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A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress.

ABSTRACT: UVA radiation can damage cells and tissues by direct photodamage of biomolecules as well as by initiating metal-catalyzed oxidative stress. In order to alleviate both concerns simultaneously, we synthesized a multifunctional prochelator PC-HAPI (2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (trans)-3-(2,4-dihydroxyphenyl)acrylate) that contains a trans-(o-hydroxy)cinnamate ester photocleavable protecting group that is cleaved upon UVA exposure to release a coumarin, umbelliferone, and an aroylhydrazone metal chelator, HAPI (N'-[1-(2-hydroxyphenyl)ethyliden]isonicotinoylhydrazide). While the prochelator PC-HAPI exhibits negligible affinity for iron, it responds rapidly to UVA irradiation and converts to an iron-binding chelator that inhibits iron-catalyzed formation of reactive oxygen species and protects cells from UVA damage.

SUBMITTER: Franks AT

PROVIDER: S-EPMC4607636 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress.

Franks Andrew T AT Wang Qin Q Franz Katherine J KJ

Bioorganic & medicinal chemistry letters 20150618 21

UVA radiation can damage cells and tissues by direct photodamage of biomolecules as well as by initiating metal-catalyzed oxidative stress. In order to alleviate both concerns simultaneously, we synthesized a multifunctional prochelator PC-HAPI (2-((E)-1-(2-isonicotinoylhydrazono)ethyl)phenyl (trans)-3-(2,4-dihydroxyphenyl)acrylate) that contains a trans-(o-hydroxy)cinnamate ester photocleavable protecting group that is cleaved upon UVA exposure to release a coumarin, umbelliferone, and an aroyl ...[more]

PMID: 26152427

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Project description:The human skin is exposed to various environmental factors including solar radiation and ambient air pollutants. Although, due to its physical and biological properties, the skin efficiently protects the body against the harm of environmental factors, their excessive levels and possible synergistic action may lead to harmful effects. Among particulate matter present in ambient air pollutants, PM2.5 is of particular importance for it can penetrate both disrupted and intact skin, causing adverse effects to skin tissue. Although certain components of PM2.5 can exhibit photochemical activity, only a limited amount of data regarding the interaction of PM2.5 with light and its effect on skin tissue are available. This study focused on light-induced toxicity in cultured human keratinocytes, which was mediated by PM2.5 obtained in different seasons. Dynamic Light Scattering (DLS) and Atomic Force Microscopy (AFM) were employed to determine sizes of the particles. The ability of PM2.5 to photogenerate free radicals and singlet oxygen was studied using EPR spin-trapping and time-resolved singlet oxygen phosphorescence, respectively. Solar simulator with selected filters was used as light source for cell treatment to model environmental lightning conditions. Cytotoxicity of photoexcited PM2.5 was analyzed using MTT assay, PI staining and flow cytometry, and the apoptotic pathway was further examined using Caspase-3/7 assay and RT-PCR. Iodometric assay and JC-10 assay were used to investigate damage to cell lipids and mitochondria. Light-excited PM2.5 were found to generate free radicals and singlet oxygen in season-dependent manner. HaCaT cells containing PM2.5 and irradiated with UV-Vis exhibited oxidative stress features-increased peroxidation of intracellular lipids, decrease of mitochondrial membrane potential, enhanced expression of oxidative stress related genes and apoptotic cell death. The data indicate that sunlight can significantly increase PM2.5-mediated toxicity in skin cells.

Project description:BackgroundCell senescence is central to a large body of age related pathology, and accordingly, cardiomyocytes senescence is involved in many age related cardiovascular diseases. In consideration of that, delaying cardiomyocytes senescence is of great importance to control clinical cardiovascular diseases. Previous study indicated that bradykinin (BK) protected endothelial cells from senescence induced by oxidative stress. However, the effects of bradykinin on cardiomyocytes senescence remain to be elucidated. In this study, we investigated the effect of bradykinin on H2O2-induced H9C2 cells senescence.Methods and resultsBradykinin pretreatment decreased the senescence induced by H2O2 in cultured H9C2 cells in a dose dependent manner. Interestingly, 1 nmol/L of BK almost completely inhibited the increase in senescent cell number and p21 expression induced by H2O2. Since H2O2 induces senescence through superoxide-induced DNA damage, we also observed the DNA damage by comet assay, and BK markedly reduced DNA damage induced by H2O2, and moreover, BK treatment significantly prevented reactive oxygen species (ROS) production in H9C2 cells treated with H2O2. Importantly, when co-incubated with bradykinin B2 receptor antagonist HOE-140 or eNOS inhibitor N-methyl-L-arginine acetate salt (L-NAME), the protective effects of bradykinin on H9C2 senescence were totally blocked. Furthermore, BK administration significantly prevented the increase in nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity characterized by increased ROS generation and gp91 expression and increased translocation of p47 and p67 to the membrane and the decrease in superoxide dismutase (SOD) activity and expression induced by H2O2 in H9C2 cells, which was dependent on BK B2 receptor mediated nitric oxide (NO) release.ConclusionsBradykinin, acting through BK B2 receptor induced NO release, upregulated antioxidant Cu/Zn-SOD and Mn-SOD activity and expression while downregulating NADPH oxidase activity and subsequently inhibited ROS production, and finally protected against cardiomyocytes senescence induced by oxidative stress.

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A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress.

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A multifunctional, light-activated prochelator inhibits UVA-induced oxidative stress.

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