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Food and Beverage Chemistry/Biochemistry

Roasted barley extract (mugi-cha) containing cyclo (D-Phe-L-Pro) prevents lowering of cutaneous blood flow and skin temperature under air-conditioning – A randomized, double-blind, placebo-controlled, crossover study Hiroshi Ashigai, Mai Mizutani, Yoshimasa Taniguchi, Yasuko Matsukura, Keiko Nakashima, Emiko Ikeshima, and Hiroaki Yajima J. Agric. Food Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jafc.8b02485 • Publication Date (Web): 24 May 2018 Downloaded from http://pubs.acs.org on May 24, 2018

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Journal of Agricultural and Food Chemistry

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Title

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Roasted barley extract (mugi-cha) containing cyclo (D-Phe-L-Pro) prevents lowering of

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cutaneous blood flow and skin temperature under air-conditioning – A randomized,

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double-blind, placebo-controlled, crossover study -

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Authors

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Hiroshi Ashigai, Mai Mizutani, Yoshimasa Taniguchi, Yasuko Matsukura, Keiko

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Nakashima, Emiko Ikeshima, Hiroaki Yajima

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†

Corresponding author: Hiroshi Ashigai

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Kirin Co. Ltd., Research Laboratories for Health Science and Food Technologies,

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1-17-5, Namamugi, Tsurumi-ku, Yokohama 230-8628 Japan

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Tel: +81-90-1930-9950,

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Fax: +81-45-500-8311,

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E-mail: [email protected]

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ACS Paragon Plus Environment


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Abstract

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Roasted barley extract (RBE), also known as mugi-cha, is a well-known healthy

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non-caffeinated beverage and its health functionality has been widely reported. Our

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previous clinical study showed that RBE affects cutaneous blood flow and skin

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temperature after cold water immersion, and that cyclo (D-Phe-L-Pro) is responsible for

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its effect. In this study, we investigated whether cyclo (D-Phe-L-Pro)-containing RBE

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prevents the decrease in cutaneous blood flow and skin temperature. Subjects remained

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in the air-conditioned room while ingesting RBE or a placebo. We measured cutaneous

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blood flow and skin temperature. We evaluated effect of RBE administration by

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two-way repeated measures ANOVA. Fifteen subjects were enrolled. The change in

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cutaneous blood flow in the RBE group and placebo group was −0.79 ± 0.38

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(ml/min/100 g) and −2.03 ± 0.35 (ml/min/100 g), p-value was 0.041. The change in skin

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temperature in the RBE group and placebo group was −1.85 ± 0.35°C and −3.02 ±

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0.30°C, p-value was < 0.001.

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We also did subclass analysis with cold feeling subjects. Seven subjects who had cold

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sensation, the change in cutaneous blood flow in the RBE group and placebo group was

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−0.48 ± 0.58 (ml/min/100 g) and −2.56 ± 0.48 (ml/min/100 g), p-value was 0.008, The

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change in skin temperature in the RBE group and placebo group was −1.46 ± 0.74°C

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and −2.89 ± 0.39°C, respectively. p-value was 0.009.

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Thus, RBE containing cyclo (D-Phe-L-Pro) prevents the decrease in cutaneous blood

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flow and skin temperature under air conditioning.

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Keywords

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roasted barley extract / cyclo (D-Phe-L-Pro) / cutaneous blood flow / skin temperature /

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air conditioning

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Introduction

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Roasted barley extract (RBE), or mugi-cha, is a popular traditional beverage in Japan.1

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RBE is also well-known as a healthy caffeine-free beverage. many Japanese people, 3



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children, infants as well as adults, drink RBE because RBE is uncaffeinated and low

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calorie. It is normally made with roasted barley, which has a slightly bitter taste. RBE

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lowers blood glucose and has an antioxidant activity.2,3 We have reported that RBE

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containing cyclo (D-Phe-L-Pro) affects cutaneous blood flow and skin temperature after

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cold water immersion.1

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2,5-Diketopyperazine is a cyclic peptide that is produced by roasting food

