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      Graptopetalum paraguayense Ameliorates Airway Inflammation and Allergy in Ovalbumin- (OVA-) Sensitized BALB/C Mice by Inhibiting Th2 Signal

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          Abstract

          Role of inflammation-induced oxidative stress in the pathogenesis and progression of chronic inflammatory airways diseases has received increasing attention in recent years. Nuclear factor erythroid 2-related factor 2 is the primary transcription factor that regulates the expression of antioxidant and detoxifying enzymes. Graptopetalum paraguayense E. Walther, a vegetable consumed in Taiwan, has been used in folk medicine for protection against liver injury through elevating antioxidation. Recently, we found that gallic acid is an active compound of Graptopetalum paraguayense E. Walther, which has been reported to inhibit T-helper 2 cytokines. Currently, we assumed that Graptopetalum paraguayense E. Walther may potentially protect against ovalbumin-induced allergy and airway inflammation. Results demonstrated that Graptopetalum paraguayense E. Walther ethanolic extracts (GPE) clearly inhibited airway inflammation, mucus cell hyperplasia, and eosinophilia in OVA-challenged mice. Additionally, GPE also prevented T-cell infiltration and Th2 cytokines, including interleukin- (IL-)4, IL-5, and IL-13 generations in bronchial alveolar lavage fluid. The adhesion molecules ICAM-1 and VCAM-1 were substantially reduced by GPE treatment mediated by Nrf2 activation. Moreover, GPE attenuated GATA3 expression and inhibited Th2 signals of the T cells. These findings suggested that GPE ameliorated the development of airway inflammation through immune regulation.

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          Most cited references40

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          Molecular mechanisms activating the Nrf2-Keap1 pathway of antioxidant gene regulation.

          Several years have passed since NF-E2-related factor 2 (Nrf2) was demonstrated to regulate the induction of genes encoding antioxidant proteins and phase 2 detoxifying enzymes. Following a number of studies, it was realized that Nrf2 is a key factor for cytoprotection in various aspects, such as anticarcinogenicity, neuroprotection, antiinflammatory response, and so forth. These widespread functions of Nrf2 spring from the coordinated actions of various categories of target genes. The activation mechanism of Nrf2 has been studied extensively. Under normal conditions, Nrf2 localizes in the cytoplasm where it interacts with the actin binding protein, Kelch-like ECH associating protein 1 (Keap1), and is rapidly degraded by the ubiquitin-proteasome pathway. Signals from reactive oxygen species or electrophilic insults target the Nrf2-Keap1 complex, dissociating Nrf2 from Keap1. Stabilized Nrf2 then translocates to the nuclei and transactivates its target genes. Interestingly, Keap1 is now assumed to be a substrate-specific adaptor of Cul3-based E3 ubiquitin ligase. Direct participation of Keap1 in the ubiquitination and degradation of Nrf2 is plausible. The Nrf2-Keap1 system is present not only in mammals, but in fish, suggesting that its roles in cellular defense are conserved throughout evolution among vertebrates. This review article recounts recent knowledge of the Nrf2-Keap1 system, focusing especially on the molecular mechanism of Nrf2 regulation.
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            Allergy and allergic diseases. First of two parts.

            A Kay (2001)
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              Disruption of Nrf2 enhances susceptibility to severe airway inflammation and asthma in mice

              Oxidative stress has been postulated to play an important role in the pathogenesis of asthma; although a defect in antioxidant responses has been speculated to exacerbate asthma severity, this has been difficult to demonstrate with certainty. Nuclear erythroid 2 p45-related factor 2 (Nrf2) is a redox-sensitive basic leucine zipper transcription factor that is involved in the transcriptional regulation of many antioxidant genes. We show that disruption of the Nrf2 gene leads to severe allergen-driven airway inflammation and hyperresponsiveness in mice. Enhanced asthmatic response as a result of ovalbumin sensitization and challenge in Nrf2-disrupted mice was associated with more pronounced mucus cell hyperplasia and infiltration of eosinophils into the lungs than seen in wild-type littermates. Nrf2 disruption resulted in an increased expression of the T helper type 2 cytokines interleukin (IL)-4 and IL-13 in bronchoalveolar lavage fluid and in splenocytes after allergen challenge. The enhanced severity of the asthmatic response from disruption of the Nrf2 pathway was a result of a lowered antioxidant status of the lungs caused by lower basal expression, as well as marked attenuation, of the transcriptional induction of multiple antioxidant genes. Our studies suggest that the responsiveness of Nrf2-directed antioxidant pathways may act as a major determinant of susceptibility to allergen-mediated asthma.
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                Author and article information

                Journal
                Evid Based Complement Alternat Med
                Evid Based Complement Alternat Med
                ECAM
                Evidence-based Complementary and Alternative Medicine : eCAM
                Hindawi Publishing Corporation
                1741-427X
                1741-4288
                2013
                17 June 2013
                17 June 2013
                : 2013
                : 237096
                Affiliations
                1Department of Food Science, National Chiayi University, Taiwan
                2Department of Science, University of Auckland, New Zealand
                Author notes

                Academic Editor: Bashar Saad

                Author information
                https://orcid.org/0000-0002-0216-7352
                Article
                10.1155/2013/237096
                3703387
                23843865
                c5e1b711-6eac-46f2-b170-7ed96f560820
                Copyright © 2013 Bao-Hong Lee et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 5 March 2013
                : 20 May 2013
                : 20 May 2013
                Categories
                Research Article

                Complementary & Alternative medicine
                Complementary & Alternative medicine

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