ABSTRACT
Polyethylene glycol-23 glyceryl distearate (GDS-23), a diacylglycerol polyethylene glycol adduct, forms niosomes with a liposome-like structure and functions as an active ingredient in drug delivery systems. In addition, it upregulates antioxidant proteins such as heme oxygenase 1 and NAD(P)H-quinone dehydrogenase 1 in cells. However, the activation of nuclear factor E2-related factor-2 (Nrf2), which plays a role in inducing the expression of antioxidant proteins, and its protective effects induced by GDS-23 treatment against oxidative stress have not been elucidated. This study aimed at verifying the activation of Nrf2 by GDS-23 and clarifying its underlying mechanisms, and investigated whether GDS-23 protects against hydroquinone-induced cytotoxicity. Normal human epidermal keratinocytes were treated with GDS-23. Real-time reverse transcription-polymerase chain reaction, western blotting, and immunostaining were used to investigate the mechanism of Nrf2 activation, and neutral red assay was performed to evaluate cytotoxicity. GDS-23-treated cells showed an increase in antioxidant protein levels and stabilization of Nrf2 in the nucleus. During Nrf2 activation, p62, an autophagy-related adaptor protein, was phosphorylated at Ser349. Inhibition of the interaction between the phosphorylated p62 and Kelch-like ECH-associated protein 1 significantly suppressed the GDS-23-mediated induction of antioxidant protein expression. In addition, hydroquinone-induced cell toxicity was significantly attenuated by GDS-23. GDS-23 induced the intracellular antioxidant system by activating Nrf2 in a p62 phosphorylation-dependent manner without generating oxidative stress in the cells. GDS-23 may be applied as a multifunctional material for drug delivery system that enhances internal antioxidant systems.
Subject(s)
Antioxidants , NF-E2-Related Factor 2 , Humans , Antioxidants/metabolism , Diglycerides/pharmacology , Heme Oxygenase-1/genetics , Heme Oxygenase-1/metabolism , Hydroquinones/toxicity , Kelch-Like ECH-Associated Protein 1/metabolism , Keratinocytes/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Polyethylene Glycols/pharmacology , Polyethylene Glycols/metabolismABSTRACT
The first BNCT antitumor effects of BNNTs toward B16 melanoma cells were demonstrated. The use of DSPE-PEG2000 was effective for preparation of the BNNT-suspended aqueous solution. BNNT-DSPE-PEG2000 accumulated in B16 melanoma cells approximately three times higher than BSH and the higher BNCT antitumor effect was observed in the cells treated with BNNT-DSPE-PEG2000 compared to those treated with BSH, indicating that BNNT-DSPE-PEG2000 would be a possible candidate as a boron delivery vehicle for BNCT.
Subject(s)
Antineoplastic Agents/administration & dosage , Boron Compounds/administration & dosage , Boron Neutron Capture Therapy/methods , Melanoma, Experimental/drug therapy , Melanoma, Experimental/radiotherapy , Nanotubes , Animals , Antineoplastic Agents/chemistry , Boron Compounds/chemistry , Cell Survival/drug effects , Cell Survival/radiation effects , Nanotubes/chemistry , Neutrons , Skin Neoplasms/drug therapy , Skin Neoplasms/radiotherapyABSTRACT
closo-Dodecaborate-encapsulating liposomes were developed as boron delivery vehicles for neutron capture therapy. The use of spermidinium as a counter cation of closo-dodecaborates was essential not only for the preparation of high boron content liposome solutions but also for efficient boron delivery to tumors.
