Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect
Abstract Background Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory disea...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2022-05-01
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| Series: | Military Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40779-022-00381-4 |
| _version_ | 1811256741831114752 |
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| author | Piao Luo Qian Zhang Tian-Yu Zhong Jia-Yun Chen Jun-Zhe Zhang Ya Tian Liu-Hai Zheng Fan Yang Ling-Yun Dai Chang Zou Zhi-Jie Li Jing-Hua Liu Ji-Gang Wang |
| author_facet | Piao Luo Qian Zhang Tian-Yu Zhong Jia-Yun Chen Jun-Zhe Zhang Ya Tian Liu-Hai Zheng Fan Yang Ling-Yun Dai Chang Zou Zhi-Jie Li Jing-Hua Liu Ji-Gang Wang |
| author_sort | Piao Luo |
| collection | DOAJ |
| description | Abstract Background Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis. Methods We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide (LPS). We screened for potential protein targets of Cel using activity-based protein profiling (ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays (CETSA) and surface plasmon resonance (SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis, and the functional effects of such binding were explored through gene knockdown. Results Cel protected mice from lethal endotoxemia and improved their survival with sepsis, and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS (P < 0.05). Cel bound to Cys424 of pyruvate kinase M2 (PKM2), inhibiting the enzyme and thereby suppressing aerobic glycolysis (Warburg effect). Cel also bound to Cys106 in high mobility group box 1 (HMGB1) protein, reducing the secretion of inflammatory cytokine interleukin (IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A (LDHA). Conclusion Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein. |
| first_indexed | 2024-04-12T17:45:52Z |
| format | Article |
| id | doaj.art-1b598b7ec7c04be6ac1055d971c085d7 |
| institution | Directory Open Access Journal |
| issn | 2054-9369 |
| language | English |
| last_indexed | 2024-04-12T17:45:52Z |
| publishDate | 2022-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Military Medical Research |
| spelling | doaj.art-1b598b7ec7c04be6ac1055d971c085d72022-12-22T03:22:40ZengBMCMilitary Medical Research2054-93692022-05-019111610.1186/s40779-022-00381-4Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effectPiao Luo0Qian Zhang1Tian-Yu Zhong2Jia-Yun Chen3Jun-Zhe Zhang4Ya Tian5Liu-Hai Zheng6Fan Yang7Ling-Yun Dai8Chang Zou9Zhi-Jie Li10Jing-Hua Liu11Ji-Gang Wang12Artemisinin Research Center, and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical SciencesLaboratory Medicine, the First Affiliated Hospital of Gannan Medical UniversityArtemisinin Research Center, and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical SciencesArtemisinin Research Center, and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical SciencesDepartment of Geriatric Medicine, Shenzhen People’s Hospital, the Second Clinical Medical College, Jinan University and the First Affiliated Hospital, Southern University of Science and TechnologyDepartment of Geriatric Medicine, Shenzhen People’s Hospital, the Second Clinical Medical College, Jinan University and the First Affiliated Hospital, Southern University of Science and TechnologyDepartment of Geriatric Medicine, Shenzhen People’s Hospital, the Second Clinical Medical College, Jinan University and the First Affiliated Hospital, Southern University of Science and TechnologyGuangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical UniversityDepartment of Geriatric Medicine, Shenzhen People’s Hospital, the Second Clinical Medical College, Jinan University and the First Affiliated Hospital, Southern University of Science and TechnologyGuangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical UniversityArtemisinin Research Center, and Institute of Chinese Materia Medica, Chinese Academy of Chinese Medical SciencesAbstract Background Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis. Methods We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide (LPS). We screened for potential protein targets of Cel using activity-based protein profiling (ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays (CETSA) and surface plasmon resonance (SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis, and the functional effects of such binding were explored through gene knockdown. Results Cel protected mice from lethal endotoxemia and improved their survival with sepsis, and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS (P < 0.05). Cel bound to Cys424 of pyruvate kinase M2 (PKM2), inhibiting the enzyme and thereby suppressing aerobic glycolysis (Warburg effect). Cel also bound to Cys106 in high mobility group box 1 (HMGB1) protein, reducing the secretion of inflammatory cytokine interleukin (IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A (LDHA). Conclusion Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein.https://doi.org/10.1186/s40779-022-00381-4CelastrolSepsisPyruvate kinase M2High mobility group box 1Aerobic glycolysis |
| spellingShingle | Piao Luo Qian Zhang Tian-Yu Zhong Jia-Yun Chen Jun-Zhe Zhang Ya Tian Liu-Hai Zheng Fan Yang Ling-Yun Dai Chang Zou Zhi-Jie Li Jing-Hua Liu Ji-Gang Wang Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect Military Medical Research Celastrol Sepsis Pyruvate kinase M2 High mobility group box 1 Aerobic glycolysis |
| title | Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect |
| title_full | Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect |
| title_fullStr | Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect |
| title_full_unstemmed | Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect |
| title_short | Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect |
| title_sort | celastrol mitigates inflammation in sepsis by inhibiting the pkm2 dependent warburg effect |
| topic | Celastrol Sepsis Pyruvate kinase M2 High mobility group box 1 Aerobic glycolysis |
| url | https://doi.org/10.1186/s40779-022-00381-4 |
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