Celastrol exerts a neuroprotective effect by directly binding to HMGB1 protein in cerebral ischemia–reperfusion
Abstract Background Celastrol (cel) was one of the earliest isolated and identified chemical constituents of Tripterygium wilfordii Hook. f. Based on a cel probe (cel-p) that maintained the bioactivity of the parent compound, the targets of cel in cerebral ischemia–reperfusion (I/R) injury were comp...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2021-08-01
|
| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12974-021-02216-w |
| _version_ | 1819138219941298176 |
|---|---|
| author | Dan-Dan Liu Piao Luo Liwei Gu Qian Zhang Peng Gao Yongping Zhu Xiao Chen Qiuyan Guo Junzhe Zhang Nan Ma Jigang Wang |
| author_facet | Dan-Dan Liu Piao Luo Liwei Gu Qian Zhang Peng Gao Yongping Zhu Xiao Chen Qiuyan Guo Junzhe Zhang Nan Ma Jigang Wang |
| author_sort | Dan-Dan Liu |
| collection | DOAJ |
| description | Abstract Background Celastrol (cel) was one of the earliest isolated and identified chemical constituents of Tripterygium wilfordii Hook. f. Based on a cel probe (cel-p) that maintained the bioactivity of the parent compound, the targets of cel in cerebral ischemia–reperfusion (I/R) injury were comprehensively analyzed by a quantitative chemical proteomics method. Methods We constructed an oxygen–glucose deprivation (OGD) model in primary rat cortical neurons and a middle cerebral artery occlusion (MCAO) model in adult rats to detect the direct binding targets of cel in cerebral I/R. By combining various experimental methods, including tandem mass tag (TMT) labeling, mass spectrometry, and cellular thermal shift assay (CETSA), we revealed the targets to which cel directly bound to exert neuroprotective effects. Results We found that cel inhibited the proinflammatory activity of high mobility group protein 1 (HMGB1) by directly binding to it and then blocking the binding of HMGB1 to its inflammatory receptors in the microenvironment of ischemia and hypoxia. In addition, cel rescued neurons from OGD injury in vitro and decreased cerebral infarction in vivo by targeting HSP70 and NF-κB p65. Conclusion Cel exhibited neuroprotective and anti-inflammatory effects by targeting HSP70 and NF-κB p65 and directly binding to HMGB1 in cerebral I/R injury. |
| first_indexed | 2024-12-22T11:03:18Z |
| format | Article |
| id | doaj.art-b532d96e759d4decab0bf7b48a44b9cf |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-22T11:03:18Z |
| publishDate | 2021-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-b532d96e759d4decab0bf7b48a44b9cf2022-12-21T18:28:26ZengBMCJournal of Neuroinflammation1742-20942021-08-0118111810.1186/s12974-021-02216-wCelastrol exerts a neuroprotective effect by directly binding to HMGB1 protein in cerebral ischemia–reperfusionDan-Dan Liu0Piao Luo1Liwei Gu2Qian Zhang3Peng Gao4Yongping Zhu5Xiao Chen6Qiuyan Guo7Junzhe Zhang8Nan Ma9Jigang Wang10Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesSchool of Biopharmacy, China Pharmaceutical UniversityArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical SciencesAbstract Background Celastrol (cel) was one of the earliest isolated and identified chemical constituents of Tripterygium wilfordii Hook. f. Based on a cel probe (cel-p) that maintained the bioactivity of the parent compound, the targets of cel in cerebral ischemia–reperfusion (I/R) injury were comprehensively analyzed by a quantitative chemical proteomics method. Methods We constructed an oxygen–glucose deprivation (OGD) model in primary rat cortical neurons and a middle cerebral artery occlusion (MCAO) model in adult rats to detect the direct binding targets of cel in cerebral I/R. By combining various experimental methods, including tandem mass tag (TMT) labeling, mass spectrometry, and cellular thermal shift assay (CETSA), we revealed the targets to which cel directly bound to exert neuroprotective effects. Results We found that cel inhibited the proinflammatory activity of high mobility group protein 1 (HMGB1) by directly binding to it and then blocking the binding of HMGB1 to its inflammatory receptors in the microenvironment of ischemia and hypoxia. In addition, cel rescued neurons from OGD injury in vitro and decreased cerebral infarction in vivo by targeting HSP70 and NF-κB p65. Conclusion Cel exhibited neuroprotective and anti-inflammatory effects by targeting HSP70 and NF-κB p65 and directly binding to HMGB1 in cerebral I/R injury.https://doi.org/10.1186/s12974-021-02216-wCelastrolChemical proteomicsTarget identificationHigh mobility group protein 1Cerebral ischemia–reperfusion |
| spellingShingle | Dan-Dan Liu Piao Luo Liwei Gu Qian Zhang Peng Gao Yongping Zhu Xiao Chen Qiuyan Guo Junzhe Zhang Nan Ma Jigang Wang Celastrol exerts a neuroprotective effect by directly binding to HMGB1 protein in cerebral ischemia–reperfusion Journal of Neuroinflammation Celastrol Chemical proteomics Target identification High mobility group protein 1 Cerebral ischemia–reperfusion |
| title | Celastrol exerts a neuroprotective effect by directly binding to HMGB1 protein in cerebral ischemia–reperfusion |
| title_full | Celastrol exerts a neuroprotective effect by directly binding to HMGB1 protein in cerebral ischemia–reperfusion |
| title_fullStr | Celastrol exerts a neuroprotective effect by directly binding to HMGB1 protein in cerebral ischemia–reperfusion |
| title_full_unstemmed | Celastrol exerts a neuroprotective effect by directly binding to HMGB1 protein in cerebral ischemia–reperfusion |
| title_short | Celastrol exerts a neuroprotective effect by directly binding to HMGB1 protein in cerebral ischemia–reperfusion |
| title_sort | celastrol exerts a neuroprotective effect by directly binding to hmgb1 protein in cerebral ischemia reperfusion |
| topic | Celastrol Chemical proteomics Target identification High mobility group protein 1 Cerebral ischemia–reperfusion |
| url | https://doi.org/10.1186/s12974-021-02216-w |
| work_keys_str_mv | AT dandanliu celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT piaoluo celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT liweigu celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT qianzhang celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT penggao celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT yongpingzhu celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT xiaochen celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT qiuyanguo celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT junzhezhang celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT nanma celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion AT jigangwang celastrolexertsaneuroprotectiveeffectbydirectlybindingtohmgb1proteinincerebralischemiareperfusion |