Breast milk secretion promoting agent, breast milk secretion function enhancing agent, breast milk secretion function inhibition improving agent, mammary gland involution inhibiting agent, stat5 phosphorylation promoting agent, stat3 phosphorylation inhibiting agent, and phosphorylated stat5 / phosphorylated stat3 ratio enhancing agent

Abstract

In one embodiment, a problem to be solved by the present invention is to provide a new agent the agent being for at least one selected from the group consisting of promoting breast milk secretion, enhancing breast milk secretion function, improving inhibition of breast milk secretion function, and inhibiting mammary gland involution, said agent comprising, as an active ingredient, a substance that has not heretofore been known to have a breast milk secretion promoting effect. The present invention provides an agent for at least one selected from the group consisting of promoting breast milk secretion, enhancing breast milk secretion function, improving inhibition of breast milk secretion function, and inhibiting mammary gland involution, said agent containing a starting material derived from at least one selected from the group consisting of oranges, aloe, carrots, American ginseng, figs, almonds, hyuganatsu, laurel, apples, soybeans, chrysanthemums, wheatgrass, pepper, ginger, ebi-imo, Japanese yams, kuugaimo, Nikko maple, poppies, and radishes.

Description

Breast milk secretion promoter, breast milk secretion function enhancer, breast milk secretion function inhibitor improver, mammary gland regression inhibitor, STAT5 phosphorylation promoter, STAT3 phosphorylation inhibitor, phosphorylated STAT5 / phosphorylated STAT3 ratio enhancer

[0001] The present invention relates to a breast milk secretion promoter, a breast milk secretion function enhancer, a breast milk secretion function inhibitory enhancer, a mammary gland regression inhibitor, a STAT5 phosphorylation promoter, a STAT3 phosphorylation inhibitor, and an enhancer of the phosphorylated STAT5 / phosphorylated STAT3 ratio.

[0002] Breast milk contains unique components essential for infant growth, such as nutrients and immune components, and the WHO promotes breastfeeding. However, despite over 90% of pregnant women wanting to breastfeed, the Ministry of Health, Labour and Welfare's 2015 Infant Nutrition Survey showed that only about half of mothers exclusively breastfed after birth. For mothers who intended to raise their infants solely on breast milk, being unable to do so can lead to significant psychological disappointment. Against this backdrop, lactation-promoting substances are used for breastfeeding mothers suffering from insufficient milk production. Among lactation-promoting drugs, domperidone is the most commonly used (Non-Patent Literature 1), followed by metoclopramide and sulpiride. In addition to these drugs, lemongrass (active ingredient citral) is known as a food that improves breast milk production (Non-Patent Literature 2). However, given the above circumstances, the development of new methods to improve breast milk production remains highly desired.

[0003] Alla Osadchy, et al., Obstet Gynecol Int. 2012, 642893. Asahi Group Foundation 2017 Annual Research Report, Ken Kobayashi, "Research on the Search for Bioactive Substances Affecting Breast Milk Secretion and Their Mechanisms of Action", https: / / www.asahigroup-foundation.com / support / pdf / report / 2017 / 01.pdf, Siew Cheng Foong, et al., Cochrane Database Syst Rev. 2020, 18(5), CD011505, Carrie H Oliver, et al., JAKSTAT. 2013, 2(2), e23228, Ken Kobayashi, et al., J Mammary Gland Biol Neoplasia, 2018, 23(1-2), 75-88, Ken Kobayashi, et al., Veterinary Research 44,119,2013, Richard W E Clarkson, et al., Mol Endocrinol. 2006 Mar;20(3):675-85

[0004] In one embodiment, the problem to be solved by the present invention is to provide a novel agent for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland involution, which contains as an active ingredient a substance that has not been known to have a breast milk secretion promoting effect heretofore. In one embodiment, the problem to be solved by the present invention is to provide a novel STAT3 phosphorylation inhibitor containing as an active ingredient a substance that has not been known to have an inhibitory effect on STAT3 phosphorylation heretofore. In one embodiment, the problem to be solved by the present invention is to provide a novel STAT5 phosphorylation promoter containing as an active ingredient a substance that has not been known to have a promoting effect on STAT5 phosphorylation heretofore.

