Therapeutic Potential of Isorhamnetin following Acetaminophen-Induced Hepatotoxicity through Targeting NLRP3/NF-κB/Nrf2

Abstract

Acetaminophen (APAP)-induced acute liver injury (ALI) is the principal cause of acute liver failure (ALF) in some countries including the United States and with few available treatments. Isorhamnetin is a bioflavonoid that is found in medicinal plants like Hippophae rhamnoides L. and Ginkgo biloba L. with promising potential to regulate inflammatory responses. In this study, we evaluated the possible effect of isorhamnetin in prevention of APAP-induced ALI and analyzed further the involvement of oxidative stress and inflammation-associated factors. Male C57BL/6 mice were given isorhamnetin (25 or 100 mg/kg b.w., p.o.) three times at 48, 24, and 1 h before APAP administration (300 mg/kg b.w., i.p.). Functional indicators of liver injury were measured as well as analysis of oxidative stress- and inflammation-associated indices and liver histopathology was also conducted. Isorhamnetin at the higher dose of 100 mg/kg significantly lowered serum levels of ALT, ALP, and AST in addition to reduction of ROS, TBARS, IL-6, TNFα, NF-kB, NLRP3, caspase 1, and MPO and significantly prevented reduction of GSH, SOD activity, sirtuin 1, and Nrf2. Additionally, isorhamnetin alleviated pathological changes of the liver tissue and suitably reversed NF-kB and Nrf2 immunoreactivity. These findings show protective effect of isorhamnetin against acetaminophen-induced liver injury through reducing oxidative stress, inflammation, and pyroptosis which is attributed to its regulation of NF-kB, Nrf2, NLRP3, and sirtuin 1.

A holistic comparison of flavor signature and chemical profile in different harvesting periods of Chrysanthemum morifolium Ramat. based on metabolomics combined with bioinformatics and molecular docking strategy

“…49 Isorhamnetin may protect the liver by regulating NF-kB, Nrf2, and NLRP3 and reducing oxidative stress, inflammation, and scorch death. 50,51 Additionally, hydroxygenkwanin has also been demonstrated to be active against liver cancer and validates its potential use as a therapeutic agent. 52…”

Role of Pyroptosis in Acetaminophen-Induced Hepatotoxicity

“…Recently, pyroptosis has been suggested to be a relevant cell death pathway in the standard murine model of APAP hepatotoxicity, i.e., 12-24 h after a dose of 300 mg/kg APAP in fasted mice [40][41][42]. Wang et al provided evidence for cleavage of gasdermin D and of caspase-1 along with a minor increase in IL-1β and IL-18 in plasma.…”

“…More recently, 2 additional manuscripts were published with the conclusion that pyroptosis may be a mode of cell death during APAP hepatotoxicity in mice [41,42]. The conclusion was based on only minor (<2-fold) increases in gasdermin-D, caspase-1 and NLRP3 protein expression at the whole liver level [41,42].…”

“…More recently, 2 additional manuscripts were published with the conclusion that pyroptosis may be a mode of cell death during APAP hepatotoxicity in mice [41,42]. The conclusion was based on only minor (<2-fold) increases in gasdermin-D, caspase-1 and NLRP3 protein expression at the whole liver level [41,42]. However, minor changes in protein expression are insufficient to explain extensive cellular necrosis and are certainly not specific for pyroptotic cell death.…”

“…This makes it unlikely that the key mode of cell death caused by APAP is ferroptosis [39]. More recently, it was suggested that the mode of cell death is actually pyroptosis [40][41][42], which raises the question whether there is any stronger evidence to support this newest idea for a mechanism of APAP hepatotoxicity than previously for apoptosis, necroptosis or ferroptosis.…”