Dietary flavonoid genistein induces Nrf2 and phase II detoxification gene expression via ERKs and PKC pathways and protects against oxidative stress in Caco‐2 cells

Zhai, Xuguang; Lin, Musen; Zhang, Feng; Hu, Yan; Xu, Xiu; Li, Yubing; Liu, Kexin; Ma, Xiaochi; Tian, Xiaofeng; Yao, Jihong

doi:10.1002/mnfr.201200536

Cited by 115 publications

(69 citation statements)

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“…In contrast to several reports on Nrf2 activation by flavonoids, 27,28 none of the flavonoids isolated from C. odoratum exerted Nrf2 activation in the reporter gene assay used (data not shown). Possibly, the concentrations tested, 10 to 30 μM, were too low to activate Nrf2 under the assay conditions utilized.…”

Section: Resultscontrasting

confidence: 99%

Identification of Chromomoric Acid C-I as an Nrf2 Activator in Chromolaena odorata

et al. 2014

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Activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) contributes to several beneficial bioactivities of natural products, including induction of an increased cellular stress resistance and prevention or resolution of inflammation. In this study, the potential of a crude leaf extract of Chromolaena odorata, traditionally used against inflammation and skin lesions, was examined for Nrf2 activation. Guided by an Nrf2-dependent luciferase reporter gene assay, the phytoprostane chromomoric acid C-I (1) was identified as a potent Nrf2 activator from C. odorata with a CD (concentration doubling the response of vehicle-treated cells) of 5.2 μM. When tested at 1–10 μM, 1 was able to induce the endogenous Nrf2 target gene heme oxygenase 1 (HO-1) in fibroblasts. Between 2 and 5 μM, compound 1 induced HO-1 in vascular smooth muscle cells (VSMC) and inhibited their proliferation in a HO-1-dependent manner, without eliciting signs of cytotoxicity.

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Section: Resultscontrasting

confidence: 99%

Identification of Chromomoric Acid C-I as an Nrf2 Activator in Chromolaena odorata

et al. 2014

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“…Caco-2/15 cell monolayers have been, by far, the most utilized cell model to predict the flux of drugs across human small intestinal tissue [47], [48]. They have also been demonstrated to be extremely useful for the screening of antioxidant defense, OxS, inflammation and intestinal barrier as highlighted by various groups [49]–[51] and our own laboratory [25]–[27], [52]. The Caco-2/15 cells develop structural characteristics like those of a small intestinal enterocyte epithelium [53] and share functional similarities with enterocytes as a model to examine oral absorption [54], providing an alternative to the use of other intestinal models [55].…”

Section: Discussionmentioning

confidence: 99%

Iron-Ascorbate-Mediated Lipid Peroxidation Causes Epigenetic Changes in the Antioxidant Defense in Intestinal Epithelial Cells: Impact on Inflammation

et al. 2013

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IntroductionThe gastrointestinal tract is frequently exposed to noxious stimuli that may cause oxidative stress, inflammation and injury. Intraluminal pro-oxidants from ingested nutrients especially iron salts and ascorbic acid frequently consumed together, can lead to catalytic formation of oxygen-derived free radicals that ultimately overwhelm the cellular antioxidant defense and lead to cell damage.HypothesisSince the mechanisms remain sketchy, efforts have been exerted to evaluate the role of epigenetics in modulating components of endogenous enzymatic antioxidants in the intestine. To this end, Caco-2/15 cells were exposed to the iron-ascorbate oxygen radical-generating system.ResultsFe/Asc induced a significant increase in lipid peroxidation as reflected by the elevated formation of malondialdehyde along with the alteration of antioxidant defense as evidenced by raised superoxide dismutase 2 (SOD2) and diminished glutathione peroxidase (GPx) activities and genes. Consequently, there was an up-regulation of inflammatory processes illustrated by the activation of NF-κB transcription factor, the higher production of interleukin-6 and cycloxygenase-2 as well as the decrease of IκB. Assessment of promoter’s methylation revealed decreased levels for SOD2 and increased degree for GPx2. On the other hand, pre-incubation of Caco-2/15 cells with 5-Aza-2′-deoxycytidine, a demethylating agent, or Trolox antioxidant normalized the activities of SOD2 and GPx, reduced lipid peroxidation and prevented inflammation.ConclusionRedox and inflammatory modifications in response to Fe/Asc -mediated lipid peroxidation may implicate epigenetic methylation.

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“…Reverse transcription was performed using the TaKaRa were reported in our previous study (20). The co-amplified PCR products were separated on a 1.5% agarose gel using electrophoresis.…”

Section: Rna Isolation and Rt-pcrmentioning

confidence: 99%

Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways

Lin

Zhai

Wang

et al. 2015

Journal of Pharmacological Sciences

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Acetaminophen (APAP) is used drugs worldwide for treating pain and fever. However, APAP overdose is the principal cause of acute liver failure in Western countries. Salvianolic acid B (SalB), a major water-soluble compound extracted from Radix Salvia miltiorrhiza, has well-known antioxidant and anti-inflammatory actions. We aimed to evaluate the ability of SalB to protect against APAP-induced acute hepatotoxicity by inducing nuclear factor-erythroid-2-related factor 2 (Nrf2) expression. SalB pretreatment ameliorated acute liver injury caused by APAP, as indicated by blood aspartate transaminase levels and histological findings. Moreover, SalB pretreatment increased the expression of Nrf2, Heme oxygenase-1 (HO-1) and glutamate-l-cysteine ligase catalytic subunit (GCLC). Furthermore, the HO-1 inhibitor zinc protoporphyrin and the GCLC inhibitor buthionine sulfoximine reversed the protective effect of SalB. Additionally, siRNA-mediated depletion of Nrf2 reduced the induction of HO-1 and GCLC by SalB, and SalB pretreatment activated the phosphatidylinositol-3-kinase (PI3K) and protein kinase C (PKC) signaling pathways. Both inhibitors (PI3K and PKC) blocked the protective effect of SalB against APAP-induced cell death, abolishing the SalB-induced Nrf2 activation and decreasing HO-1 and GCLC expression. These results indicated that SalB induces Nrf2, HO-1 and GCLC expression via activation of the PI3K and PKC pathways, thereby protecting against APAP-induced liver injury.

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Dietary flavonoid genistein induces Nrf2 and phase II detoxification gene expression via ERKs and PKC pathways and protects against oxidative stress in Caco‐2 cells

Abstract: Our studies show that genistein up-regulated HO-1 and GCLC expression through the EKR1/2 and PKC /Nrf2 pathways during oxidative stress.

Cited by 115 publications

References 50 publications

Identification of Chromomoric Acid C-I as an Nrf2 Activator in Chromolaena odorata

Identification of Chromomoric Acid C-I as an Nrf2 Activator in Chromolaena odorata

Iron-Ascorbate-Mediated Lipid Peroxidation Causes Epigenetic Changes in the Antioxidant Defense in Intestinal Epithelial Cells: Impact on Inflammation

Salvianolic acid B protects against acetaminophen hepatotoxicity by inducing Nrf2 and phase II detoxification gene expression via activation of the PI3K and PKC signaling pathways

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