Purpose: To develop an agent-based, discrete-event, synthetic model that integrates the existing knowledge about intestinal absorption and disposition of baicalein (Ba) and dynamically represents the pharmacokinetic properties of Ba. To validate the model by matching simulated observations to bi-directional Caco-2 transport profiles of Ba. / Methods: A 3D multi-agent system extending the previous 2D in silico analogue of Caco-2 cell monolayer was used to study the pharmacokinetic properties of Ba. The model specification was based on previous study findings. Our model consisted of three 3D spaces and two 2D membranes: apical space (S1), intracellular space (S2), basolateral space (S3), apical membrane (M1), and basolateral membrane (M2). Validated enzyme components (UGTs and SULTs) and binder components (BINDERs) were placed in S2. Validated efflux transporter components (BCRPs, MRP2s, MRP1s and MRP3s) were placed at M1 and M2 respectively. Initially, Solutes (BA) were loaded to either S1 or S3. From there, they penetrated into S2 according to a validated, passive transport algorithm. Within S2, BA could be transformed into Baicalein-Glucuronide (BG) by UGTs or to Baicalein-O-Sulfate (BS) by SULTs. These metabolites were pumped out to either S1 or S3 by the active transport of BCRPs, MRP2s, MRP1s and MRP3s. Simulated results were then compared to corresponding wet-lab data to assess similarity based on the pre-specified similarity criteria. An iterative refinement protocol combined with Monte-Carlo simulation was employed to parameterize the model. Finally, the in silico parameters had also been mapped to the classical pharmacokinetic parameters. / Results: The simulated results captured the preset qualitative and quantitative features of the wet-lab observations. The feasible parameter set showed that substrate inhibition happened in both conjugation pathway of Ba. The simulation results suggested that sulfation pathway was dominated at low concentrations and that SULT was more inclined to substrate inhibition than UGT. All these findings were consistent with the previous outcomes from a catenary model. In addition, a micro-hypothesis that BS’s apical efflux transporter could be inhibited by Ba at high loading concentration was implemented to address the changing preference of the distribution of BS. / Conclusion: The mechanisms represented by our model are plausible. Our novel modeling approach could dynamically represent the pharmacokinetics of bi-directional transport of Ba in Caco-2 system. Furthermore, through the model development, we suspect there is inhibition of BS’s apical efflux transporter at high loading concentration of Ba, which is worthy of further investigation. / 研究目的：建立一個基於離散事件，並由智慧單元體組成的組合模型。該模型將整合與黃芩素小腸吸收和處置相關的已有知識，從而動態呈現黃芩素的藥動學性質。黃芩素在Caco-2系統中進行的雙向轉運實驗資料將被用來對該模型進行校驗。 / 研究方法：一個新的三維多智慧體系拓展自已有的二維Caco-2單層細胞體系模型，將被用來研究黃芩素的藥動學特徵。模型的配置將基於已有的研究發現。該模型由三個三維的空間對象和兩個二維的膜對象組成，他們是：頂端空間（S1）,細胞內空間（S2）,基底空間（S3）,頂端膜（M1）,和基底膜（M2）。已校驗的酶物件（UGTs和SULTs）和結合蛋白物件（BINDERs）將被設置在空間物件S2內。已校驗的外排轉運體對象（BCRPs, MRP2s, MRP1s和MRP3s）將被分別設置在膜物件M1和M2上。起始階段，黃芩素物件(BA)將被載入到空間物件S1或S3中。從載入空間出發，BA將基於已校驗的被動轉運演算法進入細胞內空間S2。在S2內，BA將通過UDP-葡萄糖醛酸轉移酶對象（UGTs）被轉化為黃芩苷對象（BG），或是通過硫酸轉移酶對象（SULTs）轉化為硫酸黃芩素物件（BS）。這些代謝產物物件將通過乳腺癌耐藥蛋白物件（BCRPs）和多種多藥耐藥相關蛋白物件（MRP2s, MRP1s和MRP3s）主動泵出到空間S1或S3中。模擬結果將按照預先設定的相似性判斷標準與對應的實驗資料進行比對。我們將通過結合蒙特卡洛模擬的迴圈反覆運算優化方案進行模型的參數化。最終，該模型參數將與傳統的藥動學模型參數建立起相關映射關係。 / 研究結果：模擬結果能夠很好刻畫實驗觀察到的定性和定量特徵。可行的參數集顯示底物抑制效應在黃芩素的兩條代謝通路都有發生。模擬結果顯示在低濃度下硫酸化通路是主要代謝途徑，且硫酸轉移酶相較於UDP-葡萄糖醛酸轉移酶更易被底物抑制。所有這些發現都與之前鏈式模型得到的結論相吻合。此外，一個關於硫酸黃芩素的頂端外排轉運體能夠被高濃度黃芩素抑制的微假設被引入到模型中來解釋硫酸黃芩素分佈偏好的變化。 / 結論：模型所呈現的機制是可行的。我們新穎的模型化方法能夠動態地呈現黃芩素在Caco-2系統中雙向轉運的藥動學特徵。此外，通過模型，我們推測硫酸黃芩素的頂端外排轉運體可能存在被高濃度黃芩素抑制的現象，這值得進一步的深入研究。 / Zhu, Xiao. / Thesis M.Phil. Chinese University of Hong Kong 2015. / Includes bibliographical references (leaves 115-123). / Abstracts also in Chinese. / Title from PDF title page (viewed on 12, October, 2016). / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only.

