Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C

Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C

Bibliographic Details
Main Author: Udeigwe, Emeka
Language:English
Published: Case Western Reserve University School of Graduate Studies / OhioLINK 2021
Subjects:
Biochemistry
Chemistry
Molecular Biology
HOHA lactone
DHA
RPE
apoptosis
complement pathway
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=case1600871319962572
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-case16008713199625722021-08-03T07:16:22Z Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C Udeigwe, Emeka Biochemistry Chemistry Molecular Biology HOHA lactone DHA RPE apoptosis complement pathway Previous studies led to the discovery that the oxidative fragmentation of docosahexaenoic acid (DHA), the most abundant polyunsaturated fatty acid in the photoreceptor cell disc membrane, generates HOHA lactone metabolites in retinal pigmented epithelial (RPE) cells. Here, the biological activities HOHA lactone were explored – the ability to induce apoptosis, complement pathway and expression of matrix metalloproteases (MMPs) in RPE cells. I contributed to the discovery that HOHA lactone induces upregulation of the antioxidant transcription factor Nrf2 in ARPE-19 cells. This leads to the expression of three Nrf2-responsive antioxidant genes, GCLM, HO1 and NQO1. HOHA lactone also induces an increase in the expression of phosphorylated JNK in RPE cells, followed by the initiation of the intrinsic apoptotic pathway through the phosphorylation of p53, and ultimately caspase-3. The DHA-oxidative fragmentation products HOHA lactone and 4-HHE, are significantly more pro-apoptotic than 4-HNE, derived from ω-6 PUFAs. This difference is especially relevant in the photoreceptor and RPE cells where ω-3 fatty acid, e.g., DHA, are more abundant than ω-6 fatty acids. The potential of HOHA-lactone to stimulate the expression of MMPs in RPE cells was also investigated. Along with the increased protein expression of MMP1 and MMP3, I discovered that HOHA lactone induces a dose-dependent increase in the expression of pro-MMP2 but a modest increase in active-MMP2 in the extracellular medium of ARPE-19 cells. The presence or abnormalities of MMPs (particularly pro-MMP2) may contribute to the accumulation of deposits in AMD. Cells convert HNE into a glutathione derivative by Michael addition and then reduce the aldehyde group to a hydroxyl before excreting the adduct. Similar processing of HOOA phospholipids in conjunction with phospholipolysis produces an adduct, ø-LTC, that incorporates structural and functional features of cysteinyl leukotriene C4 (LTC4). The biological activities of ø-LTC were evaluated for its ability to induce phagocytosis of fluorescent microspheres in mouse microglia BV2 cells. I discovered an increased phagocytic rate in ø-LTC treated cells versus controls. The presence of and biological activities of ø-LTC are of interest because its activities may mimic those of LTC4 or LTD4 that contribute to Alzheimer's disease, as phagoptosis of neurons by microglia might contribute to neuropathology. 2021-01-22 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1600871319962572 http://rave.ohiolink.edu/etdc/view?acc_num=case1600871319962572 restricted--full text unavailable until 2023-01-15 This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Biochemistry
Chemistry
Molecular Biology
HOHA lactone
DHA
RPE
apoptosis
complement pathway
spellingShingle Biochemistry
Chemistry
Molecular Biology
HOHA lactone
DHA
RPE
apoptosis
complement pathway
Udeigwe, Emeka
Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C
author Udeigwe, Emeka
author_facet Udeigwe, Emeka
author_sort Udeigwe, Emeka
title Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C
title_short Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C
title_full Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C
title_fullStr Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C
title_full_unstemmed Biological Activities of Nonenzymatically Oxidized Lipids in RPE and Microglial Cells: HOHA Lactone and Pseudo Leukotriene C
title_sort biological activities of nonenzymatically oxidized lipids in rpe and microglial cells: hoha lactone and pseudo leukotriene c
publisher Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate 2021
url http://rave.ohiolink.edu/etdc/view?acc_num=case1600871319962572
work_keys_str_mv AT udeigweemeka biologicalactivitiesofnonenzymaticallyoxidizedlipidsinrpeandmicroglialcellshohalactoneandpseudoleukotrienec
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