Tangeretin attenuates acute lung injury in septic mice by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis.

Autor: Liu Y; State Key Laboratory of Traditional Chinese Medicine Syndrom，The second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China., Zhang Y; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China., You G; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China., Zheng D; State Key Laboratory of Traditional Chinese Medicine Syndrom，The second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China., He Z; State Key Laboratory of Traditional Chinese Medicine Syndrom，The second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China., Guo W; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China., Antonina K; No. 1 Department of Internal Diseases, Samarkand State Medical University, Samarkand, Uzbekistan., Shukhrat Z; No. 1 Department of Internal Diseases, Samarkand State Medical University, Samarkand, Uzbekistan., Ding B; State Key Laboratory of Traditional Chinese Medicine Syndrom，The second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China. banghanding@139.com., Zan J; School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China. zanj@gdut.edu.cn., Zhang Z; State Key Laboratory of Traditional Chinese Medicine Syndrom，The second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, 510120, China. doctorzzd99@163.com.
Jazyk: angličtina
Zdroj: Inflammation research : official journal of the European Histamine Research Society ... [et al.] [Inflamm Res] 2024 Jan; Vol. 73 (1), pp. 47-63. Date of Electronic Publication: 2023 Dec 26.
DOI: 10.1007/s00011-023-01819-8
Abstrakt: Objective: NLRP3 inflammasome-mediated pyroptosis of macrophage acts essential roles in the progression of sepsis-induced acute lung injury (ALI). Tangeretin (TAN), enriched in citrus fruit peel, presents anti-oxidative and anti-inflammatory effects. Here, we aimed to explore the potentially protective effect of TAN on sepsis-induced ALI, and the underlying mechanism of TAN in regulating NLRP3 inflammasome.
Material and Methods: The effect of TAN on sepsis-induced ALI and NLRP3 inflammasome-mediated pyroptosis of macrophage were examined in vivo and in vitro using a LPS-treated mice model and LPS-induced murine macrophages, respectively. The mechanism of TAN regulating the activation of NLRP3 inflammasome in sepsis-induced ALI was investigated with HE staining, Masson staining, immunofluorescent staining, ELISA, molecular docking, transmission electron microscope detection, qRT-PCR, and western blot.
Results: TAN could evidently attenuate sepsis-induced ALI in mice, evidenced by reducing pulmonary edema, pulmonary congestion and lung interstitial fibrosis, and inhibiting macrophage infiltration in the lung tissue. Besides, TAN significantly suppressed inflammatory cytokine IL-1β and IL-18 expression in the serum or bronchoalveolar lavage fluid (BALF) samples of mice with LPS-induced ALI, and inhibited NLRP3 inflammasome-mediated pyroptosis of macrophages. Furthermore, we found TAN inhibited ROS production, preserved mitochondrial morphology, and alleviated excessive mitochondrial fission in LPS-induced ALI in mice. Through bioinformatic analysis and molecular docking, Polo-like kinase 1 (PLK1) was identified as a potential target of TAN for treating sepsis-induced ALI. Moreover, TAN significantly inhibited the reduction of PLK1 expression, AMP-activated protein kinase (AMPK) phosphorylation, and Dynamin related protein 1 (Drp1) phosphorylation (S637) in LPS-induced ALI in mice. In addition, Volasertib, a specific inhibitor of PLK1, abolished the protective effects of TAN against NLRP3 inflammasome-mediated pyroptosis of macrophage and lung injury in the cell and mice septic models.
Conclusion: TAN attenuates sepsis-induced ALI by inhibiting ROS-mediated NLRP3 inflammasome activation via regulating PLK1/AMPK/DRP1 signaling axis, and TAN is a potentially therapeutic candidate against ALI through inhibiting pyroptosis.
(© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)
Databáze: MEDLINE
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