[0005] Under these circumstances, the inventors diligently researched a vast number of candidate substances and found that orange, aloe, carrot, American ginseng, fig, almond, Hyuga citrus, laurel, apple, soybean, chrysanthemum, wheat birch, pepper, Japanese ginger, shrimp taro, Japanese yam, Chinese yam, Japanese star anise, Japanese poppy, and radish have STAT3 phosphorylation inhibitory activity and STAT5 phosphorylation promoting activity. Based on this novel finding, the inventors conducted extensive trial and error regarding the type of active ingredient, the amount of ingredients, and other components, ultimately completing the present invention. Accordingly, the present invention provides the following: Item 1. Item 2. An agent for promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression, comprising a raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, kuyam, Japanese star anise, poppy, and radish. Item 2. A STAT 5 phosphorylation accelerator comprising a raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, kuyam, Japanese star anise, poppy, and radish. Item 3. STAT3 phosphorylation inhibitor comprising a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese star anise, poppy, and radish. Item 4. Phosphorylated STAT5 / phosphorylated STAT3 ratio improver comprising a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese star anise, Japanese star anise, poppy, and radish. Item 5. The agent described in any one of items 1 to 4, which is a food or beverage.Item 6. Use of raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese spindle tree, Japanese oak, poppy, and radish to produce an agent for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression. Item 7. Use of raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese spindle tree, Japanese oak, poppy, and radish to produce a STAT 5 phosphorylation accelerator. Item 8. Item 9. Use of at least one raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Chinese yam, Japanese star anise, poppy, and radish to produce an inhibitor of STAT3 phosphorylation. Item 10. Use of any one of items 6 to 9, wherein the agent is a food or beverage. Item 11. A method for promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression, comprising administering to a subject in need of such a substance a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Hyuga citrus, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, kuugai, Japanese oak, Japanese poppy, and radish, for at least one of the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression.Item 12. A method for promoting the phosphorylation of STAT 5, comprising administering to a subject requiring it a raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Chinese yam, Japanese star anise, poppy, and radish. Item 13. A method for inhibiting the phosphorylation of STAT 3, comprising administering to a subject requiring it a raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, Japanese yam, Japanese yam, Chinese star anise, poppy, and radish. Item 14. A method for improving the phosphorylated STAT5 / phosphorylated STAT3 ratio, comprising administering to a subject in need of such improvement a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Japanese yam, Japanese star anise, poppy, and radish. Item 15. The method according to any one of items 11 to 14, wherein a food or beverage containing the raw material is administered to the subject. Item 16. A raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese spinach, Japanese oak, Japanese oak, poppy, and radish, for promoting the phosphorylation of STAT 5. Item 17. A raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese oak, Japanese oak, Japanese oak, poppy, and radish, for promoting the phosphorylation of STAT 5.Item 18. Raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese star anise, poppy, and radish, for inhibiting the phosphorylation of STAT3. Item 19. Raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese star anise, poppy, and radish, for improving the phosphorylated STAT5 / phosphorylated STAT3 ratio. Item 20. Raw materials derived from any one of items 16 to 19, contained in food and beverages. Item 21. Item 22. An orange-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 23. An aloe-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 24. An American ginseng-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 25. A fig-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 26. An almond-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 27. A raw material derived from Hyuga citrus for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 28. A raw material derived from laurel for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression.Item 29. An apple-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 30. A soybean-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 31. A chrysanthemum-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 32. A wheat birch-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 33. A pepper-derived ingredient for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 34. Item 35. A raw material derived from Japanese ginger for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 36. A raw material derived from taro for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 37. A raw material derived from Japanese yam for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 38. A raw material derived from Japanese laurel for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 39. A poppy-derived raw material for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression. Item 40. A radish-derived raw material for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression.