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ingredients.4-10 RBE is made by roasting barley. Thus, RBE contained various

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2,5-diketopyperazines, which is not contained unroasted barley extract. Especially,

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cyclo (D-Phe-L-Pro) is the most quantity in RBE, and the most effective for blood flow

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circulation.1 We have previously reported that cyclo (D-Phe-L-Pro) is the key chemical

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in RBE that improves blood circulation, and that it affects vasodilatation through NO

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releasing in the endothelium.1

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Cold sensation (hiesho) is known as blood stasis (Oketsu) in traditional Chinese

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medicine.11,12 It decreases quality of life and can be related to various vascular diseases

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such as hypertension and arteriosclerosis.13,14 Cold sensation is caused by an imbalance

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of the autonomic nerve system, which causes vasoconstriction and lowers cutaneous

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blood flow.15,16 Blood flow plays a role in controlling body temperature.17 Thus,

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decreased skin temperature leads to a decline in cutaneous blood flow.18

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Air-conditioning systems are increasingly used to control the room temperature. Public

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transportation systems and workplaces sometimes make excessive use of their

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air-conditioning systems. Thus, many people, especially women, experience cold

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sensation caused by excessive air-cooling.19,20 Ameliorating cold sensation in situations

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with excessive air-conditioning is important for quality of life. Consumption of

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functional beverages is one safety way to ameliorate cold sensation in daily life. Our

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research question was that RBE with cyclo (D-Phe-L-Pro) prevents lowering of

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cutaneous blood flow and skin temperature under air-conditioning.

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In this study, we demonstrated the effect of RBE with cyclo (D-Phe-L-Pro) for

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increasing cutaneous blood flow and skin temperature in air-conditioned rooms, using a

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randomized, double-blind, placebo-controlled, crossover study design. We also

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investigated whether cold sensation severity is related to RBE effect.

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Materials and Methods

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Chemical

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Cyclo (D-Phe-L-Pro) was purchased from Peptide Institute, Inc. (Osaka, Japan).

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Its’ purity is >99% (w/w). Formic acid and acetonitrile were purchased from Wako

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FUJIFILM Wako Pure Chemical Corporation (Osaka, Japan).

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Ethics

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This clinical study followed the ethical standards of the Helsinki Declaration of 1964, as

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modified by subsequent revisions and the Ethical Guidelines for Epidemiological

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Research of the Ministry of Education, Culture, Science, and Technology and the

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Ministry of Health, Labor and Welfare of Japan, and the experimental protocol (protocol

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no. 33) was approved by the Institutional Review Board of Kirin Group Japan

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Integrated Beverages, Kirin Company Ltd. This study was registered with the UMIN

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Clinical Trials Registry as UMIN000032521 and was conducted in compliance with the 6


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protocol as registered. This clinical trial was performed from September 28th, 2012 to

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October 26th, 2012.

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Participants

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All subjects were healthy Japanese males and females; they provided informed consent

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complying with the Helsinki Declaration. The exclusion criteria were as follows: under

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treatment; possible onset of allergy symptoms; any history of serious disease (e.g., heart

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disease, diabetes, kidney disease, liver disease); and possible pregnancy, pregnancy, or

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lactation.

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Target sample size

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Based on a preliminary human study, RBE (with 250 mg Cyclo (D-Phe-L-Pro)) was

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expected to be higher cutaneous blood flow by 0.15 (ml/min/100 g) with a standard

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deviation of 0.27 compared to the placebo group. Setting the significance level at 5% by

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an unpaired Student's t-test and the power at 0.90, the number of subjects required per 7



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group was estimated to be 15.

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Test beverage

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Roasted barley was purchased from the MC Foods Company (Tokyo, Japan). RBE was

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prepared as follows: roasted barley (100 g) was added to boiling water (1000 g) and

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steeped for 30 min, and diluted with 4000 g water. RBE was divided into aliquots of

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250 g. For placebo preparation, we used food coloring into water so that the two

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beverages would not differ in appearance to ensure that the two beverages were similar

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in taste. The components of RBE and the placebo are shown in Table 1. The RBE drink

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contained 250 µg cyclo (D-Phe-L-Pro)/250 mL bottle.

