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Presented at;

The 17-19th Scientific Meeting of the Japanese Society of Anti-Aging Medicine (2-4 June 2017 Tokyo, 25-27 May 2018 Osaka, 14-16 June 2019 Yokohama, Japan), 

The 25-27th Annual Meeting of International Congress on Nutrition and Integrative Medicine (ICNIM 2017-2019)  (8-9 July 2017, 21-22 July 2018, 27-28 July 2019, Sapporo, Japan),

The 31st Annual Meeting of the Japanese Society for Alternative to Animal Experiments (23-25 November 2018 Kumamoto, Japan),

The 66th Annual Meeting of the Japanese Society for Food Science and Technology (28-31 August 2019, Sapporo, Japan),

6th International Electronic Conference on Medicinal Chemistry(1-31 November 2020, Online), 

2nd Edition of Food Science and Technology Virtual (V-Food 2022) (15-16 April 2022, Online)


To be presented at;

The 3rd International Electronic Conference on Foods: Food, Microbiome, and Health (Foods 2022)  (1-15 October 2022, Online)



Development motivation


After my father died by cancer, I thouhgt  I could do something for cancer patients, so I developed a system to select the best anti-cancer drug for patients within an hour. However, this system is not useful for people who are worried about cancer recurrence after a complete cure or who cannot use anti-cancer drugs because of physical problems.

Therefore, we searched for food products that had a potentital to be effective and that can be used safely by those people. As a result, we reached at the No. 1 anti-cancer material in U.S. sales, grape seed extract (GSE) [1].



What is grape seed extract (GSE)?


Grapes have been grown on the Caspian Sea coast and in the Caucasus since 3,000 BC and have a long history of eating habit [2]. GSE is attracting attention because wine polyphenols are derived from fermented grape seeds [3]. GSE, a polyphenol extracted from grape seeds, has been reported to have anti-cancer effects and to reduce side effects of anti-cancer drugs and radiation therapy [4].



How to maximize the potential of grape seeds?


Grape seed is a baby of grape. In order for seeds to sprout and grow, a lot of nutrients as well as life itself reside. I wanted to maximize the potential of seeds. Unfortunately, even if you simply eat it, the skin of the seed is hard, and even if you break it up into small pieces, it cannot be digested by humans.
Why don’t you just take out the contents? In fact, grape seeds are in a dormant state in that growth activity is temporarily suspended until conditions are favorable for germination, with minimal metabolism and energy consumption [5]. They fall to the ground in autumn and pass through winter, and in spring they wake up and sprout. Therefore, ingredients of grape seeds are hard to dissolve in water so that they do not flow out even if it rains. However, once seeds wake up, they can change the ingredients into a form that dissolves easily in water [6]. It is the same in humans, and those that are difficult to dissolve in water need to be changed to water soluble substances in the body, that is inefficient and can cause toxicity [7].
Extractives and extracts are not bad, but I wanted to take them as food if possible.



Which grape species should I choose?


Only the seeds of Kyoho grapes grown in Tanushimaru, Kurume City, Fukuoka Prefecture, Japan, the birthplace of Kyoho grapes, were purchased from cooperative farmers and used. Kyoho grape is tetraploid cross between European and American spices, and has rather big seeds with ca. 5mm diameter x 8mm length in a dry state. Therefore, safe and delicious fruits are carefully selected for seeds (Fig. 1).



Fig. 1  Kyoho grape garden of a cooperative farmer




How to awaken the Kyoho grape seed?


The cost increases when it takes several months to wake the seed up, and more importantly, the ingredients become uneven if they do not wake up at the same time … Therefore, we developed a method of waking up the grape seeds synchronizedly in 5 days (dormancy breaking) using our proprietary Grandir recipe™, and succeeded in picking up the vitality of the baby itself. At this time, we removed the seed skin and separated the digestible and absorbable parts (Fig. 2).

Fig. 2  Experimental scheme



Anti-cancer effect of rapid and synchronized dormancy broken Kyoho grape seed endosperm (RSDB-GSE) against human 


After treating RSDB-GSE with a human digestion and absorption model, we evaluated the direct killing effect against human pancreatic cancer cells using our proprietary HP-SPR-3D system [8] (Fig. 2). As a result, the effect on pancreatic cancer was extremely high that oral intake exceeded the injectable anti-cancer drugs of doxorubicin, paclitaxel, and gemcitabine (Fig. 3). The effect was also confirmed for breast cancer and liver cancer (Figs. 4 and 5).

In addition, the side effects of RSDB-GSE are low because it caused cell dysfunction rather than inflammation, that is the toxicity of common anti-cancer drugs [9]. Even if you take too much, you will have diarrhea. Foods with long dietary habits are found to be safe.
However, it was also found that the side effects of inflammation were high in those that did not break dormancy in order to prevent them from being eaten by animals.


