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Miso Soup Consumption Enhances the Bioavailability of the Reduced Form of Supplemental Coenzyme Q10

Miso Soup Consumption Enhances the Bioavailability of the Reduced Form of Supplemental Coenzyme Q10 Hindawi Journal of Nutrition and Metabolism Volume 2020, Article ID 5349086, 7 pages https://doi.org/10.1155/2020/5349086 Research Article Miso Soup Consumption Enhances the Bioavailability of the Reduced Form of Supplemental Coenzyme Q 1 2 1,2 1,2 Michiyo Takahashi, Mayumi Nagata, Takehiko Kaneko, and Toshikazu Suzuki Graduate School of Human Ecology, Wayo Women’s University, 2-3-1 Konodai, Ichikawa, Chiba 272-8533, Japan Department of Health and Nutrition, Wayo Women’s University, 2-3-1 Konodai, Ichikawa, Chiba 272-8533, Japan Correspondence should be addressed to Toshikazu Suzuki; t-suzuki@wayo.ac.jp Received 31 August 2019; Accepted 25 November 2019; Published 7 January 2020 Academic Editor: C. S. Johnston Copyright © 2020 Michiyo Takahashi et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Coenzyme Q (CoQ ) is an essential compound that is involved in energy production and is a lipid-soluble antioxidant. 10 10 Although it has been proposed as an antiaging and a health-supporting supplement, its low bioavailability remains a significant issue. Concurrent food intake enhances the absorption of orally administered CoQ , but it has not been fully established whether specific food substances affect intestinal CoQ absorption. -erefore, to determine whether the bioavailability of supplemental CoQ is affected by diet, P30, a granulated and reduced form of CoQ , was dispersed in four different foods, clear soup, miso 10 10 soup, milk soup, and raw egg sauce. -ose foods which contained CoQ were consumed on different occasions at intervals of 6–14 weeks by the same participants. -irteen participants were recruited in the single-dose and repeated clinical study. When miso soup containing P30 was provided, the serum CoQ concentration increased faster than when participants consumed other P30-containing soups or a P30-containing raw egg sauce. -e area under the curve for serum CoQ during the first 5h after consumption of the P30-containing miso soup was approximately 1.5 times larger than those after the consumption of other P30- containing meals. -ese data imply that the absorption of CoQ supplements can be enhanced by consuming them with food and in particular with specific food substances, such as miso soup. pressure [12], glucose metabolism in diabetes [13], and the 1. Introduction symptoms of Parkinson’s disease [14] and reduces peripheral Coenzyme Q (CoQ ), a vitamin-like substance, is in- oxidative stress and inflammation in interferon β-1a-treated 10 10 volved in energy production and is a lipid-soluble antiox- multiple sclerosis [15]. It can also increase the vitality of idant [1–3]. Many studies have reported a relationship patients undergoing medical treatment and of the elderly between CoQ and aging. For example, the amount of residents of nursing homes [16–18]. Furthermore, it alle- CoQ in muscles and organs decreases with age [4], as does viates fatigue in patients with chronic fatigue syndrome the serum CoQ concentration and that of the reduced form [19, 20], hyperlipidemia [21], and in those with end-stage [5] in healthy adults. Both blood levels and the ratio of the heart failure awaiting cardiac transplantation [22]. In older reduced form of CoQ concentration to total coenzyme Q rats, CoQ supplementation has been shown to alleviate 10 10 10 in hospitalized elderly people were lower than that in the diabetes-induced learning and memory deficits and to im- healthy elderly people [6]. Also, many studies have shown prove cognitive performance when administered at a high associations between serum CoQ status and health [7–11]. dose [23]. In the senescence-accelerated prone 8 mouse, In addition, CoQ supplementation has been shown to CoQ supplementation counteracts the deleterious effects 10 10 ameliorate the symptoms of some geriatric disorders and to of physical exercise-derived reactive oxygen species, im- improve the quality of life of humans and some laboratory proving mitochondrial function [24]. -us, CoQ may be animals. CoQ supplementation ameliorates high blood useful as an antiaging and health-supporting supplement. 10 2 Journal of Nutrition and Metabolism In general, the absorption of compounds from the CoQ was compared among the various foods that were gastrointestinal tract is one of the most important de- concurrently consumed. terminants of oral bioavailability. Intestinal absorption of supplemental CoQ is slow and limited because of the 10 2. Materials and Methods compound’s hydrophobicity and high molecular weight. 2.1. CoQ Supplements. A granulated, solubilized, and re- Many types of CoQ delivery system have been developed 10 duced form of CoQ supplement, P30, was used in the that aim to increase the bioavailability of supplemental study. P30 contains 30 w/w% of reduced CoQ (120mg per CoQ , such as self-emulsifying drug delivery systems, 10 sachet), dextrin, gum Arabic, and L-ascorbate. -ese sup- nanotechnology-based drug delivery systems, cyclodextrin plements were provided by the Kaneka Corporation (Osaka, complexes, CoQ -solanesyl poly(ethylene glycol) succinate Japan). micelles, and a reduced form of CoQ that is both emul- sified and solubilized [25–27]. In addition, the concurrent consumption of food enhances the rate of the absorption of 2.2. Study Design. -irteen healthy volunteers (1 man and 12 orally administered supplemental CoQ [28]. -erefore, the women), who were students or staff at Wayo Women’s consumption of CoQ -fortified foods may be a useful way University, participated in the study. Each participant