Schisandrin B exhibits anti-inflammatory activity through modulation of the redox-sensitive transcription factors Nrf2 and NF-κB

Checker, Rahul; Patwardhan, Raghavendra S.; Sharma, Deepak; Menon, Jisha; Thoh, Maikho; Bhilwade, Hari N.; Konishi, Tetsuya; Sandur, Santosh K.

doi:10.1016/j.freeradbiomed.2012.08.006

Cited by 100 publications

(69 citation statements)

References 60 publications

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“…Recent studies have indicated that NQO1 possesses the capacity to enzymatically reduce NAPQI to amelioriate APAP toxicity (Moffit et al, 2007). Several studies revealed that some lignans isolated from fruits of Schisandra chinensis, including Schisandrin B, a-iso-cubebenol, and Tigloylgomisin H, exhibited anti-inflammatory activities and potential liver cancer prevention effects through activating NRF2 pathway (Lee et al, 2009;Park et al, 2011;Checker et al, 2012). However, the content of the above lignans is low in WZ tablets.…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…NF-κB plays a central role in regulating immune and inflammatory processes, and thus is a target in developing novel treatments for inflammatory diseases (Checker et al, 2012;Ling et al, 2012). Before activation, NF-κB is bound in the cytoplasm by IκBα, an inhibitory protein that keeps NF-κB in an inactive state.…”

Section: Fig 5 Effect Of Punicalagin On Lps-induced Nf-κb Activationmentioning

confidence: 99%

Punicalagin protects bovine endometrial epithelial cells against lipopolysaccharide-induced inflammatory injury

Lyu

Chen

Wang

et al. 2017

J. Zhejiang Univ. Sci. B

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Abstract:Objective: Bovine endometritis is one of the most common reproductive disorders in cattle. The aim of this study was to investigate the anti-inflammation potential of punicalagin in lipopolysaccharide (LPS)-induced bovine endometrial epithelial cells (bEECs) and to uncover the underlying mechanisms. Methods: bEECs were stimulated with different concentrations (1, 10, 30, 50, and 100 μg/ml) of LPS for 3, 6, 9, 12, and 18 h. MTT assay was used to assess cell viability and to identify the conditions for inflammatory injury and effective concentrations of punicalagin. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to assess gene expression of pro-inflammatory cytokines. Western blotting was used to assess levels of inflammation-related proteins. Results: Treatment of bEECs with 30 µg/ml LPS for 12 h induced cell injury and reduced cell viability. Punicalagin (5, 10, or 20 µg/ml) pretreatment significantly decreased LPS-induced productions of interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor-α (TNF-α) in bEECs. Molecular research showed that punicalagin inhibited the activation of the upstream mediator nuclear factor-κB (NF-κB) by suppressing the production of inhibitor κBα (IκBα) and phosphorylation of p65. Results also indicated that punicalagin can suppress the phosphorylation of mitogen-activated protein kinases (MAPKs) including p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). Conclusions: Punicalagin may attenuate LPS-induced inflammatory injury and provide a potential option for the treatment of dairy cows with Escherichia coli endometritis.

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“…21,[45][46][47][48] Among them, ERK is known as an upstream kinase of Nrf2 activation as well as a signaling enzyme determining cell survival against oxidative stress. 49,50) Results of this study clearly indicate that tryptanthrin activated Nrf2 phosphorylation via ERK activation. In addition, blockade of the ERK pathway using an MEK1 chemical inhibitor attenuated tryptanthrin-mediated Nrf2 phosphorylation and protection against mitochondrial dysfunction.…”

Section: Discussionmentioning

confidence: 60%

Tryptanthrin Protects Hepatocytes against Oxidative Stress <i>via</i> Activation of the Extracellular Signal-Regulated Kinase/NF-E2-Related Factor 2 Pathway

Moon

Lee

Choi

et al. 2014

Biological & Pharmaceutical Bulletin

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Tryptanthrin [6,12-dihydro-6,12-dioxoindolo-(2,1-b)-quinazoline], originally isolated from Isatidis radix, has been characterized as having anti-microbial and anti-tumor activities. It is well-known that excess oxidative stress is one of the major factors causing cell damage in the liver. This study investigated the cytoprotective effects and molecular mechanism of tryptanthrin against tert-butyl hydroperoxide (tBHP)-induced oxidative stress in human hepatocyte-derived HepG2 cells. Tryptanthrin pre-treatment blocked the reactive oxygen species production, mitochondrial dysfunction, and cell death induced by tBHP. Moreover, tryptanthrin reversed tBHP-induced GSH reduction. This study also confirmed the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) by tryptanthrin as a plausible molecular mechanism for its cytoprotective effects. Specifically, tryptanthrin treatment induced nuclear translocation and transactivation of Nrf2 as well as phosphorylation of extracellular signal-regulated kinase (ERK), a potential upstream kinase of Nrf2. Tryptanthrin also up-regulated the expression of the heme oxygenase 1 and glutamate-cysteine ligase catalytic subunits, which are representative target genes of Nrf2. Moreover, inhibitor of ERK was used to verify the important role of the ERK-Nrf2 pathway in the hepatoprotective effects of tryptanthrin. In conclusion, this study demonstrated that tryptanthrin protects hepatocytes against oxidative stress through the activation of the ERK/Nrf2 pathway in HepG2 cells.Key words tryptanthrin; tert-butyl hydroperoxide; oxidative stress; mitochondria; nuclear factor erythroid 2-related factor 2 (Nrf2); extracellular signal-regulated kinaseThe liver is the largest organ as well as central to the regulation of several key aspects of lipid metabolism. Impairment of the response to hepatic insult with age is characteristic of the liver, which increases the incidence of liver disease in the population of elder people. Moreover, the liver has various functions related to metabolism, detoxification, synthesis of plasma proteins, and bile production.

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Schisandrin B exhibits anti-inflammatory activity through modulation of the redox-sensitive transcription factors Nrf2 and NF-κB

Cited by 100 publications

References 60 publications

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

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

Punicalagin protects bovine endometrial epithelial cells against lipopolysaccharide-induced inflammatory injury

Tryptanthrin Protects Hepatocytes against Oxidative Stress <i>via</i> Activation of the Extracellular Signal-Regulated Kinase/NF-E2-Related Factor 2 Pathway

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