MITOL production promoter

Abstract

This product provides an agent that inhibits the decrease of MITOL or promotes the production of MITOL, and addresses symptoms of cardiac aging such as decreased cardiac function, graying hair, and hair loss. Medical treatments that can prevent or improve skin aging symptoms such as hair loss, and brain aging symptoms such as Alzheimer's disease. To provide pharmaceuticals, quasi-drugs, cosmetics, or food and beverages. [Solution] From the group consisting of peony extract, arnica extract, and paeoniflorin or its derivatives An agent for inhibiting the reduction of MITOL or promoting its production, comprising at least one selected substance as an active ingredient.

Description

Technical Field

[0001] The present invention relates to an agent for suppressing the decrease of MITOL or promoting the production of MITOL.

Background Art

[0002] Mitochondria are one of the organelles present in cells, and their main function is to produce energy ATP. Therefore, maintaining mitochondrial function is linked to maintaining the function of cells and thus the body. The function of mitochondria is controlled by mitochondrial fusion and fission, also called mitochondrial dynamics, and interactions with other organelles in the cell. It has been found that MITOL, a ubiquitin ligase localized on the outer mitochondrial membrane, is involved in controlling mitochondrial dynamics and the adhesion between mitochondria and the endoplasmic reticulum (Non-Patent Document 1) . .

[0003] Mice with cardiac-specific deficiency of MITOL show reduced cardiac function, and furthermore, deposition of lipofuscin, a finding indicating cardiac aging, and enhanced expression of SA-β-gal are observed (Non-Patent Document 2). In addition, mice with epidermal-specific deficiency of MITOL in the skin show skin aging-like findings such as white hair · hair loss (Non-Patent Document 3), and in Alzheimer's disease model mice with neuronal-specific deficiency of MITOL, deterioration of the pathological condition of Alzheimer's disease is observed (Non-Patent Document 2) . .

[0004] From these facts, it is considered that decreased MITOL is involved in promoting aging symptoms such as cardiac aging, skin aging, and brain aging. In addition, in HELA cells with knockdown of MITOL Elevated expression of SA-β-gal, an aging marker, was observed, and MITOL knock-in was performed. It has been reported that rescue is possible (Non-Patent Document 4). From this, MITOL low The following studies have shown that aging is accelerated, and that restoring the decreased MITOL levels can reverse aging. It is tempting. Therefore, apps that increase or activate MITOL expression are Roaches are thought to be useful for anti-aging. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Nagashima, S. et al. (2014) Biochemistry, 86(1):63-67 [Non-Patent Document 2] Nagashima, S. et al. (2017) Japanese Journal of Pharmacology, 149(6):254-259. [Non-Patent Document 3] Yanagi, Shigeru (2016) Cosmetology Research Report, 24:149-152. [Non-Patent Document 4] Park et al. J Cell Sci. 2010;123:619-26. [Overview of the Initiative] [Problems that the invention aims to solve]

[0006] The object of the present invention is to provide an agent that inhibits MITOL reduction or promotes MITOL production. . [Means for solving the problem]

[0007] Therefore, after diligent investigation, the inventors found that, through testing using hair follicle keratinocytes, Yak extract, arnica extract, and paeoniflorin or its derivatives express MITOL gene expression We found that it has a promoting effect.

[0008] That is, the present invention (1) An agent for suppressing MITOL reduction or promoting MITOL production, comprising at least one selected from the group consisting of peony extract, arnica extract, and paeoniflorin or its derivative as an active ingredient , , (2) A pharmaceutical product, quasi-drug, cosmetic or food or drink characterized by containing the agent for suppressing MITOL reduction or promoting MITOL production according to claim 1 . That's it

Advantages of the Invention

[0009] The peony extract, arnica extract, paeoniflorin or its derivative of the present invention can suppress MITOL reduction or promote MITOL production, and thus, for example, can be expected to have a preventive or ameliorating effect on heart aging symptoms such as reduced cardiac function, skin aging symptoms such as gray hair and hair loss, and brain aging symptoms such as Alzheimer's disease. In addition, it can be used as a positive control in material screening and the like .

Brief Description of the Drawings

[0010] [Figure 1] [Figure 2] Figure 1 is a graph showing that the peony extract and arnica extract in Test Example 1 have an action of promoting MITOL gene expression in hair follicle keratinocytes [Figure 2] Figure 2 is a graph showing that paeoniflorin in Test Example 1 has an action of promoting MITOL gene expression in hair follicle keratinocytes

Modes for Carrying Out the Invention

[0011] The peony extract used in the present invention is an extract obtained from the roots of Paeonia lactiflora Pallas of the Paeoniaceae family or other related plants (Paeoniaceae Pallas) or other related plants (Paeoniaceae).

