Abstract
Graphical abstract
Abstract
Intake of a variety of vegetables and fruit is found to be effective in promoting health; one of the reasons for this is activation of nuclear factor erythroid 2-related factor 2 (Nrf2), a basic leucine zipper protein. Nrf2 is activated by chemical modification of Kelch-like ECH-associated protein 1 (Keap1), a negative regulator for this transcription factor, and specific phosphorylation of Nrf2, resulting in upregulation of its downstream gene products for antioxidant proteins, phase-II xenobiotic-metabolizing enzymes, and phase-III transporters. This type of activation plays a role in adaptive response and protection against oxidative and electrophilic stress. Multiple phytochemicals, such as curcumin, sulforaphane, and (E)-2-alkenals, have been identified as Nrf2 activators and may reduce the adverse health effects of oxidants and electrophiles. In this review, we introduce plant components that are known as Nrf2 activators and associated phytochemical-mediated reduction of risk from chemicals which cause oxidative and electrophilic stress. We also discuss the capture and inactivation of methylmercury, an electrophile, by sulfane sulfur atoms contained in garlic.
Introduction
Vegetables and fruits contain large numbers of chemicals with multiple functions. Of them, some plant chemicals serve as chemopreventive agents and are known to exhibit activation of nuclear transcription factor erythroid 2-related factor-2 (Nrf2), a basic leucine zipper protein (Andrews et al. 1993, Moi et al. 1994, Surh 2003, Surh et al. 2008). Once such a transcription factor is activated, its downstream proteins such as antioxidant proteins, phase-II xenobiotic detoxication enzymes, and phase-III transporters are upregulated (Itoh et al. 1997, Alam et al. 1999, Hayashi et al. 2003, Tanigawa et al. 2007). Electrophiles have higher toxicity because of their ability for covalent modification to endogenous nucleophiles such as thiol groups or amino groups of proteins (Lopachin et al. 2012, Kumagai & Abiko 2017). Electrophile-mediated upregulation of downstream proteins of Nrf2 plays an important role in the detoxication of the reactive compounds, which induce oxidative stress or electrophilic stress, to overcome their toxicity as Nrf2 comprehensively regulates proteins to reduce reactive oxygen species (ROS) and to facilitate the excretion of xenobiotics. Several lines of evidence have indicated that phytochemicals causing Nrf2 activation repress xenobiotic-mediated toxicity at a low dose but cause toxicity at a high dose, indicating a concept of ‘fight fire with fire by intake of phytochemicals’. Here, we provide information about phytochemicals which activate Nrf2 and examples of Nrf2 activation-mediated detoxication of xenobiotics.
The Keap1–Nrf2 pathway
E3 ubiquitin ligase Kelch-like ECH-associated protein 1 (Keap1) negatively regulates Nrf2 through degradation via the ubiquitin–proteasome pathway to keep cellular levels of Nrf2 minimal (Itoh et al. 1999, Taguchi et al. 2011). Human Keap1 has 27 Cys residues (25 Cys in mouse Keap1), which are sensitive to electrophiles or hydrogen peroxide. Cys151, Cys273, and Cys288 are known to be the highly reactive Cys among the 27 Cys residues (Kobayashi & Yamamoto 2006, Sekhar et al. 2010). Once a reactive thiol group of Keap1 is modified by hydrogen peroxide or an electrophile, Keap1 loses its function and de novo Nrf2 accumulates in the cells (Itoh et al. 1999, Suzuki et al. 2019). The accumulated Nrf2 translocates into the nucleus and then binds to small Maf protein, followed by binding to the antioxidant response element (ARE) or electrophile response element (EpRE) on DNA (Friling et al. 1990, Itoh et al. 1997, Rushmore & Pickett 1990) (Fig. 1). Inhibition of the ubiquitin–proteasome pathway also provokes accumulation and nuclear translocation of Nrf2 (Aono et al. 2003, Itoh et al. 2003). In addition, phosphorylation of Nrf2 regulates its degradation and activation. Glycogen synthase kinase 3β (GSK-3β)-mediated phosphorylation of Ser335 and Ser338 on the Neh6 domain of Nrf2 recruits E3 ubiquitin ligase β-transducin repeat-containing protein (β-TrCP) to facilitate Keap1-independent degradation via the ubiquitin–proteasome pathway (Rada et al. 2011). Phosphorylation of Ser40 of Nrf2 at the Neh2 domain, which interacts with Keap1, by protein kinase C (PKC) promotes dissociation of Nrf2 from Keap1, leading to nuclear translocation of Nrf2 (Huang et al. 2002). Cyclin-dependent kinase 5 (CDK5) promotes phosphorylation of Thr395, Ser433, and Ser439 to activate Nrf2 (Jimenez-Blasco et al. 2015) (Fig. 1). Phosphorylation of Ser550 at the nuclear exporting motif of Nrf2 by AMP-activated kinase is thought to inhibit the export of Nrf2 from the nucleus (Joo et al. 2016). Mitogen-activated protein kinase (MAPK) signaling pathways such as extracellular signal-related kinase (ERK), c-Jun N-terminal kinase, and p38 are also known to contribute to Nrf2 activation by direct and indirect phosphorylation of Nrf2 (Sun et al. 2009, Choi et al. 2016, Liu et al. 2021). As a result of Nrf2 transcriptional activation, antioxidative proteins such as NAD(P)H: quinone oxidoreductase-1 (NQO1), heme oxygenase 1 (HO-1), glutamate-cysteine ligases (GCLs), phase-II xenobiotic-metabolizing enzymes such as glutathione S-transferases (GSTs) and UDP-glucuronosyltransferases (UGTs) and phase-III transporters such as MRPs are upregulated (Fig. 1). Some environmental chemicals such as arsenite and 9,10-phenanthrene quinone induce oxidative stress following the generation of ROS and/or interference with antioxidants in cells (Hu et al. 2020, Abiko et al. 2022). Excessive ROS derived from chemical exposure causes oxidative inactivation of cellular proteins, resulting in toxicity (Fig. 2A). Antioxidative proteins, regulated by Nrf2, reduce ROS production. GCLs are a rate-limiting enzymes in the synthesis of GSH, a Cys-containing tripeptide (Griffith 1999). Electrophiles undergo GSH conjugation catalyzed by GSTs, forming their GSH adducts which are excreted into extracellular spaces through MRPs (Ballatori & Rebbeor 1998) (Fig. 2B). It should be noted that chemicals which are conjugated by GSH, such as arsenite, are also detoxified by the same pathway. UGTs catalyze glucuronic acid conjugation of hydroxy group of chemicals, leading to the detoxication of chemicals (Tukey & Strassburg 2000). Thus, Nrf2 comprehensively regulates proteins, which relate to the detoxication and excretion of xenobiotics. Therefore, Nrf2 is primed to rapidly respond to injury induced by oxidative and electrophilic stresses. The activation of the Keap1–Nrf2 pathway helps cells to detoxify chemicals, whereas the electrophilicity of the chemicals is also associated with the modification of nucleophiles in macromolecules (e.g. proteins or DNA) in cells. However, this causes a paradox; electrophiles at a lower dose selectively activate the Keap1–Nrf2 pathway, but a higher dose of them disrupts the system and cellular homeostasis because of non-specific modification by electrophiles (Kumagai & Abiko 2017, Abiko et al. 2021a ). Natural substances do not always have a health benefit and such health effects have a bell-shaped dose–response profile. Therefore, intake of phytochemicals exhibiting electrophilic properties should be at an appropriate dose, thereby activating Nrf2, giving a strategy to alleviate health risks associated with environmental chemicals (Fig. 2C).
