Asiatic acid ameliorates CC l₄-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways

Abstract

PurposeCurrently, there are no effective therapies for liver fibrosis; hence, the development of anti-liver fibrosis agents is urgently needed. Here, we attempted to investigate the therapeutic effect and mechanism of asiatic acid (AA) on liver fibrosis, mainly focusing on the impact of AA on nuclear erythroid 2-related factor 2/antioxidant response element (Nrf2/ARE), nuclear factor-kappa B (NF-κB)/IκBα, and JAK1/signal transducer and activator of transcription 3 (STAT3) signaling pathways.MethodsRats were induced liver fibrosis by carbon tetrachloride (CCl4) for 6 weeks and concomitantly treated with AA (5 and 15 mg/kg) or vehicle by daily gavage. After AA treatment, the morphology of liver tissue was analyzed by H&E and Masson’s trichrome staining, and serum biochemical indicators were also assayed. Thereafter, the protein levels of Nrf2, HO-1, NQO-1, GCLC, NF-κB, IκBα, JAK1, p-JAK1, STAT3, and p-STAT3 were determined by Western blotting.ResultsOur results showed that AA treatment dramatically ameliorated CCl4-induced oxidative stress, inflammation, and fibrosis in rats. The expression of nuclear Nrf2 was increased after AA treatment, whereas cytoplasm Nrf2 levels were decreased. The protein expression of Nrf2 target proteins including HO-1, NQO-1, and GCLC was significantly increased by AA treatment. Furthermore, AA treatment decreased the levels of nuclear NF-κB to inhibit NF-κB/IκBα signaling pathway. In addition, we also found that AA treatment regulated JAK1/STAT3 signaling by decreasing the phosphorylation levels of JAK1 and STAT3.ConclusionThese results demonstrate that AA ameliorates CCl4-induced liver fibrosis in rats by regulating Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways, which suggests that AA might be a new antifibrosis agent that improves liver fibrosis.

Metabolomics combined with network pharmacology exploration reveals the modulatory properties of Astragali Radix extract in the treatment of liver fibrosis

“…This study confirmed the advantages of AR in the treatment of liver fibrosis with multiple targets and multiple pathways. In addition, it has been reported that Asiatic acid can ameliorate CCl 4 -induced liver fibrosis in rats by regulating PI3K/AKT/mTOR, Bcl-2/Bax, Nrf2/ARE, NF-κB/IκBα and JAK1/STAT3 signaling pathways [47, 48]. Salvia miltiorrhiza could inhibit liver fibrosis by regulating TGF-β/Smad, Nrf2/HO-1 and NF-κB/IκBα signaling pathways [49, 50].…”

Hepatoprotective activity of raspberry ketone is mediated via inhibition of the NF-κB/TNF-α/caspase axis and mitochondrial apoptosis in chemically induced acute liver injury

“…24,40 It has been demonstrated that CCl 4intoxication results in the activation of liver macrophages 44 with the subsequent production of proinflammatory mediators including TNF-α which in turn exaggerate the CCl 4 -induced hepatic injury. 45,46 Furthermore, CCl 4 -induced free radicals lead to the activation of NF-κB and the release of inflammatory mediators into injured livers. 47 In parallel with these studies, our results revealed positive immunostaining of NF-κB and significant elevation of TNF-α in the hepatic tissue of the CCl 4 group compared to those of the control group.…”

NRF2 as a Therapeutic Target in Neurodegenerative Diseases

“…The medicinal plant Centella asiatica (L) Urban also contains many NRF2-activating compounds. The plant contains high levels of four triterpene compounds, Asiatic acid, madecassic acid, asiaticoside, and madecassoside (MS) that have all been shown to activate NRF2 but do not possess strong electrophilic properties (Yang et al., 2016; Jiang et al., 2017; Fan et al., 2018; Liu et al., 2019c; Meng et al., 2019). Centella asiatica also contains many caffeoylquinic acids that we and others have shown can activate NRF2 as well (Boettler et al., 2011; Gray et al., 2014; Liang et al., 2019).…”