Isoorientin Attenuated the Pyroptotic Hepatocyte Damage Induced by Benzo[a]pyrene via ROS/NF-κB/NLRP3/Caspase-1 Signaling Pathway

Abstract

Isoorientin (Iso), a natural bioactive flavonoid, possesses significant anti-tumor and anti-oxidant activities. Benzo[a]pyrene (BaP) is a food processing injurant with carcinogenicity, teratogenicity, and genotoxicity. Our preliminary study demonstrates that Iso attenuated the pyroptotic hepatocyte damage induced by BaP; however, the molecular mechanism remains unknown. The present study showed that Iso reduced the increase caused by BaP in the overflow of LDH, NO, and the electrical conductivity and the protein expressions of GSDMD-N, IL-18, and IL-1β, further showing that Iso could reduced the pyroptotic damage in HL-7702 cells induced by BaP. Caspase-1 inhibitor (Z-VAD-FMK) inhibited the characteristic pyroptosis protein expressions of Caspase-1, GSDMD-N, IL-18, and IL-1β, showing that the classic pyroptosis pathway depending on Caspase-1 was caused by BaP in HL-7702 cells. Consistent with the effects of the NLRP3 inhibitor (MCC950), NF-κB inhibitor (PDTC), ROS, and mtROS inhibitor (NAC and Mito-TEMPO), Iso weakened the stimulatory effects of BaP on the levels of ROS, the nuclear localization of NF-κB, and the activation of NLRP3 inflammasome and the characteristic indices of pyroptosis, demonstrating that Iso could alleviate the BaP-induced pyroptotic hepatocytes injury through inhibiting the ROS/NF-κB/NLRP3/Caspase-1 signaling pathway, which provides a new perspective and strategy to prevent liver injury induced by BaP.

MgIG exerts therapeutic effects on crizotinib‐induced hepatotoxicity by limiting ROS‐mediated autophagy and pyroptosis

“…Phosphorylation and nuclear translocation of P65 are implicated in NLRP3 inflammasome activation and inflammatory response regulation. [17][18][19][20] Our data showed that CRIZO treatment activated P65 in hepatic cells. These results demonstrated that CRIZO triggered hepatocyte pyroptosis via NF-κB/NLRP3/GSDMD pathway.…”

“…As anticipated, CRIZO markedly promoted phosphorylation and nuclear translocation of P65 (Figure 2C,D ), which favoured the formation of NLRP3 inflammasome. 17 , 18 , 19 , 20 …”

“…Mounting evidence has shown that ROS is one of the critical signal molecules of autophagy and pyroptosis. 17 , 48 , 49 , 50 Thus, NAC was used to partially scavenge ROS, and the results showed that ROS downregulation not only inhibited CRIZO‐triggered pyroptosis by preventing NF‐kB activation but also reduced autophagic flux via mTOR activation. This implies that CRIZO damaged the mitochondria leading to increased ROS level, which induced pyroptosis and autophagy to cause hepatotoxicity.…”

Paeoniflorin ameliorates lipopolysaccharide‐induced acute liver injury by inhibiting oxidative stress and inflammation via SIRT1/FOXO1a/SOD2 signaling in rats

“…The activation of NLRP3 is also partially related to damaged mitochondria where the bulk of reactive oxygen species (ROS) is produced (Mangan et al, 2018; Swanson, Deng, & Ting, 2019; Wang et al, 2021). There is accumulating evidence that application of mitochondrial active oxygen scavenger, mito‐TEMPO, can inhibit NLRP3 inflammasome activation (Heid et al, 2013; H. Li et al, 2021), and it has been shown that severe acute pancreatitis is alleviated in NLRP3 −/− mice (Sendler et al, 2020). In addition, Li et al have demonstrated that inhibition of NLRP3 activity can reduce hepatocyte injury (Li et al, 2021).…”

“…There is accumulating evidence that application of mitochondrial active oxygen scavenger, mito‐TEMPO, can inhibit NLRP3 inflammasome activation (Heid et al, 2013; H. Li et al, 2021), and it has been shown that severe acute pancreatitis is alleviated in NLRP3 −/− mice (Sendler et al, 2020). In addition, Li et al have demonstrated that inhibition of NLRP3 activity can reduce hepatocyte injury (Li et al, 2021). Thus, inhibition of NLRP3 inflammasome may be an important therapeutic target for LPS‐induced ALI, but its potential mechanism remains to be explored.…”