Activation of the Keap1–Nrf2 pathway by electrophiles. Under normal conditions, Nrf2 undergoes degradation via the ubiquitin–proteasome pathway, mediated by Keap1. Under electrophilic or oxidative stress, the function of Keap1 is disrupted by electrophilic modification, and newly synthesized Nrf2 accumulates. Inhibition of the ubiquitin–proteasome pathway also causes the accumulation of Nrf2. The accumulated Nrf2 translocates into the nucleus to bind to small Maf and the hetero dimer binds to ARE on DNA, leading to induction of antioxidative enzymes, phase-II xenobiotic detoxication enzymes, and phase-III transporters. Nrf2 activation is also negatively or positively regulated by phosphorylation of Nrf2. For example, protein kinase C (PKC) and cyclin-dependent kinase 5 (CDK5) are phosphorylated at Ser40, Thr395, Ser433, and Ser439 of Nrf2, leading to the activation of Nrf2. Phosphorylation at Ser335 and Ser338 in the Neh6 domain of Nrf2, which interacts with β-transducin repeat-containing protein (β-TrCP), by glycogen synthase kinase 3β (GSK-3β), leads to β-TrCP-dependent degradation of Nrf2.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-22-0021
Reduction of oxidative and electrophilic stress by downstream proteins of Nrf2. (A) Excess amount of ROS derived from exposure of chemicals irreversibly oxidize proteins, leading to loss of their function. Antioxidant proteins regulated by Nrf2 reduce the production of ROS. (B) GSH is produced from cysteine by enzymes such as GCL and electrophiles are conjugated by GSH catalyzed by GSTs. Electrophile-GSH adduct (E-SG) is excreted into extracellular spaces through MRPs, resulting in the reduction of electrophilic stress. (C) Phytochemical-mediated Nrf2 activation through Keap1 modification and/or Nrf2 phosphorylation upregulates downstream proteins of Nrf2, which relate to reduction of oxidative and electrophilic stress.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-22-0021
Nrf2 activators in edible plants
(E)-2-Alkenal
(E)-2-Alkenals have an α,β-unsaturated carbonyl moiety (Fig. 3), which acts as a Michael acceptor and is attacked by nucleophiles, forming (E)-2-alkenal–nucleophile adducts (Lopachin et al. 2012). CoriandrumSativum L. leaf (Cilantro) oil contains a series of (E)-2-alkenals (C6, C9–16) and (E)-2-decenal (C10), which is the most abundant (E)-2-alkenal in the leaf (Potter & Fagerson 1990, Potter 1996, Abiko et al. 2014). We previously demonstrated that treatment of HepG2 cells with cilantro hexane extract activates Nrf2 and that scavenging of the electrophiles in the extract by GSH markedly diminishes Nrf2 activation (Abiko et al. 2014) (Fig. 4). (E)-2-Decenal, the main component of cilantro oil, modifies Keap1 at Cys257 and His274 and activates Nrf2 in HepG2 cells (Abiko et al. 2020). The non-toxic concentration of a prototype (E)-2-alkenal, (E)-2-butenal, but not butanal, also activates Nrf2, indicating that an α,β-unsaturated carbonyl moiety is crucial for Nrf2 activation. Combined exposure of HepG2 cells to lower concentrations of (E)-2-decenal, (E)-2-dodecenal (C12), and (E)-2-hexenal (C6) activates Nrf2, whereas individual exposure to each (E)-2-alkenal does not significantly activate Nrf2 at the same concentrations (Abiko et al. 2020). A similar result was observed in an experiment with (E)-2-hexenal, atmospheric electrophile 1,2- and 1,4-naphthoquinone. (E)-2-Hexenal-mediated Nrf2 activation was enhanced by co-exposure of a low concentration, which did not activate Nrf2 of 1,2- and 1,4-naphthoquinone (Abiko et al. 2021a ). Although the concentration of each (E)-2-alkenal in Cilantro does not cause Nrf2 activation, a harmonized effect of the electrophiles can activate Nrf2 to induce its downstream proteins. (E)-2-Hexenal is generated from fatty acids such as linoleic acid in plants and is a component of the grassy smell contained in various vegetables and fruits such as cabbage, soybean, Japanese persimmon, and bananas (Hatanaka 1993). Thus, a combined effect of (E)-2-alkenals is also expected by the intake of such vegetables and fruit.
Representation of phytochemicals as Nrf2 activators in edible plants.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-22-0021
Detoxication of arsenite by Cilantro through Nrf2 activation. Cilantro contains a series of (E)-2-alkenals in the lipophilic fraction, which were detected in the cilantro hexane extract. (E)-2-Alkenals activate Nrf2 through modification of Keap1 and induce its downstream proteins such as HO-1, GCL, GSTs, and MRPs. HO-1 suppresses toxicity of inorganic arsenite (iAsIII) presumably through decreasing iAsIII-mediated oxidative stress. GCL is the rate-limiting enzyme for GSH synthesis. iAsIII is detoxified by GSH conjugation catalyzed by GSTs to from arsenic glutathione adduct (As(SG)3), which is excreted into extracellular spaces through MRPs.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-22-0021
Capsaicin
Capsaicin (8-methyl-N-vanillyl-6-nonenamide, Fig. 3), an agonist of transient receptor potential vanilloid 1 (TRPV1) sensing pain and painful heat (Caterina et al. 2000, Jordt & Julius 2002), is a phytochemical in Capsicum spp. such as Capsicum annuum L., chili pepper. Exposure of HepG2 cells to capsaicin induced HO-1, causes translocation of Nrf2 into the nucleus, and activates protein kinase B (Akt) (Joung et al. 2007). HO-1 induction was suppressed by phosphoinositide 3-kinase (PI3K) inhibitor LY29002, indicating that capsaicin-mediated HO-1 induction was, at least partly, due to transactivation of Nrf2 through the activation of the PI3K–Akt signaling pathway (Joung et al. 2007). The PI3K–Akt signaling pathway is a downstream cascade of TRPV1 and hepatocytes including HepG2 cells expressing TRPV1 (Tang & Nakata 2008, Li et al. 2012, Jiang et al. 2018), suggesting that TRPV1 contributes to Nrf2 activation by capsaicin in cells. Activation of TRPV1 by capsaicin enhanced the translocation of Nrf2 via phosphorylation of calcium/calmodulin-dependent protein kinase II in lipopolysaccharide-treated RAW264.7 cells (Lv et al. 2021). These results suggest that the phosphorylation signaling triggered by TRPV1 activation mainly contributes to the activation of Nrf2 on exposure to capsaicin in these cells. Furthermore, capsaicin transformed to electrophilic metabolites such as its epoxide, o-quinone, and radical by enzymatic reaction of cytochrome P450, two-electron oxidation following o-demethylation at the 3-methoxy group, and one-electron oxidation, respectively (Surh & Lee 1995). Using a tritium-labeled capsaicin analog, 8-methyl-N-vanillyl-nonenamide, Miller et al. have shown covalent binding of the compound to proteins in the liver, presumably due to the metabolic activation of the capsaicinoid (Miller et al. 1983). Furthermore, it has been shown that an o-quinone, 1,2-naphthoquinone, activates Nrf2 through S-modification of Keap1 (Miura et al. 2011); the o-quinone metabolite of capsaicin and capsaicinoids can modify Keap1 to activate Nrf2. Capsaicin-mediated Nrf2 activation in hepatic cells may be partially induced by electrophilic metabolites in hepatic cells.
Curcumin
Curcumin (diferuloylmethane, Fig. 3), a major component of turmeric (Curcumalonga L.), with two α,β-unsaturated carbonyl moieties has been reported to activate Nrf2 similarly to (E)-2-alkenal (Balogun et al. 2003, Dickinson et al. 2003, Surh et al. 2008). Curcumin binds to Keap1 at Cys151, which is a highly reactive Cys, and prolongs the half-life of Nrf2, leading to the transcriptional activation of Nrf2 (Shin et al. 2020). The Keap1–Nrf2 complex was disrupted by curcumin to bind ARE and induce the Ho-1 gene in rat kidney epithelial NRK-52E cells; curcumin-mediated increase of reporter activity of the Ho-1 gene promotor region detected by luciferase assay was diminished by using a p38 inhibitor (Balogun et al. 2003). This suggests that the p38 pathway also plays a role in Nrf2 activation upon curcumin exposure (Balogun et al. 2003). Furthermore, p38 is known to contribute to inactivation and activation of Nrf2 (Liu et al. 2021). Previous research has shown that a non-electrophilic analog of curcumin, tetrahydrocurcumin, neither activates Nrf2 nor induces downstream proteins such as HO-1, indicating the importance of electrophilicity of curcumin in transcriptional activation of Nrf2 (Pae et al. 2007, Shin et al. 2020). Lu et al. demonstrated that curcumin suppresses alcohol-induced toxicity in human hepatocyte-like cell line LO2 and transfection of siNrf2 cancels the cytoprotective effect of curcumin (Lu et al. 2016). In vivo experiments also revealed that curcumin inhibits alcohol-induced necroptosis through the activation of Nrf2. Therefore, curcumin is an Nrf2 activator in vitro and in vivo. However, bioavailability of curcumin is low because of its low solubility in water (1.34 ± 0.02 mg/L) (Carvalho et al. 2015), whereas Ravindranath and Chandrasekhara reported that 60–66% of curcumin (400 mg, oral administration) is absorbed in rats (Ravindranath & Chandrasekhara 1980, 1981). To increase curcumin bioavailability, several studies have increased its absorption by developing a phospholipid complex of curcumin, curcumin nanoparticles, and a γ-cyclodextrin curcumin formulation (Maiti et al. 2007, Mohanty & Sahoo 2010, Purpura et al. 2018, Feltrin et al. 2022). Such technology can be applied to supplement curcumin.
