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BET inhibitors enhance the anti-cancer effect of etoposide by suppressing the MrN-ATM axis in the dNA damage response

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Genes & diseases 2024年第1期11卷 19-22页

作者： Zhenhai Li Wenchao Xu Feng Chen Jun Zhang Wei-Guo Zhu Guangdong Key Laboratory of Genome Instability and Human disease Prevention Department of Biochemistry and Molecular BiologyShenzhen University School of MedicineShenzhenGuangdong 518055China School of Pharmaceutical sciences Shenzhen University Health Science CenterShenzhenGuangdong 518055China base for international science and technology cooperation:carson cancer stem cell vaccines r&d center International Cancer CenterShenzhen University Health Science CenterShenzhenGuangdong 518055China Shenzhen Bay Laboratory Shenzhen University School of MedicineShenzhenGuangdong 518055China Marshall Laboratory of Biomedical Engineering Shenzhen University School of MedicineShenzhenGuangdong 518055China

Etoposide is widely used for cancer chemotherapy in the clinic.However,long-term etoposide treatment can lead to adverse effects or drug resistance.To improve the situation,we evaluated the therapeutic efficiency of etoposide combined with inhibitors of bromodomain and extraterminal(BET)family proteins,which have recently emerged as novel anti-cancer targets due to their critical roles in cancer development.Firstly,we showed Brd4,one of the main targets of BET inhibitors,was involved in dNA damage response(ddr)via the homologous recombination(Hr)repair pathway.

关键词： etoposide damage cancer

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A human monoclonal antibody neutralizes SArS-CoV-2 Omicron variants bytargeting the upstream region of spike protein Hr2 motif

hLife

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hLife 2024年第3期2卷 126-140页

作者： Hang Su Jun Zhang Zhenfei Yi Sajid Khan Mian Peng Liang Ye Alan Bao Han Zhang Guangli Suo Qian Li Housheng Zheng dandan Wu Thomas J.Kipps Lanfeng Wang Zhenghong Lin Suping Zhang Shenzhen Key Laboratory of Precision Medicine for Hematological Malignancies Guangdong Key Laboratory for Genome Stability andHuman Disease PreventionDepartment of PharmacologySchool of Basic Medical SciencesBase for International Science and TechnologyCooperation:Carson Cancer Stem Cell Vaccines R&D CenterInternational Cancer CenterShenzhen University Medical SchoolShenzhenUniversityGuangdongChina School of Life sciences Chongqing UniversityChongqingChina The center for Microbes Development and HealthCAS Key Laboratory of Molecular Virology&ImmunologyShanghai Institute of Immunityand InfectionChinese Academy of SciencesUniversity of Chinese Academy of SciencesShanghaiChina College of Life sciences University of Chinese Academy of SciencesBeijingChina department of Critical Care Medicine Shenzhen Luohu People’s HospitalGuangdongChina University of California BerkeleyCaliforniaUSA Xenta Biomedical science Co. LtdGuangdongChina CAS Key Laboratory of Nano-Bio Interface Suzhou Institute of Nano-Tech and Nano-BionicsChinese Academy of SciencesJiangsuChina center of Novel Therapeutics University of CaliforniaSan DiegoCaliforniaUSA

The continuous emergence of new severe acute respiratory syndrome coronavirus 2(SArS-CoV-2)variants meansthere is a need to explore additional strategies to develop broad-spectrum vaccines or therapeutics for individuals remaining at risk of coronavirus disease 2019(COVId-19).Neutralizing monoclonal antibody(mAb)that binds to theconserved S2 subunit of the SArS-CoV-2 spike(S)protein alone,or in combination with mAb that binds to the receptor-binding domain(rBd)of S protein,might be effective in eliciting protection from infection by a variety of SArS-CoV2 variants.Using high-throughput single-cell immunoglobulin sequencing of B cells from COVId-19-convalescent donors,we identified a high-affinity S2-specific mAb-39,that could inhibit original SArS-CoV-2 strain,Omicron BA.1,BA.2.86,BA.4,BA.5,and EG.5.1 S protein-mediated membrane fusion,leading to the neutralization of these pseudoviralinfections.Moreover,mAb-39 could also improve the neutralizing activity of anti-rBd antibody against the highlyneutralization-resistant Omicron variants.Molecular docking and point mutation analyses revealed that mAb-39 recognized epitopes within the conserved upstream region of the heptad repeat 2(Hr2)motif of the S2 subunit.Collectively,these findings demonstrate that targeting the conserved upstream region of the Hr2 motif(e.g.,using mAbs)provides anovel strategy for preventing the infection of SArS-CoV-2 and its variants.

