Research and Development

Research Papers

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foodTrehalose itself plays a critical role on lipid metabolism: Trehalose increases jejunum cytoplasmic lipid droplets which negatively correlated with mesenteric adipocyte size in both HFD-fed trehalase KO and WT mice

Nutrition & Metabolism(2020)17:22

Chikako Arai, Aki Suyama, Shigeyuki Arai,Norie Arai, Chiyo Yoshizane, Satomi Koya-Miyata, Akiko Mizote, Shin Endo, Toshio Ariyasu, Hitoshi Mitsuzumi, Shimpei Ushio

Trehalose affected lipid metabolism with or without trehalase. Drinking trehalose in HFD-loaded trehalase KO mice and WT mice increased fat droplets in the jejunal epithelium and exfoliated into the intestinal lumen, thereby reducing chylomicron, in which lipids were excreted in the feces and transferred to the periphery. There were negative correlations between jejunal epithelial lipid droplet (CLDs) content and mesenteric adipocyte size, and these phenomena suggest the metabolic syndrome-suppressing effect of trehalose.

otherMolecular Inverse-Design Platform for Material Industries

KDD '20: Proceedings of the 26th ACM SIGKDD International Conference on Knowledge Discovery & Data MiningAugust 2020 Pages 2961-2969.

Seiji Takeda1*, Toshiyuki Hama*1, Hsiang-Han Hsu*1,Victoria A. Piunova*2, Dmitry Zubarev*2, Daniel P. Sanders*2, Jed W. Pitera*2,Makoto Kogoh*3, Takumi Hongo*3, Yenwei Cheng*3, Wolf Bocanett*3, Hideaki Nakashika*3,Akihiro Fujita, Yuta Tsuchiya, Katsuhiko Hino, Kentaro Yano,Shuichi Hirose*4, Hiroki Toda*4, Yasumitsu Orii*4, Daiju Nakano*1

*1 IBM Research - Tokyo
*2 IBM Almaden Research Center
*3 IBM Garage, Tokyo Laboratory
*4 NAGASE Co., Ltd.

The discovery of new materials is essential for the sustainable development of industry. However, it is realistically difficult for human professionals to examine all possibilities for new materials. In this paper, we constructed a molecular inverse design platform using artificial intelligence as a web service. In this platform, it becomes possible to output the chemical structure with the desired property to the artificial intelligence by allowing the relationship between the structure and the property of the compound to be learned to the artificial intelligence. This time, we developed a system especially for dyes and carbohydrates to obtain the target structure. The development process and results of the system are reported in this paper.

otherA cyclic tetrasaccharide, cycloisomaltotetraose, was enzymatically produced from dextran and its crystal structure was determined

Carbohydrate ResearchVolume 496, October 2020, 108104

Akihiro Fujita, Akira Kawashima, Hiromi Ota*, Hikaru Watanabe, Tetsuya Mori,Tomoyuki Nishimoto, Hajime Aga, Shimpei Ushio

* Okayama University

Two strains isolated from soils, Agreia sp. D1110 and Microbacterium trichocethenolyticum D2006, were revealed to enzymatically produce a novel cyclic tetrasaccharide cycloisomaltotetraose (CI4). Single crystals of CI4 were also obtained to clarify the stereostructure of CI4. CI4 in CI4 single crystals revealed that the two glucosyl residues each exhibited a unique 3D structure facing each other, which was greatly different from the known cyclic tetrasaccharide. This is the first report on CI4 molecules and their unique crystallographic structure.

healthcareTrehalose alleviates oxidative stress-mediated liver injury and Mallor-Denk body formation via activating autophagy in mice

Medical Molecular Morphology, 2020 Jun 25. doi: 10.1007/s00795-020-00258-2.

Yuichi Honma*, Miyuki Sato-Morita*, Yuka Katsuki*, Hitomi Mihara*, Ryoko Baba*, Katsuhiko Hino, Akira Kawashima, Toshio Ariyasu, Masaru Harada*

*Third Department of Internal Medicine, School of Medicine, University of Occupational and Environmental Health

We suggest that trehalose can be a therapeutic agent for oxidative stress-related liver diseases via activation of autophagy.

foodDaily consumption of one teaspoon of trehalose can help maintain glucose homeostasis: a double-blind, randomized controlled trial conducted in healthy volunteers

Nutrition Journal (2020) 19:68

Chiyo Yoshizane, Akiko Mizote, Chikako Arai, Norie Arai, Rieko Ogawa, Shin Endo, Hitoshi Mitsuzumi, Shimpei Ushio

One teaspoon (3.3g) of trehalose per day was consumed for 12 weeks, and a glucose tolerance test was performed before and after ingestion to examine the ease of returning postprandial blood glucose levels. As the result, the blood glucose level after meals was easily returned by the trehalose intake as well as the previously reported trehalose intake of 10g. Daily intake of one teaspoon of trehalose is easily incorporated into a meal, and may therefore contribute to the prevention of pathologies that are predisposed to by postprandial hyperglycemia.

otherMolecular analysis of cyclic α-maltosyl-(1→6)-maltose binding protein in the bacterialmetabolic pathway

PLoS ONE 15(11): e0241912 (2020)

Masaki Kohno*1, Takatoshi Arakawa*1,2, Naoki Sunagawa*3, Tetsuya Mori, Kiyohiko Igarashi*3,4, Tomoyuki Nishimoto, Shinya Fushinobu*1,2

