RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice
Elevated manganese (Mn) exposure has been implicated in a broad spectrum of neurological disorders, including motor dysfunction and cognitive deficits. Previous studies have demonstrated that Mn induces neurotoxicity by disrupting the integrity of the blood–brain barrier (BBB), a critical regulator...
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Elsevier
2025-01-01
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| Series: | Current Research in Toxicology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2666027X24000604 |
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| author | Yan Ma Honggang Chen Yuxin Jiang Diya Wang Michael Aschner Wenjing Luo Peng Su |
| author_facet | Yan Ma Honggang Chen Yuxin Jiang Diya Wang Michael Aschner Wenjing Luo Peng Su |
| author_sort | Yan Ma |
| collection | DOAJ |
| description | Elevated manganese (Mn) exposure has been implicated in a broad spectrum of neurological disorders, including motor dysfunction and cognitive deficits. Previous studies have demonstrated that Mn induces neurotoxicity by disrupting the integrity of the blood–brain barrier (BBB), a critical regulator in maintaining central nervous system homeostasis and a contributing factor in the pathogenesis of numerous neurological disorders. However, the precise molecular mechanisms underlying Mn-induced BBB disruption and its role in facilitating neurotoxicity remain incompletely understood. The primary objectives of this study were to elucidate the mechanisms underlying the relationship between Mn exposure and BBB tight junction proteins (TJPs), and to further investigate potential neuroprotective strategies for mitigating Mn-induced cognitive impairments. In this investigation, we developed Mn exposure models utilizing both murine subjects and cell culture systems to elucidate the mechanisms underlying TJPs involvement and to assess the potential neuroprotective effects of gastrodin (GAS), a bioactive compound extracted from traditional Chinese medicine. Our findings revealed a significant reduction in TJPs expression, both in vivo and in vitro, in Mn-induced BBB disruption. The overexpression of Occludin (OCLN), a crucial component of TJPs, mitigated Mn-induced BBB damage. GAS administration effectively attenuated Mn-induced disruption of the BBB, enhanced the expression of TJPs, and mitigated Mn-induced cognitive dysfunctions, potentially through the modulation of the RhoA/ROCK2 signaling pathway. This research sought to advance our understanding of the molecular pathways involved in Mn-mediated BBB disruption and to identify novel therapeutic approaches for mitigating the deleterious effects of Mn exposure on cognitive function. |
| format | Article |
| id | doaj-art-3f09d612990f4e4296f17d3dd4028707 |
| institution | Kabale University |
| issn | 2666-027X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Current Research in Toxicology |
| spelling | doaj-art-3f09d612990f4e4296f17d3dd40287072025-08-20T03:24:36ZengElsevierCurrent Research in Toxicology2666-027X2025-01-01810020710.1016/j.crtox.2024.100207RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in miceYan Ma0Honggang Chen1Yuxin Jiang2Diya Wang3Michael Aschner4Wenjing Luo5Peng Su6Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Chang Le Xi Road, Xi’an,Shaanxi 710032, ChinaDepartment of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Chang Le Xi Road, Xi’an,Shaanxi 710032, ChinaDepartment of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Chang Le Xi Road, Xi’an,Shaanxi 710032, ChinaDepartment of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Chang Le Xi Road, Xi’an,Shaanxi 710032, ChinaDepartment of Molecular Pharmacology, Albert Einstein College of Medicine, New York, United States of AmericaDepartment of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Chang Le Xi Road, Xi’an,Shaanxi 710032, China; Corresponding authors at: Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China.Department of Occupational & Environmental Health and the Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, Fourth Military Medical University, Chang Le Xi Road, Xi’an,Shaanxi 710032, China; Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China; Corresponding authors at: Department of Occupational and Environmental Health, School of Public Health, Chongqing Medical University, Chongqing 400016, China.Elevated manganese (Mn) exposure has been implicated in a broad spectrum of neurological disorders, including motor dysfunction and cognitive deficits. Previous studies have demonstrated that Mn induces neurotoxicity by disrupting the integrity of the blood–brain barrier (BBB), a critical regulator in maintaining central nervous system homeostasis and a contributing factor in the pathogenesis of numerous neurological disorders. However, the precise molecular mechanisms underlying Mn-induced BBB disruption and its role in facilitating neurotoxicity remain incompletely understood. The primary objectives of this study were to elucidate the mechanisms underlying the relationship between Mn exposure and BBB tight junction proteins (TJPs), and to further investigate potential neuroprotective strategies for mitigating Mn-induced cognitive impairments. In this investigation, we developed Mn exposure models utilizing both murine subjects and cell culture systems to elucidate the mechanisms underlying TJPs involvement and to assess the potential neuroprotective effects of gastrodin (GAS), a bioactive compound extracted from traditional Chinese medicine. Our findings revealed a significant reduction in TJPs expression, both in vivo and in vitro, in Mn-induced BBB disruption. The overexpression of Occludin (OCLN), a crucial component of TJPs, mitigated Mn-induced BBB damage. GAS administration effectively attenuated Mn-induced disruption of the BBB, enhanced the expression of TJPs, and mitigated Mn-induced cognitive dysfunctions, potentially through the modulation of the RhoA/ROCK2 signaling pathway. This research sought to advance our understanding of the molecular pathways involved in Mn-mediated BBB disruption and to identify novel therapeutic approaches for mitigating the deleterious effects of Mn exposure on cognitive function.http://www.sciencedirect.com/science/article/pii/S2666027X24000604ManganeseTight JunctionRhoAGastrodin |
| spellingShingle | Yan Ma Honggang Chen Yuxin Jiang Diya Wang Michael Aschner Wenjing Luo Peng Su RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice Current Research in Toxicology Manganese Tight Junction RhoA Gastrodin |
| title | RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice |
| title_full | RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice |
| title_fullStr | RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice |
| title_full_unstemmed | RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice |
| title_short | RhoA/ROCK2 signaling pathway regulates Mn-induced alterations in tight junction proteins leading to cognitive dysfunction in mice |
| title_sort | rhoa rock2 signaling pathway regulates mn induced alterations in tight junction proteins leading to cognitive dysfunction in mice |
| topic | Manganese Tight Junction RhoA Gastrodin |
| url | http://www.sciencedirect.com/science/article/pii/S2666027X24000604 |
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