WO2014050003A1 - Expression modulator for clock gene period - Google Patents
Expression modulator for clock gene period Download PDFInfo
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- WO2014050003A1 WO2014050003A1 PCT/JP2013/005410 JP2013005410W WO2014050003A1 WO 2014050003 A1 WO2014050003 A1 WO 2014050003A1 JP 2013005410 W JP2013005410 W JP 2013005410W WO 2014050003 A1 WO2014050003 A1 WO 2014050003A1
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
- A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
- A61K8/9783—Angiosperms [Magnoliophyta]
- A61K8/9789—Magnoliopsida [dicotyledons]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
- A61Q19/06—Preparations for care of the skin for countering cellulitis
Definitions
- the present invention relates to a clock gene expression regulator, and more particularly to a clock gene Period expression regulator and a circadian rhythm regulator containing the same.
- Biological clocks cause biological diurnal fluctuations called circadian rhythms, such as the sleep / wake cycle of organisms, body temperature, blood pressure, hormone secretion, metabolism, as well as various activities such as mental and physical activity, and eating. It is thought to dominate the diurnal variation of biological phenomena (activity).
- circadian rhythms biological diurnal fluctuations
- disturbance of circadian rhythm has been pointed out as a cause of various psychosomatic symptoms or diseases such as sleep disorders, skin diseases, lifestyle-related diseases, and neuropsychiatric diseases such as mania.
- the biological clock is controlled by a rhythm generation system including a group of genes called clock genes.
- clock genes In the case of mammals, the feedback loop formed by promoting / repressing transcription of genes encoding the four core proteins of CLOCK, BMAL1, PERIOD, and CRYPTOCHROME forms the core of the clock molecular mechanism and is involved in these core loops. If the clock gene is not expressed well, it is considered to cause various diseases such as epilepsy and lifestyle-related diseases (Non-patent Document 1).
- the circadian rhythm control center (central clock) is located in the suprachiasmatic nucleus of the hypothalamus, but the clock gene is also expressed in peripheral tissues, and it is clear that the circadian rhythm is formed by a similar system. ing.
- the clock gene is also expressed in the skin, and the homeostasis is maintained by ticking the rhythm in synchronism with the circadian rhythm center in the brain as in other organs (Non-patent Document 2).
- Non-patent Document 3 For example, in Bmal1 knockdown animals, skin atrophy and suppression of hair regeneration are observed, and if the clock gene does not work smoothly, skin health is impaired.
- the Period gene can be cited as an important clock gene in the peripheral clock system, but the Period gene has a glucocorticoid response region (GRE) as a transcriptional regulatory region and responds to cortisol, a corticosteroid, to initiate transcription. . That is, in the living body, information on the central clock is transmitted to the peripheral clock via the corticosteroid cortisol, and circadian rhythm expression in the periphery can be regulated. Therefore, when cortisol secretion fails, the central clock information is not correctly transmitted to the peripheral clock, and the central and peripheral clocks do not synchronize, causing various malfunctions. What is needed is a way to adjust the clock rhythm.
- GRE glucocorticoid response region
- Period1, Period2, and Period3 are known as Period genes, but they not only play an important role as clock genes, but are also associated with stress response and obesity.
- cortisol secretion increases, causing various stress response reactions in the living body.
- the involvement of the Period gene in the stress response has been reported (Non-patent Document 4).
- obesity is observed in Period knockdown animals (Non-patent Document 5), and it is reported that the Period gene expression rhythm of obese people is also abnormal in humans compared to normal subjects. (Non-Patent Document 6).
- Period clock gene As described above, by regulating the expression of the Period clock gene, it is possible to adjust various behavioral rhythms and circadian rhythms of physiological functions related to it, and effectively regulate the expression of the Period clock gene. Development of new drugs that can be controlled is desired.
- Patent Document 1 For example, in an evaluation system using human dermal fibroblasts, it has been reported that herbal medicines such as Arnica extract and mulberry extract and essential oils such as Juniper oil and Cedar oil promote the expression of Period clock gene (Patent Document 1). ).
- an object of the present invention is to provide a novel substance that can regulate the expression of the Period gene.
- various disorders such as circadian rhythm disorder associated with the Period gene, stress response, obesity, etc. can be improved and biological homeostasis can be maintained.
- the present inventor has found that an extract of a genus Pelargonium plant can regulate the expression of the Period gene, and has completed the present invention.
- the Period gene expression regulator of the present invention is characterized by containing an extract of a genus Pelargonium as an active ingredient. Until now, it has never been known that an extract of a genus Pelargonium can control the expression of a clock gene.
