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Sialyltransferase ST3GAL6 silencing reduces α2,3-sialylated glycans to regulate autophagy by decreasing HSPB8-BAG3 in the brain with hepatic encephalopathy

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2024年第6期25卷 485-498页

作者： Xiaocheng LI Yaqing XIAO Pengfei LI Yayun ZHU Yonghong GUO huijie bian Zheng LI Laboratory for Functional Glycomics College of Life SciencesNorthwest UniversityXi’an 710069China National Translational Science Center for Molecular Medicine Department of Cell BiologyFourth Military Medical UniversityXi’an 710032China Medical Experiment Center Shaanxi University of Chinese MedicineXianyang 712046China The Infectious Disease Department Gongli HospitalPudong New AreaShanghai 200135China

End-stage liver diseases,such as cirrhosis and liver cancer caused by hepatitis B,are often combined with hepatic encephalopathy(HE);ammonia poisoning is posited as one of its main pathogenesis *** is closely related to autophagy,but the molecular mechanism of ammonia’s regulatory effect on autophagy in HE remains *** is an essential form of *** the nervous system,abnormal sialylation affects various physiological processes,such as neural development and synapse ***3 β-galactoside α2,3-sialyltransferase 6(ST3GAL6)is one of the significant glycosyltransferases responsible for addingα2,3-linked sialic acid to substrates and generating glycan *** found that the expression of ST3GAL6 was upregulated in the brains of mice with HE and in astrocytes after ammonia induction,and the expression levels of α2,3-sialylated glycans and autophagy-related proteins microtubule-associated protein light chain 3(LC3)and Beclin-1 were upregulated in ammonia-induced *** findings suggest that ST3GAL6 is related to autophagy in ***,we aimed to determine the regulatory relationship between ST3GAL6 and *** found that silencing ST3GAL6 and blocking or degrading α2,3-sialylated glycans by way of Maackia amurensis lectin-II(MAL-II)and neuraminidase can inhibit *** addition,silencing the expression of ST3GAL6 can downregulate the expression of heat shock proteinβ8(HSPB8)and Bcl2-associated athanogene 3(BAG3).Notably,the overexpression of HSPB8 partially restored the reduced autophagy levels caused by silencing ST3GAL6 *** results indicate that ST3GAL6 regulates autophagy through the HSPB8-BAG3 complex.

关键词： Hepatic encephalopathy Hyperammonemia Autophagy ST3β-galactosideα2,3-sialyltransferase 6(ST3GAL6) Heat shock proteinβ8(HSPB8)

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Adoptive cell transfer therapy for hepatocellular carcinoma

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Frontiers of Medicine 2019年第1期13卷 3-11页

作者： Renyu Zhang Zhao Zhang Zekun Liu Ding Wei Xiaodong Wu huijie bian Zhinan Chen Department of Cell Biology National Translational Science Center for Molecular MedicineState Key Laboratory of Cancer BiologyFourth Military Medical UniversityXi'an 710032China

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. This malignancy is associated with poor prognosis and high mortality. Novel approaches for prolonging the overall survival of patients with advanced HCC are urgently needed. The antitumor activities of adoptive cell transfer therapy (ACT), such as strategies based on tumor-infiltrating lymphocytes and cytokine-induced killer cells, are more effective than those of traditional strategies. Currently, chimeric antigen receptor T-cell (CAR-T) immunotherapy has achieved numerous breakthroughs in the treatment of hematological malignancies, including relapsed or refractory lymphoblastic leukemia and refractory large B-cell lymphoma? Nevertheless, this approach only provides a modest benefit in the treatment of solid tumors. The clinical results of CAR-T immunotherapy for HCC that could be obtained at present are limited. Some published studies have demonstrated that CAR-T could inhibit tumor growth and cause severe side effects. In this review, we summarized the current application of ACT, the challenges encountered by CAR-T technology in HCC treatment, and some possible strategies for the future direction of immunotherapeutic research.