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Measurement of cyclo (D-Phe-L-Pro) levels

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Aliquots (1 µL) of the extracts were analyzed by liquid chromatography-mass

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spectrometry (LC-MS) using a Develosil column (C30-UG-3; 2.0 × 250 mm;

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Phenomenex, Torrance, CA, USA) coupled to a 4000 QTRAP LC-MS system (AB 8


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Sciex, Tokyo, Japan) in selected-ion monitoring (SIM) mode. The mobile phase

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consisted of formic acid (0.1% in water) and acetonitrile, and was set at a flow rate of

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0.2 mL/min. The analysis was started with 10% acetonitrile for 10 min. Next, the

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acetonitrile content was increased to 30% within 30 min, increased to 100% within 10

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min, and then held at 100% for 10 min. The mass spectrometry was performed in

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positive electrospray ionization mode with a quadrupole mass spectrometer with a

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ionspray voltage of 5.5 kV. The desolvation temperature was 650°C. Cyclo

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(D-Phe-L-Pro) was detected by measuring the corresponding mass traces in SIM mode

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by setting [M+H]+. Peaks at 245 (m/z) indicated the presence of cyclo (L-Pro-D-Phe).

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Study design

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This was a randomized, double-blind, placebo-controlled, crossover study. The site

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investigator enrolled the participants. Participants were divided into two groups by

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stratified randomization by the assigning controller, and each group was assigned either

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the RBE or placebo beverage before the first trial period. The assigning controller kept

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the assignment list in a sealed container until the trial was complete. Participants,

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investigators, and any persons concerned with the study, excluding the assigning

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controller, remained blinded. Participants were asked to drink the RBE beverage or

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placebo beverage on experimental day.

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During the test period, participants were asked to refrain from ingesting

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pharmaceuticals containing caffeine or vitamin K. On the one day before the experiment,

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they asked to refrain from alcoholic drinking excessively; exercising vigorously;

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drinking beverages or eating foods containing ingredients known to affect blood flow.

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On the experimental day, they were asked to refrain from smoking.

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Cold sensation questionnaire

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Cold sensation used Terasawa’s cold feeling questionnaire.20

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Measurement of cutaneous blood flow and skin temperature

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On the day of the experiment, all subjects were asked to wear thin clothing, the same 10


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clothing they would wear on the alternative experimental day. The conditions in the test

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room were as follows: the temperature was 25.5 ± 0.5°C, the humidity was 52.5 ± 7.5%,

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and air flow was < 0.1 m/s. There was no day other than set temperature between testing

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day. After entering the room, subjects were allowed to acclimate to the test room

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conditions for 30 min. Before intake of beverages, we measured cutaneous blood flow

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and skin temperature (pre-intake data, 0 min). Subjects sat in chairs without moving.11

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Then subjects removed their socks and ingested their beverages. The beverages

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temperature was 25°C for adjusting beverages temperature same as room temperature.

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We used the instep of the left foot for cutaneous blood flow and skin temperature

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measurements. Cutaneous blood flow and skin temperature were measured at intervals

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of 5 min for 90 min.21 Cutaneous blood flow measurement was performed using a Laser

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Doppler blood perfusion imager (ALF-21, Advance Company, Tokyo, Japan). Analog

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signals were converted to digital signals using an A/D converter (Power-Lab; AD

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Instruments, Dunedin, New Zealand). Skin temperature was estimated using an Infrared

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Thermography H2640 (Nippon Avionics Company, Tokyo, Japan). Fig. 1 shows a

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schematic representation of the study. 11



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Statistical analysis

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We evaluated value change from 0min for skin blood flow and temperature. Results are

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presented as mean ± standard deviation of the mean, determined using the statistical

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software Ekuseru-Toukei 2010 (Social Survey Research Information Co., Ltd., Tokyo,

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Japan). We evaluated skewness and kurtosis. Significant differences in cutaneous blood

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flow or skin temperature between the RBE and placebo groups were estimated using

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two-way, repeated measures ANOVA (p < 0.05).

