Hao Zeng, Xue Yang, Kai Liao, Xin Zuo, Lihong Liang, Dalian He, Rong Ju, Bowen Wang, Jin Yuan
{"title":"在干眼发育过程中,昼夜节律紊乱会通过时钟分子 BMAL1 减少 MUC4 的表达。","authors":"Hao Zeng, Xue Yang, Kai Liao, Xin Zuo, Lihong Liang, Dalian He, Rong Ju, Bowen Wang, Jin Yuan","doi":"10.1038/s12276-024-01269-0","DOIUrl":null,"url":null,"abstract":"Circadian disruption, as a result of shiftwork, jet lag, and other lifestyle factors, is a common public health problem associated with a wide range of diseases, such as metabolic disorders, neurodegenerative diseases, and cancer. In the present study, we established a chronic jet lag model using a time shift method every 3 days and assessed the effects of circadian disruption on ocular surface homeostasis. Our results indicated that jet lag increased corneal epithelial defects, cell apoptosis, and proinflammatory cytokine expression. However, the volume of tear secretion and the number of conjunctival goblet cells did not significantly change after 30 days of jet lag. Moreover, further analysis of the pathogenic mechanism using RNA sequencing revealed that jet lag caused corneal transmembrane mucin deficiency, specifically MUC4 deficiency. The crucial role of MUC4 in pathogenic progression was demonstrated by the protection of corneal epithelial cells and the inhibition of inflammatory activation following MUC4 replenishment. Unexpectedly, genetic ablation of BMAL1 in mice caused MUC4 deficiency and dry eye disease. The underlying mechanism was revealed in cultured human corneal epithelial cells in vitro, where BMAL1 silencing reduced MUC4 expression, and BMAL1 overexpression increased MUC4 expression. Furthermore, melatonin, a circadian rhythm restorer, had a therapeutic effect on jet lag-induced dry eye by restoring the expression of BMAL1, which upregulated MUC4. Thus, we generated a novel dry eye mouse model induced by circadian disruption, elucidated the underlying mechanism, and identified a potential clinical treatment. Dry eye disease, a long-term issue causing discomfort and vision problems, impacts millions globally. In this research, scientists studied how disturbances in our internal clock contribute to DED. Researchers made the mice experience an 8-hour shift in their day-night cycle every 3 days, imitating chronic jet lag. The findings showed that chronic jet lag resulted in a significant decrease in MUC4 expression in the cornea, leading to DED symptoms. Supplementing with MUC4 or treating the mice with melatonin, eased these symptoms. This indicates that disruptions to our internal clock can directly affect eye health by impacting key protective proteins in the eye. Researchers conclude that maintaining a healthy internal clock is vital for eye health and that treatments targeting internal clock disruptions could help DED patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":null,"pages":null},"PeriodicalIF":9.5000,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297157/pdf/","citationCount":"0","resultStr":"{\"title\":\"Circadian disruption reduces MUC4 expression via the clock molecule BMAL1 during dry eye development\",\"authors\":\"Hao Zeng, Xue Yang, Kai Liao, Xin Zuo, Lihong Liang, Dalian He, Rong Ju, Bowen Wang, Jin Yuan\",\"doi\":\"10.1038/s12276-024-01269-0\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Circadian disruption, as a result of shiftwork, jet lag, and other lifestyle factors, is a common public health problem associated with a wide range of diseases, such as metabolic disorders, neurodegenerative diseases, and cancer. In the present study, we established a chronic jet lag model using a time shift method every 3 days and assessed the effects of circadian disruption on ocular surface homeostasis. Our results indicated that jet lag increased corneal epithelial defects, cell apoptosis, and proinflammatory cytokine expression. However, the volume of tear secretion and the number of conjunctival goblet cells did not significantly change after 30 days of jet lag. Moreover, further analysis of the pathogenic mechanism using RNA sequencing revealed that jet lag caused corneal transmembrane mucin deficiency, specifically MUC4 deficiency. The crucial role of MUC4 in pathogenic progression was demonstrated by the protection of corneal epithelial cells and the inhibition of inflammatory activation following MUC4 replenishment. Unexpectedly, genetic ablation of BMAL1 in mice caused MUC4 deficiency and dry eye disease. The underlying mechanism was revealed in cultured human corneal epithelial cells in vitro, where BMAL1 silencing reduced MUC4 expression, and BMAL1 overexpression increased MUC4 expression. Furthermore, melatonin, a circadian rhythm restorer, had a therapeutic effect on jet lag-induced dry eye by restoring the expression of BMAL1, which upregulated MUC4. Thus, we generated a novel dry eye mouse model induced by circadian disruption, elucidated the underlying mechanism, and identified a potential clinical treatment. Dry eye disease, a long-term issue causing discomfort and vision problems, impacts millions globally. In this research, scientists studied how disturbances in our internal clock contribute to DED. Researchers made the mice experience an 8-hour shift in their day-night cycle every 3 days, imitating chronic jet lag. The findings showed that chronic jet lag resulted in a significant decrease in MUC4 expression in the cornea, leading to DED symptoms. Supplementing with MUC4 or treating the mice with melatonin, eased these symptoms. This indicates that disruptions to our internal clock can directly affect eye health by impacting key protective proteins in the eye. Researchers conclude that maintaining a healthy internal clock is vital for eye health and that treatments targeting internal clock disruptions could help DED patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.\",\"PeriodicalId\":50466,\"journal\":{\"name\":\"Experimental and Molecular Medicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.5000,\"publicationDate\":\"2024-07-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11297157/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Experimental and Molecular Medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.nature.com/articles/s12276-024-01269-0\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Experimental and Molecular Medicine","FirstCategoryId":"3","ListUrlMain":"https://www.nature.com/articles/s12276-024-01269-0","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Circadian disruption reduces MUC4 expression via the clock molecule BMAL1 during dry eye development
Circadian disruption, as a result of shiftwork, jet lag, and other lifestyle factors, is a common public health problem associated with a wide range of diseases, such as metabolic disorders, neurodegenerative diseases, and cancer. In the present study, we established a chronic jet lag model using a time shift method every 3 days and assessed the effects of circadian disruption on ocular surface homeostasis. Our results indicated that jet lag increased corneal epithelial defects, cell apoptosis, and proinflammatory cytokine expression. However, the volume of tear secretion and the number of conjunctival goblet cells did not significantly change after 30 days of jet lag. Moreover, further analysis of the pathogenic mechanism using RNA sequencing revealed that jet lag caused corneal transmembrane mucin deficiency, specifically MUC4 deficiency. The crucial role of MUC4 in pathogenic progression was demonstrated by the protection of corneal epithelial cells and the inhibition of inflammatory activation following MUC4 replenishment. Unexpectedly, genetic ablation of BMAL1 in mice caused MUC4 deficiency and dry eye disease. The underlying mechanism was revealed in cultured human corneal epithelial cells in vitro, where BMAL1 silencing reduced MUC4 expression, and BMAL1 overexpression increased MUC4 expression. Furthermore, melatonin, a circadian rhythm restorer, had a therapeutic effect on jet lag-induced dry eye by restoring the expression of BMAL1, which upregulated MUC4. Thus, we generated a novel dry eye mouse model induced by circadian disruption, elucidated the underlying mechanism, and identified a potential clinical treatment. Dry eye disease, a long-term issue causing discomfort and vision problems, impacts millions globally. In this research, scientists studied how disturbances in our internal clock contribute to DED. Researchers made the mice experience an 8-hour shift in their day-night cycle every 3 days, imitating chronic jet lag. The findings showed that chronic jet lag resulted in a significant decrease in MUC4 expression in the cornea, leading to DED symptoms. Supplementing with MUC4 or treating the mice with melatonin, eased these symptoms. This indicates that disruptions to our internal clock can directly affect eye health by impacting key protective proteins in the eye. Researchers conclude that maintaining a healthy internal clock is vital for eye health and that treatments targeting internal clock disruptions could help DED patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.
期刊介绍:
Experimental & Molecular Medicine (EMM) stands as Korea's pioneering biochemistry journal, established in 1964 and rejuvenated in 1996 as an Open Access, fully peer-reviewed international journal. Dedicated to advancing translational research and showcasing recent breakthroughs in the biomedical realm, EMM invites submissions encompassing genetic, molecular, and cellular studies of human physiology and diseases. Emphasizing the correlation between experimental and translational research and enhanced clinical benefits, the journal actively encourages contributions employing specific molecular tools. Welcoming studies that bridge basic discoveries with clinical relevance, alongside articles demonstrating clear in vivo significance and novelty, Experimental & Molecular Medicine proudly serves as an open-access, online-only repository of cutting-edge medical research.