Dynamic and Coordinated Regulation of KEAP1-NRF2-ARE and p53/p21 Signaling Pathways Is Associated with Acetaminophen Injury Responsive Liver Regeneration

Fan, Xiaomei; Chen, Pan; Tan, Huasen; Zeng, Hang; Jiang, Yiming; Wang, Ying; Wang, Yongtao; Hou, Xiang-Yu; Bi, Huichang; Huang, Min

doi:10.1124/dmd.114.059394

Cited by 28 publications

(19 citation statements)

References 39 publications

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“…Similar observations were made in murine T organoids bearing sh Nrf2 (Figure 5B). This is consistent with earlier reports showing a correlation between the expression of Nrf2 and some of these proteins (Fan et al, 2014; Ke et al, 2013; Malec et al, 2010; Niture and Jaiswal, 2012; Wang et al, 2016). Quantitative PCR of polysome fractions revealed an increase in the association of the mRNAs of these proteins with the translationally inactive monosome fractions (Figure 5C), while no differences were seen for Actin, Mcl-1, and interestingly, Bcl2 mRNAs (Figure S5B).…”

Section: Resultssupporting

confidence: 94%

NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Chio

Jafarnejad

Ponz-Sarvisé

et al. 2016

Cell

310

266

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Summary Pancreatic cancer is a deadly malignancy that lacks effective therapeutics. We previously reported that oncogenic Kras induced the redox master regulator Nrf2/Nfe2l2 to stimulate pancreatic and lung cancer initiation. Here, we show that NRF2 is necessary to maintain pancreatic cancer proliferation by regulating mRNA translation. Specifically, loss of NRF2 led to defects in autocrine EGFR signaling and oxidation of specific translational regulatory proteins, resulting in impaired cap-dependent and cap-independent mRNA translation in pancreatic cancer cells. Combined targeting of the EGFR effector AKT and the glutathione antioxidant pathway mimicked Nrf2 ablation to potently inhibit pancreatic cancer ex vivo and in vivo, representing a promising synthetic lethal strategy for treating the disease.

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Section: Resultssupporting

confidence: 94%

NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Chio

Jafarnejad

Ponz-Sarvisé

et al. 2016

Cell

310

266

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“…2A). Compared with the first 24 hours, much less hepatocellular injury and necrosis was observed at 48 hours but was not yet completely resolved consistent with a previous report (Fan et al, 2014a). Treatment with WZ24 hours after NAC dosing, which was not observed in APAP-treated and APAP/WZ-treated mice.…”

Section: Resultssupporting

confidence: 78%

“…In a previous study, the p53/p21 signaling pathway was reported to participate in compensatory liver regeneration after APAP-induced liver injury (Fan et al, 2014a). Thus, p53 and p21 protein expression was investigated to explore whether WZ or NAC could block p53/p21 signaling to promote liver repair in mice after APAP-induced toxicity.…”

Section: Downloaded Frommentioning

confidence: 99%

Therapeutic Efficacy of Wuzhi Tablet (Schisandra sphenanthera Extract) on Acetaminophen-Induced Hepatotoxicity through a Mechanism Distinct from N-Acetylcysteine

et al. 2014

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Acetaminophen (APAP) hepatotoxicity is the most common cause of drug-induced liver injury and N-acetylcysteine (NAC) is the primary antidote of APAP poisoning. Wuzhi tablet (WZ), the active constituents well identified and quantified, is a preparation of an ethanol extract of Schisandra sphenanthera and exerts a protective effect toward APAP-induced hepatotoxicity in mice. However, the clinical use of WZ to rescue APAP-induced acute liver injury and the mechanisms involved in the therapeutic effect of WZ remain unclear. Therefore, the effect of WZ on APAP hepatotoxicity was compared with NAC in mice, and molecular pathways contributing to its therapeutic action were investigated. Administration of WZ 4 hours after APAP treatment significantly attenuated APAP hepatotoxicity and exerted much better therapeutic effect than NAC, as revealed by morphologic, histologic, and biochemical assessments. Both WZ and NAC prevented APAP-induced c-Jun N-terminal protein kinase activation and mitochondrial glutathione depletion in livers. The protein expression of nuclear factor erythroid 2-related factor 2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was increased by WZ administration. Furthermore, p53 and p21 levels were upregulated upon APAP exposure, which were completely reversed by postdosing of WZ 4 hours after APAP treatment over 48 hours. In comparison with NAC, WZ significantly increased the expression of cyclin D1, cyclin D-dependent kinase 4, proliferating cell nuclear antigen, and augmenter of liver regeneration in APAP-injured livers. This study demonstrated that WZ possessed a therapeutic efficacy against APAP-induced liver injury by inhibiting oxidative stress and stimulating a regenerative response after liver injury. Thus WZ may represent a new therapy for APAP-induced acute liver injury.

