The possible repositioning of an oral anti-arthritic drug, auranofin, for Nrf2-activating therapy: The demonstration of Nrf2-dependent anti-oxidative action using a zebrafish model

Fuse, Yuji; Endo, Yuka; Araoi, Sho; Daitoku, Hiroaki; Suzuki, Hiroyuki; Kato, Mitsuyasu

doi:10.1016/j.freeradbiomed.2017.12.022

Cited by 12 publications

(10 citation statements)

References 37 publications

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“…Survival assays were performed as previously described [ 24 ]. At 4 dpf, larvae were exposed to 2 mM of H 2 O 2 for 120 h. Sulforaphane was administered at 3.5 dpf, 12 h prior to H 2 O 2 exposure.…”

Section: Methodsmentioning

confidence: 99%

Generation and characterization of keap1a- and keap1b-knockout zebrafish

et al. 2020

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The Keap1–Nrf2 pathway is an evolutionarily conserved mechanism that protects cells from oxidative stress and electrophiles. Under homeostatic conditions, Keap1 interacts with Nrf2 and leads to its rapid proteasomal degradation, but when cells are exposed to oxidative stress/electrophiles, Keap1 senses them, resulting in an improper Keap1–Nrf2 interaction and Nrf2 stabilization. Keap1 is therefore considered both an “inhibitor” of and “stress sensor” for Nrf2 activation. Interestingly, fish and amphibians have two Keap1s (Keap1a and Keap1b), while there is only one in mammals, birds and reptiles. A phylogenetic analysis suggested that mammalian Keap1 is an ortholog of fish Keap1b, not Keap1a. In this study, we investigated the differences and similarities between Keap1a and Keap1b using zebrafish genetics. We generated zebrafish knockout lines of keap1a and keap1b . Homozygous mutants of both knockout lines were viable and fertile. In both mutant larvae, the basal expression of Nrf2 target genes and antioxidant activity were up-regulated in an Nrf2-dependent manner, suggesting that both Keap1a and Keap1b can function as Nrf2 inhibitors. We also analyzed the effects of the Nrf2 activator sulforaphane in these mutants and found that keap1a- , but not keap1b- , knockout larvae responded to sulforaphane, suggesting that the stress/chemical-sensing abilities of the two Keap1s are different.

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Section: Methodsmentioning

confidence: 99%

Generation and characterization of keap1a- and keap1b-knockout zebrafish

et al. 2020

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“…1 ). As in the case with paraquat, other oxidative stress inducers, hydrogen peroxide (H 2 O 2 , 1.5 mM) [ 11 ] and rotenone (1.25 nM) [ 44 ], also showed augmentation of edema caused by 0.1 ppb TCDD ( Supplementary Fig. 1 ).…”

Section: Resultsmentioning

confidence: 94%

“…Eleutheroembryos were challenged with 7.5 µM U46619 and 24 µM ICI-192,605 from 48 hpf, because longer exposure of U46619 caused yolk malformation [ 57 ]. Sulforaphane (40 µM) and 2.5 µM auranofin were included, beginning at 24 hpf and 33 hpf, respectively, following our previous reports in which these Nrf2 activators were pretreated long before toxic compounds challenge [ 10 , 11 ].…”

Section: Methodsmentioning

confidence: 99%

Oxidative stress inducers potentiate 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin-mediated pre-cardiac edema in larval zebrafish