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Results

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Participants

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Fifteen individuals were evaluated for eligibility to participate and 15 healthy adults (7

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males and 8 females) were enrolled. Subject background is shown on Table 2. Fig. 2

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shows a flow diagram of the study from assessment to final analysis. No participants

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dropped out of the study, and all participated in the experiment for effect and safety 12


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evaluation. Based on the criteria of cold sensation, as assessed by Terasawa’s

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questionnaire, we divided the participants into two groups: feeling cold sensation (n =

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7) or not feeling cold sensation (n = 8).

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Cutaneous blood flow measurement

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Cutaneous blood flow in the placebo group reduced compared to that at 0 min. In the

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RBE group, the change in cutaneous blood flow was greater than that in the placebo

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group, for all participants (Fig. 3). In subjects feeling cold sensation, the change in

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cutaneous blood flow was significantly greater in the RBE group than in the placebo

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group (Fig. 4 (a)). In subjects not feeling cold sensation, the change in cutaneous blood

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flow was slightly greater in the RBE group than in the placebo group, but the difference

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was not significant (Fig. 4 (b)).

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Skin temperature

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Skin temperature of participants in the placebo group decreased compared to that at 0 13



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min. The change in skin temperature was greater in the RBE group than in the placebo

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group, in all participants (Fig. 5). In particular, it was significantly greater than that in

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the placebo group (Fig. 5). In subjects feeling cold sensation, the change in skin

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temperature was significantly greater in the RBE group than in the placebo group (Fig.

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6 (a)). In subjects not feeling cold sensation, the change in skin temperature was

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significantly greater in those who ingested RBE than in those who ingested the placebo

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(Fig. 6 (b)).

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Safety endpoints

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No adverse events occurred during the study.

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Discussion

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We found that RBE containing cyclo (D-Phe-L-Pro) prevents lowering of cutaneous

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blood flow and skin temperature under air-conditioning.

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Cold sensation (hiesho) is one of severe malaise in traditional Chinese medicine.20 It is 14


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considered a pre-symptom of severe diseases such as insomnia and dysautonomia.22,23

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To induce cold sensation in the test subjects, we set the test room conditions to cold and

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requested that subjects not wear heavy clothing. In the placebo group, cutaneous blood

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flow and skin temperature decreased compared to before the start of the experiment (Fig.

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3,5). Based on these results, we set the test room conditions to moderately cold. It leads

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to vasoconstriction in peripheral skin and a decline of cutaneous blood flow.We

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observed that intake of RBE maintained cutaneous blood flow and skin temperature

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compared to the placebo in an air-conditioned room (Fig. 3,5). In a previous report, we

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noted that RBE showed effect for maintaining cutaneous blood flow and skin

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temperature with cold water immersion.1 This study revealed that RBE shows effect for

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maintaining cutaneous blood flow and skin temperature in an air-conditioned room. We

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hypothesized that RBE’s effect for maintaining blood flow is not restricted to situations

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of acute cold sensation (cold water immersion) and can affect cutaneous blood flow and

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skin temperature in situations of chronic cold sensation (air-conditioning). In our

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previous report, we also reported that cyclo (D-Phe-L-Pro) is the key chemical for RBE

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effect of blood flow.1 We revealed that blood flow change of RBE containing 30 mg 15



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cyclo (D-Phe-L-Pro) is similar to blood flow change of 30 mg cyclo (D-Phe-L-Pro), and

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30 mg cyclo (D-Phe-L-Pro) affects vasodilatation through NO production in the

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endothelium.1 Based on this evidence, we conclude that air-conditioning induces

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vasoconstriction leading to a lower cutaneous blood flow, and that RBE, especially

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cyclo (D-Phe-L-Pro), induces vasodilatation to maintain cutaneous blood flow.

