This paper summarizes the structure, biological activities, signaling, and metabolic degradation of fungal β-1, 3-glucans. Fungal β-glucans exist both soluble and particulate forms. Conformation of the soluble β-glucan was classified into three groups : triple helix, single helix and random coil. Fungal β-1, 3-glucans exhibit a variety of biological and immuno-pharmacological activities, and the significance of these activities is dependent on the structure, such as solubility in water, molecular weight, degree of branching, and conformation. Many of the activities, such as nitrogen oxide synthesis of macrophage and limulus factor G activation, were dependent on the conformation, but some of the others were independent, such as interferon-γ and colony stimulating factor syntheses. These activities are beneficial and pharmacologically useful, while some strongly related to allergic and inflammatory adverse reactions. It should be noted that the β-glucans, once administered into the body, remain mainly in the liver and spleen for a very long period of time. The activity, at least in part, is maintained during these periods. The biochemical mechanisms of the β-glucan, especially in soluble form, mediating biological activity was still not clearly demonstrated.
This article reviews a new approach to stereoselective Horner-Wadsworth-Emmons(HWE) reactions. The HWE reaction is one of the most efficient methods for the preparation of α, β-unsaturated esters, which play an important role in the synthesis of biologically active compounds. The reactions of aldehydes with phosphonates bearing α-substituents which stabilize the carbanion, preferentially furnish the corresponding E-alkenes. However, the stereoselectivity of the HWE reactions with ketones has never been investigated in detail because of their low reactivity and low stereoselectivity. The conventional HWE reactions of aryl alkyl ketones with ethyl diethylphosphonoacetate in the presence of sodium hydride gave the corresponding α, β-unsaturated esters with modest E-selectivity. On the other hand, the treatment of aryl alkyl ketones with ethyl diethylphosphonoacetate in the presence of Sn(OSO2CF3)2 and N-ethylpiperidine afforded α, β-unsaturated esters in a highly Z-selective fashion. A significant improvement in the selectivity and yield was found when the Still's reagent, methyl bis(trifluoroethyl)phosphonoacetate, was used under Sn(II)-mediated conditions. On the basis of the experimental results, the high Z-selectivity in the Sn(II)-mediated HWE reactions of aryl alkyl ketones with these phosphonates can be rationalized in terms of six-membered transition state involving Sn(II) chelation. Similarly, the HWE reactions of aryl alkyl ketones with ethy12-fluoro-2-diethylphosphonoacetate in the presence of Sn(OSO2CF3)2 and N-ethylpiperidine gave the corresponding α-fluoro-α, β-unsaturated esters in a highly E-selective manner. Finally, the Sn(II)-mediated asymmetric HWE reactions of isopropyl 2-fluoro-2-diethylphosphonoacetate with 4-tert-butylcyclohexanone in the presence of a chiral diamine is described.
This review deals with pharmacokinetic/pharmacodynamic analysis of drugs. For the analysis of antipyretics, it was assumed that : (1) The rat body is divided into two compartments, core and skin. (2) Metabolic heat (M) is generated in the core compartment. (3) Heat loss by vaporization (V) is mainly originated from a respiratory effect and occurs in the core compartment. (4) At the skin compartment, heat is gained from the core compartment by conduction (K) and is transferred to the ambient air by radiation and convection. (5) Central nervous system commands efferent signals for M, K and V to change their values according to changes in afferent signals from core and skin temperatures. (6) The effect of antipyretics is shown as afferent signals to the controller. For loop diuretics, it was assumed that : (1) The diuretic rate can be correlated with the urinary excretion rate of diuretics. (2) If there is no intervention in a body fluid regulation system, the relationship between the diuretic rate and the corresponding urinary excretion rate can be described by a Hill equation. (3) Intensity of the body fluid regulation is also described by the Hill equation, in which the intensity is correlated with the cumulative amount of drugs excreted in the urine. For neuromuscular blockade, assumptions were : (1) There exists an acetylcholine (ACh) compartment at a motor nerve terminal. (2) ACh in the compartment is eliminated by a first-order rate process. (3) All of the ACh in the compartment is released by one electrical stimulus. (4) The compartment is replenished by two kinds of ACh mobilization. One is a slow mobilization with a constant rate and the other is a momentary mobilization which takes place just after the release of ACh. (5) The released ACh is metabolized immediately after binding to receptors and causing a twitch response. For centrally acting drugs, the quantitative electroencephalographic (EEG) method was used as a surrogate measure of a pharmacological response. Signals from two electrodes fitted on the skull of rats were continuously measured, recorded and subjected to off-line analysis. Total amplitude from aperiodic analysis was taken as an EEG parameter.