*1 Department of Biotechnology, The University of Tokyo, Tokyo, Japan,
*2 Collaborative Research Institute for Innovative Microbiology, The University
of Tokyo, Tokyo, Japan
*3 Department of Biomaterial Sciences, The University of Tokyo, Tokyo, Japan
*4 VTT Technical Research Centre of Finland Ltd., Espoo, Finland

Cyclic α-maltosyl-(1→6)-maltose (CMM) is a cyclic glucotetrasaccharide with alternating α-1,4 and α-1,6 linkages. Here, we report functional and structural analyses on CMM-binding protein (CMMBP), which is a substrate-binding protein (SBP) of an ABC importer system of the bacteria Arthrobacter globiformis. Isothermal titration calorimetry analysis revealed that CMMBP specifically bound to CMM with a Kd value of 9.6 nM. The crystal structure of CMMBP was determined at a resolution of 1.47 Å, and a panose molecule was bound in a cleft between two domains. To delineate its structural features, the crystal structure of CMMBP was compared with other SBPs specific for carbohydrates, such as cyclic α-nigerosyl-(1→6)-nigerose and cyclodextrins. These results indicate that A. globiformis has a unique metabolic pathway specialized for CMM.

foodEffects of Glucosyl Hesperidin on Skin Blood Flow and Temperature: A Randomized, Double-blind, Placebo-controlled, Crossover Study

Medical Consultation & New Remedies 57(2), 129-134 (2020)

Naoki Morishita, Saori Ogihara, Shin Endo, Hitoshi Mitsuzumi, Shimpei Ushio

Twenty-four healthy adult men and women took a single dose of 100 mg of glucosyl hesperidin and examined blood flow and the temperature of the skin after cold water loading. The results showed that intake of 100 mg of glycosylated hesperidin, as well as 340 mg previously reported, promoted the recovery of blood flow and the temperature of the skin after cold water loading.

foodOral intake of α-glucosyl-hesperidin ameliorates selenite-induced cataract formation


Yosuke Nakazawa*1, Miki Aoki*1, Sho Ishiwa*1, Naoki Morishita, Shin Endo, Noriaki Nagai*2, Naoki Yamamoto*3, Megumi Funakoshi-Tago*1, Hiroomi Tamura*1

*1 Department of Hygienic Chemistry, Faculty of Pharmacy, Keio University
*2 Department of Advanced Design for Pharmaceuticals, Faculty of Pharmacy, Kindai University
*3 Regenerative Medicine Support Promotion Facility, Center for Research Promotion and Support, Fujita Health University

The present study investigated the anti-cataract effects of α-glucosyl hesperidin in vivo and in vitro using a selenite-induced cataract model. Results show that oral consumption of α-glucosyl hesperidin could delay the onset of selenite-induced cataract, at least in part by modulating the selenite-induced cell death in lens epithelial cells.

foodInhibitory Effect of Isomaltodextrin Intake on Increase in Postprandial Blood Triglycerides―A Randomized, Placebo-controlled, Double-blind, Crossover Study―


Yuki Ishida, Tsuyoshi Sadakiyo, Shin Endo, Hitoshi Mitsuzumi, Shimpei Ushio, Nobuhiko Shioya*1, Yoshitaka Iwama*2

*1 KSO Corporation
*2 Nihonbashi Cardiology Clinic

We examined the inhibitory effect of IMD on postprandial triglycerides (TG) elevation in the subjects with high-normal to slightly-high fasting TG levels. The results showed that AUC of TG and Remnant-like Lipoprotein particle cholesterol (RLP-C) after intake of the high-fat diet with IMD was significantly lower than the placebo. Similar results were seen in a sub-group analysis of subjects with normal fasting TG levels.

foodSex-Specific Differences in the Gut Microbiome in Response to Dietary Fiber Supplementation in IL-10-Deficient Mice

Nutrients, 12: 2088; doi: 10.3390/nu12072088 (2020).

Zhengxiao Zhang*1, 2, Jae Eun Hyun*1, 2, Aducio Thiesen*1, Heekuk Park*3, Naomi Hotte*1, 2, Hikaru Watanabe, Takanobu Higashiyama, Karen L Madsen*1, 2

*1 Department of Medicine, University of Alberta
*2 The Centre of Excellence for Gastrointestinal Inflammation and Immunity Research (CEGIIR), University of Alberta
*3 Department of Medicine, Columbia University

This study examined whether the effects of isomaltodextrin on gut microbiota and inflammatory bowel disease were dependent on dose or host sex, using an Interleukin (IL)-10 deficient murine colitis model. The results show that isomaltodextrin altered the gut microbial composition linking specific immune-regulatory cytokine responses, while the interactions among fiber, microbiota and immune response were dose dependent and largely sex specific. The results further indicate that interactions between environmental and host factors can affect microbiome manipulation in the host.

foodInfluence of Trehalose Mouth Rinse on Anaerobic and Aerobic Exercise Performance

Natural Product Communications 15(11): 1-6 (2020)

Yoshio Suzuki*1, 2, Kotaro Sato*2, Norie Arai, Shin Endo

*1 Juntendo University, Graduate School of Health and Sports Science
*2 Juntendo University, Faculty of Health and Sports Science

