Mineral metabolism disorder inhibitor

Abstract

To provide a material which can proliferate cells and normalize epidermal turnover, and prevent and improve spots by improving mineral metabolism disorder in an upper epidermis.SOLUTION: A mineral metabolism disorder inhibitor applied to an upper epidermis of a spots portion of a skin, has, as an active ingredient, at least one kind selected from a group consisting of mulberry, Sanguisorba officinalis, licorice leaf, Arnica montana, mugwort, Rubus ellipticus, Isodon japonicus, Alpinia katsumadai, Clove, ginseng, rosa roxburghii, peony, tannic acid, artichoke, phellodendron bark, Gentiana lutea, oolong tea, Hedera helix, hematin, Rosae fructus, star fruit leaf, Aspalathus linearis, sage, bilberry leaf, hypericum erectum, rosemary, Houttuynia cordata, litchi, Scutellariae radix, Lonicera japonica, mangosteen, Sophora flavescens, black tea, thea sinensis, gambir, niacinamide, heparinoid, tranexamic acid, and placenta.SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to inhibitors of mineral metabolism disorders, TFRC1 production inhibitors, DMT1 production inhibitors, ACO1 production inhibitors, SLC40A1 production promoters, SLC31A1 production promoters, and SLC25A37 production inhibitors. [Background technology]

[0002] Minerals are one of the five major nutrients, along with proteins, carbohydrates, fats, and vitamins, and play important roles in the body, primarily as components of biological tissues (bones, teeth, etc.), maintaining homeostasis of body fluids (regulating pH and osmotic pressure, etc.), cofactors for enzymes, regulating the excitability of nerves, muscles, and the heart, and as components of physiologically active substances.

[0003] Minerals are broadly classified into two categories: macroelements and trace elements. Macroelements include calcium, phosphorus, potassium, sodium, sulfur, magnesium, etc. Trace elements include iron, copper, zinc, selenium, manganese, iodine, etc.

[0004] In other words, daily intake of a variety of minerals is essential for humans to maintain good health. For example, it is well known that iron deficiency causes anemia. In addition, zinc deficiency can cause skin ulcers, a weakened immune response, and hypogonadism, while copper deficiency can cause anemia and elevated plasma cholesterol levels. Conversely, excessive iron intake can cause skin pigmentation and liver damage, while excess copper can cause brain damage (Non-Patent Document 1).

[0005] There are mechanisms in the body that maintain mineral balance. For example, the sodium pump in the cell membrane consumes energy to pump sodium ions from inside the cell to the outside, maintaining a state in which there are more potassium ions inside the cell and more sodium ions outside the cell.

[0006] Naturally, mineral balance is also important for maintaining healthy skin, and it has been reported that the presence of abundant magnesium ions in the stratum corneum on the skin surface and calcium ions in the granular layer is important for skin homeostasis. It is also known that calcium ions affect the enzyme balance involved in stratum corneum desquamation (keratinization), i.e., the digestion of desmosomes.

[0007] Furthermore, trace amounts of minerals are known to be localized in the epidermis. Iron, zinc, copper, and other minerals are all necessary for various enzyme activities related to cell proliferation and antioxidant properties. Of these, iron and copper in particular are known to have narrow physiological optimum concentrations and are prone to causing oxidative damage to tissues. Abnormal localization of these minerals is thought to lead to abnormal skin turnover and oxidative pathologies (Non-Patent Document 2).

[0008] It is generally known that epidermal turnover is initiated by proliferation of basal cells and is responsible for the excretion of melanin. Age spots, such as senile lentigo, are the most common type of blemish on the face and are a major cosmetic concern for many people. It has been reported that areas affected by age spots have thickened epidermis, melanin accumulation, increased expression of molecules involved in melanin production, and decreased proliferation of basal cells.

[0009] Therefore, if it is possible to activate the reduced proliferation of epidermal cells in the skin or reduce the expression of molecules involved in melanin production, it is thought that the original skin functions can be restored, melanin can be excreted through epidermal turnover, and prevention, treatment, improvement, etc. of spots can be achieved.

[0010] Therefore, the present inventors focused on improving mineral metabolism in the skin as a method for improving such abnormalities in epidermal turnover and suppressing the expression of molecules involved in melanin production. In this study, we found that the expression of iron and copper metabolism-related genes changes in the upper epidermis of pigmented areas, promoting iron utilization and decreasing copper excretion. For example, we found that TFRC1, ACO1, and SLC25A37 (Mitoferrin1), which are involved in iron utilization, are increased in the upper epidermis of pigmented areas. We also found that CTR1, which is involved in copper utilization, is expressed in the granular layer of the upper epidermis in normal areas, but its expression in the granular layer is decreased in pigmented areas. We believe that these mineral metabolism abnormalities lead to abnormal epidermal turnover, resulting in the inability to excrete melanin and the formation of pigmented areas.

[0011] Therefore, we thought that if we could find a component that could normalize the expression of molecules related to iron and copper metabolism, in other words, that could suppress the use of iron in the upper epidermis and promote the excretion of copper, we could restore normal epidermal cell proliferation and melanin turnover, thereby improving dark spots. [Prior art documents] [Non-patent literature]

[0012] [Non-Patent Document 1] Kawabata, H. (2010) Journal of the Japanese Society of Cardiology 99:1173-1179. [Non-patent document 2] Inoue Y et al(2014)J Biol chem., 1;289(31):21451-62. [Non-patent document 3] Asano MD et al(2017)J Dermatol Sci.,87(2):101-9. [Non-patent document 4] Iwai, K. et al. (2007) Biochemistry, Vol. 79, No. 11, 1021-31 [Non-patent document 5] Hideo Harigae (2013) Journal of the Japan Society of Internal Medicine 102:2699-2704 [Non-patent document 6] Yasumitsu Ogura (2014) Japanese Journal of Hygiene, Vol. 69, No. 2, 136-45 Summary of the Invention [Problem to be solved by the invention]

[0013] The object of the present invention is to provide a material that can improve mineral metabolic abnormalities in the upper epidermis, thereby normalizing cell proliferation and epidermal turnover and preventing and improving blemishes. [Means for solving the problem]

[0014] As a result of extensive research, the inventors have discovered that certain components of mulberry, Sanguisorba officinalis, etc., have the effect of regulating the production of proteins involved in the uptake and excretion of iron and copper in cells in the upper part of the epidermis, thereby suppressing iron utilization and promoting copper excretion.

