5-Alkyl 1,2-dihydrochromeno[3,4-f]quinolines: a novel class of nonsteroidal progesterone receptor modulators

A series of nonsteroidal human progesterone receptor (hPR) agonists, 5-alkyl 1,2-dihydrochromeno[3,4-f]quinolines, was synthesized and evaluated in cotransfection and competitive receptor binding assays. The 5-alkyl substitution was shown to be responsible for the agonist activity and substitution at C9 dramatically enhanced the potency. A number of analogues in this series showed activities similar to or better than progesterone in the cotransfection and binding assays and analogue 15 exhibited similar in vivo activity as medroxyprogesterone acetate (MPA) in murine uterine wet weight/mammary gland morphology assays.     

Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based inhibitory motif-like binding motifs and substrates

Stimulation of platelet aggregation leads to tyrosine phosphorylation of a number of receptors and signaling molecules including platelet endothelial cell adhesion molecule-1 (PECAM-1). In this report, we demonstrate that both protein-tyrosine phosphatases SHP-1 and SHP-2 physically associate with different kinetics of assembly with tyrosine-phosphorylated human PECAM-1 during integrin alphaIIbbeta3-mediated platelet aggregation. Peptido-precipitation analysis revealed that tyrosine-phosphorylated peptides encompassing residues 658-668 and 681-691 of PECAM-1 bound specifically to both protein-tyrosine phosphatases SHP-1 and SHP-2. We further show that the association of SHP-1 with PECAM-1 occurs through the direct interaction of the src homology region 2 domains of SHP-1 with two highly conserved phosphotyrosine binding motifs within PECAM-1 having the sequences NSDVQpY663TEVQV and DTETVpY686SEVRK (where pY represents phosphotyrosine). In vitro dephosphorylation experiments using phosphotyrosyl PECAM-1 peptides encompassing either Tyr-663 or Tyr-686 revealed induction of SHP-1 catalytic activity, suggesting that PECAM-1 serves as a SHP-1 substrate. Surface plasmon resonance studies reveal that recombinant SHP-2 binds PECAM-1 phosphopeptides with 5-fold higher affinity than recombinant SHP-1. These data suggest that in hematopoietic cells such as platelets, PECAM-1 cellular signaling is regulated by the selective recruitment and activation of two distinct protein-tyrosine phosphatases, SHP-1 and SHP-2, via a common immunoreceptor tyrosine-based inhibitory-like motif.     

Effects of a single, daily alcoholic beverage on lipid and hemostatic markers of cardiovascular risk

There is substantial epidemiologic data, but limited experimental data, supporting the mortality benefit of low-dose alcohol consumption. A regimen of a single, daily alcoholic beverage was sufficient to increase both high-density lipoprotein (HDL) (4.4%, p = 0.03) and HDL2 (7.7%, p = 0.04) in men and women, but did not significantly affect hemostatic markers of cardiovascular risk.     

Platelet-derived growth factor induces fetal wound fibrosis

The fetal response to cutaneous injury differs markedly from that of the adult, proceeding with only minimal inflammation, minimal fibroblast proliferation, and only essential collagen deposition. Although the sequence of events in adult wound healing is well defined and thought to be controlled in part by potent polypeptide cytokines, relatively sparse information exists regarding growth factor involvement in fetal wound repair. Thus, the authors sought to examine the effect of platelet-derived growth factor (PDGF), a putative adult wound healing regulator, on the cellular and extracellular matrix events at a fetal wound site. SILASTIC wound implants containing 0, 1.0, 5.0, or 10.0 ng of human PDGF were placed subcutaneously on the backs of 24-day-gestation fetal rabbits (full term, 31 days) and then harvested after either 1, 3, or 5 days in utero. The specimens underwent standard histological processing and were evaluated in a blinded fashion. Compared with controls, PDGF-treated implants had a marked increase in acute inflammation, fibroblast recruitment, and collagen and hyaluronic acid deposition; these differences appeared to be largely time- and PDGF dose-dependent. Thus, the fetal system is responsive to an adult wound healing mediator, and these data suggest that fetal repair proceeds in the absence of PDGF.