took a of increasing the bioavailability of CoQ . CoQ supplement with a meal on four occasions, with the It is well known that the absorption of nutrients, such as food type containing the CoQ differing on each occasion. vitamins and minerals, is affected by the food items con- Table 1 shows the meal composition, the sauce of the CoQ , currently consumed or their components. For example, the the nutrient content of the meals. Using the data by Kubo enhancement of β-carotene absorption by mayonnaise et al. [42], CoQ content obtained from the meals in the consumption [29], of carotenoid absorption by avocado or clear soup, miso soup, milk soup, and raw egg source ex- avocado oil consumption [30], of vitamin E absorption by periments were estimated as 0.52, 0.55, 0.56, and 0.59mg, egg consumption [31], and of nonheme iron absorption by respectively, and these were the less than one two-hundredth meat protein and vitamin C consumption, have been re- of the CoQ supplements ingested. It suggests that the effect ported [32–34]. Conversely, some dietary fibers suppress the of CoQ content in meals itself was vanishingly low. -e absorption of β-carotene, lycopene, and lutein [35]. Addi- number of participants in each experiment is shown in tionally, tannins, phytic acid, polyphenols, and calcium Table S1. Photos of the meal components provided for the inhibit the absorption of nonheme iron [36–39]. -us, the subjects are shown in Figure S1. In the experiments, each absorption of supplemental CoQ may also be affected by participant ingested 120mg of reduced CoQ (a sachet of the food or a component with which it is consumed, al- P30) suspended in the food (indicated by red arrowheads in though no previous studies have addressed this issue. Figure S1). In the meals containing P30, the ratio of the -erefore, knowledge of the food items that could enhance concentrations of the reduced form of CoQ concentration the absorption of orally administered CoQ is crucial for the to total coenzyme Q was >99%. To minimize the number development of appropriate functional CoQ -fortified of confounding factors, the same meal was consumed in each foods. experiment, with the exception of the food item containing Previously, we investigated the association between di- the P30. etary habits and serum CoQ levels before and after long- -e nutrient content of the meals was estimated using term supplementation with a reduced form of CoQ Calorie Make software (Toyo System Science Co., Ltd., [40, 41]. People with higher basal serum CoQ concen- Yokohama, Japan). -e consumption of the meals started trations tended to consume more soy products [40], and around 12:00h, at least 3h after breakfast. -e control and those who had a higher increase in serum CoQ concen- test experiments were performed between March and De- trations after the 1-year supplementation tended to consume cember 2018 at intervals of 6–14 weeks. All subjects gave more dairy products and eggs [41]. -ese results remind us their informed consent for inclusion before they participated that soy products, dairy products, and eggs might positively in this study. -is study was conducted in accordance with affect the absorption of CoQ supplements. the Declaration of Helsinki, and the protocol was approved In this study, we investigated the effect of various by the Wayo Women’s University Human Research Ethics foods on the bioavailability of supplemental CoQ using Committee (no. 1734). P30, a granulated and reduced form of CoQ supple- ment, and a typical Japanese meal, consisting of steamed rice, grilled salmon with marinated Japanese radish, 2.3. Blood Collection and CoQ Measurements. Blood boiled spinach, and soup. P30 was suspended in the soup samples were drawn from a vein at the baseline (just before or raw egg sauce in advance, before being provided to the meal ingestion), and 1.5, 3, and 5h after the start of the meal, participants. Miso soup, milk soup, and raw egg sauce and serum was obtained by centrifugation after clot for- were used as foods containing soy products, daily mation. Quantitative analysis of serum CoQ concentration products, and eggs, respectively. Clear soup, which is was measured by Kaneka Techno Research Co., Ltd., using seasoned with salt, was used as a reference food. -e soup liquid chromatography with tandem mass spectrometry consumed was different in each experiment. Serum (LC/MS/MS) [43, 44]. In brief, 0.7mL of the isopropanol was CoQ concentration was determined before, and 1.5, 3, added to 0.1mL of serum, mixed, and stored at −80 C until and 5 h after eating the meals, and the bioavailability of just before the analysis. After centrifugation, the supernatant Journal of Nutrition and Metabolism 3 Table 1: Meal menus for each experiment. Experiment no. 1 2 3 4 Experiment Clear soup Miso soup Milk soup Raw egg sauce Meal menu Main dish Grilled salmon with Japanese radish marinated in citrus juice Side dish Boiled spinach flavored with bonito flakes and soy sauce Staple food Rice Rice Rice Rice with stirred raw egg sauce a a a Soup Clear soup Miso soup Milk soup Miso soup Other — — — — Nutrient content per serve Energy (kcal) 336 356 437 430 Protein (g) 20.1 21.5 25.1 27.5 Fat (g) 3.6 4.3 9.3 9.4 Carbohydrate (g) 54.1 56.5 61.3 56.4 CoQ (mg) 120 120 120 120 a b P30 was suspended in this food item; only CoQ obtained from P30 is recorded. was filtered through a membrane filter. -en, 200 μL aliquots compared using unpaired one-way ANOVA and Holm– were mixed with 200 μL of methanol and 50 µL of oxidized Bonferroni post hoc testing because some participants CoQ (50ng/mL in 2-propanol) as an internal standard and missed in the first and third experiments. -e concentration used as the sample for LC/MS/MS, which was performed achieved following