Diallyl sulfide
Diallyl sulfide (DAS), diallyl disulfide (DADS), and diallyl trisulfide (DATS, Fig. 3) are volatile organosulfur compounds in Allium sativum L. (garlic) which are produced by decomposition of allicin (Yamaguchi & Kumagai 2020). While the sulfur within the disulfide bond of DADS and DATS can react with thiols in other compounds or proteins and then yield allylated moieties, allyl mercaptans, or allyl disulfides through thiol exchange reactions (Fig. 5A), DAS cannot undergo thiol exchange reactions with thiolates (Viswanatharaju Ruddraraju et al. 2017). However, the allyl moiety of oxidized DAS, diallyl sulfone, is able to modify thiols (Viswanatharaju Ruddraraju et al. 2017) (Fig. 5B). These observations suggest that DADS and DATS can modify Keap1 and activate Nrf2. Consistent with this, Surh and colleagues found that DATS modified Cys151, 273, and 288 of Keap1 and identified that Cys288 was crucial for DATS-mediated Nrf2 activation (Kim et al. 2014). They also showed that DADS, but not DAS, enhances nuclear translocation of Nrf2 and induction of HO-1 in human gastric epithelial AGS cells (Kim et al. 2014). In human embryonic MRC-5 cells, Nrf2 accumulation by DAS was suppressed by ERK and a p38 inhibitor, indicating a contribution of the ERK–p38 pathway to the Nrf2 accumulation (Ho et al. 2012). S-Modifications of Keap1 and phosphorylation of Nrf2 are both important for the activation of Nrf2 as described in the previous section; the different contributions of each pathway to Nrf2 activation may depend on the expression pattern of the proteins in each cell type.
Reaction of diallyl disulfide, diallyl trisulfide (A), and oxidized diallyl sulfide (B) with thiol compounds.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-22-0021
Sulforaphane
Brassicaceae have glucosinolate in the S-cells that is cleaved to sugar and isothiocyanate (R-N=C=S) moieties by myrosinase in the myrosin cells (Koroleva et al. 2000, Shirakawa et al. 2021). Thiols easily attack the electrophilic carbon on the isothiocyanate moiety to form irreversible thiol adducts, and isothiocyanates are capable of activating the Keap1–Nrf2–ARE pathway (Morimitsu et al. 2002, Ernst et al. 2011, Shibata et al. 2011, Cheng et al. 2019). Sulforaphane [(−)-1-isothiocyanato-(4R)-(methylsulfinyl)butane, Fig. 3] in Brassica oleraceaitalica (broccoli) is a well-known isothiocyanate as an Nrf2 activator through S-modification of Keap1 at Cys253, Cys273, Cys288, and Cys297 (Zhang et al. 1992, Dinkova-Kostova et al. 2002), leading to the induction of downstream proteins of Nrf2 such as HO-1, NQO1, and GSTs in vitro and invitro (Zhang et al. 1992, Riedl et al. 2009). While a high dose of sulforaphane induces toxicity because of its high reactivity, sulforaphane is used in clinical trials to reduce health risks from, for example, air pollution, COPD, and diabetes (Yagishita et al. 2019). A randomized clinical trial in China revealed that daily intake of beverages containing glucoraphanin, which is the precursor of sulforaphane, and sulforaphane enhances excretion of GSH-derived conjugates of airborne pollutants such as benzene and acrolein (Egner et al. 2014). However, acute and chronic toxicities of sulforaphane are not well characterized in vivo. Exposure of Albino Swiss mice to a high dose of sulforaphane (200 mg/kg) reduces white blood cells and the 50% lethal dose is 212.67 mg/kg, suggesting the importance of evaluating the risk-to-benefit ratio (Socala et al. 2017).
[6]-Shogaol
ZingiberOfficinale Roscoe is commonly known as ginger and has a characteristic flavor. Many types of aromatic compounds are produced from aromatic amino acids such as phenylalanine via the phenylpropanoid pathway; [6]-gingerol, [(S)-5-hydroxy-1-(4-hydroxy-3-methoxyphenyl)-3-decanone (Fig. 3)] is produced in the pathway via the formation of p-coumaroyl-CoA as an intermediate (Neish 1960, Semwal et al. 2015). [6]-Gingerol undergoes oxidation during cooking with heat or a drying process to yield [6]-shogaol [1-(4-hydroxy-3-methoxyphenyl)-4-decen-3-one], containing an α,β-unsaturated carbonyl (Semwal et al. 2015). The levels of [6]-gingerol and [6]-shogaol in raw ginger rhizome were 9.3 and 2.3 mg/g, respectively (Lee et al. 2007). It is known that [6]-shogaol is a more powerful phytochemical than [6]-gingerol in ginger, whereas the concentration of [6]-shogaol is lower than that of [6]-gingerol (Semwal et al. 2015). Thiol-conjugated metabolites of shogaols such as mercapturic acid are found in mouse and human urine after oral administration of shogaol or drinking ginger tea, respectively (Chen et al. 2013), suggesting a covalent binding capability of shogaol to protein thiols. A 95% ethanol extract of ginger, which contains gingerols and [6]-shogaol, activates the Nrf2–ARE pathway and induces HO-1 in HepG2 cells (Bak et al. 2012). Several experiments have shown that [6]-shogaol activates the Keap1–Nrf2 pathway and induces its downstream proteins such as HO-1, NQO1, GCL, thioredoxin reductase 1, and thioredoxin 1 (Chen et al. 2014, Peng et al. 2015, Zhu et al. 2016, Du et al. 2018). Chen et al. identified that the modification site of human recombinant Keap1 by [6]-shogaol was Cys23, Cys38, Cys395, and Cys406 (Chen et al. 2014). MAPKs and Akt signals also contribute to [6]-shogaol-mediated Nrf2 activation in HCT-116 cells (Chen et al. 2014).
Others
Many phytochemicals or compounds in foods have been shown to activate Nrf2 and induce its downstream proteins; for example, epigallocatechin-3-gallate in green tea, caffeic acid phenylethyl ester in honey, resveratrol in grapes, and genistein in soybeans (Lee et al. 2010, Zhai et al. 2013, Shen et al. 2016, Sun et al. 2017) (Fig. 3). Upregulation of antioxidative proteins, phase-II xenobiotic detoxication enzymes, and phase-III transporters via Nrf2 activation may reduce oxidative stress or electrophilic stress. Detoxication of xenobiotics by Nrf2 activators is discussed in the next section.
Detoxication of environmental chemicals by phytochemicals
Benzo[a]pyrene, generated by incomplete combustion of organic compounds, is a well-known carcinogen classified as group 1 by the IARC. Electrophilic metabolites of benzo[a]pyrene, which are formed by phase-I xenobiotic-metabolizing enzymes, covalently bind to DNA and protein, thus causing toxicity (Bauer et al. 1995, Shimada et al. 2001). A phase-II xenobiotic-metabolizing enzyme inducer, oltipraz, reduces the formation of benzo[a]pyrene–DNA adducts in wild-type mice. However, the level of benzo[a]pyrene–DNA adducts was not reduced by oltipraz in nrf2-deficient mice, indicating a major contribution of Nrf2 to the induction of phase-II xenobiotic-metabolizing enzymes and suppression of adduct formation (Ramos-Gomez et al. 2003). Interestingly, adding sulforaphane (7.5 µmol/body/day) to their diet significantly reduced the benzo[a]pyrene-induced number of gastric tumors in wild-type mice but not in nrf2-deficient mice (Fahey et al. 2002). Sulforaphane also reduces the formation of tumors in 9,10-dimethyl-1,2-benzanthracene-treated Sprague–Dawley rats (Zhang et al. 1994).
