TrxR2 overexpression alleviates inflammation-mediated neuronal death via reducing the oxidative stress and activating the Akt–Parkin pathway

Abstract

Neuronal death caused by inflammatory cytokine-mediated neuroinflammation is being extensively explored. Thioredoxin reductase (TrxR) 2 is a novel mediator of inflammation response. In the current study, we focus on the mechanisms of TrxR2 overexpression in inflammation-mediated neuronal death. LPS was used to induce neuroinflammation in N2a cells in vitro. Adenovirus-loaded TrxR2 was transfected into N2a cells to up-regulate TrxR2 expression. Then, cell viability was determined via MTT assay and TUNEL assay. Apoptosis was measured via western blotting and ELISA. Oxidative stress was detected via ELISA and flow cytometry. A pathway inhibitor was used to verify the role of the Akt–Parkin pathway in the LPS-mediated N2a cell death in the presence of TrxR2 overexpression. With the help of immunofluorescence assay and western blotting, we found that TrxR2 expression was significantly reduced in response to LPS treatment, and this effect was associated with N2a cell death via apoptosis. At the molecular level, TrxR2 overexpression elevated the activity of the Akt–Parkin pathway, as evidenced by the increased expression of p-Akt and Parkin. Interestingly, inhibition of the Akt–Parkin pathway abolished the regulatory effect of TrxR2 on LPS-treated N2a cells, as evidenced by the decreased cell viability and increased apoptotic ratio. Besides, TrxR2 overexpression also reduced oxidative stress, inflammation factor transcription and mitochondrial apoptosis. However, inhibition of Akt–Parkin axis abrogated the protective effects of TrxR2 on redox balance, mitochondrial performance and cell survival. LPS-mediated neuronal death was linked to a drop in TrxR2 overexpression and the inactivation of the Akt–Parkin pathway. Overexpression of TrxR2 sustained mitochondrial function, inhibited oxidative stress, repressed inflammation response, and blocked mitochondrial apoptosis, finally sending a pro-survival signal for the N2a cells in the setting of LPS-mediated inflammation environment.

Maackiain Ameliorates 6-Hydroxydopamine and SNCA Pathologies by Modulating the PINK1/Parkin Pathway in Models of Parkinson’s Disease in Caenorhabditis elegans and the SH-SY5Y Cell Line

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Resveratrol Mitigates Oxygen and Glucose Deprivation-Induced Inflammation, NLRP3 Inflammasome, and Oxidative Stress in 3D Neuronal Culture

“…Furthermore, treatment with resveratrol significantly rescued cell survival, although this protective effect was blocked by co-treatment with an antagonist of AMPK (Compound C) ( Figure 1 A). Inflammation may severely alter the viability of neuronal cells [ 73 , 74 , 75 ]. Therefore, the treated SH-SY5Y cells were evaluated for changes in the secretion levels of pro-inflammatory cytokines by ELISA.…”

Bioactivity and Cell Imaging of Antitumor Fluorescent Agents (Curcumin Derivatives) Coated by Two‐Way Embedded Cyclodextrin Strategy

“…Thioredoxin reductase is commonly overexpressed in tumor tissues [31] . In tumors, inhibition of TrxR2 can cause cell apoptosis [32–33] . The 3D crystal structure of mitochondrial thioredoxin reductase (TrxR2) from the Protein Database (PDB) was used as the receptor for docking studies.…”

“…[31] In tumors, inhibition of TrxR2 can cause cell apoptosis. [32][33] The 3D crystal structure of mitochondrial thioredoxin reductase (TrxR2) from the Protein Database (PDB) was used as the receptor for docking studies. Since the structure of 4 J57 was similar to that of compounds, 4 J57 was downloaded from the protein database.…”