Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling

Bibliographic Details
Main Author:	Gatbonton-Schwager, Tonibelle N.
Language:	English
Published:	Case Western Reserve University School of Graduate Studies / OhioLINK 2014
Subjects:	Biology Chemistry Pharmacology Immunology triterpenoids lipid peroxidation inflammation antioxidant Nrf2 bryonolic acid 4-hydroxynonenal macrophage diversity oriented synthesis
Online Access:	http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628

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spelling	ndltd-OhioLink-oai-etd.ohiolink.edu-case13905606282021-08-03T06:21:20Z Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling Gatbonton-Schwager, Tonibelle N. Biology Chemistry Pharmacology Immunology triterpenoids lipid peroxidation inflammation antioxidant Nrf2 bryonolic acid 4-hydroxynonenal macrophage diversity oriented synthesis The immune system provides a cellular defense mechanism against harmful agents in the form of inflammatory and antioxidant responses mediated by the Nrf2-Keap1 signaling pathway. Activators of Nrf2-Keap1 signaling include endogenous molecules such as reactive oxygen species (ROS) and electrophiles, and exogenous molecules including xenobiotics, phytochemicals, and potent synthetic phytochemical derivatives. This body of work furthers the current understanding of the biology and chemistry of small molecule activators of Nrf2 with a focus on exogenously derived natural triterpenoids and related semi-synthetic triterpenoids, and endogenously derived lipid peroxidation product 4-hydroxynonenal (4-HNE). Synthetic oleanane triterpenoids (SOTs) are potent antioxidant inflammation modulators (AIMs) that target Nrf2 and demonstrate preventive and therapeutic effects against a variety of inflammation-mediated chronic diseases. The therapeutic potential of SOTs and the pleiotropic biological profile of natural triterpenoids led us to examine whether the steroid skeletal structure is a requirement for the activation of the Nrf2-Keap1 signaling pathway. We hypothesized that rearranging the triterpenoid skeletal structure would yield novel and effective Nrf2-Keap1 modulators. To test our hypothesis, we developed a unique synthetic approach utilizing Diversity Oriented Synthesis (DOS) techniques to rearrange the carbocyclic triterpenoid skeletal structure of naturally occurring triterpenoids bryonolic acid and lanosterol. In addition to our triterpenoid studies, we examined whether 4-HNE, an endogenous activator of Nrf2, exhibits auto-regulatory features. During oxidative stress, polyunsaturated fatty acids (PUFAs) are oxidized to form 4-HNE, which has been implicated in the pathology of a variety of diseases. Since 4-HNE production is initiated by ROS, we hypothesized that activation of Nrf2 by 4-HNE suppresses biological oxidant formation, leading to the inhibition of 4-HNE production. The triterpenoid studies demonstrated that rearrangement of the triterpenoid skeleton altered potency and that the steroid skeletal structure is not a requirement for Nrf2 activation. We also validated the DOS approach as a method for identifying effective Nrf2 modulators. Understanding structural requirements for activation of Nrf2 will facilitate the identification of novel Nrf2 activators. Additionally, the discovery that 4-HNE regulates its own formation via a negative feedback loop has implications that could lead to new approaches for controlling production and limit the deleterious effects of this molecule. 2014-06-11 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628 http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628 unrestricted This thesis or dissertation is protected by copyright: some rights reserved. It is licensed for use under a Creative Commons license. Specific terms and permissions are available from this document's record in the OhioLINK ETD Center.
collection	NDLTD
language	English
sources	NDLTD
topic	Biology Chemistry Pharmacology Immunology triterpenoids lipid peroxidation inflammation antioxidant Nrf2 bryonolic acid 4-hydroxynonenal macrophage diversity oriented synthesis
spellingShingle	Biology Chemistry Pharmacology Immunology triterpenoids lipid peroxidation inflammation antioxidant Nrf2 bryonolic acid 4-hydroxynonenal macrophage diversity oriented synthesis Gatbonton-Schwager, Tonibelle N. Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling
author	Gatbonton-Schwager, Tonibelle N.
author_facet	Gatbonton-Schwager, Tonibelle N.
author_sort	Gatbonton-Schwager, Tonibelle N.
title	Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling
title_short	Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling
title_full	Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling
title_fullStr	Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling
title_full_unstemmed	Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling
title_sort	biological and chemical analysis of small molecule activators of anti-inflammatory and antioxidant nrf2-keap1 signaling
publisher	Case Western Reserve University School of Graduate Studies / OhioLINK
publishDate	2014
url	http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628
work_keys_str_mv	AT gatbontonschwagertonibellen biologicalandchemicalanalysisofsmallmoleculeactivatorsofantiinflammatoryandantioxidantnrf2keap1signaling
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Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling

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