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Estrogen receptors (ERs) protect pancreatic islet survival in mice through rapid extranuclear actions. ER[alpha] also enhances insulin synthesis in cultured islets. Whether ERa stimulates insulin synthesis in vivo and, if so, through which mechanism(s) remain largely unknown. To address these issues, we generated a pancreas-specific ERa knockout mouse (PER[alpha][KO.sup.-/-]) using the Cre-loxP strategy and used a combination of genetic and pharmacologic tools in cultured islets and [beta] cells. Whereas 17[beta]-estradiol (E2) treatment up-regulates pancreatic insulin gene and protein content in control ERcdox/lox mice, these E2 effects are abolished in PER[alpha][KO.sup.-/-] mice. We find that E2-activated ER[alpha] increases insulin synthesis by enhancing glucose stimulation of the insulin promoter activity. Using a knock-in mouse with a mutated ER[alpha] eliminating binding to the estrogen response elements (EREs), we show that E2 stimulation of insulin synthesis is independent of the ERE. We find that the extranuclear ER[alpha] interacts with the tyrosine kinase Src, which activates extracellular signal-regulated [kinases.sub.1/2], to increase nuclear localization and binding to the insulin promoter of the transcription factor NeuroD1. This study supports the importance of ERa in [beta] cells as a regulator of insulin synthesis in vivo. diabetes | islet doi/ 10.1073/pnas.0914501107

Steroid hormone receptors function classically in the nucleus as transcription factors. However, recent data indicate that there are also non-nuclear subpopulations of steroid hormone receptors, including estrogen receptors (ERs), that mediate membrane-initiated signaling of unclear basis and significance. Here we have shown that an estrogen-dendrimer conjugate (EDC) that is excluded from the nucleus stimulates endothelial cell proliferation and migration via ERα, direct ERα-Gαi interaction, and endothelial NOS (eNOS) activation. Analysis of mice carrying an estrogen response element luciferase reporter, ER-regulated genes in the mouse uterus, and eNOS enzyme activation further indicated that EDC specifically targets non-nuclear processes in vivo. In mice, estradiol and EDC equally stimulated carotid artery reendothelialization in an ERα- and G protein-dependent manner, and both agents attenuated the development of neointimal hyperplasia following endothelial injury. In contrast, endometrial carcinoma cell growth in vitro and uterine enlargement and MCF-7 cell breast cancer xenograft growth in vivo were stimulated by estradiol but not EDC. Thus, EDC is a non-nuclear selective ER modulator (SERM) in vivo, and in mice, non-nuclear ER signaling promotes cardiovascular protection. These processes potentially could be harnessed to provide vascular benefit without increasing the risk of uterine or breast cancer., Introduction Steroid hormone receptors (SHRs) function classically as transcription factors. More recently, it has become apparent that steroid hormones also initiate nongenomic responses via activation of a subpopulation of these [...]

The effect of the tert-alcohol reaction medium for nucleophilic fluorination with alkali metal fluorides is examined by studying various interactions among tert-alcohols, the alkali metal fluoride (CsF) and the sulfonyloxy substrate. The protic environment of the reaction medium, as well as hydrogen bonding between the tert-alcohol and reactive heteroatoms in the substrate, has reduced the side reactions such as eliminations, hydroxylations and intramolecular alkylations.

The synthesis of 2,2-bis-(4-hydroxyphenyl)-cyclopentanone via reductive coupling reaction of 4,4'-dihydroxybenzophenone and cyclobutanone with Ti[Cl.sub.4] and Zn is demonstrated.

Previous reports showed that 17[beta]-estradiol implants attenuate in vivo coronary hyperreactivity (CH), characterized by long-duration vasoconstrictions (in coronary angiographic experiments), in menopausal rhesus monkeys. Prolonged [Ca.sup.2+] contraction signals that correspond with CH in coronary vascular muscle cells (VMC) to the same dual-constrictor stimulus, serotonin + the thromboxane analog U-46619, in estrogen-deprived VMC were suppressed by >72 h in 17[beta]-estradiol. The purpose of this study was to test whether an endogenous estrogen metabolite with estrogen receptor-[beta (ER-[beta]) binding activity, estriol ([E.sub.3]), suppresses in vivo and in vitro CH. [E.sub.3] treatment in vivo for 4 wk significantly attenuated the angiographically evaluated vasoconstrictor response to intracoronary serotonin + U-46619 challenge. In vitro treatment of rhesus coronary VMC for >72 h with nanomolar [E.sub.3] attenuated late [Ca.sup.2+] signals. This reduction of late [Ca.sup.2+] signals also appeared after >72 h of treatment with subnanomolar 5[alpha]-androstane-3[beta],17[beta]-diol (3[beta]-Adiol), an endogenous dihydrotestosterone metabolite with ER-[beta] binding activity. R,R-tetrahydrochrysene, a selective ER-[beta] antagonist, significantly blocked the [E.sub.3]- and 3[beta]-Adiol-mediated attenuation of late [Ca.sup.2+] signal increases. ER-[beta] and thromboxane-prostanoid receptor (TPR) were coexpressed in coronary arteries and aorta. In vivo [E.sub.3] treatment attenuated aortic TPR expression. Furthermore, in vitro treatment with [E.sub.3] or 3[beta]-Adiol downregulated TPR expression in VMC, which was blocked for both agonists by pretreatment with R,R-tetrahydrochrysene. [E.sub.3]- and 3[beta]-Adiol-mediated reduction in persistent [Ca.sup.2+] signals is associated with ER-[beta]-mediated attenuation of TPR expression and may partly explain estrogen benefits in coronary vascular muscle. menopause; calcium; thromboxane-prostanoid receptor; angiography

Copper‐mediated nucleophilic radiofluorination using boronic precursors is a promising, general method to label aromatic compounds with [18F]fluoride. However, in various reports, large amounts of precursor (60 μmol) were needed to achieve high radiochemical conversions (RCCs), which is neither ideal nor practical for the preparation of 18F radiopharmaceuticals. To investigate this matter, we studied alcohol‐enhanced Cu‐mediated nucleophilic radiofluorination using a variety of model reactions in which we varied the concentration of [18F]fluoride (no carrier added or isotope diluted) and the amount of precursor, base, and Cu(OTF)2(Py)4. We found that lower amounts of precursors (e.g., 15 μmol) could be used and that the amount of base (e.g., K2CO3 or KHCO3) played a critical and limiting role in the labeling reactions. Greater than one‐equivalent of base and sufficient amounts of precursors and Cu(OTf)2(Py)4 were required to achieve good to high RCCs. The RCCs were also dependent on the overall concentration of the labeling reactions, with low reaction volumes and high concentrations of reagents being preferred. Our findings will help to improve the design of radiolabeling protocols using alcohol‐enhanced copper‐mediated radiofluorination of boronic precursors for the preparation of 18F labeled radiopharmaceuticals and other radiohalogen‐labeled compounds. [ABSTRACT FROM AUTHOR]

Research has been conducted on the progesterone receptor high-affinity ligand, fluoro furanyl norprogesterone. The synthetic route developed for the synthesis of this ligand provides improvement in the yield of the fluoro furanyl norprogesterone.