Pre-exercise trehalose ingestion enhances exercise performance within 30 minutes. To examine whether the enhanced effect was due to a mouth rinse effect, ten healthy male collegiate distance runners performed an exercise assessment composed of 6-second peak power and endurance tests. Before each test, they rinsed their mouths with either trehalose (6% w/v), maltose (6% w/v) or acesulfame potassium (0.04 mg/mL) for 5 seconds. Trehalose induced the highest mean power output in peak power tests. In the endurance test, trehalose consistently showed higher mean power output than maltose.
Trehalose activates taste receptors T1R1-T1R3, T1R3-T1R3 homodimer, and T1R2-T1R3, whereas sucrose activates only T1R2-T1R3. Therefore, a difference in mouth rinse effect might be due to a specific receptor in the oral cavity that recognizes differences between trehalose and maltose.

foodCyclic nigerosylnigerose ameliorates DSS-induced colitis with restoration of goblet cell number and increase in IgA reactivity against gut microbiota in mice

Bioscience of Microbiota, Food and Health, 39(3), 188-196 (2020)

Takeshi Tsuruta*, Emiko Katsumata*, Akiko Mizote, Hou Jian Jian*, Teresia Aluoch Muhomah*, Naoki Nishino*

*Laboratory of Animal Nutrition, Graduate School of Environmental and Life Science, Okayama University

To investigate the effect of administration of CNN to promote IgA secretion on gut inflammation, experimental colitis was induced with dextran sulfate sodium (DSS) in Balb/c mice after 6 weeks of CNN pre-feeding. CNN might preserve goblet cells in the colon and promote IgA coating of gut microbiota, which synergistically ameliorate gut inflammation in mice with DSS-induced colitis.

foodIsomaltodextrin strengthens model starch gels and moderately promotes starch retrogradation

International Journal of Food Science and Technology, doi:10.1111/ijfs.14782 (2020)

Fang Fang*1, Anna M.R. Hayes*1, Hikaru Watanabe, Takanobu Higashiyama, Osvaldo H. Campanella*2 Bruce R. Hamaker*1

*1 Department of Food Science, Whistler Center for Carbohydrate Research, Purdue University
*2 Department of Food Science and Technology, The Ohio State University

In this study, the impact of Isomaltodextrin (IMD) on the viscoelasticity and microstructure of starch gels and starch retrogradation were investigated. IMD solutions displayed typical Newtonian behaviour. When maintained at relative humidity of 95%, IMD absorbed 40% water of its original weight. The addition of IMD to normal corn starch increased strength of gels and resulted in a denser and smaller pore structure, but there were no changes in elasticity. Upon storage for 7 days, addition of IMD at high concentration (starch: IMD = 2:1) significantly increased the degree of starch retrogradation.

foodLactotrehalose, an Analog of Trehalose, Increases Energy Metabolism Without Promoting Clostridioides difficile Infectionin Mice

Gastroenterology, 158:1402-1416 (2020)

Yiming Zhang*1, Nurmohammad Shaikh*1, Jeremie L. Ferey*2, Umesh D. Wankhade*3, Sree V. Chintapalli*3, Cassandra B. Higgins*1, Jan R. Crowley*4, Monique R. Heitmeier*1,Alicyn I. Stothard*5, Belgacem Mihi*1, Misty Good*1, Takanobu Higashiyama, Benjamin M. Swarts*5, Paul W. Hruz*1, Kartik Shankar*3, Phillip I. Tarr*1,6, Brian J. DeBosch*1,7

*1 Department of Pediatrics, Washington University School of Medicine
*2 Department of Obstetrics and Gynecology, Washington University School of Medicine
*3 Department of Pediatrics, University of Arkansas
Medical School
*4 Department of Medicine, Washington University School of Medicine
*5 Department of Chemistry and Biochemistry, Central Michigan University
*6 Department of Molecular Microbiology, Washington University School of Medicine
*7 Department of Cell Biology and Physiology, Washington University School of Medicine

Lactotrehalose is a trehalaseresistant analogue that increases metabolic parameters, compared with trehalose, without increasing the abundance or virulence of C. difficile strain CD027. Trehalase-resistant trehalose analogues might be developed as next-generation fastingmimetics for the treatment of diabetes and nonalcoholic fatty liver disease.

foodMaltosyltrehalose Syrup: Bacterial reverse mutation test, and 90-day feeding and 90-day repeated oral dose toxicity studies in rats

Fundamental Toxicological Sciences 7(3), 141-152 (2020)

Shuji Matsumoto, Takaharu Hashimoto, Chie Ushio, Keisuke Namekawa, Alan B. Richards*

*Vanguard Regulatory Services, Inc.

This paper presents results of standardized toxicity studies of Maltosyltrehalose syrup (TG4 syrup), including an in vitro bacterial mutagenicity test, a 90-day oral feeding study in rats, and a 90-day oral toxicity (gavage) study in rats. Taken together these data showed that TG4 syrup was safe for use in these studies, suggesting it is safe for consumption by humans.

feedEffect of trehalose supplementation on growth performance and intestinal morphology in broiler chickens

Veterinary and Animal Science 10 (2020) 100142

Yuwares Ruangpanit*1, Koichi Matsushita*2, Kazuhisa Mukai, Motoi Kikusato*3

*1 Animal Science Department, Kasetsart University
*2 Yamanashi Prefectural Livestock Dairy Technology Center
*3 Animal Nutrition, Life Sciences, Graduate School of Agricultural Science, Tohoku University

This study was conducted to evaluate the growth-promoting effect of Tre supplementation in broiler chickens.
Tre treatment increased villus height (VH)/crypt depth (CD) ratio in jejunum and ileum. Tre-0.5% group showed significantly higher BW gain and lower FCR. From these results, we suggest that Tre feeding can be beneficial for intestinal morphology and growth performance
in broiler chickens.

healthcareInflammatory M1-like macrophages polarized by NK-4 undergo enhanced phenotypic switching to an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells

Journal of Inflammation, in press

Keizo Kohno, Satomi Koya-Miyata, Akira Harashima, Takahiko Tsukuda, Masataka Katakami, Toshio Ariyasu, Shimpei Ushio and Kanso Iwaki

We demonstrated that NK-4 drove macrophage polarization toward an inflammatory M1-like phenotype with enhanced phagocytic activity, suggesting that NK-4 potentiates the first line of host defense against invaded pathogens during the inflammatory phase of wound healing. Furthermore, we showed that NK-4-induced M1-like macrophages undergo elevated phenotypic switching toward an anti-inflammatory M2-like phenotype upon co-culture with apoptotic cells. Our results suggest that NK-4 may provide a promising strategy for the resolution of chronic wounds.


foodContinuous intake of Trehalose induces white adipose tissue Browning and Enhances energy metabolism

Nutrition & Metabolism 16:45(2019)

Chikako Arai, Norie Arai, Chiyo Yosizane, Satomi Miyata, Akiko Mizote, Shin Endo, Toshio Ariyasu, Hitoshi Mitsuzumi, Shimpei Ushio

Continuous ingestion of 0.3%Tre-water for 16 weeks in normal chow-fed and C57BL/6J mice increased beige cells in white adipose tissue, increased rectal temperature, and occasional lower blood glucose levels. There was a negative correlation between white adipocyte area and beige cell rate. Beige cell increase was also corroborated by an increase in beige-related genes. By increasing beige cells and enhancing energy metabolism, the hypertrophy of the white adipocyte was suppressed.

foodTrehalose attenuates development of nonalcoholic steatohepatitis associated with type 2 diabetes in TSOD mouse

Journal of Functional Foods 56, 303-311 (2019)

Kazutoshi Murotomi*, Shigeyuki Arai, Aki Suyama, Akira Harashima, Yoshihiro Nakajima*

* Health Research Institute, National Institute of Advanced Industrial Science and Technology

Trehalose markedly improved glucose tolerance and NASH lesions in non-alcoholic steatohepatitis (NASH)-modelled TSOD mice. Trehalose inhibited the progression from type 2 diabetes mellitus to NASH by suppressing fatty accumulate and abnormal iron absorption in mesentery and liver related to insulin resistance.

healthcareAdenosine N1-Oxide Exerts Anti-inflammatory Effects through the PI3K/Akt/GSK-3β Signaling Pathway and Promotes Osteogenic and Adipocyte Differentiation

Biol. Pharm. Bull. 42(6), 968-976 (2019)

Ohashi E, Kohno K, Arai N, Harashima A, Ariyasu T, Ushio S

ANO may serve as a therapeutic candidate for inflammatory diseases. The promotion of osteogenesis and adipocyte differentiation by ANO suggests its potential application in regenerative medicine.

foodAttenuating Effect of Isomaltodextrin Contained in Bread on Postprandial Plasma Glucose Levels in Healthy Humans:A Randomized, Placebo-controlled, Double-blind Crossover Study

Medical Consultation & New Remedies 56(5), 358-364 (2019)

Takeo Sakurai, Yuki Ishida, Shin-ichiro Inoue, Mayumi Kurose, Yukinobu Uchida, Nariaki Yoshida, Tsuyoshi Sadakiyo, Hikaru Watanabe, Hitoshi Mitsuzumi, Shimpei Ushio, Junichi Hiramatsu*

* Health Research Institute, National Institute of Advanced Industrial Science and Technology

Overnight-fasted subjects consumed bread (containing 2.93 g IMD or not containing IMD) with breakfast, and blood glucose levels were determined over time from immediately before to 120 minutes after meal intake. A stratified analysis of subjects with a tendency for increased postprandial blood glucose levels showed a significant higher attenuating effect of IMD intake on blood glucose elevation compared with non-IMD intake in terms of blood glucose levels over time and area under the curve.

foodEffects of a Single Ingestion of Trehalose during Prolonged Exercise

Sports 2019, 7, 100; doi:10.3390/sports7050100

Tsuyoshi Wadazumi*1, Kanji Watanabe*2, Hitoshi Watanabe*3, Hisayo Yokoyama*3, Nobuko Hongu*4, Norie Arai

*1 Kansai University,
*2 Mukogawa Womes’s University
*3 Osaka City University
*4 University of Arizona

In the prolonged exercise test, the effect of trehalose single ingestion on exercise performance and energy utilization was investigated, and the results showed that it was effective in improving the performance at the later stages of exercise through effective utilization of glucose and lipids.

foodTherapeutic effects of isomaltodextrin in a BALB/c mouse model of egg allergy

Journal of Functional Foods 55, 305-311 (2019)

Yoshinori Mine*1, Yan Jin*1, Hua Zhang*2, Kaustav Majumder*1, Yuhan Zeng*1, Takeo Sakurai, Yoshifumi Taniguchi, Ryodai Takagaki, Hikaru Watanabe, Hitoshi Mitsuzumi

*1 Department of Food Science, University of Guelph
*2 Guelph Food Research Centre, Agriculture and Agri-Food Canada

BALB/c mice were sensitized to OVAs followed by administration of drinking water containing different doses of isomaltodextrin. As a result, the administration of isomaltodextrin remarkably alleviated the clinical symptom, and the histamine concentration in the serum was lowered. Also, the administration of isomaltodextrin did not affect the serum OVA-specific IgE concentration, but reduced the total IgE value. In addition, in the isomaltodextrin intervention group, the difference of the immune response was observed by the lowering of IL-4 production. This study suggests that oral administration of isomaltodextrin effectively attenuates the OVA-induced allergic immune response in mice.

