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

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.

Pilot Study: Nutritional and Preclinical Safety Investigation of Fermented Hispidin-Enriched Sanghuangporus sanghuang Mycelia: A Promising Functional Food Material to Improve Sleep

“…Moreover, loss of Nrf2 function in mouse fibroblasts, hepatocytes and liver can alter circadian gene expression and rhythmicity, which can disrupt normal sleep patterns and impact the timing and length of sleep ( 35 ). According to our previous study, Sanghuangporus sanghuang mycelium can regulate Nrf2-associated pathways and protect liver cells from paracetamol-induced hepatotoxicity by inhibiting oxidative stress ( 36 ). Moreover, the yellow polyphenol pigment hispidin found in Sanghuangporus sanghuang mycelium, was found to enhance the expression of Nrf2 in a dose-dependent manner ( 37 ).…”

The Activation of Nrf2/HO-1 by 8-Epi-7-deoxyloganic Acid Attenuates Inflammatory Symptoms through the Suppression of the MAPK/NF-κB Signaling Cascade in In Vitro and In Vivo Models

“…It has gained interest as a potential novel target for the treatment of inflammatory disorders [ 50 ]. NF-κB must enter the nucleus to boost proinflammatory cytokines transcription and production [ 51 , 52 ]. p65, also called RelA, is the most abundant and important NF-κB transcription factor [ 51 ].…”

“…NF-κB must enter the nucleus to boost proinflammatory cytokines transcription and production [ 51 , 52 ]. p65, also called RelA, is the most abundant and important NF-κB transcription factor [ 51 ]. The activated IκB kinase (IKKα/β) boosts the proteasomal degradation of inhibitor protein κBα (IκBα), resulting in the release of NF-κB, which translocates to the nucleus and induces the expression of target genes [ 32 ].…”

Mesenchymal stromal cells (MSCs) and their exosome in acute liver failure (ALF): a comprehensive review

“…This, in turn, activates c-Jun N-terminal kinase (JNK) through a series of events [ 27 ]. Such activation may support disruption of normal mitochondrial function , which inspires more hepatocyte necrosis and damage associated molecular patterns (DAMPs) [ 28 , 29 ]. DAMPs bring about the activation of hepatic macrophages, resulting in the formation of the inflammasome [ 30 , 31 ].…”