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Sussan TE, Rangasamy T, Blake DJ, Malhotra D, El-Haddad H, Bedja D, et al. Targeting Nrf2 with the triterpenoid CDDO-imidazolide attenuates cigarette smoke-induced emphysema and cardiac dysfunction in mice

Department of Environmental Health Sciences, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 01/2009; 106(1):250-5. DOI: 10.1073/pnas.0804333106
Source: PubMed

ABSTRACT Chronic obstructive pulmonary disease (COPD), which comprises emphysema and chronic bronchitis resulting from prolonged exposure to cigarette smoke (CS), is a major public health burden with no effective treatment. Emphysema is also associated with pulmonary hypertension, which can progress to right ventricular failure, an important cause of morbidity and mortality among patients with COPD. Nuclear erythroid 2 p45 related factor-2 (Nrf2) is a redox-sensitive transcription factor that up-regulates a battery of antioxidative genes and cytoprotective enzymes that constitute the defense against oxidative stress. Recently, it has been shown that patients with advanced COPD have a decline in expression of the Nrf2 pathway in lungs, suggesting that loss of this antioxidative protective response is a key factor in the pathophysiological progression of emphysema. Furthermore, genetic disruption of Nrf2 in mice causes early-onset and severe emphysema. The present study evaluated whether the strategy of activation of Nrf2 and its downstream network of cytoprotective genes with a small molecule would attenuate CS-induced oxidative stress and emphysema. Nrf2(+/+) and Nrf2(-/-) mice were fed a diet containing the potent Nrf2 activator, 1-[2-cyano-3-,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole (CDDO-Im), while being exposed to CS for 6 months. CDDO-Im significantly reduced lung oxidative stress, alveolar cell apoptosis, alveolar destruction, and pulmonary hypertension in Nrf2(+/+) mice caused by chronic exposure to CS. This protection from CS-induced emphysema depended on Nrf2, as Nrf2(-/-) mice failed to show significant reduction in alveolar cell apoptosis and alveolar destruction after treatment with CDDO-Im. These results suggest that targeting the Nrf2 pathway during the etiopathogenesis of emphysema may represent an important approach for prophylaxis against COPD.

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Available from: Deepti Malhotra, Dec 24, 2013
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    • "Recent studies have shown that Nrf2 also plays an essential role in protecting against acute pulmonary injury, smoke-induced emphysema, and asthma [15] [16] [17]. Thus, it is possible that Nrf2 is an excellent therapeutic target for the treatment of those inflammatory lung diseases including ALI [18] [19]. Alisma orientale Juzepzuk has been used as an herbal medicine for the treatment of a variety of disorders [20]. "
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    ABSTRACT: Although Alisma orientale, an ethnic herb, has been prescribed for treating various diseases in Asian traditional medicine, experimental evidence to support its therapeutic effects is lacking. Here, we sought to determine whether A. orientale has a therapeutic effect on acute lung injury (ALI). Ethanol extract of the tuber of A. orientale (EEAO) was prepared and fingerprinted by HPLC for its constituents. Mice received an intraperitoneal (i.p.) injection of lipopolysaccharide (LPS) for the induction of ALI. At 2 h after LPS treatment, mice received an intratracheal (i.t.) spraying of various amounts of EEAO to the lung. Bioluminescence imaging of transgenic NF- κ B/luciferase reporter mice shows that i.t. EEAO posttreatment suppressed lung inflammation. In similar experiments with C57BL/6 mice, EEAO posttreatment significantly improved lung inflammation, as assessed by H&E staining of lung sections, counting of neutrophils in bronchoalveolar lavage fluid, and semiquantitative RT-PCR analyses of proinflammatory cytokines and Nrf2-dependent genes in the inflamed lungs. Furthermore, EEAO posttreatment enhanced the survival of mice that received a lethal dose of LPS. Together, our results provide evidence that A. orientale has a therapeutic effect on ALI induced by sepsis.
    Evidence-based Complementary and Alternative Medicine 07/2013; 2013:863892. DOI:10.1155/2013/863892 · 1.88 Impact Factor
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    • "A variety of interventions have been shown to reduce myocardial infarct size in animals; however, these interventions have translated poorly to man (Yellon and Hausenloy, 2007). While other Nrf2 inducers may be cardioprotective, including sulforaphane (found in broccoli) (Mukherjee et al., 2008), hydrogen sulphide (Calvert et al., 2009), and triterpenoid CDDO-imidazolide (Sussan et al., 2009), they lack human safety data, may be difficult to administer, and may have a low therapeutic index. "
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    Cell metabolism 03/2012; 15(3):361-71. DOI:10.1016/j.cmet.2012.01.017 · 16.75 Impact Factor
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    • "Recently, it has been shown that wild-type mice exposed to cigarette smoke, when treated with CDDO-Im [imidazole and methyl ester derivative of 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO)] exhibited significant reductions in both oxidative stress and alveolar destruction with increased transcriptional induction of multiple Nrf2-regulated antioxidant genes (Biswal et al., 2008; Sussan et al., 2009). However, Nrf2 knockout mice had no significant reduction in alveolar destruction following treatment with CDDO-Im (Biswal et al., 2008; Sussan et al., 2009). These data suggest that activation of the Nrf2 pathway, stabilization of DJ1 and reversing posttranslational carbonyl modifications of Nrf2, Keap1 and DJ1 using different approaches can be developed to protect lungs against cigarette smoke/oxidative stress-induced inflammatory response and emphysema. "
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