foodInhibitory effect of isomaltodextrin on tyrosine metabolite production in rat gut microbiota

Bioscience, Biotechnology, and Biochemistry Published online, 84(4),824-831(2019)

Ryodai Takagaki, Chiyo Yoshizane, Yuki Ishida, Takeo Sakurai, Yoshifumi Taniguchi, Hikaru Watanabe, Hitoshi Mitsuzumi, Shimpei Ushio, Hidetoshi Morita*

*Graduate School of Environmental and Life Science, Okayama University

The effects of isomaltodextrin-treated rats on the production of putrefactive products by intestinal bacteria were investigated in a tyrosine administration study. Significant increases in phenolic and p-cresol concentrations were observed when tyrosine alone was administered, but not in rats co-treated with tyrosine and isomaltodextrin. This mechanism could be attributed to isomaltodextrin altering the intestinal microbiota to reduce the metabolic capacity of tyrosine and inhibit the production of phenolic or p-cresol.

foodProphylactic effects of isomaltodextrin in a Balb/c mouse model of egg allergy.

NPJ Science of Food 3.23(2019)

Mine Y*1, Jin Y*1,2, Zhang H*1, Rupa P*1, Majumder K*1,3, Sakurai T, Taniguchi Y, Takagaki R, Watanabe H, Mitsuzumi H

*1 Department of Food Science, University of Guelph
*2 Present Address: College of Food Engineering and Biotechnology, Tianjin University of Science and Technology
*3 Present Address: Department of Food Science and Technology, University of Nebraska-Lincoln

Balb/c mice were pre-treated with various doses of isomaltodextrin (1.0, 2.5, and 5.0%w/v) in drinking water for 6 weeks and subsequently sensitized with ovalbumin along with continuous administration of isomaltodextrin to assess the clinical signs of allergy. The frequency of clinical signs did not change significantly by isomaltodextrin administration, but it became a decreasing trend overall. Also, an effect on IR bias was observed with isomaltodextrin. This study revealed that isomaltodextrin is a useful prophylactic candidate to alter allergic IR bias in mice and is an immunostimulatory agent to reduce egg-induced allergic reactions.

foodAnti-Inflammatory Activity of Isomaltodextrin in a C57BL/6NCrl Mouse Model with Lipopolysaccharide-Induced Low-Grade Chronic Inflammation.

Nutrients 11(11) E2791(2019)

Hann M*, Zeng Y*, Zong L*, Sakurai T, Taniguchi Y, Takagaki R, Watanabe H, Mitsuzumi H, Mine Y*

*Department of Food Science, University of Guelph

The anti-inflammatory activity of isomaltodextrin and its mechanism were investigated using a C57BL / 6NCrl mouse model with potential risks of lipopolysaccharide (LPS) -induced systemic low-level chronic inflammation and pro-inflammatory metabolic disorders. The results showed that isomaltodextrin had an anti-inflammatory effect and a beneficial function to prevent systemic low-level chronic inflammation, providing evidence to alleviate the risk of developing insulin resistance and related metabolic diseases.

foodSafety assessment of isomaltodextrin-producing enzymes from Paenibacillus alginolyticus

Fundamental Toxicological Sciences6(9), 341-357(2019)

Tsuyoshi Sadakiyo, Hikaru Watanabe, Hitoshi Mitsuzumi, Shimpei Ushio, Mai Sugi*1, Masakatsu Natsume*2

*1 Toxicology Laboratory for Small Animals, BioSafety Research Center Inc.
*2 Genotoxicology Laboratory, BioSafety Research Center Inc.

The safety assessment of isomaltodextrin-producing enzymes (PP-enzymes) composed of two types from Paenibacillus alginolyticus was carried out, and it seemed that there was no problem in the safety as enzymes for food material production.

otherAn Information Extraction and Knowledge Graph Platform for Accelerating Biochemical Discoveries

In Proceedings of KDD 2019: Workshop on Applied Data Science for Healthcare (KDD 2019 Workshop). ACM, New York, NY, USA, 4 pages.

Matteo Manica*1, Christoph Auer*1, Valery Weber*1, Federico Zipoli*1, Michele Dolfi*1, Peter Staar*1, Teodoro Laino*1, Costas Bekas*1, Akihiro Fujita, Hiroki Toda*2, Shuichi Hirose*2, Yasumitsu Orii*2

*1 IBM Zurich

In human exploration, there are discoveries that are unnoticed due to the preconceptions of the researchers and the limited amount of information that can be processed. In this paper, we have created a knowledge graph on biochemistry by extracting information from articles and public databases in the field. It is expected that this knowledge graph will lead to discoveries that have not been noticed by humans. It is also expected to significantly reduce the search time.

foodGlucosyl hesperidin: safety studies

Fundamental Toxicological Sciences 6(8), 299-317 (2019)

Shuji Matsumoto, Takaharu Hashimoto, Chie Ushio, Keisuke Namekawa, Alan Blake Richards*

*Vanguard Regulatory Services, Inc., USA

This paper presents results of OECD-compliant toxicity studies with glucosyl hesperidin, including 4-week and 13-week sub-chronic toxicity, and teratogenicity studies in rats, and chromosomal aberration and mouse micronucleus formation tests. The results of these OECD-compliant studies support the safe use of glucosyl hesperidin as a food and beverage ingredient.