the consumption of P30 in miso soup was using an AB Sciex Triple Quad 5500 LC-MS/MS system and significantly higher than that achieved following con- a reversed-phase octadecyl-silica column (AB Sciex, Fra- sumption of the raw egg sauce after 1.5h and higher than mingham, MA, USA). -e intra- and interday coefficients of that achieved following all three other meals after 3h variation for CoQ were less than 2 and 10%, respectively. (Figure S2A). -ere were significant differences in ΔAUC 10 0–5 between the clear soup and miso soup days, and between the miso soup and raw egg sauce days (Figure S2B). -e ΔAUC 0–5 2.4. Data Analysis. -e increase in concentration of CoQ in following miso soup ingestion was 4.44±1.40 μmolh/L, the serum after the ingestion of a CoQ -suspended test meal which is approximately 1.5- and 1.6-fold higher (P<0.05) (ΔCoQ ) was calculated by subtracting the baseline value, than that on the clear soup (2.97±1.11 μmolh/L) and raw egg and numerical data are expressed as mean±SD. To compare sauce (2.84±1.36 μmolh/L) days, respectively (Table S2). the bioavailabilities of CoQ , the areas under the serum -en, we reanalyzed the data from the eight participants CoQ concentration-time curves up to 5h after ingestion (numbers 3, 4, 5, 8, 9, 11, 12, and 13) who had participated in (ΔAUC ) were calculated. -ese data were analyzed using 0–5 all of the four experiments (Table S1), using one-way one-way analysis of variance (ANOVA) with unpaired and ANOVA with repeated measures (Figure 1). -e ΔCoQ on repeated measures, and the differences between the means the miso soup day was significantly higher than on the raw were evaluated by Holm–Bonferroni post hoc testing using egg sauce days after 1.5h and higher than on all of the other 3 js-STAR ver. 9. 3. 0j web application software (http://www. days 3h after ingestion (Figure 1(a)). -e mean ΔAUC on 0–5 kisnet.or.jp/nappa/software/star/). P<0.05 was considered to the miso soup day was 4.94±1.51 μmolh/L, which was represent statistical significance. 1.6∼1.7-fold higher (P<0.05) than that on the clear soup (3.08±1.33 μmolh/L), milk soup (2.95±1.07 μmolh/L), and 3. Results raw egg sauce (3.05±1.64 μmolh/L) days, respectively (Figure 1(b)). -irteen healthy volunteers (1 man and 12 women) par- -ese results demonstrate that the absorption rate and ticipated in the study. Each ingested a CoQ supplement in bioavailability of supplemental reduced CoQ up to 5h after the form of suspended a suspension in a food item on up to ingestion was increased by suspending it in miso soup. four separate occasions. Twelve participated in the first However, this effect was abolished when the CoQ was experiment (supplemental CoQ in clear soup as a refer- suspended in raw egg sauce, even if miso soup was ingested ence), thirteen participated in the second experiment at the same time (experiment 4). (supplemental CoQ in miso soup), nine participated in the third experiment (supplemental CoQ in milk soup), and thirteen participated in the fourth experiment (supplemental 4. Discussion CoQ in a raw egg sauce). -e participation of each in- dividual and the increases in serum total CoQ concen- In this study, we determined whether the absorption of a CoQ 10 10 tration after each meal are shown in Tables S1 and S2, supplement would be affected when it was suspended in specific respectively. ΔAUC was also calculated for each partic- foods. -ere were no differences in either ΔCoQ orΔAUC 0–5 10 0–5 ipant (Table S2). among participants who consumed a clear soup and test meals First, the increase in serum total CoQ (ΔCoQ ) on different days, with the exception of the day they consumed 10 10 concentration after each of the four experiments were the supplement in miso soup. Both the ΔCoQ at 3h and the 10 4 Journal of Nutrition and Metabolism 2 7 1.5 0.5 ab ab 0 12345 Time (h) Clear soup Milk soup Miso soup Raw egg sauce (a) (b) Figure 1: Changes in serum total CoQ concentration (a) and a comparison ofΔAUC (b) after the consumption of P30 in clear soup, 10 0–5 P30 in miso soup, P30 in milk soup, or P30 in raw egg sauce. 120mg of CoQ was administered. In Figure 1(a), the open circle represents P30 in clear soup, closed circle represents P30 in miso soup, open triangle represents P30 in milk soup, and open square indicates P30 in raw egg sauce. Data are mean±SD for the eight individuals who participated in all four of the experiments. Figure 1(b) shows box plots for the ΔAUC for these eight participants. -e boundary of the box closest to zero indicates the 25th percentile, the line within the box indicates 0–5 the median, the multiplication sign within the box indicates the mean, and the boundary of the box farthest from the origin indicates the 75th percentile. Whiskers above and below the box indicate the 10th and 90th percentiles. Data were analyzed with one-way analysis of variance with repeated measures, and differences between the means were evaluated using Holm–Bonferroni post hoc tests. Different lower case letters indicate significant differences, with P<0.05. ΔAUC for CoQ after ingestion of the miso soup was proteins in miso are modified by the amino-carbonyl re- 0–5 10 significantly higher than after ingestion of clear soup, milk soup, action, which explains its brown color. -us, these modified or raw egg sauce (Figure 1(a)). -is result suggests that the proteins in miso might be candidates for the components suspension of P30 in miso soup may be an effective way of responsible for the enhancement of CoQ absorption, by increasing the bioavailability of orally administered CoQ , emulsification. Besides, miso and soybean extracts improve especially for older people, as the frequency of miso soup zinc absorption via increasing cell surface abundance of a consumption is