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Thesis (Ph. D. in Cell Biology)--Vanderbilt University, May 2004. / Title from PDF title screen. Includes bibliographical references.

published_or_final_version / Pharmacology and Pharmacy / Doctoral / Doctor of Philosophy

Drug-induced liver injury (DILI) is the major cause of pharmaceutical withdrawal from the market and cholestasis is one of the most common DILI observed. Cholestasis stem from abnormalities in the activity of bile acid transporters, namely the sodium-dependent taurocholate co-transporting polypeptide, Ntcp (Slc10a1), and the bile salt export pump, Bsep (Abcb11). The nuclear receptors, pregnane X receptor (PXR) and farnesoid X receptor (FXR), have been implicated in the regulation of Ntcp and Bsep. The aim of this study was to establish the relative roles of FXR and PXR in the regulation of Ntcp and Bsep, in the rat liver and sandwich cultured rat hepatocytes (SCRH) to establish the usefulness of SCRH as a good model for bile acid transport studies. For this purpose, male Sprague Dawley rats were treated with FXR and PXR ligands and siRNAs. Intraperitoneal (IP) injection of FXR ligand, CDCA, resulted in induction in FXR mRNA levels whereas siRNA treatment knocked down FXR transcript levels. FXR induction decreased Ntcp transcript levels that were reversed in FXR knockdown animals. CDCA treatment resulted in greater than 2-fold increase in Bsep mRNA levels that was absent in FXR knockdown animals. The PXR ligand, PCN, showed an induction in PXR mRNA levels while siRNA treatment resulted in the knockdown in PXR transcript levels. PXR induction did not cause any change in Ntcp and Bsep transcript levels. Furthermore, sandwich cultured rat hepatocytes were used to ascertain if the above in vivo findings are reproducible in vitro. Treatment of hepatocytes with FXR ligand, CDCA, and PXR ligand, PCN, caused greater than 5-fold increase in the respective mRNA levels whereas respective siRNA treatment caused >79% knocked in their transcript levels. FXR induction decreased Ntcp mRNA levels that were ablated in FXR knockdown cultures. FXR induction resulted in a 6-fold increase in Bsep mRNA levels that disappeared in FXR knockdown cultures. On the contrary, PXR induction did not influence the expression levels of Ntcp and Bsep. Taken together these data demonstrate that both FXR and PXR are inducible at mRNA and protein levels in vivo and their expression can be knocked down in the rat liver. Moreover, FXR negatively regulate Ntcp and positively regulate Bsep while PXR does not influence Ntcp and Bsep expression. Finally, the data shows that these in vivo findings can be successfully reproduced in sandwich cultured rat hepatocytes. To conclude, sandwich cultured rat hepatocytes mimic the in vivo situation and provide a good model for bile acid transport studies.

Thesis (Ph.D.)--University of California, San Francisco, 2004. / Bibliography: leaves xxx-xxx. Also available online.

Thesis (M.S.)--Indiana University, 2008. / Title from screen (viewed on August 28, 2009). Department of Pathology and Laboratory Medicine, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Raymond L. Konger, Jeffrey B. Travers, Dan F. Spandau. Includes vita. Non-Latin script record Includes bibliographical references (leaves 32-36).

Thesis (Ph. D.)--University of Massachusetts Amherst, 2009. / Includes bibliographical references (p. 83-96). Print copy also available.

Indiana University-Purdue University Indianapolis (IUPUI) / It has recently been shown that the gamma subtype of the peroxisome proliferator-activated receptor (PPARγ) is a target of ultraviolet B (290-320 nm; UVB) irradiation, and that PPARγ activation is necessary for full UVB-induced cyclooxygenase-2 (COX-2) induction. However, the biological significance of PPARγ activation in cutaneous photobiology is unknown. Acute UVB irradiation results in a characteristic series of events in the epidermis which includes: an initial edema response and subsequent inflammation, COX-2 induction, apoptosis, and a delayed hyperproliferative response. Therefore, the regulatory role of PPARγ activation was examined in this acute photoresponse using a topical application of the potent, irreversible PPARγ antagonist, GW9962. GW9662 was applied to the epidermis of SKH1 hairless albino mice at increasing doses (0.01-1.0mM) prior to UVB irradiation. The photobiological responses were examined through RT-PCR, skin thickness measurements, and immunohistochemistry, at 24 and 72 hours after UVB-irradiation. At the highest dose, GW9622 significantly inhibited UVB-induced inflammation, as measured by COX-2 induction at both 24 and 72 hrs. Inflammation assessed by skin thickness measurements indicated that lower doses mildly increased inflammation at 72 hrs, but suppressed inflammation at the highest dose. In contrast, GW9662 treatment dose dependently augmented UVB-induced apoptosis at 24 hours, while affecting the delayed hyperproliferative response at 72 hours in an inverse dose-response manner. The results from this study suggest that PPARγ is a key regulator of these photobiological responses. Because these responses are well known to be involved in tumor development and progression, this study also suggests a potential role for PPARγ in UVB-induced skin cancers.