foodEffect of Isomaltodextrin Intake on the Skin Condition and QOL of Healthy Subjects: A Randomized, Double-blind, Parallel-group, Placebo-controlled Study with Intake for 8 Consecutive Weeks

Medical Consultation & New Remedies 56(12), 907-916 (2019)

Yuki Ishida, Tsuyoshi Sasakiyo, Hikaru Watanabe, Hitoshi Mitsuzumi, Shimpei Ushio, Shuji Nakada*

*Medical Corporation Bokushinkai CLINITEXE Clinic

Healthy men and women with awareness of dry skin symptoms and a tendency toward constipation constipation consumed IMD for 8 weeks. The results showed that IMD had an improvement in skin condition with evaluation by a dermatologist. Furthermore, in those who had a relatively high serum phenol concentration, which is an indicator of the composition of the intestinal environment, the serum phenol concentration was significantly lower after intake of IMD versus placebo, and a significantly higher moisture content of the skin on the foot.

otherAqueous two-phase extraction of semiconducting single-wall carbon nanotubes with isomaltodextrin and thin-film transistor applications

Applied Physics Express 12(9), 097003.1-097003.5 (2019)

Haruka Omachi*1-2, Tomohiko Komuro*1, Kaisei Matsumoto*1, Minako Nakajima*2, Hikaru Watanabe, Jun Hirotani*3, Yutaka Ohno*3-4, Hisanori Shinohara*1

*1 Department of Chemistry, Graduate School of Science, Nagoya University
*2 Research Center for Materials Science, Nagoya University
*3 Department of Electronics, Graduate School of Engineering, Nagoya University
*4 Institute of Materials and Systems for Sustainability, Nagoya University

We developed a rapid single-step aqueous two-phase extraction of high-purity semiconducting single-wall carbon nanotubes (s-SWCNTs) using isomaltodextrin, which is a cost-effective polysaccharide that contains a large amount of α-1,6-glucosidic linkages. We also succeeded in fabricating high-density uniform films directly from the high-purity s-SWCNT extract. Fabricated thin-film transistors (TFTs) exhibited an excellent on/off ratio, carrier mobility, and on-current density.


otherStructural features of a bacterial cyclic α-maltosyl-(1→6)-maltose (CMM) hydrolase critical for CMM recognition and hydrolysis

Journal of Biological Chemistry 2018 Oct 26;293(43):16874-16888

Masaki Kohno, Takatoshi Arakawa*1, *2, Hiromi Ota*3, Tetsuya Mori, Tomoyuki Nishimoto, Shinya Fushinobu*1, *2

*1 Department of Biotechnology, The University of Tokyo
*2 Collaborative Research Institute for Innovative Microbiology, The University of Tokyo
*3 Advanced Science Research Center, Okayama University

We have previously identified cyclic α-maltosyl-(1→6)-maltose, a novel enzymatically produced cyclic glucotetrasaccharide with alternating α-1,4 and α-1,6linkages, from the soil-associated bacterium Arthrobacter globiformis. In this study, we reported the mechanistic details of the hydrolysis of CMM by CMM hydrolase with its crystal structures. Our study revealed that A. globiformis has a unique metabolic pathway specialized for CMM.

healthcareNK-4 exerts selective regulatory effects on the activation and function of allergy-related Th2 cells

PLoS One 13(6), e0199666 (2018)

Keizo Kohno, Satomi Koya-Miyata, Akira Harashima, Toshio Ariyasu, Shimpei Ushio

It was clarified that the main active ingredient NK-4 of lumin A suppressed the production of cytokine IL-4, IL-5 which induces various symptoms of allergy from Th2 cells, and suppressed the production of chemokine (TARC) produced from human dermal fibroblast by IL-4 stimulus. In addition, we also elucidated the intracellular signaling pathways leading to these phenomena.

foodEffects of isomaltodextrin in postprandial lipid kinetics: Rat study and human randomized crossover study

PLoS One 13(5) e196802 (2018)

Ryodai Takagaki, Yuki Ishida, Tsuyoshi Sadakiyo, Yoshifumi Taniguchi, Takeo Sakurai, Hitoshi Mitsuzumi, Hikaru Watanabe, Shigeharu Fukuda, Shimpei Ushio

The inhibitory effect of isomaltodextrin on blood neutral fat elevation was examined. When isomaltodextrin was administered with soybean oil in rats, the subsequent increase in blood neutral fat was suppressed in humans when 2.5 g of isomaltodextrin was ingested with a food containing lipids. The mechanism of action suggested stabilization of lipid micellar particles by isomaltodextrin and suppression of lipid absorption by elevated zeta potential.

foodCyclic nigerosyl-1,6-nigerose-based nanosponges: An innovative pH and time-controlled nanocarrier for improving cancer treatment

Carbohydrate Polymers, 194 111-121 (2018)

F. Caldera*1, M. Argenziano*2, F. Trotta*1, C. Dianzani*2, L. Gigliotti*3, M. Tannous*1, L. Pastero*4, D. Aquilano*4, T. Nishimoto, T. Higashiyama, R. Cavalli*2

*1 Dipartimento di Chimica-Università di Torino
*2 Dipartimento di Scienza e Tecnologia del Farmaco-Università di Torino
*3 Dipartimento di Scienze della Salute, UPO
*4 Dipartimento di Scienze della Terra, Università di Torino

A cross-linked polymer was obtained by reacting a tetraglucose, named cyclic nigerosyl-1-6-nigerose (CNN), with pyromellitic dianhydride. The cross-linking reaction formed solid nanoparticles, named nanosponges. CNN-nanosponges may be promising biocompatible nanocarriers for the sustained delivery of doxorubicin with potential localised application in cancer treatments.


cosmeticEffects of a non-cyclodextrin cyclic carbohydrate on mouse melanoma cells: Characterization of a new type of hypopigmenting sugar

PLoS One 12(10) e0186640 (2017)

Shuji Nakamura, Toshio Kunikata, Yohsuke Matsumoto, Toshiharu Hanaya, Akira Harashima, Tomoyuki Nishimoto, Shimpei Ushio.

