Naturally occurring phenylpropanoids, hinokiresinol (trans-hinokiresinol) and nyasol (cis-hinokiresinol) were found to possess appreciable estrogen receptor binding activity. Strong differences in activity were observed between the geometrical isomers and enantiomers. Among these, (3S)-cis-hinokiresinol displayed the highest activity, one order of magnitude greater than the activity of genistein. Furthermore, cis- and trans-hinokiresinol stimulated the proliferation of estrogen-dependent T47D breast cancer cells, and their stimulatory effects were blocked by an estrogen antagonist, indicating that the compounds are estrogen agonists. In addition, the absolute configuration of C-3 in (+)-cis-hinokiresinol has been assigned as S by comparison with the circular dichroism spectra of the hydrogenated products prepared from cis and trans ((3S)-trans-hinokiresinol: previously assigned) isomers. These results incidentally provide us with an unambiguous answer to contradictory reports regarding the assignment of the full stereochemisry of cis- and trans-hinokiresinol that have existed in the literature for more than two decades.
Abstract.We investigated the role of interferon regulatory factor 8 (IRF8) in a model of chronic pain in which repeated cold stress (RCS) exposure produces tactile allodynia. RCS exposure produced a decrease in paw withdrawal threshold (PWT) to mechanical stimulation. Spinal microglia of RCS-exposed mice were morphologically activated. Expression of IRF8 was significantly increased in the spinal cord of RCS-exposed mice and was localized in microglia. IRF8-knockout mice failed to show the RCS-induced decrease in PWT. Thus, RCS exposure activates spinal microglia and upregulation of IRF8 in these cells is involved in the development of tactile allodynia after RCS exposure.
Although a large number of microbial metabolites have been discovered as inhibitors of bacterial peptidoglycan biosynthesis, only a few inhibitors were reported for the pathway of UDP-MurNAc-pentapeptide formation, partly because of the lack of assays appropriate for natural product screening. Among the pathway enzymes, D-Ala racemase (Alr), D-Ala:D-Ala ligase (Ddl) and UDPMurNAc-tripeptide:D-Ala-D-Ala transferase (MurF) are particularly attractive as antibacterial targets, because these enzymes are essential for growth and utilize low-molecular-weight substrates. Using dansylated UDP-MurNAc-tripeptide and L-Ala as the substrates, we established a cell-free assay to measure the sequential reactions of Alr, Ddl and MurF coupled with translocase I. This assay is sensitive and robust enough to screen mixtures of microbial metabolites, and enables us to distinguish the inhibitors for D-Ala-D-Ala formation, MurF and translocase I. D-cycloserine, the D-Ala-D-Ala pathway inhibitor, was successfully detected by this assay (IC 50 ¼1.7 lg ml À1 ). In a large-scale screening of natural products, we have identified inhibitors for D-Ala-D-Ala synthesis pathway, MurF and translocase I.
The activity of haemagglutinins in plasmodia of Physanrm polycephalum was measured under different culture conditions. The activity was markedly increased when the plasmodia were incubated in a non-nutrient salt medium. During starvation, significant amounts of haemagglutinins were found in the slime layer on the surface of the plasmodia. An increase in activity was not observed in the presence of actinomycin D or cycloheximide. Under starvation conditions, plasmodia are known to differentiate into either sclerotia (spherules) or fruiting bodies. Acceleration of haemagglutinin synthesis, however, was not always observed during spherulation and fruiting-body formation. Attempts to detect endogenous glycoconjugates that bind to the haemagglutinins were unsuccessful but we found that the haemagglutinins could bind to acidic polysaccharides produced by Escherichia coli K12. The bacterial glycoconjugates were purified and partially characterized. They contained N-acetylhexosamine residues which appeared to be important for binding with the haemagglutinins. It is possible that the haemagglutinins play a physiological role in the interaction with these organisms.
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