[0012] The peony extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (such as methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (such as propylene glycol, 1,3- butylene glycol, glycerin, dipropylene glycol, etc.), lower aliphatic ketones (such as acetone, etc.) or a mixture thereof. However, it is most preferred to extract with 1,3-butylene glycol. Or, a mixture of ethanol and water, or a mixture of polyhydric alcohol and water, or a mixture of ethanol, polyhydric alcohol and water is preferably used for extraction. The polyhydric alcohol is preferably 1,3-butylene glycol. In addition, the form of the extract is not particularly limited, and it can be made into dry extract powder, extract powder, soft extract, liquid extract, etc. by treatments such as heat treatment, freeze drying or vacuum drying. It is also possible to use those purchased from various reagent raw material manufacturers. Commercially available products of such peony extracts include Peony Extract - J (manufactured by Maruzen Pharmaceutical Co., Ltd.), Falcorex Peony B (manufactured by Ichimaru Pharcos Co., Ltd.), Peony Extract BG-50 (manufactured by Koei Kogyo Co., Ltd.), etc.

[0013] The arnica extract used in the present invention is an extract obtained from the flowers of arnica (scientific name Arnica montana) of the Asteraceae family.

[0014] The arnica extract used in the present invention can be extracted with solvents such as water, lower aliphatic alcohols (such as methanol, ethanol, isopropyl alcohol, etc.), polyhydric alcohols (such as propylene glycol, 1,3- butylene glycol, glycerin, dipropylene glycol, etc.), lower aliphatic ketones (such as acetone, etc.) or a mixture thereof. ​​​​​​Extracts using solvents such as acetone or mixtures thereof can be used. However, a mixture of ethanol and water, or a mixture of polyhydric alcohol and water, or ethanol and polyhydric alcohol Extraction is preferably carried out with a mixture of coal and water, and the polyhydric alcohol is propylene glycol or This is 1,3-butylene glycol, or propylene glycol and 1,3-butylene glycol A mixture of 1,3-butylene glycol and water is preferred. When extraction is performed with a solvent consisting of 1,3-butylene glycol and water, the 1,3- The butylene glycol content is preferably 30-70% by volume. Furthermore, the form of the extract is particularly important. It is not limited to, but can be dried by processes such as heat treatment, freeze-drying or vacuum drying. It can be processed into dried extract powder, extract powder, soft extract, fluid extract, etc. It can also be used in various reagents. It is also possible to use arnica extract purchased from a raw material manufacturer. Commercially available products include Arnica Extract BG (manufactured by Maruzen Pharmaceutical Co., Ltd.) and Arnica Extract (manufactured by Koei Kogyo Co., Ltd.). These are some examples.

[0015] In this invention, paeoniflorin is a type of monoterpene glycoside. It is a compound identified by CAS number 23180-57-6. It is mainly found in the Paeoniaceae family, specifically in the Paeoniaceae plant (Paeonia japonica). It is found in the roots of *Onion lactiflora*, and its pharmacological effects include mildly inducing gastric and uterine motility in rats. It inhibits, and when used in combination with glycyrrhizin, a component of licorice, in mouse phrenic nerve specimens... It has been reported that they act synergistically and exhibit muscle relaxant effects. Paeoniflorin is paeonif Lorin can be extracted from plants and other materials containing it, and commercially available products can be purchased from various reagent manufacturers. It is also possible to do so. Commercially available paeoniflorin products include paeoniflorin (Fujifilm Wako Pure Examples include pharmaceutical companies such as Yakuhin Co., Ltd. and Tokyo Chemical Industry Co., Ltd. Furthermore, paeoniflorin derivatives are also used. For example, oxypaeoniflorin and benzoylpaeoniflorin. Paeoniflorin, Benzoyloxypaeoniflorin, Galoy Examples include lupeoniflorin (Galloylpaeoniflorin).

[0016] In this invention, MITOL production promotion refers to MITOL mRNA or MITOL protein This refers to the expression-promoting effect of MITOL mRNA or MITOL. MITOL reduction inhibition refers to the inhibition of MITOL mRNA or MITOL This refers to the effect of suppressing protein reduction. The effect of promoting or suppressing MITOL production is related to cells. This can be confirmed by evaluating the amount of MITOL expressed in organs, but the method is not particularly limited. It's not something that can be done.

[0017] The form of administration is not particularly limited, but examples include topical application and oral administration. When applied externally, the dosage forms include, for example, lotions, liquids, creams, and ointments. Examples include preparations, gels, sprays, shampoos, conditioners, soaps, etc., and are suitable for oral administration. The dosage forms in which it can be used include tablets, powders, granules, liquids, capsules, and dry tablets. Examples include lozenges, gels, liquid foods, semi-solid foods, and solid foods.

[0018] These can be manufactured by known methods. In manufacturing, the effects of the present invention will not be impaired. Within limits, various additives that can be contained in cosmetics, quasi-drugs, pharmaceuticals, food and beverages, or reagents. It can be formulated with [the specified ingredients].