[0006] In one embodiment, the present invention provides a novel agent for promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression, using a substance previously not known to have a breast milk secretion-promoting effect as an active ingredient. In one embodiment, the present invention provides a novel STAT3 phosphorylation inhibitor, using a substance previously not known to have a STAT3 phosphorylation inhibitory effect as an active ingredient. In one embodiment, the present invention provides a novel STAT5 phosphorylation promoter, using a substance previously not known to have a STAT5 phosphorylation-promoting effect as an active ingredient. In addition to the aforementioned citral, other natural milk secretion promoters include fenugreek, fennel, thistle, tolbangun leaves, shatavari, anise, and aniseed (Non-Patent Literature 3). However, the effects of oranges, aloe, carrots, American ginseng, figs, almonds, Hyuga citrus, laurel, apples, soybeans, chrysanthemums, birch, pepper, Japanese ginger, taro, yam, Japanese yam, Japanese star anise, Japanese poppy, and radish on promoting milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression were completely unknown. Therefore, the effects of the present invention could not have been predicted from the prior art.

[0007] This study demonstrates the stimulating effect of plant extracts on phosphorylated STAT5 / phosphorylated STAT3 expression. The control group is represented as 1. As a membrane correction, the average value of phosphorylated STAT5 / phosphorylated STAT3 expression in the citral-added group was calculated, and the expression intensity of each plant extract-added group was compared with the average value of the citral-added group to calculate a relative value.

[0008] In one embodiment, the present invention provides a STAT 5 phosphorylation accelerator comprising a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese laurel, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Japanese yam, Japanese star anise, Japanese poppy, and radish.

[0009] The STAT 5 phosphorylation accelerator of the present invention contains, as an active ingredient, a raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Chinese yam, Japanese star anise, poppy, and radish. In the present invention, "at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, Japanese yam, Japanese yam, Chinese star anise, poppy, and radish" may also be simply referred to as orange, etc. Similarly, "raw materials derived from at least one selected from the group consisting of oranges, aloe, carrots, American ginseng, figs, almonds, Hyuga citrus, laurel, apples, soybeans, chrysanthemums, birch, pepper, Japanese ginger, taro, yam, Japanese yam, Japanese star anise, poppy, and radish" may simply be referred to as raw materials derived from oranges, etc.

[0010] For obtaining raw materials derived from oranges, etc., which are used as extraction raw materials, the following parts can be used: leaves, fruits, peels, flowers, flower spikes, seeds, seed coats, stems, roots, root bark, etc. More specifically, examples include almond seed coats, birch leaves, aloe leaves, carrot roots, pepper fruits, ginger flower spikes, soybean seeds, fig peels, taro roots, laurel leaves, citrus peels, yam root bark, yam roots, Japanese star anise leaves, chrysanthemum flowers, apple peels, orange peels, American carrot roots, poppy seeds, radish roots, etc. These raw materials can be used individually or in combination of two or more. The varieties, origins, and harvest times of the leaves, fruits, peels, flowers, flower spikes, seeds, seed coats, stems, roots, root bark, etc., of oranges, etc., are not particularly limited. Furthermore, the leaves, fruits, peels, flowers, flower spikes, seeds, seed coats, stems, roots, root bark, etc. of oranges, etc., may be subjected to pretreatment such as finely chopping or grinding as a pretreatment before being subjected to the extraction process. In addition, raw materials derived from oranges, etc., include, for example, orange extracts, pressed products, ground products (such as almond milk), and pulverized products. Methods known to the public can be appropriately applied to obtain these raw materials. For example, in embodiments using orange extracts, the extract can be obtained using general methods for extracting extracts from plants. Examples include steam distillation, leaching, decoction, and vacuum low-temperature distillation. For example, an extraction method may involve extracting from the leaves, fruits, peels, flowers, flower spikes, seeds, seed coats, stems, roots, root bark, etc. of oranges, etc., using alcohol (e.g., ethanol) or water containing alcohol (e.g., 99% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 10% by mass or less, etc.). Commercially available raw materials derived from oranges, etc., can also be used. Furthermore, the form of the obtained raw material derived from oranges, etc., may be any form, such as liquid, solid, or powder. In the case of a liquid, it may be the liquid in the solvent used for extraction, etc., but it may also be a liquid concentrate obtained by concentration, for example. It may also be a suspension in which a part of the extract or fraction has precipitated during the concentration process.Liquid raw materials, such as those derived from oranges, may be subjected to drying treatments such as freeze-drying to obtain solid raw materials or fractions. These raw materials can be used individually or in combination of two or more.

