，immunofluorescence and wound-healing assay respectively. 【Results】 Compare with NC group，stretch stress markedly induced VSMC proliferation and migration ，which could be inhibited significantly by berberine. Stretch stress obviously increased phosphorylation of MAPK （ERK，JNK，p38），which could be inhibited by berberine in a concentration dependent manner. 【Conclusion】 Berberine inhibits hypertension-induced proliferation and migration of VSMC through MAPK pathway. The results revealed the new use and mechanism of berberine，and provided important data for further study on the prevention and treatment of vascular remodeling caused by abnormal increase of mechanical stress in hypertension.

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Whole Genome Bisulfite Sequencing Study on Parkinson′s Disease Model Mice Genetically Modified by A53T Mutant α-Synuclein in Midbrain

Ting WU ; Lin LIU ; Zhao LI ; Xian LIN

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):53-59.

【Objective】To investigate the effect of PD-related gene SNCA mutated in A53T on methylation modification in the dopaminergic neurons from the mouse midbrain.【Methods】The midbrain tissue from the A53T mutant human α-synuclein（hA53T α-syn）transgenic mice and non-transgenic（nTg）mice were isolated α-synmice. Bisulfite-sequencing（BS-seq）was utilized for analyzing the DNA methylation of 12-month-old of hA53T α-synmice and nTg mice at a whole genome level. Subsequently，differentially methylated regions（DMRs）were screened for GO enrichment analyses.【Results】Through comparative analyses，481 DMRs were found. Among the data ，hypermethylated and hypomethylated DMRs accounted for 257 and 224 respectively. These DMRs involved in ubiquitin degradation pathway-related genes， including Ubqln2，HECTD4，Rnf157 genes；serine/threonine protein kinase PINK1 gene，etc. Enrichment data revealed that the genes containing DMRs projected to 545 GO sub-terms，and significantly enriched in anatomical structure development，dendrite development，nervous system development，neuronal projection，etc.【Conclusion】The A53T mutation of SNCA gene which is related to PD could introduce DNA methylation alterations in mouse midbrain.

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Long Non-Coding RNA HULC Enhances Tumor Growth in Orthotopic Xenograft Model of Glioblastoma

Yu-chen HU ; Tian-tian YIN ; Qian LI ; Shan YE ; Jing WU ; Jie HE

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):60-68.

【Objective】To investigate the mechanism of action of long non-coding RNA highly up-regulated in liver cancer（LncRNA HULC）on the growth of glioblastoma U87 cells in vitro and in vivo.【Methods】The cultured glioblastoma U87 cells were divided into four groups：overexpression group（HULC-over）and its vector control group（VEC），silent expression group（HULC- siRNA）and its negative control group（NC）.Quantitative real- time polymerase chain reaction PCR（qRT-PCR）was used to verify the expression levels of HULC. CCK8 proliferation assay and colony formation assay were adopted to monitor the proliferation of glioblastoma U87 cells. Flow cytometry was utilized to detect the apoptosis of glioblastoma U87 cells. By injecting U87 cells，we divided the orthotopic xenograft mouse model into HULC- over group（n=10），VEC group（n=10），HULC-siRNA group（n=10）and NC group（n=10）accordingly. The survival of the mice in each group was observed. The expression of Ki67 was analyzed by immunohistochemistry. 【Results】 The expression level of HULC was significantly higher in HULC-over group than that in VEC group and significantly lower in HULC-siR NA group than that in NC group（P < 0.01）. The cell proliferation ability was significantly increased in HULC-over group compared with that in VEC group and significantly decreased in HULC- siRNA group compared with that in NC group（P < 0.01 on days2，3and4）. The colony formation rates in VEC group，HULC-over group，NC group and HULC-siRNA group were，respectively，（34.47 ± 1.56）% ，（95.4 ± 2.74）% ，（23.83 ± 0.92）% and （10.23 ± 0.61）% ，which revealed that overexpression of HULC elevated the colony formation rate and silencing expression of HULC reduced the colony formation rate（P < 0.01）. The early apoptosis rates in VEC group，HULC- over group，NC group and HULC- siRNA group were，respectively，（3.55±0.56）% ，（0.09±0.01）% ，（2.89±0.67）% ，and（7.13±0.14）% ，which showed that overexpression of HULC elevated the early apoptosis rate and silencing expression of HULC reduced the early apoptosis rate （P <0.01）. The survival curve of nude mouse indicated shorter survival time in HULC-over group than that in VEC group and longer survival time in HULC-siRNA group than that in NC group（P < 0.05）. Ki67 protein expression was up-regulated in the HULC-over group compared with that in VEC group and down-regulated in the HULC-siRNA group compared with that in NC group（P < 0.05）.【Conclusion】LncRNA HULC can enhance the growth of glioblastoma U87 cells in vitro and in vivo.

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Fuzi Polysaccharide Inhibits Vascular Smooth Muscle Cell Calcification via Ceramide Signaling

Yan-ting CHEN ; Yan SONG ; Li-he LU

Journal of Sun Yat-sen University(Medical Sciences).2020;41(1):69-75.

【Objective】The aim of this study is to investigate whether Fuzi polysaccharide（FPS）inhibits calcification of vascular smooth muscle cells（VSMC）and its underlying mechanism involving ceramide signaling.【Methods】We used Ox- LDL to induce in vitro model of human VSMC calcification in this study. FPS at different concentrations was used to treat human VSMC. Cell calcification was assessed by alizarin red staining. The mRNA expressions of osteogenic differentiation markers including Msx2，Osterix and BMP2，and contractile marker SMA were analyzed by qRT- PCR. The protein expressions of Msx2 and BMP2 were analyzed by western blot. Cell apoptosis was examined by TUNEL. Additionally，we investigated the effect of FPS on ceramide levels and N- SMase activity in VSMC. 【Results】We found that FPS inhibits Ox- LDL- induced VSMC apoptosis and calcification. Ceramide participates in Ox- LDL- induced apoptosis and calcification of VSMC. FPS reduces N- SMase activity and ceramide levels in Ox- LDL- treated VSMC. Collectively ， reducing N-SMase activity and ceramide levels could become a promising strategy for the treatment of vascular calcification.【Conclusion】We demonstrate that FPS attenuates VSMC calcification via targeting ceramide signaling.

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