S.M. Attia , S.F. Ahmad , A. Nadeem , M.S.M. Attia , M.A. Ansari , N.B. Alsaleh , A.F. Alasmari , M.A. Al-Hamamah , A. Alanazi , A.A. Alshamrani , S.A. Bakheet , G.I. Harisa
{"title":"小分子Erk1/2信号通路抑制剂PD98059改善多发性硬化症实验性自身免疫性脑脊髓炎SJL/J小鼠模型的DNA修复","authors":"S.M. Attia , S.F. Ahmad , A. Nadeem , M.S.M. Attia , M.A. Ansari , N.B. Alsaleh , A.F. Alasmari , M.A. Al-Hamamah , A. Alanazi , A.A. Alshamrani , S.A. Bakheet , G.I. Harisa","doi":"10.1016/j.mrgentox.2023.503650","DOIUrl":null,"url":null,"abstract":"<div><p>Multiple sclerosis (MS) is a demyelinating disorder in which the myelin sheath covering the central nervous system axons is damaged or lost, disrupting action potential conduction and leading to various neurological complications. The pathogenesis of MS remains unclear, and no effective therapies are currently available. MS is triggered by environmental factors in genetically susceptible individuals. DNA damage and DNA repair failure have been proposed as MS genetic risk factors; however, inconsistent evidence has been found in multiple studies. Therefore, more investigations are needed to ascertain whether DNA damage/repair is altered in this disorder. In this context, therapies that prevent DNA damage or enhance DNA repair could be effective strategies for MS treatment. The overactivation of the extracellular-signal-related kinase 1 and 2 (Erk1/2) pathway can lead to DNA damage and has been linked to MS pathogenesis. In our study, we observed substantially elevated oxidative DNA damage and slower DNA repair rates in an experimentally autoimmune encephalomyelitis animal model of MS (EAE). Moreover, statistical decreases in oxidative DNA strand breaks and faster repair rates were observed in EAE animals injected with the Erk1/2 inhibitor PD98059 (PD). Moreover, the expression of several genes associated with DNA strand breaks and repair changed in EAE mice at both the mRNA and protein levels, as revealed by the RT<sup>2</sup> Profiler PCR array and verified by RT-PCR and protein analyses. The treatment with PD mitigated these changes and improved DNA repair gene expression. Our results demonstrate clear associations between Erk1/2 activation, DNA damage/repair, and MS pathology, and further suggest that PD therapy may be a promising adjuvant therapeutic strategy.</p></div>","PeriodicalId":18799,"journal":{"name":"Mutation research. Genetic toxicology and environmental mutagenesis","volume":null,"pages":null},"PeriodicalIF":2.3000,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"The small molecule Erk1/2 signaling pathway inhibitor PD98059 improves DNA repair in an experimental autoimmune encephalomyelitis SJL/J mouse model of multiple sclerosis\",\"authors\":\"S.M. Attia , S.F. Ahmad , A. Nadeem , M.S.M. Attia , M.A. Ansari , N.B. Alsaleh , A.F. Alasmari , M.A. Al-Hamamah , A. Alanazi , A.A. Alshamrani , S.A. Bakheet , G.I. Harisa\",\"doi\":\"10.1016/j.mrgentox.2023.503650\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>Multiple sclerosis (MS) is a demyelinating disorder in which the myelin sheath covering the central nervous system axons is damaged or lost, disrupting action potential conduction and leading to various neurological complications. The pathogenesis of MS remains unclear, and no effective therapies are currently available. MS is triggered by environmental factors in genetically susceptible individuals. DNA damage and DNA repair failure have been proposed as MS genetic risk factors; however, inconsistent evidence has been found in multiple studies. Therefore, more investigations are needed to ascertain whether DNA damage/repair is altered in this disorder. In this context, therapies that prevent DNA damage or enhance DNA repair could be effective strategies for MS treatment. The overactivation of the extracellular-signal-related kinase 1 and 2 (Erk1/2) pathway can lead to DNA damage and has been linked to MS pathogenesis. In our study, we observed substantially elevated oxidative DNA damage and slower DNA repair rates in an experimentally autoimmune encephalomyelitis animal model of MS (EAE). Moreover, statistical decreases in oxidative DNA strand breaks and faster repair rates were observed in EAE animals injected with the Erk1/2 inhibitor PD98059 (PD). Moreover, the expression of several genes associated with DNA strand breaks and repair changed in EAE mice at both the mRNA and protein levels, as revealed by the RT<sup>2</sup> Profiler PCR array and verified by RT-PCR and protein analyses. The treatment with PD mitigated these changes and improved DNA repair gene expression. Our results demonstrate clear associations between Erk1/2 activation, DNA damage/repair, and MS pathology, and further suggest that PD therapy may be a promising adjuvant therapeutic strategy.