Sanghuangporus sanghuang Mycelium Prevents Paracetamol-Induced Hepatotoxicity through Regulating the MAPK/NF-κB, Keap1/Nrf2/HO-1, TLR4/PI3K/Akt, and CaMKKβ/LKB1/AMPK Pathways and Suppressing Oxidative Stress and Inflammation.

Wen-Ping Jiang,Hui-Yi Lin,Shyh-Shyun Huang,Sheng-Hua Wu,Jung-Chun Liao,Chin-Chu Chen,Guan-Jhong Huang,Jeng-Shyan Deng,Hung-Yi Chen

doi:10.3390/antiox10060897

Abstract

Liver damage induced by paracetamol overdose is the main cause of acute liver failure worldwide. In order to study the hepatoprotective effect of Sanghuangporus sanghuang mycelium (SS) on paracetamol-induced liver injury, SS was administered orally every day for 6 days in mice before paracetamol treatment. SS decreased serum aminotransferase activities and the lipid profiles, protecting against paracetamol hepatotoxicity in mice. Furthermore, SS inhibited the lipid peroxidation marker malondialdehyde (MDA), hepatic cytochrome P450 2E1 (CYP2E1), and the histopathological changes in the liver and decreased inflammatory activity by inhibiting the production of proinflammatory cytokines in paracetamol-induced acute liver failure. Moreover, SS improved the levels of glutathione (GSH), superoxide dismutase (SOD), glutathione peroxidase (GPx), and catalase in the liver. Significantly, SS diminished mitogen-activated protein kinase (MAPK), Toll-like receptor 4 (TLR4), phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt), and the nuclear factor-kappa B (NF-κB) axis, as well as upregulated the Kelch-like ECH-associated protein 1 (Keap1)/erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway, in paracetamol-induced mice. SS mainly inhibited the phosphorylation of the liver kinase B1 (LKB1), Ca2+/calmodulin-dependent kinase kinase β (CaMKKβ), and AMP-activated protein kinase (AMPK) protein expression. Furthermore, the protective effects of SS on paracetamol-induced hepatotoxicity were abolished by compound C, an AMPK inhibitor. In summary, we provide novel molecular evidence that SS protects liver cells from paracetamol-induced hepatotoxicity by inhibiting oxidative stress and inflammation.

Highlights

Primary antibodies for Western blotting against the proteins COX-2, p-JNK, catalase, glutathione peroxidase (GPx), superoxide dismutase (SOD), cytochrome P450 2E1 (CYP2E1), AMPK, liver kinase B1 (LKB1), calmodulin-dependent kinase kinase β (CaMKKβ), p-AMPK, p-LKB1, and p-CaMKKβ were purchased from GeneTex (San Antonio, TX, USA)
Sanghuangporus sanghuang mycelium (SS) and NAC significantly inhibited the increase in the serum AST, ALT, and lipid markers; these results demonstrate that SS prevented the paracetamol-induced liver toxicity
SS and NAC significantly inhibited the increase in the serum AST, ALT, and lipid of 19 toxmarkers; these results demonstrate that SS prevented the paracetamol-induced6liver icity

Summary

Introduction

Paracetamol (N-acetyl-p-aminophenol), known as acetaminophen, is the most common drug used to treat pain and fever, and is considered safe at the recommended creativecommons.org/licenses/by/ 4.0/). 150 mg/kg (or 12 g for the average person) is a toxic dose for adults and confers a high risk of liver damage, which may cause acute liver failure and even death. The toxicity induced by paracetamol is triggered by the formation of a metabolite, N-acetyl-p-benzoquinoneimine (NAPQI), which is catalyzed by cytochrome P450 CYP2E1, an enzyme whose excessive activity can cause liver damage by depleting glutathione (GSH) [3,4]. When GSH is depleted, the NAPQI formed reacts with cellular proteins and induces oxidative stress, leading to the necrosis of hepatocytes [4].

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