关键词： coronavirus disease 2019(COVId-19) severe acute respiratory syndrome coronavirus 2(SArS-CoV-2)Omicron variants monoclonal antibody upstream region of heptad repeat 2(Hr2) immunoglobulin repertoiresequencing

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HdAC6 inhibitor loaded bimetallene nanosheets with antagonizing thermoresistance for augmented mild photothermal therapy

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中国化学快报:英文版 2023年第9期34卷 235-242页

作者： Lingyu Qiu Shan Lei Jing Zhang ruhan Yan Wansi Chen Jing Lin Wei-Guo Zhu Peng Huang Guangdong Key Laboratory of Genome Instability and Human disease Prevention Department of Biochemistry and Molecular BiologyShenzhen University Medical SchoolShenzhen 518055China base for international science and technology cooperation:carson cancer stem cell vaccines r&d center International Cancer CenterShenzhen University Medical SchoolShenzhen 518055China Marshall Laboratory of Biomedical Engineering International Cancer CenterLaboratory of Evolutionary Theranostics(LET)School of Biomedical EngineeringShenzhen University Medical SchoolShenzhen 518060China

Photothermal therapy(PTT)induces thermoresistance through cellular heat shock response,which impairs the therapeutic efficacy of the PTT.To resolve this problem,we developed a photothermal theranostics(denoted as PMH),which integrated the photothermal conversion agent of PdMo bimetallene with histone deacetylase 6(HdAC6)selected inhibitor(ACY-1215),showing the synergistic antitumor effect both in vitro and in vivo.Mechanistically,under the photoacoustic imaging(PA)navigation,the released ACY-1215 triggered by NIr laser irradiation decrease the heat shock proteins(HSPs)expression and weaken the HdAC6-regulated HSP90 deacetylation,thus hindering the degradation of PTT-induced misfolded or unfold proteins through proteasome dependent pathway.Moreover,mild photothermal therapy(mPTT)treatment compromised the autophagy,which induced by HdAC6 inhibition,leading to mPTTinduced misfolded or unfold proteins further accumulation.Given that inhibition of HdAC6 plus m PTT contribute to tumor eradication.This study develops a promising combination strategy based on m PTT for future cancer treatment.

关键词： Mild photothermal therapy Thermoresistance Histone deacetylase 6 Heat shock proteins Autophagy

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The function and clinical application of extracellular vesicles in innate immune regulation

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cellular & Molecular Immunology 2020年第4期17卷 323-334页

作者： Xiaoxue Zhou Feng Xie Lin Wang Long Zhang Suping Zhang Meiyu Fang Fangfang Zhou Jiangsu Key Laboratory of Infection and Immunity Institutes of Biology and Medical SciencesSoochow UniversitySuzhou 215123China department of Chemotherapy Zhejiang Cancer HospitalHangzhou 310058China Guangdong Key Laboratory for Genome Stability and Human disease Prevention Department of PharmacologyBase for International Science and Technology Cooperation:Carson Cancer Stem Cell Vaccines R&D CenterInternational Cancer CenterShenzhen University Health Science CenterShenzhen 518055China

The innate immune system plays a crucial role in the host defense against viral and microbial infection.Exosomes constitute a subset of extracellular vesicles(EVs)that can be released by almost all cell types.Owing to their capacity to shield the payload from degradation and to evade recognition and subsequent removal by the immune system,exosomes efficiently transport functional components to recipient cells.Accumulating evidence has recently shown that exosomes derived from tumor cells,host cells and even bacteria and parasites mediate the communication between the invader and innate immune cells and thus play an irreplaceable function in the dissemination of pathogens and donor cell-derived molecules,modulating the innate immune responses of the host.In this review,we describe the current understanding of EVs(mainly focusing on exosomes)and summarize and discuss their crucial roles in determining innate immune responses.Additionally,we discuss the potential of using exosomes as biomarkers and cancer vaccines in diagnostic and therapeutic applications.

关键词： extracellular vesicles exosome innate immune cancer diagnosis immunotherapy

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