Dihydroquercetin ameliorated acetaminophen-induced hepatic cytotoxicity via activating JAK2/STAT3 pathway and autophagy

Abstract

Acetaminophen (APAP) overdose is currently the leading cause of acute liver disease, but therapeutic treatment strategies are commonly limited. Although dihydroquercetin (DHQ) is an attractive botanical antioxidant, its protective potential for liver disease remains elusive. The present study investigated the protective effects of DHQ against APAP-induced hepatic cytotoxicity. Primary mouse hepatocytes were treated with different concentrations of DHQ followed by APAP administration. Our data showed that DHQ relieved APAP-induced growth inhibition and lactate dehydrogenase (LDH) release in a dose-dependent manner, as well as inhibited APAP-induced necrosis and extracellular signal regulated kinase-c-Jun-N-terminal kinase (ERK-JNK) stress. In addition, reactive oxygen species (ROS) accumulation and mitochondria dysfunction were also reversed by DHQ treatment. Further study revealed that DHQ induced phosphorylation of Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) cascade and thus modulated expression of anti-apoptotic Bcl-2 family proteins. Moreover, DHQ induced autophagy which mediated its protective effects in hepatocytes. The protection was abrogated through pharmacological blockage of autophagy by chloroquine (CQ). These studies demonstrated, for the first time, that DHQ possessed hepatocellular protective effects in the context of APAP-induced cytotoxicity and subsequently revealed that the mechanisms comprised activation of JAK2/STAT3 signaling pathway and autophagy. These altogether highlighted the significant therapeutic potential of this agent during acute liver failure and other types of liver diseases.

Carveol a Naturally-Derived Potent and Emerging Nrf2 Activator Protects Against Acetaminophen-Induced Hepatotoxicity

“…Currently, paracetamol is considered the chief causative agent of acute liver failure due to accidental overdose, which requires a liver transplant in some extreme cases (Gopal et al, 2011;Du et al, 2016). At a high dose, APAP is metabolized to glucuronic acid or sulfate conjugates (Sharma et al, 2016) and is transformed into the pro-reactive cytotoxic intermediate N-acetyl-phenzoquinoneimine (NAPQI), which is responsible for oxidative stress and intracellular glutathione (GSH) depletion (Shah et al, 2014;Hellerbrand et al, 2017;Zai et al, 2018). The covalent binding of NAPQI to mitochondria initiates cascading pathological processes, such as free radical formation and peroxynitrite accumulation, further supplemented by the release of pro-inflammatory cytokines and mediators, all of which collectively exacerbate acute and chronic liver necrosis (Dalaklioglu et al, 2013;Hennig et al, 2018).…”

Network Pharmacology Revealed the mechanism of Platycodon grandiflorum in Lung Cancer Treatment

“…It had a strong anti-proliferation effect on breast cancer, ovarian cancer, cervical cancer cells [35][36][37] . Dihydroquercetin was a botanical antioxidant capable to protect from the damage caused by oxidative [38,39] . Luteolin was also a natural avonoid compound, which possessed antioxidant, antiin ammation and anti-cancer properties.…”

Dissecting pharmacological effects of chloroquine in cancer treatment: interference with inflammatory signaling pathways

“…37,68 Likewise, cells can activate autophagic degradation of proteins as a compensatory mechanism under drug-induced cytotoxic stress. 109 CQ-AMPK synergy can also lead to cancer cell death. 37,103 Endoplasmic reticulum stress otherwise kills the cell by inducing the unfolded protein response, mitochondrial membrane depolarization, and ensuing activation of caspases and degradation of DNA.…”

“…108 In some cases, the combination of CQ and AMPK activators, such as acetaminophen, can lead to side effects, such as liver toxicity. 109 CQ-AMPK synergy can also lead to cancer cell death. 110 Examples include synergy of CQ with the two AMPK activators, the glucose analog 2deoxyglucose in killing prostate cancer cells, and with OSU-53 in killing triple-negative breast cancer cells.…”