[0011] The phosphorylation of STAT5 can be measured and evaluated by the method described in the embodiments of this application, which will be described later. Preferably, the phosphorylated STAT5 value (value after standardization and correction with total STAT5) of the STAT5 phosphorylation accelerator of the present invention is 1.30 times or more, more preferably 1.50 times or more, more preferably 1.75 times or more, more preferably 2.00 times or more, more preferably 2.50 times or more, and more preferably 3.00 times or more compared to the phosphorylated STAT5 in the control without the STAT5 phosphorylation accelerator of the present invention. There is no upper limit to the degree of STAT5 phosphorylation acceleration by the STAT5 phosphorylation accelerator of the present invention, but examples include 10 times or less, 7 times or less, 5 times or less, etc.

[0012] In the present invention, the active ingredient of the present invention may be the raw material derived from oranges, etc., itself, or it may be used as a composition in which the combination is used with various carriers that are pharmaceutically acceptable or can be added to food (for example, isotonic agents, chelating agents, stabilizers, pH adjusters, preservatives, antioxidants, solubilizers, viscosity enhancers, excipients, binders, lubricants (or flow improvers), etc.). In this embodiment, the content of the raw material derived from oranges, etc., in the composition of the present invention is not limited and can be appropriately set in the range of 0.0001% by mass to 100% by mass. For example, 0.0001 mass% or more, 0.0005 mass% or more, 0.001 mass% or more, 0.005 mass% or more, 0.01 mass% or more, 0.05 mass% or more, 0.1 mass% or more, 0.5 mass% or more, 1 mass% or more, 3 mass% or more, 5 mass% or more, 7 mass% % or more, 10 mass% or more, 15 mass% or more, 20 mass% or more, 30 mass% or more, 40 mass% or more, 50 mass% or more, 60 mass% or more, 70 mass% or more, 80 mass% or more, 90 mass% or more, 95 mass% or more, 99 mass% or more. There is no upper limit on the content of raw materials derived from oranges, etc., but it may be 100% by mass, and can be set appropriately within the range of 99% by mass or less, 95% by mass or less, 90% by mass or less, 80% by mass or less, 70% by mass or less, 60% by mass or less, 50% by mass or less, 40% by mass or less, 30% by mass or less, 20% by mass or less, 15% by mass or less, 10% by mass or less, 7% by mass or less, 5% by mass or less, 3% by mass or less, 1% by mass or less, 0.1% by mass or less, etc.

[0013] Examples of isotonic agents include sugars such as glucose, trehalose, lactose, fructose, mannitol, xylitol, and sorbitol; polyhydric alcohols such as glycerin, polyethylene glycol, and propylene glycol; and inorganic salts such as sodium chloride, potassium chloride, and calcium chloride. These isotonic agents can be used individually or in combination of two or more.

[0014] Examples of chelating agents include edetates such as disodium edetate, disodium calcium edetate, trisodium edetate, tetrasodium edetate, and calcium edetate, ethylenediaminetetraacetate, nitrilotriacetic acid or its salts, sodium hexametaphosphate, and citric acid. These chelating agents can be used individually or in combination of two or more.

[0015] Examples of stabilizers include sodium bisulfite.

[0016] Examples of pH adjusting agents include acids such as hydrochloric acid, carbonic acid, acetic acid, and citric acid, as well as alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, alkali metal carbonates or bicarbonates such as sodium carbonate, alkali metal acetates such as sodium acetate, alkali metal citrates such as sodium citrate, and bases such as trometamol. These pH adjusting agents can be used individually or in combination of two or more.

