Traditional Chinese medicine (TCM) has received much attention as a source of novel therapeutic agents due to their multiple beneficial effects and absence of toxic and/or side effects. TCM influences changes at multi-system and multi-organ levels. However, there has been virtually no attempt to logically analyze multi-target strategies in TCM. In this review, we have summarized the therapeutic evidence for Kangen-karyu, one of our major interests among TCM agents, from pre-clinical animal experiments related to several human diseases. These pre-clinical experimental results provide scientific evidence that may explain the efficacy of TCM at multi-organ levels and may also help to identify the common mechanism underlying the therapeutic effects against distinct diseases. The beneficial effect of Kangen-karyu on cardiovascular diseases is related to the suppression of platelet aggregation. Kangen-karyu showed beneficial effects on type 1 diabetes and related complications through the suppression of protein expressions related to advanced glycation endproducts and oxidative stress. Also, Kangen-karyu exerts its renoprotective potential mainly through its antioxidant properties during the development of diabetic nephropathy in type 2 diabetes. Kangen-karyu showed neuroprotective effects by attenuating elevation of the blood pressure and the development of cerebral ischemia, and preventing the spatial memory impairment and neuronal death induced by repeated cerebral ischemia by increasing cerebral blood flow. Kangen-karyu counteracts oxidative stress and ameliorates tissue damage possibly associated with aging. Taken together, the therapeutic effects of Kangen-karyu at multi-system and multi-organ levels are closely related to the regulation of blood flow and oxidative stress.

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In our search for novel materials possessing anti-hyperuricemic effects, we examined immature Citrus unshiu fruit. Extracts of immature C. unshiu fruit showed moderate anti-hyperuricemic effects in a hyperuricemic model; the extract reduced increased serum urate level by 36% at 500 mg/kg, p.o. The extract did not show significant xanthine oxidase inhibitory activity, but the metabolite of the main flavanone glycoside in the fruit, hesperetin, showed potent anti-hyperuricemic effects; hesperetin reduced increased serum urate level by 44% at 200 mg/kg, p.o. Furthermore, hesperetin showed dose-dependent xanthine oxidase inhibitory activity of 52% at 200 μM. Thus, the anti-hyperuricemic effects of immature C. unshiu may be attributed to hesperetin, a metabolite of hesperidin via xanthine oxidase inhibition.

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Accumulating evidence obtained from clinical studies as well as animal studies suggests that nerve growth factor (NGF) may play a crucial role in the pathogenic mechanism of atopic dermatitis (AD), involving severe scratching due to itching. Shishihakuhito is a Kampo medicine for AD. In the current study, we for the first time report that shishihakuhito extract has the activity to prevent NGF-induced stimulation of phoshorylation of MEK and ERK which has been demonstrated to mediate neurite outgrowth induced by this neurotrophic factor, and actually inhibit NGF-induced neurite extension in PC12D cells, a cellular model of peripheral sensory neurons. These findings suggest that shishihakuhito might prevent NGF signaling, thereby reducing the induction of severe itching and scratching in AD.

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We evaluated the outcome of 10 patients (age range: 13-62 years; 8 males and 2 females) with acute traumatic muscle injury of lower extremity who were treated with only Kampo medicine keishibukuryogan and no analgesic. The therapeutic response was determined by the influence on daily life and comparing local pain using a visual analogue scale (VAS). For a more objective evaluation of the therapeutic response, magnetic resonance imaging (MRI) findings were also used. The results showed to be markedly effective in 5 cases, effective in 2 cases, and ineffective in 3 cases. In the 7 cases in markedly effective or effective, pain relief was associated with attenuation of MRI signal intensities reflecting edema and hematoma of the injured area. In addition, the therapeutic outcome was analyzed in relation to the MRI findings obtained at first presentation; pain tended to be alleviated more rapidly in cases shown as having muscular contusion on the initial MRI, while pain and MRI high signal intensity areas tended to persist in cases shown as having injury of musculo-tendinous junction. In 2 of the 3 cases in ineffective, the initial MRI had shown rupture of muscle tissue. Keishibukuryogan was effective against traumatic muscle injury of lower extremity and MRI was useful for evaluating responses to the treatment and predicting the therapeutic outcome.

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