increased with age in Japanese [45]. zinc transporter [49, 50]. Some components in miso might Interestingly, the effect of miso soup on the absorption of affect the expression and the activity of a CoQ transporter CoQ was abolished when P30 was suspended in raw egg protein. However, further studies are required to determine sauce, despite miso soup also being consumed. -is suggests the identity of the active component(s) and the mechanisms that an interaction between the reduced form of CoQ and a involved in the enhanced absorption of CoQ . -e miso 10 10 component of miso might be necessary for the increase in used in the present study contained only 3.76 and 0.02 μg of bioavailability of CoQ achieved by the consumption of the reduced and oxidized forms of CoQ per g miso (data 10 10 miso soup. -e absorption of orally administered CoQ is not shown), and 10g of the miso was used for the prepa- improved when emulsified with a surfactant that has a ration of one serving of miso soup; therefore, it is unlikely higher hydrophile-lipophile balance value [46]. Soy proteins that the CoQ contributed by the miso is involved in the have emulsifying and interfacial properties [47], and the enhancement in bioavailability of CoQ . amino-carbonyl reaction of soy proteins with sugar im- We also estimated theΔAUC value for the reduced form proves their emulsifying properties [48]. Some of the soy of CoQ in the previously published study to compare these ΔCoQ (µM) ΔAUC (µMol·h/L) 0–5 Clear soup Miso soup Milk soup Raw egg sauce Journal of Nutrition and Metabolism 5 with the ΔAUC values obtained in the present study. 0–5 Disclosure Hosoe et al. performed a single-dose experiment after meal -e sponsors had no role in the design, execution, in- ingestion using 150mg of the reduced form of CoQ in a terpretation, or writing of the study. soft capsule [27]. -e estimated ΔAUC for the first 6h after ingestion (ΔAUC ) in this study was 2.9 μmolh/L, whereas 0–6 Conflicts of Interest theΔAUC in our control experiment, in which 120mg of 0–5 the reduced form of CoQ was consumed in a clear soup -e authors declare that there are no conflicts of interest was 2.97±1.11 μmolh/L (Experiment 1 in Table S2), sug- regarding the publication of this paper. gesting that similar results can be obtained when the reduced form of CoQ is administered. -e ΔAUC associated 10 0–5 Authors’ Contributions with P30-plus-miso ingestion (4.44±1.40 μmolh/L, Exper- iment 2 in Table S2) was >1.5 times higher than those as- T. S. conceptualized the study; M. T. and T. S. took part in sociated with the ingestion of other foods (clear soup, milk clinical study design, collection of laboratory data, and soup, and raw egg sauce), implying that the ingestion of writing of the original draft; and M. T., M. N., T. K., and T. S. CoQ suspended in miso soup is one of the best ways of conducted the clinical study and read, revised, and approved increasing its bioavailability, at least, when P30 is used. the final version of the manuscript. One limitation of our study was that the serum concen- trations ofCoQ were determinedonly upto 5hafter ingestion Acknowledgments because of the research environment and availability of the participants. In contrast, in most previous studies, these con- -e authors thank Dr. Kenji Fujii of Kaneka Corporation for centrations were determined up to 12 or 24h after a single dose providing the granulated reduced CoQ supplement and of CoQ .One could arguethat misosoup may acceleraterather 10 analyzing the serum CoQ concentrations. -ey also thank than enhance CoQ absorption, as the maximum CoQ 10 10 Ms. Hitomi Kobayashi, Ms. Miku Hatsushiba, and Ms. concentration or the maximum CoQ concentration-time 10 Ayaka Hanada for their help with meal preparation for the could not be determined. -e half-life of CoQ in plasma may 10 clinical study. Finally, they thank Mark Cleasby, Ph.D., from reach 33h, and 5 to 6 days were required for plasma CoQ 10 Edanz Group (http://www.edanzediting.com/ac) for editing levels to return to baseline following a single dose [51]. -e a draft of this manuscript. -is study was supported by possibilityofoverestimationoftheeffectofmisosoupon CoQ funding from the Kaneka Corporation (Osaka, Japan), on absorption cannot be denied. the basis of a contract between Kaneka and Wayo Women’s Another limitationof ourstudy wasthatthere isno negative University. control, i.e., meals alone. In the previous reports, there was no placebo control for the determination of the absorption/bio- Supplementary Materials availability of CoQ supplements [25–27, 52–55]. Also, the Figure S1: Meals provided to the participants. Figure S2: effect of CoQ contents in the provided meals seemed to be Changes in serum total CoQ using unpaired one-way extremely low as the estimated CoQ amount was less than one ANOVA. Table S1: Participation in each of the four ex- two-hundredth of the CoQ supplements ingested. However, periments. Table S2: -e increase in serum total CoQ these remain in a matter of speculation. concentration of each subject after the consumption of each To further characterize the effects of miso soup ingestion food type. (Supplementary Materials) on the bioavailability of CoQ , it would be of interest to compare the serum concentrations of CoQ after multiple References meals of miso soup or water containing P30 with or after meals for several weeks. -e significance of the present [1] F. L. Crane, “Biochemical functions of coenzyme Q ,” findings will be evaluated by performing such a clinical Journal of the American College of Nutrition, vol. 20, no. 6, experiment in the near future. pp. 591–598, 2001. [2] G. Lopez-Lluch, ´ J. C. Rodr´ıguez-Aguilera, C. Santos-Ocaña, 5. Conclusions and P. 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Miso Soup Consumption Enhances the Bioavailability of the Reduced Form of Supplemental Coenzyme Q10

