{"title":"在DMD基因敲除斑马鱼和患者源性成肌细胞培养中,Jagged1影响下病理参数的缓解","authors":"","doi":"10.56042/ijbb.v60i9.3895","DOIUrl":null,"url":null,"abstract":"Duchenne muscular dystrophy (DMD) is an X-linked, degenerative disease mainly affecting male children, with progressive weakness of whole-body skeletal muscles and the heart. There is a gradual loss of ambulation, heart weakness, and breathing capacity by late teens. Heart or lung dysfunction causes early death in patients during the second or third decade. Steroid treatment delays disease progression by 2-3 years, albeit with serious side effects. The few FDA-approved gene therapies are mutation-specific and exorbitantly priced. There is an unmet medical need for the children affected with DMD. Interestingly, a previous study showed that single nucleotide change caused Jagged1 overexpression, which resulted in avoidance of early death and ambulatory loss in 1-1.5-year-old golden retriever dogs severely affected with muscular dystrophy. Identifying the pathological processes mitigated by Jagged1 overexpression might help understand the mechanism of this rescue. Hence, we generated DMD knockout in zebrafish, another severe model of DMD with overexpression of the human Jagged1 (JAG1). Pathological aspects like cell death, cell proliferation, cytoplasmic and mitochondrial oxidative stress were compared between dystrophic, rescued, and control groups. Surprisingly, JAG1 increased mitochondrial oxidative stress during rescue, while reducing other pathological processes. Similarly, increased mitochondrial ROS production occurred with Jag1 peptide treatment in in vitro differentiated patient-derived myotubes, suggesting a conserved mechanism involved in the rescue.","PeriodicalId":13281,"journal":{"name":"Indian journal of biochemistry & biophysics","volume":"160 47 1","pages":"0"},"PeriodicalIF":1.5000,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Mitigation of pathological parameters under Jagged1 influence in DMD knockout zebrafish and patient-derived myoblast cultures\",\"authors\":\"\",\"doi\":\"10.56042/ijbb.v60i9.3895\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Duchenne muscular dystrophy (DMD) is an X-linked, degenerative disease mainly affecting male children, with progressive weakness of whole-body skeletal muscles and the heart. There is a gradual loss of ambulation, heart weakness, and breathing capacity by late teens. Heart or lung dysfunction causes early death in patients during the second or third decade. Steroid treatment delays disease progression by 2-3 years, albeit with serious side effects. The few FDA-approved gene therapies are mutation-specific and exorbitantly priced. There is an unmet medical need for the children affected with DMD. Interestingly, a previous study showed that single nucleotide change caused Jagged1 overexpression, which resulted in avoidance of early death and ambulatory loss in 1-1.5-year-old golden retriever dogs severely affected with muscular dystrophy. Identifying the pathological processes mitigated by Jagged1 overexpression might help understand the mechanism of this rescue. Hence, we generated DMD knockout in zebrafish, another severe model of DMD with overexpression of the human Jagged1 (JAG1). Pathological aspects like cell death, cell proliferation, cytoplasmic and mitochondrial oxidative stress were compared between dystrophic, rescued, and control groups. Surprisingly, JAG1 increased mitochondrial oxidative stress during rescue, while reducing other pathological processes. Similarly, increased mitochondrial ROS production occurred with Jag1 peptide treatment in in vitro differentiated patient-derived myotubes, suggesting a conserved mechanism involved in the rescue.\",\"PeriodicalId\":13281,\"journal\":{\"name\":\"Indian journal of biochemistry & biophysics\",\"volume\":\"160 47 1\",\"pages\":\"0\"},\"PeriodicalIF\":1.5000,\"publicationDate\":\"2023-01-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Indian journal of biochemistry & biophysics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.56042/ijbb.v60i9.3895\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Indian journal of biochemistry & biophysics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.56042/ijbb.v60i9.3895","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Mitigation of pathological parameters under Jagged1 influence in DMD knockout zebrafish and patient-derived myoblast cultures
Duchenne muscular dystrophy (DMD) is an X-linked, degenerative disease mainly affecting male children, with progressive weakness of whole-body skeletal muscles and the heart. There is a gradual loss of ambulation, heart weakness, and breathing capacity by late teens. Heart or lung dysfunction causes early death in patients during the second or third decade. Steroid treatment delays disease progression by 2-3 years, albeit with serious side effects. The few FDA-approved gene therapies are mutation-specific and exorbitantly priced. There is an unmet medical need for the children affected with DMD. Interestingly, a previous study showed that single nucleotide change caused Jagged1 overexpression, which resulted in avoidance of early death and ambulatory loss in 1-1.5-year-old golden retriever dogs severely affected with muscular dystrophy. Identifying the pathological processes mitigated by Jagged1 overexpression might help understand the mechanism of this rescue. Hence, we generated DMD knockout in zebrafish, another severe model of DMD with overexpression of the human Jagged1 (JAG1). Pathological aspects like cell death, cell proliferation, cytoplasmic and mitochondrial oxidative stress were compared between dystrophic, rescued, and control groups. Surprisingly, JAG1 increased mitochondrial oxidative stress during rescue, while reducing other pathological processes. Similarly, increased mitochondrial ROS production occurred with Jag1 peptide treatment in in vitro differentiated patient-derived myotubes, suggesting a conserved mechanism involved in the rescue.
期刊介绍:
Started in 1964, this journal publishes original research articles in the following areas: structure-function relationships of biomolecules; biomolecular recognition, protein-protein and protein-DNA interactions; gene-cloning, genetic engineering, genome analysis, gene targeting, gene expression, vectors, gene therapy; drug targeting, drug design; molecular basis of genetic diseases; conformational studies, computer simulation, novel DNA structures and their biological implications, protein folding; enzymes structure, catalytic mechanisms, regulation; membrane biochemistry, transport, ion channels, signal transduction, cell-cell communication, glycobiology; receptors, antigen-antibody binding, neurochemistry, ageing, apoptosis, cell cycle control; hormones, growth factors; oncogenes, host-virus interactions, viral assembly and structure; intermediary metabolism, molecular basis of disease processes, vitamins, coenzymes, carrier proteins, toxicology; plant and microbial biochemistry; surface forces, micelles and microemulsions, colloids, electrical phenomena, etc. in biological systems. Solicited peer reviewed articles on contemporary Themes and Methods in Biochemistry and Biophysics form an important feature of IJBB.
Review articles on a current topic in the above fields are also considered. They must dwell more on research work done during the last couple of years in the field and authors should integrate their own work with that of others with acumen and authenticity, mere compilation of references by a third party is discouraged. While IJBB strongly promotes innovative novel research works for publication as full length papers, it also considers research data emanating from limited objectives, and extension of ongoing experimental works as ‘Notes’. IJBB follows “Double Blind Review process” where author names, affiliations and other correspondence details are removed to ensure fare evaluation. At the same time, reviewer names are not disclosed to authors.