Glycogen synthase kinase-3 (GSK3) is involved in signaling from the insulin receptor. Inhibitors of GSK3 are expected to effect lowering of plasma glucose similar to insulin, making GSK3 an ...attractive target for the treatment of type 2 diabetes. Herein we report the discovery of a series of potent and selective GSK3 inhibitors. Compounds 7 − 12 show oral activity in an in vivo model of type II diabetes, and 9 and 12 have desirable PK properties.
Alcohol consumption is known to predispose the host to more frequent and severe bacterial infections, suggesting that alcohol compromises the normal immune function of the lung. The pulmonary ...alveolar macrophage is the resident host defense cell in the lung and forms the first line of defense against invading microorganisms. One of the mechanisms whereby alveolar macrophages kill bacteria is by releasing toxic oxygen radical species, such as superoxide anion and hydrogen peroxide. We hypothesized that chronic alcohol consumption caused alveolar macrophage dysfunction leading to inhibition of oxidant production when stimulated. Our data demonstrate that alveolar macrophages harvested from alcohol-treated rats release significantly lower quantity (p < 0.05) of both superoxide anion and hydrogen peroxide when stimulated with several different types of stimuli including heat-killed Staphylococcus aureus, soluble immune complexes or phorbol myristate acetate. Pair-fed control rats who received isocaloric quantities of maltose dextrin in their diet to compensate for the alcohol were able to produce oxidants in equal quantities when stimulated, to rats who were fed a normal diet. Similar results were noted in vitro experiments when alveolar macrophages harvested from normal rats were incubated in vitro in alcohol-containing media and then stimulated with the aforementioned stimuli. Alveolar macrophages, which had been incubated in alcohol for 4 hr, showed significant decreases in their ability to produce superoxide anion. This defect was noticeable for a period up to 8 hr following removal of alveolar macrophages from the alcohol-containing media.
Pneumocystis carinii synthesizes folates de novo from exogenous p‐aminobenzoic acid (pABA). Lung‐derived organisms take up 3HpABA in vitro except in the presence of sulfamethoxazole. Supernatants ...from spinner‐flask cultures take up 3HpABA if they were inoculated with lungs from infected rats, but not if they were inoculated with lungs from uninfected rats. P. carinii folates consist primarily of pteroylpentaglutamates. Plasmodium falciparum, in contrast, contains primarily pteroyltetraglutamates. Culture‐derived organisms synthesize folates at a four‐fold higher specific activity than lung‐derived organisms, possibly because they contain less contaminating lung debris. These data suggest that P. carinii remains metabolically active in culture for at least 4 days.
Pneumocystis carinii synthesizes folates de novo from exogenous
p-aminobenzoic acid (pABA). Lung-derived organisms take up
3HpABA in vitro except in the presence of sulfamethoxazole. Supernatants ...from spinner-flask cultures take up
3HpABA if they were inoculated with lungs from infected rats, but not if they were inoculated with lungs from uninfected rats.
P. carinii folates consist primarily of pteroylpentaglutamates.
Plasmodium falciparum, in contrast, contains primarily pteroyltetraglutamates. Culture-derived organisms synthesize folates at a four-fold higher specific activity than lung-derived organisms, possibly because they contain less contaminating lung debris. These data suggest that
P. carinii remains metabolically active in culture for at least 4 days.
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