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Copyright © 2020 Michiyo Takahashi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Journal of Nutrition and Metabolism Volume 2020, Article ID 5349086, 7 pages https://doi.org/10.1155/2020/5349086 Research Article Miso Soup Consumption Enhances the Bioavailability of the Reduced Form of Supplemental Coenzyme Q 1 2 1,2 1,2 Michiyo Takahashi, Mayumi Nagata, Takehiko Kaneko, and Toshikazu Suzuki Graduate School of Human Ecology, Wayo Women’s University, 2-3-1 Konodai, Ichikawa, Chiba 272-8533, Japan Department of Health and Nutrition, Wayo Women’s University, 2-3-1 Konodai, Ichikawa, Chiba 272-8533, Japan Correspondence should be addressed to Toshikazu Suzuki; t-suzuki@wayo.ac.jp Received 31 August 2019; Accepted 25 November 2019; Published 7 January 2020 Academic Editor: C. S. Johnston Copyright © 2020 Michiyo Takahashi et al. -is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Coenzyme Q (CoQ ) is an essential compound that is involved in energy production and is a lipid-soluble antioxidant. 10 10 Although it has been proposed as an antiaging and a health-supporting supplement, its low bioavailability remains a significant issue. Concurrent food intake enhances the absorption of orally administered CoQ , but it has not been fully established whether specific food substances affect intestinal CoQ absorption. -erefore, to determine whether the bioavailability of supplemental CoQ is affected by diet, P30, a granulated and reduced form of CoQ , was dispersed in four different foods, clear soup, miso 10 10 soup, milk soup, and raw egg sauce. -ose foods which contained CoQ were consumed on different occasions at intervals of 6–14 weeks by the same participants. -irteen participants were recruited in the single-dose and repeated clinical study. When miso soup containing P30 was provided, the serum CoQ concentration increased faster than when participants consumed other P30-containing soups or a P30-containing raw egg sauce. -e area under the curve for serum CoQ during the first 5h after consumption of the P30-containing miso soup was approximately 1.5 times larger than those after the consumption of other P30- containing meals. -ese data imply that the absorption of CoQ supplements can be enhanced by consuming them with food and in particular with specific food substances, such as miso soup. pressure [12], glucose metabolism in diabetes [13], and the 1. Introduction symptoms of Parkinson’s disease [14] and reduces peripheral Coenzyme Q (CoQ ), a vitamin-like substance, is in- oxidative stress and inflammation in interferon β-1a-treated 10 10 volved in energy production and is a lipid-soluble antiox- multiple sclerosis [15]. It can also increase the vitality of idant [1–3]. Many studies have reported a relationship patients undergoing medical treatment and of the elderly between CoQ and aging. For example, the amount of residents of nursing homes [16–18]. Furthermore, it alle- CoQ in muscles and organs decreases with age [4], as does viates fatigue in patients with chronic fatigue syndrome the serum CoQ concentration and that of the reduced form [19, 20], hyperlipidemia [21], and in those with end-stage [5] in healthy adults. Both blood levels and the ratio of the heart failure awaiting cardiac transplantation [22]. In older reduced form of CoQ concentration to total coenzyme Q rats, CoQ supplementation has been shown to alleviate 10 10 10 in hospitalized elderly people were lower than that in the diabetes-induced learning and memory deficits and to im- healthy elderly people [6]. Also, many studies have shown prove cognitive performance when administered at a high associations between serum CoQ status and health [7–11]. dose [23]. In the senescence-accelerated prone 8 mouse, In addition, CoQ supplementation has been shown to CoQ supplementation counteracts the deleterious effects 10 10 ameliorate the symptoms of some geriatric disorders and to of physical exercise-derived reactive oxygen species, im- improve the quality of life of humans and some laboratory proving mitochondrial function [24]. -us, CoQ may be animals. CoQ supplementation ameliorates high blood useful as an antiaging and health-supporting supplement. 10 2 Journal of Nutrition and Metabolism In general, the absorption of compounds from the CoQ was compared among the various foods that were gastrointestinal tract is one of the most important de- concurrently consumed. terminants of oral bioavailability. Intestinal absorption of supplemental CoQ is slow and limited because of the 10 2. Materials and Methods compound’s hydrophobicity and high molecular weight. 2.1. CoQ Supplements. A granulated, solubilized, and re- Many types of CoQ delivery system have been developed 10 duced form of CoQ supplement, P30, was used in the that aim to increase the bioavailability of supplemental study. P30 contains 30 w/w% of reduced CoQ (120mg per CoQ , such as self-emulsifying drug delivery systems, 10 sachet), dextrin, gum Arabic, and L-ascorbate. -ese sup- nanotechnology-based drug delivery systems, cyclodextrin plements were provided by the Kaneka Corporation (Osaka, complexes, CoQ -solanesyl poly(ethylene glycol) succinate Japan). micelles, and a reduced form of CoQ that is both emul- sified and solubilized [25–27]. In addition, the concurrent consumption of food enhances the rate of the absorption of 2.2. Study Design. -irteen healthy volunteers (1 man and 12 orally administered supplemental CoQ [28]. -erefore, the women), who were students or staff at Wayo Women’s consumption of CoQ -fortified foods may be a useful way University, participated in the study. Each participant took