Sulforaphane protects Microcystin-LR-induced toxicity through activation of the Nrf2-mediated defensive response

Abstract

Microcystins (MCs), a cyclic heptapeptide hepatotoxins, are mainly produced by the bloom-forming cyanobacerium Microcystis, which has become an environmental hazard worldwide. Long term consumption of MC-contaminated water may induce liver damage, liver cancer, and even human death. Therefore, in addition to removal of MCs in drinking water, novel strategies that prevent health damages are urgently needed. Sulforaphane (SFN), a natural-occurring isothiocyanate from cruciferous vegetables, has been reported to reduce and eliminate toxicities from xenobiotics and carcinogens. The purpose of the present study was to provide mechanistic insights into the SFN-induced antioxidative defense system against MC-LR-induced cytotoxicity. We performed cell viability assays, including MTS assay, colony formation assay and apoptotic cell sorting, to study MC-LR-induced cellular damage and the protective effects by SFN. The results showed that SFN protected MC-LR-induced damages at a nontoxic and physiological relevant dose in HepG2, BRL-3A and NIH 3 T3 cells. The protection was Nrf2-mediated as evident by transactivation of Nrf2 and activation of its downstream genes, including NQO1 and HO-1, and elevated intracellular GSH level. Results of our studies indicate that pretreatment of cells with 10 μM SFN for 12 h significantly protected cells from MC-LR-induced damage. SFN-induced protective response was mediated through Nrf2 pathway.

Sulforaphane induces ROS mediated induction of NKG2D ligands in human cancer cell lines and enhances susceptibility to NK cell mediated lysis

“…These results thus suggest the involvement of ROS in SFN induced increase in MICA/MICB expression. This is in agreement with many reports which confirm that the ROS mediated signaling pathway is the major mediator of SFN including induction of Antioxidant Response Element (ARE) genes as well as mediating mitotic arrest or apoptosis [24,39,40]. Increase in the expression of cyclin B1 and the phosphorylation of Cdk1 on treatment with sulforaphane was also found to be reversed by NAC pretreatment confirming that ROS is the major player in mediating the effects of SFN [41].…”

“…They include (a) inhibition of phase 1 metabolism enzymes that convert procarcinogens to carcinogens and induction of phase 2 metabolism enzymes that promote excretion of carcinogens [22], (b) induction of apoptosis and cell cycle arrest associated with regulation of many molecules including Bcl-2 family proteins, caspases, p21, cyclins, and cyclindependent kinases [5], (c) suppression of angiogenesis and metastasis by downregulating vascular endothelial growth factor, HIF-1α, matrix metalloproteinase-2 and matrix metalloproteinase-9 [5], (d) induction of cytoprotective proteins via the Nrf2 pathway and reduction of oxidative stress [23,24] and (e) inhibition of histone deacetylases [25].…”

Cystathionine γ-Lyase Deficiency Protects Mice from Galactosamine/Lipopolysaccharide-Induced Acute Liver Failure

“…These observations appear to be in conflict with a number of publications that suggest that protective effects of H 2 S are mediated by upregulating Nrf2-dependent signaling via sulfhydration (7). However, it has been reported that expression of Nrf2 depends on stress levels; low oxidative stress could increase the expression of Nrf2, whereas high oxidative stress might decrease Nrf2 and Nrf2-dependent antioxidant genes (6,31). It was recently reported that hydrogen peroxide activates Nrf2 by inactivation of Kelch-like ECH-associated protein 1 (Keap1) via formation of an intramolecular disulfide bridge releasing inhibition of Keap1 on Nrf2 (7).…”

“…In mammalian tissues, H 2 S is generated by cystathionine b-synthase (CBS), cystathionine c-lyase (CSE) (22), and 3-mercaptopyruvate sulfurtransferase (3MST) (21). On the other hand, H 2 S is serially oxidized to persulfide, sulfite (SO 3 2 -), thiosulfate (S 2 O 3 2 -), and sulfate (SO 4 2 -) in reactions catalyzed by several enzymes including sulfide:quinone oxidoreductase (SQR), sulfur dioxygenase ethylmalonic encephalopathy 1 (ETHE1), sulfurtransferase rhodanese, and sulfite oxidase (SUOX) (6,8). H 2 S can exert a host of biological effects on various targets ranging from cytotoxicity to cytoprotection.…”

Responses in population growth and reproduction of the freshwater rotiferBrachionus calyciflorusto microcystin-LR at different temperatures

“…Toxic cyanobacterial blooms in freshwater rivers, lakes, reservoirs, and recreational waters have increasingly become a nuisance (Cohen, 1989;Chorus and Bartram, 1999;Carmichael, 2001;Paerl et al, 2001;Vasconcelos and Pereira, 2001;Huisman et al, 2005;Liu et al, 2006;Vareli et al, 2009;Ye et al, 2009;Gan et al, 2010). It is well known that many species of cyanobacteria are able to produce microcystins (MCs) (van Apeldoorn et al, 2007), which can accumulate in the food chain (Xie et al, 2005;Chen et al, 2009a) and negatively affect aquatic organisms, animals, and human beings due to their potent hepatotoxicity and probable tumor promoters (Andersen et al, 1993;Carmichael and Falconer, 1993;Chorus and Bartram, 1999;Matsunaga et al, 1999;Carmichael et al, 2001;Zimba et al, 2001;Chen et al, 2002Chen et al, , 2009bQiu et al, 2007).…”