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Current Medical Science 2024年第2期44卷 261-272页

作者： Meng-jie WANG Yu XIA Qing-lei GAO Department of Obstetrics and Gynecology National Clinical Research Center for Obstetrics and GynecologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China Key Laboratory of Cancer Invasion and Metastasis(Ministry of Education) Hubei Key Laboratory of Tumor Invasion and MetastasisTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

dna damage occurs across tumorigenesis and tumor development.Tumor intrinsic dna damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment(TIME)and dominate tumor progression.Accumulating evidence documents that multiple signaling pathways,including cyclic GMP-AMP synthase-stimulator of interferon genes(cGAS-STING)and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein(ATM/ATR),are activated downstream of dna damage and they are associated with the secretion of diverse cytokines.These cytokines possess multifaced functions in the anti-tumor immune response.Thus,it is necessary to deeply interpret the complex TIME reshaped by damaged dna and tumor-derived cytokines,critical for the development of effective tumor therapies.This manuscript comprehensively reviews the relationship between the dna damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines.We also summarize clinical trials targeting signaling pathways and cytokines associated with dna damage and provide future perspectives on emerging technologies.

关键词： dna damage tumor immune microenvironment inflammatory cytokines cancer therapy

Aluminum exposure impairs oocyte quality via subcellular structure disruption and dna damage-related apoptosis in mice

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Journal of Environmental Sciences 2024年第5期139卷 308-319页

作者： Hongge Li Jingcai Liu Weihua Nong Mengying Shen Sheng Dou Shaochen Sun Junli Wang The Affiliated Hospital of Youjiang Medical University for Nationalities Guangxi 533000China College of Animal Science and Technology Nanjing Agricultural UniversityNanjing 210095China School of Medical Laboratory Youjiang Medical University for NationalitiesGuangxi 533000China Industrial College of Biomedicine and Health Industry Youjiang Medical University for NationalitiesGuangxi 533000China Reproductive Medicine Guangxi Medical and Health Key Discipline Construction ProjectThe Affiliated Hospital of Youjiang Medical University for NationalitiesGuangxi 533000China

Aluminum(Al)can lead to an exposure of creature in varieties ways for its universality,and it could disturb normal physiological metabolism,with the damage to multisystem including reproduction.Since the oocyte quality is critical for female reproduction,we inspected the toxicity of Al on mouse oocyte maturation.We constructed in vitro exposure mouse model,and we found that 5 mmol/L Al had adverse effects on oocyte maturation by impairing organelle and cytoskeleton.Aberrant spindle and misaligned chromosomes which might be considered to be caused by elevated levels of acetylation,as well as abnormal distribution of actin dynamics could hinder normal meiosis of oocytes.Organelle dysfunction indicated that Al affected proteins synthesis,transport and digestion,which would further damage oocyte maturation.In order to explore the mechanism of Al toxicity,our further investigation demonstrated that Al caused mitochondrial dysfunction and imbalance calcium homeostasis,resulting in limited energy supply.Moreover,high level of reactive oxygen species,dna damage and apoptosis caused by oxidative stress were also the manifestation of Al toxicity on oocytes.In conclusion,our study provided the evidence that Al exposure affected oocyte quality through its effects on spindle organization,actin dynamics,organelle function and the induction of dna damage-related apoptosis with mouse model.

关键词： Aluminum Oocyte Cytoskeleton Organelle dna damage

Metal nanoparticles for cancer therapy:Precision targeting of dna damage

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Acta Pharmaceutica Sinica B 2024年第3期14卷 1132-1149页

作者： Qian Chen Chunyan Fang Fan Xia Qiyue Wang Fangyuan Li Daishun Ling Institute of Pharmaceutics Hangzhou Institute of Innovative MedicineCollege of Pharmaceutical SciencesZhejiang UniversityHangzhou 310058China Frontiers Science Center for Transformative Molecules School of Chemistry and Chemical EngineeringNational Center for Translational MedicineShanghai Jiao Tong UniversityShanghai 200240China World Laureates Association(WLA)Laboratories Shanghai 201203China Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province Hangzhou 310009China

