Innovation and regulation are sometimes understood to engender conflicting forces, but this is not generally applicable in the medical field. Innovation in medicine should undoubtedly be supported by adequate progress in regulatory sciences for medical care. Over the past several years, the Science Council of Japan has published documents with proposals encouraging development of regulatory sciences in the pharmaceutical and medical fields. These reports suggested future direction of basic research in parallel to that of regulation. Innovative medical technology in fields such as new drug development, novel medical devices, and cell therapy could thus be realized along with development of appropriate regulatory science. Especially, development of regenerative therapy employing iPS cells needs progress in various aspects of regulatory affairs concerning handling and quality control. Recently, evolution has become obvious also with regard to pharmaceutical affairs. Enactment of a new law, “The Law on Securing Quality, Efficacy and Safety of Products including Pharmaceuticals and Medical Devices”, commencement of a new reviewing system in the Pharmaceuticals and Medical Devices Agency (PMDA), and establishment of collaborative research programs between academia and regulatory authorities on new regulations should facilitate true innovation in medical care.

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It has become clear that medical expenses in Japan amounted to 40 trillion yen or more in 2015, and they continue to increase with development of more sophisticated medical treatments. In order to decrease medical outlays a greater focus on preventive medicine appears necessary. Although Kampo medicines are examples with preventive properties, they are already controlled by the national health insurance. Therefore, claims for health foods and/or natural products with particular functions started to be important targets from April 2015. This special issue in response focuses on “Development of functional medicines from natural products”. In the screening field of the editor invited two articles “Construction of a gastric-cell-based assay system and its application in screening for possible inhibitors of octanoylated-ghrelin secretion” and “Screening of natural products for influence on cellular signaling involved in cancer development” submitted by Prof. Kariyazono and collaborators and Prof. Ishibashi, respectively. Three articles “Searching for and functional analysis of natural products with anti-obesity effects”, “Recent scientific evidence for multi-medicinal effects of fruiting bodies of Ganoderma lingzhi” and “Multifunctions of crocin from saffron” were submitted by Prof. Matsuda, Prof. Shimizu and myself, respectively. The authors provide a comprehensive summary of our most recent knowledge on a range of natural products. Moreover, the more than 86 references found at the end of the chapters will make this special issue useful not only for all those working on identification and characterization of natural products but also many scientists contemplating exploration of novel applications.

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Ghrelin, a growth hormone-releasing peptide hormone consisting of 28 amino acid residues, is predominantly produced by endocrine cells of the gastric mucosa. It also has orexigenic potential, and its serine 3 acyl modification with octanoic acid is essential for this activity. Therefore, inhibition of ghrelin octanoylation may prevent obesity. To identify such inhibitors, we attempted to establish a cell-based assay system. We found that human gastric carcinoma AGS cells express substantial levels of mRNA of obligatory factors for posttranslational modification of ghrelin, such as furin (a prohormone convertase responsible for the processing of proghrelin into mature ghrelin) and ghrelin O-acyl transferase (GOAT; the enzyme catalyzing acyl modification of ghrelin). Nevertheless, these cells featured weak expression of ghrelin. Accordingly, we transfected ghrelin cDNA into AGS cells and successfully isolated a cell line (AGS-GHRL8) stably expressing ghrelin. AGS-GHRL8 cells were found to secrete octanoylated ghrelin depending on the concentration of octanoic acid in the culture medium. It has been reported that ingested heptanoic acid, but not butyric acid, is utilized for acyl modification of ghrelin in mice. Consequently, heptanoic acid, but not butyric acid, may suppress production of octanoylated ghrelin by competing with octanoic acid for GOAT-mediated acylation. Therefore, we studied the effects of heptanoic acid and butyric acid on octanoylated-ghrelin secretion by AGS-GHRL8 cells and found that, as expected, heptanoic acid, but not butyric acid, inhibited this process. Thus, we demonstrated potential utility of the AGS-GHRL8 cell line for screening of possible inhibitors of octanoylated-ghrelin production. Next, we examined the effects of fatty acids (such as acetic acid, stearic acid, oleic acid, linoleic acid, and α-linolenic acid)- that are often present in foods or food oils - on octanoylated-ghrelin secretion by AGS-GHRL8 cells. Acetic acid did not suppress octanoylated-ghrelin production, whereas stearic acid, oleic acid, linoleic acid, and α-linolenic acid did (statistically significantly), with the effect of oleic acid being the strongest. Oleic acid also decreased the plasma concentration of octanoylated ghrelin in mice. Thus, oleic acid is a likely inhibitor of octanoylated-ghrelin production, and our assay system is useful for screening compounds with such inhibitory properties. The AGS-GHRL8 cell-based assay system may help to develop functional foods or food ingredients that can exert antiobesity effects via inhibition of octanoylated-ghrelin production.

