Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles

Liu, Hua; Dinkova‐Kostova, Albena T.; Talalay, Paul

doi:10.1073/pnas.0808346105

Cited by 109 publications

(95 citation statements)

References 54 publications

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“…ITCs 5 and 8 are at least partially responsible for this effect, because they inhibited NO formation at 5 µM by 69% and 39%, respectively. Reduced iNOS expression and NO production by inducers of the phase 2 response, such as the isothiocyanate SF, have been correlated to suppression of inflammation (Liu, Dinkova-Kostova, & Talalay, 2008). The improved reduction by MC treatment over individual ITCs was also evident in NO production, but to a lesser degree than observed in the TNFa production experiments.…”

Section: Anti-inflammatory Activitymentioning

confidence: 66%

Stable, water extractable isothiocyanates from Moringa oleifera leaves attenuate inflammation in vitro

Waterman¹,

Cheng²,

Rojas-Silva³

et al. 2014

Planta Med

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Moringa (Moringa oleifera Lam.) is an edible plant used as food and medicine throughout the tropics. A moringa concentrate (MC) made by extracting fresh leaves with water utilized naturally occurring myrosinase to convert four moringa glucosinolates (1-4) into moringa isothiocyanates (5-8). Optimum conditions maximizing MC yield, compound 5 (4-[(α-Lrhamnosyloxy)benzyl]isothiocyanate), and compound 8 (4-[(4'-O-acetyl-α-Lrhamnosyloxy)benzyl]isothiocyanate) content were established (1:5 fresh leaf weight to water ratio at room temperature). The optimized MC contained 1.66% isothiocyanates and 3.82% total polyphenols. Compound 8 exhibited 80% stability at 37 °C for 30 days. MC, 5, and 8 significantly decreased gene expression and production of inflammatory markers in RAW macrophages. Specifically, 5 and 8 attenuated expression of iNOS and IL-1β and production of nitric oxide and TNFβ at 1 and 5 µM. Our results suggest a potential for stable and concentrated moringa isothiocyanates (5-8), delivered in MC as a food-grade product, to alleviate low-grade inflammation associated with chronic diseases.

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Section: Anti-inflammatory Activitymentioning

confidence: 66%

Stable, water extractable isothiocyanates from Moringa oleifera leaves attenuate inflammation in vitro

Waterman¹,

Cheng²,

Rojas-Silva³

et al. 2014

Planta Med

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“…Plots of log fa/fu with respect to log D are linear and a simple computer program permits determination of goodness of fit to linearity, the linear correlation coefficient, and the slope (Hill coefficient) of the lines. Application of this procedure to the increase (induction) of NQO1 have been described (37).…”

Section: Methodsmentioning

confidence: 99%

An Exceptionally Potent Inducer of Cytoprotective Enzymes

Dinkova‐Kostova

Talalay

Sharkey

et al. 2010

Journal of Biological Chemistry

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The Keap1/Nrf2/ARE pathway controls a network of cytoprotective genes that defend against the damaging effects of oxidative and electrophilic stress, and inflammation. Induction of this pathway is a highly effective strategy in combating the risk of cancer and chronic degenerative diseases, including atherosclerosis and neurodegeneration. An acetylenic tricyclic bis(cyano enone) bearing two highly electrophilic Michael acceptors is an extremely potent inducer in cells and in vivo. We demonstrate spectroscopically that both cyano enone functions of the tricyclic molecule react with cysteine residues of Keap1 and activate transcription of cytoprotective genes. Novel monocyclic cyano enones, representing fragments of rings A and C of the tricyclic compound, reveal that the contribution to inducer potency of the ring C Michael acceptor is much greater than that of ring A, and that potency is further enhanced by spatial proximity of an acetylenic function. Critically, the simultaneous presence of two cyano enone functions in rings A and C within a rigid three-ring system results in exceptionally high inducer potency. Detailed understanding of the structural elements that contribute to the reactivity with the protein sensor Keap1 and to high potency of induction is essential for the development of specific and selective lead compounds as clinically relevant chemoprotective agents.

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“…Inducers react with specific cysteine residues of the protein sensor Kelch-like ECH-associated protein 1 (Keap1) which loses its ability to target transcription factor NF-E2-related factor 2 (Nrf2) for ubiquitination and proteasomal degradation, resulting in stabilization of Nrf2, binding to the antioxidant response element (ARE) and transcriptional activation of cytoprotective genes, such as NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferases (GST), heme oxygenase 1, thioredoxin reductase, aldo-keto reductases (3)(4)(5)(6). Inducers are also antiinflammatory agents, and there is a linear correlation between these two biologic activities that spans 6 orders of magnitude of inducer concentrations (7,8). Semisynthetic pentacyclic triterpenoids (9)(10)(11) and related synthetic tricyclic compounds (12)(13)(14)(15) which contain Michael acceptors are the most potent inducers known to date, activating Nrf2 and inhibiting proinflammatory responses at sub-to low nanomolar concentrations (7,16,17).…”

Section: Introductionmentioning

confidence: 99%

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

Kalra

Knatko

Zhang

et al. 2012

Cancer Prevention Research

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Chronic treatment with azathioprine, a highly effective anti-inflammatory and immunosuppressive agent, profoundly increases the risk for development of unusually aggressive cutaneous squamous cell carcinoma. Its ultimate metabolite, 6-thioguanine (6-TG) nucleotide, is incorporated in DNA of skin cells, and upon exposure to UVA radiation, causes oxidative stress, followed by damage of DNA and associated proteins. The acetylenic tricyclic bis(cyano enone) TBE-31 is a strong inhibitor of inflammation and a potent inducer of the Keap1/Nrf2/ARE pathway, which orchestrates the expression of a large network of cytoprotective genes. We now report that long-term (five days per week for four weeks) topical daily applications of small (200 nmol) quantities of TBE-31 cause a robust systemic induction of the Keap1/Nrf2/ ARE pathway and decreases the 6-TG incorporation in DNA of skin, blood, and liver of azathioprine-treated mice, indicating extraordinary bioavailability and efficacy. In addition, TBE-31, at nanomolar concentrations, protects cells with 6-TG in their genomic DNA against oxidative stress caused by UVA radiation through induction of the Keap1/Nrf2/ARE pathway. At the same 6-TG DNA levels, Keap1-knockout cells, in which the pathway is constitutively upregulated, are highly resistant to UVA radiation-induced oxidative stress. The protective effects of both the Keap1-knockout genotype and TBE-31 are completely lost in the absence of transcription factor Nrf2. Our findings suggest that compounds of this kind are excellent candidates for mechanism-based chemoprotective agents against conditions in which oxidative stress and inflammation underlie disease pathogenesis. Moreover, their potential skin patch incorporation for transdermal delivery is an exciting possibility. Cancer Prev Res; 5(7); 973-81. Ó2012 AACR.

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Coordinate regulation of enzyme markers for inflammation and for protection against oxidants and electrophiles

Abstract: Keap1 ͉ NAD(P)H:quinone oxidoreductase ͉ Nrf2 ͉ sulforaphane ͉ inducible NOS

Cited by 109 publications

References 54 publications

Stable, water extractable isothiocyanates from Moringa oleifera leaves attenuate inflammation in vitro

Stable, water extractable isothiocyanates from Moringa oleifera leaves attenuate inflammation in vitro

An Exceptionally Potent Inducer of Cytoprotective Enzymes

Highly Potent Activation of Nrf2 by Topical Tricyclic Bis(Cyano Enone): Implications for Protection against UV Radiation during Thiopurine Therapy

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