a of increasing the bioavailability of CoQ . CoQ supplement with a meal on four occasions, with the It is well known that the absorption of nutrients, such as food type containing the CoQ differing on each occasion. vitamins and minerals, is affected by the food items con- Table 1 shows the meal composition, the sauce of the CoQ , currently consumed or their components. For example, the the nutrient content of the meals. Using the data by Kubo enhancement of β-carotene absorption by mayonnaise et al. [42], CoQ content obtained from the meals in the consumption [29], of carotenoid absorption by avocado or clear soup, miso soup, milk soup, and raw egg source ex- avocado oil consumption [30], of vitamin E absorption by periments were estimated as 0.52, 0.55, 0.56, and 0.59mg, egg consumption [31], and of nonheme iron absorption by respectively, and these were the less than one two-hundredth meat protein and vitamin C consumption, have been re- of the CoQ supplements ingested. It suggests that the effect ported [32–34]. Conversely, some dietary fibers suppress the of CoQ content in meals itself was vanishingly low. -e absorption of β-carotene, lycopene, and lutein [35]. Addi- number of participants in each experiment is shown in tionally, tannins, phytic acid, polyphenols, and calcium Table S1. Photos of the meal components provided for the inhibit the absorption of nonheme iron [36–39]. -us, the subjects are shown in Figure S1. In the experiments, each absorption of supplemental CoQ may also be affected by participant ingested 120mg of reduced CoQ (a sachet of the food or a component with which it is consumed, al- P30) suspended in the food (indicated by red arrowheads in though no previous studies have addressed this issue. Figure S1). In the meals containing P30, the ratio of the -erefore, knowledge of the food items that could enhance concentrations of the reduced form of CoQ concentration the absorption of orally administered CoQ is crucial for the to total coenzyme Q was >99%. To minimize the number development of appropriate functional CoQ -fortified of confounding factors, the same meal was consumed in each foods. experiment, with the exception of the food item containing Previously, we investigated the association between di- the P30. etary habits and serum CoQ levels before and after long- -e nutrient content of the meals was estimated using term supplementation with a reduced form of CoQ Calorie Make software (Toyo System Science Co., Ltd., [40, 41]. People with higher basal serum CoQ concen- Yokohama, Japan). -e consumption of the meals started trations tended to consume more soy products [40], and around 12:00h, at least 3h after breakfast. -e control and those who had a higher increase in serum CoQ concen- test experiments were performed between March and De- trations after the 1-year supplementation tended to consume cember 2018 at intervals of 6–14 weeks. All subjects gave more dairy products and eggs [41]. -ese results remind us their informed consent for inclusion before they participated that soy products, dairy products, and eggs might positively in this study. -is study was conducted in accordance with affect the absorption of CoQ supplements. the Declaration of Helsinki, and the protocol was approved In this study, we investigated the effect of various by the Wayo Women’s University Human Research Ethics foods on the bioavailability of supplemental CoQ using Committee (no. 1734). P30, a granulated and reduced form of CoQ supple- ment, and a typical Japanese meal, consisting of steamed rice, grilled salmon with marinated Japanese radish, 2.3. Blood Collection and CoQ Measurements. Blood boiled spinach, and soup. P30 was suspended in the soup samples were drawn from a vein at the baseline (just before or raw egg sauce in advance, before being provided to the meal ingestion), and 1.5, 3, and 5h after the start of the meal, participants. Miso soup, milk soup, and raw egg sauce and serum was obtained by centrifugation after clot for- were used as foods containing soy products, daily mation. Quantitative analysis of serum CoQ concentration products, and eggs, respectively. Clear soup, which is was measured by Kaneka Techno Research Co., Ltd., using seasoned with salt, was used as a reference food. -e soup liquid chromatography with tandem mass spectrometry consumed was different in each experiment. Serum (LC/MS/MS) [43, 44]. In brief, 0.7mL of the isopropanol was CoQ concentration was determined before, and 1.5, 3, added to 0.1mL of serum, mixed, and stored at −80 C until and 5 h after eating the meals, and the bioavailability of just before the analysis. After centrifugation, the supernatant Journal of Nutrition and Metabolism 3 Table 1: Meal menus for each experiment. Experiment no. 1 2 3 4 Experiment Clear soup Miso soup Milk soup Raw egg sauce Meal menu Main dish Grilled salmon with Japanese radish marinated in citrus juice Side dish Boiled spinach flavored with bonito flakes and soy sauce Staple food Rice Rice Rice Rice with stirred raw egg sauce a a a Soup Clear soup Miso soup Milk soup Miso soup Other — — — — Nutrient content per serve Energy (kcal) 336 356 437 430 Protein (g) 20.1 21.5 25.1 27.5 Fat (g) 3.6 4.3 9.3 9.4 Carbohydrate (g) 54.1 56.5 61.3 56.4 CoQ (mg) 120 120 120 120 a b P30 was suspended in this food item; only CoQ obtained from P30 is recorded. was filtered through a membrane filter. -en, 200 μL aliquots compared using unpaired one-way ANOVA and Holm– were mixed with 200 μL of methanol and 50 µL of oxidized Bonferroni post hoc testing because some participants CoQ (50ng/mL in 2-propanol) as an internal standard and missed in the first and third experiments. -e concentration used as the sample for LC/MS/MS, which was performed achieved following the