- gene expression regulation includes regulating gene expression rhythm (phase or cycle) in addition to promoting gene expression.
- Pelargonium graveolens Pelargonium radula, Pelargonium roseum, Pelargonium capitium ⁇ Perargonium capitatum ⁇ ⁇ , but not limited as a pelargonium genus plant preferably used in the present invention Pelargonium odoratissimum), Pelargonium denticulatum, and the like.
- Period1, Period2, and Period3 are listed as Period genes.
- the circadian rhythm adjusting agent of the present invention includes the Period gene expression regulating agent described above. By regulating the expression of the Period clock gene, it is possible to adjust various behavioral rhythms and circadian rhythms of physiological functions related thereto.
- the Period gene expression regulator of the present invention can improve the various mental and physical symptoms or diseases caused by the circadian rhythm disorder by regulating the expression of the Period gene and promoting the maintenance of homeostasis.
- the Period gene expression regulator of the present invention contains an extract of a genus Pelargonium as an active ingredient.
- Pelargonium plants are plants belonging to the genus Pelargonium genus, such as Pelargonium graveolens, Pelargonium radula, Pelargonium roseum, Pelargonium roseum (Pelargonium roseum), Pelargonium capitium Pelargonium odoratissimum), Pelargonium denticulatum, and the like.
- the extract of the genus Pelargonium plant used in the present invention can be prepared by extracting from the leaves, stems or flowers of the genus Pelargonium plant, or whole plants containing them by steam distillation or solvent extraction.
- the solvent used for extraction is not limited, but for example, one or two or more selected from water, alcohol, acetone, ethyl acetate, petroleum ether, etc. can be used, and preferably petroleum ether is used.
- the whole plant of the genus Pelargonium is allowed to stand for about a day and then steam distilled to obtain oil.
- the Period gene expression regulator of the present invention may be an extract of one plant belonging to the genus Pelargonium or a mixture of two or more plant extracts.
- the circadian rhythm adjusting agent of the present invention includes one or more of the above-mentioned extracts of the genus Pelargonium as a Period gene expression adjusting agent.
- the Period gene expression regulator of the present invention may contain any other component in addition to the above essential components as long as the effects of the present invention are not impaired. Moreover, although it may be used independently, you may use it in combination with the chemical
- the period gene expression-regulating agent of the present invention is not particularly limited in its administration method because the Period gene is expressed not only in the brain but also in various peripheral organs.
- a composition containing an extract of a pelargonium genus plant that promotes the expression of the Period gene is applied to the skin, it regulates the Period gene expression in the skin to promote homeostasis and maintain a healthy skin condition. It is possible to maintain.
- the Period gene expression regulator of the present invention can be included in various objects, and can further include an optional component in addition to the essential components described above, depending on the type of the object.
- the dosage form eg, liquid, powder, granule, aerosol, solid, gel, patch, suppository, etc.
- product form eg, cosmetics, pharmaceuticals
- any component usually contained in such an external preparation for skin may be included together with the Period gene expression regulator of the present invention.
- the topical skin preparation is a concept that encompasses all compositions applied to the skin (including the scalp, hair, and nails). For example, basic cosmetics, makeup cosmetics, hair cosmetics, skin or hair cleansing agents, etc. Cosmetics, ointments, patches, suppositories, various drugs such as dentifrices and quasi drugs.
- the dosage form is not particularly limited.
- an aqueous solution system for example, a solubilization system, an emulsification system, an oil liquid system, a gel system, a paste system, an ointment system, an aerosol system, a water-oil two-layer system, a water-oil-powder 3
- any dosage form such as a layer.
- the skin external preparation is a cosmetic, for example, perfume, eau de toilette, eau de cologne, cream, milky lotion, lotion, foundations, powdered white powder, lipstick, soap, shampoo / rinse, body shampoo, body rinse, body powder And bath agents.
- Period expression regulator of the present invention may be included in various forms of supplements (nutritional supplements) such as powders, granules, tablets and capsules, confectionery, beverages and other foods, medicines and the like.
- supplements nutritional supplements
- the blending amount of the Period gene expression regulator of the present invention in the subject can be appropriately selected depending on the type of the subject, etc., and is not limited as long as the effects of the present invention can be exhibited, but when blended in a skin external preparation,
- the compounding amount of the extract of the genus Pelargonium as an active ingredient is usually 0.01 to 1000 ppm, more preferably 0.1 to 100 ppm, based on the total mass of the external preparation for skin.
- the specific application of the Period gene expression regulator of the present invention and the object containing the same is not particularly limited as long as it relates to the regulation of Period gene expression.
