Paeoniflorin Protects against Acetaminophen-Induced Liver Injury in Mice via JNK Signaling Pathway

Abstract

Background: Drug-induced liver injury (DILI), represented by acetaminophen (APAP), is a common cause of acute liver failure in clinics. Paeoniflorin (PF) has been proven to demonstrate a significant hepatoprotective effect. However, it is still unclear whether it can be a potential agent against hepatotoxicity induced by APAP. This study aimed to explore the preventive and therapeutic effects and mechanisms of PF on APAP-induced liver injury. Methods: Different doses of PF (50, 100, and 200 mg/kg) were given to C57BL/6 male mice for five consecutive days. After 12 h of APAP (250 mg/kg i.p.) treatment, blood and liver tissues were collected and isolated for detection. Results: The results showed that the therapeutic effects of PF on APAP mice were presented in the downregulation of the content of serum indices and significantly improved hepatic tissue edema and inflammatory infiltration. Meanwhile, PF reduces the level of the mitochondrial metabolic enzyme. Ulteriorly, it was found that PF has a downregulating effect on the apoptotic reaction and could inhibit the protein expression of CYP2E1/JNK signaling, which in turn reduces the damage of APAP. Conclusion: Our findings showed that PF acted as a protective agent against APAP-induced hepatotoxicity by inhibiting JNK-related signals, suggesting a novel insight into treating APAP-induced liver injury.

Kaempferol sophoroside glucoside mitigates acetaminophen-induced hepatotoxicity: Role of Nrf2/NF-κB and JNK/ASK-1 signaling pathways

“…JNK is regulated by other upstream kinases including ASK-1 [ 11 ] which is activated in response to oxidative and inflammatory stimuli such as ROS or cytokines. Previous reports demonstrated inhibition of ASK1 inhibitor [ 65 ] or JNK phosphorylation [ 2 , 68 ]significantly attenuated APAP hepatotoxicity. Our data indicated that APAP injection markedly elevated the levels of hepatic ASK-1 and JNK.…”

“…In the United States and several other Western countries, APAP toxicity constitutes roughly half of all acute liver failure cases. Till now, NAC (N-acetylcysteine) is the only approved antidote for APAP-induced hepatotoxicity despite its narrow therapeutic window [ [1] , [2] , [3] ].…”

“…Following APAP overdose, the excessive generation of oxidative ROS (reactive oxygen species) and other inflammatory stimuli such as TNF-α can activate ASK-1, leading to JNK and p38 signaling pathways' activation that contributes to ALI [ 11 , 12 ]. P-JNK transfers to the mitochondria and causes the permeability transition pore to open, as well as the loss of the potential of the mitochondrial membrane, further mitochondrial dysfunction and the resultant release of apoptotic factors [ 2 , 13 ].…”

Sesamin Protects against APAP-Induced Acute Liver Injury by Inhibiting Oxidative Stress and Inflammatory Response via Deactivation of HMGB1/TLR4/NFκB Signal in Mice

“…Typically, detoxification of NAPQI involves binding GSH. However, after an overdose of APAP, the formation of NAPQI exceeds the detoxification ability of GSH, hepatotoxicity occurs when 70% of GSH is depleted in animal tests, and it will covalently bind with the protein sulfide group to form the APAP-cysteine protein adduct (APAP-CYS), eventually leads to mitochondrial dysfunction and oxidative stress to induce hepatocyte necrosis [ 13 , 14 ]. Furthermore, the necrotic hepatocytes release a large number of damage-associated molecular patterns (DAMPs), including the protein high-mobility group box 1 (HMGB1) and mitochondria-derived DNA (mtDNA), which then activates innate immunity [ 15 ].…”