scholarly journals LAS0811: From Combinatorial Chemistry to Activation of Antioxidant Response Element

2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Ming Zhu ◽  
Hyounggee Baek ◽  
Ruiwu Liu ◽  
Aimin Song ◽  
Kit Lam ◽  
...  
Keyword(s):  
Small Molecules ◽  
Combinatorial Chemistry ◽  
High Throughput Screening ◽  
Cancer Chemoprevention ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Antioxidant Response Element ◽  
Response Element ◽  
Enhanced Production

The antioxidant response element (ARE) and its transcription factor, nuclear factor-erythroid 2 p45-related factor 2 (Nrf2), are potential targets for cancer chemoprevention. We sought to screen small molecules synthesized with combinatorial chemistry for activation of ARE. By high-throughput screening of 9400 small molecules from 10 combinatorial chemical libraries using HepG2 cells with an ARE-driven reporter, we have identified a novel small molecule, 1,2-dimethoxy-4,5-dinitrobenzene (LAS0811), as an activator of the ARE. LAS0811 upregulated the activity of NAD(P)H:quinone oxidoreductase 1 (NQO1), a representative antioxidative enzyme regulated by ARE. It enhanced production of an endogenous reducing agent, glutathione (GSH). In addition, LAS0811 induced expression of heme oxygenase 1 (HO1), which is an ARE-regulated enzyme with anti-inflammatory activity. Furthermore, LAS0811 reduced cell death due to the cytotoxic stress of a strong oxidant, t-butyl hydroperoxide (t-BOOH). Mechanistically, LAS0811 upregulated the expression of Nrf2 and promoted its translocation into the nuclei leading to subsequent ARE activation. Taken together, LAS0811 is a novel activator of the ARE and its associated detoxifying genes and, thus, a potential agent for cancer chemoprevention.

scholarly journals Astragaloside IV Protects Against Oxidative Stress in Calf Small Intestine Epithelial Cells via NFE2L2-Antioxidant Response Element Signaling

2019 ◽  
Vol 20 (24) ◽  
pp. 6131 ◽  
Author(s):  
Yafang Wang ◽  
Fugui Jiang ◽  
Haijian Cheng ◽  
Xiuwen Tan ◽  
Yifan Liu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Small Intestine ◽  
Epithelial Cells ◽  
Reactive Oxygen Species Generation ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Antioxidant Response Element ◽  
Astragaloside Iv ◽  
Response Element

Oxidative stress can damage intestinal epithelial cell integrity and function, causing gastrointestinal disorders. Astragaloside IV (ASIV) exhibits a variety of biological and pharmacological properties, including anti-inflammatory and antioxidant effects. The purpose of this research was to investigate the cytoprotective action of ASIV and its mechanisms in calf small intestine epithelial cells with hydrogen peroxide (H2O2)-induced oxidative stress. ASIV pretreatment not only increased cell survival, but it also decreased reactive oxygen species generation and apoptosis, enhanced superoxide dismutase, catalase, and glutathione peroxidase levels, and it reduced malondialdehyde formation. Furthermore, pretreatment with ASIV elevated the mRNA and protein levels of nuclear factor erythroid 2-related factor 2 (NFE2L2), heme oxygenase-1 (HMOX1), and NAD(P)H quinone dehydrogenase 1 (NQO1). The NFE2L2 inhibitor ML385 inhibited NFE2L2 expression and then blocked HMOX1 and NQO1 expression. These results demonstrate that ASIV treatment effectively protects against H2O2-induced oxidative damage in calf small intestine epithelial cells through the activation of the NFE2L2-antioxidant response element signaling pathway.

Shenduning Granule Attenuates Renal Injury from Oxidative Stress through the Nuclear Factor Erythroid 2-Related Factor 2/Antioxidant Response Element Pathway

Pharmacology ◽  
2019 ◽  
Vol 103 (5-6) ◽  
pp. 236-245
Author(s):  
Xiao-Jun Fu ◽  
Shuang-Yan Hu
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Response ◽  
Urinary Protein ◽  
Heme Oxygenase 1 ◽  
High Dose ◽  
Related Factor ◽  
Nuclear Factor ◽  
Antioxidant Response Element ◽  
Response Element ◽  
Operation Group

