Carboxylesterase1/Esterase-X Regulates Chylomicron Production in Mice.

Carboxylesterase1/Esterase-x Regulates Chylomicron Production in Mice.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e49515
Quiroga AD, Lian J, Lehner R

Elevated postprandial plasma triacylglycerol (TG) concentrations are commonly associated with obesity and the risk of cardiovascular disease. Dietary fat contributes to this condition through the production of chylomicrons. Carboxylesterases have been mainly studied for their role in drug metabolism, but recently they have been shown to participate in lipid metabolism; however, their role in intestinal lipid metabolism is unknown. Carboxylesterase1/esterase-x (Ces1/Es-x) deficient mice become obese, hyperlipidemic and develop hepatic steatosis even on standard chow diet. Here, we aimed to explore the role of Ces1/Es-x in intestinal lipid metabolism. Six-month old wild-type and Ces1/Es-x deficient mice were maintained on chow diet and intestinal lipid metabolism and plasma chylomicron clearance were analyzed. Along the intestine Ces1/Es-x protein is expressed only in proximal jejunum. Ablation of Ces1/Es-x expression results in postprandial hyperlipidemia due to increased secretion of chylomicrons. The secreted chylomicrons have aberrant protein composition, which results in their reduced clearance. In conclusion, Ces1/Es-x participates in the regulation of chylomicron assembly and secretion. Ces1/Es-x might act as a lipid sensor in enterocytes regulating chylomicron secretion rate. Ces1/Es-x might represent an attractive pharmacological target for the treatment of lipid abnormalities associated with obesity, insulin resistance and fatty liver disease.
HubMed – drug

Lysosomotropic Properties of Weakly Basic Anticancer Agents Promote Cancer Cell Selectivity In Vitro.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e49366
Ndolo RA, Luan Y, Duan S, Forrest ML, Krise JP

Drug distribution in cells is a fundamentally important, yet often overlooked, variable in drug efficacy. Many weakly basic anticancer agents accumulate extensively in the acidic lysosomes of normal cells through ion trapping. Lysosomal trapping reduces the activity of anticancer drugs, since anticancer drug targets are often localized in the cell cytosol or nucleus. Some cancer cells have defective acidification of lysosomes, which causes a redistribution of trapped drugs from the lysosomes to the cytosol. We have previously established that such differences in drug localization between normal and cancer cells can contribute to the apparent selectivity of weakly basic drugs to cancer cells in vitro. In this work, we tested whether this intracellular distribution-based drug selectivity could be optimized based on the acid dissociation constant (pKa) of the drug, which is one of the determinants of lysosomal sequestration capacity. We synthesized seven weakly basic structural analogs of the Hsp90 inhibitor geldanamycin (GDA) with pKa values ranging from 5 to 12. The selectivity of each analog was expressed by taking ratios of anti-proliferative IC(50) values of the inhibitors in normal fibroblasts to the IC(50) values in human leukemic HL-60 cells. Similar selectivity assessments were performed in a pair of cancer cell lines that differed in lysosomal pH as a result of siRNA-mediated alteration of vacuolar proton ATPase subunit expression. Optimal selectivity was observed for analogs with pKa values near 8. Similar trends were observed with commercial anticancer agents with varying weakly basic pKa values. These evaluations advance our understanding of how weakly basic properties can be optimized to achieve maximum anticancer drug selectivity towards cancer cells with defective lysosomal acidification in vitro. Additional in vivo studies are needed to examine the utility of this approach for enhancing selectivity.
HubMed – drug

Prevalence of Anti-Tuberculosis Drug Resistance in Foreign-Born Tuberculosis Cases in the U.S. and in Their Countries of Origin.

Filed under: Drug and Alcohol Rehabilitation

PLoS One. 2012; 7(11): e49355
Taylor AB, Kurbatova EV, Cegielski JP

BACKGROUND: Foreign-born individuals comprise >50% of tuberculosis (TB) cases in the U.S. Since anti-TB drug resistance is more common in most other countries, when evaluating a foreign-born individual for TB, one must consider the risk of drug resistance. Naturally, clinicians query The Global Project on Anti-tuberculosis Drug Resistance Surveillance (Global DRS) which provides population-based data on the prevalence of anti-TB drug resistance in 127 countries starting in 1994. However, foreign-born persons in the U.S. are a biased sample of the population of their countries of origin, and Global DRS data may not accurately predict their risk of drug resistance. Since implementing drug resistance surveillance in 1993, the U.S. National TB Surveillance System (NTSS) has accumulated systematic data on over 130,000 foreign-born TB cases from more than 200 countries and territories. Our objective was to determine whether the prevalence of drug resistance among foreign-born TB cases correlates better with data from the Global DRS or with data on foreign-born TB cases in the NTSS. METHODS AND FINDINGS: We compared the prevalence of resistance to isoniazid and rifampin among foreign-born TB cases in the U.S., 2007-2009, with US NTSS data from 1993 to 2006 and with Global DRS data from 1994-2007 visually with scatterplots and statistically with correlation and linear regression analyses. Among foreign-born TB cases in the U.S., 2007-2009, the prevalence of isoniazid resistance and multidrug resistance (MDR, i.e. resistance to isoniazid and rifampin), correlated much better with 1993-2006 US surveillance data (isoniazid: r?=?0.95, P<.001, MDR: r?=?0.75, P<.001) than with Global DRS data, 1994-2007 (isoniazid: r?=?0.55, P?=?.001; MDR: r?=?0.50, P<.001). CONCLUSION: Since 1993, the US NTSS has accumulated sufficient data on foreign-born TB cases to estimate the risk of drug resistance among such individuals better than data from the Global DRS. HubMed – drug

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