consumption of P30 in miso soup was using an AB Sciex Triple Quad 5500 LC-MS/MS system and significantly higher than that achieved following con- a reversed-phase octadecyl-silica column (AB Sciex, Fra- sumption of the raw egg sauce after 1.5h and higher than mingham, MA, USA). -e intra- and interday coefficients of that achieved following all three other meals after 3h variation for CoQ were less than 2 and 10%, respectively. (Figure S2A). -ere were significant differences in ΔAUC 10 0–5 between the clear soup and miso soup days, and between the miso soup and raw egg sauce days (Figure S2B). -e ΔAUC 0–5 2.4. Data Analysis. -e increase in concentration of CoQ in following miso soup ingestion was 4.44±1.40 μmolh/L, the serum after the ingestion of a CoQ -suspended test meal which is approximately 1.5- and 1.6-fold higher (P<0.05) (ΔCoQ ) was calculated by subtracting the baseline value, than that on the clear soup (2.97±1.11 μmolh/L) and raw egg and numerical data are expressed as mean±SD. To compare sauce (2.84±1.36 μmolh/L) days, respectively (Table S2). the bioavailabilities of CoQ , the areas under the serum -en, we reanalyzed the data from the eight participants CoQ concentration-time curves up to 5h after ingestion (numbers 3, 4, 5, 8, 9, 11, 12, and 13) who had participated in (ΔAUC ) were calculated. -ese data were analyzed using 0–5 all of the four experiments (Table S1), using one-way one-way analysis of variance (ANOVA) with unpaired and ANOVA with repeated measures (Figure 1). -e ΔCoQ on repeated measures, and the differences between the means the miso soup day was significantly higher than on the raw were evaluated by Holm–Bonferroni post hoc testing using egg sauce days after 1.5h and higher than on all of the other 3 js-STAR ver. 9. 3. 0j web application software (http://www. days 3h after ingestion (Figure 1(a)). -e mean ΔAUC on 0–5 kisnet.or.jp/nappa/software/star/). P<0.05 was considered to the miso soup day was 4.94±1.51 μmolh/L, which was represent statistical significance. 1.6∼1.7-fold higher (P<0.05) than that on the clear soup (3.08±1.33 μmolh/L), milk soup (2.95±1.07 μmolh/L), and 3. Results raw egg sauce (3.05±1.64 μmolh/L) days, respectively (Figure 1(b)). -irteen healthy volunteers (1 man and 12 women) par- -ese results demonstrate that the absorption rate and ticipated in the study. Each ingested a CoQ supplement in bioavailability of supplemental reduced CoQ up to 5h after the form of suspended a suspension in a food item on up to ingestion was increased by suspending it in miso soup. four separate occasions. Twelve participated in the first However, this effect was abolished when the CoQ was experiment (supplemental CoQ in clear soup as a refer- suspended in raw egg sauce, even if miso soup was ingested ence), thirteen participated in the second experiment at the same time (experiment 4). (supplemental CoQ in miso soup), nine participated in the third experiment (supplemental CoQ in milk soup), and thirteen participated in the fourth experiment (supplemental 4. Discussion CoQ in a raw egg sauce). -e participation of each in- dividual and the increases in serum total CoQ concen- In this study, we determined whether the absorption of a CoQ 10 10 tration after each meal are shown in Tables S1 and S2, supplement would be affected when it was suspended in specific respectively. ΔAUC was also calculated for each partic- foods. -ere were no differences in either ΔCoQ orΔAUC 0–5 10 0–5 ipant (Table S2). among participants who consumed a clear soup and test meals First, the increase in serum total CoQ (ΔCoQ ) on different days, with the exception of the day they consumed 10 10 concentration after each of the four experiments were the supplement in miso soup. Both the ΔCoQ at 3h and the 10 4 Journal of Nutrition and Metabolism 2 7 1.5 0.5 ab ab 0 12345 Time (h) Clear soup Milk soup Miso soup Raw egg sauce (a) (b) Figure 1: Changes in serum total CoQ concentration (a) and a comparison ofΔAUC (b) after the consumption of P30 in clear soup, 10 0–5 P30 in miso soup, P30 in milk soup, or P30 in raw egg sauce. 120mg of CoQ was administered. In Figure 1(a), the open circle represents P30 in clear soup, closed circle represents P30 in miso soup, open triangle represents P30 in milk soup, and open square indicates P30 in raw egg sauce. Data are mean±SD for the eight individuals who participated in all four of the experiments. Figure 1(b) shows box plots for the ΔAUC for these eight participants. -e boundary of the box closest to zero indicates the 25th percentile, the line within the box indicates 0–5 the median, the multiplication sign within the box indicates the mean, and the boundary of the box farthest from the origin indicates the 75th percentile. Whiskers above and below the box indicate the 10th and 90th percentiles. Data were analyzed with one-way analysis of variance with repeated measures, and differences between the means were evaluated using Holm–Bonferroni post hoc tests. Different lower case letters indicate significant differences, with P<0.05. ΔAUC for CoQ after ingestion of the miso soup was proteins in miso are modified by the amino-carbonyl re- 0–5 10 significantly higher than after ingestion of clear soup, milk soup, action, which explains its brown color. -us, these modified or raw egg sauce (Figure 1(a)). -is result suggests that the proteins in miso might be candidates for the components suspension of P30 in miso soup may be an effective way of responsible for the enhancement of CoQ absorption, by increasing the bioavailability of orally administered CoQ , emulsification. Besides, miso and soybean extracts improve especially for older people, as the frequency of miso soup zinc absorption via increasing cell surface abundance of a consumption is increased