- it when applied to the skin, It can be applied to moisturizing, improving flexibility, preventing or improving wrinkles, preventing, improving or treating various skin symptoms such as rough skin.
- the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples.
- various cells such as dermal fibroblasts, epithelial cells, endothelial cells, pigment cells, fat cells and nerve cells can be used.
- human skin fibroblasts are used for evaluation. It was.
- three types of Period genes, Period1, Period2, and Period3, are known.
- the expression of Period1 was measured as a representative.
- fibroblasts For cultured human skin fibroblasts, purchase normal adult skin-derived fibroblasts (Cell Application, Inc), used for experiments. The cells were inoculated in DMEM medium supplemented with 10% FBS, 20 mM HEPES, Glutamax, and an antibacterial agent, and cultured at 37 ° C. and 5% CO 2 . On the 6th day of culture, the medium was replaced with a medium containing 50 ng / ml of cortisol, and the cells were sampled over time, with 0 hour immediately after the replacement.
- RNA is extracted from the collected cells using a commercially available RNA extraction kit, and the expression levels of Period1 and Bmal1 genes are determined by RT-PCR using a commercially available PCR primer (Perfect Real Time Primer, Takara Bio Inc.). It was measured. Similarly, the expression level of the housekeeping gene RPLP0 was quantified and used as an internal standard, and the relative expression level of the target gene relative to the expression level of RPLP0 was calculated.
- Period1 and Bmal1 were expressed with circadian rhythms in opposite phases, and Period1 showed an expression pattern that was high 2 hours after addition and low after 16 hours. Therefore, in the following experiment, the effect of the test substance on the expression of Period1 gene was evaluated using the gene expression level after 2 hours and 16 hours after stimulation as an index.
- the expression level of the housekeeping gene RPLP0 was quantified and used as an internal standard, and the relative expression level of the target gene relative to the expression level of RPLP0 was calculated. Dunnett's multiple comparison test was performed on the obtained values, and those having a significant difference in the risk rate of 5% on one side compared with the control (no addition of the test substance) were judged to be effective.
- Figure 2 shows the results. At both concentrations of 25 ppm and 50 ppm, the pelargonium plant extract significantly increased the expression of the Period1 gene 2 hours after stimulation.
- Granule (1) Sucralose 0.1 (2) Pelargonium plant extract 0.1 (3) Flavoring 5.0 (4) Excipient (Theolus) 10.0 (5) Maltitol residual
- the products of these combination examples can adjust the circadian rhythm of the living body by promoting the expression of the Period gene by the use test in the typical usage mode of each product form.
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Abstract
[Problem] To provide a substance capable of safely and effectively modulating expression of a period gene. [Solution] An expression modulator for a period gene containing Pelargonium plant extract as an effective component.
Description
本発明は、時計遺伝子の発現調節剤に関するものであり、より詳しくは、時計遺伝子Periodの発現調節剤、ならびにそれを含む概日リズム調整剤に関する。
The present invention relates to a clock gene expression regulator, and more particularly to a clock gene Period expression regulator and a circadian rhythm regulator containing the same.
地球上の殆ど全ての生物は体内に約２４時間周期で自律振動する「生体時計」を持っている。生体時計は、概日リズムという生物学的な日周変動を引き起こし、生物の睡眠・覚醒サイクルをはじめ、体温、血圧、ホルモン分泌、代謝、さらには、心身の活動、摂食などの、様々な生体現象（活動）の日周変動を支配すると考えられている。近年、概日リズムの乱れが、睡眠障害、皮膚疾患、生活習慣病、さらには欝病等の精神神経疾患など、様々な心身の症状または疾患の発症要因として指摘されている。
殆 ど Almost all living organisms on the earth have “biological clocks” that vibrate autonomously in a cycle of about 24 hours. Biological clocks cause biological diurnal fluctuations called circadian rhythms, such as the sleep / wake cycle of organisms, body temperature, blood pressure, hormone secretion, metabolism, as well as various activities such as mental and physical activity, and eating. It is thought to dominate the diurnal variation of biological phenomena (activity). In recent years, disturbance of circadian rhythm has been pointed out as a cause of various psychosomatic symptoms or diseases such as sleep disorders, skin diseases, lifestyle-related diseases, and neuropsychiatric diseases such as mania.