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During our search for bioactive natural products, we recently examined screening programs targeting biological pathways such as those involving Wnt, Hedghog, TRAIL and bHLH transcriptional factors with various natural resources including microorganisms (myxomycetes and actinomycetes) as well as plants collected from South Asian countries. Here we describe our recent studies of natural product screening focusing on TRAIL and Wnt cancer-related signaling pathways.
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) has emerged as a promising anticancer agent due to its ability to kill cancer cells selectively. However, TRAIL resistance is a major problem and understanding the mechanisms underlying such resistance and developing strategies to overcome it are important for the successful application of TRAIL for cancer therapy. We have identified a number of natural products having synergistic effects on TRAIL-induced apoptosis in cancer cells. Here we describe our recent findings from screening programs targeting bioactive compounds with activity overcoming TRAIL-resistance. Wnt signaling is conserved in various species, and has been implicated in numerous aspects of development, cell biology, and physiology. Wnt signaling may contribute not only to tumorigenesis but also diabetes, schizophrenia, and various other diseases. On the basis of our screening program targeting Wnt signal activity using a cell-based luciferase system assessing TCF/β-catenin transcriptional activity, we have isolated a series of terpenoids and heterocyclic aromatic compounds having effects on the Wnt pathway with different points of action.

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Obesity is increasingly becoming one of the most prevalent health concerns, with the significant rise in mortality and morbidity related to diabetes, hypertension, and coronary heart diseases, for example. Prevention and treatment of such life style-related diseases are important areas for research. In the course of our search for and functional analysis of effective natural products, we have reported many findings for anti-diabetes, anti-obesity, and anti-allergic compounds from medicinal plants and functional foods. In this paper, our studies on anti-obesity medicinal plants and their active principles, such as chakasaponins from the flowers of Camellia sinensis, trans-tiliroside from the seeds of Carina canina, vaticanols from the bark and wood of Cotylelobium melanoxylon, and chrogenic acid derivatives from the leaves of Ilex paraguariensis, are reviewed.

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The objective of this paper is to review recent scientific evidence for multi-functional therapeutic potential of Ganoderma lingzhi (Reishi in Japanese, Ling Zhi in Chinese), a basidiomycete white rot fungus used for medicinal purposes as the “mushroom of immortality” in China, Japan, Korea and other Asian countries for over 2000 years. Since this mushroom is relatively rare in nature, artificial cultivation of fruiting bodies has developed. Recently, pharmacological studies of its active components have attracted great attention across the world. A great deal of work about its medicinal effects has been carried out and it is now clear that medicinal metabolites are mainly polysaccharides such as β-glucans and lanostane-type triterpenoids such as ganoderic acid DM. Research has focused on numerous pharmacological anti-metabolic syndrome, anti-benign prostate hyperplasia, anti-cancer, anti-androgen, anti-aging, immune-stimulating, tubulin-modulating, anti-dementia, and anti-influenza effects. However, the exact molecular mechanisms remain largely unclear and the identification of target-protein of active compounds is still a high priority. Future studies should put emphasis on improvement in methodological quality, and further clinical investigations of effects of this mushroom on different diseases are needed. Important problems and developments in this research area are a particular focus of discussion in this review.

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We have focused on functions of ingredients of saffron and for example have confirmed that crocin inhibits the tumor necrosis factor-α-induced apoptosis of PC-12 cells resulting from rapid increase in cellular ceramide levels and serum/glucose deprivation. Production of ceramide is dependent on activation of neutral sphingomyelinase, rather than on de novo synthesis and oxidative stress decreases the cellular levels of glutathione, which is a potent inhibitor of this enzyme. Crocin treatment resulted in the prevention of neutral sphingomyelinase activation and thus ceramide production. Exploration of crocin's preventive mechanism in relation to oxidative stress-induced cell death revealed glutathione reductase activity. Effects of saffron extract and crocin on improving ethanol-induced impairment of learning behaviors of mice in passive avoidance tasks have been an additional focus of attention. Based on the available results, the agents appear to prevent the inhibitory effects of ethanol on long-term potentiation in the dentate gyrus in vivo. We also have investigated sleep-promoting activity of crocin by monitoring locomotor activity and performing electroencephalography in mice, establishing an increase in the total time of non-rapid eye sleep. Finally, anti-colorectal cancer activity in vitro and in vivo was also investigated.