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RBE-ingesting participants maintained their skin temperature compared to participants

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who received a placebo.

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Nitrate supplementation induces reflex cutaneous vasodilatation in heat-stressed healthy

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human24,25. On the other hand, nitrate does not response skin blood flow from cold

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water immersion in subject who have cold sensitivity26. Comparing to these evidences,

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we firstly demonstrated nitrate supplementation response to skin blood flow and skin

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temperature in subject who have cold sensitivity. Cooling method was differnt between

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our experiment and previous report. We think that cold water immersion induced strong

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vasodilatation compared to air-cooling room. Thus, previous report was not detected

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nitrate supplementation effect for skin blood flow.

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In the subclass analysis according to cold sensation, RBE had a stronger effect on

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cutaneous blood flow in subjects with cold sensation than in those without cold

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sensation (Fig. 4 (a), (b)). Comparing the change in cutaneous blood flow in subjects

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who received the placebo, subjects feeling cold sensation tended to show a decline in

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blood flow compared to subjects not feeling cold sensation (Fig. 4 (a), (b)). However,

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the change in skin temperature was similar between subjects with or without cold

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sensation (Fig. 6 (a), (b)). In this experiment, we exposed all subjects to

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air-conditioning. We assume that our intervention had the same effect on skin

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temperature for all subjects, but the effect of declining skin temperature on cutaneous

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blood flow was different between subjects with or without cold sensation. In general,

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dysfunction of blood flow causes cold sensation.27,28 Thus, we believed that cutaneous

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blood flow of subjects with cold sensation tended to be affected by room temperature.

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This does not contradict the concept of cold sensation (Hiesho).20 From these results,

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we assumed that subjects with cold sensation have dysfunctional blood circulation

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compared to subjects without cold sensation. Thus, the effects of air-conditioning

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(declining cutaneous blood flow) were stronger for subjects with cold sensation. We 17



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conclude that RBE’s effect was easily detected in subjects with cold sensation.

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In our previous study, we reported that cyclo (D-Phe-L-Pro) and RBE with cyclo

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(D-Phe-L-Pro) affect vasodilatation and increase blood flow in the tails of rats. Thus,

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we assume that that the effect of RBE for increasing blood flow in this air-conditioned

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room was also mediated by vasodilatation induced by cyclo (D-Phe-L-Pro).

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Hesperidin has been reported to have an effect on vasodilatation through autonomic

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nervous system.21 It also increased skin temperature and improved “hiesho” symptoms

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in a clinical study.21 These reports also support our discussion. Generally, cutaneous

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blood flow and skin temperature are related to cold sensation (Hiesyo).20,24,25 RBE

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containing cyclo (D-Phe-L-Pro) might affect cold sensation.

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This study has several limitations, such as that the subjects in this experiment were all

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Japanese. This limitation could be addressed by performing similar studies on subjects

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of different ancestry, and we hope that clinical studies of RBE will be performed in

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other countries. The tastes difference between test beverages, was one of the limitation

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of this study. In our experiment, the number of subjects was limited number, we will

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need larger clinical trial for more adequately powered. Number of subject especially

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with cold sensation for sub-analysis is small, was another one of the limitation of this 18


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study.

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In conclusion, RBE containing cyclo (D-Phe-L-Pro) prevents lowering of cutaneous

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blood flow and skin temperature under cold sensation conditions in humans, and RBE

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has a stronger effect on subjects who experience cold sensation.

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Non-standard abbreviations: roasted barley extract: RBE,

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Acknowledgments

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We would like to thank Kyoko Kato, Rie Sano, and Guanying Wang for valuable

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discussions and technical support.

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Conflict of interest

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We certify that there is no conflict of interest with any financial organization regarding

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the material discussed in the manuscript. This study was founded by Kirin company

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Ltd.

