Psychedelic-inspired drug discovery using an engineered biosensor

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An asparaginase of Aspergillus nidulans is subject to oxygen repression in addition to nitrogen metabolite repression

Summary Of five amidohydrolase activities subject to nitrogen metabolite repression in Aspergillus nidulans, l-asparaginase shows clearest evidence of also being subject to repression by atmospheric oxygen. Such oxygen repressibility is only evident under nitrogen metabolite derepressed conditions. Asparaginase levels are also considerably elevated by areA300, an altered function allele of the positive acting wide domain regulatory gene areA mediating nitrogen metabolite repression and are drastically reduced by loss of function mutations in areA. A. nidulans has two l-asparaginase enzymes and it has been shown by the use of appropriate mutants that these regulatory effects are exerted on the expression of that specified by the ahrA gene but probably not that specified by the apnA gene. Present address: (until 25 August, 1988) Department of Genetics, University of Georgia, Athens, GA 30602, USA     

Effect of prolactin and cyclic AMP on 125I-labelled low density lipoprotein uptake and metabolism by luteinized porcine granulosa cells in culture

The present study examines the effect of prolactin (PRL) and N6-2(1)-O-dibutyryladenosine 3'5'-cyclic monophosphate (cAMP) on low density lipoprotein (LDL) uptake and metabolism by luteinized porcine granulosa cells in culture. Granulosa cells from preovulatory follicles were plated with 1% serum and 1 microgram/mL of insulin for the first 48 h. Following plating (day 3) the cells were cultured in serum-free media with the same dose of insulin. The next day the medium was replaced with serum- and insulin-free medium, and to some cultures 1.23 IU/mL of human chorionic gonadotrophin (hCG) was added. On day 5 the medium was again replaced and graded amounts of PRL (0, 0.03, 0.3, and 3 micrograms/mL) were added. Following 48 h of incubation with PRL, 20 micrograms/mL of 125I-labelled LDL was added to cultures. Surface-bound, internalized, and degraded LDLs were quantitated at 12 h following addition of LDL. To examine the effect of cAMP on LDL metabolism, the cells were exposed for 24 h to cAMP (3mM) on day 6 of culture. PRL had a stimulatory effect on LDL degradation by luteinized granulosa cells. Pre-exposure of cells to hCG augmented the stimulatory effect of PRL. Addition of cAMP also enhanced LDL degradation by luteinized granulosa cells. Both PRL and cAMP increased surface binding of LDL in cells pre-exposed to hCG, but there was no effect on internalization. The increase in cell surface binding of LDL with PRL and cAMP was less than their effect on LDL degradation.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of Lipoprotein-X on lipid metabolism in rat kidney

Lipoprotein-X (Lp-X) is found in the plasma of patients with familiallecithin: cholesterol acyltransferase (LCAT) deficiency syndromes. Themajority of the patients with this disorder develop progressiveglomerulosclerosis. In this study, the effect of Lp-X on lipid metabolism inperfused rat kidney was investigated. Lp-X was isolated from plasma ofpatients with familial LCAT deficiency by sequential ultracentrifugation andgel filtration column chromatography. Rat kidneys were perfused for 1-2 hwith Krebs-Henseleit buffer containing 20 µM [1-14C]acetate or 20µM [Me-3H]choline. In the presence of Lp-X, no significant differencein the incorporation of radioactivity into triglycerides, cholesterol,phosphocholine, CDP-choline and sphingomyelin was observed. However,incorporation of radioactivity into cholesteryl esters andphosphatidylcholine was significantly elevated in Lp-X perfused kidneys. Thecontents of cholesterol, cholesteryl esters and phosphatidylcholine werealso significantly increased in Lp-X perfused kidneys. The increase in lipidcontent in the Lp-X perfused kidney is attributed to the direct depositionof Lp-X lipids into the organ. The increase in the labelling of cholesterylesters was attributed to the increase of available substrate (cholesterol)for the acyl-CoA:cholesterol acyltransferase (ACAT) reaction. The increasein phosphatidylcholine labelling was caused by a reduced turnover of thenewly synthesized labelled phosphatidylcholine during Lp-X perfusion.     

Malignant mesothelioma: facts, myths, and hypotheses

Malignant mesothelioma (MM) is a neoplasm arising from mesothelial cells lining the pleural, peritoneal, and pericardial cavities. Over 20 million people in the US are at risk of developing MM due to asbestos exposure. MM mortality rates are estimated to increase by 5–10% per year in most industrialized countries until about 2020. The incidence of MM in men has continued to rise during the past 50 years, while the incidence in women appears largely unchanged. It is estimated that about 50–80% of pleural MM in men and 20–30% in women developed in individuals whose history indicates asbestos exposure(s) above that expected from most background settings. While rare for women, about 30% of peritoneal mesothelioma in men has been associated with exposure to asbestos. Erionite is a potent carcinogenic mineral fiber capable of causing both pleural and peritoneal MM. Since erionite is considerably less widespread than asbestos, the number of MM cases associated with erionite exposure is smaller. Asbestos induces DNA alterations mostly by inducing mesothelial cells and reactive macrophages to secrete mutagenic oxygen and nitrogen species. In addition, asbestos carcinogenesis is linked to the chronic inflammatory process caused by the deposition of a sufficient number of asbestos fibers and the consequent release of pro‐inflammatory molecules, especially HMGB‐1, the master switch that starts the inflammatory process, and TNF‐alpha by macrophages and mesothelial cells. Genetic predisposition, radiation exposure and viral infection are co‐factors that can alone or together with asbestos and erionite cause MM. J. Cell. Physiol. 227: 44–58, 2012. © 2011 Wiley Periodicals, Inc.