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The primary aim of this review is to summarize the current literature on the effects of acute exercise and regular exercise on nuclear factor erythroid 2-related factor 2 (Nrf2) activity and downstream targets of Nrf2 signaling. Nrf2 (encoded in humans by the NFE2L2 gene) is the master regulator of antioxidant defenses, a transcription factor that regulates expression of more than 200 cytoprotective genes. Increasing evidence indicates that Nrf2 signaling plays a key role in how oxidative stress mediates the beneficial effects of exercise. Episodic increases in oxidative stress induced through bouts of acute exercise stimulate Nrf2 activation and when applied repeatedly, as with regular exercise, leads to upregulation of endogenous antioxidant defenses and overall greater ability to counteract the damaging effects of oxidative stress. The evidence of Nrf2 activation in response to exercise across variety of tissues may be an important mechanism of how exercise exerts its well-known systemic effects that are not limited to skeletal muscle and myocardium. Additionally there are emerging data that results from animal studies translate to humans., Graphical abstract fx1, Highlights • This review summarizes the current literature on the effects of exercise on Nrf2 signaling. • Acute exercise stimulates Nrf2 signaling through ROS production. • Nrf2 signaling plays a key role in how ROS mediate the beneficial effects of exercise. • Emerging data support translation of data from animal studies to humans.

MicroRNAs (miRNAs) are a class of short noncoding RNAs that modulate gene expression at both transcriptional and post-transcriptional levels. Many studies have extensively revealed the significance of miRNAs in mediating liver development and diseases. However, their role in hepatic detoxification processes has been explored only recently. In this review, we summarized the up-to-date knowledge about miRNA dependent regulation of enzymes involved in all three phases of the drugs and xenobiotics detoxification process. We also discussed the role of miRNA in regulating some upstream nuclear receptors involving gene expression of enzymes for detoxification process in liver. The toxicological significance of miRNAs in liver diseases and future research perspectives are finally presented.

Health benefits associated with consumption of cruciferous vegetables have received considerable attention with a hitherto focus on the role and bioactivity of glucosinolate degradation products. We investigated the in vivo metabolism of intact glucosinolates by following their fate in digesta and in the endogenous metabolism in pigs. This is the first study to show an intact glucosinolate, sinalbin, being absorbed and transformed to a sinalbin metabolite in the liver by glucuronidation expectedly performed by liver phase II enzymes with subsequent excretion to the urine. From LC–MS/MS data we propose a structure of the sinalbin metabolite as containing two 4-oxybenzyl groups. Sinalbin and the metabolite were detected in plasma from the hepatic vein with a ratio of metabolite to sinalbin of approximately 12:1 after 2–4 hours. Induction of liver phase II enzymes by intact glucosinolates indicates that these also themselves are bioactive compounds with potential health risks or beneficial effects.

Olive oil, the primary source of dietary fat in the Mediterranean diet, is reported to have benefits on bone health, mechanisms of which remain obscure. Here we investigated the protective effects of hydroxytyrosol (HT), a major polyphenol in olive on preosteoblast toxicity induced by acrolein, the major component of cigarette smoke. Acrolein at 75 µM, induced significant oxidative stress which was attributed to the inhibition of Nrf2 nuclear translocation and suppression of phase II enzymes. And HT could efficiently promote Phase II enzymes activation and prevent the decrease of antioxidative enzymes, protect the autophagy pathway and maintain the normal level of mitochondrial complexes. These results indicated that cigarettes smoking could damage preosteoblast cells by inducing oxidative stress and mitochondrial dysfunction. While through activation of Keap1/Nrf2 pathway, olive component HT could contribute to cellular protection and potential bone health.

Solids from wastewater of the tortilla industry, known as nejayote, are a potential source of chemopreventive phenolic compounds. Phenolic compounds were identified and quantified in nejayote solids obtained by filtration, as well as its antioxidant activity and chemopreventive effect. Bound phenolics and antioxidant capacity of nejayote were concentrated in the nejayote solution obtained after filtration (FSS) through 280 μm. Additionally, FSS contained 84, 79, 72 and 97% more bound ferulic, coumaric, 8-O-4-diferulic and 5-5′-diferulic acids, respectively, compared to total nejayote solids. Feruloyl putrescines, especially coumaroyl-feruloyl putrescine, isolated from bound FSS exerted 105% and 12.45% higher chemopreventive effect than nejayote and bound FSS, respectively. Feruloyl putrescines are potent phase II inducers due to their double nitrogen linked Michael acceptors structure. Feruloyl putrescines in nejayote are a source of natural chemopreventive agents capable of inducing phase II enzymes.