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References

292

1. Ashigai, H.; Yoshimasa, T.; Matsukura, Y.; Ikeshima, E.; Mizutani, M.; Yajima, H.

293

Roasted barley extract affects blood flow in the rat tail and increases cutaneous

294

blood flow and skin temperature in humans. J. Agric. Food Chem. 2018, 66:

295

1251-1257..

296

2. Duh, P.D.; Yen, G.C.; Yen, W.J.; Chang, L.W. Antioxidant effects of water extracts

297

from barley (Hordeum vulgare L.) prepared under different roasting temperatures. J.

298

Agric. Food Chem. 2001, 49: 1455–1463.

299 300

301 302

3. Kajimoto, G.; Murakami, C. Antioxidant activity of several commercial teas and their components. J. Jpn. Soc. Nutr. Food Sci. 1999, 52: 209–218.

4. Borthwick, A.D. 2,5-Diketopiperazines: Synthesis, reactions, medicinal chemistry, and bioactive natural products. Chem. Rev. 2012, 112, 3641–3716.

20


Page 20 of 36

Page 21 of 36


303 304

5. Borthwick, A.D.; Da Costa, N.C. 2,5-diketopiperazines in food and beverages: Taste and bioactivity. Crit. Rev. Food Sci. Nutr. 2017, 57, 718–742.

305

6. Ryan, L.A.; Dal Bello, F.; Arendt, E.K.; Koehler, P. Detection and quantitation of

306

2,5-diketopiperazines in wheat sourdough and bread. J. Agric. Food Chem. 2009,

307

57, 9563–9568.

308 309

7. Ginz, M.; Engelhardt, U.H. Identification of proline-based diketopiperazines in roasted coffee. J. Agric. Food Chem. 2000, 48, 3528–3532.

310

8. Stark, T.; Hofmann, T. Structures, sensory activity, and dose/response functions of

311

2,5-diketopiperazines in roasted cocoa nibs (Theobroma cacao). J. Agric. Food

312

Chem. 2005, 53, 7222–7231.

313

9. Chen, M.Z.; Dewis, M.L.; Kraut, K.; Merritt, D.; Reiber, L.; Trinnaman, L.; Da

314

Costa, N.C. 2, 5-diketopiperazines (cyclic dipeptides) in beef: Identification,

315

synthesis, and sensory evaluation. J. Food Sci. 2009, 74, C100–C105.

316

10. Taga, Y.; Kusubata, M.; Ogawa-Goto, K.; Hattori, S. Identification of

317

collagen-derived hydroxyproline (Hyp)-containing cyclic dipeptides with high oral

21



318

bioavailability: Efficient formation of cyclo (X-Hyp) from X-Hyp-Gly-type

319

tripeptides by heating. J. Agric. Food Chem. 2017, 65, 9514–9521.

320 321

11. Kimura, T.; Asami, T. Discrimination of hie and hiesho using toe blood pressure in young women. J. Integr. Med. 2016, 14: 436–446.

322

12. Nakamura, S.; Ichisato, S.M.; Horiuchi, S.; Mori, T.; Momoi, M. Pregnant women’s

323

awareness of sensitivity to cold (hiesho) and body temperature observational study:

324

A comparison of Japanese and Brazilian women. BMC Res. Notes 2011, 4: 278.

325

13. Burnstock, G.; Ralevic, V. Purinergic signaling and blood vessels in health and

326

327 328

disease. Pharmacol. Rev. 2013, 66: 102–192.

14. Prior, B.M.; Lloyd, P.G.; Ren, J.; Li, Z.; Yang, H.T.; Laughlin, M.H.; Terjung, R.L. Arteriogenesis: role of nitric oxide. Endothelium. 2003, 10: 207–216.

329

15. Charkoudian, N.; Wallin, B.G. Sympathetic neural activity to the cardiovascular

330

system: integrator of systemic physiology and interindividual characteristics.

331

Compr. Physiol. 2014, 4: 825–850.

