Zinc oxide nanoparticles modulate the gene expression of ZnT1 and ZIP8 to manipulate zinc homeostasis and stress-induced cytotoxicity in human neuroblastoma SH-SY5Y cells
Journal
PLoS ONE
Journal Volume
15
Journal Issue
9
Date Issued
2020
Author(s)
Abstract
Zinc ions (Zn2+) are important messenger molecules involved in various physiological functions. To maintain the homeostasis of cytosolic Zn2+ concentration ([Zn2+]c), Zrt/Irt-related proteins (ZIPs) and Zn2+ transporters (ZnTs) are the two families of proteins responsible for decreasing and increasing the [Zn2+]c, respectively, by fluxing Zn2+ across the membranes of the cell and intracellular compartments in opposite directions. Most studies focus on the cytotoxicity incurred by a high concentration of [Zn2+]c and less investigate the [Zn2+]c at physiological levels. Zinc oxide-nanoparticle (ZnO-NP) is blood brain barrier-permeable and elevates the [Zn2+]c to different levels according to the concentrations of ZnO-NP applied. In this study, we mildly elevated the [Zn2+]c by ZnO-NP at concentrations below 1 μg/ml, which had little cytotoxicity, in cultured human neuroblastoma SH-SY5Y cells and characterized the importance of Zn2+ transporters in 6-hydroxy dopamine (6-OHDA)-induced cell death. The results show that ZnO-NP at low concentrations elevated the [Zn2+]c transiently in 6 hr, then declined gradually to a basal level in 24 hr. Knocking down the expression levels of ZnT1 (located mostly at the plasma membrane) and ZIP8 (present in endosomes and lysosomes) increased and decreased the ZnO-NP-induced elevation of [Zn2+]c, respectively. ZnO-NP treatment reduced the basal levels of reactive oxygen species and Bax/Bcl-2 mRNA ratios; in addition, ZnO-NP decreased the 6-OHDA-induced ROS production, p53 expression, and cell death. These results show that ZnO-NP-induced mild elevation in [Zn2 +]c activates beneficial effects in reducing the 6-OHDA-induced cytotoxic effects. Therefore, brain-delivery of ZnO-NP can be regarded as a potential therapy for neurodegenerative diseases. Copyright: ? 2020 Pan et al.
Subjects
messenger RNA; oxidopamine; protein Bax; protein bcl 2; protein p53; reactive oxygen metabolite; zinc oxide nanoparticle; cation transport protein; metal nanoparticle; reactive oxygen metabolite; SLC30A1 protein, human; zinc; zinc oxide; Zip8 protein, human; Article; blood brain barrier; cell membrane; controlled study; cytotoxicity; endosome; gene; gene expression; gene knockdown; human; human cell; incubation time; lysosome; MTT assay; oxidative stress; protein expression; real time polymerase chain reaction; SH-SY5Y cell line; zinc homeostasis; ZIP8 gene; ZnT1 gene; apoptosis; cell death; cell survival; drug effect; gene expression; metabolism; tumor cell line; Apoptosis; Cation Transport Proteins; Cell Death; Cell Line, Tumor; Cell Survival; Gene Expression; Humans; Metal Nanoparticles; Oxidopamine; Reactive Oxygen Species; Zinc; Zinc Oxide
SDGs
Other Subjects
messenger RNA; oxidopamine; protein Bax; protein bcl 2; protein p53; reactive oxygen metabolite; zinc oxide nanoparticle; cation transport protein; metal nanoparticle; reactive oxygen metabolite; SLC30A1 protein, human; zinc; zinc oxide; Zip8 protein, human; Article; blood brain barrier; cell membrane; controlled study; cytotoxicity; endosome; gene; gene expression; gene knockdown; human; human cell; incubation time; lysosome; MTT assay; oxidative stress; protein expression; real time polymerase chain reaction; SH-SY5Y cell line; zinc homeostasis; ZIP8 gene; ZnT1 gene; apoptosis; cell death; cell survival; drug effect; gene expression; metabolism; tumor cell line; Apoptosis; Cation Transport Proteins; Cell Death; Cell Line, Tumor; Cell Survival; Gene Expression; Humans; Metal Nanoparticles; Oxidopamine; Reactive Oxygen Species; Zinc; Zinc Oxide
Type
journal article