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

Gatbonton-Schwager, Tonibelle N
http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628

Abstract Details

2014, Doctor of Philosophy, Case Western Reserve University, Pharmacology.
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.
Gregory Tochtrop, Ph.D. (Advisor)
John Letterio, M.D. (Advisor)
Monica Montano, Ph.D. (Committee Chair)
John Mieyal, Ph.D. (Committee Member)
Marvin Nieman, Ph.D. (Committee Member)
Sanjay Gupta, Ph.D. (Committee Member)
238 p.
Biology; Chemistry; Immunology; Pharmacology
triterpenoids; lipid peroxidation; inflammation; antioxidant; Nrf2; bryonolic acid; 4-hydroxynonenal; macrophage; diversity oriented synthesis

Recommended Citations

Citations

  • Gatbonton-Schwager, T. N. (2014). Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628

    APA Style (7th edition)

  • Gatbonton-Schwager, Tonibelle. Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling . 2014. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628.

    MLA Style (8th edition)

  • Gatbonton-Schwager, Tonibelle. "Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling ." Doctoral dissertation, Case Western Reserve University, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=case1390560628

    Chicago Manual of Style (17th edition)

case1390560628
662
© 2014, some rights reserved.Creative Commons License Biological and Chemical Analysis of Small Molecule Activators of Anti-inflammatory and Antioxidant Nrf2-Keap1 Signaling by Tonibelle N Gatbonton-Schwager is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. Based on a work at etd.ohiolink.edu.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.