Cancer,a complex and heterogeneous disease,arises from genomic instability.Currently,dna damage-based cancer treatments,including radiotherapy and chemotherapy,are employed in clinical practice.However,the efficacy and safety of these therapies are constrained by various factors,limiting their ability to meet current clinical demands.Metal nanoparticles present promising avenues for enhancing each critical aspect of dna damage-based cancer therapy.Their customizable physicochemical properties enable the development of targeted and personalized treatment platforms.In this review,we delve into the design principles and optimization strategies of metal nanoparticles.We shed light on the limitations of dna damage-based therapy while highlighting the diverse strategies made possible by metal nanoparticles.These encompass targeted drug delivery,inhibition of dna repair mechanisms,induction of cell death,and the cascading immune response.Moreover,we explore the pivotal role of physicochemical factors such as nanoparticle size,stimuli-responsiveness,and surface modification in shaping metal nanoparticle platforms.Finally,we present insights into the challenges and future directions of metal nanoparticles in advancing dna damage-based cancer therapy,paving the way for novel treatment paradigms.

关键词： dna damage Metal nanoparticles Nucleus-targeting dna repair inhibition Immune response Size optimization Stimuli-responsiveness Surface modification

dna damage-mediated cellular senescence promotes hand-foot syndrome that can be relieved by thymidine prodrug

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Genes & Diseases 2023年第6期10卷 2557-2571页

作者： Bingxue Yang Xinran Xie Zhaoyu Wu Dazhao Lv Jiajun Hu Yuyun Chen Jiaxing Li Shuyue Luo Jiacheng Li Jie Luo Shiyi Zhang School of Pharmacy Shanghai Jiao Tong UniversityShanghai 200240China School of Pharmacy and School of Biomedical Engineering Shanghai Jiao Tong UniversityShanghai 200240China

Hand-foot syndrome(HFS)is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes.Even though the cause and pathophysiology of HFS are relatively widely reported,how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied.Additionally,prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce.In our study,we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS.Mechanistically,dna damage,as the primary cytotoxic cause,in keratinocytes induces cell cycle arrest,activates the cGAS-STING signaling pathway,and subsequently mediates cellular senescence,ultimately fueling a robust secondary inflammatory response that results in HFS.More importantly,the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of dna and thus causing the escape from cellular senescence.These data highlight the importance of dna damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.

关键词： Cellular senescence cGAS-STING Cutaneous toxicity dna damage Fluoropyrimidine Hand-foot syndrome Keratinocytes Thymidine prodrug

Design,synthesis,and biological evaluation of novel chrysin derivatives as poly(ADP-ribose)polymerase 1(PARP1)inhibitors for the treatment of breast cancer

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Chinese Journal of Natural Medicines 2024年第5期22卷 455-465页

作者： YANG Yao TONG Jing XIE Xianshun CAO Hong FU Yong LUO Yong LIU Shan CHEN Wen YANG Ning Hengyang Medical School University of South ChinaHengyang 421200China Emergency Department Hengyang Medical SchoolThe Second Affiliated HospitalUniversity of South ChinaHengyang 421200China Hengyang Medical School The Second Affiliated HospitalUniversity of South ChinaHengyang 421200China Hemato-oncology Department Hengyang Medical SchoolThe Second Affiliated HospitalUniversity of South ChinaHengyang 421200China Department of Breast and Thyroid Surgery Hengyang Medical SchoolThe Second Affiliated HospitalUniversity of South ChinaHengyang 421200China

In this study,we reported the discovery and structure-activity relationship analysis of chrysin derivatives as a new class of inhibitors targeting poly(ADP-ribose)polymerase 1(PARP1).Among these derivatives,compound 5d emerged as the most effective chrysin-based inhibitor of PARP1,with an IC50 value of 108 nmol·L^(-1).This compound significantly inhibited the proliferation and migration of breast cancer cell lines HCC-1937 and MDA-MB-436 by inducing dna damage.Furthermore,5d induced apoptosis and caused an extended G1/S-phase in these cell lines.Molecular docking studies revealed that 5d possesses a strong binding affinity toward PARP1.In vivo,in a xenograft model,5d effectively reduced tumor growth by downregulating PARP1 expression.Overall,compound 5d shows promise as a potential therapeutic agent for the treatment of BRCA wild-type breast cancer.

