We found that passive sensitization with anti-DNP IgE antibody followed by the challenge with DNFB to the mouse ear can induce the triphasic cutaneous reactions (ear swelling) of immediate phase response (IPR), late phase response (LPR) and very late phase response (vLPR), peaking at 1 h, 24 h and 8 days after the challenge, respectively. IPR was absent in mast cell-deficient mice but LPR was sufficiently observed, and vLPR was partly attenuated. LPR is a T cell-independent response, while vLPR is almost completely absent in T cell-deficient nude mice. Thus, the third phase response (vLPR) with massive infiltration of eosinophil actually represents an important inflammatory reaction mediated by T cells and partially mast cells. In this model, some Kampo formulations and synthetic anti-allergic agents inhibited the IgE-mediated triphasic cutaneous reaction. The inhibitory effects of the Kampo formulations on the triphasic cutaneous reaction were divided into several groups according to the efficacies for IPR/LPR/vLPR. For instance, the group consisting of formulations such as Tokaku-joki-to (Tao-He-Cheng-Qi-Tang), Ji-zuso-ippo (Zhi-Tou-Chuang-Yi-Fan), Sho-sei-ryu-to (Xiao-Qing-Long-Tang) and Sho-saiko-to (Xiao-Chai-Hu-Tang) significantly inhibited IPR, LPR and vLPR (i.e. +/+/+ group that showed inhibitory effects against the triphasic response), similar to the effect of prednisolone as a positive control. Oral administration of Yokukan-san (Yi-Gan-San), an anti-psychosis drug in Kampo medicine, attenuated the isolation stress-exacerbated triphasic skin reactions in a dose-dependent manner, while it had almost no effect on the cutaneous reactions in the unstressed group-housed mice. On the other hand, the i.p. administration of diazepam, a classic benzodiazepine receptor agonist, suppressed the enhanced IPR and LPR in socially isolated mice, but surprisingly stimulated vLPR in both stressed and unstressed mice, differing from the efficacy of Yokukan-san.
This article focuses on the anti-allergic properties of Kampo formulations and describes the effect of some Kampo formulations on IgE-mediated triphasic skin reaction in group-housed or socially isolated mice. We also discuss the mechanism of the inhibitory action and the importance of the formulation and the constituent drugs in determining the efficacy.

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The polysaccharide (PS) fractions isolated from fungi and higher plants have been shown as potent biological response modifiers exhibiting immunostimulating and antitumor activities through the functions involving activation of macrophages, cell-mediated immunity and cytokine induction. The primary structure of these PSs exhibits β(1->3), β(1->4)-linkage glycan as the common form of main chain, while the side chains involve β(1->3), β(1->4), β(1->6) or α(1->4) linkages. The hydrogen bond, tertiary structure of triple helix, and high molecular weight contribute to the stability and biological activities of the PSs. The degree of substitution on the backbone chain and the length of the side chains are important for the conformation of structure and their immunologic activity. Here we review the biochemical characterization, immunomodulating activities, and clinical application of important PSs isolated from fungi including Lentinus, Ganoderma, Hoelen, Polyporus, and Ascomyces and higher plants such as Radix Astragali, Angelica, Ginseng, and others. Immunomodulating PSs thus far have been used to prevent disease and promote restoration of the body's homeostasis, and current evaluations focus on treatment of pathogenic factors. Development of these polysaccharides into drugs for therapeutic use needs research on structure-activity relationship and quality assurance for polysaccharide molecules and final products.

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For the purpose of evaluating phytoestrogenic activity of medicinal plant extracts, a naringinase-pretreatment method was developed, monitoring with proliferation of MCF-7 human breast cancer cells and induction of β-galactosidase in a yeast two-hybrid assay system. Of various medicinal plant extracts examined, the extracts of Alpinia katsumadai (seeds), Glycyrrhiza uralensis (roots) and Moghania philippinensis (roots) showed higher estrogenic activity by per-treatment with naringinase than the original extract themselves. The contents of liquiritigenin and isoliquiritigenin having potent estrogenic activity, appreciably increased after the naringinase treatment of the extract of G. uralensis. These findings suggested that orally administered crude drugs would increase their estrogenic activity, due to the hydrolysis of some glycosylated constituents by intestinal flora.