[0017] Examples of preservatives include sorbic acid, potassium sorbate, parahydroxybenzoic acid esters such as methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate, and butyl parahydroxybenzoate, chlorhexidine gluconate, benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, and other quaternary ammonium salts, alkyl polyaminoethylglycine, chlorobutanol, polyquad, polyhexamethylene biguanide, and chlorhexidine. These preservatives can be used individually or in combination of two or more.

[0018] Examples of antioxidants include sodium bisulfite, anhydrous sodium sulfite, sodium pyrosulfite, and concentrated mixed tocopherols. These antioxidants can be used individually or in combination of two or more.

[0019] Examples of solubilizers include sodium benzoate, glycerin, D-sorbitol, glucose, propylene glycol, hydroxypropyl methylcellulose, polyvinylpyrrolidone, macrogol, and D-mannitol. These solubilizers can be used individually or in combination of two or more.

[0020] Examples of viscosity-reducing agents include polyethylene glycol, methylcellulose, ethylcellulose, carmellose sodium, xanthan gum, chondroitin sulfate sodium, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, and polyvinyl alcohol. These viscosity-reducing agents can be used individually or in combination of two or more.

[0021] Examples of excipients include lactose, corn starch, L-cysteine, trehalose, maltitol, and sorbitol. These excipients can be used individually or in combination of two or more.

[0022] Examples of binders include crystalline cellulose, starch, sucrose, hydroxypropylcellulose, gelatin, acacia powder, polyvinylpyrrolidone, pullulan, dextrin, cyclodextrin, methylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyethylene glycol, and the like. These binders can be used individually or in combination of two or more.

[0023] Examples of lubricants (or fluidity improvers) include silicon dioxide, calcium stearate, magnesium stearate, talc, and polyethylene glycol. These lubricants can be used individually or in combination of two or more. Furthermore, the composition of the present invention may further incorporate at least one component selected from the group consisting of components known to promote the phosphorylation of STAT 5, components known to inhibit the phosphorylation of STAT 3, and components known to improve the phosphorylated STAT 5 / phosphorylated STAT 3 ratio.

[0024] The STAT5 phosphorylation accelerator of the present invention may also be in the form of an oral composition. Accordingly, in this embodiment, the present invention provides a STAT5 phosphorylation accelerator that is an oral composition containing raw materials derived from oranges, etc. Furthermore, the STAT5 phosphorylation accelerator of the present invention includes foods and beverages, pharmaceuticals, etc. Foods and beverages in the present invention also include health functional foods (nutrient functional foods, foods for specified health uses, foods with functional claims), etc. Examples of foods and beverages include beverages such as tea beverages, vegetable juice beverages, fruit juice beverages, mixed vegetable and fruit juice beverages, milk beverages, fermented milk beverages, and almond-containing beverages; and foods such as cookies, biscuits, ice cream, frozen desserts, almond-containing foods, chocolates (including semi-chocolate, etc.), fermented milk foods (yogurt, cheese), gummies, candies, jellies and mousses, snack foods, rice crackers, and Japanese sweets. Supplements are also included in the foods and beverages in the present invention. In the present invention, among these foods and beverages, cookies, supplements, and beverages are preferred. Examples of supplements include capsules, powders, and tablets, with capsules being preferred. The dosage form in the embodiment of the pharmaceutical product is not limited and includes oral preparations such as capsules, powders, granules, and tablets; injections; and patches, with oral preparations being preferred.

