The role of domperidone in the regulation of prolactin release in rats

Effects of domperidone, a dopamine antagonist, on prolactin release in female rats were studied. Oral administration of domperidone for 14 days caused a significant increase in serum prolactin levels in mature female rats. The routes by which domperidone exerted its effects on prolactin release were studied by a in vitro incubation system using rat pituitary tissues. Pituitary halves were incubated with (1) domperidone, (2) dopamine, (3) dopamine plus domperidone, (4) hypothalamic extracts from rats which had been treated with control meal (control hypothalamic extract), (5) control hypothalamic extract plus domperidone, and with (6) hypothalamic extract from rats which had been treated with domperidone for 14 days (domperidone-treated hypothalamic extract). Pituitary halves, when incubated alone, released a significant amount of prolactin into the incubation medium after 24 hours incubation, which was completely inhibited by dopamine or control hypothalamic extract. The addition of domperidone could not reverse the inhibitory effect of dopamine or control hypothalamic extract. On the other hand, domperidone-treated hypothalamic extract showed no inhibitory effects on prolactin release. These results indicated that domperidone could increase serum prolactin levels in female rats by acting primarily at the hypothalamus.     

Factor VIIa inhibitors: target hopping in the serine protease family using X-ray structure determination

Selective factor VIIa-tissue factor complex (FVIIa/TF) inhibition is regarded as a promising target for developing new anticoagulant drugs. Compound 1 was discovered from focused screening of serine protease-directed compounds from our internal collection. Using parallel synthesis supported by structure-based drug design, we identified peptidemimetic FVIIa/TF inhibitors (compounds 4-11) containing L-Gln or L-Met as the P2 moiety. However, these compounds lacked the selectivity of other serine proteases in the coagulation cascade, especially thrombin. Further optimization of these compounds was carried out with a focus on the P4 moiety. Among the optimized compounds, 12b-f showed improved selectivity.     

Suppression of the floral activator Hd3a is the principal cause of the night break effect in rice

A short exposure to light in the middle of the night causes inhibition of flowering in short-day plants. This phenomenon is called night break (NB) and has been used extensively as a tool to study the photoperiodic control of flowering for many years. However, at the molecular level, very little is known about this phenomenon. In rice (Oryza sativa), 10 min of light exposure in the middle of a 14-h night caused a clear delay in flowering. A single NB strongly suppressed the mRNA of Hd3a, a homolog of Arabidopsis thaliana FLOWERING LOCUS T (FT), whereas the mRNAs of OsGI and Hd1 were not affected. The NB effect on Hd3a mRNA was maximal in the middle of the 14-h night. The phyB mutation abolished the NB effect on flowering and Hd3a mRNA, indicating that the NB effect was mediated by phytochrome B. Because expression of the other FT-like genes was very low and not appreciably affected by NB, our results strongly suggest that the suppression of Hd3a mRNA is the principal cause of the NB effect on flowering in rice.     

Helical structure of sugar-carrying polystyrene in aqueous solution by circular dichroism

Radical polymerization of N-p-vinylbenzyl-D-lactonamide (VLA) gave an optically active helical polymer. The stereoregularity of poly(N-p-vinylbenzyl-D-lactonamide) (PVLA) measured by 13C NMR spectroscopy showed a well-resolved sharp-line width, which was assigned to the phenyl C-1 carbon of the isotactic polystyrene (PS). The helical structure of PVLA shown by circular dichroism (CD) indicated that the aromatic groups were chirally supramolecular-packed giving optically active disaccharide units in the side chain covalently linked via an amide linkage with PS, the original PS not being optically active. The intensity of CD for PVLA (a) decreased with increasing temperature due to the change in the conformation of the phenyl group or to the breakdown of intermolecular hydrogen bonding of amide groups and (b) increased in a mixture of water and alcohol due to the increased hydrophobicity. The CD intensity for maltose-carrying PS (PVMA) was slightly higher than that of PVLA CD due to the more hydrophobic property of PVMA than PVLA.     