Chiang Yee-Ting. / Thesis submitted in: December 2002. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2003. / Includes bibliographical references (leaves 116-130). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract --- p.ii / List of Abbreviations --- p.iv / List of Tables --- p.v / List of Figures --- p.vi / Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- "Free radical, oxidative stress and antioxidants" --- p.2 / Chapter 1.1.1 --- Free radicals and reactive oxygen species (ROS) --- p.2 / Chapter 1.1.2 --- Oxidative stress and human diseases --- p.3 / Chapter 1.1.3 --- Dietary antioxidants --- p.5 / Chapter 1.1.4 --- Synthetic antioxidants --- p.5 / Chapter 1.2 --- Flavonoids ´ؤ polyphenolic compounds in plants --- p.8 / Chapter 1.2.1 --- Sources and biosynthesis of flavonoids --- p.8 / Chapter 1.2.2 --- Classification and dietary occurrence of flavonoids --- p.11 / Chapter 1.2.3 --- Functions of flavonoids in plants --- p.15 / Chapter 1.2.4 --- Effects of flavonoids in mammals --- p.16 / Chapter 1.2.5 --- Therapeutic application of flavonoids --- p.17 / Chapter 1.2.6 --- Absorption and metabolism of flavonoids --- p.26 / Chapter 1.3 --- Plant of interest --- p.28 / Chapter 1.4 --- Method used to characterize flaovnoid antioxidants in Vigna sinensis seeds --- p.30 / Chapter 1.5 --- Method used to evaluate the antioxidant activity --- p.31 / Chapter 1.5.1 --- p-carotene bleaching method --- p.31 / Chapter 1.5.2 --- "a,a-diphenyl- --- p.32 / Chapter 1.5.3 --- Single cell gel electrophoresis assay (Comet assay) --- p.32 / Chapter 1.6 --- Research objectives --- p.34 / Chapter 2 --- Materials and Methods --- p.35 / Chapter 2.1 --- Plant materials and chemicals --- p.35 / Chapter 2.2 --- Sample preparation --- p.36 / Chapter 2.2.1 --- Methanolic extraction method --- p.36 / Chapter 2.2.2 --- Acidic methanolic extraction method --- p.36 / Chapter 2.2.3 --- Optimization of extraction time --- p.37 / Chapter 2.3 --- Standards preparation --- p.37 / Chapter 2.4 --- Characterization of flavonoid antioxidants in V. sinensis seed extracts --- p.38 / Chapter 2.5 --- Evaluation of antioxidant activity --- p.39 / Chapter 2.6 --- Determination of free radical scavenging ability --- p.41 / Chapter 2.7 --- Evaluation of the protective effects on DNA damage --- p.42 / Chapter 2.7.1 --- Preparation of reagents --- p.42 / Chapter 2.7.2 --- Blood sample --- p.43 / Chapter 2.7.3 --- Hydrogen peroxide treatment --- p.43 / Chapter 2.7.3.1 --- Co-incubation system --- p.43 / Chapter 2.7.3.2 --- Pre-incubation system --- p.43 / Chapter 2.7.4 --- Establishment of optimal assay conditions --- p.44 / Chapter 2.7.4.1 --- Hydrogen peroxide concentration --- p.44 / Chapter 2.7.4.2 --- Sample volume --- p.44 / Chapter 2.7.4.3 --- Incubation time --- p.44 / Chapter 2.7.4.4 --- Hydrogen peroxide treatment time --- p.44 / Chapter 2.7.5 --- Ethidium bromide-acridine orange cell viability determination --- p.45 / Chapter 2.7.6 --- Slide preparation --- p.45 / Chapter 2.7.7 --- Comet assay --- p.45 / Chapter 2.7.8 --- Quantification of DNA damage --- p.47 / Chapter 2.7.9 --- Statistical analysis --- p.47 / Chapter 3 --- Results / Chapter 3.1 --- Comparison on the free radical scavenging abilities on two different V. sinensis seed extracts --- p.48 / Chapter 3.1.1 --- Optimal extraction time of methanolic extraction method --- p.48 / Chapter 3.1.2 --- Optimal extraction time of acidic methanolic extraction method --- p.48 / Chapter 3.1.3 --- pH values of two different V. sinensis seed extracts --- p.49 / Chapter 3.1.4 --- Free radical scavenging abilities of the two different V. sinensis seed extracts --- p.49 / Chapter 3.2 --- Determination of the stability of the V. sinensis seed extracts --- p.50 / Chapter 3.2.1 --- Effects of storage on the free radical scavenging ability of methanolic V. sinensis seed extract --- p.50 / Chapter 3.2.2 --- Effects of storage on the free radical scavenging ability of acidic V. sinensis seed extract --- p.50 / Chapter 3.2.3 --- Effect of storage on the antioxidant activity of methanolic V.sinensis seed extract --- p.51 / Chapter 3.2.4 --- Effect of storage on the antioxidant activity of acidic V. sinensis seed extract --- p.52 / Chapter 3.3 --- Identification of the flavonoid antioxidants in the acidic V. sinensis seed extract --- p.53 / Chapter 3.4 --- Evaluation of free radical scavenging abilitiesof identified flavonoids using the DPPH radical scavenging method --- p.54 / Chapter 3.5 --- Evaluation of antioxidant activities of the identified flavonoids using the β-carotene bleaching assay --- p.56 / Chapter 3.6 --- Evaluation of protective effects on DNA damage using the Comet assay --- p.57 / Chapter 3.6.1 --- Optimal comet assay conditions --- p.57 / Chapter 3.6.1.1 --- Hydrogen peroxide concentration --- p.57 / Chapter 3.6.1.2 --- Sample volume --- p.58 / Chapter 3.6.1.3 --- Incubation time with the seed extract in the co-incubation system --- p.58 / Chapter 3.6.1.4 --- Hydrogen peroxide treatment time --- p.58 / Chapter 3.6.1.5 --- Incubation time with the seed extract in the pre-incubation system --- p.59 / Chapter 3.6.2 --- Protective effects of the V. sinensis seed extracts and phenolic compounds --- p.59 / Chapter 3.6.2.1 --- Protective effects in pre-incubation system --- p.59 / Chapter 3.6.2.2 --- Protective effects in co-incubation system --- p.60 / Chapter 3.6.3 --- Protective effects of the identified flavonoids in acidic V.sinensis seed extracts and phenolic compounds --- p.60 / Chapter 3.6.3.1 --- Protective effects in pre-incubation system --- p.60 / Chapter 3.6.3.1.1 --- At 0.5 mM concentration --- p.60 / Chapter 3.6.3.1.2 --- At 1 mM concentration --- p.61 / Chapter 3.6.3.2 --- Protective effects in co-incubation system --- p.62 / Chapter 3.6.3.2.1 --- At 0.5 mM concentration --- p.62 / Chapter 3.6.3.2.2 --- At 1 mM concentration --- p.62 / Chapter 4 --- Discussion --- p.100 / Chapter 4.1 --- Comparison on the two different extraction methods --- p.100 / Chapter 4.1.1 --- Methanolic extraction and acidic methanolic extraction --- p.100 / Chapter 4.1.2 --- Free radical scavenging abilities on the two different V sinensis seed extracts --- p.100 / Chapter 4.2 --- Stabilities of two different V. sinensis seed extracts --- p.101 / Chapter 4.2.1 --- Change in antioxidant activity during storage --- p.101 / Chapter 4.2.2 --- Comparison on the stabilities of the extracts assayed under different conditions --- p.102 / Chapter 4.3 --- Identification of flavonoid antioxidants in the acidic methanolic V sinensis seed extract --- p.103 / Chapter 4.4 --- Antioxidant activities of the individual identified flavonoid antioxidants --- p.104 / Chapter 4.4.1 --- Antioxidant activities of the identified flavonoid antioxidants and the selected phenolic compounds in hydrophilic assay system --- p.106 / Chapter 4.4.2 --- Antioxidant activities of the identified flavonoid antioxidants and the selected phenolic compounds in lipophilic assay system --- p.107 / Chapter 4.5 --- Evaluation of protective effects on DNA damage using Comet assay --- p.109 / Chapter 4.5.1 --- Optimal conditions in Comet assay --- p.109 / Chapter 4.5.1.1 --- Effect of hydrogen peroxide concentration --- p.109 / Chapter 4.5.1.2 --- Effect of sample volume --- p.109 / Chapter 4.5.1.3 --- Effect of hydrogen treatment time --- p.110 / Chapter 4.5.1.4 --- Pre-incubation and co-incubation systems --- p.110 / Chapter 4.5.2 --- Protective effects of two different V. sinensis seed extracts and six phenolic compounds --- p.111 / Chapter 4.5.3 --- Protective effects of the identified flavonoids and the phenolic compounds --- p.112 / Chapter 4.6 --- Health beneficial properties of V. sinensis seeds --- p.113 / Chapter 5 --- Conclusion --- p.114 / References --- p.116

