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

Abstract

Zinc ions (Zn 2+) are important messenger molecules involved in various physiological functions. To maintain the homeostasis of cytosolic Zn 2+ concentration ([Zn 2+ ] c), Zrt/Irt-related proteins (ZIPs) and Zn 2+ transporters (ZnTs) are the two families of proteins responsible for decreasing and increasing the [Zn 2+ ] c , respectively, by fluxing Zn 2+ across the membranes of the cell and intracellular compartments in opposite directions. Most studies focus on the cytotoxicity incurred by a high concentration of [Zn 2+ ] c and less investigate the [Zn 2+ ] c at physiological levels. Zinc oxide-nanoparticle (ZnO-NP) is blood brain barrier-permeable and elevates the [Zn 2+ ] c to different levels according to the concentrations of ZnO-NP applied. In this study, we mildly elevated the [Zn 2+ ] 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 Zn 2+ transporters in 6-hydroxy dopamine (6-OHDA)-induced cell death. The results show that ZnO-NP at low concentrations elevated the [Zn 2+ ] c transiently in 6 hr, then declined gradually to a basal level in 24 hr. Knocking down the expression levels of ZnT 1 (located mostly at the plasma membrane) and ZIP 8 (present in endosomes and lysosomes) increased and decreased the ZnO-NP-induced elevation of [Zn 2+ ] 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 [Zn 2 + ] 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.

Proton-Pump Inhibitors Suppress T Cell Response by Shifting Intracellular Zinc Distribution

“…To investigate the molecular mechanism of shifted intracellular-free zinc redistribution after PPI treatment, we measured the expression of Zip8, a membrane zinc transporter localized in the lysosomal membrane [ 39 ]. Zip8 is the most important zinc transporter that transports free zinc from the lysosome to the cytoplasm.…”

Biocompatibility and Connectivity of Semiconductor Nanostructures for Cardiac Tissue Engineering Applications

“…Last, besides a number of biomedical, health- and sustainability-related applications [ 35 , 36 ]. it is worth noting that the ZnO NWs’ cytotoxicity makes them potential candidates for the targeted elimination of cancer cells [ 37 , 38 ]. Our work, in line with others reported elsewhere, shows some degree of cytotoxicity when cells were cultured on the ZnO NWs substrates.…”

Single-gene knockout-coupled omics analysis identifies C9orf85 and CXorf38 as two uncharacterized human proteins associated with ZIP8 malfunction

“…The ZIP8 is a transmembrane protein that involves in the uptake of Fe, Mn, Zn, and Se, and therefore, cells with impaired ZIP8 are often associated with dysregulated intracellular levels of these essential micronutrients ( McDermott et al, 2016 ; Zang et al, 2016 ; Lin et al, 2017 ; Liang et al, 2021 ). Although studies have indicated that the expression of ZIP8 can be affected by different physiological conditions (e.g., during lactation, Cd exposure, ZnO nanoparticle treatment, and inflammation) ( Kelleher et al, 2012 ; Gao et al, 2017 ; Xu et al, 2017 ; Pan et al, 2020 ; Hatano et al, 2021 ), it is largely unclear how impaired ZIP8 will affect the cells other than having an impact on the intracellular homeostasis of micronutrients.…”