title: 3H-1,2-dithiole-3-thione protects retinal pigment epithelium cells against Ultra-violet radiation via activation of Akt-mTORC1-dependent Nrf2-HO-1 signaling.
abstract: Excessive UV radiation and reactive oxygen species (ROS) cause retinal pigment epithelium (RPE) cell injuries. Nrf2 regulates transcriptional activation of many anti-oxidant genes. Here, we tested the potential role of 3H-1,2-dithiole-3-thione (D3T) against UV or ROS damages in cultured RPE cells (both primary cells and ARPE-19 line). We showed that D3T significantly inhibited UV-/H2O2-induced RPE cell death and apoptosis. UV-stimulated ROS production was dramatically inhibited by D3T pretreatment. D3T induced Nrf2 phosphorylation in cultured RPE cells, causing Nrf2 disassociation with KEAP1 and its subsequent nuclear accumulation. This led to expression of antioxidant response elements (ARE)-dependent gene heme oxygenase-1 (HO-1). Nrf2-HO-1 activation was required for D3T-mediated cytoprotective effect. Nrf2 shRNA knockdown or S40T dominant negative mutation as well as the HO-1 inhibitor Zinc protoporphyrin (ZnPP) largely inhibited D3T's RPE cytoprotective effects against UV radiation. Yet, exogenous overexpression Nrf2 enhanced D3T's activity in RPE cells. Further studies showed that D3T activated Akt/mTORC1 in cultured RPE cells. Akt-mTORC1 inhibitors, or Akt1 knockdown by shRNA, not only inhibited D3T-induced Nrf2-HO-1 activation, but also abolished the RPE cytoprotective effects. In vivo, D3T intravitreal injection protected from light-induced retinal dysfunctions in mice. Thus, D3T protects RPE cells from UV-induced damages via activation of Akt-mTORC1-Nrf2-HO-1 signaling axis.
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China.|The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ke-Ran
authors.initials: KR
authors.lastname: Li
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Su-Qing
authors.initials: SQ
authors.lastname: Yang
authors.affiliation: The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yi-Qing
authors.initials: YQ
authors.lastname: Gong
authors.affiliation: The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Yang
authors.affiliation: The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Xiu-Miao
authors.initials: XM
authors.lastname: Li
authors.affiliation: The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yu-Xia
authors.initials: YX
authors.lastname: Zhao
authors.affiliation: The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Yao
authors.affiliation: The Affiliated Eye Hospital of Nanjing Medical University, Nanjing 210029, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Jiang
authors.affiliation: Institute of Neuroscience, Soochow University, Suzhou, Jiangsu 215021, China.
authors.forename: Cong
authors.initials: C
authors.lastname: Cao
mesh_terms: D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D051547:Heme Oxygenase-1; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D008565:Membrane Proteins; D008810:Mice, Inbred C57BL; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011837:Radiation-Protective Agents / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000528:radiation effects*; D015398:Signal Transduction; D013871:Thiones / Q000378:metabolism*; D013876:Thiophenes / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D008565:Membrane Proteins; D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D011837:Radiation-Protective Agents; D017382:Reactive Oxygen Species; D013871:Thiones; D013876:Thiophenes; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; C049325:1,2-dithiol-3-thione