8 pages, 1 figure, 5 tables, The measurement of enzymatic activities involved in xenobiotic biotransformation was carried out in adults of Solea solea and Solea senegalensis. The hepatic enzymes analysed were cytochrome P450 (CYP) related activities using eight fluorometric substrates and carboxylesterases (CbE). The conjugating activities of glutathione S-transferase (GST) and UPD-glucuronosyltransferase (UDPGT) were also assessed. Specific mammalian inhibitors were used as diagnostic tools for related activities of CYP1A (α-naphthoflavone; αNF), CYP2B6 and CYP2C19 (ticlopidine) and CYP3A4 (ketoconazole). The in vitro sensitivity to organophosphorous pesticides (OP) was tested in the S10 homogenate of brain (acetylcholinesterase-AChE) and liver (CbE). Furthermore, the pesticide chlorpyrifos oxon (CLPO) was used to explore the OP sensitivity of CbE of both species in two subcellular fractions (microsomes and cytosol), using two substrates. Overall, only two parameters confirmed species differences: EROD and cytosolic CbE being significantly elevated (p < 0.05) in the common sole, S. solea. A high inhibition of CYP1A related activities using several fluorometric substrates (ER, MR and CEC) after in vitro incubation with αNF confirmed all measure CYP1A1-related activities whereas ketoconazole was more specific for BFCOD (CYP3A4). Pesticide sensitivity was similar for brain AChE but hepatic CbE had a protective role that was species and pesticide dependent, This work was financed by the Ministry of Science and Innovation of Spain (ref CTM2010-16611). Samuel Koenig holds a PhD grant (AFR 08/067) from the Fonds National de la recherche (FNR), Luxembourg

Sulforaphane is a type of sulfur-containing isothiocyanates hydrolyzed from glucosinolates by myrosinase found in Brassica plants. Sulforaphane is a naturally occurring inducer of phase II enzymes in human and animal bodies to detoxify cancer-causing chemicals. Glucoraphanin is the precursor of sulforaphane and its content is greatly influenced by plant species and genotype, plant organs, pre-harvest factors, and post-harvest processing, thus sulforaphane formation is also directly influenced. Here, we review the formation mechanism of sulforaphane and the factors influencing sulforaphane formation. In the end, the future directions are also discussed.

Green plant-origin electrophilic compounds are a newly-recognized class of neuroprotective compounds that provide neuroprotection through activation of the Nrf2/ARE pathway. Electrophilic hydroquinones are of particular interest due to their ability to become electrophilic quinones upon auto-oxidation. Although marine organisms frequently produce a variety of electrophilic compounds, the detailed mechanisms of action of these compounds remain unknown. Here, we focused on the neuroprotective effects of strongylophorine-8 (STR8), a para-hydroquinone-type pro-electrophilic compound from the sponge Petrosia (Strongylophora) corticata. STR8 activated the Nrf2/ARE pathway, induced phase 2 enzymes, and increased glutathione, thus protecting neuronal cells from oxidative stress. Microarray analysis indicated that STR8 induced a large number of phase 2 genes, the regulation of which is controlled by the Nrf2/ARE pathway. STR8 is the first example of a neuroprotective pro-electrophilic compound from marine organisms.

This review summarizes the epidemiologic, biochemical and genetic evidence associating occupational, environmental or experimental exposure to 1,3-butadiene (BD) with subsequent development of cardiovascular disease, with the primary focus on atherosclerosis. The potential role of BD in the known atherosclerotic effects of environmental tobacco smoke as well as correlations between polymorphisms in BD phase II enzymes and development of atherosclerosis are presented.

