Direct and Indirect endocrine-mediated suppression of human endometrial CD8+T cell cytotoxicity.

Regulation of endometrial (EM) CD8+T cells is essential for successful reproduction and protection against pathogens. Suppression of CD8+T cells is necessary for a tolerogenic environment that promotes implantation and pregnancy. However, the mechanisms regulating this process remain unclear. Sex hormones are known to control immune responses directly on immune cells and indirectly through the tissue environment. When the actions of estradiol (E2), progesterone (P) and TGFß on EM CD8+T cells were evaluated, cytotoxic activity, perforin and granzymes were directly suppressed by E2 and TGFß but not P. Moreover, incubation of polarized EM epithelial cells with P, but not E2, increased TGFß secretion. These findings suggest that E2 acts directly on CD8+T cell to suppress cytotoxic activity while P acts indirectly through induction of TGFß production. Understanding the mechanisms involved in regulating endometrial CD8+T cells is essential for optimizing reproductive success and developing protective strategies against genital infections and gynecological cancers.

Discovery of inhibitors of cell adhesion molecule expression in human endothelial cells. 1. Selective inhibition of ICAM-1 and E-selectin expression.

A critical early event in the inflammatory cascade is the induced expression of cell adhesion molecules on the lumenal surface of vascular endothelial cells. These adhesion molecules include E-selectin, ICAM-1, and VCAM-1, which serve to recruit circulating leukocytes to the site of the inflammation. These adhesive interactions allow the leukocytes to firmly adhere to and cross the vascular endothelium and migrate to the site of tissue injury. Pharmaceutical agents which would prevent the induced expression of one or more of the cell adhesion molecules on the endothelium might be expected to provide a novel mechanism to attenuate the inflammatory responses associated with chronic inflammatory diseases. A thieno[2,3-d]pyrimidine, A-155918, was identified from a whole-cell high-throughput assay for compounds which inhibited the tumor necrosis factor-alpha (TNFalpha)-induced expression of E-selectin, ICAM-1, or VCAM-1 on human vascular endothelial cells. Traditional medicinal chemistry methods were applied to this low-micromolar inhibitor, resulting in the 2,4-disubstituted thieno[2,3-c]pyridine A-205804, a potent and selective lead inhibitor of E-selectin and ICAM-1 expression (IC(50) = 20 and 25 nM, respectively). The relative position of the nitrogen atom in the thienopyridine isomer was shown to be critical for activity, as was a small amide 2-substituent.

Effect of surface charge on the stability of oil/water emulsions during steam sterilization.

Intravenous lipid emulsions are used for total parenteral nutrition and as carriers for lipophilic drugs. Exposure to the high temperature (121 degrees C) required for steam sterilization may cause coalescence and an increase in droplet size. The purpose of this study was to investigate whether an increase in the electrostatic repulsive force between oil droplets produced by formulation modification improves the thermal stability of lipid emulsions during autoclaving. The addition of a small amount, 0.66 or 1.32 mmol/kg (mm), of purified anionic phospholipid fractions (phosphatidic acid, phosphatidylglycerol, or phosphatidylinositol) to the standard formula increased the zeta potential from its normal value of -11 mV to -39 mV. Emulsions with the larger negative zeta potential did not exhibit any change in oil droplet size or distribution during steam sterilization at 121 degrees C for 15 min. The autoclaved emulsions having the larger negative zeta potential did not exhibit any evidence of coalescence when samples were stored for 1 month at 4 degrees C, room temperature, or 40 degrees C. Reduction of the negative surface charge of the oil droplets by the addition of stearylamine confirmed that the surface charge was an important factor, as emulsions having a reduced negative surface charge separated into two phases during autoclaving.