Arsenic pollution is a worldwide environmental issue, especially in East Asia, where drinking arsenic-contaminated well water is a health risk. Arsenic exposure induces ROS which causes oxidative damage (Hu et al. 2020); however, HO-1 reduces arsenite-mediated cytotoxicity (Abiko et al. 2010). Our 13-month study in Inner Mongolia found that replacing the drinking water with low-arsenic level reduced arsenicosis (Pi et al. 2005), suggesting that reduction of the arsenic level in the body reduces its toxicity. Arsenic is taken up by aquaglyceroporins such as arsenite, which is metabolized to methylarsenite species or GSH adducts of arsenite by an enzymatic reaction of S-adenosylmethionine-dependent arsenic methyltransferase or GSTs, respectively (Healy et al. 1999, Kumagai & Sumi 2007). Monomethylarsenite is also conjugated by GSH (Kumagai & Sumi 2007). The arsenic–GSH adducts, but not the dimethylarsenic-GSH adducts, are excreted into extracellular spaces (Kala et al. 2000, Leslie et al. 2004) (Fig. 4). Sulforaphane, as an Nrf2 activator, increases expression levels of downstream proteins of Nrf2 (e.g. HO-1, GCL, GSTs, and MRP1) and intracellular GSH concentration in primary mouse hepatocytes (Shinkai et al. 2006). Under the conditions, the accumulation of arsenic and arsenite-mediated cytotoxicity was reduced by pretreatment with sulforaphane (Shinkai et al. 2006). As described above, sulforaphane is produced from its glucosinolate by enzymatic reaction of myrosinase in plants or by decomposition in the intestine by intestinal bacterial flora (Shapiro et al. 1998). We looked for phytochemicals, which were not glycosides, that were easily absorbed in the body, exhibited low toxicity, and were a major component of the plant and found that cilantro contains a variety of (E)-2-alkenals with different carbon numbers (Fig. 4). As expected, the lipophilic fraction of cilantro and (E)-2-alkenals activated the Keap1–Nrf2 pathway (Abiko et al. 2014, Abiko et al. 2020) (Fig. 4). Similar to the experiments with sulforaphane, pretreatment with the cilantro extract prior to arenite exposure reduced intracellular level of arsenic in vivo and in vitro and reduced cytotoxicity in vitro (Abiko et al. 2020). Major (E)-2-alkenals in the herb, (E)-2-decenal and (E)-2-dodecenal, and a prototype (E)-2-alkenal, (E)-2-butenal, also reduced arsenic concentration and cytotoxicity in HepG2 cells (Abiko et al. 2020), indicating that cilantro, containing a series of (E)-2-alkenals as an Nrf2 activator, is an effective herb for reducing health risks of arsenic exposure (Fig. 4). Facilitation of excretion of arsenite could be used for reduction of arsenicosis. Supporting this hypothesis, dietary supplementation of curcumin for 3 months suppressed the generation of ROS and reduced DNA damage in individuals drinking arsenic-polluted water (Biswas et al. 2010). This may be due to, at least in part, increasing GSH, GST, GSH peroxidase, catalase, and superoxide dismutase concentration by curcumin treatment (Biswas et al. 2010). Enzymes in intestinal microbes, such as NADPH-dependent curcumin/dihydrocurcumin reductase in Escherichia coli, reduce curcumin to tetrahydrocurcumin, which may be absorbed easier than curcumin and are generated in vivo (Ireson et al. 2002, Hassaninasab et al. 2011, Tan et al. 2014). The radical scavenging capability of tetrahydrocurcumin is stronger than that of curcumin and both compounds suppress iron chelate-induced oxidative stress (Okada et al. 2001). Studies have shown that curcumin alters the composition of gut microbiota (Scazzocchio et al. 2020, Jabczyk et al. 2021). For example, oral administration of curcumin increases Lactobacillaceae (McFadden et al. 2015, Chen et al. 2020), which are beneficial intestinal microbes (Bengmark 2013, Ding et al. 2018). These observations indicate that gut microbiota contribute, at least in part, to the protective effects of curcumin against environmental chemicals such as arsenic.
Methylmercury (MeHg), which is an electrophilic organometal, exists ubiquitously in the environment and accumulates in large predatory fish such as tuna. MeHg easily binds to thiolate anions of proteins, leading to toxicity (Clarkson 1997). We found that MeHg activates the Keap1–Nrf2 system that facilitates the excretion of MeHg and reduction of MeHg toxicity in vivo and in vitro (Toyama et al. 2007). Inhibitors of GCL, GST, and MRP increased the Hg content in mouse primary hepatocytes and cause cytotoxicity, indicating that GSH conjugation of MeHg and excretion of the conjugate into the extracellular space are important for the detoxication of MeHg (Toyama et al. 2011) (Figs. 2B and 7). Isothiocyanates such as 6-methylsulfinylhexyl isothiocyanate, isolated from Eutremajaponicum (Miq.) Koidz. (wasabi) and sulforaphane activate Nrf2 to induce downstream proteins such as antioxidative proteins, phase-II xenobiotic detoxication enzymes, and phase-III transporters (Zhang et al. 1992, Morimitsu et al. 2002). Pretreatment with 6-methylsulfinylhexyl isothiocyanate or sulforaphane for 12 h markedly reduces Hg content and cytotoxicity in mouse primary hepatocytes (Toyama et al. 2011). A single injection of sulforaphane 16 h before MeHg administration to wild-type mice, but not Nrf2-deficient mice, suppresses accumulation of MeHg, MeHg-mediated hind-limb flaccidity and mortality (Toyama et al. 2011).
Hydrogen sulfide (H2S), hydropersulfide species (R–S2H), and hydropolysulfide species (R–SnH, n ≥ 3) have lower pKa values and thus are highly reactive compared with GSH because of the α-effect of the adjacent sulfur (Fina & Edwards 1973, Ono et al. 2014). We previously clarified that MeHg is trapped by H2S, R–S2H, and R–SnH to yield bis MeHg sulfide ((MeHg)2S) with little electrophilicity (Abiko et al. 2015, Yoshida et al. 2011). (MeHg)2S was also formed during the reaction of MeHg with a sulfane sulfur, which is a sulfur atom with no charge and six valence electrons (Toohey 1989), of polysulfide species (R–Sn–R, n ≥ 3) such as GSH polysulfide (GSSSG) (Fig. 6) (Abiko et al. 2015). While the toxicity of MeHg was suppressed by the formation of (MeHg)2S, we found that this sulfur adduct undergoes spontaneous degradation, yielding HgS and dimethylmercury that was excreted through the lungs because of its high volatility (Abiko et al. 2021c). Using the hexane extract of garlic, which contains Nrf2 inducers such as DAS and DATS, simultaneous treatment of the extract and MeHg diminished MeHg-mediated toxicity in vitro and in vivo (Abiko et al. 2021b). Treatment of C57BL/6 mice with the garlic extract increased concentrations of endogenous R–S2H such as hydrogen disulfide, cysteine persulfide, and GSH persulfide in the serum (Abiko et al. 2021b). These observations suggest that there are phytochemicals containing not only Nrf2 activators responsible for increased MeHg-SG adduct formation but also unidentified aliphatic hydrocarbons with sulfane sulfur atoms, which are also capable of forming persulfides in the hexane extract of garlic. Because MeHg did not convert to (MeHg)2S during incubation with DADS, DATS, and diallyl tetrasulfide (DATTS) (Yoshida et al. unpublished observation), there is little doubt that these sulfur compounds do not contain sulfane sulfur atoms. Therefore, we speculate that reduction of a disulfide bond in DADS, DATS, and DATTS in garlic is essential for sulfane sulfur-mediated production of (MeHg)2S (see Fig. 7).
(MeHg)2S by reaction of MeHg with GSH polysulfide. GSH polysulfide (GS-S-SG, 100 µM) was incubated with 5 mM of MeHg in 20 mM potassium phosphate buffer (pH 7.5) for 15 min at 37°C. Generation of (MeHg)2S was detected by high-performance liquid chromatography–atomic absorption spectrometry as described in Yoshida et al. (Yoshida et al. 2011). Gray bars and blue bars indicate MeHg and (MeHg)2S, respectively.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-22-0021
Detoxication of MeHg by garlic extract. Garlic contains several persulfides and polysulfides such as diallyl (or dialkyl) disulfide and their polysulfides. Diallyl trisulfide (DATS) is shown as an example in this figure. DATS activates Nrf2, presumably through modification of Keap1 thiol via a thiol exchange reaction, leading to upregulation of downstream proteins of Nrf2 such as GCL, GSTs, and MRPs. MeHg undergoes GSH conjugation with or without GST to yield MeHg–GSH adduct (MeHgSG). This MeHgSG is excreted into extracellular spaces through MRPs. Because MeHg reacts with sulfane sulfur in hydropersulfides or hydropersulfides yielding bis MeHg sulfide ((MeHg)2S), (MeHg)2S can be produced by reaction of MeHg and allyl hydropersulfide. (MeHg)2S is decomposed into HgS and dimethylmercury (DMeHg), which is exhaled in the breath.
Citation: Redox Experimental Medicine 2023, 1; 10.1530/REM-22-0021
Conclusion
Reduction of oxidative stresses and electrophilic stresses can be achieved by (1) inactivation of oxidants and electrophiles and (2) excretion of the compounds and their conjugates. Nrf2 comprehensively regulates proteins, which relate to reduction of these stresses. Intake of suitable amounts of Nrf2 activators and scavengers of electrophiles such as super sulfides in foods might convey a reduction in risk for xenobiotics causing oxidative and electrophilic stresses.
Declaration of interest
There are no conflicts of interest.
Funding
This work was supported by Grants-in-Aid (#18H05293 to Y.K. and #20K12180 to Y.A.) for scientific research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
Author contribution statement
YA drafted the manuscript and designed the figures. AT edited the manuscript. YK edited the manuscript and designed the figures. All authors contributed to the final manuscript.
Acknowledgement
The authors thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.