Herbs have been utilized to treat acute and chronic disorders for thousands of years. The scientific basis for such utilization, however, has been poorly understood. Nonetheless, in the past few decades, significant advances in experimental methodology and molecular biology enabled researchers to investigate the potential use of phytochemicals to treat or manage a plethora of chronic diseases including various types of cancer, inflammatory diseases and cardiovascular abnormalities. This review summarizes some of the molecular mechanisms through which several phytochemicals may inhibit inflammation and cancer. In addition, the review discusses basic definitions, ethical and clinical aspects and some guidelines for the use of phytochemicals as chemopreventive or therapeutic agents.

Little is known about the effects of aging on the hepatic drug metabolizing capacity of horses despite the relatively long lifespan characterizing this species. A wide array of cytochrome P450 (CYP)-dependent monooxygenases, carboxylesterases and transferases were assayed in liver microsomes from 50 female horses in an age range between less than 1 year to over 12 years. Rather unexpectedly, both the CYP content and the activity of NADPH cytochrome c reductase rose as a function of age. Accordingly, a general increasing trend was recorded in the rate of the in vitro metabolism of the substrates reported to be related to CYP2B-, CYP2E- or CYP3A, although, as detected by Western immunoblotting, only the levels of proteins recognized by anti-rat CYP3A- and CYP2B antibodies appeared to increase consistently. Also the carboxylesterases and uridindiphosphoglucuronyl-transferase (UGT) activity toward 1-naphthol displayed a similar trend, glutathione S-transferase accepting 3,4-dichloronitrobenzene as a substrate being the only enzyme activity showing an age-related decline. A positive correlation was also found between liver cadmium content and CYP amount as well as the activities of most monooxygenases (except for those related to CYP1A), carboxylesterases, and UGT. While confirming that a number of enzyme activities are less expressed in foals, our results contradict the general view that the drug metabolizing capacity drops in elder individuals. Although several other factors can influence the kinetics of foreign compounds in aged animals, data from this study may provide insight in understanding possible age-related differences in drug efficacy and the response to toxic substances in horses.

The recognition that oxidative stress plays a major role in the pathophysiology of cardiac disorders has led to extensive investigation of the protective effects of exogenous antioxidants. Another strategy may be through induction of the endogenous antioxidants/phase 2 enzymes. Accordingly, this study was undertaken to investigate the inducibility of endogenous antioxidants/phase 2 enzymes (reduced glutathione (GSH), GSH peroxidase (GPx), glutathione reductase (GR), GSH S-transferase (GST), and NAD(P)H:quinone oxidoreductase 1 (NQO1)) by the isothiocyanate sulforaphane (SF) in cultured rat cardiomyocytes. Due to the role of the nuclear factors E2-related factor 1 (nrf1) and 2 (nrf2) in inducing phase 2 enzymes, we also investigated the role of SF in the translocation of these factors from cytosol to the nucleus. Enzymatic activities were determined spectrophotometrically, GSH by the fluorescent indicator monochlorobimane, reactive oxygen species (ROS) formation spectrofluorimetrically by 2′,7′-dichlorofluorescein diacetate, cell viability by MTT assay, nrf1 and nrf2 translocation to nucleus by laser confocal microscopy. GPx activity was not affected by SF, but GR, GST and NQO1 activities and GSH levels increased with a time-dependent pattern following SF supplementation. As a consequence SF supplementation led to decreased ROS levels and increased cell viability following oxidative stress. Laser confocal microscopy revealed the translocation of both nrf1 and nrf2 to the nucleus. In conclusion, SF acts as an indirect antioxidant leading to cardioprotection against oxidative stress.

TO THE EDITORSequence variation in genes coding forphase I and phase II enzymes, includingmembers of cytochrome P450 (CYP)family may alter individual suscepti-bility to cancer (Hashibe et al., 2003) aswell as other chronic diseases includingcoronary heart disease and psoriasis.The observation by Kra¨mer and Esser(2006) of a stronger association be-tween smoking and psoriasis in subjectswith non-variant CYP1A1 genotype andpsoriasis in current smokers comparedto non or former smokers, goes alongthis line. This is therefore a usefulobservation. However, there is no sig-nificant heterogeneity across strata ofsmoking status in Table 1 of the originalpaper by Kra¨mer and Esser, this under-lines the difficulties in studying gene–environmental interaction and the re-quirement of very large sample size (ie,in the order of thousand rather thanhundred subjects) for studying it (Wangand Zhao, 2003; Wacholder et al., 2004).Luigi Naldi