Inhibition of nitric oxide synthesis in vascular smooth muscle by retinoids.

1. These studies examine the effect of retinoids on interleukin 1 beta (IL-1 beta)-induced nitric oxide synthase (NOS) activity in cultured rat aortic vascular smooth muscle (VSM) cells and isolated rat aortic rings. 2. All-trans-retinoic acid (all-trans-RA, 0.1-10 microM) and its active analogues produced concentration-dependent inhibition of IL-1 beta (0.1-10 ng ml-1)-induced nitrite production in cultured VSM cells. In contrast, the inactive retinoid, Ro 14-6113 (0.1-10 microM), had no effect on IL-1 beta-induced nitrite production. 3. Since some of the actions of retinoids are mediated by induction of transforming growth factor beta (TGF-beta), its effect on inducible NOS activity in VSM cells was examined. TGF-beta produced concentration-dependent (0.1-10 ng ml-1) inhibition of IL-1 beta-induced nitrite production and the maximum effect (approximately 90% inhibition) was significantly greater than that seen with all-trans-RA (approximately 70% with 10 microM). However, an anti-TGF-beta antibody (50 micrograms ml-1) which blocked the effect of exogenous TGF-beta (5 ng ml-1) did not significantly reverse the inhibitory action of all-trans-RA (10 microM). 4. In addition to inhibiting IL-1 beta-induced nitrite production, all-trans-RA (10 microM) reduced substantially inducible NOS mRNA and protein levels in IL-1 beta-induced VSM cells (P < 0.01). 5. Incubation of isolated rat aortic rings with IL-1 beta (10 ng ml-1) caused a progressive resistance of the rings to the vasoconstrictor action of phenylephrine (10 nM to 10 microM).(ABSTRACT TRUNCATED AT 250 WORDS)     

C20型二萜生物碱的药理活性研究进展

c20型二萜生物碱是一类结构复杂、活性多样的化合物,一直以来为化学家和药理学家所重视,近十年来,有关发现其新药理活性的报道不断涌现。综述c20型二萜生物碱药理活性的研究情况。     

Studies on WB-3559 A, B, C and D, new potent fibrinolytic agents. II. Structure elucidation and synthesis

The structures of WB-3559 A, B, C and D, new fibrinolytic agents isolated from Flavobacterium sp. No. 3559, have been elucidated to be as shown in 1, 2, 3 and 4, respectively, on the basis of chemical and spectroscopic evidence. Total synthesis of WB-3559 D (4) was achieved starting from the optically active aldehyde 14.     

Structure-activity relationships of retinoids in developmental toxicology. II. Influence of the polyene chain of the vitamin A molecule

The comparative teratogenic potencies of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, 9,10-dihydroretinoic acid, 9-cis-retinal, hydroxenin, oxenin, the C15 analog of all-trans-retinoic acid, abscissic acid, beta-C14 aldehyde, beta-ionone, and psuedoionone were determined in golden Syrian hamsters and compared with that of all-trans-retinoic acid. A single oral dose of each retinoid on Day 8 of gestation failed to induce signs of retinoid intoxication in the dams and the maternal weight gain was not affected significantly, except after treatment with beta-C14 aldehyde, pseudoionone, and the lowest dose of 9-cis-retinal, where maternal weight was depressed. A significant teratogenic response was observed after intubation of 7,8-dihydroretinoic acid, 7,8-dehydroretinoic acid, or 9-cis-retinal. The highest dose of hydroxenin (equivalent to nearly seven times an equimolar teratogenic dose of all-trans-retinoic acid) showed a limited teratogenic response. None of the remaining retinoids induced terata. The results suggest that the side chain plays an important role in retinoid embryotoxicity and that even minor structural alterations of retinoids at the side chain can abolish teratogenic activity. The present results indicate that a polyene chain of greater than five carbon atoms was necessary for retinoid teratogenic activity and that the presence of the ring, the nine-carbon side chain, and the acidic polar terminus was insufficient to ensure teratogenic activity. Retinoid teratogenicity in hamsters required the hydrophobic ring, a terminal polar group with an acidic pKa, and the hydrophobic, curved plane of the tetraene chain.     

Immunological effects of retinoids.

Vitamin A treatment (100,000 U daily) of systemic lupus erythematosus, non-Hodgkin's lymphoma and chronic lymphocytic leukemia patients, children suffering from recurrent respiratory tract infections and healthy controls resulted in an enhancement of antibody-dependent cell-mediated cytotoxicity, natural killer activity and blastogenic response to mitogens. In vitro, retinoids, depending on the concentration, stimulated mitogen- and interleukin-2-induced blastogenesis and lectin-dependent T cell cytotoxicity. Retinoids caused an early plasma membrane hyperpolarization of cells of various origin. This effect was similar to that seen by interferon alpha. Retinoids also slightly inhibited intracellular calcium accumulation.     

Studies on WF-3681, a novel aldose reductase inhibitor. II. Structure determination and synthesis

The structure of WF-3681, a novel aldose reductase inhibitor produced by Chaetomella raphigera Swift No. 3681, was deduced to be 1 on the basis of its spectroscopic and chemical evidences and confirmed by a total synthesis starting from (E)-5-phenyl-4-pentenol.