[0015] That is, the present invention is (1) An agent for inhibiting mineral metabolism abnormalities in the upper epidermis of skin blemishes, comprising at least one active ingredient selected from the group consisting of mulberry, burnet, licorice leaf, arnica, mugwort, wild strawberry, Japanese knotweed, alpinia kamatsudai, clove, carrot, Rosa robur, peony, tannic acid, artichoke, Phellodendron bark, gentian, oolong tea, English ivy, hematin, star fruit leaf, Aspalathus linearis, sage, bilberry leaf, St. John's wort, rosemary, Houttuynia cordata, lychee, Scutellaria root, honeysuckle, mangosteen, Sophora flavescens, black tea, camellia sinensis, niacinamide, heparinoids, tranexamic acid, and placenta; (2) A mineral metabolism disorder inhibitor according to (1), wherein the active ingredient is at least one selected from the group consisting of mulberry, burnet, licorice leaf, arnica, mugwort, wild strawberry, Japanese knotweed, alpinia kamatsudai, clove, carrot, and Rosa rosa, and is based on the inhibitory effect on TFRC1 production; (3) A mineral metabolism disorder inhibitor according to (1), wherein the active ingredient is at least one selected from the group consisting of arnica, wild strawberry, clove, peony, mulberry, licorice leaf, burnet, tannic acid, artichoke, Alpinia kamatsudai, Japanese holly, Phellodendron bark, gentian, and oolong tea, and is based on an inhibitory effect on DMT1 production; (4) A mineral metabolism disorder inhibitor according to (1), wherein the active ingredient is at least one selected from the group consisting of wild strawberry, ivy, mulberry, clove, peony, licorice leaf, burnet, and tannic acid, and is based on an ACO1 production inhibitory effect; (5) A mineral metabolism disorder inhibitor according to (1), which is based on the SLC40A1 production-promoting effect and contains at least one active ingredient selected from the group consisting of hematin, star fruit, star fruit leaf, aspalathus linearis, alpinia kamatsudai, sage, bilberry leaf, St. John's wort, Rosa rosa, oolong tea, carrot, rosemary, Houttuynia cordata, lychee, burnet, Scutellaria root, honeysuckle, mangosteen, niacinamide, heparinoids, tranexamic acid, and placenta; (6) A mineral metabolism disorder inhibitor according to (1), wherein the active ingredient is at least one selected from the group consisting of peony, hematin, tannic acid, St. John's wort, starfruit leaf, and Sophora flavescens, and is based on the SLC31A1 production promoting effect. (7) A mineral metabolism disorder inhibitor according to (1), which is based on an inhibitory effect on SLC25A37 production and contains at least one active ingredient selected from the group consisting of peony, tannic acid, burnet, clove, wild strawberry, arnica, mulberry, licorice leaf, black tea, tea, oolong tea, acacia, and star anise; (8) A TFRC1 production inhibitor containing at least one active ingredient selected from the group consisting of mulberry, burnet, licorice leaf, arnica, mugwort, wild strawberry, Japanese knotweed, Alpinia kamatsudai, clove, carrot, and Rosa rosa, (9) A DMT1 production inhibitor containing at least one active ingredient selected from the group consisting of arnica, wild strawberry, clove, peony, mulberry, licorice leaf, burnet, tannic acid, artichoke, Alpinia kamatsudai, Japanese holly, Phellodendron bark, gentian, and oolong tea; (10) An ACO1 production inhibitor containing at least one active ingredient selected from the group consisting of wild strawberry, ivy, mulberry, clove, peony, licorice leaf, burnet, and tannic acid; (11) An SLC40A1 production promoter containing at least one active ingredient selected from the group consisting of hematin, star fruit, star fruit leaf, Aspalathus linearis, Alpinia kamathus, sage, bilberry leaf, St. John's wort, Rosa rosa, oolong tea, carrot, rosemary, Houttuynia cordata, lychee, burnet, Scutellaria root, honeysuckle, mangosteen, niacinamide, heparinoids, tranexamic acid, and placenta; (12) An SLC31A1 production promoter containing at least one active ingredient selected from the group consisting of peony, hematin, tannic acid, St. John's wort, star fruit leaf, and Sophora flavescens. (13) An SLC25A37 production inhibitor containing at least one active ingredient selected from the group consisting of peony, tannic acid, burnet, clove, wild strawberry, arnica, mulberry, licorice leaf, black tea, tea, oolong tea, acacia, and rhododendron; (14) A method for screening for agents for preventing or improving spots, using as an indicator the expression level of one or more genes selected from the group consisting of the TFRC1 gene, DMT1 gene, ACO1 gene, SLC40A1 gene, SLC31A1 gene, and SLC25A37 gene when a test substance is applied to differentiated human epidermal keratinocytes. is. [Effects of the Invention]

[0016] The mineral metabolism disorder inhibitor of the present invention regulates the production of proteins involved in mineral utilization, such as TFRC1, DMT1, ACO1, SLC40A1, SLC31A1, and SLC25A37, thereby suppressing iron utilization in upper epidermal cells and promoting copper excretion, thereby normalizing epidermal cell proliferation and epidermal turnover, thereby preventing and improving pigmentation. Furthermore, by inhibiting TFRC1 production, DMT1 production, ACO1 production, SLC40A1 production, SLC31A1 production, and SLC25A37 production, the inhibitor can treat and improve various symptoms and diseases caused by excess or decreased expression of these proteins. Furthermore, the inhibitor can also be used as a positive control when screening for materials involved in the expression of these proteins or genes. Furthermore, the screening method of the present invention allows efficient screening of ingredients that can prevent and improve pigmentation. [Brief explanation of the drawings]

[0017] [Figure 1] FIG. 1 is a graph showing the ΔΔCt values ​​of the TFRC1 gene in Test Example 1. [Figure 2] FIG. 2 is a graph showing the ΔΔCt values ​​of the DMT1 gene in Test Example 1. [Figure 3] FIG. 3 is a graph showing the ΔΔCt values ​​of the ACO1 gene in Test Example 1. [Figure 4] FIG. 4 is a graph showing the ΔΔCt values ​​of the SLC40A1 gene in Test Example 1. [Figure 5] FIG. 5 is a graph showing the ΔΔCt values ​​of the SLC31A1 gene in Test Example 1. [Figure 6] FIG. 6 is a graph showing the ΔΔCt values ​​of the SLC25A37 gene in Test Example 1. DETAILED DESCRIPTION OF THE INVENTION

[0018] In the present invention, the following ingredients are used as active ingredients.

[0019] The mulberry used in the present invention is a herbal medicine or plant derived from the root bark of Morus alba Linne, a member of the Moraceae family of the Rosales order, or other plants of the same genus (Moraceae), and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0020] The mulberry extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0021] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available mulberry extracts include "Mulberry Hibiscus Extract-J," "Mulberry Hibiscus Extract BG," and "Mulberry Hibiscus Extract BG100" manufactured by Maruzen Pharmaceutical Co., Ltd.

