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mTOR regulates TLR-induced c-fos and Th1 responses to HBV and HCV vaccines

Virologica Sinica 2015年第3期30卷 174-189页

作者： Li He Aiping Zang Min Du Dapeng Ma Chuanping Yuan Chun Zhou Jing Mu Huanjing Shi Dapeng Li Xulin Huang Qiang Deng Jianhua Xiao Huimin Yan Lijian Hui Ke Lan Sidong Xiong Xiaoxia Li Zhong Huang Hui Xiao Institute of Biology and Medical Sciences Soochow University unit of Immune Signaling and Regulation Key Laboratory of Molecular Virology & Immunology Institut Pasteur of Shanghai Chinese Academy of Sciences unit of Vaccinology and Anti-viral Strategies Key Laboratory of Molecular Virology & Immunology Institut Pasteur of Shanghai Chinese Academy of Sciences unit of tumor virology Key Laboratory of Molecular Virology & Immunology Institut Pasteur of ShanghaiChinese Academy of Sciences Institute of Pathogenic Biology University of South China Mucosal Immunity Research Group State Key Laboratory of Virology Wuhan Institute of Virology Chinese Academy of Sciences State Key Laboratory of Cell Biology Institute of Biochemistry and Cell Biology Shanghai Institutes for Biological Sciences Chinese Academy of Sciences Department of Immunology Lerner Research Institute Cleveland Clinic Foundation Vaccine Center Institut Pasteur of Shanghai Chinese Academy of Sciences

Although IL-12 plays a critical role in priming Th1 and cytotoxic T lymphocyte(CTL) responses, Toll-like receptor(TLR) signaling only induces low amounts of IL-12 in dendritic cells and macrophages, implying the existence of stringent regulatory mechanisms. In this study, we sought to uncover the mechanisms underlying TLR-induced IL-12 expression and the Th1 response. By systemic screening, we identified a number of protein kinases involved in the regulation of TLRinduced IL-12 expression. In particular, PI3 K, ERK, and m TOR play critical roles in the TLR-induced Th1 response by regulating IL-12 and IL-10 production in innate immune cells. Moreover, we identified c-fos as a key molecule that mediates m TOR-regulated IL-12 and IL-10 expression in TLR signaling. Mechanistically, m TOR plays a crucial role in c-fos expression, thereby modulating NFκB binding to promoters of IL-12 and IL-10. By controlling the expression of a special innate gene program, m TOR can specifically regulate the TLR-induced T cell response in vivo. Furthermore, blockade of m TOR by rapamycin efficiently boosted TLR-induced antigen-specific T and B cell responses to HBV and HCV vaccines. Taken together, these results reveal a novel mechanism through which m TOR regulates TLR-induced IL-12 and IL-10 production, contributing new insights for strategies to improve vaccine efficacy.

关键词： Toll-like receptor(TLR) mTOR vaccine hepatitis B virus(HBV) hepatitis C virus(HCV) adjuvant c-fos

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Prion Protein Protects Cancer Cells against Endoplasmic Reticulum Stress Induced Apoptosis

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Virologica Sinica 2019年第2期34卷 222-234页

作者： Zhenxing Gao Min Peng Liang Chen Xiaowen Yang Huan Li Run Shi Guiru Wu Lili Cai Qibin Song Chaoyang Li State Key Laboratory of virology Wuhan Institute of Virology Chinese Academy of Sciences Wuhan 430071 China Department of Oncology Renmin Hospital of Wuhan University Wuhan 430060 China Department of the First Abdominal Surgery Jiangxi Tumor Hospital Nanchang 330029 China

Unfolded protein response(UPR) is an adaptive reaction for cells to reduce endoplasmic reticulum(ER) stress. In many types of cancers, such as lung cancer and pancreatic cancer, cancer cells may harness ER stress to facilitate their survival and growth. Prion protein(PrP) is a glycosylated cell surface protein that has been shown to be up-regulated in many cancer cells. Since PrP is a protein prone to misfolding, ER stress can result in under-glycosylated PrP, which in turn may activate ER stress. To assess whether ER stress leads to the production of under-glycosylated PrP and whether underglycosylated PrP may contribute to ER stress thus leading to cancer cell apoptosis, we treated different cancer cells with brefeldin A(BFA), thapsigargin(Thps), and tunicamycin(TM). We found that although BFA, Thps, and TM treatment activated UPR, only ATF4 was consistently activated by these reagents, but not other branches of ER stress. However, the canonical PERK-eIF2α-ATF4 did not account for the observed activation of ATF4 in lung cancer cells. In addition, BFA,but neither Thps nor TM, significantly stimulated the expression of cytosolic PrP. Finally, we found that the levels of PrP contributed to anti-apoptosis activity of BFA-induced cancer cell death. Thus, the pathway of BFA-induced persistent ER stress may be targeted for lung and pancreatic cancer treatment.

