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Sulforaphane Protects the Liver against CdSe Quantum Dot-Induced Cytotoxicity.

Wang W, He Y, Yu G, Li B, Sexton DW, Wileman T, Roberts AA, Hamilton CJ, Liu R, Chao Y, Shan Y, Bao Y - PLoS ONE (2015)

Bottom Line: Wortmannin inhibition of SFN-induced autophagy significantly suppressed the protective effect of SFN on CdSe QD-induced cell death.CdSe QDs caused significant liver damage in mice, and this was decreased by SFN treatment.In conclusion, SFN attenuated the cytotoxicity of CdSe QDs in both human hepatocytes and in the mouse liver, and this protection was associated with the induction of Nrf2 pathway and autophagy.

View Article: PubMed Central - PubMed

Affiliation: Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom.

ABSTRACT
The potential cytotoxicity of cadmium selenide (CdSe) quantum dots (QDs) presents a barrier to their use in biomedical imaging or as diagnostic and therapeutic agents. Sulforaphane (SFN) is a chemoprotective compound derived from cruciferous vegetables which can up-regulate antioxidant enzymes and induce apoptosis and autophagy. This study reports the effects of SFN on CdSe QD-induced cytotoxicity in immortalised human hepatocytes and in the livers of mice. CdSe QDs induced dose-dependent cell death in hepatocytes with an IC50 = 20.4 μM. Pre-treatment with SFN (5 μM) increased cell viability in response to CdSe QDs (20 μM) from 49.5 to 89.3%. SFN induced a pro-oxidant effect characterized by depletion of intracellular reduced glutathione during short term exposure (3-6 h), followed by up-regulation of antioxidant enzymes and glutathione levels at 24 h. SFN also caused Nrf2 translocation into the nucleus, up-regulation of antioxidant enzymes and autophagy. siRNA knockdown of Nrf2 suggests that the Nrf2 pathway plays a role in the protection against CdSe QD-induced cell death. Wortmannin inhibition of SFN-induced autophagy significantly suppressed the protective effect of SFN on CdSe QD-induced cell death. Moreover, the role of autophagy in SFN protection against CdSe QD-induced cell death was confirmed using mouse embryonic fibroblasts lacking ATG5. CdSe QDs caused significant liver damage in mice, and this was decreased by SFN treatment. In conclusion, SFN attenuated the cytotoxicity of CdSe QDs in both human hepatocytes and in the mouse liver, and this protection was associated with the induction of Nrf2 pathway and autophagy.

No MeSH data available.


Related in: MedlinePlus

Induction of LC3-II by SFN and CdSe QD in HHL-5 cells.HHL-5 cells 48 h after seeding were (A) exposed to SFN for 6 or 24 h, or (B) treated with varying levels of CdSe QD for 6 or 24 h. The expression of LC-3-II was analysed by Western blot analysis.
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pone.0138771.g005: Induction of LC3-II by SFN and CdSe QD in HHL-5 cells.HHL-5 cells 48 h after seeding were (A) exposed to SFN for 6 or 24 h, or (B) treated with varying levels of CdSe QD for 6 or 24 h. The expression of LC-3-II was analysed by Western blot analysis.

Mentions: Deceased cellular GSH levels activate autophagy [40], and SFN is a known inducer of autophagy in cultured tumour cells [25]. Autophagy involves the formation of autophagosomes, which encapsulate cytoplasm and organelles and fuse with lysosomes, leading to the degradation of the contents of the autophagosome [41]. Light chain protein 3-II (LC3-II) is the major protein of the autophagosome membrane. LC3 has two forms: LC3-I is cytosolic, whereas LC3-II is membrane-bound. During autophagy, LC3-I is converted to LC3-II and increased levels of LC-3II correlate with the extent of autophagosome formation [42]. SFN induces autophagy in different cells, such as human breast cancer cells [43] and human colon cancer cells [44]. In this study, SFN induced LC3-II production in HHL-5 cells in a dose- and time-dependent manner (Fig 5A). Western blot analysis showed that SFN at 5 and 10 μM increased LC3-II (16 kDa) production 2- to 3-fold (6 h), and at 24 h this increased to 3- and 7-fold, respectively, compared to corresponding controls. When cells were incubated with CdSe for 6 or 24 h, LC3-II was induced by 20–30 μM CdSe (Fig 5B). The results suggest CdSe QDs activate autophagy in human hepatocytes. The interplay between SFN-induced autophagy and apoptosis has been reported in cultured tumour cells, and the inhibition of autophagy can enhance SFN-induced tumour cell death [25, 43, 44].