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Replicative senescence (RS) of human diploid fibroblasts (HDFs) has become a classical model of aging and HDFs, such as WI-38 cells, display increased cellular oxidant production associated with RS. Several phenomena associated with RS are also observed in stress-induced replicative senescence (SIPS). In particular, SIPS of WI-38 cells caused by hydrogen peroxide (H₂O₂) is a useful and reasonable cellular aging model for evaluating the effects of potential anti-aging agents against oxidative stress. We used this well-established model to evaluate the anti-aging effect of Kangen-karyu, focusing on its antioxidant activity. Treatment of WI-38 cells undergoing SIPS caused by H₂O₂ with Kangen-karyu extract significantly reduced reactive oxygen species (ROS) generation and lipid peroxidation levels. In addition, the intracellular GSH levels, reflecting cellular ROS generation, were reduced by treatment with Kangen-karyu extract. These results suggest that Kangen-karyu attenuated the age-associated increase of cellular oxidative damage. Moreover, Kangen-karyu extract normalized the G₀/G₁ phase arrest and reversed the diminished cell viability resulting from exposure to H₂O₂. Furthermore, the extract prolonged the lifespan of WI-38 cells undergoing SIPS. This study suggests that Kangen-karyu may delay the aging process in cells undergoing SIPS by attenuating oxidative damage.

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We investigated the anti-angiogenic effect of curcumin, curcumin ethylenediamine derivative (curcumin ED) and curcumin ethylenediamine manganese complex (curcumin EDMn) through the inhibition of the formation of tube-like structures by human umbilical vascular endothelial cells (HUVEC). Curcumin, curcumin ED, curcumin EDMn did not show cytotoxicity to HUVEC at concentrations equal and lower than 10 μM. At the concentration of 10 μM, curcumin, curcumin ED and curcumin EDMn inhibited the tube formation by approximately 94%, 40% and 65%, respectively. These results suggest that curcumin ED and curcumin EDMn might be useful as anti-angiogenic drugs in addition to their anti-lipid peroxidase and superoxide dismutase activities as described in our previous studies.

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Nei-Wai-Shang-Bian-Huo-Lun (Naigaisho-benwaku-ron in Japanese) written in the 13 th century is a traditional Chinese medical formulary discussing differentiation on endogenous and exogenous diseases. The endogenous diseases (Nei-Shang in Chinese and Naisho in Japanese) manifested as dyspepsia, anorexia, short breath and fatigue are morbid conditions of deficiency of pi-and wei qi (Hi-I-Ki-Kyo in Japanese), which is correspondent to decline in digestive function. For curing the deficiency of pi- and wei-qi caused by intemperance in eating and drinking, overwork, and excessive emotional changes, the formulary was recommended Bu-Zhong-Yi-Qi-Tang (Hochu-Ekki-To in Japanese), in which 4 drugs (Astragali, Glycyrrhizae and Ginseng Radices, and Atractilodes Rhizome) act as a principle drugs replenishing qi, which means the functions (vital energy) of various organs of the body. The use of two drugs (Cimicifugae and Bupleuri Radices) in the formulation, which is used for morbid condition of muscle and loosening organs as prolapsed uterus, is a noteworthy theory in the formulary. Furthermore, the use of the drugs with sweet in taste and cold in nature used in the formulation Shang-Mai-San (Sho-Myaku-San in Japanese), which is used for syndrome of dry cough with short breath and palpitation to improve the heat syndrome induced by deficiency of yin (In-Kyo in Japanese), is also characteristic of the formulary.

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From studies on the reactivity of Chinese traditional (Kampo) medicines, Rikko-san, Daio-kanzo-to, their six herbal constituents, and other substances with human whole saliva, we discussed here a possibility that the human whole saliva plays an important role in both medical effects and oral hygiene. The polyphenol contents of those were measured and the polyphenol's capabilities of complex formation with either saliva or gelatin were determined. Furthermore, their inhibitory effects on in vitro formation of calcium phosphate precipitates together with synergistic effects on it and chelating ability were investigated. From these data, it was concluded that the reactivity of polyphenols of Chinese traditional (Kampo) medicines with human whole saliva might be associated with medical effects and oral hygiene, e.g. anti-calculus formation.

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