Reported here is an investigation to determine the in vitro and in vivo metabolism of xanthohumol (XN). XN is the major prenylated flavonoid of the female inflorescences (cones) of the hop plant (Humulus lupulus). It is also a constituent of beer, the major dietary source of prenylated flavonoids. Recent studies have suggested that XN may have potential cancer chemopreventive activity but little is known about its metabolism. We investigated the in vitro metabolism of XN by rat and human liver microsomes, and cDNA-expressed cytochrome P450s, and the in vivo metabolism of XN by rats. The metabolites and conjugates were identified by using high-pressure liquid chromatography, liquid chromatography-mass spectrometry, and nuclear magnetic resonance. The antioxidant properties of two metabolites and two glucuronides were examined. The possible risk of XN consumption from beer or dietary supplements is discussed. The involvement of metabolites of XN in cancer chemoprevention remains to be established. / Graduation date: 2001

Thesis (Ph. D.)--Ohio State University, 2006. / Available online via OhioLINK's ETD Center; full text release delayed at author's request until 2007 Aug 4

A wide variety of sorghum genotypes with a pigmented pericarp were grown in varying environments and were analyzed for total phenols, condensed tannins, flavan-4-ols, and in vitro antioxidant activity. In addition, sorghum flavonoids were separated, characterized, and quantified using HPLC-PDA and LC-MS. Total phenols and in vitro antioxidant activity increased when sorghums had a pigmented testa causing the presence of condensed tannins. Flavan-4-ol levels were highest in sorghums with a black pericarp (5.8-16.1 abs/mL/g), followed by those with a red pericarp (1.1-9.2 abs/mL/g). Sorghums with a black pericarp had the highest 3-deoxyanthocyanin levels (308-1885 µg/g) and these were increased when the grain had minimal weathering and was darkest in color. Sorghums with a lemon-yellow pericarp had the highest flavanone levels (260-3586 µg/g) with eriodictyol being the main flavanone. Flavanone levels were increased when the grain was bright yellow with minimum weathering and were high compared to those found in common sources (238-574 µg/g, fresh wts.). No flavonoids were predominant in sorghums with a red pericarp. Flavonoid composition varied when all sorghums were grouped by secondary plant color. Sorghums with tan secondary plant color, including those with a white pericarp, had higher levels of flavones (50-932 µg/g) than those with red/purple secondary plant color (0-172 µg/g). On the other hand, 3-deoxyanthocyanin levels were higher in red/purple plant sorghums (14-1885 µg/g) than in tan plant sorghums (0-24 µg/g). Among red/purple plant sorghums, lemon-yellow pericarp sorghums had the highest levels of flavones (51-172 µg/g). Environment and weathering had an effect on flavonoid levels. The 3-deoxyanthocyanins were reduced for sorghums grown in a dry environment (i.e. Lubbock, TX) and flavonoid levels were increased in grains with minimum weathering or molding. This study reports that all sorghums, including those with a white pericarp, have flavonoids and their levels and compositions are affected by the genotype. This information will be helpful for plant breeders, food scientists, and the pharmaceutical/nutraceutical industries in selecting sorghums with desired healthy components.