关键词： adoptive cell transfer therapy hepatocellular carcinoma T cell chimeric antigen receptor immunotherapy

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Nonclinical safety, tolerance and pharmacodynamics evaluation for meplazumab treating chloroquine-resistant Plasmodium falciparum

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Acta Pharmaceutica Sinica B 2020年第9期10卷 1680-1693页

作者： Kun Zhang Yu Zhao Zheng Zhang Mengyao Zhang Xiaodong Wu huijie bian Ping Zhu Zhinan Chen College of Life Science and Bioengineering School of ScienceBeijing Jiaotong UniversityBeijing 100044China National Translational Science Center for Molecular Medicine&Department of Cell Biology the Fourth Military Medical UniversityXi’an 710032China Department of Clinical Immunology Xijing Hospitalthe Fourth Military Medical UniversityXi’an 710032China Beijing Institute of Biotechnology Beijing 100071China Center of Anesthesiology&Operation Chinese PLA General HospitalBeijing 100853China

Meplazumab is an anti-CD147 humanized IgG2 *** purpose of this study was to characterize the nonclinical safety,tolerance and efficacy evaluation of meplazumab treating chloroquine resistant Plasmodium *** was well tolerated in repeat-dose toxicology studies in cynomolgus *** observed adverse effect level was 12 mg/*** difference between genders in the primary toxicokinetic parameters after repeat intravenous injection of *** increased levels of drug exposure and drug accumulation were observed in different gender and dose *** had a low cross-reactivity rate in various tissues and did not cause hemolysis or aggregation of red blood *** biodistribution and excretion results indicated that meplazumab was mainly distributed in the plasma,whole blood,and hemocytes,and excreted in the ***,meplazumab effectively inhibited the parasites from invading erythrocytes in humanized mice in a time-dependent manner and the efficacy is superior to that of *** these studies suggested that meplazumab is safe and well tolerated in cynomolgus monkeys,and effectively inhibits *** from invading into human red blood *** nonclinical data facilitated the initiation of an ongoing clinical trial of meplazumab for antimalarial therapy.

关键词： Meplazumab CD147 Safety Tolerance Efficacy Nonclinical Plasmodium falciparum Antimalarial therapy

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Chimeric antigen receptor T cell targeting EGFRvIII for metastatic lung cancer therapy

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Frontiers of Medicine 2019年第1期13卷 57-68页

作者： Zhao Zhang Jun Jiang Xiaodong Wu Mengyao Zhang Dan Luo Renyu Zhang Shiyou Li Youwen He huijie bian Zhinan Chen National Translational Science Center for Molecular Medicine Xi'an 710032China Department of Cell Biology Fourth Military Medical UniversityXi'an 710032China Beijing Institute of Genomics Chinese Academy of ScienceBeijing 100101China Beijing Institute of Biotechnology Academy of Military Medical SciencesBeijing 100142China Department of Immunology Duke University Medical CenterDurhamNC 27710USA

Lung cancer is the most common incident cancer and the leading cause of cancer death. In recent years, the development of tumor immunotherapy especially chimeric antigen receptor T (CAR-T) cell has shown a promising future. Epidermal growth factor receptor variant III (EGFRvlll) is a tumor-specific mutation expressed in various types of tumors and has been detected in non-small cell lung cancer with a mutation rate of 10%. Thus, EGFRvIII is a potential antigen for targeted lung cancer therapy. In this study, CAR vectors were constructed and transfected into virus-packaging cells. Then, activated T cells were infected with retrovirus harvested from stable virus-producing single clone cell lines. CAR expression on the surfaces of the T cells was detected by flow cytometry and Western blot. The function of CAR-T targeting EGFRvIII was then evaluated. The EGFRvIII-CAR vector was successfully constructed and confirmed by DNA sequencing. A stable virus-producing cell line was produced from a single clone by limited dilution. The culture conditions for the cell line, including cell density, temperature, and culture medium were optimized. After infection with retrovirus, CAR was expressed on more than 90% of the T cells. The proliferation of CAR-T cells were induced by cytokine and specific antigen in vitro. More importantly, EGFRvIII-CART specifically and efficiently recognized and killed A549-EGFRvIII cells with an effector/target ratio of 10:1 by expressing and releasing cytokines, including perforin, granzyme B, IFN-γ, and TNF-α. The in vivo study indicated that the metastasis of A549-EGFRvIII cells in mice were inhibited by EGFRvIII-CART cells, and the survival of the mice was significantly prolonged with no serious side effects. EGFRvIII-CART showed significantly efficient antitumor activity against lung cancer cells expressing EGFRvlll in vivo and in vitro. Therefore, CAR-T targeting EGFRvIII is a potential therapeutic strategy in preventing recurrence and metastasis

