During our screening of fermentation broths, culture UC 11136 was identified as producing potent inhibitor(s) of the in vitro cholesteryl ester transfer protein (CETP) reaction. Subsequent chemical isolation work identified two inhibitors of CETP produced by this culture. One of these inhibitors, U-106305, represented a novel CETP inhibitor as well as a structural class of compounds not previously reported from microbial fermentations. The structure of U-106305 was elucidated as V-isobutyl-tii(-rrtins-4,5:6,7:8,9:10,ll:12,13:16,17-hexamethylene-(£,£)-2,14-octadecadienamide by extensive NMR studies. Biogenetically, the backbone of U-106305 was found to derive from nine acetates linked in a head-to-tail fashion, while the cyclopropyl methylene carbons were derived from the methyl group of L-methionine. A biosynthetic pathway is proposed based on these findings.

No abstract

No abstract

No abstract

The effects of prostaglandins (PGs) on muscular activity of the oviductal isthmus and on the rate of tubal egg transport are reviewed. In consideration of the available data a mechanism by which PGs contribute to the physiological control of egg transport is suggested. Invivo experiments have demonstrated that E-series PGs relax while F-series PGs stimulate muscular activity of the oviduct in humans, subhuman primates and rabbits. These effects are mutually antagonistic. The response of oviductal muscle to PGs appears to be affected by ovarian steroids; progesterone increases the response to PGE₁ and decreases the response to PGF₂Α. Oviductal tissue concentrations of PGF increase in a distal to proximal sequence following ovulation-induction in the rabbit. Also, proximal isthmus binding of PGE₁ tended to be greater in 72-hour pregnant rabbits than in estrous rabbits, while binding of PGF₂Α was greater in estrous than in 72-hour pregnant animals. It is suggested that the preovulatory increase in ovarian estradiol secretion stimulates PGF synthesis in the oviductal tissue in a sequential fashion, the peak value occurring when the oviductal isthmus is most sensitive to stimulation by PGF₂Α. The changes in tissue concentration of PGF and in sensitivity to PGF₂Α could contribute to occlusion of the isthmus and prevent premature passage of eggs into the uterus. An increase in ovarian progesterone secretion after ovulation may decrease tissue PGF, decrease the response to PGF₂Α stimulation, and increase the response to PGE₁. These changes may then allow a progressive movement of eggs through the isthmus into the uterus. Several questions regarding this proposed mechanism remain unanswered.

Diabetes is associated with altered cholesterol metabolism that may contribute to cardiovascular complications. Treatment of rats with pioglitazone hydrochloride, a novel antidiabetic compound that improves the general response of target cells to insulin, significantly lowered cholesterol levels in rats fed a hypercholesterolemic diet and produced a significant reduction in cholesterol absorption. Drug treatment was ineffective in rats that were not given dietary cholesterol. To determine whether these effects of pioglitazone hydrochloride might be related to the known ability of this compound to improve the response to circulating insulin, similar studies were conducted in streptozocin-induced diabetic rats with and without insulin replacement. Diabetic rats absorbed a greater percentage of dietary cholesterol than control rats. Treatment of insulin-deficient diabetic rats with pioglitazone alone did not affect cholesterol absorption; however, the combination of insulin and pioglitazone was synergistic to lower absorption of cholesterol and circulating cholesterol and triglycerides. Treatment of either normal rats or diabetic rats receiving insulin with pioglitazone hydrochloride produced a twofold decrease in the ratio of total cholesterol to high-density lipoprotein cholesterol. These results suggest that treatments that improve insulin sensitivity may also have a positive impact on coronary artery disease associated with diabetes.

New Zealand White rabbits were used to measure oviductal mortiity amplitude in vivo and ovarian vein concentrations of estrone (E,), estradiol (E2), progesterone (P) and 20o-hydroxypregn4

No abstract