Identification and Mechanistic Study of Immunostimulatory Lipids in Juzen-Taiho-To
Item
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Title
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Identification and Mechanistic Study of Immunostimulatory Lipids in Juzen-Taiho-To
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Identifier
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d_2009_2013:05788528335e:11534
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identifier
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12045
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Creator
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Takaoka, Anna,
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Contributor
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Akira Kawamura
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Date
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2012
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Language
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English
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Publisher
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City University of New York.
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Subject
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Biochemistry | Immunology
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Abstract
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Juzen-taiho-to (JTT) is an herbal medicine known to exhibit safe and effective immunostimulatory activity. It is clinically used to improve the immune functions of cancer patients undergoing chemotherapy and radiation therapy in Japan. The chemical constituents responsible for its therapeutic effects are poorly characterized due to the chemical complexity of this formulation and possible synergism. Identification of the active constituents would be the first step to systemically characterize the safety and efficacy of JTT and to understand the mechanism. The main objective of this thesis was the identification of macrophage (Mphi)-stimulating compound(s) in JTT by biomarker-guided screening, and the characterization of individual components to identify possible new biological effects of those compounds.;In this thesis, chapter 1 describes the establishment of the technique we used, biomarker-guided screening, to identify therapeutically relevant compounds from herbal medicines. The technique was established in our lab and refined using two different herbal medicines, namely Keishi-bukuryo-gan and Toki-shakuyaku-san. Chapter 2 describes the identification of common chemical components in Mphi-stimulating fractions from two different batches of JTT. This is an important achievement because batch-to-batch variability is a major concern in the natural product research. Chapter 3 describes the characterization of individual compounds identified in Mphi-stimulating fractions, which led to the discovery of one system that exhibit significant synergistic Mphi-stimulating activity, i.e. beta-Glucocerebroside (GlcCer) and C16:0-ceramide (Cer). This finding is important because it is a rare example of a structurally defined, small molecule mixture that exhibited synergistic Mphi-stimulating activity. In addition, the activity assay showed that Mphi-stimulating activity of GlcCer/Cer mixture was time-sensitive and diminished within 3 hr of sample reconstitution in DMSO. Further mechanistic study of GlcCer/Cer mixture using transmission electron microscope (TEM) and dynamic light scattering (DLS) revealed that GlcCer/Cer mixture forms nanoparticles in both DMSO and an aqueous environment, and the size of the nanoparticles correlated with the Mphi-stimulating activity. Our study provided a new basis of novel combinational therapy, and served as an important step to systemically characterize the safe and effective immunostimulatory herbal medicine, JTT.
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Type
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dissertation
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Source
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2009_2013.csv
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degree
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Ph.D.
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Program
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Biochemistry