关键词： Chrysin derivatives PARP1 Antitumor dna damage Small molecules

AZD1775 and anti-PD-1 antibody synergistically sensitize hepatoma to radiotherapy

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Chinese Medical Journal 2024年第2期137卷 222-231页

作者： Yichun Yin Jian Wang Junxuan Yi Kaiyue Zhang Zimeng Yin Shunzi Jin Baisong Zheng Public Health of College Jilin UniversityJilinChangchun 130021China Institute of Virology and AIDS Research The First Hospital of Jilin UniversityJilinChangchun 130021China NHC Key Laboratory of Radiobiology(Jilin University) JilinChangchun 130021China

Background:Radiation(IR)-induced dna damage triggers cell cycle arrest and has a suppressive effect on the tumor microenvironment(TME).Wee1,a cell cycle regulator,can eliminate G2/M arrest by phosphorylating cyclin-dependent kinase 1(CDK1).Meanwhile,programed death-1/programed death ligand-1(PD-1/PDL-1)blockade is closely related to TME.This study aims to investigate the effects and mechanisms of Wee1 inhibitor AZD1775 and anti-PD-1 antibody(anti-PD-1 Ab)on radiosensitization of hepatoma.Methods:The anti-tumor activity of AZD1775 and IR was determined by 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyltetrazolium bromide(MTT)assay on human and mouse hepatoma cells HepG2,Hepa1-6,and H22.The anti-hepatoma mechanism of AZD1775 and IR revealed by flow cytometry and Western blot in vitro.A hepatoma subcutaneous xenograft mice model was constructed on Balb/c mice,which were divided into control group,IR group,AZD1775 group,IR+AZD1775 group,IR+anti-PD-1 Ab group,and the IR+AZD1775+anti-PD-1 Ab group.Cytotoxic CD8^(+)T cells in TME were analyzed by flow cytometry.Results:Combining IR with AZD1775 synergistically reduced the viability of hepatoma cells in vitro.AZD1775 exhibited antitumor effects by decreasing CDK1 phosphorylation to reverse the IR-induced G2/M arrest and increasing IR-induced dna damage.AZD1775 treatment also reduced the proportion of PD-1^(+)/CD8^(+)T cells in the spleen of hepatoma subcutaneous xenograft mice.Further studies revealed that AZD1775 and anti-PD-1 Ab could enhance the radiosensitivity of hepatoma by enhancing the levels of interferonγ(IFNγ)^(+)or Ki67^(+)CD8 T cells and decreasing the levels of CD8^(+)Tregs cells in the tumor and spleen of the hepatoma mice model,indicating that the improvement of TME was manifested by increasing the cytotoxic factor IFNγexpression,enhancing CD8^(+)T cells proliferation,and weakening CD8^(+)T cells depletion.Conclusions:This work suggests that AZD1775 and anti-PD-1 Ab synergistically sensitize hepatoma to radiotherapy by enhancing IR-induced dna damage and improv

关键词： Hepatoma Radiation AZD1775 Anti-PD-1 antibody dna damage Tumor microenvironment

Phosphoproteomics Reveals the AMPK Substrate Network in Response to dna damage and Histone Acetylation

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Genomics, Proteomics & Bioinformatics 2022年第4期20卷 597-613页

作者： Yuejing Jiang Xiaoji Cong Shangwen Jiang Ying Dong Lei Zhao Yi Zang Minjia Tan Jia Li National Center for Drug Screening State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China Chemical Proteomics Center State Key Laboratory of Drug ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai 201203China University of Chinese Academy of Sciences Beijing 100049China Open Studio for Druggability Research of Marine Natural Products Pilot National Laboratory for Marine Science and Technology(Qingdao)Qingdao 266237China