[0022] The burnet used in the present invention is a herbal medicine or plant derived from the roots and rhizomes of Sanguisorba officinalis Linne (Rosaceae), which belongs to the Rosales family and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0023] The burnet extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0024] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available burnet extract products include "Jiyu Extract Liquid-R," "Jiyu Extract Liquid BG-R," and "Jiyu Extract Powder" manufactured by Maruzen Pharmaceuticals.

[0025] The licorice leaves used in the present invention are a herbal medicine or plant derived from the leaves of Glycyrrhiza glabra (Leguminosae), a member of the Fabaceae family of the Leguminosae order, and are used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0026] The licorice leaf extract used in the present invention can be extracted using solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents.

[0027] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available licorice leaf extracts include "Licorice Leaf Extract BG" by Maruzen Pharmaceuticals.

[0028] The arnica used in the present invention is a crude drug or plant derived from the flowers of Arnica montana Linne (compositae) of the Asteraceae family, and is used in the form of a crude drug or plant powder, a crude drug extract, or a plant extract. The crude drug powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0029] The arnica extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0030] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available arnica extracts include "Arnica Extract BG" from Maruzen Pharmaceuticals and "Falcorex (registered trademark) Arnica" from Ichimaru Falcos (registered trademark).

[0031] The mugwort used in the present invention is a herbal medicine or plant derived from the leaves of Artemisia princeps Pampanini, Artemisia mongolia Fischer, or Artemisia montana Pampanini (Compositae), which belong to the Asteraceae family of the Asterales order, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0032] The mugwort extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0033] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available mugwort extracts include Maruzen Pharmaceutical's "Guaiyo Extract," "Guaiyo Extract BG," and "Waism (registered trademark) <Guaiyo>," and Ichimaru Pharcos' "Mugwort Liquid."

[0034] Rubus ellipticus used in the present invention is a herb or plant derived from the root of Rubus ellipticus, which belongs to the family Rosaceae, and is used in the form of a herb or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0035] The Rubus serrata extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0036] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available products of wild strawberry extract include "Himalayan Raspberry Extract BG80" manufactured by Maruzen Pharmaceuticals.

[0037] The herb Plectranthus japonicus used in the present invention is a herb or plant derived from the aerial parts of Isodon japonicus Hara (Amethystamtus japonicus Nakai, Plectranthus japonicus (Burm.) Koidz) or Isodon trichocarpus Kudo (Plectranthus trichocarpus Maxim.) (Labiatae), which belong to the Lamiales, Lamiaceae, and is used in the form of a herb or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product further finely pulverized into a powder.

[0038] The extract of the Japanese knotweed used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but it is most preferable to extract with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these.

[0039] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available scutellaria extract products include "Enmeiso Extract-JC" and "Enmeiso Extract BG" from Maruzen Pharmaceuticals.

[0040] The Alpinia katsumadai used in the present invention is a herbal medicine or plant derived from the seeds of Alpinia katsumadai Hayata (Zingiberaceae), which belongs to the family Zingiberaceae, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0041] The Alpinia kamadai extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of the above solvents.

[0042] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available Alpinia kamazudai extracts include "Alpinia White" and "Alpinia White HS" by Ichimaru Falcos.

[0043] The cloves used in the present invention are herbal medicines or plants derived from the dried buds of Syzygium aromaticum Merrill et Perry (Eugenia caryophyllata Thunberg) (Myrtaceae), a member of the Myrtaceae family, and are used in the form of herbal medicine or plant powder, herbal medicine extract, or plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0044] The clove extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents, but extraction with water, a lower aliphatic alcohol, or a mixture of these is most preferred.

[0045] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available clove extract products include "Clove Extract-J" from Maruzen Pharmaceuticals and "Falcorex Clove" from Ichimaru Falcos.

[0046] The ginseng used in the present invention is a herbal medicine or plant derived from the root or the steamed and dried fresh root of Panax ginseng (C.A. Meyer) (Panax schinseng Nees) (Araliaceae) of the Apiaceae family, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product, which is further finely pulverized into a powder.

[0047] The carrot extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents. Of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0048] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available ginseng extract products include "Ginseng Extract," "Ginseng Extract LA-20," "Ginseng Extract Powder MF," and "Ginseng Extract D(N)" from Maruzen Pharmaceuticals, and "Shinhongginsin (registered trademark) LV," "Shinhongginsin LV-2," and "Falcorex Ninjin B" from Ichimaru Falcos.

[0049] The Rosa roxburghii used in the present invention is a herbal medicine or plant derived from the fruit of Rosa roxburghii Tratt.f.normalis Rehd.et Wils (Rosaceae), which belongs to the genus Rosaceae, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further finely pulverized into a powder.

[0050] The Rosa robur extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents. Of these, it is most preferable to extract the extract with a lower aliphatic alcohol or a mixture of these, coagulate it under reduced pressure, and then further extract the extract with water, a polyhydric alcohol, or a mixture of these.

[0051] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available products of Rosa robur extract include "Togenashi Extract Liquid BG" and "Togenashi Extract Powder C" from Maruzen Pharmaceuticals, and "IZAYOI" and "IZAYOI G" from Ichimaru Falcos.

[0052] The peony used in the present invention is a herb or plant derived from the root bark of Paeonia suffruticosa Andrews (Paeonia moutan Sims) (Paeoniaceae), a member of the family Paeoniaceae, in the order Saxifragales, and is used in the form of a herb or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0053] The peony extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, or mixtures of these is most preferred.

[0054] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available peony extract products include "Moutan Peony Extract Liquid" from Maruzen Pharmaceuticals, and "Falcorex Peony Peony B" and "Falcorex Peony Peony E" from Ichimaru Falcos.

[0055] The tannic acid used in the present invention is used in the form of a purified compound, or in the form of a crude drug powder or plant powder of Chinese gallnut or gall nut, or a crude drug extract or plant extract. The crude drug powder or plant powder used in the present invention may be, for example, a dried, chopped product further finely pulverized into a powder.

[0056] The extract of Chinese gallnut or gall nut used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or a mixture of the above solvents.

[0057] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, or other treatments.

[0058] The artichoke used in the present invention is a herbal medicine or plant derived from the leaves of Cynara scolymus Linne (Compositae), a member of the Asteraceae family, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0059] The artichoke extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0060] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available artichoke extract products include Ichimaru Falcos' BioBenefity (registered trademark), BioBenefity G, BioBenefity HS, Cynaropicrin F, and BioBenefity F.

[0061] The Phellodendron bark used in the present invention is a herbal medicine or plant derived from the bark of Phellodendron amurense Ruprecht (Ruprecht), family Rutaceae, or other plants of the same genus (Rutaceae), with the periderm removed, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further finely pulverized into a powder.