References
Abiko Y, Aoki H & Kumagai Y 2021a Effect of combined exposure to environmental aliphatic electrophiles from plants on Keap1/Nrf2 activation and cytotoxicity in HepG2 cells: a model of an electrophile exposome. Toxicology and Applied Pharmacology 413 115392. (https://doi.org/10.1016/j.taap.2020.115392)
Abiko Y, Katayama Y, Akiyama M & Kumagai Y 2021b Lipophilic compounds in garlic decrease the toxicity of methylmercury by forming sulfur adducts. Food and Chemical Toxicology 150 112061. (https://doi.org/10.1016/j.fct.2021.112061)
Abiko Y, Katayama Y, Zhao W, Horai S, Sakurai K & Kumagai Y 2021c The fate of methylmercury through the formation of bismethylmercury sulfide as an intermediate in mice. Scientific Reports 11 17598. (https://doi.org/10.1038/s41598-021-96579-y)
Abiko Y, Mizokawa M & Kumagai Y 2014 Activation of the kelch-like ECH-associated protein 1 (Keap1)/NF-E2-related factor 2 (Nrf2) pathway through covalent modification of the 2-alkenal group of aliphatic electrophiles in Coriandrum sativum L. Journal of Agricultural and Food Chemistry 62 10936–10944. (https://doi.org/10.1021/jf5030592)
Abiko Y, Okada M, Aoki H, Mizokawa M & Kumagai Y 2020 A strategy for repression of arsenic toxicity through nuclear factor E2 related factor 2 activation mediated by the (E)-2-alkenals in Coriandrum sativum L. leaf extract. Food and Chemical Toxicology 145 111706. (https://doi.org/10.1016/j.fct.2020.111706)
Abiko Y, Shinkai Y, Sumi D & Kumagai Y 2010 Reduction of arsenic-induced cytotoxicity through Nrf2/HO-1 signaling in HepG2 cells. Journal of Toxicological Sciences 35 419–423. (https://doi.org/10.2131/jts.35.419)
Abiko Y, Taguchi K, Hisamori M, Hiyoshi-Arai K, Luong NC, Toriba A & Kumagai Y 2022 Redox homeostasis is disturbed by redox cycling between reactive cysteines of thioredoxin 1 and 9,10-phenanthrenequinone, an atmospheric electron acceptor. Chemical Research in Toxicology 35 1425–1432. (https://doi.org/10.1021/acs.chemrestox.2c00174)
Abiko Y, Yoshida E, Ishii I, Fukuto JM, Akaike T & Kumagai Y 2015 Involvement of reactive persulfides in biological bismethylmercury sulfide formation. Chemical Research in Toxicology 28 1301–1306. (https://doi.org/10.1021/acs.chemrestox.5b00101)
Alam J, Stewart D, Touchard C, Boinapally S, Choi AM & Cook JL 1999 Nrf2, a Cap'n'Collar transcription factor, regulates induction of the heme oxygenase-1 gene. Journal of Biological Chemistry 274 26071–26078. (https://doi.org/10.1074/jbc.274.37.26071)
Andrews NC, Erdjument-Bromage H, Davidson MB, Tempst P & Orkin SH 1993 Erythroid transcription factor NF-E2 is a haematopoietic-specific basic-leucine zipper protein. Nature 362 722–728. (https://doi.org/10.1038/362722a0)
Aono J, Yanagawa T, Itoh K, Li B, Yoshida H, Kumagai Y, Yamamoto M & Ishii T 2003 Activation of Nrf2 and accumulation of ubiquitinated A170 by arsenic in osteoblasts. Biochemical and Biophysical Research Communications 305 271–277. (https://doi.org/10.1016/s0006-291x(0300728-9)
Bak MJ, Ok S, Jun M & Jeong WS 2012 6-shogaol-rich extract from ginger up-regulates the antioxidant defense systems in cells and mice. Molecules 17 8037–8055. (https://doi.org/10.3390/molecules17078037)
Ballatori N & Rebbeor JF 1998 Roles of MRP2 and oatp1 in hepatocellular export of reduced glutathione. Seminars in Liver Disease 18 377–387. (https://doi.org/10.1055/s-2007-1007171)
Balogun E, Hoque M, Gong P, Killeen E, Green CJ, Foresti R, Alam J & Motterlini R 2003 Curcumin activates the haem oxygenase-1 gene via regulation of Nrf2 and the antioxidant-responsive element. Biochemical Journal 371 887–895. (https://doi.org/10.1042/BJ20021619)
Bauer E, Guo Z, Ueng YF, Bell LC, Zeldin D & Guengerich FP 1995 Oxidation of benzo[a]pyrene by recombinant human cytochrome P450 enzymes. Chemical Research in Toxicology 8 136–142. (https://doi.org/10.1021/tx00043a018)
Bengmark S 2013 Gut microbiota, immune development and function. Pharmacological Research 69 87–113. (https://doi.org/10.1016/j.phrs.2012.09.002)
Biswas J, Sinha D, Mukherjee S, Roy S, Siddiqi M & Roy M 2010 Curcumin protects DNA damage in a chronically arsenic-exposed population of West Bengal. Human and Experimental Toxicology 29 513–524. (https://doi.org/10.1177/0960327109359020)
Carvalho DdM, Takeuchi KP, Geraldine RM, Moura CJd & Torres MCL 2015 Production, solubility and antioxidant activity of curcumin nanosuspension. Food Science and Technology 35 115–119. (https://doi.org/10.1590/1678-457X.6515)
Caterina MJ, Leffler A, Malmberg AB, Martin WJ, Trafton J, Petersen-Zeitz KR, Koltzenburg M, Basbaum AI & Julius D 2000 Impaired nociception and pain sensation in mice lacking the capsaicin receptor. Science 288 306–313. (https://doi.org/10.1126/science.288.5464.306)
Chen H, Fu J, Chen H, Hu Y, Soroka DN, Prigge JR, Schmidt EE, Yan F, Major MB & Chen X et al.2014 Ginger compound [6]-shogaol and its cysteine-conjugated metabolite (M2) activate Nrf2 in colon epithelial cells in vitro and in vivo. Chemical Research in Toxicology 27 1575–1585. (https://doi.org/10.1021/tx500211x)
Chen H, Soroka DN, Hu Y, Chen X & Sang S 2013 Characterization of thiol-conjugated metabolites of ginger components shogaols in mouse and human urine and modulation of the glutathione levels in cancer cells by [6]-shogaol. Molecular Nutrition and Food Research 57 447–458. (https://doi.org/10.1002/mnfr.201200679)
Chen YM, Chiu WC, Chiu YS, Li T, Sung HC & Hsiao CY 2020 Supplementation of nano-bubble curcumin extract improves gut microbiota composition and exercise performance in mice. Food and Function 11 3574–3584. (https://doi.org/10.1039/c9fo02487e)
Cheng D, Gao L, Su S, Sargsyan D, Wu R, Raskin I & Kong AN 2019 Moringa Isothiocyanate Activates Nrf2: Potential Role in Diabetic Nephropathy. AAPS Journal 21 31. (https://doi.org/10.1208/s12248-019-0301-6)
Choi HY, Lee JH, Jegal KH, Cho IJ, Kim YW & Kim SC 2016 Oxyresveratrol abrogates oxidative stress by activating ERK-Nrf2 pathway in the liver. Chemico-Biological Interactions 245 110–121. (https://doi.org/10.1016/j.cbi.2015.06.024)
Clarkson TW 1997 The toxicology of mercury. Critical Reviews in Clinical Laboratory Sciences 34 369–403. (https://doi.org/10.3109/10408369708998098)
Dickinson DA, Iles KE, Zhang H, Blank V & Forman HJ 2003 Curcumin alters EpRE and AP-1 binding complexes and elevates glutamate-cysteine ligase gene expression. FASEB Journal 17 473–475. (https://doi.org/10.1096/fj.02-0566fje)
Ding C, Tang W, Fan X & Wu G 2018 Intestinal microbiota: a novel perspective in colorectal cancer biotherapeutics. OncoTargets and Therapy 11 4797–4810. (https://doi.org/10.2147/OTT.S170626)
Dinkova-Kostova AT, Holtzclaw WD, Cole RN, Itoh K, Wakabayashi N, Katoh Y, Yamamoto M & Talalay P 2002 Direct evidence that sulfhydryl groups of Keap1 are the sensors regulating induction of phase 2 enzymes that protect against carcinogens and oxidants. Proceedings of the National Academy of Sciences of the United States of America 99 11908–11913. (https://doi.org/10.1073/pnas.172398899)
Du YT, Zheng YL, Ji Y, Dai F, Hu YJ & Zhou B 2018 Applying an electrophilicity-based strategy to develop a novel Nrf2 activator inspired from dietary [6]-shogaol. Journal of Agricultural and Food Chemistry 66 7983–7994. (https://doi.org/10.1021/acs.jafc.8b02442)
Egner PA, Chen JG, Zarth AT, Ng DK, Wang JB, Kensler KH, Jacobson LP, Munoz A, Johnson JL & Groopman JD et al.2014 Rapid and sustainable detoxication of airborne pollutants by broccoli sprout beverage: results of a randomized clinical trial in China. Cancer Prevention Research 7 813–823. (https://doi.org/10.1158/1940-6207.CAPR-14-0103)
Ernst IM, Wagner AE, Schuemann C, Storm N, Hoppner W, Doring F, Stocker A & Rimbach G 2011 Allyl-, butyl- and phenylethyl-isothiocyanate activate Nrf2 in cultured fibroblasts. Pharmacological Research 63 233–240. (https://doi.org/10.1016/j.phrs.2010.11.005)