[0025] The STAT5 phosphorylation accelerator of the present invention can be used by ingestion by a target (preferably a mammal such as a human). The amount of STAT5 phosphorylation accelerator of the present invention to be ingested is not limited, but the daily intake of the active ingredient, which is derived from oranges, etc., is preferably, for example, 1 mg or more, more preferably 10 mg or more, more preferably 100 mg or more, more preferably 200 mg or more, more preferably 300 mg or more, more preferably 400 mg or more, and more preferably 450 mg or more. The upper limit of the amount of STAT5 phosphorylation accelerator of the present invention to be ingested is also not limited, but the daily intake of the active ingredient, which is derived from oranges, etc., is preferably, for example, 30 g or less, more preferably 20 g or less, more preferably 10 g or less, more preferably 5 g or less, more preferably 1 g or less, and more preferably 500 mg or less. The recommended daily intake range for the STAT5 phosphorylation accelerator of the present invention is, for example, 1 mg to 30 g, more preferably 100 mg to 20 g, more preferably 200 mg to 10 g, more preferably 300 mg to 5 g, more preferably 400 mg to 1 g, and more preferably 450 mg to 500 mg, based on the active ingredient derived from oranges or the like. The number of times the STAT5 phosphorylation accelerator of the present invention is taken per day is not limited, but can be appropriately set within the range of 1 to 4 times, 1 to 3 times, 1 to 2 times, or 1 time per day. If taken multiple times a day, for example, the amount taken per dose can be adjusted so that the total daily intake falls within the above range. The STAT5 phosphorylation accelerator of the present invention may be taken before, during, or after a meal. If taken after a meal, it is preferably within 3 hours after the end of the meal, more preferably within 1 hour, even more preferably within 30 minutes, and particularly preferably within 15 minutes. It is preferable to administer the STAT5 phosphorylation enhancer before meals, preferably within 3 hours of the start of a meal, and more preferably within 1 hour. Furthermore, it is preferable to administer it within 30 minutes, and particularly preferably within 15 minutes. In addition, the STAT5 phosphorylation enhancer of the present invention can be ingested between meals (for example, as a snack). Furthermore, in the present invention, the STAT5 phosphorylation enhancer may be used in vivo, but it may also be added in vitro to cells, biological tissues constructed from cells, etc.

[0026] An agent for at least one selected from the group consisting of a STAT3 phosphorylation inhibitor, an agent for improving the phosphorylated STAT5 / phosphorylated STAT3 ratio, a breast milk secretion promoter, a breast milk secretion function promoter, a breast milk secretion function promoter, a breast milk secretion function inhibitor, and a mammary gland regression inhibitor. In one embodiment, the present invention provides a STAT3 phosphorylation inhibitor comprising a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, laurel, apple, soybean, chrysanthemum, wheat birch, pepper, Japanese ginger, shrimp taro, Japanese yam, Japanese yam, Japanese yam, Japanese star anise, poppy, and radish. In one embodiment, the present invention provides an agent for improving the phosphorylated STAT5 / phosphorylated STAT3 ratio, comprising a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Japanese yam, Japanese star anise, poppy, and radish.

[0027] As mentioned above, according to the present invention, by using raw materials derived from oranges, etc., it is possible to suppress the phosphorylation of STAT3 and promote the phosphorylation of STAT5. Here, STAT5 and STAT3 have been reported as transcription activators involved in milk production (Non-Patent Documents 4 and 5). It has also been reported that the expression ratio of phosphorylation of STAT5 and STAT3 is related to milk secretion (Non-Patent Document 6). Furthermore, Non-Patent Document 5 states that STAT5 and STAT3 are involved in mammary gland secretion function. There are also reports that STAT5 and STAT3 are involved in suppressing breast milk secretion function (Non-Patent Document 6). In addition, there are reports that STAT5 and STAT3 are involved in mammary gland regression (Non-Patent Document 7).

[0028] Accordingly, in one embodiment, the present invention provides an agent for at least one of the following: promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression, comprising a raw material selected from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Japanese yam, Japanese star anise, Japanese poppy, and Japanese radish.

