Nuclear receptors, bile-acid detoxification, and cholestasis

Faculty of Science, Technology and Engineering, La Trobe University, Melbourne, Victoria, Australia
The Lancet (Impact Factor: 45.22). 03/2006; 367(9509):454-6. DOI: 10.1016/S0140-6736(06)68156-7
Source: PubMed
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    • "The accumulation of anticancer drugs in cancer cells is closely associated with anticancer effects. Drug resistance is often caused by activation of the cellular detoxification system, which includes the drug pump, permeability glycoprotein (P-gp), and the drug metabolism enzyme, cytochrome P450 (CYP).97,98 Both P-gp and CYP are regulated by several nuclear receptors, such as pregnane X receptor (PXR), farnesoid X receptor (FXR), and constitutive androstane receptor (CAR). "
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    ABSTRACT: Melanoma is the most aggressive type of skin cancer and has very high rates of mortality. An early stage melanoma can be surgically removed, with a survival rate of 99%. However, metastasized melanoma is difficult to cure. The 5-year survival rates for patients with metastasized melanoma are still below 20%. Metastasized melanoma is currently treated by chemotherapy, targeted therapy, immunotherapy and radiotherapy. The outcome of most of the current therapies is far from optimistic. Although melanoma patients with a mutation in the oncogene v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) have an initially higher positive response rate to targeted therapy, the majority develop acquired drug resistance after 6 months of the therapy. To increase treatment efficacy, early diagnosis, more potent pharmacological agents, and more effective delivery systems are urgently needed. Nanotechnology has been extensively studied for melanoma treatment and diagnosis, to decrease drug resistance, increase therapeutic efficacy, and reduce side effects. In this review, we summarize the recent progress on the development of various nanoparticles for melanoma treatment and diagnosis. Several common nanoparticles, including liposome, polymersomes, dendrimers, carbon-based nanoparticles, and human albumin, have been used to deliver chemotherapeutic agents, and small interfering ribonucleic acids (siRNAs) against signaling molecules have also been tested for the treatment of melanoma. Indeed, several nanoparticle-delivered drugs have been approved by the US Food and Drug Administration and are currently in clinical trials. The application of nanoparticles could produce side effects, which will need to be reduced so that nanoparticle-delivered drugs can be safely applied in the clinical setting.
    Full-text · Article · Jul 2013 · International Journal of Nanomedicine
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    • "References Bile acid absorption Decreased Conversion of cholesterol into bile acids is Ellegard and Andersson 2007 increased and blood cholesterol level is decreased CYP7A1 Increased Conversion of cholesterol into bile acids is increased Ellegard and Andersson 2007 LDLR Increased Cholesterol transport into hepatocytes is increased Watkins 2004 CYP3A4 Not known CYP3A4 increased bile acid metabolism Chen and Raymond 2006 HMG CoA reductase Increased Cholesterol synthesis is increased Ellegard and Andersson 2007 Cholesterol absorption Decreased Blood level of cholesterol is decreased Ellegard and Andersson 2007, and Watkins 2004 on the absorption of glucose (Wood and others 1994). Due to a decrease in bile acid content in the small intestine, emulsification of fats is decreased, which in addition to the viscosity effects mentioned reduces fat absorption. "
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    ABSTRACT: This article presents an overview of the recent advances into the health promoting potentials of oat β‐glucan. Oat β‐glucan (OβG) consists mainly of the linear polysaccharide (1→3), (1→4)‐β‐D‐glucan and is often called β‐glucan. This soluble oat fiber is able to attenuate blood postprandial glycemic and insulinemic responses, to lower blood total cholesterol and low‐density lipoprotein (LDL) cholesterol, and to improve high‐density lipoprotein (HDL) cholesterol and blood lipid profiles as well as to maintain body weight. Thus, OβG intake is beneficial in the prevention, treatment, and control of diabetes and cardiovascular diseases. In addition, OβG can stimulate immune functions by activating monocytes/macrophages and increasing the amounts of immunoglobulin, NK cells, killer T‐cells, and so on, which will improve resistance to cancer and infectious and parasitic diseases, as well as increase biological therapies and their prevention. All these health benefits of OβG may be explained by its physicochemical properties (such as viscosity, molecular weight) which can be affected by extraction methods and its behavior in gastrointestinal tract. Articles documenting these health benefits and effects are reviewed.
    Preview · Article · Jul 2012 · Comprehensive Reviews in Food Science and Food Safety
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    • "A single dose of 5 mg CD/kg to C57BL/6 mice also significantly alters tissue distribution of exogenous [ 14 C]CD or [ 14 C]CH, decreasing hepatic disposition and increasing distribution to other tissues (Carpenter and Curtis 1991). CH is an important constituent of cell membranes and a precursor of steroid hormones and bile acids (Chen and Raymond 2006; Tabas 2002). However accumulation of excess CH contributes to several diseases especially heart attacks and stroke by promoting atherosclerosis (Krieger 1999). "
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    ABSTRACT: Organochlorine (OC) insecticides continue to occur in tissues of humans and wildlife throughout the world although they were banned in the United States a few decades ago. Low doses of the OC insecticide chlordecone (CD) alter hepatic disposition of lipophilic xenobiotics and perturb lipid homeostasis in rainbow trout, mice and rats. CD pretreatment altered tissue and hepatic subcellular distribution of exogenous [(14)C]cholesterol (CH) equivalents 4 and 16 h after a bolus intraperitoneal (ip) injection of 5 ml corn oil/kg that contained 10 mg CH/kg. CD pretreatment altered tissue distribution of exogenously administered [(14)C]CH by decreased hepatic and renal accumulation, and increased biliary excretion up to 300%. Biliary excretion of polar [(14)C]CH metabolites was not altered by CD. CD pretreatment decreased subcellular distribution of [(14)C]CH equivalents in hepatic cytosol and microsomes and lipoprotein-rich fraction-to-homogenate ratio. CD pretreatment increased the ratio of [(14)C]CH equivalents in high density lipoprotein (HDL) to that in plasma and reduced [(14)C]CH equivalents in the non-HDL fraction 4 h after a bolus lipid dose. CD pretreatment increased plasma non-HDL total CH by 80% 4 h after a bolus lipid dose. Scavenger receptor class B type I (SR-BI) and ATP-binding cassette transporter G8 (ABCG8) proteins were quantified by western blotting in hepatic membranes from control and CD treated mice. Liver membrane contents of SR-BI and ABCG8 proteins were unchanged by CD pretreatment. The data demonstrated that a single dose of CD altered CH homeostasis and lipoprotein metabolism.
    Full-text · Article · Jul 2008 · Toxicology and Applied Pharmacology
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