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“…Several studies have shown that acute liver injury induced by moderate doses of APAP is a dynamic process including initiation of injury, progression of injury, and compensatory liver repair (Mehendale, 2005;Bajt et al, 2008;Fan et al, 2014). In the present study, WZ suppresses NAPQI generation required for initiating cellular toxicity through inhibition of P450 enzyme activities and induction of UGT, sulfotransferase, and multidrug resistance-associated protein expression and prevents oxidative stress induced progression of liver injury by activating the NRF2-ARE pathway.…”

Section: Discussionmentioning

confidence: 66%

Wuzhi Tablet (Schisandra SphenantheraExtract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways

et al. 2014

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Schisandra sphenanthera is widely used as a tonic and restorative in many countries to enhance the function of liver and other organs. Wuzhi tablet (WZ) is a preparation of an ethanol extract of Schisandra sphenanthera. Our previous study demonstrated that WZ exerted a protective effect toward acetaminophen (APAP)-induced hepatotoxicity. However, the molecular mechanisms of this protection remain unclear. This study aimed to determine what molecular pathways contributed to the hepatoprotective effects of WZ against APAP toxicity. Administration of WZ 3 days before APAP treatment significantly attenuated APAP hepatotoxicity in a dose-dependent manner and reduced APAP-induced JNK activation. Treatment with WZ resulted in potent inhibition of CYP2E1, CYP3A11, and CYP1A2 activities and then caused significant inhibition of the formation of the oxidized APAP metabolite N-acetyl-p-benzoquinone imine-reduced glutathione. The expression of NRF2 was increased after APAP and/or WZ treatment, whereas KEAP1 levels were decreased. The protein expression of NRF2 target genes including Gclc, Gclm, Ho-1, and Nqo1 was significantly increased by WZ treatment. Furthermore, APAP increased the levels of p53 and its downstream gene p21 to trigger cell cycle arrest and apoptosis, whereas WZ pretreatment could inhibit p53/p21 signaling to induce cell proliferation-associated proteins including cyclin D1, CDK4, PCNA, and ALR to promote hepatocyte proliferation. This study demonstrated that WZ prevented APAP-induced liver injury by inhibition of cytochrome P450-mediated APAP bioactivation, activation of the NRF2-antioxidant response element pathway to induce detoxification and antioxidation, and regulation of the p53, p21, cyclin D1, CDK4, PCNA, and ALR to facilitate liver regeneration after APAP-induced liver injury.

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Dynamic and Coordinated Regulation of KEAP1-NRF2-ARE and p53/p21 Signaling Pathways Is Associated with Acetaminophen Injury Responsive Liver Regeneration

Cited by 28 publications

References 39 publications

NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

NRF2 Promotes Tumor Maintenance by Modulating mRNA Translation in Pancreatic Cancer

Therapeutic Efficacy of Wuzhi Tablet (Schisandra sphenanthera Extract) on Acetaminophen-Induced Hepatotoxicity through a Mechanism Distinct from N-Acetylcysteine

Wuzhi Tablet (Schisandra SphenantheraExtract) Protects against Acetaminophen-Induced Hepatotoxicity by Inhibition of CYP-Mediated Bioactivation and Regulation of NRF2-ARE and p53/p21 Pathways

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