蒲公英赛醇通过激活SIRT1抑制M1极化并减轻脓毒症诱导的急性肺损伤。

Taraxerone inhibits M1 polarization and alleviates sepsis-induced acute lung injury by activating SIRT1.

作者信息

Deng Lang, Xie Weixi, Lin Miao, Xiong Dayan, Huang Lei, Zhang Xiaohua, Qian Rui, Huang Xiaoting, Tang Siyuan, Liu Wei

机构信息

Xiangya Nursing School, Central South University, Changsha, 410013, Hunan, China.

Occupational Disease Department, Hunan Prevention and Treatment Institute for Occupational Diseases, Changsha, 410021, Hunan, China.

出版信息

Chin Med. 2024 Nov 14;19(1):159. doi: 10.1186/s13020-024-01002-z.

DOI:10.1186/s13020-024-01002-z

PMID:39543653

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11566926/

Abstract

BACKGROUND

Acute lung injury (ALI) is the most lethal disease associated with sepsis, and there is a lack of effective drug treatment. As the major cells of sepsis-induced ALI, macrophages polarize toward the proinflammatory M1 phenotype and secrete multiple inflammatory cytokines to accelerate the disease process through nuclear factor kappa-B (NF-κB) and NLR family pyrin domain containing 3 (NLRP3) inflammasome signaling pathways. Taraxerone, the main component of the Chinese medicinal Sedum, possesses numerous biological activities. However, uncertainty remains regarding the potential of taraxerone to protect against sepsis-induced ALI. This study aimed to investigate the effects and mechanisms of taraxerone against ALI.

METHODS

An animal model for ALI was established by cecal ligation and puncture and treated with taraxerone via intraperitoneal administration. The protective effect of taraxerone on the lungs was analyzed using H&E staining, dihydroethidium staining, ELISA kits, cell counting, myeloperoxidase kit, malondialdehyde kit, glutathione kit, superoxide dismutase kit and flow cytometry. Western blotting, RT-PCR, flow cytometry, co-immunoprecipitation, and immunofluorescence were used to investigate the regulatory of taraxerone on SIRT1.

RESULTS

Our study demonstrates for the first time that taraxerone can activate SIRT1 in macrophages, promoting SIRT1 activity. This activation inhibited the NF-κB signaling pathway primarily through the dephosphorylation and deacetylation of p65. Simultaneously, taraxerone disrupted the NLRP3 inflammasome signaling pathway, thereby alleviating M1 polarization of macrophages and mitigating sepsis-induced pulmonary inflammation and oxidative stress. In vivo, EX527 was used to validate the anti-inflammatory and anti-oxidative stress effects of taraxerone mediated by SIRT1.

CONCLUSION

SIRT1-mediated anti-inflammatory and anti-oxidative stress effects may be important targets for taraxerone in treating ALI.

摘要

背景

急性肺损伤（ALI）是与脓毒症相关的最致命疾病，且缺乏有效的药物治疗。作为脓毒症诱导的ALI的主要细胞，巨噬细胞向促炎M1表型极化，并通过核因子κB（NF-κB）和含NLR家族吡咯结构域3（NLRP3）炎性小体信号通路分泌多种炎性细胞因子，加速疾病进程。中药垂盆草的主要成分蒲公英赛酮具有多种生物学活性。然而，蒲公英赛酮对脓毒症诱导的ALI的保护潜力仍存在不确定性。本研究旨在探讨蒲公英赛酮对ALI的作用及其机制。

方法

通过盲肠结扎和穿刺建立ALI动物模型，并通过腹腔注射给予蒲公英赛酮进行治疗。使用苏木精-伊红染色、二氢乙锭染色、酶联免疫吸附测定试剂盒、细胞计数、髓过氧化物酶试剂盒、丙二醛试剂盒、谷胱甘肽试剂盒、超氧化物歧化酶试剂盒和流式细胞术分析蒲公英赛酮对肺的保护作用。采用蛋白质免疫印迹法、逆转录-聚合酶链反应、流式细胞术、免疫共沉淀和免疫荧光法研究蒲公英赛酮对沉默信息调节因子1（SIRT1）的调控作用。

结果

我们的研究首次证明蒲公英赛酮可激活巨噬细胞中的SIRT1，促进SIRT1活性。这种激活主要通过p65的去磷酸化和去乙酰化抑制NF-κB信号通路。同时，蒲公英赛酮破坏NLRP3炎性小体信号通路，从而减轻巨噬细胞的M1极化，减轻脓毒症诱导的肺部炎症和氧化应激。在体内，使用EX527验证SIRT1介导的蒲公英赛酮的抗炎和抗氧化应激作用。