Role of CYP27A in cholesterol and bile acid metabolism

The CYP27A gene encodes a mitochondrial cytochrome P450 enzyme, sterol 27-hydroxylase, that is expressed in many different tissues and plays an important role in cholesterol and bile acid metabolism. In humans, CYP27A deficiency leads to cerebrotendinous xanthomatosis. To gain insight into the roles of CYP27A in the regulation of cholesterol and bile acid metabolism, cyp27A gene knockout heterozygous, homozygous, and wild-type littermate mice were studied. In contrast to homozygotes, heterozygotes had increased body weight and were mildly hypercholesterolemic, with increased numbers of lipoprotein particles in the low density lipoprotein size range. Cyp7A expression was not increased in heterozygotes but was in homozygotes, suggesting that parts of the homozygous phenotype are secondary to increased cyp7A expression and activity. Homozygotes exhibited pronounced hepatomegaly and dysregulation in hepatic cholesterol, bile acid, and fatty acid metabolism. Hepatic cholesterol synthesis and synthesis of bile acid intermediates were increased; however, side chain cleavage was impaired, leading to decreased bile salt concentrations in gallbladder bile. Expression of Na-taurocholate cotransporting polypeptide, the major sinusoidal bile salt transporter, was increased, and that of bile salt export pump, the major canalicular bile salt transporter, was decreased. Gender played a modifying role in the homozygous response to cyp27A deficiency, with females being generally more severely affected. Thus, both cyp27A genotype and gender affected the regulation of hepatic bile acid, cholesterol, and fatty acid metabolism.     

Effects of camptothecin on double-strand break repair by non-homologous end-joining in DNA mismatch repair-deficient human colorectal cancer cell lines

Loss of a functional mismatch repair (MMR) system in colorectal cancer (CRC) cells is associated with microsatellite instability and increased sensitivity to topoisomerase inhibitors. In this study, we have investigated whether a defect in double-strand break (DSB) repair by non-homologous end-joining (NHEJ) could explain why MMR-deficient CRC cells are hypersensitive to camptothecin (CPT), a topoisomerase I inhibitor. To evaluate the efficiency and the fidelity of DSB repair, we have transiently transfected plasmids containing cohesive or non-complementary ends in cells with various MMR defects. We have observed that the repair efficiency of DSB with cohesive and non-complementary ends is comparable in all cell lines. In contrast to the MMR-proficient cell line HT29, the MMR-deficient cell lines were highly accurate in repairing DSB with cohesive ends, but this characteristic could not be directly assigned to the primary MMR deficiency. Furthermore, CPT treatment had no detectable effect on the repair of cohesive ends but significantly decreased the repair efficiency of non-complementary DSB. In conclusion, although our observations show that DSB repair efficiency by NHEJ decreases upon treatment with CPT, which possibly contributes to its cytotoxicity, it is quite unlikely that it accounts for the hypersensitivity of MMR-deficient cells to topoisomerase inhibitors.     

Polar lipids in cosmetics: recent trends in extraction,separation, analysis and main applications

Demand for active, natural, safe and biomimetic (similar to human molecules) plantderived cosmetic ingredients is always greater because consumers are increasingly suspicious of the potential toxicity of current ingredients. In this context, interest has increased for polar lipids like ceramides, sphingolipids or glycolipids that share structural properties with the skin lipids. In the same manner, processes to obtain such lipids should be driven by the principles of green chemistry and sustainable development. The identified needs are biodegradability, biocompatibility, efficiency, quality and profitability. In this research for new and novel natural or ‘green’ compounds, the development of bioactive lipids thanks to ecofriendly processes has obviously intensified, especially for cosmetic and agro-food industries. This paper reviews extraction methods for polar lipids (glycolipids and phospholipids), especially ecoprocesses (supercritical fluid extraction, microwaves, sonication, enzyme extraction…), and promising chromatographic methods like countercurrent chromatography, supercritical fluid chromatography or high performance chromatography coupled to mass spectrometry Interests of polar lipids for cosmetic industries are exemplified to show their broad applications mostly relying on their amphiphilic properties allowing them to play functional roles (liposome or micelle structures for example) or physiological roles (skin barrier function or anti-ageing effect).     

Exercise through a cardiac rehabilitation program attenuates oxidative stress in patients submitted to coronary artery bypass grafting*

Background: Cardiovascular disease is the main cause of morbidity and mortality in the world and oxidative stress has been implicated in the pathogenesis. Cardiac rehabilitation in patients with coronary artery disease submitted to coronary artery bypass grafting may prevent cardiovascular events probably through the attenuation of oxidative stress. The aim of this study was to evaluate the benefits of a cardiac rehabilitation program in the control of the systemic oxidative stress.

