Asiatic acid enhances Nrf2 signaling to protect HepG2 cells from oxidative damage through Akt and ERK activation

Qi, Zhimin; Ci, Xinxin; Huang, Jingbo; Liu, Qinmei; Yu, Qiaoling; Zhou, Junfeng; Deng, Xuming

doi:10.1016/j.biopha.2017.01.067

Cited by 67 publications

(41 citation statements)

References 39 publications

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“… 10 , 32 , 33 In addition, several studies have reported that AA could activate Nrf2 pathways to exhibit antioxidant and anti-inflammatory activities. 34 , 35 In the current study, AA markedly increased the expression level of nuclear Nrf2 as compared to the model group. Furthermore, the expressions of Nrf2-target proteins HO-1, NQO-1, and GCLC were increased in the AA-treated group.…”

Section: Discussionsupporting

confidence: 53%

Asiatic acid ameliorates CC l<sub>4</sub>-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways

Fan

Chen

Wei

et al. 2018

DDDT

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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.

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Section: Discussionsupporting

confidence: 53%

Asiatic acid ameliorates CC l<sub>4</sub>-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways

Fan

Chen

Wei

et al. 2018

DDDT

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“…Our previous study indicated that AA inhibited cellular damage and oxidative stress by regulating Nrf2 signaling dependent upon activation of the AKT and ERK signals in HepG2 cells (24). Accordingly, to investigate the protective mechanism of AA treatment on L/D-induced FHF, the ERK and PI3K/AKT activities were analyzed by Western blotting.…”

Section: Resultsmentioning

confidence: 99%

Asiatic Acid Exhibits Anti-inflammatory and Antioxidant Activities against Lipopolysaccharide and d-Galactosamine-Induced Fulminant Hepatic Failure

Wang

et al. 2017

Front. Immunol.

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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 O2−), 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.

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“…This result was different from the study on Hep G2 culture cells induced by tert-butyl hydroperoxide (t-BHP) by modulating Nrf2 signaling through activation of Akt and ERK. 53 While Toninelli et al, was able to prove the antioxidant role of dopamine pramipexole agonists through SH-SY5Y neuroblastoma culture cells where pramipexole prevents cell death induced by H 2 O 2 and inhibits the formation of mitochondrial ROS. 23 Associated with the phenomenon of locomotory enhancement in pramipexole and C. asiatica group, it is required to do further research to know whether there is a high expression of Nrf2 in each group which is proportional to the oxidation process that goes on a cell such as examination of MDA.…”

Section: Discussion Locomotor Activitymentioning

confidence: 99%

COMPARISON EFFECT BETWEEN PEGAGAN (Centella asiatica) EXTRACT AND PRAMIPEXOLE TOWARD LOCOMOTOR ACTIVITIES, α - SYNUCLEIN, AND NRF2 EXPRESSION IN ZEBRAFISH PARKINSON MODEL

Trisnawati

Anasrulloh

Rianawati

et al. 2019

MNJ

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Background: Parkinson disease is characterized with deposition of Lewy Bodies containing αsynuclein happened due to the effect of chronic neuroinflammation that causes the death of dopaminergic neurons through oxidative stress processes, so it involves the response of Nuclear factor erythroid 2-like 2 (Nrf2). Centella asiatica (C.asiatica) contains antioxidant effect, inhibits the aggregation of α-synuclein and improves the locomotor on Parkinson-model animals so it needs to compare to the standard medication. Objective: To compare the C. asiatica extract and Pramipexole to the zebrafish Parkinson model by determining the locomotor activity, α-synuclein expression, and Nrf2. Methods: This study used six groups of zebrafish: negative control, rotenone rotenone [5 μg/L], pramipexole1, 2, 3 (rotenone + pramipexole [3,5] ng/mL, [7] ng/mL, [14] ng/mL), and C. asiatica (rotenone + C. asiatica [10] μg/mL). The observations of locomotor activity of day 0, 14, and 28 were continued to the α-synuclein immunohistochemical examination, and Nrf2 on the midbrain area. Results: There are significant differences in locomotor activity on day 28 among the C. asiatica group with rotenone (p<0,05), while there are no significant differences among the C. asiatica group with pramipexole [7] ng/mL and [14] ng/mL (p>0,05). α-synuclein expression of the C. asiatica group is the lowest and significantly different from all groups (p<0,05), while Nr2 had no significant differences (p>0,05). Conclusion: C. asiatica extract [10] μg/mL is equal to pramipexole [7] ng/mL and [14] ng/mL in improving locomotor activity, but C. asiatica extract holds excellence as it decreases α-synuclein expression better than pramipexole, while Nrf2 expression shows no differences.

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Asiatic acid enhances Nrf2 signaling to protect HepG2 cells from oxidative damage through Akt and ERK activation

Cited by 67 publications

References 39 publications

Asiatic acid ameliorates CC l<sub>4</sub>-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways

Asiatic acid ameliorates CC l<sub>4</sub>-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways

Asiatic Acid Exhibits Anti-inflammatory and Antioxidant Activities against Lipopolysaccharide and d-Galactosamine-Induced Fulminant Hepatic Failure

COMPARISON EFFECT BETWEEN PEGAGAN (Centella asiatica) EXTRACT AND PRAMIPEXOLE TOWARD LOCOMOTOR ACTIVITIES, α - SYNUCLEIN, AND NRF2 EXPRESSION IN ZEBRAFISH PARKINSON MODEL

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Asiatic acid enhances Nrf2 signaling to protect HepG2 cells from oxidative damage through Akt and ERK activation

Cited by 67 publications

References 39 publications

Asiatic acid ameliorates CC l<sub>4</sub>-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-&kappa;B/I&kappa;B&alpha;, and JAK1/STAT3 signaling pathways

Asiatic acid ameliorates CC l<sub>4</sub>-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-&kappa;B/I&kappa;B&alpha;, and JAK1/STAT3 signaling pathways

Asiatic Acid Exhibits Anti-inflammatory and Antioxidant Activities against Lipopolysaccharide and d-Galactosamine-Induced Fulminant Hepatic Failure

COMPARISON EFFECT BETWEEN PEGAGAN (Centella asiatica) EXTRACT AND PRAMIPEXOLE TOWARD LOCOMOTOR ACTIVITIES, α - SYNUCLEIN, AND NRF2 EXPRESSION IN ZEBRAFISH PARKINSON MODEL

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Asiatic acid ameliorates CC l<sub>4</sub>-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways

Asiatic acid ameliorates CC l<sub>4</sub>-induced liver fibrosis in rats: involvement of Nrf2/ARE, NF-κB/IκBα, and JAK1/STAT3 signaling pathways