CNNs, a cyclic tetrasaccharide, exhibit a remarkable and long-term whitening effect in the cell culture system of in vitro without cell damage, as well as provide a new sugar whitening material because their mechanism of action is a novel one accompanied by a morphological change of organelles in the cell in addition to direct enzyme inhibition.

foodThe attenuating effect of isomaltodextrin on postprandial blood glucose level in healthy human subjects: a randomized, placebo-controlled, double-blind crossover study


Yuki Ishida, Tsuyoshi Sadakiyo, Shin-ichiro Inoue, Hikaru Watanabe, Hitoshi Mitsuzumi, Shigeharu Fukuda, Shimpei Ushio, Jun-ichi Hiramatsu*

* Hiramatsu Clinic

Subjects ingested a solution containing 50 g glucose with(test diet)or without(control diet)2.5 g IMD. Analysis of the subjects with a tendency for increased postprandial blood glucose levels revealed a significant attenuating effect confirmed by measurements of blood glucose and Δblood glucose levels 45 minutes after ingestion. Furthermore, the maximum blood glucose level(Cmax)and ΔCmax following ingestion of the test diet were significantly lower than those following ingestion of the control diet.

foodIsomaltodextrin prevents DSS-induced colitis by strengthening tight junctions in mice

Food Science and Technology Research, 23(2), 305-317 (2017)

Chikako Arai, Takeo Sakurai, Satomi Koya-Miyata,Shigeyuki Arai, Yoshifumi Taniguchi, Takashi Kamiya, Chiyo Yoshizane, Kazue Tsuji-Takayama, Hikaru Watanabe, Shimpei Ushio and Shigeharu Fukuda

IMD preloading of mice reduced the signs of DSS-induced colitis compared with the Water group. Immunohistochemical and western blotting analyses of the colon in the IMD group revealed enhanced claudin-3 and ZO-1 expression, indicating the role of IMD-induced TJ strengthening in the alleviation of colitis. The ingestion of IMD has beneficial effects on colon health by improving TJ integrity.

foodSafety assessment of a soluble dietary fiber, isomaltodextrin, enzymatically produced from starch

Fundamental Toxicological Sciences 4(2), 57-75 (2017)

Tsuyoshi Sadakiyo, Shin-ichiro Inoue, Yuki Ishida, Hikaru Watanabe, Hitoshi Mitsuzumi, Shimpei Ushio

No genotoxicity was observed when IMD was assayed in standardized bacterial reverse mutation, micronucleus, and chromosome aberration tests. The LD50 of IMD was found to be more than 2,000 mg/kg in an acute toxicity study in rats, and the NOAEL was determined to be 1,000 mg/kg/day in a 90-day subacute gavage toxicity study in rats. No animals died, and no abnormal findings due to consumption of IMD were observed in either of these studies. Based on two clinical studies, the NOAEL for IMD-related loose stools was considered to be 0.8 g/kg-BW. In a 4-week high-dose ingestion study in humans and a 12-week low-dose ingestion study in humans, laboratory values were found to be within the normal range of variation.

foodAttenuation of postprandial blood glucose in humans consuming isomaltodextrin: carbohydrate loading studies

Food & Nutrition Research 61(1), 1325306 (2017)

Tsuyoshi Sadakiyo, Yuki Ishida, Shin-ichiro Inoue, Yoshifumi Taniguchi, Takeo Sakurai, Ryodai Takagaki, Mayumi Kurose, Tetsuya Mori, Akiko Yasuda-Yamashita, Hitoshi Mitsuzumi, Michio Kubota, Hikaru Watanabe, Shigeharu Fukuda

Ingestion of 10 g of isomaltodextrin at the same time as maltodextrin or sucrose challenge in subjects prone to elevated blood glucose levels inhibited elevated blood glucose levels compared to those not ingested. In addition, when isomaltodextrin was simultaneously ingested in subjects prone to elevated blood glucose levels even when glucose was loaded, the increase in blood glucose levels was significantly attenuated at 5 g, and a attenuative trend was exhibited at 10 g.

foodThe Effect of a Beverage Containing Isomaltodextrin on Bowel Movements in Healthy Subjects: A Randomized, Double-blind, Placebo-controlled, Crossover Study


Yuki Ishida, Tsuyoshi Sadakiyo, Hikaru Watanabe, Hitoshi Mitsuzumi, Shimpei Ushio, Isao Takehara*1, Kazuhiko Takano*2

*1 Clinical Support Corporation Ltd.
*2 Medical Corporation Hokubu-kai Utsukushigaoka Hospital

Twenty healthy adults were given drinks containing 5 g isomaltodextrin (test beverage) or not (control beverage) daily for 2 weeks. After excluding three individuals at the discretion of the investigators, analysis revealed that the number of days of bowel movements and bowel movements were significantly higher when the study beverage was consumed than when the control beverage was consumed.

foodGlycemic, insulinemic and incretin responses after oral trehalose ingestion in healthy subjects