[0062] The Phellodendron Bark extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents. Of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0063] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available Phellodendron bark extracts include "Phellodendron Bark Extract-J" and "Phellodendron Bark Extract BG-J" from Maruzen Pharmaceuticals, and "Phellodendron Bark Liquid B" and "Phellodendron Bark Liquid E" from Ichimaru Pharcos.

[0064] The gentian used in the present invention is a herbal medicine or plant derived from the roots and rhizomes of Gentiana lutea Linne (Gentianaceae), which belongs to the order Gentianales, family Gentianaceae, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0065] The gentian extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or diethylene glycol ethyl ether, or a mixture of these solvents, but of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, diethylene glycol ethyl ether, or a mixture of these is most preferred.

[0066] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available gentian extracts include "Gentian Extract BG-J" from Maruzen Pharmaceuticals and "Falcorex Gentian B" from Ichimaru Falcos.

[0067] The oolong tea used in the present invention is a herbal medicine or plant derived from the leaves of Thea sinensis Linne (Theaceae), which belongs to the Ericales family and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0068] The oolong tea extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with a low-molecular-weight aliphatic alcohol or a mixture of these is most preferred.

[0069] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available oolong tea extracts include Maruzen Pharmaceutical's "Oolong Tea Extract," "Oolong Tea Extract BG," "Oolong Tea Extract M Powder," and "Oolong Tea Extract M Aqueous," as well as Ichimaru Falcos' "Falcorex Oolong E."

[0070] The ivy used in the present invention is a herbal medicine or plant derived from the leaves and stems of Hedera helix Linne (Araliaceae), a member of the Araliaceae family of the Umbelliferales, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0071] The ivy extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0072] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available ivy extracts include Maruzen Pharmaceutical's "Ivy Extract BG-J" and Ichimaru Falcos' "Falcorex Ivy B."

[0073] The hematin used in the present invention is a component derived from pig blood, and is used as a purified compound or as an extract of pig blood.

[0074] The hematin extract used in the present invention can be extracted using solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents.

[0075] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available hematin extracts include "Glosfilin (registered trademark) P (PF)" by Ichimaru Falcos.

[0076] The rosehip used in the present invention is a herb or plant derived from the fruit of Rosa multiflora Thunberg or other related plants (Rosaceae), and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0077] The Zoysia extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0078] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available rhododendron extracts include "rhododendron extract-R," "rhododendron extract BG-R," and "rhododendron extract BG-01" manufactured by Maruzen Pharmaceutical Co., Ltd., and "Falcorex rhododendron B" manufactured by Ichimaru Falcos.

[0079] The star fruit leaves used in the present invention are a herbal medicine or plant derived from the leaves of Averrhoa carambola, which belongs to the Oxalidaceae family and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0080] The star fruit leaf extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0081] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available star fruit leaf extract products include "Star Fruit Leaf Extract Liquid BG30" and "Star Fruit Leaf Extract Powder MF" manufactured by Maruzen Pharmaceuticals.

[0082] Aspalathus linearis used in the present invention is a herbal medicine or plant derived from the whole plant of Aspalathus linearis (NL Burm.) R. Dahlgren (Leguminosae) of the genus Aspalathus, which belongs to the family Fabaceae, order Fabaceae, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product further finely pulverized into a powder.

[0083] The Aspalathus linearis extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water, polyhydric alcohols, or mixtures of these is most preferred.

[0084] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available Aspalathus linearis extract products include "Rooibos Tea Extract Powder MF" and "Rooibos Tea Dried Extract F" from Maruzen Pharmaceutical, and "Falcorex Rooibos B(N)" from Ichimaru Falcos.

[0085] The sage used in the present invention is a herbal medicine or plant derived from the flowers, leaves, or whole plant of Salvia officinalis Linne (Labiatae) of the Lamiales, Lamiaceae family, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product that is further finely pulverized into a powder.

[0086] The sage extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents, or a mixture of these solvents containing urea. Of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these, or a mixture of these containing urea is most preferred.

[0087] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available sage extract products include "Salvia Extract" and "Salvia Extract BG-J" from Maruzen Pharmaceuticals, and "Ecofarm (registered trademark) Sage B," "Ecofarm Sage E," "Falcorex Sage B," and "Falcorex Sage E" from Ichimaru Falcos.

[0088] The bilberry leaves used in the present invention are a herbal medicine or plant derived from the leaves of Vaccinium myrtillus L. (Ericaceae), which belongs to the Ericaceae family of the Ericales order, and are used in the form of a herbal medicine powder or plant powder, a herbal medicine extract or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, powdered product obtained by further finely pulverizing a dried, chopped product.

[0089] The bilberry leaf extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), or lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0090] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available bilberry leaf extract products include Ichimaru Falcos' "Ecofarm Bilberry Leaf E," "Ecofarm Bilberry Leaf G," and "Cureberry (registered trademark)."

[0091] The St. John's wort used in the present invention is a herb or plant derived from the aerial parts of Hypericum perforatum Linne or Hypericum erectum Thunberg (Guttiferae) of the family Hypericaceae of the orders Cantharaneales, and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, chopped product further finely pulverized into a powder.

[0092] The St. John's wort extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0093] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available products of St. John's Wort extract include "St. John's Wort Extract BG" from Maruzen Pharmaceutical, and "Falcorex St. John's Wort B" and "Falcorex St. John's Wort E" from Ichimaru Falcos.

[0094] Rosemary used in the present invention is a herbal medicine or plant derived from the leaves or leaves and flowers of Rosmarinus officinalis Linne (Labiatae), a member of the Lamiales, Lamiaceae family, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0095] The rosemary extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents, or a mixture of these solvents containing urea. Of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these, or a mixture of these containing urea is most preferred.

[0096] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available rosemary extract products include "Rosemary Extract BG-J" and "Rosemary Extract MF" from Maruzen Pharmaceuticals, and "Ecofarm Rosemary B," "Ecofarm Rosemary E," "Falcorex Rosemary B," and "Falcorex Rosemary E" from Ichimaru Falcos.

[0097] The Houttuynia cordata used in the present invention is a herbal medicine or plant derived from the aerial parts of the flowering genus Houttuynia, Houttuynia cordata Thunberg (Saururaceae), belonging to the family Houttuyniaceae, order Piperaceae, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further finely pulverized into a powder.

[0098] The Houttuynia cordata extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0099] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available Houttuynia cordata extracts include Maruzen Pharmaceutical's "Houttuynia Cordata Extract Liquid," "Houttuynia Cordata Extract Liquid BG," and "Houttuynia Cordata Extract Powder MF," and Ichimaru Falcos's "Falcorex Houttuynia Cordata B," "Falcorex Houttuynia Cordata E," "Falcorex Houttuynia Cordata W," and "Houttuynia Cordata DXP100."