Fahey JW, Haristoy X, Dolan PM, Kensler TW, Scholtus I, Stephenson KK, Talalay P & Lozniewski A 2002 Sulforaphane inhibits extracellular, intracellular, and antibiotic-resistant strains of Helicobacter pylori and prevents benzo[a]pyrene-induced stomach tumors. Proceedings of the National Academy of Sciences of the United States of America 99 7610–7615. (https://doi.org/10.1073/pnas.112203099)
Feltrin FDS, Agner T, Sayer C & Lona LMF 2022 Curcumin encapsulation in functional PLGA nanoparticles: a promising strategy for cancer therapies. Advances in Colloid and Interface Science 300 102582. (https://doi.org/10.1016/j.cis.2021.102582)
Fina NJ & Edwards JO 1973 The alpha effect. A review. International Journal of Chemical Kinetics 5 1–26. (https://doi.org/10.1002/kin.550050102)
Friling RS, Bensimon A, Tichauer Y & Daniel V 1990 Xenobiotic-inducible expression of murine glutathione S-transferase Ya subunit gene is controlled by an electrophile-responsive element. Proceedings of the National Academy of Sciences of the United States of America 87 6258–6262. (https://doi.org/10.1073/pnas.87.16.6258)
Griffith OW 1999 Biologic and pharmacologic regulation of mammalian glutathione synthesis. Free Radical Biology and Medicine 27 922–935. (https://doi.org/10.1016/s0891-5849(9900176-8)
Hassaninasab A, Hashimoto Y, Tomita-Yokotani K & Kobayashi M 2011 Discovery of the curcumin metabolic pathway involving a unique enzyme in an intestinal microorganism. Proceedings of the National Academy of Sciences of the United States of America 108 6615–6620. (https://doi.org/10.1073/pnas.1016217108)
Hatanaka A 1993 The biogeneration of green odour by green leaves. Phytochemistry 34 1201–1218. (https://doi.org/10.1016/0031-9422(9180003-J)
Hayashi A, Suzuki H, Itoh K, Yamamoto M & Sugiyama Y 2003 Transcription factor Nrf2 is required for the constitutive and inducible expression of multidrug resistance-associated protein 1 in mouse embryo fibroblasts. Biochemical and Biophysical Research Communications 310 824–829. (https://doi.org/10.1016/j.bbrc.2003.09.086)
Healy SM, Wildfang E, Zakharyan RA & Aposhian HV 1999 Diversity of inorganic arsenite biotransformation. Biological Trace Element Research 68 249–266. (https://doi.org/10.1007/BF02783907)
Ho CY, Cheng YT, Chau CF & Yen GC 2012 Effect of diallyl sulfide on in vitro and in vivo Nrf2-mediated pulmonic antioxidant enzyme expression via activation ERK/p38 signaling pathway. Journal of Agricultural and Food Chemistry 60 100–107. (https://doi.org/10.1021/jf203800d)
Hu Y, Li J, Lou B, Wu R, Wang G, Lu C, Wang H, Pi J & Xu Y 2020 The role of reactive oxygen species in arsenic toxicity. Biomolecules 10. (https://doi.org/10.3390/biom10020240)
Huang HC, Nguyen T & Pickett CB 2002 Phosphorylation of Nrf2 at Ser-40 by protein kinase C regulates antioxidant response element-mediated transcription. Journal of Biological Chemistry 277 42769–42774. (https://doi.org/10.1074/jbc.M206911200)
Ireson CR, Jones DJ, Orr S, Coughtrie MW, Boocock DJ, Williams ML, Farmer PB, Steward WP & Gescher AJ 2002 Metabolism of the cancer chemopreventive agent curcumin in human and rat intestine. Cancer Epidemiology, Biomarkers and Prevention 11 105–111.
Itoh K, Chiba T, Takahashi S, Ishii T, Igarashi K, Katoh Y, Oyake T, Hayashi N, Satoh K & Hatayama I et al.1997 An Nrf2/small Maf heterodimer mediates the induction of phase II detoxifying enzyme genes through antioxidant response elements. Biochemical and Biophysical Research Communications 236 313–322. (https://doi.org/10.1006/bbrc.1997.6943)
Itoh K, Wakabayashi N, Katoh Y, Ishii T, Igarashi K, Engel JD & Yamamoto M 1999 Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes and Development 13 76–86. (https://doi.org/10.1101/gad.13.1.76)
Itoh K, Wakabayashi N, Katoh Y, Ishii T, O'Connor T & Yamamoto M 2003 Keap1 regulates both cytoplasmic-nuclear shuttling and degradation of Nrf2 in response to electrophiles. Genes to Cells : Devoted to Molecular and Cellular Mechanisms 8 379–391. (https://doi.org/10.1046/j.1365-2443.2003.00640.x)
Jabczyk M, Nowak J, Hudzik B & Zubelewicz-Szkodzinska B 2021 Curcumin and its potential impact on microbiota. Nutrients 13. (https://doi.org/10.3390/nu13062004)
Jiang XX, Liu GY, Lei H, Li ZL, Feng QP & Huang W 2018 Activation of transient receptor potential vanilloid 1 protects the heart against apoptosis in ischemia/reperfusion injury through upregulating the PI3K/Akt signaling pathway. International Journal of Molecular Medicine 41 1724–1730. (https://doi.org/10.3892/ijmm.2017.3338)
Jimenez-Blasco D, Santofimia-Castano P, Gonzalez A, Almeida A & Bolanos JP 2015 Astrocyte NMDA receptors' activity sustains neuronal survival through a Cdk5-Nrf2 pathway. Cell Death and Differentiation 22 1877–1889. (https://doi.org/10.1038/cdd.2015.49)
Joo MS, Kim WD, Lee KY, Kim JH, Koo JH & Kim SG 2016 AMPK facilitates nuclear accumulation of Nrf2 by phosphorylating at serine 550. Molecular and Cellular Biology 36 1931–1942. (https://doi.org/10.1128/MCB.00118-16)
Jordt SE & Julius D 2002 Molecular basis for species-specific sensitivity to "hot" chili peppers. Cell 108 421–430. (https://doi.org/10.1016/s0092-8674(0200637-2)
Joung EJ, Li MH, Lee HG, Somparn N, Jung YS, Na HK, Kim SH, Cha YN & Surh YJ 2007 Capsaicin induces heme oxygenase-1 expression in HepG2 cells via activation of PI3K-Nrf2 signaling: NAD(P)H:quinone oxidoreductase as a potential target. Antioxidants and Redox Signaling 9 2087–2098. (https://doi.org/10.1089/ars.2007.1827)
Kala SV, Neely MW, Kala G, Prater CI, Atwood DW, Rice JS & Lieberman MW 2000 The MRP2/cMOAT transporter and arsenic-glutathione complex formation are required for biliary excretion of arsenic. Journal of Biological Chemistry 275 33404–33408. (https://doi.org/10.1074/jbc.M007030200)
Kim S, Lee HG, Park SA, Kundu JK, Keum YS, Cha YN, Na HK & Surh YJ 2014 Keap1 cysteine 288 as a potential target for diallyl trisulfide-induced Nrf2 activation. PLoS One 9 e85984. (https://doi.org/10.1371/journal.pone.0085984)
Kobayashi M & Yamamoto M 2006 Nrf2-Keap1 regulation of cellular defense mechanisms against electrophiles and reactive oxygen species. Advances in Enzyme Regulation 46 113–140. (https://doi.org/10.1016/j.advenzreg.2006.01.007)
Koroleva OA, Davies A, Deeken R, Thorpe MR, Tomos AD & Hedrich R 2000 Identification of a new glucosinolate-rich cell type in Arabidopsis flower stalk. Plant Physiology 124 599–608. (https://doi.org/10.1104/pp.124.2.599)
Kumagai Y & Abiko Y 2017 Environmental electrophiles: protein adducts, modulation of redox signaling, and interaction with persulfides/polysulfides. Chemical Research in Toxicology 30 203–219. (https://doi.org/10.1021/acs.chemrestox.6b00326)
Kumagai Y & Sumi D 2007 Arsenic: signal transduction, transcription factor, and biotransformation involved in cellular response and toxicity. Annual Review of Pharmacology and Toxicology 47 243–262. (https://doi.org/10.1146/annurev.pharmtox.47.120505.105144)
Lee S, Khoo C, Halstead CW, Huynh T & Bensoussan A 2007 Liquid chromatographic determination of 6-, 8-, 10-gingerol, and 6-shogaol in ginger (Zingiber officinale) as the raw herb and dried aqueous extract. Journal of AOAC International 90 1219–1226. (https://doi.org/10.1093/jaoac/90.5.1219)
Lee Y, Shin DH, Kim JH, Hong S, Choi D, Kim YJ, Kwak MK & Jung Y 2010 Caffeic acid phenethyl ester-mediated Nrf2 activation and IkappaB kinase inhibition are involved in NFkappaB inhibitory effect: structural analysis for NFkappaB inhibition. European Journal of Pharmacology 643 21–28. (https://doi.org/10.1016/j.ejphar.2010.06.016)