关键词： chimeric antigen receptor T cells epidennal growth factor receptor lung cancer immunotherapy tumor immunology

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CD147 regulates antitumor CD8^(+)T-cell responses to facilitate tumor-immune escape

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Cellular & Molecular Immunology 2021年第8期18卷 1995-2009页

作者： Yatong Chen Jing Xu Xiaodong Wu Hui Yao Zhou Yan Ting Guo Wenjing Wang Peixiao Wang Yu Li Xiangmin Yang Hao Li huijie bian Zhi-Nan Chen National Translational Science Center for Molecular Medicine&Department of Cell Biology Fourth Military Medical University710032Xi’anChina Medical Research Center Southern University of Science and Technology Hospital518055ShenzhenChina Center of Anesthesiology&Operation Chinese PLA General Hospital100853BeijingChina Department of Radiation Oncology First Peoples’Hospital of ChangzhouThird Affiliated Hospital of Soochow University213000ChangzhouChina Department of Gastroenterology Henan Children’s Hospital450018ZhengzhouChina

Negative regulation of antitumor T-cell-immune responses facilitates tumor-immune ***,we show that deletion of CD147,a type I transmembrane molecule,in T cells,strongly limits in vivo tumor growth of mouse melanoma and lung cancer in a CD8^(+)T-cell-dependent *** mouse tumor models,CD147 expression was upregulated on CD8^(+)tumor-infiltrating lymphocytes(TILs),and CD147 was coexpressed with two immune-checkpoint molecules,Tim-3 and *** publicly available gene-profiling data for CD8^(+)TILs in tumor biopsies from metastatic melanoma patients showed a higher level of CD147 expression in exhausted CD8^(+)TILs than in other subsets of CD8^(+)TILs,along with expression of PD-1 and ***,CD147 deletion increased the abundance of TILs,cytotoxic effector function of CD8^(+)T cells,and frequency of PD-1^(+)CD8^(+)TILs,and partly reversed the dysfunctional status of PD-1^(+)Tim-3^(+)CD8^(+)*** cytotoxic transcription factors Runx3 and T-bet mediation enhanced antitumor responses by CD147^(-/-)CD8^(+)T ***,CD147 deletion in T cells increased the frequency of TRM-like cells and the expression of the T-cell chemokines CXCL9 and CXCL10 in the tumor *** of tumor tissue samples from patients with non-small-cell lung cancer showed negative correlations between CD147 expression on CD8^(+)TILs and the abundance of CD8^(+)TILs,histological grade of the tumor tissue samples,and survival of patients with advanced ***,we found a novel function of CD147 as a negative regulator of antitumor responses mediated by CD8^(+)TILs and identified CD147 as a potential target for cancer immunotherapy.

关键词： CD147 CD8+T cells Anti-tumor immunity

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UBE2S interacting with TRIM28 in the nucleus accelerates cell cycle by ubiquitination of p27 to promote hepatocellular carcinoma development

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Signal Transduction and Targeted Therapy 2021年第3期6卷 938-949页

作者： Ren-Yu Zhang Ze-Kun Liu Ding Wei Yu-Le Yong Peng Lin Hao Li Man Liu Nai-Shan Zheng Ke Liu Cai-Xia Hu Xiao-Zhen Yang Zhi-Nan Chen huijie bian National Translational Science Center for Molecular Medicine Department of Cell BiologyFourth Military Medical UniversityXi'an 710032China School of Life Sciences Central China Normal UniversityWuhan 430079China Oncology and Hepatobiliary Minimally Invasive Interventional Center Beijing Youan HospitalCapital Medical UniversityBeijing 100069China