AMP-activated protein kinase(AMPK)is a conserved energy sensor that plays roles in diverse biological processes via phosphorylating various substrates.Emerging studies have demonstrated the regulatory roles of AMPK in dna repair,but the underlying mechanisms remain to be fully understood.Herein,using mass spectrometry-based proteomic technologies,we systematically investigate the regulatory network of AMPK in dna damage response(DDR).Our system-wide phosphoproteome study uncovers a variety of newly-identified potential substrates involved in diverse biological processes,whereas our system-wide histone modification analysis reveals a link between AMPK and histone acetylation.Together with these findings,we discover that AMPK promotes apoptosis by phosphorylating apoptosis-stimulating of p53 protein 2(ASPP2)in an irradiation(IR)-dependent manner and regulates histone acetylation by phosphorylating histone deacetylase 9(HDAC9)in an IR-independent manner.Besides,we reveal that disrupting the histone acetylation by the bromodomain BRD4 inhibitor JQ-1 enhances the sensitivity of AMPKdeficient cells to IR.Therefore,our study has provided a resource to investigate the interplay between phosphorylation and histone acetylation underlying the regulatory network of AMPK,which could be beneficial to understand the exact role of AMPK in DDR.

关键词： AMPK Phosphoproteomics Histone modification dna damage Apoptosis

Histone post-translational modification and the dna damage response

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Genes & Diseases 2023年第4期10卷 1429-1444页

作者： Haoyun Song Rong Shen Xiangwen Liu Xuguang Yang Kun Xie Zhao Guo Degui Wang School of Basic Medical Sciences Lanzhou UniversityLanzhouGansu 730000China

dna is highly vulnerable to spontaneous and environmental timely damage in living cells.dna damage may cause genetic instability and increase cancer risk if the damages are not repaired timely and efficiently.Human cells possess several dna damage response(DDR)mechanisms to protect the integrity of their genome.Clarification of the mechanisms under-lying the dna damage response following lethal damage will facilitate the identification of therapeutic targets for cancers.Histone post-translational modifications(PTMs)have been indicated to play different roles in the repair of dna damage.In this context,histone PTMs regulate recruitment of downstream effectors,and facilitate appropriate repair response.This review outlines the current understanding of different histone PTMs in response to dna dam-age repair,besides,enumerates the role of new type PTMs such as histone succinylation and crotonylation in regulating dna damage repair processes.

关键词： dna damage dna damage response Histone Post-translational modifications(PTMs)

Hydroxyproline alleviates 4-hydroxy-2-nonenal-induced dna damage and apoptosis in porcine intestinal epithelial cells

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Animal Nutrition 2022年第2期9卷 7-15页

作者： Yun Ji Yu He Ying Yang Zhaolai Dai Zhenlong Wu State Key Laboratory of Animal Nutrition Department of Animal Nutrition and Feed ScienceChina Agricultural UniversityBeijing 100193China Beijing Advanced Innovation Center for Food Nutrition and Human Health China Agricultural UniversityBeijing 100193China

Oxidative stress has been confirmed in relation to intestinal mucosa damage and multiple bowel diseases.Hydroxyproline (Hyp) is an imino acid abundant in sow's milk. Compelling evidence has beengathered showing the potential antioxidative properties of Hyp. However, the role and mechanism ofHyp in porcine intestinal epithelial cells in response to oxidative stress remains unknown. In this study,small intestinal epithelial cell lines of piglets (IPEC-1) were used to evaluate the protective effects of Hypon 4-hydroxy-2-nonenal (4-HNE)-induced oxidative dna damage and apoptosis. IPEC-1 pretreated with0.5 to 5 mmol/L Hyp were exposed to 4-HNE (40 mmol/L) in the presence or absence of Hyp. Thereafter,the cells were subjected to apoptosis detection by Hoechst staining, flow cytometry, and Western blot ordna damage analysis by comet assay, immunofluorescence, and reverse-transcription quantitative PCR(RT-qPCR). Cell apoptosis and the upregulation of cleaved-caspase-3 induced by 4-HNE (40 mmol/L) wereinhibited by 5 mmol/L of Hyp. In addition, 5 mmol/L Hyp attenuated 4-HNE-induced reactive oxygenspecies (ROS) accumulation, glutathione (GSH) deprivation and dna damage. The elevation in transcriptionof GADD45a (growth arrest and dna-damage-inducible protein 45 alpha) and GADD45b(growth arrest and dna-damage-inducible protein 45 beta), as well as the phosphorylation of H2AX(H2A histone family, member X), p38 MAPK (mitogen-activated protein kinase), and JNK (c-Jun N-terminalkinase) in cells treated with 4-HNE were alleviated by 5 mmol/L Hyp. Furthermore, Hyp supplementationincreased the protein abundance of Krüppel like factor 4 (KLF4) in cells exposed to 4-HNE.Suppression of KLF4 expression by kenpaulone impeded the resistance of Hyp-treated cells to dnadamage and apoptosis induced by 4-HNE. Collectively, our results indicated that Hyp serves to protectagainst 4-HNE-induced apoptosis and dna damage in IPEC-1 cells, which is partially pertinent with theenhanced expression of KLF4. Our data provides an updated explanation for

关键词： Hydroxyproline Apoptosis dna damage 4-Hydroxy-2-nonenal Oxidative stress

TBC1D15 deficiency protects against doxorubicin cardiotoxicity via inhibiting dnaPKcs cytosolic retention and dna damage

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4823-4839页

作者： Wenjun Yu Haixia Xu Zhe Sun Yuxin Du Shiqun Sun Miyesaier Abudureyimu Mengjiao Zhang Jun Tao Junbo Ge Jun Ren Yingmei Zhang Department of Cardiology and Shanghai Institute of Cardiovascular Diseases Zhongshan HospitalFudan UniversityShanghai 200032China National Clinical Research Center for Interventional Medicine Shanghai 200032China Department of Cardiovascular Surgery Zhongnan Hospital of Wuhan UniversityWuhan 430071China Hubei Provincial Engineering Research Center of Minimally Invasive Cardiovascular Surgery Wuhan 430071China Department of Cardiology Affiliated Hospital of Nantong UniversityNantong 226001China Cardiovascular Department Shanghai Xuhui Central HospitalZhongshan-Xuhui HospitalFudan UniversityShanghai 200030China Department of Cardiovascular Surgery Sun Yat-sen Memorial HospitalSun Yat-sen UniversityGuangzhou 510000China

Clinical application of doxorubicin(DOX)is heavily hindered by DOX cardiotoxicity.Several theories were postulated for DOX cardiotoxicity including dna damage and dna damage response(DDR),although the mechanism(s)involved remains to be elucidated.This study evaluated the potential role of TBC domain family member 15(TBC1D15)in DOX cardiotoxicity.Tamoxifen-induced cardiac-specific Tbcldi5 knockout(Tbcldi5^(CKO))or Tbcldi5 knockin(Tbcldi5^(CKI))male mice were challenged with a single dose of DOx prior to cardiac assessment 1 week or 4 weeks following DOX challenge.Adenoviruses encoding TBC1D15 or containing shRNA targeting Tbcld15 were used for Tbcld15 overexpression or knockdown in isolated primary mouse cardiomyocytes.Our results re-vealed that DOX evoked upregulation of TBC1D15 with compromised myocardial function and overt mortality,the effects of which were ameliorated and accentuated by Tbcldi5 deletion and Tbcld15 overexpression,respectively.DOX overtly evoked apoptotic cell death,the effect of which was alleviated and exacerbated by Tbcld15 knockout and overexpression,respectively.Meanwhile,DOX provoked mitochondrial membrane potential collapse,oxidative stress and dna damage,the effects of which were mitigated and exacerbated by Tbcld15 knockdown and overexpression,respectively.Further scrutiny revealed that TBC1D15 fostered cytosolic accumulation of the cardinal DDR element dna-dependent protein kinase catalytic subunit(dna-PKcs).Liquid chromatography-tandem mass spectrometry and coimmunoprecipitation denoted an interaction between TBCID15 and dna-PKcs at the segment 594-624 of TBC1D15.Moreover,overexpression of TBC1D15 mutant(A594-624,deletion of segment 594-624)failed to elicit accentuation of DOX-induced cytosolic retention of dna-PKcs,dna damage and cardiomyocyte apoptosis by TBC1D15 wild type.However,Tbcld15 deletion ameliorated DOXinduced cardiomyocyte contractile anomalies,apoptosis,mitochondrial anomalies,dna damage and cytosolic dna-PKcs accumulation,which were canceled off by dna-PKcs inhibition

关键词： Doxorubicin Cardiotoxicity dna damage dna damage response Mitochondrial anomalies Cardiomyocyte apoptosis TBC1D15 dna-PKcS