[0100] The lychee used in the present invention is a herbal medicine or plant derived from the fruit of Litchi chinensis Sonn. (Sapindaceae), which belongs to the family Sapindaceae, order Sapindales, and is used in the form of a herbal medicine powder or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, powdered product obtained by further finely pulverizing a dried, chopped product.

[0101] The lychee extract used in the present invention can be extracted with a solvent such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or a mixture of these solvents.

[0102] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available lychee extract products include Ichimaru Falcos' "ADS-Oligonol" and "Oligonol-CS."

[0103] The Scutellaria root used in the present invention is a herb or plant derived from the root of Scutellaria baicalensis Georgi (Labiatae) of the family Lamiaceae, with the periderm removed, and is used in the form of a herb powder or plant powder, a herb extract, or a plant extract. The herb powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0104] The Rehmannia root extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents, but extraction with water, lower aliphatic alcohols, polyhydric alcohols, or mixtures of these is most preferred.

[0105] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, or vacuum drying. Commercially available Scutellaria root extract products include Maruzen Pharmaceutical's "Scutellaria root Extract Liquid-J" and Ichimaru Falcos' "Scutellaria root Extract Powder," "Scutellaria root Liquid B," "Scutellaria root Liquid G," and "Scutellaria root Liquid SE."

[0106] The honeysuckle used in the present invention is a herbal medicine or plant derived from the flowers, leaves, or stems of Lonicera japonica Thunberg or other plants of the same genus (Caprifoliaceae) in the family Caprifoliaceae, order Dipodium, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0107] The honeysuckle extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0108] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available honeysuckle extracts include "Honeysuckle Extract-J" from Maruzen Pharmaceuticals, and "Falcorex Honeysuckle FB" and "Falcorex Honeysuckle FE" from Ichimaru Falcos.

[0109] The mangosteen used in the present invention is a herbal medicine or plant derived from the pericarp of Garcinia mangostana, which belongs to the family Garcinaceae, order Garciniales, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product further pulverized into a powder.

[0110] The mangosteen extract used in the present invention can be extracted using solvents such as water, lower aliphatic alcohols (methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin, etc.), lower aliphatic ketones (acetone, etc.), or mixtures of the above solvents.

[0111] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available mangosteen extract products include "Mangosteen Aqua" and "Mangosteen α20" manufactured by Nippon Shinyaku.

[0112] Sophora flavescens used in the present invention is a herbal medicine or plant derived from the root of Sophora flavescens Aiton (Laguminosae) of the genus Sophora, belonging to the family Fabaceae, order Fabaceae, either as is or with most of the periderm removed, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, chopped product that is further finely pulverized into a powder.

[0113] The sophora flavescens extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0114] The form of the extract is not particularly limited, and it can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available products of Sophora flavescens extract include Maruzen Pharmaceutical's "Sophora flavescens Extract Liquid" and "Sophora flavescens Extract Liquid BG-J," and Ichimaru Falcos' "Falcorex Clara" and "Falcorex Clara B."

[0115] The black tea used in the present invention is a herbal medicine or plant derived from black tea made from the leaves of Thea sinensis L. var. assamica Pierre (Theaceae), which belongs to the Theaceae family of the Ericales order, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product that is further finely pulverized into a powder.

[0116] The black tea extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of the above solvents, but extraction with water, a lower aliphatic alcohol, or a mixture of these is most preferred.

[0117] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available black tea extracts include Maruzen Pharmaceutical's "Black Tea Extract Liquid BG" and "Black Tea Extract Liquid LA-J," and Ichimaru Falcos' "Black Tea Liquid."

[0118] The tea used in the present invention is a herbal medicine or plant derived from the leaves (green tea) of Thea sinensis Linne (Theaceae), which belongs to the family Theaceae, order Ericales, and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product that is further finely pulverized into a powder.

[0119] The tea extract used in the present invention can be extracted with a solvent such as water, a lower aliphatic alcohol (e.g., methanol, ethanol, isopropyl alcohol), a polyhydric alcohol (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), a lower aliphatic ketone (e.g., acetone), or a mixture of these solvents. Of these, extraction with water, a lower aliphatic alcohol, a polyhydric alcohol, or a mixture of these is most preferred.

[0120] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available tea extract products include "Wa-ism <Green Tea>", "Wa-ism <Uji Tea>", and "Green Tea Extract MF" from Maruzen Pharmaceuticals, and "Green Tea Liquid" from Ichimaru Falcos.

[0121] The Uncaria gambir used in the present invention is a herbal medicine or plant derived from the leaves and young branches of Uncaria gambir Roxburgh (Rubiaceae), which belongs to the Rubiaceae family and is used in the form of a herbal medicine or plant powder, a herbal medicine extract, or a plant extract. The herbal medicine powder or plant powder used in the present invention may be, for example, a dried, shredded product that is further finely pulverized into a powder.

[0122] The aceca extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (e.g., methanol, ethanol, isopropyl alcohol), polyhydric alcohols (e.g., 1,3-butylene glycol, propylene glycol, dipropylene glycol, glycerin), lower aliphatic ketones (e.g., acetone), or mixtures of the above solvents. Of these, it is most preferable to extract the liquid (aceca) obtained by extracting with water and drying it, and then further extract it with a lower aliphatic alcohol or a polyhydric alcohol.

[0123] The form of the extract is not particularly limited, and can be made into a dried extract powder, extract powder, soft extract, liquid extract, etc. by heat treatment, freeze-drying, vacuum drying, etc. Commercially available Acacia extract products include "Acacia Extract Liquid" and "Acacia Extract Liquid BG" manufactured by Maruzen Pharmaceuticals.

[0124] The niacinamide used in the present invention is a compound designated as Cas No. 98-92-0, and the tranexamic acid is designated as Cas No. 1197-18-8. Heparinoids are mucopolysaccharide polysulfate esters. Placenta is obtained by extracting it from pig placenta or other animals using a sterile water-based method such as freezing and thawing. Sources include, for example, human, bovine, porcine, equine, and ovine, with porcine being preferred. Alternatively, commercially available placenta extracts (e.g., Biocatalyzer Placenta APF(G)) may be used.

[0125] Skin is broadly divided into three layers: the epidermis, dermis, and subcutaneous tissue. The main constituent cells of the epidermis are keratinocytes, which undergo four stages of morphological change during differentiation. Basal cells in the lowest layer contact the basement membrane, synthesize DNA, and divide and proliferate. These divided cells migrate upward and become spinous cells. Further differentiation leads to granular cells, which ultimately differentiate into corneocytes, forming the stratum corneum (stratum corneum). Keratinocytes at these stages of differentiation are layered within the epidermis. The stratum corneum's keratinocytes are adhered to each other by desmosomes. However, in healthy skin, this adhesion mechanism gradually weakens, leading to spontaneous detachment of the stratum corneum in response to physical stimuli (stratum corneum desquamation). In this way, the epidermis undergoes a rhythmic cycle of proliferation, differentiation, and exfoliation (epidermal turnover). In addition to keratinocytes, melanocytes exist in the epidermis and produce melanin. Normally, melanin is transferred to keratinocytes and excreted with the stratum corneum peeling during epidermal turnover. However, if abnormalities in epidermal turnover occur, such as a decrease in differentiation and proliferation from basal cells or excessive proliferation of keratinocytes, resulting in stratification and thickening, melanin is not excreted and accumulates in the epidermis, resulting in the formation of age spots. In this specification, the lower epidermis refers to the layer containing basal cells among the keratinocytes that make up the epidermis, and the upper epidermis refers to the layer containing keratinocytes.

[0126] Transferrin receptor 1 (TFRC1) is expressed in various cells in the body, and after serum iron binds to transferrin and is transported, the iron is taken up into cells via TFRC1. When cells are iron deficient, TFRC1 expression decreases, indicating that TFRC1 plays an important role in the uptake of iron into cells. When TFRC1 production is suppressed in keratinocytes in the upper epidermis, intracellular iron uptake is suppressed, resulting in a decrease in intracellular iron concentration, which in turn normalizes epidermal turnover and epidermal layer regeneration, resulting in the prevention and / or improvement of pigmentation (Non-Patent Documents 1 and 3).

[0127] Among the above active ingredients, mulberry, burnet, licorice leaf, arnica, mugwort, wild strawberry, Japanese knotweed, alpinia kamatsudai, clove, carrot, and Rosa robur have the effect of inhibiting TFRC1 production.

[0128] DMT1, a divalent metal transporter, is responsible for iron uptake from the intestinal tract and iron transport from endosomes. DMT1 binds various divalent metals, including cadmium (Cd 2+ ), copper (Cu 2+ ), and zinc (Zn 2+ ), but is best known for its role in iron (Fe 2+ ) transport. DMT1 expression is regulated by the body's iron stores to maintain iron homeostasis. In the gastrointestinal tract, it is located on the apical membrane of enterocytes and is known to bind and transport divalent metal cations from the intestinal lumen into the cells. Recently, it has been reported that DMT1 is also expressed in the epidermis of skin tissue. Inhibition of DMT1 production in keratinocytes in the upper epidermis inhibits intracellular iron uptake, reduces intracellular iron concentration, and normalizes epidermal turnover and epidermal layer regeneration, resulting in the prevention and / or improvement of pigmentation.

[0129] Of the active ingredients listed above, arnica, wild strawberry, clove, peony, mulberry, licorice leaf, burnet, tannic acid, artichoke, alpinia kamatsudai, hollyhock, Phellodendron bark, gentian, and oolong tea have the effect of inhibiting DMT1 production.

[0130] ACO1 functions as an essential enzyme in the TCA cycle, catalyzing the reaction from citrate to aconitate and then isocitrate. When intracellular iron levels are high, this protein functions as aconitase. When cellular iron levels are low, the protein binds to the iron response element (IRE). Inhibition of ACO1 production in keratinocytes in the upper epidermis not only suppresses mitochondrial activation, but also normalizes iron utilization by stabilizing intracellular iron concentrations, thereby normalizing epidermal turnover and epidermal layer regeneration, resulting in the prevention and / or improvement of pigmentation (Non-Patent Document 4).

[0131] Among the active ingredients listed above, wild strawberry, ivy, mulberry, clove, peony, licorice leaf, burnet, and tannic acid have the effect of inhibiting ACO1 production.

[0132] SLC40A1 (ferroportin) is responsible for the excretion of iron from cells. Ferroportin expression is regulated in response to intracellular iron deficiency and at the protein level by hepcidin in response to iron deficiency at the individual level. Ferroportin is known to be a protein that excretes iron from intestinal epithelial cells and macrophages into the bloodstream, but in recent years, it has been reported that it is also expressed in skin tissue. When SLC40A1 production is promoted in keratinocytes in the upper epidermis, it reduces the intracellular iron concentration of the cells, normalizing epidermal turnover and epidermal layer regeneration, thereby preventing and / or improving pigmentation (Non-Patent Documents 1, 3, 5).

[0133] Of the above active ingredients, hematin, star fruit leaf, aspalathus linearis, alpinia kamatsudai, sage, bilberry leaf, St. John's wort, Rosa rosa, oolong tea, carrot, rosemary, Houttuynia cordata, lychee, burnet, Scutellaria root, honeysuckle, mangosteen, niacinamide, heparinoids, tranexamic acid, and placenta have the effect of promoting SLC40A1 production.

[0134] Mitochondria are the main intracellular organelles that utilize iron, and SLC25A37 (Mitoferrin 1) functions as an iron uptake transporter in the inner mitochondrial membrane. It exists as a key molecule in iron metabolism in intracellular mitochondria. When SLC25A37 production is suppressed in keratinocytes in the upper epidermis, the intracellular iron concentration is reduced due to the inhibition of iron transport to mitochondria within the cells, normalizing epidermal turnover and epidermal layer regeneration, thereby preventing and / or improving pigmentation (Non-Patent Document 5).

[0135] Among the active ingredients listed above, tree peony, tannic acid, burnet, clove, wild strawberry, arnica, mulberry, licorice leaf, black tea, green tea, oolong tea, acacia, and angelica have the effect of inhibiting SLC25A37 production.

[0136] SLC31A1 (CTR1) functions as a transporter that takes up copper into cells. In mice, it is expressed in all tissues, with particularly high expression observed in the liver, small intestine, heart, and kidney. It has also been shown that CTR1 expression changes depending on the nutritional status of copper. Enhanced SLC31A1 production promotes copper uptake into keratinocytes, reducing oxidative stress and normalizing epidermal turnover and epidermal layer regeneration, resulting in the prevention and / or improvement of pigmentation (Non-Patent Document 6).

[0137] Among the active ingredients listed above, tree peony, hematin, tannic acid, St. John's wort, star fruit leaf, and sophora flavescens have the effect of promoting SLC31A1 production.

[0138] As described above, the present invention provides the effects of inhibiting TFRC1 production by at least one plant selected from the group consisting of mulberry, burnet, licorice leaf, arnica, mugwort, wild strawberry, Japanese knotweed, Alpinia kamatsudai, clove, carrot, and Rosa izayoi; and the effects of inhibiting TFRC1 production by at least one plant selected from the group consisting of arnica, wild strawberry, clove, peony, mulberry, licorice leaf, burnet, tannic acid, artichoke, Alpinia kamatsudai, Japanese knotweed, Phellodendron bark, gentian, and oolong tea. and the inhibitory effect of at least one selected from the group consisting of wild strawberry, ivy, mulberry, clove, peony, licorice leaf, burnet, and tannic acid on ACO1 production. The inhibitory effect of hematin, star fruit, star fruit leaf, aspalathus linearis, alpinia kamatsudai, sage, bilberry leaf, St. John's wort, Rosa rosa, oolong tea, carrot, rosemary, Houttuynia cordata, lychee, burnet, Scutellaria root, honeysuckle, mangosteen, niacin. the effect of promoting SLC40A1 production by at least one selected from the group consisting of peony, hematin, tannic acid, St. John's wort, star fruit leaf, and sophora flavescens; or the effect of promoting SLC31A1 production by at least one selected from the group consisting of peony, tannic acid, burnet, clove, wild strawberry, arnica, mulberry, licorice leaf, black tea, tea, oolong tea, acacia, and star fruit. The active ingredients in this product include an inhibitor of mineral metabolism abnormalities in the upper epidermis of skin blemishes based on the SLC25A37 inhibitory effect of at least one of the active ingredients, and an inhibitor of TFRC1 production, DMT1 production, ACO1 production, SLC40A1 production, SLC31A1 production, and SLC25A37 production, each of which is an inhibitor of TFRC1, DMT1, ACO1, or SLC25A37, and further has the effect of preventing and improving diseases and symptoms caused by an excess of TFRC1, DMT1, ACO1, or SLC25A37, or a decrease in SLC40A1 or SLC31A1.

[0139] The mineral metabolism disorder inhibitor, TFRC1 production inhibitor, DMT1 production inhibitor, ACO1 production inhibitor, SLC40A1 production promoter, SLC31A1 production promoter, or SLC25A37 production inhibitor of the present invention can be provided as a cosmetic, quasi-drug, pharmaceutical, food or drink, etc. The dosage form is not particularly limited, but from the viewpoint of acting on keratinocytes in the upper epidermis to normalize mineral metabolism disorder, an external preparation applied to the skin is preferred. It is preferably applied to humans, but can also be applied to animals other than humans as long as the functional effects are achieved.

[0140] The mineral metabolism abnormality inhibitor, TFRC1 production inhibitor, DMT1 production inhibitor, ACO1 production promoter, SLC40A1 production promoter, SLC31A1 production promoter, or SLC25A37 production inhibitor of the present invention can be used, for example, for researching related symptoms or diseases, or for normalizing mineral metabolism abnormalities at the site of age spots, or as a reagent for inhibiting TFRC1 production, inhibiting DMT1 production, promoting ACO1 production, promoting SLC40A1 production, promoting SLC31A1 production, or inhibiting SLC25A37 production, and can preferably be used as a positive control drug when performing material screening, etc.

[0141] The present invention includes methods for inhibiting TFRC1 production, DMT1 production, ACO1 production, or SLC25A37 production, as well as methods for promoting SLC40A1 and SLC31A1 production in such tests and studies. The method for inhibiting TFRC1 production includes adding mulberry, burnet, licorice leaf, arnica, mugwort, wild strawberry, Japanese knotweed, Alpinia kamatsudai, clove, carrot, Rosa izayoi, or an extract of each, to epidermal keratinocytes or cells in which TFRC1 production is desired to be inhibited. The method for inhibiting DMT1 production includes adding arnica, wild strawberry, clove, peony, mulberry, licorice leaf, burnet, tannic acid, artichoke, Alpinia kamatsudai, Japanese knotweed, Phellodendron bark, gentian, oolong tea, or an extract of each, to epidermal keratinocytes or cells in which DMT1 production is desired to be inhibited. Methods for inhibiting ACO1 production include adding wild strawberry, ivy, mulberry, clove, peony, licorice leaf, burnet, tannic acid, or an extract of each to epidermal keratinocytes or cells in which ACO1 production is desired to be inhibited. Methods for promoting SLC40A1 production include adding hematin, star fruit, star fruit leaf, Aspalathus linearis, Alpinia kamatsudai, sage, bilberry leaf, Hypericum perforatum, Rosa izayoi, oolong tea, carrot, rosemary, Houttuynia cordata, lychee, burnet, Scutellaria root, honeysuckle, mangosteen, niacinamide, heparinoids, tranexamic acid, placenta, or an extract of each to epidermal keratinocytes or cells in which SLC40A1 promotion is desired. The method for promoting SLC31A1 production includes adding peony, hematin, tannic acid, St. John's wort, starfruit leaf, Sophora flavescens, or an extract of each, to epidermal keratinocytes or cells in which SLC31A1 production is desired to be promoted.The method for inhibiting SLC25A37 production includes adding peony, tannic acid, burnet, clove, wild strawberry, arnica, mulberry, licorice leaf, black tea, tea, oolong tea, Acacia japonica, Star fruit, or an extract of each, to epidermal keratinocytes or cells in which SLC25A37 production is desired to be inhibited.

[0142] The dosage form is not particularly limited, but a skin-applied preparation is preferred. Examples of the dosage form of a skin-applied preparation include lotions, creams, patches, sprays, gels, ointments, lotions, emulsions, and serums. These can be produced by known methods. During production, various additives that can be contained in quasi-drugs, pharmaceuticals, foods and beverages, or reagents can be blended within a range that does not impair the effects of the present invention.

[0143] The amount of the active ingredient in the present invention is not particularly limited, but when provided as a cosmetic, quasi-drug, pharmaceutical, food or beverage, or reagent, it is 0.000001 to 10% by mass, preferably 0.0001 to 5% by mass, and more preferably 0.001 to 1% by mass, based on the total mass of the composition.

[0144] The mineral metabolism disorder inhibitors, TFRC1 production inhibitors, DMT1 production inhibitors, ACO1 production inhibitors, SLC40A1 production promoters, SLC31A1 production promoters, or SLC25A37 production inhibitors for pigmentation sites of the present invention (drugs, quasi-drugs, foods, beverages, reagents, etc.) and their instructions may be labeled with a label indicating that they are used for inhibiting TFRC1 production, a label indicating that they are used for inhibiting DMT1 production, a label indicating that they are used for inhibiting ACO1 production, a label indicating that they are used for promoting SLC40A1 production, a label indicating that they are used for promoting SLC31A1 production, or a label indicating that they are used for inhibiting SLC25A37 production. Here, "labeled" includes a label indicating that the label is on the product itself, container, packaging, etc. containing the production promoter or reduction promoter, or in documents such as instructions, package inserts, pamphlets, and other printed materials disclosing product information, and in advertisements used for promotion, including various flyers and the Internet.

[0145] The screening method of the present invention uses differentiated human epidermal keratinocytes. The medium used for cell culture is not particularly limited, and known mediums can be used, and the cells can be cultured under standard culture conditions. A test substance is added to the medium for the undifferentiated human epidermal keratinocytes cultured in this manner, and after culturing for a predetermined period of time, the expression levels of one or more genes selected from the group consisting of TFRC1, DMT1, ACO1, SLC40A1, SLC31A1, and SLC25A37 are measured. Gene expression levels are not particularly limited, and known methods can be used. An untreated group, to which no test substance has been added, is similarly cultured, and the expression levels of each gene are measured. By comparing the gene expression levels with those of the test substance-treated group, the presence or absence of the test substance's effect on preventing or improving age spots can be determined. For example, genes involved in iron utilization, such as TFRC1, ACO1, and SLC25A37 (Mitoferrin 1), are expressed primarily in the lower epidermis in normal areas, whereas their expression levels are elevated in the upper epidermis in areas with pigmentation. Therefore, by comparing the expression levels of these genes in a model of pigmented skin to those of a test substance, the effectiveness of the test substance in preventing or improving pigmented skin can be assessed. Furthermore, by performing similar tests using undifferentiated human epidermal keratinocytes, we can select test substances that reduce the expression of these genes in differentiated cells but not in undifferentiated cells. By combining these indicators of gene expression changes specific to areas with pigmented skin, we can identify ingredients with superior effects in preventing or improving pigmented skin. [Example]

[0146] The present invention will be explained in more detail below with reference to examples and test examples, but the present invention is not limited to these examples.

[0147] (Test Example 1) Evaluation of gene expression promotion or suppression in differentiated human epidermal keratinocytes <Test Method> Human epidermal keratinocytes (Kurashiki Boseki) were placed in a 12-well plate at 3.8 × 10 4Cells were seeded at a density of 1000 cells / well and cultured in an incubator set at 37°C and 5% CO2. Humedia-KG2 (Kurashiki Boseki) medium was used. Three days after seeding, the medium was replaced with test substance-supplemented medium and cultured in a CO2 incubator for 1 day. Cells were then lysed by adding lysate buffer, and the cell lysate was collected. RNA was extracted from the cell lysate using an RNeasy Mini Kit (Qiagen) according to the attached protocol. Using this as a template, cDNA was synthesized by reverse transcription using Prime Script RT Master mix (Takara Bio). The mRNA expression levels of RPLP0, TFRC1, DMT1, ACO1, SLC40A1, SLC31A1, and SLC25A37 were measured using a real-time PCR system (Step One Plus, Thermo Fisher Scientific) using the SYBR Green method. The ΔCt value was calculated by subtracting the Ct value of the internal control gene RPLP0 from the Ct value of each sample for TFRC1, DMT1, ACO1, SLC40A1, SLC31A1, and SLC25A37. Furthermore, the ΔCt value was calculated by subtracting the ΔCt value of the untreated group from the ΔCt value of the test substance-treated group. For example, a ΔΔCt value of -1 indicates a 2-fold change in gene expression, and a value of 1 indicates a 1 / 2-fold change. The primers used were those with the following sequences or product numbers: RPLP0: (F) 5'-GAAGCCACGCTGCTGAACA-3' (R) 5'-CTGGCAACATTGCGGACA-3', SLC25A37: (F) 5'-GAAGCAGCAGTACATTTGTCATTCA-3' (R) 5'-CTGGCAACATTGCGGACA-3' (primer synthesis), TFRC1: HA277353, DMT1: HA142595, ACO1: HA210761, SLC40A1: HA161921, SLC31A1: HA158357 (Takara Bio). All test substances were used at a final concentration of 1%, except for tannic acid (0.1%), lychee (0.01%), mangosteen (0.01%), sophora flavescens (0.01%), niacinamide (0.05%), and heparinoid (0.05%). The untreated group was cultured in medium without the addition of any test substance, and all other conditions were the same as those in the test substance-added group.

[0148] <Test Results> Figure 1 is a graph showing the ΔΔCt values ​​of the TFRC1 gene. Compared to the untreated group, arnica, wild strawberry, licorice leaf, mulberry, Japanese knotweed, mugwort, burnet, Rosa rosa, Alpinia kamatsudai, clove, and carrot reduced TFRC1 gene expression. Figure 2 is a graph showing the ΔΔCt values ​​of the DMT1 gene. Compared to the untreated group, arnica, Phellodendron bark, wild strawberry, licorice leaf, Morus alba, Japanese knotweed, tree peony, burnet, artichoke, Alpinia kamatsudai, oolong tea, gentian, tannic acid, and clove reduced DMT1 gene expression. Figure 3 is a graph showing the ΔΔCt values ​​of the ACO1 gene. Compared to the untreated group, wild strawberry, licorice leaf, mulberry, peony, burnet, English ivy, tannic acid, and clove reduced ACO1 gene expression. Figure 4 is a graph showing the ΔΔCt values ​​of the SLC40A1 gene. Compared to the untreated group, the treatments of Chinese lantern fruit, Scutellaria root, star fruit leaf, Burntwood, Rosa rosa, Alpinia kamatsudai, oolong tea, St. John's wort, bilberry leaf, hematin, lychee, Aspalathus linearis, carrot, Houttuynia cordata, rosemary, sage, mangosteen, honeysuckle, niacinamide, heparinoids, tranexamic acid, and placenta increased SLC40A1 gene expression. Figure 5 is a graph showing the ΔΔCt values ​​of the SLC31A1 gene. Compared to the untreated group, Sophora flavescens, star fruit leaf, tree peony, Hypericum perforatum, tannic acid, and hematin increased SLC31A1 gene expression. Figure 6 is a graph showing the ΔΔCt values ​​of the SLC25A37 gene. Compared to the untreated group, Acacia, Arnica, Star Anemone, Wild Rubus, Licorice leaf, Mulberry, Peony, Burntwood, Oolong tea, Tannic acid, Tea, Clove, and Black tea reduced SLC25A37 gene expression. [Industrial Applicability]

[0149] The mineral metabolism disorder inhibitor in the upper epidermis of the pigmented spot site of the present invention has an effect of preventing and improving pigmented spots based on its inhibitory effect on TFRC1 production, DMT1 production, ACO1 production, SLC40A1 production, SLC31A1 production, or SLC25A37 production, and can therefore be used in the fields of quasi-drugs, pharmaceuticals, and food and beverages. Furthermore, the TFRC1 production inhibitor, DMT1 production inhibitor, ACO1 production inhibitor, SLC40A1 production promoter, SLC31A1 production promoter, and SLC25A37 production inhibitor of the present invention can be used as a positive control drug when conducting material screening, etc.

Claims

1. An agent that suppresses abnormal iron metabolism in the upper epidermis of skin blemishes, containing a heparin-like substance as its active ingredient.

2. The agent for suppressing abnormal iron metabolism according to claim 1, which is based on the action of promoting SLC40A1 production.

3. An agent for promoting SLC40A1 production in epidermal keratinocytes, which comprises a heparinoid as an active ingredient.

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