Inflammatory signs, such as heat, redness, swelling and pain, have been described from the Greek era. In these phenomena various endogenous active substances, i.e., inflammatory mediators, could cause and manifest vascular dilatation, a vascular permeability increase and sensitization of pain receptors, etc. In order to evaluate the roles of inflammatory mediators, we have studied the time courses of inflammatory reaction along with detection of various active substances directly or indirectly in the experimental animal model of pleurisy, such as rat carrageenin-induced, and zymosan-induced pleurisy. These pleurisies showed almost similar time courses of pleural exudate accumulation and neutrophil migration. However, mediators detected in the exudates of such pleurisies were different; in carrageenininduced pleurisy bradykinin and prostacyclin (PGI2) caused exudate formation, while zymosan-induced pleurisy showed early degradation of mast cells and activation of complements, followed by an increase in platelet activating factor (PAF). In both pleurisies TNFα, IL-1, IL-6 and CINC (cytokine-induced neutrophil chemoattractant) appeared similarly in the exudates to cause chemoattractant for neutrophils. TNFα and IL-1 could stimulate to produce IL-6 and IL-8. While prostaglandins may regulate cytokine production via a cellular cAMP-dependent mechanism. Thus one should consider the time for application of anti-inflammatory drugs, such as cyclooxygenase inhibitor, indomethacin, since it causes increases in TNFα and IL-1 production by reducing PGI2 and prostaglandin E2 (PGE2) levels. In conclusion, inflammatory reaction has its own automatic regulation mechanism through complex cross talks between inflammatory mediators.
Cadmium and lead are heavy metals that cause vascular lesions such as atherosclerosis and hypertension. Toxicity of cadmium and lead on the regulation of fibrinolysis by vascular-composing cells was investigated using a cell culture system. It was found that cadmium promotes the synthesis of plasminogen activator inhibitor-1(PAI-1) whereas lead inhibits the synthesis of tissue plasminogen activator (t-PA) in vascular endothelial cells; consequently, both heavy metals reduced fibrinolytic activity in the liquid phase. The responses of endothelial cells to cadmium and lead were different from those to other heavy metals and the release of the fibrinolytic proteins from vascular smooth muscle cells and fibroblasts was perturbed by cadmium and lead in different manners. In conclusion, the present study showed that cadmium and lead exhibit their toxicity on fibrinolysis regulated by vascular cells in different manners among cell types and the individual cell types respond to cadmium and lead in different manners with respect to the release of fibrinolytic proteins.
The water decoction of leaves of kumis kucing, Orthosiphon aristatus (BL.) MIQ (Lamiaceae) which has been prescribed in Javanese traditional medicine (jamu) for the treatment of hypertension etc., was partitioned into a mixture of chloroform and water. The chloroform-soluble portion showed an inhibitory effect on the contractile responses on rat thoracic aorta smooth muscle stimulated with KCl beforehand, while the water-soluble portion showed no effect. The chloroform-soluble portion was separated to afford a new benzochromene [orthochromene A (7)], two new isopimaranetype diterpenes [orthosiphonone A (10), orthosiphonone B (11)], and two novel migrated pimarane-type diterpenes [neoorthosiphol A (12), neoorthosiphol B (13)], together with eight known compounds (1-6, 8, 9). Among those thirteen substances, it was found that a major constituent in the water decoction of leaves, methylripariochromene A (5), exhibited a continuous decrease in systolic blood pressure after subcutaneous administration in conscious stroke-prone spontaneously hypertensive rats(SHRSP).
Nine kinds of human cultured cells, including fetus cells(smooth chorion trophoblast cells, amnion epithelial cells and HE-21), adult non-carcinoma cells (HCF), and carcinoma cells (KATO-III, COLO 201, Lu-134-AH, SK-OV-3 and SKG-3a) were stimulated with Actinomycin (Act.) D for 24 h. Apoptosis induction was investigated by agarose gel electrophoresis for DNA fragmentation analysis and by flow cytometric analysis of stained cells using in situ terminal deoxynucleotidyl-transferase (TdT)-mediated dUTP nick-end labeling TUNEL) staining techniques for the quantification of apoptosis, and simultaneously using propidium iodide for the gain of some information about cell cycle. By agarose gel electrophoresis, DNA fragmentation of these cells except amnion epithelial and SKG-3a cells was detected, depending on concentration of Act. D. Using flow cytometric analysis, these cells were separated into four groups according to the information about cell cycle. Group 1 included amnion epithelial and SKG-3a cells, which were TUNEL negative. In group 2, all cell populations at G0/G1 and G2/M phases of HCC, KATO-III and SK-OV-3 were TUNEL staining positive. A portion of each G0/G1 or G2/M phase cell of Lu-134-AH and COLO 201 in group 3 was TUNEL stain positive. In group 4, G2/M phase cells of smooth chorion trophoblast cells and HE-21 were mostly stained and a small population of G0/G1 phase cells were also TUNEL stain positive. These results show that the stages of the cell cycle at which apoptosis was arisen by Act. D stimulation were significantly different depending on the cells types.