Sulforaphane Protects the Liver against CdSe Quantum Dot-Induced Cytotoxicity.

Wang W, He Y, Yu G, Li B, Sexton DW, Wileman T, Roberts AA, Hamilton CJ, Liu R, Chao Y, Shan Y, Bao Y - PLoS ONE (2015)

Induction of LC3-II by SFN and CdSe QD in HHL-5 cells.HHL-5 cells 48 h after seeding were (A) exposed to SFN for 6 or 24 h, or (B) treated with varying levels of CdSe QD for 6 or 24 h. The expression of LC-3-II was analysed by Western blot analysis.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581733&req=5

pone.0138771.g005: Induction of LC3-II by SFN and CdSe QD in HHL-5 cells.HHL-5 cells 48 h after seeding were (A) exposed to SFN for 6 or 24 h, or (B) treated with varying levels of CdSe QD for 6 or 24 h. The expression of LC-3-II was analysed by Western blot analysis.
Mentions: Deceased cellular GSH levels activate autophagy [40], and SFN is a known inducer of autophagy in cultured tumour cells [25]. Autophagy involves the formation of autophagosomes, which encapsulate cytoplasm and organelles and fuse with lysosomes, leading to the degradation of the contents of the autophagosome [41]. Light chain protein 3-II (LC3-II) is the major protein of the autophagosome membrane. LC3 has two forms: LC3-I is cytosolic, whereas LC3-II is membrane-bound. During autophagy, LC3-I is converted to LC3-II and increased levels of LC-3II correlate with the extent of autophagosome formation [42]. SFN induces autophagy in different cells, such as human breast cancer cells [43] and human colon cancer cells [44]. In this study, SFN induced LC3-II production in HHL-5 cells in a dose- and time-dependent manner (Fig 5A). Western blot analysis showed that SFN at 5 and 10 μM increased LC3-II (16 kDa) production 2- to 3-fold (6 h), and at 24 h this increased to 3- and 7-fold, respectively, compared to corresponding controls. When cells were incubated with CdSe for 6 or 24 h, LC3-II was induced by 20–30 μM CdSe (Fig 5B). The results suggest CdSe QDs activate autophagy in human hepatocytes. The interplay between SFN-induced autophagy and apoptosis has been reported in cultured tumour cells, and the inhibition of autophagy can enhance SFN-induced tumour cell death [25, 43, 44].

Bottom Line: Wortmannin inhibition of SFN-induced autophagy significantly suppressed the protective effect of SFN on CdSe QD-induced cell death.CdSe QDs caused significant liver damage in mice, and this was decreased by SFN treatment.In conclusion, SFN attenuated the cytotoxicity of CdSe QDs in both human hepatocytes and in the mouse liver, and this protection was associated with the induction of Nrf2 pathway and autophagy.

View Article: PubMed Central - PubMed

Affiliation: Norwich Medical School, University of East Anglia, Norwich, Norfolk, United Kingdom.

ABSTRACT
The potential cytotoxicity of cadmium selenide (CdSe) quantum dots (QDs) presents a barrier to their use in biomedical imaging or as diagnostic and therapeutic agents. Sulforaphane (SFN) is a chemoprotective compound derived from cruciferous vegetables which can up-regulate antioxidant enzymes and induce apoptosis and autophagy. This study reports the effects of SFN on CdSe QD-induced cytotoxicity in immortalised human hepatocytes and in the livers of mice. CdSe QDs induced dose-dependent cell death in hepatocytes with an IC50 = 20.4 μM. Pre-treatment with SFN (5 μM) increased cell viability in response to CdSe QDs (20 μM) from 49.5 to 89.3%. SFN induced a pro-oxidant effect characterized by depletion of intracellular reduced glutathione during short term exposure (3-6 h), followed by up-regulation of antioxidant enzymes and glutathione levels at 24 h. SFN also caused Nrf2 translocation into the nucleus, up-regulation of antioxidant enzymes and autophagy. siRNA knockdown of Nrf2 suggests that the Nrf2 pathway plays a role in the protection against CdSe QD-induced cell death. Wortmannin inhibition of SFN-induced autophagy significantly suppressed the protective effect of SFN on CdSe QD-induced cell death. Moreover, the role of autophagy in SFN protection against CdSe QD-induced cell death was confirmed using mouse embryonic fibroblasts lacking ATG5. CdSe QDs caused significant liver damage in mice, and this was decreased by SFN treatment. In conclusion, SFN attenuated the cytotoxicity of CdSe QDs in both human hepatocytes and in the mouse liver, and this protection was associated with the induction of Nrf2 pathway and autophagy.

No MeSH data available.


Related in: MedlinePlus