Protective effect of 7,3′,4′-flavon-3-ol (fisetin) on acetaminophen-induced hepatotoxicity in vitro and in vivo

Oxidative Medicine and Cellular Longevity

et al. 2020

Acetaminophen (APAP) toxicity leads to severe acute liver injury (ALI) by inducing excessive oxidative stress, inflammatory response, and hepatocyte apoptosis. Imperatorin (IMP) is a furanocoumarin from Angelica dahurica, which has antioxidant and anti-inflammatory effects. However, its potential to ameliorate ALI is unknown. In this study, APAP-treated genetic knockout of Farnesoid X receptor (FXR) and Sirtuin 1 (SIRT1) mice were used for research. The results revealed that IMP could improve the severity of liver injury and inhibit the increase of proinflammatory cytokines, oxidative damage, and apoptosis induced by overdose APAP in an FXR-dependent manner. We also found that IMP enhanced the activation and translocation of FXR by increasing the expression of SIRT1 and the phosphorylation of AMPK. Besides, single administration of IMP at 4 h after APAP injection can also improve necrotic areas and serum transaminase, indicating that IMP have both preventive and therapeutic effects. Taken together, it is the first time to demonstrate that IMP exerts protective effects against APAP overdose-induced hepatotoxicity by stimulating the SIRT1-FXR pathway. These findings suggest that IMP is a potential therapeutic candidate for ALI, offering promise for the treatment of hepatotoxicity associated with APAP overdose.

mentioning

confidence: 58%

The Protective Effects of Imperatorin on Acetaminophen Overdose-Induced Acute Liver Injury

Gao

Oxidative Medicine and Cellular Longevity

et al. 2020

“…ROS in cells was measured using an H2DCFDA probe as described previously (Zhao et al, 2019). To measure ROS levels in the liver, cold liver homogenate was centrifuged (10,000 g, 15 min, 4°C); supernatants were incubated with 10 μM H 2 DCFDA in the dark for 1 h and subsequently transferred to a black-walled clear-bottomed 96-well plate.…”

Section: Measurement Of Reactive Oxygen Species In the Liver And Cellsmentioning

confidence: 99%

“…Apigenin (API) or versulin (4′,5,7-trihydroxyflavone) is a natural flavonoid derived from Matricaria chamomilla with high antioxidant capacity. Previous studies have revealed that flavonoids can protect against different types of hepatopathy through anti-inflammatory and antioxidant mechanisms, especially hepatopathy that is associated with AP-induced liver damage (Jing et al, 2018;Shi et al, 2018;Zhao et al, 2019). In addition, previous studies have demonstrated that API can protect against various liver injuries caused by alcohol (Wang et al, 2017), lipopolysaccharides (Zhou et al, 2017), and ischemia/reperfusion (Tsaroucha et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Apigenin Attenuates Acetaminophen-Induced Hepatotoxicity by Activating AMP-Activated Protein Kinase/Carnitine Palmitoyltransferase I Pathway

Liang

et al. 2020

Front. Pharmacol.

Self Cite

Overuse of acetaminophen (APAP) is a major cause of drug-induced liver failure at the clinics. Apigenin (API) is a natural flavonoid derived from Matricaria chamomilla. The aim of the present study was to investigate the amelioration function of API in APAP-induced hepatotoxicity both in vitro and in vivo and investigate its potential mechanisms. Analysis results of the activities of serum alanine and aspartate aminotransferases (ALT and AST), malondialdehyde, myeloperoxidase (MPO), and reactive oxygen species (ROS) demonstrated therapeutic effects of API. MTT assay results revealed that API attenuated APAP and its metabolic product, N-acetyl-p-benzoquinone imine (NAPQI) induced cytotoxicity in a dose-dependent manner in human liver cells, L-02 cells. Subsequently, metabolomic results of cells and serum analyses demonstrated an aberrant level of carnitine palmitoyltransferase I (CPT1A). We established that API stimulated CPT1A activity in mice liver tissues and L-02 cells. Molecular docking analyses revealed potential interaction of API with CPT1A. Further investigation of the role of CPT1A in L0-2 cells revealed that API reversed cytotoxicity via the AMP-activated protein kinase (AMPK)/GSK-3β signaling pathway and compound C, which is a selective AMPK inhibitor, inhibited activation of CPT1A induced by API. API was bound to the catalytic region of AMPK as indicated by molecular docking results. In addition, compound C suppressed nuclear translocation of nuclear factor erythroid 2–related factor 2 (NRF2) that is enhanced by API and inhibited the antioxidative function of API. In summary, the study demonstrates that API attenuates APAP-induced hepatotoxicity by activating the AMPK/GSK-3β signaling pathway, which subsequently promotes CPT1A activity and activates the NRF2 antioxidant pathway.

“…4',5,7-trihydroxyflavone (Apigenin, API, Versulin) is a wellknown flavonoid isolated from Matricaria chamomilla. In our previous research, we found that flavonoids can protect against various liver diseases, especially acetaminophen-induced liver damage, via anti-oxidation and anti-inflammatory mechanisms (Jing et al, 2018;Shi et al, 2018;Zhao et al, 2019). API can protect against various liver injuries caused by alcohol (Wang et al, 2017), lipopolysaccharide (Zhou et al, 2017), ischemia/ reperfusion (Tsaroucha et al, 2016), and CCl 4 (Simeonova et al, 2014).…”

Section: Introductionmentioning

confidence: 98%

Apigenin Prevents Acetaminophen-Induced Liver Injury by Activating the SIRT1 Pathway

Zhao

et al. 2020

Front. Pharmacol.

Self Cite

Acetaminophen (APAP) overdose is the main cause of acute liver failure. Apigenin (API) is a natural dietary flavonol with high antioxidant capacity. Herein, we investigated protection by API against APAP-induced liver injury in mice, and explored the potential mechanism. Cell viability assays and mice were used to evaluate the effects of API against APAPinduced liver injury. Western blotting, immunofluorescence staining, RT-PCR, and Transmission Electron Microscope were carried out to determine the signalling pathways affected by API. Analysis of mouse serum levels of alanine/aspartate aminotransferase (ALT/AST), malondialdehyde (MDA), liver myeloperoxidase (MPO) activity, glutathione (GSH), and reactive oxygen species (ROS) revealed that API (80 mg/kg) owned protective effect on APAP-induced liver injury. Meanwhile, API ameliorated the decreased cell viability in L-02 cells incubated by APAP with a dose dependent. Furthermore, API promoted SIRT1 expression and deacetylated p53. Western blotting showed that API promoted APAP-induced autophagy, activated the NRF2 pathway, and inhibited the transcriptional activation of nuclear p65 in the presence of APAP. Furthermore, SIRT1 inhibitor EX-527 reduced protection by API against APAP-induced hepatotoxicity. Molecular docking results indicate potential interaction between API and SIRT1. API prevents APAP-induced liver injury by regulating the SIRT1-p53 axis, thereby promoting APAP-induced autophagy and ameliorating APAP-induced inflammatory responses and oxidative stress injury.