Background: Systemic oxidative stress has been reported to play a central role in the pathogenesis of kidney function decline. The nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway is one of the important endogenous antioxidant stress pathways in cells. This study aims to investigate whether shenduning granule can ameliorate oxidative stress in kidney tissues by activating the Nrf2/ARE pathway, and explores the detailed underlying mechanism. Methods: A total of 120 male Sprague-Dawley rats were randomly assigned to the sham-operated and operation groups. Rats in the operation group underwent 5/6 nephrectomy. Two weeks later, rats in the operation group were further randomly divided into 5 groups: model group, low-dose, medium-dose and high-dose shenduning granule groups, and losartan group. Rats in each group were given the same volume of corresponding liquid orally. Serum creatinine (SCr), blood urea nitrogen (BUN), 24-h urinary protein, malondialdehyde (MDA) and superoxide dismutase (SOD), Nrf2, heme oxygenase-1 (HO-1), and γ-glutamyl-cysteine synthetase (γ-GCS) were determined. Results: Shenduning granule could markedly elevate HO-1, NRF2, γ-GCS and SOD (p < 0.05), and significantly decreased MDA, 24-h urinary protein, SCr and BUN in rats (p < 0.05). Conclusion: Shenduning granule can improve renal antioxidative stress activity in rats, exhibiting a renoprotective effect. The potential mechanism is likely exerted by the activation of the Nrf2/ARE pathway.

scholarly journals Μελέτη του μεταγραφικού παράγοντα Nrf2 ως διαμεσολαβητή της δράσης των στατινών

2010 ◽  
Author(s):  
Διονύσιος Χαρτουμπέκης
Keyword(s):  
Glutathione Peroxidase ◽  
Heme Oxygenase ◽  
Antioxidant Response ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Antioxidant Response Element ◽  
Response Element

Τα ευεργετικά αποτελέσματα των αναστολέων της αναγωγάσης του HMG-CoA (3-υδροξυ-3-μεθυλ-γλουταρυλ-συνένζυμο Α) έχουν αποδοθεί όχι μόνο στη μείωση των επιπέδων χοληστερόλης αλλά και στις πλειοτροπικές τους δράσεις και ιδιαίτερα στις αντιοξειδωτικές τους δράσεις. Ο Nrf2 (NF-E2-related factor 2) είναι ένας μεταγραφικός παράγοντας που ενορχηστρώνει τη μεταγραφική απάντηση των κυττάρων στο οξειδωτικό στρες και σε ηλεκτροφιλικά ξενοβιοτικά με την έκφραση αντιοξειδωτικών-κυτταροπροστατευτικών γονιδίων. Στην παρούσα μελέτη, χρησιμοποιήθηκαν επίμυες Wistar, πρωτογενείς καλλιέργειες ηπατοκυττάρων, ST-2 κύτταρα και πρωτογενείς εμβρυϊκοί ινοβλάστες από μυς C57BL6J αγρίου τύπου (WT) ή με απαλοιφή του Nrf2 (KO-Nrf2) για τη μελέτη του ρόλου του Nrf2 στη διαμεσολάβηση των αντιοξειδωτικών δράσεων των στατινών. Η σιμβαστατίνη ενεργοποίησε τον Nrf2, δηλαδή οδήγησε στη μετακίνησή του στον πυρήνα στο ήπαρ επίμυων και σε πρωτογενή καλλιέργεια ηπατοκυττάρων. Η ανωτέρω δράση ήταν εξαρτώμενη από το μεβαλονικό και ανεξάρτητη από τη χοληστερόλη. Σε πυρηνικά πρωτεϊνικά εκχυλίσματα από ήπαρ επίμυων που έλαβαν σιμβαστατίνη, η μεταγραφική ενεργότητα του Nrf2 αυξήθηκε σημαντικά και το mRNA δύο γνωστών στόχων του Nrf2, ΗΟ-1 (Heme Oxygenase 1) και GPX-2 (Glutathione Peroxidase 2) αυξήθηκε. Σε ST-2 κύτταρα μόνιμα διαμολυσμένα με πλασμίδιο που φέρει αλληλουχία DNA στην οποία προσκολλάται ο Nrf2 (ARE-Antioxidant Response Element) (ARE-ST2 κύτταρα), η σιμβαστατίνη αύξησε τη μεταγραφική ενεργότητα του Nrf2 με τρόπο εξαρτώμενο από το μεβαλονικό και ανεξάρτητο από τη χοληστερόλη. Επίσης, χρησιμοποιώντας πρωτογενείς καλλιέργειες εμβρυϊκών ινοβλαστών από μυς WT και ΚΟ-Nrf2 και μετρώντας τα επίπεδα των αντιδραστικών ειδών οξυγόνου (ROS) μετά από επώαση με οξειδάση της γλυκόζης έπειτα από επίδραση ή μη με σιμβαστατίνη, διαπιστώθηκε ότι η σιμβαστατίνη μειώνει τα επίπεδα των παραχθέντων ROS στους WT ινοβλάστες και όχι σε μεγάλο βαθμό στους KO-Nrf2 ινοβλάστες. Τέλος, με τη χρήση αναστολέων του μονοπατιού της PI3K/Akt σε ARE-ST2 κύτταρα στα οποία είχαμε επιδράσει με σιμβαστατίνη, διαπιστώθηκε ότι αίρεται σε μεγάλο βαθμό η ενεργοποίηση του Nrf2 από τη σιμβαστατίνη. Στην παρούσα μελέτη παρουσιάζεται για πρώτη φορά α) η ενεργοποίηση του Keap1/Nrf2 σηματοδοτικού μονοπατιού σε in vivo και in vitro μοντέλα από τη σιμβαστατίνη με τρόπο εξαρτώμενο από το μεβαλονικό και ανεξάρτητο από τη χοληστερόλη και β) ότι η σιμβαστατίνη μειώνει τα παραγόμενα αντιδραστικά είδη οξυγόνου (ROS) μέσω της ενεργοποίησης του Nrf2 διαμέσου του μοριακού μονοπατιού της PI3K/Akt. H ενεργοποίηση αυτή του Nrf2 από τη σιμβαστατίνη εκτός του ότι προσφέρει αποτελεσματική προστασία του κυττάρου από τις δυσμενείς επιπτώσεις του οξειδωτικού στρες, εξηγεί και μέρος των πλειοτροπικών δράσεων των στατινών.