[0029] In these embodiments, the details of the type, amount, and method of use of raw materials derived from oranges, etc., are the same as those described for the STAT5 phosphorylation promoter. Furthermore, the STAT3 phosphorylation inhibitor and the phosphorylated STAT5 / phosphorylated STAT3 ratio improver of the present invention may be further combined with at least one selected from the group consisting of components known to promote STAT5 phosphorylation, components known to inhibit STAT3 phosphorylation, and components known to improve the phosphorylated STAT5 / phosphorylated STAT3 ratio. Examples of such components known to inhibit STAT3 phosphorylation include raw materials derived from burdock, sweet potato, ginger, etc. Furthermore, the agent for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and inhibiting mammary gland regression of the present invention may be further combined with components known to promote breast milk secretion, improve breast milk secretion function, improve suppression of breast milk secretion function, inhibit mammary gland regression, etc. Examples of ingredients known to have such breast milk secretion-promoting effects include raw materials derived from fenugreek, ginger, fennel, chaste tree, sweet potato, camellia, lotus, burdock, olive, water cabbage, corn, etc.

[0030] The phosphorylation of STAT3 can be measured and evaluated by the method described in the examples of this application, which will be described later. Preferably, the phosphorylated STAT3 inhibitor of the present invention has a phosphorylated STAT3 value (value after standardization and correction with total STAT3) that is 0.95 times or less, more preferably 0.90 times or less, more preferably 0.85 times or less, more preferably 0.80 times or less, more preferably 0.75 times or less, more preferably 0.70 times or less, more preferably 0.60 times or less, and more preferably 0.50 times or less compared to the phosphorylated STAT3 in the control without the phosphorylated STAT3 inhibitor of the present invention.

[0031] The phosphorylated STAT5 / phosphorylated STAT3 ratio refers to the ratio of phosphorylated STAT5 to phosphorylated STAT3, and can be measured and evaluated by the method described in the examples of this application, which will be described later. Preferably, the phosphorylated STAT5 / phosphorylated STAT3 ratio improver of the present invention results in a phosphorylated STAT5 / phosphorylated STAT3 ratio (value after standardization and correction with total STAT5 and total STAT3) that is 1.50 times or more, more preferably 2.00 times or more, more preferably 2.50 times or more, more preferably 3.00 times or more, more preferably 4.00 times or more, and more preferably 5.00 times or more, compared to the phosphorylated STAT5 / phosphorylated STAT3 ratio in the control without the phosphorylated STAT5 / phosphorylated STAT3 ratio improver of the present invention. There is no upper limit to the phosphorylated STAT5 / phosphorylated STAT3 ratio achieved by the phosphorylated STAT5 / phosphorylated STAT3 ratio improver of the present invention, but examples include 20 times or less, 17 times or less, 15 times or less, etc.

[0032] Although the present invention has been described above using the specific embodiments described above, it is not limited to these embodiments. For example, the present invention further includes the use of raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Chinese yam, Japanese star anise, Japanese poppy, and radish for the production of agents for at least one selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression; and the use of raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, Japanese yam, Japanese yam, Chinese star anise, Japanese poppy, and radish for the production of STAT 5 phosphorylation accelerators; Use of a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Chinese yam, Japanese star anise, poppy, and radish to produce a STAT3 phosphorylation inhibitor; Use of a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, Japanese yam, Japanese yam, Chinese star anise, Japanese star anise, poppy, and radish to produce a phosphorylated STAT5 / phosphorylated STAT3 ratio improver; A method for promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression, comprising administering to a subject in need of such a substance a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Japanese yam, Japanese star anise, poppy, and radish, for at least one of the following:A method for promoting STAT 5 phosphorylation, comprising administering to a subject in need of it a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Chinese yam, Japanese star anise, poppy, and radish; A method for inhibiting STAT 3 phosphorylation, comprising administering to a subject in need of it a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, Japanese yam, Japanese yam, Chinese star anise, poppy, and radish; A method for improving the phosphorylated STAT5 / phosphorylated STAT3 ratio, comprising administering to subjects in need of this treatment a raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese star anise, poppy, and radish; a raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese star anise, Japanese star anise, poppy, and radish; Raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, bay leaf, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Japanese yam, Japanese star anise, Japanese poppy, and radish, for promoting the phosphorylation of STAT 5;The present invention also provides raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese yam, Japanese star anise, poppy, and radish to suppress the phosphorylation of STAT3; and raw materials derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese yam, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, Chinese star anise, Japanese star anise, poppy, and radish to improve the phosphorylated STAT5 / phosphorylated STAT3 ratio. In these embodiments, the details of the type, amount, and method of use of the raw materials derived from orange, etc., are the same as described above. Furthermore, in the present invention, the embodiments of the methods described above do not have to be methods for treating humans. The following examples illustrate specific embodiments of the present invention in more detail, but the present invention is not limited to such embodiments.

[0033] 1. The plants used for extracting plant extracts are as follows:

[0034]

[0035] (1) The obtained plants were sorted into fruits, seeds, or seed coats. (2) The sorted materials were dried and powdered, and 30 mL of 99.5 vol% ethanol was added to 3.0 g of the dried powder. (3) The mixture was stirred at room temperature for 30 minutes using a stirrer, and then the solids were removed by filtration. (4) The filtrate was distilled to dryness using a rotary evaporator to obtain a dried extract. (5) It was dissolved in DMSO and used as an extract.

[0036] 2. Seed STAT5, STAT3 expressing MCF-7 cells into a 24-well plate (4 x 10 5Cells were prepared (cells / well) and cultured in a 37°C, 5% CO2 incubator. After 24 hours, the serum medium in the plate was replaced with serum-free medium, and the cells were cultured for a further 2 hours at 37°C. Plant extract was added to a final concentration of 40 μg / mL. Citral (Fujifilm, #C520000) was used as a positive control. Thirty minutes after adding the plant extract, the protein was collected and subjected to Western blotting. The primary antibodies used for Western blotting were as follows: Phosphorylated STAT5 (Phospho-Stat5 (Tyr694) #4322, Cell signaling), Phosphorylated STAT3 (Phospho-Stat3 (Tyr705) #9145, Cell signaling), Total STAT5 (Stat5 #25656, Cell signaling), Total STAT3 (Stat3 #12640, Cell signaling). The chemiluminescent bands were detected using Vilber Bio Imaging FUSION SOLO. Band intensity was quantified using Evolution Capt software. Phosphorylated STAT5 and phosphorylated STAT3 expression were standardized by total STAT5 and total STAT3 expression. Specifically, phosphorylated STAT5 / phosphorylated STAT3 expression was calculated according to the following formula: [Phosphorylated STAT5 / Phosphorylated STAT3 Expression] = (Phosphorylated STAT5 Expression Value / Total STAT5 Expression Value) ÷ (Phosphorylated STAT3 Expression Value / Total STAT3 Expression Value)

[0037] Test Results: Promotion of Phosphorylated STAT5 / Phosphorylated STAT3 Expression by Plant Extracts In cells stimulated with each plant extract (40 μg / mL), compared to the unstimulated control, the expression of phosphorylated STAT5 was promoted, the expression of phosphorylated STAT3 was decreased, and the expression of phosphorylated STAT5 / phosphorylated STAT3 was promoted (Figure 1, Table 2).

[0038]

Claims

1. An agent for at least one of the following purposes, selected from the group consisting of promoting breast milk secretion, improving breast milk secretion function, improving suppression of breast milk secretion function, and suppressing mammary gland regression, comprising a raw material derived from at least one selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese cinnamon, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Japanese yam, Japanese star anise, Japanese poppy, and Japanese radish.

2. A STAT 5 phosphorylation accelerator comprising a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese citrus, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Japanese yam, Japanese star anise, poppy, and radish.

3. A STAT3 phosphorylation inhibitor comprising a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Japanese citrus, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, Japanese yam, Japanese yam, Japanese star anise, poppy, and radish.

4. A phosphorylated STAT 5 / phosphorylated STAT 3 ratio improver comprising a raw material selected from the group consisting of orange, aloe, carrot, American ginseng, fig, almond, Hyuga citrus, laurel, apple, soybean, chrysanthemum, birch, pepper, Japanese ginger, taro, yam, kuugai, sorghum, poppy, and radish.

5. The agent according to any one of claims 1 to 4, which is a food or beverage.

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