Salidroside mediates apoptosis and autophagy inhibition in concanavalin A-induced liver injury

Salidroside (Sal) is a glycoside extract from Rhodiola rosea L. with anti-inflammatory, antioxidant, anticancer and cardioprotective properties. The present study explored the protective effects and the possible mechanisms of Sal on concanavalin A (ConA)-induced liver injury in mice. Balb/C mice were divided into five groups: Normal control (injected with normal saline), ConA (25 mg/kg), Sal (10 mg/kg) +ConA, Sal (20 mg/kg) + ConA (Sal injected 2 h prior to ConA injection) and Sal (20 mg/kg) only. The serum levels of liver enzymes, pro-inflammatory cytokines, and apoptosis- and autophagy-associated marker proteins were determined at 2, 8 and 24 h after ConA injection. LY294002 was further used to verify whether the phosphoinositide 3-kinase (PI3K)/Akt pathway was activated. Primary hepatocytes were isolated to verify the effect of Sal in vitro. The results indicated that Sal was a safe agent to reduce pathological damage and serum liver enzymes in ConA-induced liver injury. Sal suppressed inflammatory reactions in serum and liver tissues, and activated the PI3K/Akt signaling pathway to inhibit apoptosis and autophagy in vivo and in vitro, which could be reversed by LY294002. In conclusion, Sal attenuated ConA-induced liver injury by modulating PI3K/Akt pathway-mediated apoptosis and autophagy in mice.

[1]  Xiaoming Fan,et al.  Quercetin Pretreatment Attenuates Hepatic Ischemia Reperfusion-Induced Apoptosis and Autophagy by Inhibiting ERK/NF-κB Pathway , 2017, Gastroenterology research and practice.

[2]  Xiaoming Fan,et al.  Pretreatment with propylene glycol alginate sodium sulfate ameliorated concanavalin A‐induced liver injury by regulating the PI3K/Akt pathway in mice , 2017, Life sciences.

[3]  Xiaoming Fan,et al.  Salidroside pretreatment attenuates apoptosis and autophagy during hepatic ischemia–reperfusion injury by inhibiting the mitogen-activated protein kinase pathway in mice , 2017, Drug design, development and therapy.

[4]  Fan Wang,et al.  The protective effects of shikonin on hepatic ischemia/reperfusion injury are mediated by the activation of the PI3K/Akt pathway , 2017, Scientific Reports.

[5]  Fan Wang,et al.  15-Deoxy-Δ12,14-prostaglandin J2 alleviates hepatic ischemia-reperfusion injury in mice via inducing antioxidant response and inhibiting apoptosis and autophagy , 2017, Acta Pharmacologica Sinica.

[6]  Xianguang Fan,et al.  Salidroside induces apoptosis and autophagy in human colorectal cancer cells through inhibition of PI3K/Akt/mTOR pathway. , 2016, Oncology reports.

[7]  Zhiming Bai,et al.  Salidroside reduces renal cell carcinoma proliferation by inhibiting JAK2/STAT3 signaling. , 2016, Cancer biomarkers : section A of Disease markers.

[8]  Y. Oo,et al.  Autoimmune Hepatitis: Progress from Global Immunosuppression to Personalised Regulatory T Cell Therapy , 2016, Canadian journal of gastroenterology & hepatology.

[9]  Jiao Feng,et al.  Shikonin Attenuates Concanavalin A-Induced Acute Liver Injury in Mice via Inhibition of the JNK Pathway , 2016, Mediators of inflammation.

[10]  Fan Wang,et al.  15d-PGJ2 alleviates ConA-induced acute liver injury in mice by up-regulating HO-1 and reducing hepatic cell autophagy. , 2016, Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie.

[11]  Hui-fang Wang,et al.  Salidroside alleviates oxidative stress in the liver with non- alcoholic steatohepatitis in rats , 2016, BMC Pharmacology and Toxicology.

[12]  Shengdi Chen,et al.  Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer’s disease models , 2016, Drug design, development and therapy.

[13]  Fan Wang,et al.  Pretreatment with Fucoidan from Fucus vesiculosus Protected against ConA-Induced Acute Liver Injury by Inhibiting Both Intrinsic and Extrinsic Apoptosis , 2016, PloS one.

[14]  A. Palmeri,et al.  Salidroside, a Bioactive Compound of Rhodiola Rosea, Ameliorates Memory and Emotional Behavior in Adult Mice. , 2016, Journal of Alzheimer's disease : JAD.

[15]  Fan Wang,et al.  Epigallocatechin-3-gallate attenuates apoptosis and autophagy in concanavalin A-induced hepatitis by inhibiting BNIP3 , 2016, Drug design, development and therapy.

[16]  E. Yeh,et al.  Autophagy and Apoptotic Crosstalk: Mechanism of Therapeutic Resistance in HER2-Positive Breast Cancer , 2016, Breast cancer : basic and clinical research.

[17]  Xiaoming Fan,et al.  Ghrelin reduces liver impairment in a model of concanavalin A-induced acute hepatitis in mice , 2015, Drug design, development and therapy.

[18]  T. Han,et al.  Salidroside Protects against Cadmium-Induced Hepatotoxicity in Rats via GJIC and MAPK Pathways , 2015, PloS one.

[19]  Fan Wang,et al.  The Protective Effect of Resveratrol on Concanavalin-A-Induced Acute Hepatic Injury in Mice , 2015, Gastroenterology research and practice.

[20]  F. Tacke,et al.  The concanavalin A model of acute hepatitis in mice , 2015, Laboratory animals.

[21]  Fan Wang,et al.  Protective Effects of Astaxanthin on ConA-Induced Autoimmune Hepatitis by the JNK/p-JNK Pathway-Mediated Inhibition of Autophagy and Apoptosis , 2015, PloS one.