Leslie EM, Haimeur A & Waalkes MP 2004 Arsenic transport by the human multidrug resistance protein 1 (MRP1/ABCC1). Evidence that a tri-glutathione conjugate is required. Journal of Biological Chemistry 279 32700–32708. (https://doi.org/10.1074/jbc.M404912200)
Li L, Chen J, Ni Y, Feng X, Zhao Z, Wang P, Sun J, Yu H, Yan Z & Liu D et al.2012 TRPV1 activation prevents nonalcoholic fatty liver through UCP2 upregulation in mice. Pflugers Archiv 463 727–732. (https://doi.org/10.1007/s00424-012-1078-y)
Liu T, Lv YF, Zhao JL, You QD & Jiang ZY 2021 Regulation of Nrf2 by phosphorylation: consequences for biological function and therapeutic implications. Free Radical Biology and Medicine 168 129–141. (https://doi.org/10.1016/j.freeradbiomed.2021.03.034)
Lopachin RM, Gavin T, Decaprio A & Barber DS 2012 Application of the Hard and Soft, Acids and Bases (HSAB) theory to toxicant--target interactions. Chemical Research in Toxicology 25 239–251. (https://doi.org/10.1021/tx2003257)
Lu C, Xu W, Zhang F, Shao J & Zheng S 2016 Nrf2 knockdown disrupts the protective effect of curcumin on alcohol-induced hepatocyte necroptosis. Molecular Pharmaceutics 13 4043–4053. (https://doi.org/10.1021/acs.molpharmaceut.6b00562)
Lv Z, Xu X, Sun Z, Yang YX, Guo H, Li J, Sun K, Wu R, Xu J & Jiang Q et al.2021 TRPV1 alleviates osteoarthritis by inhibiting M1 macrophage polarization via Ca(2+)/CaMKII/Nrf2 signaling pathway. Cell Death and Disease 12 504. (https://doi.org/10.1038/s41419-021-03792-8)
Maiti K, Mukherjee K, Gantait A, Saha BP & Mukherjee PK 2007 Curcumin-phospholipid complex: preparation, therapeutic evaluation and pharmacokinetic study in rats. International Journal of Pharmaceutics 330 155–163. (https://doi.org/10.1016/j.ijpharm.2006.09.025)
McFadden RM, Larmonier CB, Shehab KW, Midura-Kiela M, Ramalingam R, Harrison CA, Besselsen DG, Chase JH, Caporaso JG & Jobin C et al.2015 The role of curcumin in modulating colonic microbiota during colitis and colon cancer prevention. Inflammatory Bowel Diseases 21 2483–2494. (https://doi.org/10.1097/MIB.0000000000000522)
Miller MS, Brendel K, Burks TF & Sipes IG 1983 Interaction of capsaicinoids with drug-metabolizing systems. Relationship to toxicity. Biochemical Pharmacology 32 547–551. (https://doi.org/10.1016/0006-2952(8390537-3)
Miura T, Shinkai Y, Jiang HY, Iwamoto N, Sumi D, Taguchi K, Yamamoto M, Jinno H, Tanaka-Kagawa T & Cho AK et al.2011 Initial response and cellular protection through the Keap1/Nrf2 system during the exposure of primary mouse hepatocytes to 1,2-naphthoquinone. Chemical Research in Toxicology 24 559–567. (https://doi.org/10.1021/tx100427p)
Mohanty C & Sahoo SK 2010 The in vitro stability and in vivo pharmacokinetics of curcumin prepared as an aqueous nanoparticulate formulation. Biomaterials 31 6597–6611. (https://doi.org/10.1016/j.biomaterials.2010.04.062)
Moi P, Chan K, Asunis I, Cao A & Kan YW 1994 Isolation of NF-E2-related factor 2 (Nrf2), a NF-E2-like basic leucine zipper transcriptional activator that binds to the tandem NF-E2/AP1 repeat of the beta-globin locus control region. Proceedings of the National Academy of Sciences of the United States of America 91 9926–9930. (https://doi.org/10.1073/pnas.91.21.9926)
Morimitsu Y, Nakagawa Y, Hayashi K, Fujii H, Kumagai T, Nakamura Y, Osawa T, Horio F, Itoh K & Iida K et al.2002 A sulforaphane analogue that potently activates the Nrf2-dependent detoxification pathway. Journal of Biological Chemistry 277 3456–3463. (https://doi.org/10.1074/jbc.M110244200)
Neish AC 1960 Biosynthetic pathways of aromatic compounds. Annual Review of Plant Physiology 11 55–80. (https://doi.org/10.1146/annurev.pp.11.060160.000415)
Okada K, Wangpoengtrakul C, Tanaka T, Toyokuni S, Uchida K & Osawa T 2001 Curcumin and especially tetrahydrocurcumin ameliorate oxidative stress-induced renal injury in mice. Journal of Nutrition 131 2090–2095. (https://doi.org/10.1093/jn/131.8.2090)
Ono K, Akaike T, Sawa T, Kumagai Y, Wink DA, Tantillo DJ, Hobbs AJ, Nagy P, Xian M & Lin J et al.2014 Redox chemistry and chemical biology of H2S, hydropersulfides, and derived species: implications of their possible biological activity and utility. Free Radical Biology and Medicine 77 82–94. (https://doi.org/10.1016/j.freeradbiomed.2014.09.007)
Pae HO, Jeong GS, Jeong SO, Kim HS, Kim SA, Kim YC, Yoo SJ, Kim HD & Chung HT 2007 Roles of heme oxygenase-1 in curcumin-induced growth inhibition in rat smooth muscle cells. Experimental and Molecular Medicine 39 267–277. (https://doi.org/10.1038/emm.2007.30)
Peng S, Yao J, Liu Y, Duan D, Zhang X & Fang J 2015 Activation of Nrf2 target enzymes conferring protection against oxidative stress in PC12 cells by ginger principal constituent 6-shogaol. Food and Function 6 2813–2823. (https://doi.org/10.1039/c5fo00214a)
Pi J, Yamauchi H, Sun G, Yoshida T, Aikawa H, Fujimoto W, Iso H, Cui R, Waalkes MP & Kumagai Y 2005 Vascular dysfunction in patients with chronic arsenosis can be reversed by reduction of arsenic exposure. Environmental Health Perspectives 113 339–341. (https://doi.org/10.1289/ehp.7471)
Potter TL 1996 Essential oil composition of cilantro. Journal of Agricultural and Food Chemistry 44 1824–1826. (https://doi.org/10.1021/jf950814c)
Potter TL & Fagerson IS 1990 Composition of coriander leaf volatiles. Journal of Agricultural and Food Chemistry 38 2054–2056. (https://doi.org/10.1021/jf00101a011)
Purpura M, Lowery RP, Wilson JM, Mannan H, Munch G & Razmovski-Naumovski V 2018 Analysis of different innovative formulations of curcumin for improved relative oral bioavailability in human subjects. European Journal of Nutrition 57 929–938. (https://doi.org/10.1007/s00394-016-1376-9)
Rada P, Rojo AI, Chowdhry S, McMahon M, Hayes JD & Cuadrado A 2011 SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner. Molecular and Cellular Biology 31 1121–1133. (https://doi.org/10.1128/MCB.01204-10)
Ramos-Gomez M, Dolan PM, Itoh K, Yamamoto M & Kensler TW 2003 Interactive effects of nrf2 genotype and oltipraz on benzo[a]pyrene-DNA adducts and tumor yield in mice. Carcinogenesis 24 461–467. (https://doi.org/10.1093/carcin/24.3.461)
Ravindranath V & Chandrasekhara N 1980 Absorption and tissue distribution of curcumin in rats. Toxicology 16 259–265. (https://doi.org/10.1016/0300-483x(8090122-5)
Ravindranath V & Chandrasekhara N 1981 Metabolism of curcumin--studies with [3H]curcumin. Toxicology 22 337–344. (https://doi.org/10.1016/0300-483x(8190027-5)
Riedl MA, Saxon A & Diaz-Sanchez D 2009 Oral sulforaphane increases Phase II antioxidant enzymes in the human upper airway. Clinical Immunology 130 244–251. (https://doi.org/10.1016/j.clim.2008.10.007)
Rushmore TH & Pickett CB 1990 Transcriptional regulation of the rat glutathione S-transferase Ya subunit gene. Characterization of a xenobiotic-responsive element controlling inducible expression by phenolic antioxidants. Journal of Biological Chemistry 265 14648–14653. (https://doi.org/10.1016/S0021-9258(1877351-1)
Scazzocchio B, Minghetti L & D'Archivio M 2020 Interaction between gut microbiota and curcumin: a new key of understanding for the health effects of curcumin. Nutrients 12. (https://doi.org/10.3390/nu12092499)
Sekhar KR, Rachakonda G & Freeman ML 2010 Cysteine-based regulation of the CUL3 adaptor protein Keap1. Toxicology and Applied Pharmacology 244 21–26. (https://doi.org/10.1016/j.taap.2009.06.016)
Semwal RB, Semwal DK, Combrinck S & Viljoen AM 2015 Gingerols and shogaols: important nutraceutical principles from ginger. Phytochemistry 117 554–568. (https://doi.org/10.1016/j.phytochem.2015.07.012)
Shapiro TA, Fahey JW, Wade KL, Stephenson KK & Talalay P 1998 Human metabolism and excretion of cancer chemoprotective glucosinolates and isothiocyanates of cruciferous vegetables. Cancer Epidemiology, Biomarkers and Prevention 7 1091–1100.