Methods: The studied population consisted of 40 patients, with chronic stable coronary artery disease submitted to coronary artery bypass grafting, who attended a cardiac rehabilitation program. Biomarkers of oxidative stress were evaluated in the blood of these patients at different moments.

Results: After the onset of cardiac rehabilitation, there was a significant and progressive decrease in thiobarbituric acid reactive substances levels and protein carbonyls, an initial increase and subsequent decrease in superoxide dismutase, catalase and glutathione peroxidase activities. Also, a progressive increase of uric acid, while ferric reducing antioxidant power levels increased only at the end of the cardiac rehabilitation and a tendency to increase of glutathione contents.

Conclusions: The results suggest that regular exercise through a cardiac rehabilitation program can attenuate oxidative stress in chronic coronary artery disease patients submitted to coronary artery bypass grafting.     

Low-Protein Diet Induces IRE1α-Dependent Anticancer Immunosurveillance

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Desiccation decreases abscisic acid content in hybrid larch (Larix X leptoeuropaea) somatic embryos

Previous studies indicated that the high endogenous abscisic acid (ABA) content of hybrid larch ( Larix X leptoeuropaea ) somatic embryos was correlated with low germination frequency. However, when dried, the germination rate of the somatic embryos improved. Therefore, our present objective was to study the effect of desiccation on the levels of ABA and its glucose ester metabolite. Cotyledonary somatic embryos were subjected to drying treatments at 4⁰C under relative humidities of 98 and 59% for one week and the levels of both ABA and abscisic acid glucose ester (ABAGE) were followed by enzyme-linked immunoassay (ELISA). During desiccation at 98% relative humidity (RH) both ABA and ABAGE levels decreased in an irregular fashion. Regardless of RH, transient increases in ABA were observed that were paralleled by marked decreases in ABAGE. It is concluded that the desiccation of somatic embryos which leads to a decrease in ABA content, could explain the enhanced germination capacity of such embryos.     

Increased thermostability of three mesophilic β-galactosidases under high pressure

High pressure (>200Mpa) or high temperature (>45°C) can both induce an irreversible inactivation of the -galactosidases of Aspergillus oryzae, Kluyveromyces lactis and Escherichia coli. Moderate pressures (50MPa-250 MPa) exerted a protective effect against thermal inactivation for the three -galactosidases investigated. High pressure could thus be used to carry out b-galactosidase catalysed reactions such as lactose hydrolysis, at higher temperatures.     

Transformation by T-antigen and other oncogenes delays Hsp25 accumulation in heat shocked NIH 3T3 fibroblasts

We have recently reported that transformation of murine NIH 3T3 cells by v-fos oncogene interfered with Hsp70 and Hsp25 accumulation after heat shock. Here, we have investigated the effect mediated by other oncogenes on the accumulation of these stress proteins. We report that T-antigen transformation of NIH 3T3 cells delayed and reduced the accumulation of Hsp25 after heat shock and decreased the heat-mediated phosphorylation of this protein. This decreased level of Hsp25 correlated with a reduced accumulation of the corresponding mRNA and was related to T-antigen level. In contrast, T-antigen had no effect on the expression of the major stress protein Hsp70 nor did it interfere with the level of Hsp90 or Hsp60. We report also that v-src or Ha-ras oncogenes delayed Hsp25 accumulation after heat shock but that only v-src reduced the heat-induced phosphorylation of this protein. v-src, but not Ha-ras, interfered with Hsp70 expression and none of these oncogenes had an effect on Hsp60 or Hsp90 levels. Taken together, these observations suggest that an altered accumulation of Hsp25 after heat shock is a common characteristic of NIH 3T3 fibroblasts transformed by different oncogenes.     

Protracted release of the LHRH agonist avorelin (MF 6001) from two depot formulations in dogs and men

Summary Avorelin is a new superagonist of natural luteinizing-hormone-releasing-hormone. Avorelin has been formulated in high molecular weight polylactic glycolic acid to afford protracted and continuous release of the peptide from subcutaneous implants. Two different formulations (10 and 15 mg) were tested first in dogs and then in men during a clinical phase II trial. Chemical castration was maintained for at least 6 months in dogs with both formulations. A similar duration of activity (approximately 6 months) was observed in men.