生体時計は、時計遺伝子と呼ばれる遺伝子群を含むリズム発生システムにより制御されている。哺乳類の場合、CLOCK, BMAL1, PERIOD, CRYPTOCHROMEの４つのコアとなるタンパク質をコードする遺伝子の転写の促進/抑制により形成されるフイードバックループが時計分子機構の中核（コア）をなし、これらコアループに関わる時計遺伝子がうまく発現しないと、欝や生活習慣病をはじめ、様々な疾病を引き起こすと考えられている（非特許文献１）。
The biological clock is controlled by a rhythm generation system including a group of genes called clock genes. In the case of mammals, the feedback loop formed by promoting / repressing transcription of genes encoding the four core proteins of CLOCK, BMAL1, PERIOD, and CRYPTOCHROME forms the core of the clock molecular mechanism and is involved in these core loops. If the clock gene is not expressed well, it is considered to cause various diseases such as epilepsy and lifestyle-related diseases (Non-patent Document 1).
概日リズムの制御中枢（中枢時計）は視床下部の視交叉上核に存在しているが、末梢組織においても時計遺伝子が発現し、同様のシステムで概日リズムを形成することが明らかになっている。皮膚でも時計遺伝子は発現しており、他の臓器と同様に、脳内の概日リズム中枢と同調して時計遺伝子がリズムを刻むことにより、生体恒常性が維持されている（非特許文献２）。例えば、Bmal1ノックダウン動物では、皮膚の萎縮や体毛再生の抑制が見られ、時計遺伝子が順調に働かないと、皮膚の健康が損なわれる（非特許文献３）。
The circadian rhythm control center (central clock) is located in the suprachiasmatic nucleus of the hypothalamus, but the clock gene is also expressed in peripheral tissues, and it is clear that the circadian rhythm is formed by a similar system. ing. The clock gene is also expressed in the skin, and the homeostasis is maintained by ticking the rhythm in synchronism with the circadian rhythm center in the brain as in other organs (Non-patent Document 2). ). For example, in Bmal1 knockdown animals, skin atrophy and suppression of hair regeneration are observed, and if the clock gene does not work smoothly, skin health is impaired (Non-patent Document 3).
末梢時計システムにおいて重要な時計遺伝子としてPeriod遺伝子をあげることができるが、Period遺伝子は、転写調節領域としてグルココルチコイド応答領域（GRE）を持ち、副腎皮質ホルモンであるコルチゾールに応答し、転写を開始する。すなわち、生体においては、中枢時計の情報が、副腎皮質ホルモンコルチゾールを介して、末梢時計へと伝達され、末梢における概日リズム発現を調節することができる。従って、コルチゾール分泌が不調になると、中枢時計の情報が、末梢時計に正しく伝達されず、中枢と末梢の時計が同調せず、様々な不調が引き起こされる原因となることから、Period遺伝子に作用し、時計リズムを調節する方法が求められる。
The Period gene can be cited as an important clock gene in the peripheral clock system, but the Period gene has a glucocorticoid response region (GRE) as a transcriptional regulatory region and responds to cortisol, a corticosteroid, to initiate transcription. . That is, in the living body, information on the central clock is transmitted to the peripheral clock via the corticosteroid cortisol, and circadian rhythm expression in the periphery can be regulated. Therefore, when cortisol secretion fails, the central clock information is not correctly transmitted to the peripheral clock, and the central and peripheral clocks do not synchronize, causing various malfunctions. What is needed is a way to adjust the clock rhythm.
Period遺伝子は、Period1、Period2、Period3が知られているが、時計遺伝子として重要な働きをするばかりでなく、ストレス応答や、肥満とも関連することが報告されている。生体は、急性ストレスに応答して、コルチゾール分泌が上昇し、様々なストレス応答反応を生体に引き起こす。このストレスによるコルチゾール分泌に対しても、Period遺伝子発現量が上昇することから、Period遺伝子のストレス応答への関与が報告されている（非特許文献４）。また、肥満との関連については、Periodノックダウン動物では肥満が観察され（非特許文献５）、またヒトでも肥満者のPeriod遺伝子発現リズムが、健常者と比較し異常となっていることが報告されている（非特許文献６）。
Period1, Period2, and Period3 are known as Period genes, but they not only play an important role as clock genes, but are also associated with stress response and obesity. In the living body, in response to acute stress, cortisol secretion increases, causing various stress response reactions in the living body. In relation to cortisol secretion due to stress, since the expression level of the Period gene is increased, the involvement of the Period gene in the stress response has been reported (Non-patent Document 4). As for the relation with obesity, obesity is observed in Period knockdown animals (Non-patent Document 5), and it is reported that the Period gene expression rhythm of obese people is also abnormal in humans compared to normal subjects. (Non-Patent Document 6).
