The emerging role of Nrf2 in mitochondrial function.

Endothelial dysfunction is an important risk factor for cardiovascular disease, and it represents the initial step in the pathogenesis of atherosclerosis. Failure to protect against oxidative stress-induced cellular damage accounts for endothelial dysfunction in the majority of pathophysiological conditions. Numerous antioxidant pathways are involved in cellular redox homeostasis, among which the nuclear factor-E2-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 (Keap1)-antioxidant response element (ARE) signaling pathway is perhaps the most prominent. Nrf2, a transcription factor with a high sensitivity to oxidative stress, binds to AREs in the nucleus and promotes the transcription of a wide variety of antioxidant genes. Nrf2 is located in the cytoskeleton, adjacent to Keap1. Keap1 acts as an adapter for cullin 3/ring-box 1-mediated ubiquitination and degradation of Nrf2, which decreases the activity of Nrf2 under physiological conditions. Oxidative stress causes Nrf2 to dissociate from Keap1 and to subsequently translocate into the nucleus, which results in its binding to ARE and the transcription of downstream target genes. Experimental evidence has established that Nrf2-driven free radical detoxification pathways are important endogenous homeostatic mechanisms that are associated with vasoprotection in the setting of aging, atherosclerosis, hypertension, ischemia, and cardiovascular diseases. The aim of the present review is to briefly summarize the mechanisms that regulate the Nrf2/Keap1-ARE signaling pathway and the latest advances in understanding how Nrf2 protects against oxidative stress-induced endothelial injuries. Further studies regarding the precise mechanisms by which Nrf2-regulated endothelial protection occurs are necessary for determining whether Nrf2 can serve as a therapeutic target in the treatment of cardiovascular diseases.

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The role of Nrf2 in oxidative stress-induced endothelial injuries

Molecular mechanisms of ethanol-associated oro-esophageal squamous cell carcinoma

The average length of human life is increasing, but so does the incidence of age- and lifestyle-related diseases. Improving diet and lifestyle is a key strategy for lifelong health and underlying mechanisms may well include increasing resilience pathways. The purpose of this review is to highlight and evaluate novel mechanisms by which dietary pro-oxidants, including bioactive phytochemicals and fatty acids, increase reactive oxygen species (ROS) concentrations just enough to activate transcription factor activation of nuclear factor erythroid 2 related factor 2 (Nrf-2) and heat shock factor (HSF), leading to an increase in levels of antioxidant enzymes and heat shock proteins that protect against the damaging effects of ROS. An increasing number of in vivo studies have now shown that dietary pro-oxidant compounds can increase the production of such resilience products. In most studies, dietary pro-oxidants normalized levels of antioxidant enzymes that were decreased by a range of different challenges, rather than raising levels of resilience products per se. Also, it is important to consider that the antioxidant response can be different for different organs. For future studies, however, the measurement of resilience markers may significantly improve our ability to prove the efficacy by which dietary bioactives with pro-oxidant capacities improve lifelong health.

Role of dietary pro-oxidants in the maintenance of health and resilience to oxidative stress.

Crosstalk between Nrf2 signaling and mitochondrial function in Parkinson's disease

Aims: Many East Asians are highly intolerant to even modest alcohol consumption. These individuals accumulate acetal- dehyde, the primary metabolite of ethanol, because of a genetic polymorphism of aldehyde dehydrogenase (ALDH) that metabolizes acetaldehyde to nontoxic acetate. The aim of these studies is to upregulate ALDH by dietary means, thereby reducing acetaldehyde tox- icity. Methods: Sulforaphane (SF, 1-isothiocyano-4-(methylsulfinyl)butane) derived from its glucosinolate precursor contained in cru- ciferous vegetables and related inducers of the Keap1/Nrf2/ARE pathway were assessed for their potencies to induce ALDH in murine hepatoma Hepa1c1c7 cells. Inducer potencies for ALDH were compared with those for NQO1, a prototypical cytoprotective enzyme present downstream of the Keap1/Nrf2/ARE pathway. SF (5 or 20 µmol/day) was fed to CD-1 mice for 7 days prior to a single adminis- tration of ethanol, and then ALDH induction in organs and pharmacokinetics of acetaldehyde was examined. Results: In addition to SF, other electrophiles, including many Michael reaction acceptors, induce ALDH. Potencies of these agents as inducers parallel their activ- ities in inducing NQO1, and are also dependent on Nrf2. In mice, in vivo, feeding of SF induced tissue ALDH and dramatically increased (doubled) the rate of elimination of acetaldehyde arising from the administration of ethanol. Conclusion: SF and other edible phytochemicals may ameliorate the alcohol intolerance of individuals who are polymorphic with respect to ALDH.

ORIGINAL ARTICLE Sulforaphane Accelerates Acetaldehyde Metabolism by Inducing Aldehyde Dehydrogenases: Relevance to Ethanol Intolerance

The present invention comprises methods and compositions for reducing ethanol toxicity due to accumulation of acetaldehyde in a cell. A method comprises administering to a cell a composition comprising a compound that increases the expression, the amount of, and/or the activity of at least one member of the aldehyde dehydrogenase superfamily.

Methods and compositions for reducing alcohol toxicity

La presente invention concerne des procedes et des compositions pour reduire la toxicite de l'ethanol due a l'accumulation d'acetaldehyde dans une cellule. Un procede consiste a administrer a une cellule une composition comprenant un compose qui augmente l'expression, la quantite et/ou l'activite d'au moins un membre de la superfamille des aldehyde deshydrogenases.

Yusuke Ushida

Papers

ORIGINAL ARTICLE Sulforaphane Accelerates Acetaldehyde Metabolism by Inducing Aldehyde Dehydrogenases: Relevance to Ethanol Intolerance

Methods and compositions for reducing alcohol toxicity

Procédés et compositions pour réduire la toxicité de l'alcool