Nutrition Jounal 16:9 (2017) DOI 10.1186/s12937-017-0233-x

Chiyo Yoshizane, Akiko Mizote, Mika Yamada, Norie Arai, Shigeyuki Arai, Kazuhiko Maruta, Hitoshi Mitsuzumi, Toshio Ariyasu, Shimpei Ushio, Shigeharu Fukuda

Twenty healthy adults were subjected to a 25 g trehalose or glucose challenge test in a crossover. Trehalose ingestion did not evoke rapid increases in blood glucose levels, and had a lower stimulatory potency of insulin secretion compared with glucose ingestion. In addition, GIP secretion, which causes adiposity, was markedly lower with trehalose ingestion compared with glucose ingestion. These results suggest that trehalose may be a useful saccharide for health.

foodImprovement on bowel movement by isomaltdextrin in women - A double-blind crossover placebo-controlled study-


Shin-ichiro Inoue, Tsuyoshi Sadakiyo, Yuki Ishida, Hikaru Watanabe, Hitoshi Mitsuzumi, Shigeharu Fukuda, Shimpei Ushio, Makoto Terashima*1, Naoki Miura*2

*1 Oneness Support Co. Ltd.
*2 Miura Clinic

Ten healthy adult women with 2-4 bowel movements per week received 15 g/day of isomaltodextrin or maltodextrin for 4 weeks. As a result of analyzing except for one person who fell under the exclusion rule, the stool day in the fourth week was significantly higher in the isomaltodextrin ingestion compared with the maltodextrin ingestion. Also, the amount of change in short-chain fatty acids in stool at week 2 was significantly higher.


foodDaily intake of trehalose is effective in the prevention of lifestyle-related diseases in individuals with risk factors for metabolic syndrome

Journal of Nutritional Science and Vitaminology, 62(6), 380-387 (2016)

Akiko Mizote, Mika Yamada, Chiyo Yoshizane, Norie Arai, Kazuhiko Maruta, Shigeyuki Arai, Shin Endo, Rieko Ogawa, Hitoshi Mitsuzumi, Toshio Ariyasu, Shigeharu Fukuda

A 10g daily trehalose or sucrose intake study (12 weeks) was performed. Consequently, trehalose improved blood glucose levels 2 h after glucose challenge in subjects with BMI 23 or higher, and reduced body weight, abdominal circumference, and blood pressure in subjects with higher trunk fat rates. It was indicated that the continuous ingestion of trehalose could help in the prevention of metabolic syndrome.

healthcareTumor-specific delivery of biologics by a novel T-cell line HOZOT

Scientific Reports 6, 38060 (2016)

Teppei Onishi*1, Hiroshi Tazawa*1,2, Yuuri Hashimoto*1, Makoto Takeuchi, Takeshi Otani, Shuji Nakamura, Fuminori Sakurai*3, Hiroyuki Mizuguchi*3, Hiroyuki Kishimoto*1, Yuzo Umeda*1, Yasuhiro Shirakawa*1, Yasuo Urata*4, Shunsuke Kagawa*1 and Toshiyoshi Fujiwara*1

*1 Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
*2 Center for Innovative Clinical Medicine, Okayama University Hospital
*3 Laboratory of Biochemistry and Molecular Biology, Graduate School of Pharmaceutical Sciences, Osaka University
*4 Oncolys BioPharma, Inc.

A HOZOT with oncolytic virus was produced by utilizing Cell-in-Cell activity of HOZOT, and a technique for delivering oncolytic virus selectively to cancer cells was developed using animal models. The new treatment for the intractable peritoneal seeding metastasis is expected by this technology.

healthcareCholesteryl pullulan nanoparticles-encapsulated TNF-α: an effective mucosal vaccine adjuvant against influenza

"Steps Forwards in Diagnosing and Controlling Influenza" edited by Manal Mohammad Baddour, InTech, 139-159 (2016)

Tsunetaka Ohta

Cholesterol pullulan encapsulating TNF-α functions as an effective immunoadjuvant capable of efficiently protecting mice from the lethal infection of influenza virus.

foodInvolvement of splenic iron accumulation in the development of nonalcoholic steatohepatitis in Tsumura Suzuki Obese Diabetes mice

Scietific Reports 6, 22476 (2016)

Kazutoshi Murotomi*, Shigeyuki Arai, Satoko Uchida, Shin Endo, Hitoshi Mitsuzumi, Yosuke Tabei*, Yasukazu Yoshida*, and Yoshihiro Nakajima*

* Health Research Institute, National Institute of Advanced Industrial Science and Technology

We investigated effect of glucosyl hesperidin (GHes) on pathological symptoms of non-alcoholic steatohepatitis (NASH) using TSOD mice. GHes suppressed the hepatic inflammation and cell injury in the early stage of NASH. We also found that splenic iron levels are correlated with the severity of NASH, and GHes attenuated splenic iron overload in TSOD mice.

feedEffects of trehalose supplementation on the growth performance and intestinal innate immunity of juvenile chicks

British Poultry Science 57(3), 375-380 (2016)

Motoi Kikuzato*, Fumika Nanto*, Kazuhisa Mukai, and Masaaki Toyomizu*

* Animal Nutrition, Life Sciences, Graduate School of Agricultural Science, Tohoku University

The present study investigated the effect of feeding a trehalose-supplemented diet on the growth performance, as well as the intestinal innate immunity of juvenile chicks.Trehalose feeding significantly increased body weights at 14 and 18 days of age. It was indicated that this was due to the improvement of intestinal innate immunity.