scholarly journals Identification of a novel Nrf2-regulated antioxidant response element (ARE) in the mouse NAD(P)H:quinone oxidoreductase 1 gene: reassessment of the ARE consensus sequence

2003 ◽  
Vol 374 (2) ◽  
pp. 337-348 ◽  
Author(s):  
Paul NIOI ◽  
Michael McMAHON ◽  
Ken ITOH ◽  
Masayuki YAMAMOTO ◽  
John D. HAYES
Keyword(s):  
Consensus Sequence ◽  
Constitutive Expression ◽  
Antioxidant Response ◽  
Upstream Region ◽  
Virus Protein ◽  
Related Factor ◽  
Antioxidant Response Element ◽  
Mobility Shift ◽  
Enhancer Activity ◽  
Response Element

NQO1 [NAD(P)H:quinone oxidoreductase 1] has an integral role in cellular responses to oxidative stress. The expression of NQO1 is up-regulated in the mouse following challenge with electrophilic chemicals, in an Nrf2 (NF-E2 p45-related factor 2)-dependent fashion, but the molecular basis for this observation remains unexplained. Through characterization of the murine nqo1 5′-upstream region, we now show that Nrf2 regulates this gene directly via an ARE (antioxidant response element) that lies within a 24 bp region spanning nt −444 to −421. A comprehensive mutation study of this ARE revealed that it does not conform to the currently accepted ARE consensus sequence [(5′-TMAnnRTGAYnnnGCRwwww-3′, with essential nucleotides shown in capitals); two cytosine residues (shown in bold in the following sequence) that have been designated ‘n’ previously because they were thought to be redundant (5′-gagTcACaGTgAGtCggCAaaatt-3′) have now been found to be essential for enhancer activity; two guanines (also shown in bold) previously regarded as essential for ARE function (5′-gagTcACaGTgAGtCggCAaaatt-3′) have proven to be dispensable]. Examination of wild-type and nrf2−/− mouse embryonic fibroblasts demonstrated that Nrf2 is essential for both constitutive expression of NQO1 and its induction by sulphoraphane. Electrophoretic mobility-shift and chromatin immunoprecipitation assays revealed that Nrf2 associates, in low amounts, with the nqo1 ARE under constitutive conditions, and following sulphoraphane challenge of cells, Nrf2 is recruited to the ARE in substantially greater quantities, as a heterodimer with the small Maf (musculoaponeurotic fibrosarcoma virus) protein, MafK. Also, MafK was found to bind the nqo1 ARE in an Nrf2-independent fashion, and may contribute to transcriptional repression of the oxidoreductase gene. These findings allow a model for transcriptional control of nqo1 through the ARE to be proposed. Furthermore, our results indicate that distinct AREs have differential sequence requirements, and a universally applicable consensus sequence cannot be derived.

scholarly journals Activation of the Nuclear Factor E2-Related Factor 2/Antioxidant Response Element Pathway Is Neuroprotective after Spinal Cord Injury

2012 ◽  
Vol 29 (5) ◽  
pp. 936-945 ◽  
Author(s):  
Xiaoliang Wang ◽  
Juan Pablo de Rivero Vaccari ◽  
Handong Wang ◽  
Paulo Diaz ◽  
Ramon German ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
Antioxidant Response ◽  
Related Factor ◽  
Nuclear Factor ◽  
Antioxidant Response Element ◽  
Response Element ◽  
Cord Injury
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