Shuxie-1 Decoction Alleviated CUMS -Induced Liver Injury via IL-6/JAK2/STAT3 Signaling

Abstract

Introduction: 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.Methods: 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.Results: 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 (CoCl2) 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.Conclusion: 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.

18β-Glycyrrhetinic Acid Ameliorates Neuroinflammation Linked Depressive Behavior Instigated by Chronic Unpredictable Mild Stress via Triggering BDNF/TrkB Signaling Pathway in Rats

“…In our study, a 1-week therapy with 18βGA (50 mg/kg) significantly diminished the concentration of hepatic enzymes ALT, AST, and ALP increased by chronic stress, proving that 18βGA may also repair hepatic damage. Our findings corroborate earlier studies on hepatic enzyme increase during CUMS [ 46 , 81 , 82 ]. Therefore, depression might be connected to liver damage, and that 18βGA can alleviate depressive-like behavior by suppressing the liver-brain inflammatory axis.…”

“…To investigate the relationship between 18βGA and stress level, its effects on CORT and ACTH levels were investigated in CUMS animals. Increasing evidence also suggests that stress may harm the liver in addition to causing mental changes, with oxidative stress and inflammation possibly playing a role [ 46 ]. To comprehend the connection between chronic stress, neuroinflammation, and altered liver indicators, we also examined how CUMS altered liver enzymes and how 18βGA impacted the altered liver markers.…”

Shu-Xie decoction alleviates oxidative stress and colon injury in acute sleep-deprived mice by suppressing p62/KEAP1/NRF2/HO1/NQO1 signaling

“…SX contains promising drug candidates that may prevent and treat colitis and reduce inflammation-related gastrointestinal dysfunction, such as Salvia miltiorrhiza ( Wen et al, 2013 ). In this study, we investigated the affinity of SX-major active components, baicalin (BAI) and paeoniflorin (PAE) ( Zhang et al, 2022 ), and oxidative stress response proteins using molecular docking techniques. Our results demonstrated high affinity binding between SX-related components such as BAI and PAE and the antioxidant response proteins, NQO1, HO1, p62, NRF2, and KEAP1.…”

“…Shu-Xie Decoction (SX) is an herbal formula developed by Dr. Shuyu Yang and colleagues using a combination of Suanzaoren Decoction and Huanglian Jiedu Decoction, also called Yangxue Rougan decoction. The quality and composition of the SX decoction was confirmed by UHPLC-QE-MS ( Zhang et al, 2022 ). SX is used in the First Affiliated Hospital of Xiamen University (Xiamen, China) for the management of diabetic patients with sleep disturbances, mood disorders, and gastrointestinal dysfunction, which are collectively referred to as a triad of ‘Shu-Xie.’ A previous study reported that SX suppresses inflammation and depression in mice ( Zhang et al, 2022 ).…”

“…The quality and composition of the SX decoction was confirmed by UHPLC-QE-MS ( Zhang et al, 2022 ). SX is used in the First Affiliated Hospital of Xiamen University (Xiamen, China) for the management of diabetic patients with sleep disturbances, mood disorders, and gastrointestinal dysfunction, which are collectively referred to as a triad of ‘Shu-Xie.’ A previous study reported that SX suppresses inflammation and depression in mice ( Zhang et al, 2022 ). However, the underlying mechanisms by which SX protects against SD-induced colon dysfunction are poorly understood.…”