Expression of specific genes can be controlled by some compounds (gene expression modifiers) which can be divided into two categories, i.e. ; (a) compounds which directly bind to nucleic acids having specific sequences and (b) compounds which bind specific transcription factors (including nuclear receptors) or related factors. Recent results on the structural development and mechanistic studies into the gene expression modifiers, mainly retinoids, phorbol ester, hemin, antisense molecules, and thalidomide analogs, have been reviewed. Some of these gene expression modifiers elicit cell differentiation inducing, tumor promoting, and biological response modifying activities. Development of more potent and/or more specific gene expression modifiers might be useful in cancer chemotherapy.
An asymmetric modification of the cell membrane lipid bilayer of erythrocytes by means of exogenous phospholipase (PL) treatment or of phospholipid addition induced an echinocyte- or stomatocyte-type shape change of the cells. Such membrane shape change was demonstrated to be due to asymmetric swelling or shrinkage of the lipid bilayer halves, from the simultaneous determination of the change or intra-bilayer transfer of the phospholipid molecules. In the collagen-induced activation of blood platelets, the importance of PLA2 activation as the initial reaction of the signaling system was demonstrated, and the regulatory effects of the membrane fluidity change on the enzyme activation were also shown. In the antigen-induced activation of peritoneal mast cells, a pathway through the PLD activation appeared to be more important. Phosphatidic acid produced from the membrane phospholipids through the PLD activation was shown to act as an intracellular mediator to stimulate the PLA2 activation. Various amphiphilic drugs, including benzylisoquinoline alkaloids such as cepharanthine, were shown to inhibit the platelet activation and the mechanism was studied. The anti-platelet activity appeared to be mainly due to inhibition of the PLA2 activation.
In view of the recent investigation, highly reactive oxygen-derived free radicals may play a role in cerebral ischemia and brain damage, free radical scavenging activity of kampo formulations (Oren-gedoku-to, Keishi-bukuryogan, Saiko-ka-ryukotsu-borei-to and Daio-botampi-to) and Kampo components (Ityou, Shini, Menamomi, Arinosudama and Denshiti), used for the attenuation of brain damage, was investigated in vitro. The used experimental system was a radical scavenging action against 1, 1-diphenyl-2-picrylhydrazyl (DPPH), superoxide anion radical (O2&mcomma;) and hydroxyl radical (OH·) by the electron spin resonance technique at room temperature. All kampo formulations and kampo components showed radical scavenging activity in a concentration-dependent manner. This result indicates that kampo formulations, treated for brain damage, were good radical scavenger that could possibly prevent ischemic complications such as formation of brain damage. The intensity of scavenging activity of kampo formulations for three types of radicals were as follows ; 1. DPPH : Daiobotampi-to > Saiko-ka-ryukotsu-borei-to=Keishi-bukuryo-gan > Oren-gedoku-to, 2. O2&mcomma; : Daio-botampi-to=Keishi-bukuryo-gan > Saiko-ka-ryukotsu-borei-to > Oren-gedoku-to, 3. OH· : Daio-botampi-to=Saiko-ka-ryukotsu-borei-to > Keishi-bukuryo-gan=Oren-gedoku-to. Daio-botampi-to indicated the strongest scavenging activity against three types of radicals. Ischemic brain damage is thought to be an "oketsu" syndrome, which is correlated with abnormalities of the microcirculation. Therefore, Daio-botampi-to, which has been used for "oketsu"syndrome, showed superior free-radical scavenging activity.
Nicotinamide (NAA) forms a crystalline complex with docosanoic acid (C22), C22-NAA. The molar ratio of C22 to NAA is 1 : 1. The release rate of NAA from C22-NAA was measured above 47°C at pH 1.2 and pH 6.8, and the thermodynamic quantities for the release of NAA from C22-NAA were estimated. The value of activation energy (E&nedot;) at pH 6.8 was about three times larger than that at pH 1.2. The effect of temperature on the release rate of NAA from C22-NAA at pH 6.8 was larger than that at pH 1.2. It has been reported that the values of activation enthalpy (ΔH&nedot;) and activation entropy (ΔS&nedot;) at pH 1.2 for the release of NAA from fatty acid (FA)-NAA complex whose carbon number of constituent FA is 14-18 were positive and negative, respectively. On the contrary, the values of ΔH&nedot; and ΔS&nedot; for the release of NAA from C22-NAA at pH 1.2 and pH 6.8 were positive. Furthermore, the values of ΔH&nedot; and ΔS&nedot; at pH 6.8 were larger than those at pH 1.2. The value of activation Gibbs energy (ΔG&nedot;) was positive. It was found that the release of NAA from C22-NAA was enthalpically controlled reaction.
In order to develop new bioactive functions of Hydrangeae Dulcis Folium, the fermented and dried leaves of Hydrangea macrophylla SERINGE var. thunbergii MAKINO, effects of the methanolic extract from the crude drug on antiulcer, antiallergic, cholagoic, and various pharmacological actions were investigated. Consequently, the methanolic extract was found to exhibit potent antiulcer, antiallergic, and cholagoic activities. By monitoring with these activities, it was found that the active constituents were contained in the lipophilic portion of the methanolic extract. Furthermore, the known lipophilic constituents such as phyllodulcin and hydrangenol were found to show little antiulcer and cholagoic activities, while it was also found that they showed antiallergic activity on Schultz-Dale reactions.
Conformations of benzanilide (1), N-methylbenzanilide (2) and those with a methyl group (s) ortho to the amide bond (11-16, 21-26) in solution and in the crystal have been studied. N-Methylbenzanilide (2) exists in cis-amide (E) form in the crystal. In CDCl3 solution, cis-amide form is also predominant (99%), while benzanilide (1) exists in trans-amide (Z) form in the crystal and in solution. In the crystal, all the methyl-substituted benzanilides (11-16) exist in trans-amide conformation and the introduction of an ortho-methyl group (s) makes the interplanar angles of the aromatic rings and the amide group (Ar-amide) larger. N-Methylbenzanilides (21-25) exist in cis form in the crystal except the compound (26) which has four methyl groups ortho to the amide bond. For the N-methylbenzanilides, the effects of introduction of one or two ortho-methyl groups on the dihedral angles of Ar-amide are smaller than that for the secondary benzanilides. In solution, benzanilides (11-16) exist exclusively in trans conformation except for the compound 12 which has a minor cis conformer (3%) in CDCl3, whereas N-methylbenzanilides (21-25) exist in equilibrium between the major cis-form and the minor trans-form. The tetramethyl derivative (26) exists in trans conformation in solution as observed in the crystal. For N-methyl-benzanilides, an introduction of a methyl group (s) ortho to the amide bond seems to destabilize the cis-amide conformation in solution, resulting in an increased ratio of the trans-amide conformation.
The effects of Oren-gedoku-to on the hypnotic duration induced by hexobarbital, and on the change of this duration in chlorpromazine-treated mice were investigated. Single dose of Oren-gedoku-to (1.0 or 2.0 g/kg, p.o.) or chlorpromazine (10 mg/kg, p.o.) prolonged the hexobarbital hypnosis time. And the simultaneous dose of chlorpromazine (6.0 mg/kg, p.o.) and Oren-gedoku-to (1.0 g/kg, p.o.) indicated the equal effect for the administration of chlorpromazine (10.0 mg/kg, p.o.) alone. Although the mechanism of the action remains to be unknown, administration of Oren-gedoku-to in combination with chlorpromazine seems to be useful from the standpoint of alleviation of the side-effects caused by less dose.