332

16. Simon, E. Thermoregulation as a switchboard of autonomic nervous and endocrine 22


Page 22 of 36

Page 23 of 36


333

334 335

336 337

control. Jpn. J. Physiol. 1999, 49: 297–323.

17. Gonzálbloodez-Alonso, J. Human thermoregulation and the cardiovascular system. Exp. Physiol. 2012, 97: 340–346.

18. Elam, M.; Wallin, B.G. Skin blood flow responses to mental stress in man depend on body temperature. Acta Physiol. Scand. 1987, 129: 429–431.

338

19. Nagashima, K.; Yoda, T.; Yagishita, T.; Taniguchi, A.; Hosono, T.; Kanosue, K.

339

Thermal regulation and comfort during a mild-cold exposure in young Japanese

340

women complaining of unusual coldness. J. Appl. Physiol. 2002, 92: 1029–1035.

341

20. Terasawa, K. On the recognition and treatment of "Hie-Sho" (Chilphobia) in the

342

traditional Kampoh medicine. Jpn. J. Pharmacogn. 1987, 41: 85–96.

343

21. Takumi, H.; Fujishima, N.; Shiraishi, K.; Mori, Y.; Ariyama, A.; Kometani, T.

344

Hashimoto, S.; Nadamoto, T. Effects of alpha-glucosylhesperidin on the peripheral

345

body temperature and autonomic nervous system. Biosci. Biotechnol. Biochem.

346

2010, 74, 707–715.

347

22. Yan, S.; Zhang, R.; Zhou, X.; Li, P.; He, L.; Liu, B. Exploring effective core drug 23



348

patterns in primary insomnia treatment with Chinese herbal medicine: Study

349

protocol for a randomized controlled trial. Trials. 2013, 14, 61.

350

23. Li, Q.Q.; Shi, G.X.; Fu, X.X.; Han, L.L.; Liu, L.Y.; Liu, C.Z.; Wang, L.P.; Hou, N.

351

Effects of deqi on autonomic balance in adult tinnitus patients: Study design of a

352

randomized controlled trial. J. Evid. Complement. Altern. Med. 2013, 2013,

353

756012.

354

24. Levitt EL,; Keen JT,; Wong BJ. Augmented reflex cutaneous vasodilatation

355

following short-term dietary nitrate supplementation in humans. Exp Physiol. 2015,

356

100: 708-18.

357

25. Keen JT.; Levitt EL.; Hodges GJ.; Wong BJ. Short-term dietary nitrate

358

supplementation augments cutaneous vasodilatation and reduces mean arterial

359

pressure in healthy humans. Microvasc Res. 2015 98:48-53.

360

26. Eglin CM.; Costello JT.; Bailey SJ.; Gilchrist M.; Massey H.; Shepherd AI. Effects

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of dietary nitrate supplementation on the response to extremity cooling and

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endothelial function in individuals with cold sensitivity. A double blind, placebo 24


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controlled, crossover, randomised control trial. Nitric Oxide. 2017, 70: 76-85.

27. Liu, C.; Yavar, Z.; Sun, Q. Cardiovascular response to thermoregulatory challenges. Am. J. Physiol. Heart Circ. Physiol. 2015, 309: H1793–1812.

28. González-Alonso, J. Human thermoregulation and the cardiovascular system. Exp. Physiol. 2012, 97, 340–346.

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Table 1 Nutrient Components of Test Beverages

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Table 2 Subject background

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List of figure caption

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Fig. 1 Schematic representation of intervention.

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Subject was acclimatized with test room condition for 30 min. Before intake of test

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beverage, we measured subject skin blood flow and skin temperature. After drinking

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test beverage, subject had to keep their body position same (not moving), and we

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measured their skin blood flow and skin temperature every 5 min for 90 min.

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Fig. 2 Flow diagram of the progress through the study.

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Fig. 3 skin blood flow change on intaking roasted barley extract (RBE) with cyclo

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(D-Phe-L-Pro).

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administration was statistically significant by two-way repeated measurement ANOVA

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(p

Roasted barley extract (mugi-cha) - ACS Publications

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