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Fig. 5 | BMC Pharmacology and Toxicology

Fig. 5

From: Nuclear factor erythroid 2 – related factor 2 and its relationship with cellular response in nickel exposure: a systems biology analysis

Fig. 5

Molecular models of the potential role of proteins involved in the Nrf2 – mediated response to NCC exposure. a NiSO4 allows the release of Ni2+ ion which increases ROS production in the cytoplasm, inducing 1) hypomethylation and HAT inhibition through increased HDACs and NCoRs activity, which reduces Keap1/Nrf2 dissociation and posterior Nrf2/ARE transcription, and 2) inhibition of DNA repair process; b) Ni3S2 uptake is facilitated via phagocytosis, delaying Ni2+ dissolution inside the cytoplasm. However both Ni3S2 and NiSO4 releases Ni2+ outside alveolar cells increasing production of Ni-protein complexes which acts as antigens for APC cells following differentiation to Ni2+-specific interferon γ (IFN-γ)-producing effector T cells, whereas inside the cell increase NF-kB transcription and proinflammatory response; c) Ni3S2 is capable of the release of high levels of the Ni2+ ion and ROS as a product of Ni3S2 mediated-phagocytosis. Retention of Ni3S2 and slow dissolution in endosomes are the primary cause of a possible chronic inflammation response. Ni2+ from Ni3S2 can induce ER stress through the activation of PERK, IRE1, and ATF6 pathways. During ER-stress conditions proteins that fail the ER quality control are transported back to the cytosol where they are rapidly destroyed by the ER-associated degradation (ERAD) pathway. Additionally, redox status generated by Ni2+ regulates the nuclear activity of NF-kB proteins by altering the binding of NF-kB proteins to DNA in part via the Nrf2-signaling pathway. The absence of Nrf2 can exacerbate NF-κB activity leading to increased cytokine production

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