[22]  Fan Wang,et al.  Protective Effects of N-Acetylcysteine in Concanavalin A-Induced Hepatitis in Mice , 2015, Mediators of inflammation.

[23]  A. Czaja Targeting Apoptosis in Autoimmune Hepatitis , 2014, Digestive Diseases and Sciences.

[24]  Fan Wang,et al.  Hydrogen Sulfide Ameliorates Ischemia/Reperfusion-Induced Hepatitis by Inhibiting Apoptosis and Autophagy Pathways , 2014, Mediators of inflammation.

[25]  Shanshan Liu,et al.  Salidroside Attenuates Concanavalin A-Induced Hepatitis via Modulating Cytokines Secretion and Lymphocyte Migration in Mice , 2014, Mediators of inflammation.

[26]  Rodrigo Liberal,et al.  Diagnostic criteria of autoimmune hepatitis. , 2014, Autoimmunity reviews.

[27]  P. Panda,et al.  Autophagy and apoptosis: where do they meet? , 2014, Apoptosis.

[28]  J. Yang,et al.  Inhibition of the phosphoinositide 3-kinase pathway decreases innate resistance to lipopolysaccharide toxicity in TLR4 deficient mice , 2014, Journal of Biomedical Science.

[29]  Jianxun Liu,et al.  Pharmacokinetics, Tissue Distribution, and Excretion of Salidroside in Rats , 2013, Planta Medica.

[30]  M. Mulholland,et al.  Peripheral Effects of Nesfatin-1 on Glucose Homeostasis , 2013, PloS one.

[31]  P. Codogno,et al.  Autophagy in the liver. , 2013, Journal of hepatology.

[32]  C. V. van Nieuwkerk,et al.  Auto immune hepatitis. , 2016, World journal of gastroenterology.

[33]  D. Vergani,et al.  Autoimmune hepatitis: a comprehensive review. , 2013, Journal of autoimmunity.

[34]  T. Hung,et al.  Salidroside Improves Behavioral and Histological Outcomes and Reduces Apoptosis via PI3K/Akt Signaling after Experimental Traumatic Brain Injury , 2012, PloS one.

[35]  Udo Albus,et al.  Book Review: Guide for the Care and use of Laboratory Animals , 1998 .

[36]  Man Liu,et al.  Immune mechanisms of Concanavalin A model of autoimmune hepatitis. , 2012, World journal of gastroenterology.

[37]  You-Wen He,et al.  The crosstalk between autophagy and apoptosis: where does this lead? , 2012, Protein & Cell.

[38]  Dan Wu,et al.  Salidroside protects against hydrogen peroxide-induced injury in cardiac H9c2 cells via PI3K-Akt dependent pathway. , 2011, DNA and cell biology.

[39]  P. Vogt,et al.  Phosphorylation of AKT: a Mutational Analysis , 2011, Oncotarget.

[40]  Matthew Greenwood,et al.  Anti-apoptosis and cell survival: a review. , 2011, Biochimica et biophysica acta.

[41]  C. Kilkenny,et al.  Guidelines for reporting experiments involving animals: the ARRIVE guidelines , 2010, British journal of pharmacology.

[42]  Shuifeng Qiu,et al.  Salidroside induces cell-cycle arrest and apoptosis in human breast cancer cells. , 2010, Biochemical and biophysical research communications.

[43]  S. Kaveri,et al.  Control of T Cell Reactivation by Regulatory Qa-1–Restricted CD8+ T Cells , 2010, The Journal of Immunology.

[44]  Shuifeng Qiu,et al.  A preliminary study: the anti-proliferation effect of salidroside on different human cancer cell lines , 2010, Cell Biology and Toxicology.

[45]  G. Du,et al.  Protective effects of salidroside on endothelial cell apoptosis induced by cobalt chloride. , 2009, Biological & pharmaceutical bulletin.

[46]  J. Nan,et al.  Protective effects of salidroside against acetaminophen-induced toxicity in mice. , 2008, Biological & pharmaceutical bulletin.

[47]  L. Mattioli,et al.  Adaptogenic and central nervous system effects of single doses of 3% rosavin and 1% salidroside Rhodiola rosea L. extract in mice , 2007, Phytotherapy research : PTR.

[48]  Joo‐Hang Kim,et al.  Essential Roles of Atg5 and FADD in Autophagic Cell Death , 2005, Journal of Biological Chemistry.

[49]  C. Lehr,et al.  Lectin-mediated drug targeting: history and applications. , 2004, Advanced drug delivery reviews.

[50]  F. Brancati,et al.  The prevalence and etiology of elevated aminotransferase levels in the United States , 2003, American Journal of Gastroenterology.

[51]  R. Simon,et al.  Activation of Bcl-2-Associated Death Protein and Counter-Response of Akt within Cell Populations during Seizure-Induced Neuronal Death , 2002, The Journal of Neuroscience.

[52]  E. Henson,et al.  Epidermal growth factor protects epithelial-derived cells from tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis by inhibiting cytochrome c release. , 2002, Cancer research.

[53]  Thomas D. Schmittgen,et al.  Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. , 2001, Methods.

[54]  G. Mills,et al.  In vivo and in vitro ovarian carcinoma growth inhibition by a phosphatidylinositol 3-kinase inhibitor (LY294002). , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[55]  John Calvin Reed,et al.  Regulation of cell death protease caspase-9 by phosphorylation. , 1998, Science.

[56]  M. Leist,et al.  Concanavalin A—induced T‐cell—mediated hepatic injury in mice: The role of tumor necrosis factor , 1995, Hepatology.

[57]  A. Wendel,et al.  A T cell-dependent experimental liver injury in mice inducible by concanavalin A. , 1992, The Journal of clinical investigation.