No description available.

A wide variety of sorghum genotypes with a pigmented pericarp were grown in varying environments and were analyzed for total phenols, condensed tannins, flavan-4-ols, and in vitro antioxidant activity. In addition, sorghum flavonoids were separated, characterized, and quantified using HPLC-PDA and LC-MS. Total phenols and in vitro antioxidant activity increased when sorghums had a pigmented testa causing the presence of condensed tannins. Flavan-4-ol levels were highest in sorghums with a black pericarp (5.8-16.1 abs/mL/g), followed by those with a red pericarp (1.1-9.2 abs/mL/g). Sorghums with a black pericarp had the highest 3-deoxyanthocyanin levels (308-1885 µg/g) and these were increased when the grain had minimal weathering and was darkest in color. Sorghums with a lemon-yellow pericarp had the highest flavanone levels (260-3586 µg/g) with eriodictyol being the main flavanone. Flavanone levels were increased when the grain was bright yellow with minimum weathering and were high compared to those found in common sources (238-574 µg/g, fresh wts.). No flavonoids were predominant in sorghums with a red pericarp. Flavonoid composition varied when all sorghums were grouped by secondary plant color. Sorghums with tan secondary plant color, including those with a white pericarp, had higher levels of flavones (50-932 µg/g) than those with red/purple secondary plant color (0-172 µg/g). On the other hand, 3-deoxyanthocyanin levels were higher in red/purple plant sorghums (14-1885 µg/g) than in tan plant sorghums (0-24 µg/g). Among red/purple plant sorghums, lemon-yellow pericarp sorghums had the highest levels of flavones (51-172 µg/g). Environment and weathering had an effect on flavonoid levels. The 3-deoxyanthocyanins were reduced for sorghums grown in a dry environment (i.e. Lubbock, TX) and flavonoid levels were increased in grains with minimum weathering or molding. This study reports that all sorghums, including those with a white pericarp, have flavonoids and their levels and compositions are affected by the genotype. This information will be helpful for plant breeders, food scientists, and the pharmaceutical/nutraceutical industries in selecting sorghums with desired healthy components.

Thesis (PhD(Pharmacology-Faculty of Health Sciences))--University of Pretoria, 2001. / Includes bibliographical references.

Thesis (M. Sc.)--University of Hong Kong, 1961. / Accompanied by The triterpenoid constituents of the Hong Kong Ericaceae ([4] p. 24 1/2 cm) by H.R. Arthur [and] S.W. Tam. Melbourne, Commonwealth Scientific & Industrial Research Organization. 1960. In pocket. Reprinted from the Australian Journal of Chemistry. v.13, no. 4. pp. 506-509. Accompanied by Matteucinin (a new flavanoid glycoside) and other constituents of the Ericaceae of Hong Kong ([4] p. 25 1/2 cm.) by H.R. Arthur and S.W. Tam. London, Chemical Society, 1960. Reprinted from the Journal of the Chemical Society, August, 1960. pp. 3197-3200. Typewritten copy. Includes bibliographical references (leaves 90-102).

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences