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POLYUNSATURATED LIPID OXIDATION PRODUCTS AND THEIR BIOLOGICAL ACTIVITIES: SYNTHESIS, GENERATION, EFFECTS AND PROTECTION

Cheng, Yu-Shiuan
http://orcid.org/0000-0002-7408-7888
http://rave.ohiolink.edu/etdc/view?acc_num=case1553850446781064

Abstract Details

2019, Doctor of Philosophy, Case Western Reserve University, Chemistry.
Oxidized lipids are generated from polyunsaturated fatty acid-containing phospholipids under conditions of oxidative stress, and are increasingly believed to be associated with age-related diseases. Oxidation of arachidonic acid (AA)-containing phospholipids generates levuglandins that possess reactive γ-ketoaldehyde functional arrays that avidly react with the primary amino groups in biomolecules, which are then transformed into pyrrole derivatives. These protein modifications can interfere with their functions. Recently, an oxidized form of levuglandin (LG)D2 (ox-LGD2) was isolated from the red alga Gracilaria edulis. It is presumably a detoxification metabolite of levuglandins. In order to confirm its structure, a concise total synthesis, implementing an efficient three-component coupling to assemble the main body, was developed in this study. Other than ox-LGD2, its regioisomer ox-LGE2 and unexpected rearranged isomer Δ6-ox-LGD2 were also successfully synthesized and well characterized. Oxidation of phospholipids containing docosahexaenoic acid (DHA) generates truncation products, 4-hydroxy-7-oxo-hept-5-enoic acid (HOHA) phospholipids (PLs), which undergo spontaneous deacylation forming a biologically active compound, HOHA-lactone. HOHA-lactone is a precursor of ω-carboxyethylpyrrole (CEP) that has significant pathological and physiological relevance to age-related macular degeneration (AMD). It can also be metabolized by RPE cells through conjugation with glutathione GSH, forming a Michael adduct HOHA-lactone GSH that is reduced to an alcohol 4,7-dihydroxyhept-5-enoic acid (DHHA)-lactone GSH and transported out of the cells. DHHA-lactone GSH is considered as a relatively stable metabolite of HOHA-lactone. It can be used for monitoring the generation of HOHA-lactone. Two in vitro models were utilized to study light damage in retina. First, in a bovine retina tissue model, elevated levels of HOHA-lactone GSH and DHHA-lactone GSH were found in the bovine retina extract exposed to UVA or white light. Second, in a RPE cell model, elevated levels of DHHA-lactone GSH were generated in DHA-rich cells upon light exposure of and even higher levels were generated in DHA-rich/A2E-laden cells. The increasing levels of DHHA-lactone GSH in RPE cells, which indicates the increase of HOHA-lactone, were strongly correlated with a decrease of cell viability, cellular GSH levels, mitochondrial membrane potential, lysosome integrity, the increase of CEP levels and cellular senescence. HOHA-lactone that had previously found to induce angiogenesis, apoptosis and activate the complement pathway, was now also found to cause mitochondrial dysfunction by impairing mitochondrial respiratory chain complexes – also called the oxidative phosphorylation system (OXPHOS) or the electron transport chain (ETC) – in this study. Damage of mitochondrial respiratory chain complexes leads to generation of mitochondrial reactive oxygen species (mtROS) and depletion of cell energy current and ATP and then induce oxidative stress and eventually cell death. The utility of L-histidyl hydrazide as a drug to scavenge HOHA-lactone to rescue cells from HOHA-lactone induced damage was tested to protect cells from oxidative stress, prevent mitochondrial damage, alleviate the metabolic burden and, most importantly, protect the cells from death. Furthermore, a family of L-histidyl hydrazide derivatives was developed as potential drug candidates for future screening studies.
Robert Salomon (Advisor)
Michael Zagorski (Committee Chair)
Blanton Tolbert (Committee Member)
Fu-Sen Liang (Committee Member)
Masaru Miyagi (Committee Member)
Chemistry

Recommended Citations

Citations

  • Cheng, Y.-S. (2019). POLYUNSATURATED LIPID OXIDATION PRODUCTS AND THEIR BIOLOGICAL ACTIVITIES: SYNTHESIS, GENERATION, EFFECTS AND PROTECTION [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1553850446781064

    APA Style (7th edition)

  • Cheng, Yu-Shiuan. POLYUNSATURATED LIPID OXIDATION PRODUCTS AND THEIR BIOLOGICAL ACTIVITIES: SYNTHESIS, GENERATION, EFFECTS AND PROTECTION. 2019. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1553850446781064.

    MLA Style (8th edition)

  • Cheng, Yu-Shiuan. "POLYUNSATURATED LIPID OXIDATION PRODUCTS AND THEIR BIOLOGICAL ACTIVITIES: SYNTHESIS, GENERATION, EFFECTS AND PROTECTION." Doctoral dissertation, Case Western Reserve University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1553850446781064

    Chicago Manual of Style (17th edition)

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This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.