A macrocyclic molecule with multiple antioxidative activities protects the lens from oxidative damage

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dc.creatorZhang, Jinmin
dc.creatorYu, Yu
dc.creatorMekhail, Magy A.
dc.creatorWu, Hongli
dc.creatorGreen, Kayla N.
dc.date.accessioned2023-02-16T14:25:41Z
dc.date.available2023-02-16T14:25:41Z
dc.date.issued2022-11-18
dc.description.abstractGrowing evidence links oxidative stress to the development of a cataract and other diseases of the eye. Treatments for lens-derived diseases are still elusive outside of the standard surgical interventions, which still carry risks today. Therefore, a potential drug molecule (OH)Py(2)N(2) was explored for the ability to target multiple components of oxidative stress in the lens to prevent cataract formation. Several pathways were identified. Here we show that the (OH)Py(2)N(2) molecule activates innate catalytic mechanisms in primary lens epithelial cells to prevent damage induced by oxidative stress. This protection was linked to the upregulation of Nuclear factor erythroid-2-related factor 2 and downstream antioxidant enzyme for glutathione-dependent glutaredoxins, based on Western Blot methods. The anti-ferroptotic potential was established by showing that (OH)Py(2)N(2) increases levels of glutathione peroxidase, decreases lipid peroxidation, and readily binds iron (II) and (III). The bioenergetics pathway, which has been shown to be negatively impacted in many diseases involving oxidative stress, was also enhanced as evidence by increased levels of Adenosine triphosphate product when the lens epithelial cells were co-incubated with (OH)Py(2)N(2). Lastly, (OH)Py(2)N(2) was also found to prevent oxidative stress-induced lens opacity in an ex vivo organ culture model. Overall, these results show that there are multiple pathways that the (OH)Py(2)N(2) has the ability to impact to promote natural mechanisms within cells to protect against chronic oxidative stress in the eye.
dc.description.sponsorshipThe authors acknowledge National Institutes of Health 2R15GM123463-02 (to KG and HW) and Welch Foundation P-2063-20210327 (to KG). BrightFocus Foundation [rant no: M2015180 (HW)]; California Table Grape Commission Research Grant (HW); and the United States Department of Defense [VRP Research Award no: W81XWH2010896 (HW)].
dc.identifier.citationZhang, J., Yu, Y., Mekhail, M. A., Wu, H., & Green, K. N. (2022). A macrocyclic molecule with multiple antioxidative activities protects the lens from oxidative damage. Frontiers in chemistry, 10, 996604. https://doi.org/10.3389/fchem.2022.996604
dc.identifier.issn2296-2646
dc.identifier.urihttps://hdl.handle.net/20.500.12503/32028
dc.identifier.volume10
dc.publisherFrontiers Media S.A.
dc.relation.urihttps://doi.org/10.3389/fchem.2022.996604
dc.rights.holder© 2022 Zhang, Yu, Mekhail, Wu and Green.
dc.rights.licenseAttribution 4.0 International (CC BY 4.0)
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.sourceFrontiers in Chemistry
dc.subjectNrf2
dc.subjectOHPy2N2
dc.subjectferroptosis
dc.subjectglutaredoxin
dc.subjectlens
dc.subjectoxidative stress
dc.titleA macrocyclic molecule with multiple antioxidative activities protects the lens from oxidative damage
dc.typeArticle
dc.type.materialtext

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