Firefly luciferase exhibits bimodal action depending on the luciferin chirality

Firefly luciferase is able to convert L-luciferin into luciferyl-CoA even under ordinary aerobic luciferin-luciferase reaction conditions. The luciferase is able to recognize strictly the chirality of the luciferin structure, serving as the acyl-CoA synthetase for L-luciferin, whereas d-luciferin is used for the bioluminescence reaction. D-Luciferin inhibits the luciferyl-CoA synthetase activity of L-luciferin, whereas L-luciferin retards the bioluminescence reaction of D-luciferin, meaning that both enzyme activities are prevented by the enantiomer of its own substrate.     

Deficiency of interleukin-1 receptor antagonist deteriorates fatty liver and cholesterol metabolism in hypercholesterolemic mice

Although the anti-inflammatory effect of interleukin-1 (IL-1) receptor antagonist (IL-1Ra) has been described, the contribution of this cytokine to cholesterol metabolism remains unclear. Our aim was to ascertain whether deficiency of IL-1Ra deteriorates cholesterol metabolism upon consumption of an atherogenic diet. IL-1Ra-deficient mice (IL-1Ra(-/-)) showed severe fatty liver and portal fibrosis containing many inflammatory cells following 20 weeks of an atherogenic diet when compared with wild type (WT) mice. Expectedly, the levels of total cholesterol in IL-1Ra(-/-) mice were significantly increased, and the start of lipid accumulation in liver was observed earlier when compared with WT mice. Real-time PCR analysis revealed that IL-1Ra(-/-) mice failed to induce mRNA expression of cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, with concurrent up-regulation of small heterodimer partner 1 mRNA expression. Indeed, IL-1Ra(-/-) mice showed markedly decreased bile acid excretion, which is elevated in WT mice to maintain cholesterol level under atherogenic diet feeding. Therefore, we conclude that the lack of IL-1Ra deteriorates cholesterol homeostasis under atherogenic diet-induced inflammation.     

A Novel Calibration-Minimum Method for Prediction of Mole Fraction in Non-Ideal Mixture

This article proposes a novel concentration prediction model that requires little training data and is useful for rapid process understanding. Process analytical technology is currently popular, especially in the pharmaceutical industry, for enhancement of process understanding and process control. A calibration-free method, iterative optimization technology (IOT), was proposed to predict pure component concentrations, because calibration methods such as partial least squares, require a large number of training samples, leading to high costs. However, IOT cannot be applied to concentration prediction in non-ideal mixtures because its basic equation is derived from the Beer–Lambert law, which cannot be applied to non-ideal mixtures. We proposed a novel method that realizes prediction of pure component concentrations in mixtures from a small number of training samples, assuming that spectral changes arising from molecular interactions can be expressed as a function of concentration. The proposed method is named IOT with virtual molecular interaction spectra (IOT-VIS) because the method takes spectral change as a virtual spectrum x _nonlin,i into account. It was confirmed through the two case studies that the predictive accuracy of IOT-VIS was the highest among existing IOT methods.     

Degradation of d-Biotin by Microorganisms

For the classical solution synthesis of human epidermal growth factor (h-EGF), five protected peptide derivatives, Boc-Leu-Asp(OcHex)-Lys(Cl-Z)-Tyr(Br-Z)-Ala-OH (5), Boc-Val-Cys(MeBzl)-Met-Tyr(Br-Z)-Ile-Glu(OcHex)-Ala-OH (12), Boc-Tyr(Br-Z)-Cys(MeBzl)-Leu-His-Asp(OcHex)-Gly-OH (18), Boc-Cys(MeBzl)-Pro-Leu-Ser(Bzl)-His-Asp(OcHex)-Gly-O H (23) and Boc-Asn-Ser(Bzl)-Asp(OcHex)-Ser(Bzl)-Glu(OcHex)-OH (28) were synthesized to build up the sequence corresponding to 1–30.