with age in Japanese [45]. zinc transporter [49, 50]. Some components in miso might Interestingly, the effect of miso soup on the absorption of affect the expression and the activity of a CoQ transporter CoQ was abolished when P30 was suspended in raw egg protein. However, further studies are required to determine sauce, despite miso soup also being consumed. -is suggests the identity of the active component(s) and the mechanisms that an interaction between the reduced form of CoQ and a involved in the enhanced absorption of CoQ . -e miso 10 10 component of miso might be necessary for the increase in used in the present study contained only 3.76 and 0.02 μg of bioavailability of CoQ achieved by the consumption of the reduced and oxidized forms of CoQ per g miso (data 10 10 miso soup. -e absorption of orally administered CoQ is not shown), and 10g of the miso was used for the prepa- improved when emulsified with a surfactant that has a ration of one serving of miso soup; therefore, it is unlikely higher hydrophile-lipophile balance value [46]. Soy proteins that the CoQ contributed by the miso is involved in the have emulsifying and interfacial properties [47], and the enhancement in bioavailability of CoQ . amino-carbonyl reaction of soy proteins with sugar im- We also estimated theΔAUC value for the reduced form proves their emulsifying properties [48]. Some of the soy of CoQ in the previously published study to compare these ΔCoQ (µM) ΔAUC (µMol·h/L) 0–5 Clear soup Miso soup Milk soup Raw egg sauce Journal of Nutrition and Metabolism 5 with the ΔAUC values obtained in the present study. 0–5 Disclosure Hosoe et al. performed a single-dose experiment after meal -e sponsors had no role in the design, execution, in- ingestion using 150mg of the reduced form of CoQ in a terpretation, or writing of the study. soft capsule [27]. -e estimated ΔAUC for the first 6h after ingestion (ΔAUC ) in this study was 2.9 μmolh/L, whereas 0–6 Conflicts of Interest theΔAUC in our control experiment, in which 120mg of 0–5 the reduced form of CoQ was consumed in a clear soup -e authors declare that there are no conflicts of interest was 2.97±1.11 μmolh/L (Experiment 1 in Table S2), sug- regarding the publication of this paper. gesting that similar results can be obtained when the reduced form of CoQ is administered. -e ΔAUC associated 10 0–5 Authors’ Contributions with P30-plus-miso ingestion (4.44±1.40 μmolh/L, Exper- iment 2 in Table S2) was >1.5 times higher than those as- T. S. conceptualized the study; M. T. and T. S. took part in sociated with the ingestion of other foods (clear soup, milk clinical study design, collection of laboratory data, and soup, and raw egg sauce), implying that the ingestion of writing of the original draft; and M. T., M. N., T. K., and T. S. CoQ suspended in miso soup is one of the best ways of conducted the clinical study and read, revised, and approved increasing its bioavailability, at least, when P30 is used. the final version of the manuscript. One limitation of our study was that the serum concen- trations ofCoQ were determinedonly upto 5hafter ingestion Acknowledgments because of the research environment and availability of the participants. In contrast, in most previous studies, these con- -e authors thank Dr. Kenji Fujii of Kaneka Corporation for centrations were determined up to 12 or 24h after a single dose providing the granulated reduced CoQ supplement and of CoQ .One could arguethat misosoup may acceleraterather 10 analyzing the serum CoQ concentrations. -ey also thank than enhance CoQ absorption, as the maximum CoQ 10 10 Ms. Hitomi Kobayashi, Ms. Miku Hatsushiba, and Ms. concentration or the maximum CoQ concentration-time 10 Ayaka Hanada for their help with meal preparation for the could not be determined. -e half-life of CoQ in plasma may 10 clinical study. Finally, they thank Mark Cleasby, Ph.D., from reach 33h, and 5 to 6 days were required for plasma CoQ 10 Edanz Group (http://www.edanzediting.com/ac) for editing levels to return to baseline following a single dose [51]. -e a draft of this manuscript. -is study was supported by possibilityofoverestimationoftheeffectofmisosoupon CoQ funding from the Kaneka Corporation (Osaka, Japan), on absorption cannot be denied. the basis of a contract between Kaneka and Wayo Women’s Another limitationof ourstudy wasthatthere isno negative University. control, i.e., meals alone. In the previous reports, there was no placebo control for the determination of the absorption/bio- Supplementary Materials availability of CoQ supplements [25–27, 52–55]. Also, the Figure S1: Meals provided to the participants. Figure S2: effect of CoQ contents in the provided meals seemed to be Changes in serum total CoQ using unpaired one-way extremely low as the estimated CoQ amount was less than one ANOVA. Table S1: Participation in each of the four ex- two-hundredth of the CoQ supplements ingested. However, periments. Table S2: -e increase in serum total CoQ these remain in a matter of speculation. concentration of each subject after the consumption of each To further characterize the effects of miso soup ingestion food type. (Supplementary Materials) on the bioavailability of CoQ , it would be of interest to compare the serum concentrations of CoQ after multiple References meals of miso soup or water containing P30 with or after meals for several weeks. -e significance of the present [1] F. L. Crane, “Biochemical functions of coenzyme Q ,” findings will be evaluated by performing such a clinical Journal of the American College of Nutrition, vol. 20, no. 6, experiment in the near future. pp. 591–598, 2001. [2] G. Lopez-Lluch, ´ J. C. Rodr´ıguez-Aguilera, C. Santos-Ocaña, 5. Conclusions and P. 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