This book gives you an updated and expert overview of nuclear hormone receptors in drug metabolism and drug development and equips you with the interdisciplinary understanding of these receptors and how they can be regulated. Pharmaceutical researchers will find this extremely useful in developing drugs for cancer, heart disease, and diabetes treatment. This comprehensive resource collects scattered materials into one handy, informative volume.

Edited by two experts working at the pioneering pharmaceutical company and major global player in hormone-derived drugs, this handbook and reference systematically treats the drug development aspects of all human nuclear receptors, including recently characterized receptors such as PPAR, FXR and LXR. Authors from leading pharmaceutical companies around the world present examples and real-life data from their own work.

Nuclear receptors (NR) are ligand-induced activated transcription factors that are involved in numerous biological processes. Since the 1990's when the first structures were determined by means of X ray diffraction, the number of NR structures has increased considerably. Moreover several 'omics' projects (genomics, pharmcogenomics and proteomics) have opened up great opportunities for the discovery of new targets, the characterization of abnormal protein patterns, the selection of "tailored" drugs and the evaluation of drug efficacy even with a lack of structural data. Furthermore, structure-based drug design, computational methods for in silico screening and nanobiotechnology- based tools are simplifying this time-consuming and money-intensive research of lead compounds and, possibly, new drugs. Biological interactions such as those that occur between a protein and ligand are concerted events where flexible molecules interact. Thus understanding flexibility of large molecules or biological complexes is of primary importance to help define the right model to approximate the reality for drug discovery, virtual screening, food safety analysis, etc. NRs are known as flexible targets, with many structural similarities, in particular for their Ligand Binding Domain: these similarities could be assumed to share behavioural qualities that belong to this class of compounds. Thus to supply a possible, complete and exhaustive answer to questions about the behaviour of NRs, their interactions with new potential drugs, endocrine disruptors such as animal and human food toxins, food additives or industry residuals, it is mandatory to approach the problem from a different point of view: a molecular modelling approach, steered synthesis, and in vitro and in vivo tests, etc. The aim of this book is to provide a state of the art review on investigations into Nuclear Receptors.

Bridging the gap between basic scientific advances and the understanding of liver disease — the extensively revised new edition of the premier text in the field. The latest edition of The Liver: Biology and Pathobiology remains a definitive volume in the field of hepatology, relating advances in biomedical sciences and engineering to understanding of liver structure, function, and disease pathology and treatment. Contributions from leading researchers examine the cell biology of the liver, the pathobiology of liver disease, the liver’s growth, regeneration, metabolic functions, and more. Now in its sixth edition, this classic text has been exhaustively revised to reflect new discoveries in biology and their influence on diagnosing, managing, and preventing liver disease. Seventy new chapters — including substantial original sections on liver cancer and groundbreaking advances that will have significant impact on hepatology — provide comprehensive, fully up-to-date coverage of both the current state and future direction of hepatology. Topics include liver RNA structure and function, gene editing, single-cell and single-molecule genomic analyses, the molecular biology of hepatitis, drug interactions and engineered drug design, and liver disease mechanisms and therapies. Edited by globally-recognized experts in the field, this authoritative volume: Relates molecular physiology to understanding disease pathology and treatment Links the science and pathology of the liver to practical clinical applications Features 16 new “Horizons” chapters that explore new and emerging science and technology Includes plentiful full-color illustrations and figures The Liver: Biology and Pathobiology, Sixth Edition is an indispensable resource for practicing and trainee hepatologists, gastroenterologists, hepatobiliary and liver transplant surgeons, and researchers and scientists in areas including hepatology, cell and molecular biology, virology, and drug metabolism.

An overview of the supergene family made up of those nuclear hormone receptors which recognize thyroid and steroid hormones, vitamen D and retinoic acid and which are characterized by their ability to bind both ligands and the genes which respond to them.

