An active marine halophenol derivative attenuates lipopolysaccharide-induced acute liver injury in mice by improving M2 macrophage-mediated therapy.
An active marine halophenol derivative attenuates lipopolysaccharide-induced acute liver injury in mice by improving M2 macrophage-mediated therapy.
复制标题
DOI：
10.1016/j.intimp.2021.107676
复制
发表时间：
2021-05
影响因子：
5.6
通讯作者：
Fan Yang;Hong-Hong Cai-Hong;Xuan Zhang;Jian Sun;Xiu E. Feng;Hongxia Yuan;Xiaoyan Zhang;B. Xiao;Qingshan Li
中科院分区：
文献类型：
--
作者：
Fan Yang;Hong-Hong Cai-Hong;Xuan Zhang;Jian Sun;Xiu E. Feng;Hongxia Yuan;Xiaoyan Zhang;B. Xiao;Qingshan Li
2，4 ′，5 ′-三羟基-5，2 ′-二溴二苯甲酮（LM 49）是本课题组合成的一种活性卤代苯酚衍生物，具有抗氧化、抗炎等多种治疗活性。本研究发现，LM 49可通过极化巨噬细胞，明显减轻脂多糖（LPS）诱导的小鼠急性肝损伤。以降低肝脏炎症反应和改善肝功能为指标，采用天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）测定法观察其保护作用。进一步的研究表明，LM 49预处理诱导Kupffer细胞（KCs）向M2极化，并减少炎性细胞因子的产生。在RAW 264.7巨噬细胞中的作用机制表明，LM 49可诱导JAK 1/STAT 6信号通路的激活和TLR-4/NF-kB轴的抑制。此外，LM 49还上调SOCS 1和FLK-4的表达，SOCS 1和FLK-4可通过与STAT 6协同作用促进M2极化，并通过降低JAK 1/STAT 1抑制M1形成。我们的研究结果表明，LM 49可以通过抗炎信号通路和随后的M2 Kupffer细胞诱导来保护小鼠免受LPS诱导的急性肝损伤。该结果为活性卤代酚类化合物通过靶向M2巨噬细胞进行抗炎治疗提供了首次实验证据。
2,4′,5′-Trihydroxyl-5,2′-dibromo diphenylmethanone (LM49), an active halophenol derivative synthesized by our group, which exhibits a broad spectrum of therapeutic properties, such as antioxidant and anti-inflammatory activities. In this study, we found LM49 could obviously attenuate acute liver injury induced by lipopolysaccharide (LPS) in mice by polarizing macrophages. The protective effect was described by reducing the hepatic inflammation and improving hepatic function using aspartate transaminase (AST) and alanine transaminase (ALT) assay. Further study revealed that LM49 pretreatment induced the Kupffer cells (KCs) to M2 polarization and decreased the production of inflammatory cytokines. The action mechanism in RAW 264.7 macrophages showed that LM49 could induce the activation of JAK1/STAT6 signaling pathway and the inhibition of TLR-4/NF-kB axis. Morever, LM49 also upregulated the expression of SOCS1 and FLK-4, which can promote M2 polarization by cooperating with STAT6 and inhibit M1 formation by reducing JAK1/STAT1. Our results suggested that LM49 could protect against LPS-induced acute liver injury in mice via anti-inflammatory signaling pathways and subsequent induction of M2 Kupffer cells. The results provided the first experimental evidence of active halophenols for the anti-inflammatory therapy by targeting M2 macrophages.