Synthetic condensed 1,4-naphthoquinone derivative shifts neural stem cell differentiation by regulating redox state.
Naphthoquinones are bioactive compounds widespread in nature that impact on several cellular pathways, including cell proliferation and survival, by acting as prooxidants and electrophiles. We have previously described the role of the synthetic isoxazole condensed 1,4-naphthoquinone derivative 1a in preventing apoptosis induced by distinct stimuli in several cell models. In addition, apoptosis regulators and executioners may control neural stem cell (NSC) fate, without involving cell death per se. Here, we hypothesize that 1a might also play a role in NSC fate decision. We found that exposure to 1a shifts NSC differentiation potential from neurogenic to gliogenic lineage and involves the generation of reactive oxygen species, without increasing cell death. Modulation of caspases and calpains, using cysteine protease inhibitors, failed to mimic 1a effects. In addition, incubation with the naphthoquinone derivative resulted in upregulation and nuclear translocation of antioxidant responsive proteins, Nrf2 and Sirt1, which in turn may mediate 1a-directed shift in NSC differentiation. In fact, antioxidants halted the shift in NSC differentiation potential from neurogenic to gliogenic lineage, while strongly reducing reactive oxygen species generation and Nrf2 and Sirt1 nuclear translocation in NSC exposed to 1a. Collectively, these data support a new role for a specific naphthoquinone derivative in NSC fate decision and underline the importance of redox environment control.
Research Institute for Medicines and Pharmaceutical Sciences (iMed.UL), Faculty of Pharmacy, University of Lisbon, Lisbon, Portugal.
Daniela M
DM
Santos
Maria M M
MM
Santos
Rui
R
Moreira
Susana
S
Solá
Cecília M P
CM
Rodrigues
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D009285:Naphthoquinones / Q000494:pharmacology*; D058953:Neural Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009457:Neuroglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D056564:Sirtuin 1 / Q000378:metabolism
D000975:Antioxidants; D015853:Cysteine Proteinase Inhibitors; D009285:Naphthoquinones; D017382:Reactive Oxygen Species; D020169:Caspases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C035342:1,4-naphthoquinone