Fig. 3  Comparison of anti-pancreatic cancer effect of rapid and synchronized dormancy broken Kyoho grape seed endpsperm (RSDB-GSE) with commercially available drugs against human




Fig. 4  Anti-breast cancer effect of rapid and synchronized dormancy broken Kyoho grape seed endpsperm (RSDB-GSE) against human




Fig. 5  Anti-liver cancer effect of rapid and synchronized dormancy broken Kyoho grape seed endpsperm (RSDB-GSE) against human




Pro-immune effect of rapid and syncronized dormancy broken Kyoho grape seed endosperm (RSDB-GSE) against human


Anti-cancer therapy also involves the activation of the immune system. In particular, the activation of natural killer (NK) cells, that are immune cells, is important not only for cancer treatment but also for preventing cancer recurrence and maintaining health [10]. Therefore, we investigated the activation of NK cells by RSDB-GSE. As a result, a very high level of activation was observed at a concentration equivalent to the direct killing effect (Fig. 6). Therefore, two types of effects can be obtained simultaneously: direct killing and indirect killing (Fig. 7). A synergetic effect is expected.


Fig. 6  Pro-immune effect of rapid and synchronized dormancy broken Kyoho grape seed endosperm (RSDB-GSE) against human




Fig. 7  Doublet anti-cancer effects of rapid and synchronized domancy broken Kyoho grape seed endosperm (RSDB-GSE)




Anti-cancer effect of rapid and synchronized dormancy broken Kyoho grape seed endosperm (RSDB-GSE) against canine


Using breast cancer cells, that are said to be the second most common occurrence in dogs [11], we evaluated the direct killing effect of the cancer cells by three-dimensional cell culture after treatment with a human digestion and absorption model that is almost same to dog one. As a result, it was confirmed that the drug efficacy against canine breast cancer was very high as in humans (Fig. 8). Also, the side effects are low because it caused the cell to stop functioning instead of inflammation, that is the toxicity of common anti-cancer drugs. Even if your lovely dog takes too much, the dog will have diarrhea.
On the other hand, the immunity of dogs is similar to that of humans, so the doublet effects of direct action and indirect action by immunity are expected.

Fig. 8  Anti-breast cancer effect of rapid and synchronized dormancy broken Kyoho grape seed endosperm (RSDB-GSE) against canine




Rapid and synchronized dormancy broken Kyoho grape seed endosperm (RSDB-GSE)


We have succeeded in developing safe and highly functional food products without extraction or concentration of ingredients. We lose youthfulness and healthiness that declines with age. The vitality of Kyoho grape babies works on our body’s natural strength to help keeping us in good condition. The product has been developed as a health food and is now being developed as a pharmaceutical product. Also for your precious dog!




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[2] Myles, S., Boyko, A. R., Owens, C. L., Brown, P. J., Grassi, F., Aradhya, M. K., Prins, B., Reynolds, A., Chia, J.-M., Ware, D., Bustamante, C. D., & Bustamante, C. D. (2011). Genetic structure and domestication history of the grape. Proceedings of the National Academy of Sciences108(9), 3530-3535.

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[4] Sharma, G., Tyagi, A. K., Singh, R. P., Chan, D. C., & Agarwal, R. (2004). Synergistic anti-cancer effects of grape seed extract and conventional cytotoxic agent doxorubicin against human breast carcinoma cells. Breast cancer research and treatment85(1), 1-12.

[5] Finch‐Savage, W. E., & Leubner‐Metzger, G. (2006). Seed dormancy and the control of germination. New phytologist171(3), 501-523.

[6] Kigel, J. (Ed.). (1995). Seed development and germination (Vol. 41). CRC press.

[7] Gibson, G. G., & Skett, P. (2013). Introduction to drug metabolism. Springer.

[8] Johzuka, J., Ona, T., & Nomura, M. (2018). One hour in vivo-like phenotypic screening system for anti-cancer drugs using a high precision surface Plasmon resonance device. Analytical Sciences34(10), 1189-1194.

[9] Nurgali, K., Jagoe, R. T., & Abalo, R. (2018). Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae?. Frontiers in pharmacology9, 245.

[10] Capuano, C., Pighi, C., Battella, S., Santoni, A., Palmieri, G., & Galandrini, R. (2019). Memory NK Cell Features Exploitable in Anticancer Immunotherapy. Journal of immunology research2019, 8795673.

[11] Nikzad, R., Angelo, L. S., Aviles-Padilla, K., Le, D. T., Singh, V. K., Bimler, L., Vukmanovic-Stejic, M., Vendrame, E., Ranganath, T., Simpson, L., Haigwood, N. L., Blish, C. A., Akbar, A. N., & Paust, S. (2019). Human natural killer cells mediate adaptive immunity to viral antigens. Science immunology4(35), eaat8116.

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