Du Zhenhua, Zhang Shuhui, Lin Yukun, Zhou Lin, Wang Yuehua, Yan Guixi, Zhang Mengdi, Wang Mengqi, Li Jiahuan, Tong Qiaozhen, Duan Yongjian, Du Gangjun
Institute of Pharmacy, College of Pharmacy, Henan University, Kaifeng, China.
College of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.
Front Pharmacol. 2019 Mar 29;10:321. doi: 10.3389/fphar.2019.00321. eCollection 2019.
Momordicoside G is a bioactive component from , this study explores the contributions of macrophages to the effects of momordicoside G on lung injury and carcinoma lesion. , when administered at the dose that has no effect on cell viability in M2-like macrophages, momordicoside G decreased ROS and promoted autophagy and thus induced apoptosis in M1-like macrophages with the morphological changes. In the urethane-induced lung carcinogenic model, prior to lung carcinoma lesions, urethane induced obvious lung injury accompanied by the increased macrophage infiltration. The lung carcinoma lesions were positively correlated with lung tissue injury and macrophage infiltration in alveolar cavities in the control group, these macrophages showed mainly a M1-like (iNOS/CD68) phenotype. ELISA showed that the levels of IL-6 and IL-12 were increased and the levels of IL-10 and TGF-β1 were reduced in the control group. After momordicoside G treatment, lung tissue injury and carcinoma lesions were ameliorated with the decreased M1-like macrophages and the increased M2-like (arginase/CD68) macrophages, whereas macrophage depletion by liposome-encapsulated clodronate (LEC) decreased significantly lung tissue injury and carcinoma lesions and also attenuated the protective efficacy of momordicoside G. The M2 macrophage dependent efficacy of momordicoside G was confirmed in a LPS-induced lung injury model in which epithelial closure was promoted by the transfer of M2-like macrophages and delayed by the transfer of M1-like macrophages. To acquire further insight into the underlying molecular mechanisms by which momordicoside G regulates M1 macrophages, we conduct a comprehensive bioinformatics analysis of momordicoside G relevant targets and pathways involved in M1 macrophage phenotype. This study suggests a function of momordicoside G, whereby it selectively suppresses M1 macrophages to stimulate M2-associated lung injury repair and prevent inflammation-associated lung carcinoma lesions.
苦瓜苷G是一种来自[具体来源未提及]的生物活性成分，本研究探讨巨噬细胞对苦瓜苷G对肺损伤和癌病变影响的作用。当以对M2样巨噬细胞的细胞活力无影响的剂量给药时，苦瓜苷G可降低活性氧（ROS）并促进自噬，从而在具有形态学变化的M1样巨噬细胞中诱导凋亡。在氨基甲酸乙酯诱导的肺癌模型中，在肺癌病变出现之前，氨基甲酸乙酯诱导明显的肺损伤，并伴有巨噬细胞浸润增加。对照组中，肺癌病变与肺组织损伤以及肺泡腔内巨噬细胞浸润呈正相关，这些巨噬细胞主要表现为M1样（诱导型一氧化氮合酶/iNOS/CD68）表型。酶联免疫吸附测定（ELISA）显示，对照组中白细胞介素-6（IL-6）和白细胞介素-12（IL-12）水平升高，白细胞介素-10（IL-10）和转化生长因子-β1（TGF-β1）水平降低。苦瓜苷G治疗后，肺组织损伤和癌病变得到改善，M1样巨噬细胞减少，M2样（精氨酸酶/CD68）巨噬细胞增加，而脂质体包裹的氯膦酸盐（LEC）清除巨噬细胞可显著降低肺组织损伤和癌病变，同时也削弱了苦瓜苷G的保护作用。在脂多糖（LPS）诱导的肺损伤模型中证实了苦瓜苷G对M2巨噬细胞的依赖性作用，其中M2样巨噬细胞的转移促进上皮闭合，而M1样巨噬细胞的转移则延迟上皮闭合。为了进一步深入了解苦瓜苷G调节M1巨噬细胞的潜在分子机制，我们对与M1巨噬细胞表型相关的苦瓜苷G靶点和途径进行了全面的生物信息学分析。本研究表明了苦瓜苷G的一种功能，即它选择性地抑制M1巨噬细胞，以刺激与M2相关的肺损伤修复并预防与炎症相关的肺癌病变。
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