关键词： Endoplasmic reticulum stress Brefeldin A (BFA) Prion protein (PrP)- Glycosylation Apoptosis

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Viral Regulation of RNA Granules in Infected Cells

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Virologica Sinica 2019年第2期34卷 175-191页

作者： Qiang Zhang Nishi R. Sharma Zhi-Ming Zheng Mingzhou Chen State Key Laboratory of virology and Modern virology Research Center College of Life Sciences Wuhan UniversityWuhan 430072 China tumor Virus RNA Biology Section RNA Biology Laboratory National Cancer Institute National Institutes of Health Frederick MD 21702 USA

RNA granules are cytoplasmic, microscopically visible, non-membrane ribo-nucleoprotein structures and are important posttranscriptional regulators in gene expression by controlling RNA translation and stability. TIA/G3BP/PABP-specific stress granules(SG) and GW182/DCP-specific RNA processing bodies(PB) are two major distinguishable RNA granules in somatic cells and contain various ribosomal subunits, translation factors, scaffold proteins, RNA-binding proteins, RNA decay enzymes and helicases to exclude m RNAs from the cellular active translational pool. Although SG formation is inducible due to cellular stress, PB exist physiologically in every cell. Both RNA granules are important components of the host antiviral defense. Virus infection imposes stress on host cells and thus induces SG formation. However, both RNA and DNA viruses must confront the hostile environment of host innate immunity and apply various strategies to block the formation of SG and PB for their effective infection and multiplication. This review summarizes the current research development in the field and the mechanisms of how individual viruses suppress the formation of host SG and PB for virus production.

关键词： Stress granules (SG) P-bodies (PB) RNA virus - DNA virus

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Simultaneous determination of LY3214996,abemaciclib,and M2 and M20 metabolites in human plasma,cerebrospinal fluid,and brain tumor by LC-MS/MS

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Journal of Pharmaceutical Analysis 2022年第4期12卷 601-609页

作者： Tigran Margaryan Mackenna Elliott Nader Sanai Artak Tovmasyan Ivy Brain tumor Center Barrow Neurological InstitutePhoenixAZ85013USA

A sensitive and rapid liquid chromatography tandem mass spectrometry(LC-MS/MS)method was established for the quantification of total and unbound concentrations of LY3214996,an extracellular signal-regulated kinase inhibitor;abemaciclib,a cyclin-dependent kinase 4/6 inhibitor;and abemaciclib active metabolites,M2 and M20,in human plasma,brain tumor,and cerebrospinal fluid *** method was validated over a concentration range of 0.2e500 nM within a total run time of 3.8 min using isocratic elution on a Kinetex^(TM) F_(5) *** was performed on a Sciex QTRAP 6500t mass spectrometer employing multiple reaction monitoring mode under positive electrospray *** intra-and inter-batch accuracy as well as the precision of the method for all matrices was within ±20% and ≤20% at the lower limit of quantification,and within ±15% and ≤15% for other quality control levels for all *** unbound fractions of drugs and metabolites in spiked and patient samples were determined using an optimized equilibrium *** validated method was successfully applied in a phase 0/2 clinical trial to assess the central nervous system penetration of LY3214996 and abemaciclib.

关键词： LC-MS/MS LY3214996 Abemaciclib Brain tumor penetration Equilibrium dialysis

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Role of tumor necrosis factor-alpha in zebrafish retinal neurogenesis and myelination

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International Journal of Ophthalmology(English edition) 2016年第6期9卷 831-837页

作者： Xu-Dan Lei Yan Sun Shi-Jiao Cai Yang-Wu Fang Jian-Lin Cui Yu-Hao Li Key Laboratory of tumor Microenvironment and Neurovascular Regulation Nankai University School of Medicine

AIM： To investigate the role of tumor necrosis factoralpha （TNF-α） in zebrafish retinal development and myelination. METHODS： Morpholino oligonucleotides （MO）, which are complementary to the translation start site of the wild-type embryonic zebrafish TNF-α mRNA sequence, were synthesized and injected into one to four-cell embryos. The translation blocking specificity was verified by Western blotting using an anti-TNF-α antibody, whole-mount in sltuhybridization using a hepatocytespecific mRNA probe ceruloplasmin （cp）, and coinjection of TNF-α MO and TNF-α mRNA. An atonel homolog 7 （atoh7） mRNA probe was used to detect neurogenesis onset. The retinal neurodifferentiation was analyzed by immunohistochemistry using antibodies Zn12, Zprl, and Zpr3 to label ganglion cells, cones, and rods, respectively. Myelin basic protein （mbp）was used as a marker to track and observe the myelination using whole-mount in situ hybridization. RESULTS： Targeted knockdown of TNF-α resulted in specific suppression of TNF-α expression and a severely underdeveloped liver. The co-injection of TNF-α MO and mRNA rescued the liver development. Retinal neurogenesis in TNF-cc morphants was initiated on time. The retina was fully laminated, while ganglion cells, cones, and rods were well differentiated at 72 hours post-fertilization （hpf）. mbp was expressed in Schwann cells in the lateral line nerves and cranial nerves from 3 days post -fertilization （dpf） as well as in oligodendrocytes linearly along the hindbrain bundles and the spinal cord from 4 dpf, which closely resembled its endogenous profile. CONCLUSION： TNF-α is not an essential regulator for retinal neurogenesis and optic myelination.

关键词： tumor necrosis factor-alpha retina neurogenesis myelination zebrafish

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A Mn-porphyrinic metal–organic framework immobilizing glucose oxidase for combined photodynamic/chemodynamic/starvation therapy

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Tungsten 2025年第1期 183-194页

作者： Xin-Ran Sun Hao-Ming Yuan Guo-Da Zhang Chao Wang Shu-Juan Sun Peng-Fei Shi Shandong Provincial Key Laboratory of Detection Technology for tumor Markers School of Chemistry and Chemical Engineering Linyi University

The combination of photodynamic therapy（PDT） and chemodynamic therapy（CDT） in tumor treatment has attracted considerable ***,tumor hypoxia and glutathione（GSH） overproduction in the tumor tissue restricted the progress of their ***,a Mn-porphyrinic metal-organic framework（Mn-TCPP） was constructed by the one-pot method and further used for immobilizing glucose oxidase（GOx） to obtain GOx@*** would rapidly exhaust endogenous glucose into hydrogen peroxide（H2O2） and gluconic acid,thus shutting off the energy supply of tumor cells for starvation ***-TCPP catalyzed H2O2to produce oxygen,regulating the hypoxic tumor microenvironment and in turn improving1O2generation under laser ***,Mn-TCPP can reduce reactive oxygen species consumption owing to the redox reaction between Mn3+and GSH,thus greatly enhancing ***,benefiting from GOx-mediated starvation therapy,Mn2+produced by Mn3+reduction can react with sufficient intracellular H2O2to generate ·OH with high cytotoxicity through a Fenton-like *** treatment by GOx@Mn-TCPP under laser irradiation in vitro,the cell viability of 4T1 and A549 tumor cells reached to 20%,reflecting GOx@Mn-TCPP could give full play to the advantages of PDT/CDT/starvation *** results in vivo demonstrated that GOx@Mn-TCPP mediated synergistic cascade therapy could significantly inhibit tumor growth and improve the therapeutic effect.

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Intensify standardized therapy for esophageal and stomach cancer in tumor hospitals

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World Journal of Gastroenterology 2001年第1期7卷 80-82页

作者： Shi Jie Wang Deng Gui Wen Jing Zhang Xin Man Hui Liu Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, Hebei Province, China Hebei tumor Hospital 5 Jiankanglu Shijiazhuang 050011 Hebei Province China.

INTRODUCTIONCancer treatment situation in tumor hospitals inChina has its own unique characteristics which arenot found in other parts of the world. Because ofthe huge population and high incidence rates ofesophageal ... 详细信息

关键词： Antineoplastic Agents Antineoplastic Protocols China Combined Modality Therapy Esophageal Neoplasms Hospital Mortality Humans Oncology Service, Hospital administration numerical data Program Evaluation Radiotherapy Research Support, Non-U.S. Gov't Stomach Neoplasms Survival Rate

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Paradoxical Roles of IL-4 in tumor Immunity

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Cellular & Molecular Immunology 2009年第6期6卷 415-422页

作者： Zhiguang Li Lin Chen Zhihai Qin National Laboratory of Biomacromolecules China-Japan Joint Laboratory of Structural Virology and ImmunologyInstitute of BiophysicsChinese Academy of SciencesBeijingChina National Laboratory of Biomacro-molecules China-Japan Joint Laboratory of Structural Virology and ImmunologyInstitute of BiophysicsChinese Academy of SciencesBeijingChina

Interleukin(IL)-4 is a crucial cytokine in tumor *** the initial murine experiments,IL-4 exhibited potent anti-tumor *** genetically modified to produce IL-4 were rejected,while parental tumors grew *** rejected IL-4-producing tumors got long-lasting anti-tumor *** comparative study showed that IL-4 induced the most effective immune response among several cytokines in both prophylactic and therapeutic *** of these indicate IL-4 has strong potential as a tumor therapy ***,contrary evidence indeed exists,and is becoming more and more abundant which shows IL-4 is a tumor-promoting ***-4 amounts are usually elevated in human cancer ***-4 knockout mice are more resistant to tumor challenge than IL-4 competent ***,tumor cells of various histological origins often express increased levels of IL-4 receptor in comparison to their normal *** carefully examining presently available data,we found the effects of IL-4 in tumor immunity are closely related to its sources,expressing time and dose,as well as the molecular and cellular *** this mini-review,we concentrate on illustrating the paradoxical roles and underlying mechanisms of IL-4 in tumor immunity and try to understand how one molecule has opposite effects.

