Luo Weixu, Han Yuanshan, Meng Pan, Yang Qin, Zhao Hongqing, Ling Jia, Wang Yuhong
Institute of Innovation and Applied Research in Chinese Medicine, Hunan University of Chinese Medicine, Changsha, Hunan, People's Republic of China.
Medical Experimental Innovation Center, The First Affiliated Hospital, Hunan University of Chinese Medicine, Changsha, Hunan, People's Republic of China.
Cancer Manag Res. 2020 Dec 18;12:13003-13014. doi: 10.2147/CMAR.S279800. eCollection 2020.
Breast cancer is one of the most common cancer with high risk in females all over the world. It is usually complicated with depression, which can further accelerate the development and progression of breast tumors. We aim to identify a new drug and identify its functional mechanism in the regulation of hippocampal microglia (MG) in breast cancer complicated with depression (BCCD).
The activation model of MG was established by treatments from corticosterone (CORT) or lipopolysaccharides (LPS). The inhibitory effects of resatorvid on MG were investigated by CCK-8, ROS, immunofluorescence, TUNEL, scratch test, ELISA, RT-qPCR and Western blot. BCCD animal model was established using 4T1 inflammatory breast cancer cells and CORT treatment in vitro. Open field experiment (OFE), tail suspension test (TST), ELISA, RT-qPCR and Western blot experiments were utilized to examine the effects of resatorvid on the animal model in vivo.
The cell viability and migration ability of the BCCD model group were suppressed. The expressions of inflammatory factors, ROS, and the apoptotic rate of the BCCD model group were up-regulated, in contrast to the control group. The expressions related to the TLR4/NF-κB/NLRP3 signaling in the BCCD model group were also elevated. Resatorvid reversed the above changes, which showed good therapeutic effects in depression-related behavioral changes, tumor treatment, and blood-brain barrier function.
In summary, resatorvid inhibited the activation of hippocampal MG in BCCD by regulating TLR4/NF-κB/NLRP3 signaling pathway.
乳腺癌是全球女性中最常见的高风险癌症之一。它通常并发抑郁症，这会进一步加速乳腺肿瘤的发展和进展。我们旨在鉴定一种新药，并确定其在调节乳腺癌合并抑郁症（BCCD）中海马小胶质细胞（MG）方面的功能机制。
通过皮质酮（CORT）或脂多糖（LPS）处理建立MG激活模型。通过CCK-8、ROS、免疫荧光、TUNEL、划痕试验、ELISA、RT-qPCR和蛋白质免疫印迹法研究瑞斯托霉素对MG的抑制作用。使用4T1炎性乳腺癌细胞和体外CORT处理建立BCCD动物模型。利用旷场实验（OFE）、尾悬架试验（TST）、ELISA、RT-qPCR和蛋白质免疫印迹实验检测瑞斯托霉素对体内动物模型的影响。
BCCD模型组的细胞活力和迁移能力受到抑制。与对照组相比，BCCD模型组的炎症因子、ROS表达及凋亡率上调。BCCD模型组中与TLR4/NF-κB/NLRP3信号传导相关的表达也升高。瑞斯托霉素逆转了上述变化，在抑郁相关行为改变、肿瘤治疗和血脑屏障功能方面显示出良好的治疗效果。
综上所述，瑞斯托霉素通过调节TLR4/NF-κB/NLRP3信号通路抑制BCCD中海马MG的激活。
