Abstract
Inflammation and oxidative stress are essential for the pathogenesis of fulminant hepatic failure (FHF). Asiatic acid (AA), which is a pentacyclic triterpene that widely occurs in various vegetables and fruits, has been reported to possess antioxidant and anti-inflammatory properties. In this study, we investigated the protective effects of AA against lipopolysaccharide (LPS) and d-galactosamine (GalN)-induced FHF and the underlying molecular mechanisms. Our findings suggested that AA treatment effectively protected against LPS/d-GalN-induced FHF by lessening the lethality; decreasing the alanine transaminase and aspartate aminotransferase levels, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α production, malondialdehyde formation, myeloperoxidase level and reactive oxygen species generation (i.e., H2O2, NO, and ), and increasing the glutathione and superoxide dismutase contents. Moreover, AA treatment significantly inhibited mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) signaling pathway activation via the partial induction of programmed cell death 4 (PDCD4) protein expressions, which are involved in inflammatory responses. Furthermore, AA treatment dramatically induced the expression of the glutamate-cysteine ligase modifier subunit, the glutamate-cysteine ligase catalytic subunit, heme oxygenase-1, and NAD (P) H: quinoneoxidoreductase 1 (NQO1), which are largely dependent on activation of the nuclear factor-erythroid 2-related factor 2 (Nrf2) through the induction of AMP-activated protein kinase (AMPK) and glycogen synthase kinase-3β (GSK3β) phosphorylation. Accordingly, AA exhibited protective roles against LPS/d-GalN-induced FHF by inhibiting oxidative stress and inflammation. The underlying mechanism may be associated with the inhibition of MAPK and NF-κB activation via the partial induction of PDCD4 and upregulation of Nrf2 in an AMPK/GSK3β pathway activation-dependent manner.
Highlights
The liver is a vital organ that is vulnerable to multiple factors, including alcohol, chemical substances, oxidative products, and the hepatitis viruses, which lead to hepatic failure [1]
Our results indicated that Asiatic acid (AA) treatment attenuated LPS/d-GalN-induced hepatotoxicity and inhibited inflammatory responses and oxidative stress, which possibly involved in the suppression of mitogen-activated protein kinase (MAPK) and NF-κB activation via the partial induction of programmed cell death-4 (PDCD4) and upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) in an AMPK/glycogen synthase kinase-3β (GSK3β) pathway activationdependent manner
This increase was markedly reduced by AA pretreatment, suggesting that AA treatment efficiently protected against L/D-induced Fulminant hepatic failure (FHF) (Figures 1G,H) (p < 0.01)
Summary
The liver is a vital organ that is vulnerable to multiple factors, including alcohol, chemical substances, oxidative products, and the hepatitis viruses, which lead to hepatic failure [1]. Previous abundant reports have shown that LPS/GalNinduced FHF, which is a type of toxin-induced liver injury, is dependent upon macrophage-derived inflammatory cytokines, such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. These cytokines are regulated by the activation of multiple signaling pathways, including toll-like receptor 4-mediated mitogen-activated protein kinase (MAPK); this pathway includes the c-Jun NH2-terminal kinase (JNK), extracellular signal-regulated kinase (ERK), p38, and nuclear factor-kappa B (NF-κB), which comprise the p50/p65 and the inhibitor of κB (IκB) protein signaling pathways [5, 6]. Our results indicated that AA treatment attenuated LPS/d-GalN-induced hepatotoxicity and inhibited inflammatory responses and oxidative stress, which possibly involved in the suppression of MAPK and NF-κB activation via the partial induction of PDCD4 and upregulation of Nrf in an AMPK/GSK3β pathway activationdependent manner
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