Yu Lu, Liu Zhili, He Wendi, Chen Huifen, Lai Zelin, Duan Yanhong, Cao Xiaohua, Tao Jie, Xu Chuan, Zhang Qiujuan, Zhao Zheng, Zhang Jun
Comprehensive Department of Traditional Chinese Medicine, Putuo Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200062, China.
Key Laboratory of Brain Functional Genomics (East China Normal University), Ministry of Education, School of Life Sciences, East China Normal University, Shanghai, 200062, China.
Cell Mol Neurobiol. 2020 Nov;40(8):1271-1281. doi: 10.1007/s10571-020-00812-7. Epub 2020 Feb 14.
Natural bioactive compounds have increasingly proved to be promising in evidence- or target-directed treatment or modification of a spectrum of diseases including cerebral ischemic stroke. Hydroxysafflor yellow A (HSYA), a major active component of the safflower plant, has drawn more interests in recent year for its multiple pharmacological actions in the treatment of cerebrovascular and cardiovascular diseases. Although the Janus kinase signaling, such as JAK2/STAT3 pathway, has been implicated in the modulation of the disease, the inhibition or activation of the pathway that contributed to the neuronal prevention from ischemic damages remains controversial. In this study, a series of experiments were performed to examine the dose- and therapeutic time window-related pharmacological efficacies of HSYA with emphasis on the HSYA-modulated interaction of JAK2/STAT3 and SOCS3 signaling in the MCAO rats. We found that HSYA treatment significantly rescued the neurological and functional deficits in a dose-dependent manner in the MCAO rats within 3 h after ischemia. HSYA treatment with a dosage of 8 mg/kg or higher markedly downregulated the expression of the JAK2-mediated signaling that was activated in response to ischemic insult, while it also promoted the expression of SOCS3 coordinately. In the subsequent experiments with the use of the JAK2 inhibitor WP1066, we found that the treatment of WP1066 alone or combination of WP1066/HSYA all exhibited inhibitory effects on JAK2-mediated signaling, while there was no influence on the SOCS3 activity of corresponding efficacious data in the MCAO rats, suggesting that excessive activation of JAK2/STAT3 might be necessary for HSYA to provoke SOCS3-negative feedback signaling. Taking together, our study demonstrates that HSYA might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways that eventually contributed to its therapeutic roles against cerebral ischemic stroke.
天然生物活性化合物已越来越多地被证明在包括脑缺血性中风在内的一系列疾病的循证或靶向治疗或改善方面具有广阔前景。羟基红花黄色素A（HSYA）是红花植物的主要活性成分，近年来因其在治疗脑血管和心血管疾病中的多种药理作用而备受关注。尽管Janus激酶信号通路，如JAK2/STAT3通路，已被认为与疾病的调节有关，但该通路的抑制或激活对神经元缺血损伤的预防作用仍存在争议。在本研究中，我们进行了一系列实验，以研究HSYA的剂量和治疗时间窗相关的药理作用，重点关注HSYA在大脑中动脉闭塞（MCAO）大鼠中调节JAK2/STAT3和SOCS3信号的相互作用。我们发现，HSYA治疗能在缺血后3小时内以剂量依赖的方式显著改善MCAO大鼠的神经功能缺损。8mg/kg及以上剂量的HSYA治疗可显著下调缺血损伤后激活的JAK2介导的信号表达，同时也协同促进SOCS3的表达。在随后使用JAK2抑制剂WP1066的实验中，我们发现单独使用WP1066或WP1066与HSYA联合治疗均对JAK2介导的信号有抑制作用，但对MCAO大鼠相应有效数据的SOCS3活性无影响，这表明JAK2/STAT3的过度激活可能是HSYA引发SOCS3负反馈信号所必需的。综上所述，我们的研究表明，HSYA可能调节JAK2/STAT3和SOCS3信号通路之间的相互作用，最终促成其对脑缺血性中风的治疗作用。
