Zhang Mengting, Wu Wanhong, Huang Caoxin, Cai Teng, Zhao Nengjiang, Liu Suhuan, Yang Shuyu
Research Studio of Traditional Chinese Medicine, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, China.
Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, China.
Front Pharmacol. 2022 Apr 6;13:848355. doi: 10.3389/fphar.2022.848355. eCollection 2022.
Chronic stress has been shown to cause liver damage in addition to psychological depression. Besides, drug-induced liver injury is frequently caused by antidepressants. Shuxie-1 decoction (SX-1) is a formula of traditional Chinese medicine commonly used in nourishing liver blood, and relieving depression. However, the underlying molecular mechanism remains unclear. Therefore, this study was designed to explore the effects and mechanisms of SX-1 in treating chronic stress-induced depression as well as liver injury. Chronic unpredictable mild stress (CUMS) was applied to male Wistar rats for 4 weeks, with or without administration of SX-1 at low-dose and high-dose for 6 weeks, using Fluoxetine (Flu) as a positive control. Body weight was monitored once every 2 weeks. In the sixth week, the sugar preference test and open field test were carried out to evaluate the depression status. After that, the serum and liver tissues were collected. The quality control of SX-1 decoctions and drug-containing serum was controlled by UHPLC-QE-MS. The cell viability was measured by Cell Counting Kit-8 (CCK8). Enzyme-linked immunosorbent assay (Elisa), Western Blot and immunohistochemistrical staining was obtained to detect the protein levels in the plasma and the hepatic tissues, respectively. CUMS led to decreased 1) body weight, 2) the preference for sugar water, 3) the desire to explore in open field, and increased serum levels of corticosterone. All these factors were completely reversed by SX-1 treatment. Hematoxylin-eosin staining (HE) showed that SX-1 improved the hepatocyte vacuolization in CUMS treated rats, decreased the serum levels of alanine aminotransferase (ALT) and the deposition of type I collagen (Col I) in hepatocytes as well. CUMS increased the levels of hepatic Interleukin-6 (IL-6), and provoked the activation of Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3), which was abrogated by SX-1 treatment. Cobalt chloride (CoCl) increased the protein expression of IL-6 and p-STAT3 in AML12 cells. Besides, nuclear pyknosis was observed under electron microscope, which were recovered after rat SX serum. SX-1 effectively ameliorated CUMS-induced depression-like behaviors as well as hepatic injuries, probably by the blockade of hepatic IL-6/JAK2/STAT3 signaling.
慢性应激已被证明除了会导致心理抑郁外，还会引起肝损伤。此外，药物性肝损伤常由抗抑郁药引起。舒泄-1汤（SX-1）是一种常用于滋养肝血、缓解抑郁的中药方剂。然而，其潜在的分子机制仍不清楚。因此，本研究旨在探讨SX-1治疗慢性应激诱导的抑郁以及肝损伤的作用和机制。对雄性Wistar大鼠施加慢性不可预测温和应激（CUMS）4周，同时给予低剂量和高剂量的SX-1，持续6周，以氟西汀（Flu）作为阳性对照。每2周监测一次体重。在第6周，进行糖水偏好试验和旷场试验以评估抑郁状态。之后，收集血清和肝组织。通过超高效液相色谱-四极杆-静电场轨道阱高分辨质谱（UHPLC-QE-MS）对SX-1汤和含药血清进行质量控制。通过细胞计数试剂盒-8（CCK8）测定细胞活力。分别采用酶联免疫吸附测定（Elisa）、蛋白质免疫印迹法（Western Blot）和免疫组织化学染色检测血浆和肝组织中的蛋白质水平。CUMS导致：1）体重下降；2）对糖水的偏好降低；3）旷场试验中探索欲望降低，同时血清皮质酮水平升高。而SX-1治疗可使所有这些因素完全逆转。苏木精-伊红染色（HE）显示，SX-1改善了CUMS处理大鼠的肝细胞空泡化，降低了血清丙氨酸氨基转移酶（ALT）水平以及肝细胞中I型胶原蛋白（Col I）的沉积。CUMS增加了肝脏白细胞介素-6（IL-6）水平，并激活了Janus激酶2（JAK2）和信号转导及转录激活因子3（STAT3），而SX-1治疗可消除这种激活。氯化钴（CoCl）增加了AML12细胞中IL-6和磷酸化STAT3的蛋白表达。此外，在电子显微镜下观察到细胞核固缩，而大鼠SX血清处理后可恢复。SX-1可能通过阻断肝脏IL-6/JAK2/STAT3信号通路有效改善CUMS诱导的抑郁样行为以及肝损伤。