Nuclear receptors are a family of transcription factors consisting of 49 members identified in the human genome. Nuclear receptors regulate transcription by binding to response elements in the regulatory regions of target genes and thereby affect expression of genes involved in differentiation, growth, lipid homeostasis, inflammation and immunity. Over the past two decades significant advances have been made in the understanding of the regulation of gene expression by nuclear receptors. The knowledge on nuclear receptors has delivered novel therapies for lipid control and hormone replacement, and for management of cancer and diabetes. Therefore, nuclear receptors are attractive molecular targets for design of therapy for diabetes, obesity, atherosclerosis, cancer, inflammation and neurodegeneration. The focus of this volume is centered on the mechanistic involvement of nuclear receptors in cardiological, metabolic and neurological disorders, on possible explanation of pathways involved in pathogenesis, on susceptibility to and prevention of metabolic and neurological disorders and on the aspects of drug finding including chemistry and rational drug design. This volume reviews recent progress on nuclear receptors critically and will intrigue those pursuing interest in physiology, pathology and medicine.

Understanding the relationship between nuclear receptors and drug metabolizing enzymes (DMEs) is important because it is closely associated with the metabolism of endogenous and xenobiotic compounds as well as drug-drug interactions. This study is divided into two parts : 1) the creation of a PXR transgenic mouse model and 2) the regulation of the UDP-glucuronosyltransferase 1A (UGT1A) locus through activation of the liver x receptor [alpha] (LXR[alpha]). The transgenic mouse line that contains the human pregnane X receptor (hPXR) transgene was established and the PXR transgene was determined to be functional by elevated levels of cytochrome p450 3a11 (Cyp3a11) in response to hPXR activator rifampicin. Crossing this transgenic mouse line with the mouse line Tg(UGT1A1*1)Ugt-/-Pxr-/- (hUGT1*1/Pxr-/-) line, previously established in the lab, we created a Tg(UGT1A1*1)Ugt-/-Tg(Pxr)Pxr-/- (hUGT1*1/hPXR) mouse line. For the second aim of this study, humanized UGT1A (hUGT1) mice were administered the LXR agonist, T090137, and the results show a significant induction of UGT1A1 in the liver and intestinal tissues compared with the control mice, suggesting that the LXR[alpha] regulates the UGT1A locus. These results are further supported by a significant reduction of serum bilirubin levels in response to T090137 treatment. Work is ongoing to create Lxr[alpha]-null mice on a hUGT1A background (hUGT1/- Lxr-/ mice). In conclusion, these two mice lines, hUGT1*1/hPXR and hUGT1A/Lxr[alpha]-/-, are potentially useful to study the roles of PXR and LXR in the UGT1A locus regulation that may have significant implications in altering glucuronidation activity of xenobiotics and endogenous compounds, including bilirubin.

Nuclear receptors are ligand activated transcription factors that control numerous biological functions. Consequently, altering activity of these receptors is proposed, and indeed documented, to affect many physiological and pathological conditions in experimental animals and humans. Thus, nuclear receptors have become a major target in the effort to treat numerous diseases. This book will shed light on and emphasize intricate processes involved in designing as well as discovering physiological and pharmacological modulators of these important proteins. World-renowned scientists will share with the reader their professional expertise and extensive experience acquired through decades working with nuclear receptors. Chapters address the various means and consequences of modulating nuclear receptor activity will be presented and discussed. These modulators cover a wide span of moieties ranging from synthetic chemicals to natural products. In addition, the classification of these chemicals ranges from pan agonists to selective agonists and inverse agonists to antagonists. They also include proteolytic means to obliterate the receptor in the event that modulating its activity through canonical pharmacological agents becomes less effective and/or less desirable due to anticipated or experienced toxicities. Modulation of receptor activity may also take place in the absence of a ligand or through manipulating the structure of the receptor itself by controlling posttranslational events.

This book is devoted to innovative medicine, comprising the proceedings of the Uehara Memorial Foundation Symposium 2014. It remains extremely rare for the findings of basic research to be developed into clinical applications, and it takes a long time for the process to be achieved. The task of advancing the development of basic research into clinical reality lies with translational science, yet the field seems to struggle to find a way to move forward. To create innovative medical technology, many steps need to be taken: development and analysis of optimal animal models of human diseases, elucidation of genomic and epidemiological data, and establishment of “proof of concept”. There is also considerable demand for progress in drug research, new surgical procedures, and new clinical devices and equipment. While the original research target may be rare diseases, it is also important to apply those findings more broadly to common diseases. The book covers a wide range of topics and is organized into three complementary parts. The first part is basic research for innovative medicine, the second is translational research for innovative medicine, and the third is new technology for innovative medicine. This book helps to understand innovative medicine and to make progress in its realization.