Genomic sequencing analysis of tumors provides potential molecular therapeutic targets for precision ***,identifying a key driver gene or mutation that can be used for hepatocellular carcinoma(HCC)treatment remains ***,we performed whole-exome sequencing on genomic DNA obtained from six pairs of HCC and adjacent tissues and identified two novel somatic mutations of UBE2S(***57Ala and ***63Asn).Predictions of the functional effects of the mutations showed that two amino-acid substitutions were potentially ***,we observed that wild-type UBE2S,especially in the nucleus,was significantly higher in HCC tissues than that in adjacent tissues and closely related to the clinicopathological features of patients with *** assays revealed that overexpression of UBE2S promoted the proliferation,invasion,metastasis,and G1/S phase transition of HCC cells in vitro,and promoted the tumor growth significantly in ***,UBE2S interacted with TR1M28 in the nucleus,both together enhanced the ubiquitination of p27 to facilitate its degradation and cell cycle *** importantly,the small-molecule cephalomannine was found by a luciferase-based sensitive high-throughput screen(HTS)to inhibit UBE2S expression and significantly attenuate HCC progression in vitro and in vivo,which may represent a promising strategy for HCC therapy.

关键词： hepatocellular invasion ubiquitin

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HMMR alleviates endoplasmic reticulum stress by promoting autophagolysosomal activity during endoplasmic reticulum stress-driven hepatocellular carcinoma progression

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Cancer Communications 2023年第9期43卷 981-1002页

作者： Lin He Hao Li Can Li Ze-Kun Liu Meng Lu Ren-Yu Zhang Dong Wu Ding Wei Jie Shao Man Liu Hao-Lin Wei Cong Zhang Zhe Wang Ling-Min Kong Zhi-Nan Chen huijie bian National Translational Science Centre for Molecular Medicine & Department of Cell Biology Fourth Military Medical UniversityXi'anShaanxiP. R. China Department of Gastroenterology the General Hospital of Western Theatre CommandChengduSichuanP. R. China State Key Laboratory of Cancer Biology Department of PathologyXijing Hospital and School of Basic MedicineFourth Military Medical UniversityXi'anShaanxiP. R. China

Background The mechanism of hepatitis B virus(HBV)-induced carcinogenesis remains an area of *** accumulation of hepatitis B surface antigen in the endoplasmic reticulum(ER)of hepatocytes stimulates persistent ER *** of the unfolded protein response(UPR)pathway of ER stress may play an important role in inflammatory cancer *** the protective UPR pathway is hijacked by cells as a tool for malignant transformation in HBV-related hepatocellular carcinoma(HCC)is still ***,we aimed to define the key molecule hyaluronan-mediated motility receptor(HMMR)in this process and explore its role under ER stress in HCC *** An HBV-transgenic mouse model was used to characterize the pathological changes during the tumor *** and transcriptomics analyses were performed to identify the potential key molecule,screen the E3 ligase,and define the activation *** real-time PCR and Western blotting were conducted to detect the expression of genes in tissues and cell *** reporter assay,chromatin immunoprecipitation,coimmunoprecipitation,immunoprecipitation,and immunofluorescence were employed to investigate the molecular mechanisms of HMMR under ER *** was used to clarify the expression patterns of HMMR and related molecules in human *** We found sustained activation of ER stress in the HBV-transgenic mouse model of *** was transcribed by c/EBP homologous protein(CHOP)and degraded by tripartite motif containing 29(TRIM29)after ubiquitination under ER stress,which caused the inconsistent expression of mRNA and *** expression of TRIM29 in the HCC progression regulated the dynamic expression of *** could alleviate ER stress by increasing autophagic lysosome *** negative correlation between HMMR and ER stress,positive correlation between HMMR and autophagy,and negative correlation between ER stress and

关键词： autophagy endoplasmic reticulum stress hepatitis B virus hepatocellular carcinoma HMMR TRIM29 ubiquitination and proteasomal degradation

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问题导向教学法在医学本科生课外科研实践中的应用

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细胞与分子免疫学杂志 2024年第7期40卷 666-670页

作者：王珂边惠洁空军军医大学国家分子医学转化中心陕西西安710032

问题导向教学法是以实际问题为导向、以学生为中心的新型探究式教学方法,旨在通过实际问题引导学生分析问题、解决问题,逐步培养学生自主学习能力。该研究以嵌合抗原受体T细胞疗法优化在非小细胞肺癌治疗中的探索为例,充分展示问题导向... 详细信息

问题导向教学法是以实际问题为导向、以学生为中心的新型探究式教学方法,旨在通过实际问题引导学生分析问题、解决问题,逐步培养学生自主学习能力。该研究以嵌合抗原受体T细胞疗法优化在非小细胞肺癌治疗中的探索为例,充分展示问题导向教学法在医学本科生课外科研实践中的应用,以期为开展本科生第二课堂教学提供参考。

关键词：问题导向教学法课外科研 CAR-T细胞疗法肿瘤治疗

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CD147 contributes to SARS-CoV-2-induced pulmonary fibrosis

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Signal Transduction and Targeted Therapy 2022年第12期7卷 4422-4434页

作者： Jiao Wu Liang Chen Chuan Qin Fei Huo Xue Liang Xu Yang Kui Zhang Peng Lin Jiangning Liu Zhuan Feng Jiansheng Zhou Zhuo Pei Yatao Wang Xiu-Xuan Sun Ke Wang Jiejie Geng Zhaohui Zheng Xianghui Fu Man Liu Qingyi Wang Zheng Zhang huijie bian Ping Zhu Zhi-Nan Chen Department of Cell Biology of National Translational Science Center for Molecular Medicine and Department of Clinical Immunology of Xijing Hospital Fourth Military Medical UniversityXi’an710032China Shanghai Engineering Research Center of Organ Repair School of MedicineShanghai UniversityShanghai200444China Institute of Laboratory Animals Science Chinese Academy of Medical SciencesBeijing100071China

COVID‐19 patients can develop clinical and histopathological features associated with fibrosis,but the pathogenesis of fibrosis remains poorly ***147 has been identified as a universal receptor for SARS-CoV-2 and its variants,which could initiate COVID-19-related cytokine ***,we systemically analyzed lung pathogenesis in SARS-CoV-2-and its delta variant-infected humanized CD147 transgenic *** and Transmission Electron Microscopy revealed inflammation,fibroblast expansion and pronounced fibrotic remodeling in SARS-CoV-2-infected ***,RNA-sequencing identified a set of fibrosis signature ***,we identified CD147 as a crucial regulator for fibroblast activation induced by *** found conditional knockout of CD147 in fibroblast suppressed activation of fibroblasts,decreasing susceptibility to bleomycin-induced pulmonary ***,a CD147 antibody,was able to inhibit the accumulation of activated fibroblasts and the production of ECM proteins,thus alleviating the progression of pulmonary fibrosis caused by *** conclusion,we demonstrated that CD147 contributed to SARS-CoV-2-triggered progressive pulmonary fibrosis and identified CD147 as a potential therapeutic target for treating patients with post-COVID-19 pulmonary fibrosis.

关键词： CD147 inflammation fibrosis

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Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines,anti-PD-1 and poly I:C

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Journal of Pharmaceutical Analysis 2023年第6期13卷 616-624页

作者： Ping Zhu Shi-You Li Jin Ding Zhou Fei Sheng-Nan Sun Zhao-Hui Zheng Ding Wei Jun Jiang Jin-Lin Miao San-Zhong Li Xing Luo Kui Zhang Bin Wang Kun Zhang Su Pu Qian-Ting Wang Xin-Yue Zhang Gao-Liu Wen Jun OLiu John Thomas August huijie bian Zhi-Nan Chen You-Wen He Department of Clinical Immunology Xijing HospitalDepartment of Cell BiologyNational Translational Science Center for Molecular MedicineFourth Military Medical UniversityXi'an710032China Beijing Tricision Biotherapeutics Inc. Beijing100176China Department of Neurosurgery Xijing HospitalFourth Military Medical UniversityXi'an710032China Zhuhai Tricision Biotherapuetics Inc. ZhuhaiGuangdong519040China Department of Pharmacology and Molecular Sciences Johns Hopkins University School of MedicineBaltimoreMD21205USA

Glioblastoma(GBM)is a lethal cancer with limited therapeutic *** cell(DC)-based cancer vaccines provide a promising approach for GBM *** studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor ***,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 *** patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor ***,mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex(MHC)class I and II antigen *** treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC *** patient also received 28 doses of cyclophosphamide for depletion of regulatory T *** immunotherapy-related adverse events were observed during the *** antitumor CD4t and CD8t T-cell responses were *** patient remains free of disease *** is the first case report on the combination of the above three agents to treat glioblastoma *** results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

关键词： Glioblastoma multiforme DC vaccine Tumor-associated antigens Neoantigens

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