{"title":"高温所需的丝氨酸蛋白酶 A2 抑制剂 UCF-101 可通过 AMPK/NF-κB 通路改善脑外伤大鼠受损的神经元。","authors":"Tian-Wen Qiu, Zhan Jin, Zhi-Zhan Fu, Xin-Jiang Yan, Cheng-Peng Zhan, Hui-Wen Zheng, Mei-Ying Li, Guo-Feng Yu","doi":"10.1515/biol-2022-0971","DOIUrl":null,"url":null,"abstract":"<p><p>Traumatic brain injury (TBI) leads to permanent damage, including neurological deficits, cognitive deficits, and cerebral edema. The specific inhibitor of serine protease Omi/high-temperature requirement A2 (Omi/HtrA2), UCF-101, exerts neuroprotective effects, but its role in TBI remains unclear. Eighty-four male Sprague Dawley rats were randomized to control, TBI, UCF-101 of low dose (1.5 μmol/kg), middle dose (3.0 μmol/kg), and high dose (6.0 μmol/kg), Compound C (AMPK inhibitor, 20 mg/kg), and high dose + Compound C groups. TBI rat modeling was operated by the controlled cortical impact method. Modified neurological severity score (mNSS) cognitive function, cerebral edema index, hematoxylin-eosin staining, TUNEL staining for apoptosis, ethidium bromide staining for blood-brain barrier (BBB) permeability, enzyme-linked immunosorbent assay for inflammation response, and Western blot analysis were performed. In TBI rats, UCF-101 caused decreased mNSS score, brain edema, neuronal apoptosis, as well as P-NF-κBp65/NF-κBp65, tumor necrosis factor-α, interleukin (IL)-1β, and IL-8 expression, while P-AMPK/AMPK, zonula occludens protein, Occludin, and Claudin-5 expression increased, accompanied with up-regulated cognitive function. Moreover, Compound C further exacerbated brain tissue lesions, neuronal damage, inflammation response, and neuronal apoptosis, while high-dose UCF-101 offset its effect. UCF-101 may inhibit apoptosis and BBB permeability to exert neuroprotective effects in TBI rats by regulating the AMPK/NF-κB pathway, advancing UCF-101 clinical applications for TBI treatment.</p>","PeriodicalId":19605,"journal":{"name":"Open Life Sciences","volume":"20 1","pages":"20220971"},"PeriodicalIF":1.7000,"publicationDate":"2025-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889502/pdf/","citationCount":"0","resultStr":"{\"title\":\"High-temperature requirement serine protease A2 inhibitor UCF-101 ameliorates damaged neurons in traumatic brain-injured rats by the AMPK/NF-κB pathway.\",\"authors\":\"Tian-Wen Qiu, Zhan Jin, Zhi-Zhan Fu, Xin-Jiang Yan, Cheng-Peng Zhan, Hui-Wen Zheng, Mei-Ying Li, Guo-Feng Yu\",\"doi\":\"10.1515/biol-2022-0971\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Traumatic brain injury (TBI) leads to permanent damage, including neurological deficits, cognitive deficits, and cerebral edema. The specific inhibitor of serine protease Omi/high-temperature requirement A2 (Omi/HtrA2), UCF-101, exerts neuroprotective effects, but its role in TBI remains unclear. Eighty-four male Sprague Dawley rats were randomized to control, TBI, UCF-101 of low dose (1.5 μmol/kg), middle dose (3.0 μmol/kg), and high dose (6.0 μmol/kg), Compound C (AMPK inhibitor, 20 mg/kg), and high dose + Compound C groups. TBI rat modeling was operated by the controlled cortical impact method. Modified neurological severity score (mNSS) cognitive function, cerebral edema index, hematoxylin-eosin staining, TUNEL staining for apoptosis, ethidium bromide staining for blood-brain barrier (BBB) permeability, enzyme-linked immunosorbent assay for inflammation response, and Western blot analysis were performed. In TBI rats, UCF-101 caused decreased mNSS score, brain edema, neuronal apoptosis, as well as P-NF-κBp65/NF-κBp65, tumor necrosis factor-α, interleukin (IL)-1β, and IL-8 expression, while P-AMPK/AMPK, zonula occludens protein, Occludin, and Claudin-5 expression increased, accompanied with up-regulated cognitive function. Moreover, Compound C further exacerbated brain tissue lesions, neuronal damage, inflammation response, and neuronal apoptosis, while high-dose UCF-101 offset its effect. UCF-101 may inhibit apoptosis and BBB permeability to exert neuroprotective effects in TBI rats by regulating the AMPK/NF-κB pathway, advancing UCF-101 clinical applications for TBI treatment.</p>\",\"PeriodicalId\":19605,\"journal\":{\"name\":\"Open Life Sciences\",\"volume\":\"20 1\",\"pages\":\"20220971\"},\"PeriodicalIF\":1.7000,\"publicationDate\":\"2025-03-06\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11889502/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Open Life Sciences\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1515/biol-2022-0971\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/1 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q3\",\"JCRName\":\"BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Open Life Sciences","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1515/biol-2022-0971","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q3","JCRName":"BIOLOGY","Score":null,"Total":0}
High-temperature requirement serine protease A2 inhibitor UCF-101 ameliorates damaged neurons in traumatic brain-injured rats by the AMPK/NF-κB pathway.
Traumatic brain injury (TBI) leads to permanent damage, including neurological deficits, cognitive deficits, and cerebral edema. The specific inhibitor of serine protease Omi/high-temperature requirement A2 (Omi/HtrA2), UCF-101, exerts neuroprotective effects, but its role in TBI remains unclear. Eighty-four male Sprague Dawley rats were randomized to control, TBI, UCF-101 of low dose (1.5 μmol/kg), middle dose (3.0 μmol/kg), and high dose (6.0 μmol/kg), Compound C (AMPK inhibitor, 20 mg/kg), and high dose + Compound C groups. TBI rat modeling was operated by the controlled cortical impact method. Modified neurological severity score (mNSS) cognitive function, cerebral edema index, hematoxylin-eosin staining, TUNEL staining for apoptosis, ethidium bromide staining for blood-brain barrier (BBB) permeability, enzyme-linked immunosorbent assay for inflammation response, and Western blot analysis were performed. In TBI rats, UCF-101 caused decreased mNSS score, brain edema, neuronal apoptosis, as well as P-NF-κBp65/NF-κBp65, tumor necrosis factor-α, interleukin (IL)-1β, and IL-8 expression, while P-AMPK/AMPK, zonula occludens protein, Occludin, and Claudin-5 expression increased, accompanied with up-regulated cognitive function. Moreover, Compound C further exacerbated brain tissue lesions, neuronal damage, inflammation response, and neuronal apoptosis, while high-dose UCF-101 offset its effect. UCF-101 may inhibit apoptosis and BBB permeability to exert neuroprotective effects in TBI rats by regulating the AMPK/NF-κB pathway, advancing UCF-101 clinical applications for TBI treatment.
期刊介绍:
Open Life Sciences (previously Central European Journal of Biology) is a fast growing peer-reviewed journal, devoted to scholarly research in all areas of life sciences, such as molecular biology, plant science, biotechnology, cell biology, biochemistry, biophysics, microbiology and virology, ecology, differentiation and development, genetics and many others. Open Life Sciences assures top quality of published data through critical peer review and editorial involvement throughout the whole publication process. Thanks to the Open Access model of publishing, it also offers unrestricted access to published articles for all users.