</p></div>\",\"PeriodicalId\":18799,\"journal\":{\"name\":\"Mutation research. Genetic toxicology and environmental mutagenesis\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.3000,\"publicationDate\":\"2023-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Mutation research. Genetic toxicology and environmental mutagenesis\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1383571823000682\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mutation research. Genetic toxicology and environmental mutagenesis","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1383571823000682","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
The small molecule Erk1/2 signaling pathway inhibitor PD98059 improves DNA repair in an experimental autoimmune encephalomyelitis SJL/J mouse model of multiple sclerosis
Multiple sclerosis (MS) is a demyelinating disorder in which the myelin sheath covering the central nervous system axons is damaged or lost, disrupting action potential conduction and leading to various neurological complications. The pathogenesis of MS remains unclear, and no effective therapies are currently available. MS is triggered by environmental factors in genetically susceptible individuals. DNA damage and DNA repair failure have been proposed as MS genetic risk factors; however, inconsistent evidence has been found in multiple studies. Therefore, more investigations are needed to ascertain whether DNA damage/repair is altered in this disorder. In this context, therapies that prevent DNA damage or enhance DNA repair could be effective strategies for MS treatment. The overactivation of the extracellular-signal-related kinase 1 and 2 (Erk1/2) pathway can lead to DNA damage and has been linked to MS pathogenesis. In our study, we observed substantially elevated oxidative DNA damage and slower DNA repair rates in an experimentally autoimmune encephalomyelitis animal model of MS (EAE). Moreover, statistical decreases in oxidative DNA strand breaks and faster repair rates were observed in EAE animals injected with the Erk1/2 inhibitor PD98059 (PD). Moreover, the expression of several genes associated with DNA strand breaks and repair changed in EAE mice at both the mRNA and protein levels, as revealed by the RT2 Profiler PCR array and verified by RT-PCR and protein analyses. The treatment with PD mitigated these changes and improved DNA repair gene expression. Our results demonstrate clear associations between Erk1/2 activation, DNA damage/repair, and MS pathology, and further suggest that PD therapy may be a promising adjuvant therapeutic strategy.
期刊介绍:
Mutation Research - Genetic Toxicology and Environmental Mutagenesis (MRGTEM) publishes papers advancing knowledge in the field of genetic toxicology. Papers are welcomed in the following areas:
New developments in genotoxicity testing of chemical agents (e.g. improvements in methodology of assay systems and interpretation of results).
Alternatives to and refinement of the use of animals in genotoxicity testing.
Nano-genotoxicology, the study of genotoxicity hazards and risks related to novel man-made nanomaterials.
Studies of epigenetic changes in relation to genotoxic effects.
The use of structure-activity relationships in predicting genotoxic effects.
The isolation and chemical characterization of novel environmental mutagens.
The measurement of genotoxic effects in human populations, when accompanied by quantitative measurements of environmental or occupational exposures.
The application of novel technologies for assessing the hazard and risks associated with genotoxic substances (e.g. OMICS or other high-throughput approaches to genotoxicity testing).
MRGTEM is now accepting submissions for a new section of the journal: Current Topics in Genotoxicity Testing, that will be dedicated to the discussion of current issues relating to design, interpretation and strategic use of genotoxicity tests. This section is envisaged to include discussions relating to the development of new international testing guidelines, but also to wider topics in the field. The evaluation of contrasting or opposing viewpoints is welcomed as long as the presentation is in accordance with the journal''s aims, scope, and policies.