关键词： endogenous IL-4 exogenous IL-4 tumor immunity

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Functional Mechanism of Resveratrol in Inhabiting Growth of Cells ls174t and Its Mechanism in Subcutaneously Transplanted tumor of Nude Mice

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Chemical Research in Chinese Universities 2008年第6期24卷 756-761页

作者： CHEN Jie DONG Xin-shu GUO Xing-gang The Affiliated tumor Hospital Harbin Medical University Harbin 150040 P. R. China

To explore the functional mechanism of Resveratrol against colon cancer cells ls174t and the growth of colon cancer tissue of tumor-bearing mice, MTT method was used to observe the functions of resveratrol for inhibition against cells ls174t in vitro. Transmission electron microscope was used to observe the cell apoptosis. FCM assay was performed to measure the change of the cell apoptosis rate and of cell cycle. RT-PCR method was used to detect the expressions of bcl-2 and bax mRNA. Western blot method was used to detect the expressions of bcl-2 and bax protein. Ceils ls174t were transplanted subcutaneously to nude mice to observe the effect of resveratrol on the growth of subcutaneously transplanted tumor, RT-PCR method was used to detect the expressions of bcl-2 and bax mRNA in the tumor tissue. Western blot method was used to detect the expressions of bcl-2 and bax protein in the tumor tissue. Resveratrol has an effect of inhibiting proliferation of cells ls174t in vitro（P〈0.01）. It is able to induce the apoptosis of cells ls174t, causing the decrease in the expression of bcl-2 and the increase in the expression of bax. Resveratrol could inhibit the growth of subcutaneously transplanted tumor of nude mice（P〈0.05）, causing the decrease in the expression of bcl-2 and the increase in the expression of bax. Resveratrol can inhibit the growth of cells 174t and the growth of subcutaneously transplanted tumor. The mechanism is possibly related to the induction of the cell apoptosis and the regulation of bcl-2/bax expression.

关键词： Resveratrol Colon cancer tumor cell Cell apoptosis Nude mice

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Identification of residues in Lassa virus glycoprotein 1 involved in receptor switch

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Virologica Sinica 2024年第4期39卷 600-608页

作者： Jiao Guo Yi Wan Yang Liu Xiaoying Jia Siqi Dong Gengfu Xiao Wei Wang State Key Laboratory of virology Wuhan Institute of VirologyCenter for Biosafety Mega-ScienceChinese Academy of SciencesWuhan 430071China University of the Chinese Academy of Sciences Beijing 100049China The Xi'an Key Laboratory of Pathogenic Microorganism and tumor Immunity School of Basic MedicineXi'an Medical UniversityXi'an 710021China

Lassa virus(LASV)is an enveloped,negative-sense RNA virus that causes Lassa hemorrhagic *** entry of LASV requires the viral glycoprotein 1(GP1)to undergo a receptor switch from its primary receptor alpha-dystroglycan(α-DG)to its endosomal receptor lysosome-associated membrane protein 1(LAMP1).A conserved histidine triad in LASV GP1 has been reported to be responsible for receptor *** test the hypothesis that other non-conserved residues also contribute to receptor switch,we constructed a series of mutant LASV GP1 proteins and tested them for binding to *** residues,L84,K88,L107,and H170,were identified as critical for receptor *** any of the four residues with the corresponding lymphocytic choriomeningitis virus(LCMV)residue(L84 N,K88E,L10F,and H170S)reduced the binding affinity of LASV GP1 for ***,all mutations caused decreases in glycoprotein precursor(GPC)-mediated membrane fusion at both pH 4.5 and *** infectivity of pseudotyped viruses bearing either GPCL84N or GPCK88E decreased sharply in multiple cell types,while L107F and H170S had only mild effects on *** biolayer light interferometry assay,we found that all four mutants had decreased binding affinity to LAMP1,in the order of binding affinity being L84 N>L107F>K88E>*** four amino acid loci identified for the first time in this study have important reference significance for the in-depth investigation of the mechanism of receptor switching and immune escape of LASV occurrence and the development of reserve anti-LASV infection drugs.

关键词： Lassa virus(LASV) Lysosome-associated membrane protein 1 (LAMP1) Glycoprotein Receptor switch Membrane fusion

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