[0019] The MITOL reduction inhibitor or production promoter of the present invention is not particularly limited, but for example, Symptoms of cardiac aging such as decreased heart function, symptoms of skin aging such as graying hair and hair loss, and Alzheimer's disease. To prevent or improve any symptoms of brain aging, or to promote MITOL production It can also be used as a reagent, preferably for material screening and other applications where a positive result is detected. It can be used as a control drug.

[0020] Furthermore, the MITOL reduction inhibitor or MITOL production promoter of the present invention is used in products containing it (medical Pharmaceuticals, quasi-drugs, cosmetics, food and beverages, or reagents) or their instructions may contain phrases indicating MITOL reduction inhibition. Alternatively, it may be labeled to indicate that it is used to promote the production of MITOL. Here, "marked on the product or its instruction manual" means that the product itself, its container, packaging, etc. The labeling, or the instruction manual, accompanying documents, promotional materials, and application documents that disclose product information. This means that the mark has been placed on other printed materials or advertisements. Therefore, prevention or treatment of diseases or symptoms caused by suppression of MITOL reduction or promotion of MITOL production. It may include information regarding its use for that purpose.

[0021] The amount of peony extract, the amount of arnica extract, or peony extract used in this invention. The amount of lorin or its derivatives included (if multiple paeoniflorin or its derivatives are included, the total amount) (Measurement) When providing cosmetics, quasi-drugs, pharmaceuticals, food and beverages, or reagents, the respective components are used. 0.000001 to 10% by mass, preferably 0.0001 to 5% by mass, relative to the entire product. More preferably, it is 0.001 to 1% by mass. [Examples]

[0022] The present invention will be described in more detail below with reference to examples and test examples, but the present invention is not applicable. This is not limited to the example.

[0023] (Test Example 1) The MITOL gene expression-promoting effects of peony extract, arnica extract, and paeoniflorin. Evaluation Human hair follicle keratinocytes (CosmoBio) were seeded onto a culture plate and cultured at 37°C with CO2 The cells were cultured in an incubator set to 5%. The culture medium used was Humedia-KG2 (Kurabo Industries Ltd.). ) was used. After culturing, the test substance (peony extract, arnica extract, or paeoniflorin) was used. The cells were cultured for another two days after adding ) lysate buffer. The cells were dissolved and the lysate was collected. From the lysate, RNeasy Mini Kit (Qiagen) or Maxwe Using the 1(registered trademark) RSC simplyRNA Cells Kit (Promega), follow the attached protocol. Therefore, the RNA was recovered and used as a template for Prime Script RT Master mix (Takara Bio). cDNA was synthesized using the reverse transcription reaction. From the synthesized cDNA, a real-time PCR system was used. (Step One Plus, Thermo Fisher Scientific) enables RPLP2 and The expression levels of each MITOL mRNA were measured (SYBR Green method), and the expression levels of MITOL were measured in R The results were corrected based on PLP2 expression levels. The following primer was used: RPLP2:HA067 804 (Takara Bio), MITOL:HA192576 (Takara Bio). The test substances, peony extract and arnica extract, were added at a final concentration of 0.3 v / v%. Paeoniflorin was added at a final concentration of 5 mM. The control shown in Figure 1 was peony extract. The extract remaining after removing the extract from the group of exudates and arnica extracts (all other conditions such as solvents remain the same). The yak extract and arnica extract were the same. The control shown in Figure 2 was 1% DM. This group was designated as the SO-added group.

[0024] <Test Results> Figure 1 shows the results of evaluating the MITOL production-promoting effects of peony extract and arnica extract. The following shows the relative expression levels of MITOL in each group, with the expression level of the control group set to 1. Peony extract and arnica extract significantly increased MITOL expression levels.

[0025] Figure 2 shows the results of evaluating the MITOL production-promoting effect of paeoniflorin. This shows the relative expression level of MITOL in each group, with the expression level of the group set to 1. Paeoniflorin is M It significantly increased ITOL expression levels. [Industrial applicability]

[0026] The MITOL reduction inhibitor or production promoter of the present invention is, for example, a cardiac aging symptom such as decreased cardiac function. , preventing or improving skin aging symptoms such as gray hair and hair loss, and brain aging symptoms such as Alzheimer's disease. It can be used in the fields of cosmetics, quasi-drugs, pharmaceuticals, or food and beverages for the purpose of improving health. When screening for ingredients that promote ITOL production or ingredients that suppress MITOL reduction, It can be used as a positive control.

Claims

1. From the group consisting of peony extract, arnica extract, and paeoniflorin or its derivatives An agent for inhibiting the reduction of MITOL or promoting its production, comprising at least one selected substance as an active ingredient.

2. A pharmaceutical product characterized by containing the MITOL reduction inhibitor or production promoter described in claim 1. External products, cosmetics, or food and beverages.

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