Kushenol C Prevents Tert-Butyl Hydroperoxide and Acetaminophen-Induced Liver Injury

Abstract

Sophora flavescens, also known as Kushen, has traditionally been used as a herbal medicine. In the present study we evaluated the ameliorative effects of kushenol C (KC) from S. flavescens against tBHP (tert-Butyl hydroperoxide)-induced oxidative stress in hepatocellular carcinoma (HEPG2) cells and acetaminophen (APAP)-induced hepatotoxicity in mice. KC pretreatment protected the HEPG2 cells against oxidative stress by reducing cell death, apoptosis and reactive oxygen species (ROS) generation. KC pretreatment also upregulated pro-caspase 3 and GSH (glutathione) as well as expression of 8-Oxoguanine DNA Glycosylase (OGG1) in the HEPG2 cells. The mechanism of action was partly related by KC’s activation of Akt (Protein kinase B (PKB)) and Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) in the HepG2 cells. In in vivo investigations, coadministration of mice with KC and APAP significantly attenuated APAP-induced hepatotoxicity and liver damage, as the serum enzymatic activity of aspartate aminotransferase and alanine aminotransferase, as well as liver lipid peroxidation and cleaved caspase 3 expression, were reduced in APAP-treated mice. Coadministration with KC also up-regulated antioxidant enzyme expression and prevented the production of proinflammatory mediators in APAP-treated mice. Taken together, these results showed that KC treatment has potential as a therapeutic agent against liver injury through the suppression of oxidative stress.

Recommendations for the use of the acetaminophen hepatotoxicity model for mechanistic studies and how to avoid common pitfalls

“…Given the central role of mitochondrial dysfunction in APAP-induced cell death, it is critical to specifically assess mitochondrial function. Unfortunately, most studies neglect to evaluate the above-mentioned, well-defined pathways of the APAP pathophysiology and generally omit analysis of mitochondrial function when using the model 93 , 94 . The mere focus on measurement of BAX protein levels rather than its mitochondrial translocation, which is the pathophysiological relevant feature, is another common issue 93 , 95 .…”

“…Unfortunately, most studies neglect to evaluate the above-mentioned, well-defined pathways of the APAP pathophysiology and generally omit analysis of mitochondrial function when using the model 93 , 94 . The mere focus on measurement of BAX protein levels rather than its mitochondrial translocation, which is the pathophysiological relevant feature, is another common issue 93 , 95 . Even studies which purport to evaluate JNK activation merely examine changes in the whole liver rather than a more relevant examination of its mitochondrial translocation 95 .…”

The Preventive Mechanism of Anserine on Tert-Butyl Hydroperoxide-Induced Liver Injury in L-02 Cells via Regulating the Keap1-Nrf2 and JNK-Caspase-3 Signaling Pathways

“…When L-02 cells were treated with 400 µmol/L of TBHP for 4 h, the L-02 cell injury model was successfully established. The results showed that anserine could effectively alleviate L-02 cell injury induced by TBHP, and no significant proliferative effects or toxic side effects were found for treatment with 5–80 mmol/L of anserine in L-02 cells within 12 h. Similarly, Cho BO, et al successfully established a model of TBHP-induced liver injury in HepG2 cells to evaluate the liver injury repair function of kushenol C [ 28 ]. Rutin has also been proven to attenuate oxidative damage induced by TBHP in HepG2 cells [ 29 ].…”

Antioxidant Effects of Irisin in Liver Diseases: Mechanistic Insights

“…Hussein and colleagues found that chlorogenic acid, quercetin, coenzyme Q10, and silymarin reduced hepatic cell death and decreased ROS production [46]. Furthermore, another scientific research reported that Kushenol C reduced cell death by downregulating ROS levels and upregulating antioxidant enzyme expression, giving a more direct evidence that less oxidative stress induced less cell death [47]. Irisin exhibited antioxidant effects by improving abnormal cell death.…”