Shen C, Cheng W, Yu P, Wang L, Zhou L, Zeng L & Yang Q 2016 Resveratrol pretreatment attenuates injury and promotes proliferation of neural stem cells following oxygen-glucose deprivation/reoxygenation by upregulating the expression of Nrf2, HO-1 and NQO1 in vitro. Molecular Medicine Reports 14 3646–3654. (https://doi.org/10.3892/mmr.2016.5670)
Shibata T, Kimura Y, Mukai A, Mori H, Ito S, Asaka Y, Oe S, Tanaka H, Takahashi T & Uchida K 2011 Transthiocarbamoylation of proteins by thiolated isothiocyanates. Journal of Biological Chemistry 286 42150–42161. (https://doi.org/10.1074/jbc.M111.308049)
Shimada T, Oda Y, Gillam EM, Guengerich FP & Inoue K 2001 Metabolic activation of polycyclic aromatic hydrocarbons and other procarcinogens by cytochromes P450 1A1 and P450 1B1 allelic variants and other human cytochromes P450 in Salmonella typhimurium NM2009. Drug Metabolism and Disposition: The Biological Fate of Chemicals 29 1176–1182.
Shin JW, Chun KS, Kim DH, Kim SJ, Kim SH, Cho NC, Na HK & Surh YJ 2020 Curcumin induces stabilization of Nrf2 protein through Keap1 cysteine modification. Biochemical Pharmacology 173 113820. (https://doi.org/10.1016/j.bcp.2020.113820)
Shinkai Y, Sumi D, Fukami I, Ishii T & Kumagai Y 2006 Sulforaphane, an activator of Nrf2, suppresses cellular accumulation of arsenic and its cytotoxicity in primary mouse hepatocytes. FEBS Letters 580 1771–1774. (https://doi.org/10.1016/j.febslet.2006.02.031)
Shirakawa M, Tanida M & Ito T 2021 The cell differentiation of idioblast myrosin cells: similarities with vascular and guard cells. Frontiers in Plant Science 12 829541. (https://doi.org/10.3389/fpls.2021.829541)
Socala K, Nieoczym D, Kowalczuk-Vasilev E, Wyska E & Wlaz P 2017 Increased seizure susceptibility and other toxicity symptoms following acute sulforaphane treatment in mice. Toxicology and Applied Pharmacology 326 43–53. (https://doi.org/10.1016/j.taap.2017.04.010)
Sun W, Liu X, Zhang H, Song Y, Li T, Liu X, Liu Y, Guo L, Wang F & Yang T et al.2017 Epigallocatechin gallate upregulates NRF2 to prevent diabetic nephropathy via disabling KEAP1. Free Radical Biology and Medicine 108 840–857. (https://doi.org/10.1016/j.freeradbiomed.2017.04.365)
Sun Z, Huang Z & Zhang DD 2009 Phosphorylation of Nrf2 at multiple sites by MAP kinases has a limited contribution in modulating the Nrf2-dependent antioxidant response. PLoS One 4 e6588. (https://doi.org/10.1371/journal.pone.0006588)
Surh YJ 2003 Cancer chemoprevention with dietary phytochemicals. Nature Reviews. Cancer 3 768–780. (https://doi.org/10.1038/nrc1189)
Surh YJ, Kundu JK & Na HK 2008 Nrf2 as a master redox switch in turning on the cellular signaling involved in the induction of cytoprotective genes by some chemopreventive phytochemicals. Planta Medica 74 1526–1539. (https://doi.org/10.1055/s-0028-1088302)
Surh YJ & Lee SS 1995 Capsaicin, a double-edged sword: toxicity, metabolism, and chemopreventive potential. Life Sciences 56 1845–1855. (https://doi.org/10.1016/0024-3205(9500159-4)
Suzuki T, Muramatsu A, Saito R, Iso T, Shibata T, Kuwata K, Kawaguchi SI, Iwawaki T, Adachi S & Suda H et al.2019 Molecular mechanism of cellular oxidative stress sensing by Keap1. Cell Reports 28 746–758.e4. (https://doi.org/10.1016/j.celrep.2019.06.047)
Taguchi K, Motohashi H & Yamamoto M 2011 Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution. Genes to Cells : Devoted to Molecular and Cellular Mechanisms 16 123–140. (https://doi.org/10.1111/j.1365-2443.2010.01473.x)
Tan S, Rupasinghe TW, Tull DL, Boughton B, Oliver C, McSweeny C, Gras SL & Augustin MA 2014 Degradation of curcuminoids by in vitro pure culture fermentation. Journal of Agricultural and Food Chemistry 62 11005–11015. (https://doi.org/10.1021/jf5031168)
Tang HB & Nakata Y 2008 The activation of transient receptor potential vanilloid receptor subtype 1 by capsaicin without extracellular Ca2+ is involved in the mechanism of distinct substance P release in cultured rat dorsal root ganglion neurons. Naunyn-Schmiedeberg’s Archives of Pharmacology 377 325–332. (https://doi.org/10.1007/s00210-007-0211-5)
Tanigawa S, Fujii M & Hou DX 2007 Action of Nrf2 and Keap1 in ARE-mediated NQO1 expression by quercetin. Free Radical Biology and Medicine 42 1690–1703. (https://doi.org/10.1016/j.freeradbiomed.2007.02.017)
Toohey JI 1989 Sulfane sulfur in biological-systems - a possible regulatory role. Biochemical Journal 264 625–632. (https://doi.org/10.1042/bj2640625)
Toyama T, Shinkai Y, Yasutake A, Uchida K, Yamamoto M & Kumagai Y 2011 Isothiocyanates reduce mercury accumulation via an Nrf2-dependent mechanism during exposure of mice to methylmercury. Environmental Health Perspectives 119 1117–1122. (https://doi.org/10.1289/ehp.1003123)
Toyama T, Sumi D, Shinkai Y, Yasutake A, Taguchi K, Tong KI, Yamamoto M & Kumagai Y 2007 Cytoprotective role of Nrf2/Keap1 system in methylmercury toxicity. Biochemical and Biophysical Research Communications 363 645–650. (https://doi.org/10.1016/j.bbrc.2007.09.017)
Tukey RH & Strassburg CP 2000 Human UDP-glucuronosyltransferases: metabolism, expression, and disease. Annual Review of Pharmacology and Toxicology 40 581–616. (https://doi.org/10.1146/annurev.pharmtox.40.1.581)
Viswanatharaju Ruddraraju K, Parsons ZD, Lewis CD & Gates KS 2017 Allylation and alkylation of biologically relevant nucleophiles by diallyl sulfides. Journal of Organic Chemistry 82 776–780. (https://doi.org/10.1021/acs.joc.6b02517)
Yagishita Y, Fahey JW, Dinkova-Kostova AT & Kensler TW 2019 Broccoli or sulforaphane: is it the source or dose that matters? Molecules 24. (https://doi.org/10.3390/molecules24193593)
Yamaguchi Y & Kumagai H 2020 Characteristics, biosynthesis, decomposition, metabolism and functions of the garlic odour precursor, S-allyl-L-cysteine sulfoxide. Experimental and Therapeutic Medicine 19 1528–1535. (https://doi.org/10.3892/etm.2019.8385)
Yoshida E, Toyama T, Shinkai Y, Sawa T, Akaike T & Kumagai Y 2011 Detoxification of methylmercury by hydrogen sulfide-producing enzyme in Mammalian cells. Chemical Research in Toxicology 24 1633–1635. (https://doi.org/10.1021/tx200394g)
Zhai X, Lin M, Zhang F, Hu Y, Xu X, Li Y, Liu K, Ma X, Tian X & Yao J 2013 Dietary flavonoid genistein induces Nrf2 and phase II detoxification gene expression via ERKs and PKC pathways and protects against oxidative stress in Caco-2 cells. Molecular Nutrition and Food Research 57 249–259. (https://doi.org/10.1002/mnfr.201200536)
Zhang Y, Kensler TW, Cho CG, Posner GH & Talalay P 1994 Anticarcinogenic activities of sulforaphane and structurally related synthetic norbornyl isothiocyanates. Proceedings of the National Academy of Sciences of the United States of America 91 3147–3150. (https://doi.org/10.1073/pnas.91.8.3147)
Zhang Y, Talalay P, Cho CG & Posner GH 1992 A major inducer of anticarcinogenic protective enzymes from broccoli: isolation and elucidation of structure. Proceedings of the National Academy of Sciences of the United States of America 89 2399–2403. (https://doi.org/10.1073/pnas.89.6.2399)
Zhu Y, Wang P, Zhao Y, Yang C, Clark A, Leung T, Chen X & Sang S 2016 Synthesis, evaluation, and metabolism of novel [6]-shogaol derivatives as potent Nrf2 activators. Free Radical Biology and Medicine 95 243–254. (https://doi.org/10.1016/j.freeradbiomed.2016.03.026)