Tanaka

Adachi

Akasaka

et al. 2021

The Journal of Veterinary Medical Science

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We reported the involvement of oxidative stress and prostaglandins including thromboxane and prostacyclin in pre-cardiac edema (early edema) caused by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD). While the involvement of oxidative stress in TCDD-induced toxicity has been frequently reported, the mechanism of its action is still unclear. In the present study, oxidative stress inducers including paraquat, hydrogen peroxide (H 2 O 2 ) and rotenone augmented early edema (edema) induced by a low concentration of TCDD (0.1 ppb) at 55 hr post fertilization (hpf), while each of them alone did not cause edema. Edema caused by TCDD plus oxidative stress inducers was almost abolished by antioxidants, an antagonist for thromboxane receptor (ICI-192,605) and an agonist for prostacyclin receptor (beraprost), suggesting that the site of action of these inducers was in the regular signaling pathway after activation of aryl hydrocarbon receptor type 2 (AHR2) by TCDD. Oxidative stress inducers also enhanced edema caused by an agonist for the thromboxane receptor (U46619), and the enhancement was also inhibited by antioxidants. Sulforaphane and auranofin, activators of Nrf2 that is a master regulator of anti-oxidative response, did not affect U46619-evoked edema but almost abolished TCDD-induced edema and potentiation by paraquat in both TCDD- and U46619-induced edema. Taken together, the results suggest that oxidative stress augments pre-cardiac edema caused by TCDD via activation of thromboxane receptor-mediated signaling in developing zebrafish. As paraquat and other oxidative stress inducers used also are environmental pollutants, interaction between dioxin-like compounds and exogenous source of oxidative stress should also be considered.

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“…We have been evaluating the antioxidant activity of Nrf2-activating compounds based on the improvement of the survival rate of zebrafish larvae exposed to toxic oxidative stress [15,27,28]. While the previous method of evaluation required 5 mL of compound solution for each sample (20 larvae in a 35-mm dish), it was better to reduce the volume as much as possible, since many phytochemicals are valuable and expensive.…”

Section: Establishment Of the Zebrafish-based Assay System For Evaluamentioning

confidence: 99%

“…We have studied the Nrf2 pathway using zebrafish for two decades and found that the functions and regulatory mechanism of the Nrf2 pathway are highly conserved among vertebrates [17][18][19][20][21][22][23][24][25][26]. We also established a mutant line of zebrafish Nrf2 (nfe2l2a fh318 ) and demonstrated that the antioxidant activity of zebrafish larvae was increased by the treatment of sulforaphane and other Nrf2-activating compounds in an Nrf2-dependent manner [15,27,28].…”

Section: Introductionmentioning

confidence: 99%

Evaluation of Antioxidant Activity of Spice-Derived Phytochemicals Using Zebrafish

Endo

Muraki

Fuse

2020

IJMS

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Various dietary phytochemicals seem to display antioxidant activity through the NF-E2-related factor 2 (Nrf2) pathway. However, few studies have demonstrated its antioxidant effect and Nrf2 dependency at the animal level. We constructed a zebrafish-based assay system to analyze the in vivo antioxidant activity of phytochemicals and examined the activity of 10 phytochemicals derived from spices, using this system as a pilot study. Hydrogen peroxide and arsenite were used as oxidative stressors, and Nrf2 dependency was genetically analyzed using an Nrf2-mutant zebrafish line. The activities of curcumin, diallyl trisulfide and quercetin were involved in the reduction of hydrogen peroxide toxicity, while those of cinnamaldehyde, isoeugenol and 6-(methylsulfinyl)hexyl isothiocyanate were involved in the reduction of arsenite toxicity. The antioxidant activities of these phytochemicals were all Nrf2 dependent, with the exception of cinnamaldehyde, which showed strong antioxidant effects even in Nrf2-mutant zebrafish. In summary, we succeeded in constructing an assay system to evaluate the in vivo antioxidant activity of various phytochemicals using zebrafish larvae. Using this system, we found that each spice-derived phytochemical has its own specific property and mechanism of antioxidant action.

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The possible repositioning of an oral anti-arthritic drug, auranofin, for Nrf2-activating therapy: The demonstration of Nrf2-dependent anti-oxidative action using a zebrafish model

Cited by 12 publications

References 37 publications

Generation and characterization of keap1a- and keap1b-knockout zebrafish

Generation and characterization of keap1a- and keap1b-knockout zebrafish

Oxidative stress inducers potentiate 2,3,7,8-tetrachlorodibenzo-<i>p</i>-dioxin-mediated pre-cardiac edema in larval zebrafish

Evaluation of Antioxidant Activity of Spice-Derived Phytochemicals Using Zebrafish

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