Labilization of ester bonds in aminodeoxyinositol derivatives as mediated by molecular conformation

Zusammenfassung Eine neue Art von Esterlabilisierung wurde in der Gruppe der Polyacetate tertiärer und (mono)quaternärer Inosamine und Streptamine entdeckt. Im Gegensatz zu den vergleichsweise beständigen Azetaten der quartärencis- undtrans-Dimethylaminocyclohexanole zeigten Penta-O-acetyl-2-desoxy-2-trimethylammoniumscyllitol als auchd,l-Tetra-O-acetyl-1, 3-bisdesoxy-1-dimethylamino-3-trimethylammoniumscyllitol rasche spontane Esterhydrolyse in wässrigem neutralen Medium, die grössenordnungsmässig vergleichbar war mit der unter Einwirkung von Cholinesterase beobachteten hydrolytischen Aktivität des — ohne Enzym beständigen — quartären Pentaacetats in der Myoinositol-Reihe. Offenbar spielt beim Zustandekommen solcher Labilisierungen die Totalkonformation der Molekel eine bisher nicht vermutete Rolle.     

Peroxovanadate inhibits Ca2+ release from mitochondria

Mitochondria contain a specific Ca²⁺ release pathway which operates when oxidized mitochondrial pyridine nucleotides are hydrolyzed. NAD⁺ hydrolysis and therefore Ca²⁺ release is possible when some vicinal thiols are cross-linked. Here we report that the thiol oxidant peroxovanadate inhibits the specific Ca²⁺ release pathway. In mitochondria, peroxovanadate causes a complete loss of reduced glutathione, which is not accompanied by formation of glutathione disulfide, and a partial loss of protein thiols. In model reactions, peroxovanadate oxidizes reduced glutathione predominantly to the sulfonate derivative, but does not react with glutathione disulfide. When the vicinal thiols relevant for Ca²⁺ release are cross-linked, Ca²⁺ release is no longer inhibited by peroxovanadate. Conversely, pretreatment of mitochondria with peroxovanadate makes them insensitive to compounds promoting the disulfide state. These results suggest that peroxovanadate inhibits the prooxidant-induced Ca²⁺ release from mitochondria by (i) depleting mitochondria of reduced glutathione and (ii) oxidizing the vicinal thiols relevant for Ca²⁺ release to a state higher than disulfide, presumably the sulfonate state. The findings provide further insight into the regulation of Ca²⁺ release from intact mitochondria, and may be relevant for a better understanding of the action of peroxovanadate in cells, where the compound can be insulin mimetic. Received 28 March 2002; received after revision 8 May 2002; accepted 15 May 2002     

Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) has an extremely poor prognosis. To improve diagnosis and treatment, key mechanisms of deregulated molecular functions have to be identified. Using microarray analysis, the expression patterns of 5600 human genes were assessed in PDAC by comparison with the normal pancreas and chronic pancreatitis (CP). The expression of 467 of 5600 genes was increased in PDAC in comparison to the normal pancreas, and the expression of 120 of these genes was not increased in CP. In addition, 341 of 5600 genes were expressed at decreased levels in PDAC tissues, of which 96 were decreased in comparison to both normal and CP tissues. Thus, a total of 808 of 5600 human genes were differentially expressed in pancreatic cancer. The identification of a large panel of altered genes in PDAC will stimulate additional studies that will lead to improved understanding of the molecular mechanisms underlying pancreatic malignant growth.     

Acetylcholinesterase inhibitory activities of muscarine and muscarone derivatives

Zusammenfassung Die Anticholinesterase-Wirkung von synthetischemd,l-Muscarin und weiteren 9 Derivaten wurde an einem hochgereinigten, ausElectrophorus electricus gewonnenen Enzympräparat durch Titration bei konstantem pH ermittelt. Als wirksamster Hemmstoff erwies sich O-Acetyl-d,l-muscarin, das als Substrat ungeeignet ist. Die enzymatischen werden mit den pharmakologischen Befunden verglichen.

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The opinions in this paper are those of the authors and do not necessarily reflect the views of the Navy Department or the naval service at large.