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The increase in the number of food allergy cases is a serious social problem in developed countries. In Japan, where seafood provides 40 % of animal protein intake, seafood is recognized as one of the major allergenic foods, the other three being egg, milk, and wheat. The morbidity of seafood-allergic patients has reached 10 % among elementary school children and their families, and seven kinds of seafood (shrimp, crab, abalone, squid, salmon, mackerel, and salmon roe) are listed as allergenic foods in Japan's food allergen labeling system.
Seafood contains IgE-reactive proteins, which act as a trigger for immediate hypersensitivity. Parvalbumin and collagen in fish meat, tropomyosin in invertebrates (shellfish/mollusk, prawn, crab, squid and octopus), and β'-component in fish roe were identified as seafood allergens and their structures were clarified. The widely ranged IgE cross-reactivity is a common characteristic of seafood allergens. For example, people suffering from a fish allergy have specific IgE that reacts with more than one fish parvalbumin, and salmon-roe-llergic patients' sera contain specific IgE that react with β'-component of another fish. Additionally, invertebrate tropomyosin, called “pan-allergen,” contains IgE- binding sites with similar amino-acid sequences to each other. Apparently, the information of allergen cross-reactivity contributes to ensuring food safety and preventing excess evasion of seafood materials in dietary instruction for allergic patients; for example, fish roe has no cross-reaction with egg. This review introduces the characteristic of seafood allergens and their allergen-cross reactivity.

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Are colors selected instinctively and sensuously? The answer is that multifaceted and complex factors are actually involved in color selection. It can also be said that sense is directed based on various aspects such as the colors of the landscape in the region where we grew up, culture that we have experienced, likes and tastes, and predetermined rules of colors.
In the fashion business industry, fashion trend colors are semiannually announced by the organization called Intercolor, or the International Study Commission for Color, about two years prior to the actual season. The selection of color trends are in fact pre-planned to some extent. The same holds true for the food industry. The combination of different ingredients (colors) and also of colors of dishes that food is served on is designed according to certain rules, and additionally every effort is always made to make people feel comfortable when eating.
Design is closely related to colors and tends to be regarded as being seemingly ambiguous. Design, however, is not created based solely on our senses alone.
It is thought that we can enjoy more comfortable living by understanding and analyzing color harmony and basic design that are recognized to be favorable by chromatologists in their long-term research, and also by successfully using the combinations of colors. After all design and color significantly contribute to making our life more comfortable.

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Acorns are the nut of the trees in the family Fagaceae, which are widespread in the Temperate Zone of the Northern Hemisphere. The edible portion of the acorn is the cotyledon in the seeds. In the pre-farming period, acorns were an important part of the diet as a staple food for the people in the zone. The general nutritional components of acorns (100 g) except beech on the basis of dry weight are protein (2.3～6.5 g), lipid (0.4～3.8 g), carbohydrate (87.7～93.2 g) and ash (1.4～3.0 g), and the beech is 28.8 g, 44.6 g, 21.9 g and 4.7 g, respectively. The main carbohydrate of acorn is starch. Accordingly, acorns except beech are starchy foodstuffs, and beech is only an oil foodstuff. The starch is contained in the granule in the cotyledon. The granular sizes are 5～30 μm. The content of the apparent amylose is 25.9～28.3 %. The chain length distribution of amylopectin of the acorn starch is low amounts of short chains and high amounts of long chains in comparison to rice and maize starches. Each acorn starch has a different gelatinization temperature by DSC. On the heat of gelatinization, the acorn starches are different from rice and maize starches and similar to potato and sweet potato starches.
Peak viscosities of the acorn starches by RVA are higher than rice and maize starches and similar to sweet potato starch. The saturated fatty acid of acorn lipid accounts for 10～17 % of total fatty acid and the main fatty acid is palmitic acid. The unsaturated fatty acid accounts for 83～90 % and the main fatty acid is oleic acid. Acorn is the best forage food for the production of delicious pork. At present pasturing in acorn forests is still carried out for pig-breeding in the Iberian Peninsula.

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