Cheng, Cho Yiu. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 186-217). / Abstracts in English and Chinese. / Acknowledgements --- p.1 / Abstract of thesis --- p.2 / Abstract of thesis in Chinese --- p.7 / Presentation attended --- p.9 / Chapter Chapter 1: --- Introduction and Background --- p.13 / Chapter 1.1 --- Anatomy and functions of human prostate gland --- p.13 / Chapter 1.2 --- Worldwide epidemiology of prostate cancer --- p.15 / Chapter 1.3 --- Prostate cancer stages and treatments in clinic --- p.21 / Chapter 1.4 --- Introduction to nuclear receptors --- p.23 / Chapter 1.5 --- Nuclear receptor structure --- p.24 / Chapter 1.6 --- Nuclear receptors nomenclature and classification --- p.28 / Chapter 1.7 --- Mode of action for nuclear receptors --- p.34 / Chapter 1.8 --- Co-regulators of nuclear receptors --- p.35 / Chapter 1.9 --- Nuclear receptors related to prostate cancer --- p.43 / Chapter Chapter 2: --- Aim of study and experimental design --- p.59 / Chapter 2.1 --- Aim of study --- p.59 / Chapter 2.2 --- In vitro cell lines models used in the study --- p.60 / Chapter Chapter 3: --- Materials and methods --- p.64 / Chapter 3.1 --- Apparatus and preparation throughout the study --- p.64 / Chapter 3.2 --- Cells culture --- p.64 / Chapter 3.3 --- RNA extraction --- p.67 / Chapter 3.4 --- Reverse transcription --- p.68 / Chapter 3.5 --- Primers specificity checking --- p.69 / Chapter 3.6 --- Real time quantitative polymerase chain reaction --- p.84 / Chapter 3.7 --- Data analysis --- p.90 / Chapter Chapter 4: --- Results --- p.92 / Chapter 4.1 --- Expression of nuclear receptors transcripts in each prostatic cell lines used --- p.92 / Chapter 4.2 --- Expression of nuclear receptor transcripts in immortalized prostatic epithelial BPH-1 and BPH-1 derived cell lines model --- p.116 / Chapter 4.3 --- Expression of nuclear receptor transcripts in androgen-dependent and androgen-independent classical prostatic cancer cell lines model --- p.121 / Chapter 4.4 --- Expression of nuclear receptor transcripts in androgen-independent and antiandrogen-resistant LNCaP derived cell lines model --- p.125 / Chapter Chapter 5: --- Discussion --- p.129 / Chapter 5.1 --- Special expression pattern of some nuclear receptors in the prostatic cell lines or prostatic cancer cell lines --- p.129 / Chapter 5.2 --- BPH-1 and BPH-1 derived cell lines model --- p.138 / Chapter 5.2.1 --- Prostatic cell lines model studying the transformation and invasion in prostate cancer (BPH-1 Snail & BPH-1 CAFTDs versus BPH-1) --- p.138 / Chapter 5.2.2 --- Prostatic cell lines model studying the transformation and invasion in prostate cancer (BPH-1 Snail & BPH-1 CAFTDs versus BPH-1 AR) --- p.159 / Chapter 5.3.3 --- classical prostatic cancer cell lines model --- p.162 / Chapter 5.3.1 --- Prostatic cancer cell lines model studying androgen-dependence and androgen-independence (DU145 & PC-3 versus LNCaP) --- p.163 / Chapter 5.4 --- LNCaP and LNCaP derived cell lines model --- p.170 / Chapter 5.4.1 --- Prostatic cancer cell lines model studying androgen-independence and antiandrogen-resistance (LNCaP-abl & LNCaP-BCs versus LNCaP) --- p.171 / Chapter Chapter 6: --- Conclusion --- p.179 / References --- p.186