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In Vivo Improvements in Facial Appearance and in Vitro Changes in Gene Expression Using a Topical Formulation Designed to repair Environmentally Induced dna Damage

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Journal of Cosmetics, Dermatological Sciences and Applications 2024年第2期14卷 141-173页

作者： Amaryllis Aganahi Richard Parker Yohei Tanaka RATIONALE Kyneton Australia Clinica Tanaka Plastic Reconstructive Surgery and Anti-aging Center Matsumoto Japan

Background: While sunscreen has been accepted as a mainline defence against photodamage from ultraviolet, visible light and near-infrared radiation, there appears to be a lack of research into photorepair. The concept of protecting the skin during the day and repairing cellular damage at night is intuitive, yet specific strategies revolving around combinations of proven reparative active ingredients remain unelucidated. Purpose: To investigate the efficacy of a solar repair Formulation following ultraviolet and environmental exposure in order to improve overall skin health and appearance through three hypotheses: The Formulation increases expression of dna repair mechanisms markers;The Formulation enhances overall skin appearance through reducing signs of inflammation, elevating hydration, reinforcing skin firmness and amplifying radiance;In-Vivo efficacy test results are aligned with measured gene expression changes. Methods: The Formulation (#6NIC1.V1.1-1) was tested for: In-vitro LDH cytotoxicity activity, In-vitro qPCR gene expression with and without ultraviolet exposure on a reconstructed 3-dimensional skin model, and In-Vivo efficacy study on a panel of 22 participants objectively and subjectively. Results: Skin radiance, firmness, hydration, redness, and inflammation are significantly improved after In-Vivo skin exposure to the Formulation and environmental challenges such as ultraviolet radiation. These outcomes were confirmed by in-vitro genetic testing on a reconstructed human skin model. Conclusion: The studies allowed us to identify and group results in four main skin functions that were significantly enhanced following the application of the Formulation: firmness, hydration, radiance and soothing.

关键词： Photoprotection Photorepair dna repair Anti-Photoaging Gene Expression Antioxidant Rejuvenation

SET8 Inhibition Potentiates Radiotherapy by Suppressing dna Damage repair in Carcinomas

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Biomedical and Environmental Sciences 2022年第3期35卷 194-205页

作者： PAN Dong DU Ya Rong LI Rong SHEN Ai Hua LIU Xiao Dong LI Chuan Yuan HU Bu Rong Department of Radiological Health and Radiation Medicine School of Public Health and ManagementWenzhou Medical UniversityWenzhou 325035ZhejiangChina Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences&Key laboratory of Space Radiobiology of Gansu province Institute of Modern PhysicsChinese Academy of SciencesLanzhou 730000GansuChina Department of Dermatology Duke University Medical CenterDurhamNC27710USA

Objective SET8 is a member of the SET domain-containing family and the only known lysine methyltransferase(KMT)that monomethylates lysine 20 of histone H4(H4 K20 me1).SET8 has been implicated in many essential cellular processes,including cell cycle regulation,dna replication,dna damage response,and carcinogenesis.There is no conclusive evidence,however,regarding the effect of SET8 on radiotherapy.In the current study we determined the efficacy of SET8 inhibition on radiotherapy of tumors and the underlying mechanism.Methods First,we explored the radiotherapy benefit of the SET8 expression signature by analyzing clinical data.Then,we measured a series of biological endpoints,including the xenograft tumor growth in mice and apoptosis,frequency of micronuclei,and foci of 53 BP1 andγ-H2 AX in cells to detect the SET8 effects on radiosensitivity.RNA sequencing and subsequent experiments were exploited to verify the mechanism underlying the SET8 effects on radiotherapy.Results Low expression of SET8 predicted a better benefit to radiotherapy in lung adenocarcinoma(LUAD)and invasive breast carcinoma(BRCA)patients.Furthermore,genetic deletion of SET8 significantly enhanced radiation treatment efficacy in a murine tumor model,and A549 and MCF7 cells;SET8 overexpression decreased the radiosensitivity.SET8 inhibition induced more apoptosis,the frequency of micronuclei,and blocked the kinetics process of dna damage repair as 53 BP1 andγ-H2 AX foci remained in cells.Moreover,RNF8 was positively correlated with the SET8 impact on dna damage repair.Conclusion Our results demonstrated that SET8 inhibition enhanced radiosensitivity by suppressing dna damage repair,thus suggesting that SET8 potentiated radiotherapy of carcinomas.As new inhibitors of SET8 are synthesized and tested in preclinical and clinical settings,combining SET8 inhibitors with radiation warrants consideration for precise radiotherapy.

关键词： SET8 Histone methylation dna repair Radiotherapy Carcinoma

Targeting dna repair for cancer treatment: Lessons from PARP inhibitor trials

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Oncology Research 2023年第4期31卷 405-421页

作者： DHANYA K.NAMBIAR DEEPALI MISHRA RANA P.SINGH Department of Radiation Oncology Stanford University School of MedicineStanfordCA94305USA Cancer Biology Laboratory School of Life SciencesJawaharlal Nehru UniversityNew Delhi110067India Special Centre for Systems Medicine Jawaharlal Nehru UniversityNew Delhi10067India

Ionizing radiation is frequently used to treat solid tumors,as it causes dna damage and kill cancer cells.However,damaged dna is repaired involving poly-(ADP-ribose)polymerase-1(PARP-1)causing resistance to radiation therapy.Thus,PARP-1 represents an important target in multiple cancer types,including prostate cancer.PARP is a nuclear enzyme essential for single-strand dna breaks repair.Inhibiting PARP-1 is lethal in a wide range of cancer cells that lack the homologous recombination repair(HR)pathway.This article provides a concise and simplified overview of the development of PARP inhibitors in the laboratory and their clinical applications.We focused on the use of PARP inhibitors in various cancers,including prostate cancer.We also discussed some of the underlying principles and challenges that may affect the clinical efficacy of PARP inhibitors.

关键词： PARP inhibitors Synthetic lethality dna repair BRCA mutations

Multifaceted Influence of Histone Deacetylases on dna Damage repair:Implications for Hepatocellular Carcinoma

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Journal of Clinical and Translational Hepatology 2023年第1期11卷 231-243页

作者： Gan Du Ruizhe Yang Jianguo Qiu Jie Xia Key Laboratory of Molecular Biology on Infectious Diseases Ministry of EducationChongqing Medical UniversityChongqingChina The First Clinical College Chongqing Medical UniversityChongqingChina Department of Hepatobiliary Surgery The First Affiliated Hospital of Chongqing Medical UniversityChongqingChina.

Hepatocellular carcinoma(HCC)is one of the most commonly diagnosed cancers and a leading cause of cancerrelated mortality worldwide,but its pathogenesis remains largely unknown.Nevertheless,genomic instability has been recognized as one of the facilitating characteristics of cancer hallmarks that expedites the acquisition of genetic diversity.Genomic instability is associated with a greater tendency to accumulate dna damage and tumor-specific dna repair defects,which gives rise to gene mutations and chromosomal damage and causes oncogenic transformation and tumor progression.Histone deacetylases(HDACs)have been shown to impair a variety of cellular processes of genome stability,including the regulation of dna damage and repair,reactive oxygen species generation and elimination,and progression to mitosis.In this review,we provide an overview of the role of HDAC in the different aspects of dna repair and genome instability in HCC as well as the current progress on the development of HDAC-specific inhibitors as new cancer therapies.

关键词： Histone deacetylases dna repair Hepatocellular carcinoma

dna repair and synthetic lethality

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International Journal of Oral Science 2011年第4期3卷 176-179页

作者： Gong-she Guo Feng-mei Zhang Rui-jie Gao Robert Delsite Zhi-hui Feng Simon N. Powell School of Public Health Shandong University Jinan 250012 China Second People＇s Hospital of Weifang Weifang 261041 China Department of Radiation Oncology Washington University in St Louis St Louis MO 63108 USA Department of Radiation Oncology Memorial Sloan Kettering Cancer Center New York NY10065 USA

Tumors often have dna repair defects, suggesting additional inhibition of other dna repair pathways in tumors may lead to synthetic lethality. Accumulating data demonstrate that dna repair-defective tumors, in particular homologous recombination （HR）, are highly sensitive to dna-damaging agents. Thus, HR-defective tumors exhibit potential vulnerability to the synthetic lethality approach, which may lead to new therapeutic strategies. It is well known that poly （adenosine diphosphate （ADP）-ribose） polymerase （PARP） inhibitors show the synthetically lethal effect in tumors defective in BRCA1 or BRCA2 genes encoded proteins that are required for efficient HR. In this review, we summarize the strategies of targeting dna repair pathways and other dna metabolic functions to cause synthetic lethality in HR-defective tumor cells.

关键词： dna repair homologous recombination synthetic lethality BRCA Rad52

Mass spectrometry-based protein-protein interaction techniques and their applications in studies of dna damage repair

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2021年第1期22卷 1-20页

作者： Zhen CHEN Junjie CHEN Department of Experimental Radiation Oncology The University of Texas MD Anderson Cancer CenterHoustonTX77030USA

Proteins are major functional units that are tightly connected to form complex and dynamic networks.These networks enable cells and organisms to operate properly and respond efficiently to environmental cues.Over the past decades,many biochemical methods have been developed to search for protein-binding partners in order to understand how protein networks are constructed and connected.At the same time,rapid development in proteomics and mass spectrometry(MS)techniques makes it possible to identify interacting proteins and build comprehensive protein-protein interaction networks.The resulting interactomes and networks have proven informative in the investigation of biological functions,such as in the field of dna damage repair.In recent years,a number of proteins involved in dna damage response and dna repair pathways have been uncovered with MS-based protein-protein interaction studies.As the technologies for enriching associated proteins and MS become more sophisticated,the studies of protein-protein interactions are entering a new era.In this review,we summarize the strategies and recent developments for exploring protein-protein interaction.In addition,we discuss the application of these tools in the investigation of protein-protein interaction networks involved in dna damage response and dna repair.

关键词： Protein-protein interaction Interactome Proteomics Mass spectrometry dna repair dna damage response

CAS9 is a genome mutator by directly disrupting dna-PK dependent dna repair pathway

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Protein & Cell 2020年第5期11卷 352-365页

作者： Shuxiang Xu Jinchul Kim Qingshuang Tang Qu Chen Jingfeng Liu Yang Xu Xuemei Fu Cancer Research Institute Guangdong Provincial Key Laboratory of Cancer ImmunotherapySchool of Basic Medical SciencesSouthern Medical UniversityGuangzhou 510515China The Eighth Affiliated Hospital Sun Yat-sen UniversityShenzhen 518033China Division of Biological Sciences University of CaliforniaSan Diego9500 Gilman DriveLa JollaCA 92093USA Shenzhen Children’s Hospital Shenzhen 518026China

With its high efficiency for site-specific genome editing and easy manipulation,the clustered regularly interspaced short palindromic repeats(CRISPR)/CRISPR associated protein 9(CAS9)system has become the most widely used gene editing technology in biomedical research.In addition,significant progress has been made for the clinical development of CRISPR/CAS9 based gene therapies of human diseases,several of which are entering clinical trials.Here we report that CAS9 protein can function as a genome mutator independent of any exogenous guide RNA(gRNA)in human cells,promoting genomic dna double-stranded break(DSB)damage and genomic instability.CAS9 interacts with the KU86 subunit of the dna-dependent protein kinase(dna-PK)complex and disrupts the interaction between KU86 and its kinase subunit,leading to defective dna-PK-dependent repair of dna DSB damage via non-homologous end-joining(NHEJ)pathway.XCAS9 is a CAS9 variant with potentially higher fidelity and broader compatibility,and dCAS9 is a CAS9 variant without nuclease activity.We show that XCAS9 and dCAS9 also interact with KU86 and disrupt dna DSB repair.Considering the critical roles of dna-PK in maintaining genomic stability and the pleiotropic impact of dna DSB damage responses on cellular proliferation and survival,our findings caution the interpretation of data involving CRISPR/CAS9-based gene editing and raise serious safety concerns of CRISPR/CAS9 system in clinical application.

关键词： KEYWORDS CAS9 dna-PK dna double-stranded breaks genetic instability dna repair

Upregulation of the APE1 and H2AX genes and miRNAs involved in dna damage response and repair in gastric cancer

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Genes & Diseases 2019年第2期6卷 176-184页

作者： Fernanda S.Manoel-Caetano Ana Flávia T.Rossi Gabriela Calvet de Morais Fábio Eduardo Severino Ana Elizabete Silva Department of Biology UNESPSāo Paulo State UniversityCampus of Sāo Josédo Rio PretoRua Cristòvāo Colombo226515.054-000Sāo Josédo Rio PretoSāo PauloBrazil Department of Surgery and Orthopedics Faculty of MedicineUNESPSāo Paulo State UniversityCampus of BotucatuAv.Prof.Mário Rubens Guimarāes Montenegros/n18.618-687BotucatuSāo PauloBrazil

Gastric cancer remains one of the leading causes of cancer-related death worldwide,and most of the cases are associated with Helicobacter pylori infection.This bacterium promotes the production of reactive oxygen species(ROS),which cause dna damage in gastric epithelial cells.In this study,we evaluated the expression of important genes involved in the recognition of dna damage(ATM,ATR,and H2AX)and ROS-induced damage repair(APE1)and the expression of some miRNAs(miR-15a,miR-21,miR-24,miR-421 and miR-605)that target genes involved in the dna damage response(DDR)in 31 fresh tissues of gastric cancer.Cytoscape v3.1.1 was used to construct the postulated miRNA:mRNA interaction network.Analysis performed by real-time quantitative PCR exhibited significantly increased levels of the APE1(RQ=2.55,prepair of dna damage,which could confer an advantage to cell survival and proliferation in the tumor microenvironment.

关键词： dna damage response dna repair Gastric cancer Gene expression microRNA

Evolving insights:how dna repair pathways impact cancer evolution

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Cancer Biology & Medicine 2020年第4期17卷 805-827页

作者： Jiadong Zhou Xiao Albert Zhou Ning Zhang Jiadong Wang Department of Radiation Medicine Institute of Systems BiomedicineSchool of Basic Medical SciencesPeking University Health Science CenterBeijing 100191China Biomedical Pioneering Irmovation Center(BIOPIC)and Translational Cancer Research Center School of Life SciencesFirst HospitalPeking UniversityBeijing 100871China Laboratory of Cancer Cell Biology Tianjin Medical University Cancer Instituteand HospitalNational Clinical Research Center for CancerKey Laboratory of Cancer Prevention and TherapyTianjinTianjin's Clinical Research Center for CancerTianjin 300060China

Viewing cancer as a large,evolving population of heterogeneous cells is a common perspective.Because genomic instability is one of the fundamental features of cancer,this intrinsic tendency of genomic variation leads to striking intratumor heterogeneity and functions during the process of cancer formation,development,metastasis,and relapse.With the increased mutation rate and abundant diversity of the gene pool,this heterogeneity leads to cancer evolution,which is the major obstacle in the clinical treatment of cancer.Cells rely on the integrity of dna repair machineries to maintain genomic stability,but these machineries often do not function properly in cancer cells.The deficiency of dna repair could contribute to the generation of cancer genomic instability,and ultimately promote cancer evolution.With the rapid advance of new technologies,such as single-cell sequencing in recent years,we have the opportunity to better understand the specific processes and mechanisms of cancer evolution,and让s relationship with dna repair.Here,we review recent findings on how dna repair affects cancer evolution,and discuss how these mechanisms provide the basis for critical clinical challenges and therapeutic applications.

关键词： dna repair cancer evolution intratumor heterogeneity genomic instability drug resistance