上述したように、Period時計遺伝子の発現を調節することにより、それに関連する生体の様々な行動リズムや生理機能の概日リズムを調整することが可能であり、効果的にPeriod時計遺伝子の発現を調節できる新規薬剤の開発が望まれている。
As described above, by regulating the expression of the Period clock gene, it is possible to adjust various behavioral rhythms and circadian rhythms of physiological functions related to it, and effectively regulate the expression of the Period clock gene. Development of new drugs that can be controlled is desired.
例えば、ヒト皮膚線維芽細胞を用いた評価系で、アルニカエキス、コウホネエキス等の生薬およびジュニパーオイル、セダーオイル等の精油がPeriod時計遺伝子の発現を促進することが報告されている（特許文献１）。
For example, in an evaluation system using human dermal fibroblasts, it has been reported that herbal medicines such as Arnica extract and mulberry extract and essential oils such as Juniper oil and Cedar oil promote the expression of Period clock gene (Patent Document 1). ).
本発明は、上記のような事情に鑑み、Period遺伝子の発現を調節できる新規物質を提供することを目的とするものである。Period遺伝子の発現を調節することにより、Period遺伝子が関連する概日リズム不調や、ストレス応答、肥満などの様々な不調を改善し、生体恒常性を維持することができる。
In view of the circumstances as described above, an object of the present invention is to provide a novel substance that can regulate the expression of the Period gene. By regulating the expression of the Period gene, various disorders such as circadian rhythm disorder associated with the Period gene, stress response, obesity, etc. can be improved and biological homeostasis can be maintained.
本発明者は、ペラルゴニウム属植物の抽出物が、Period遺伝子の発現を調節し得ることを見出し、本発明を完成するに至った。
The present inventor has found that an extract of a genus Pelargonium plant can regulate the expression of the Period gene, and has completed the present invention.
本発明のPeriod遺伝子発現調節剤は、ペラルゴニウム属植物の抽出物を有効成分として含むことを特徴とする。ペラルゴニウム属植物の抽出物が時計遺伝子の発現を調節できることは今まで全く知られていなかった。
The Period gene expression regulator of the present invention is characterized by containing an extract of a genus Pelargonium as an active ingredient. Until now, it has never been known that an extract of a genus Pelargonium can control the expression of a clock gene.
本発明において、遺伝子発現調節とは、遺伝子の発現を促進させることに加え、遺伝子の発現リズム（位相または周期）を調節することを含む。
In the present invention, gene expression regulation includes regulating gene expression rhythm (phase or cycle) in addition to promoting gene expression.
本発明において好ましく使用されるペラルゴニウム属植物として、限定はされないが、ペラゴニウム グラベオレンス（Pelargonium graveolens）、ラデュラ ゼラニウム（Pelargonium radula）、ペラルゴニウム ロゼム（Pelargonium roseum）、ペラルゴニウム カピタツム（Pelargonium capitatum）、ペラルゴニウム オドラティシマム（Pelargonium odoratissimum）、およびペラルゴニウム デンティクラタム（Pelargonium denticulatum）等が挙げられる。
Pelargonium graveolens, Pelargonium radula, Pelargonium roseum, Pelargonium capitium ペ Perargonium capitatum ラ ル, but not limited as a pelargonium genus plant preferably used in the present invention Pelargonium odoratissimum), Pelargonium denticulatum, and the like.
また、Period遺伝子として、Period1、Period2およびPeriod3が挙げられる。
Also, Period1, Period2, and Period3 are listed as Period genes.
本発明の概日リズム調整剤は、上記のPeriod遺伝子発現調節剤を含む。Period時計遺伝子の発現を調節することにより、それに関連する生体の様々な行動リズムや生理機能の概日リズムを調整することができる。
The circadian rhythm adjusting agent of the present invention includes the Period gene expression regulating agent described above. By regulating the expression of the Period clock gene, it is possible to adjust various behavioral rhythms and circadian rhythms of physiological functions related thereto.
本発明のPeriod遺伝子発現調節剤は、Period遺伝子の発現を調節し、恒常性維持を促進して、概日リズムの不調に起因する様々な心身の症状または疾患を改善することが可能である。
The Period gene expression regulator of the present invention can improve the various mental and physical symptoms or diseases caused by the circadian rhythm disorder by regulating the expression of the Period gene and promoting the maintenance of homeostasis.
本発明のPeriod遺伝子発現調節剤は、ペラルゴニウム属植物の抽出物を有効成分とする。
The Period gene expression regulator of the present invention contains an extract of a genus Pelargonium as an active ingredient.
ペラルゴニウム属植物は、フウロソウ科ペラルゴニウム属に属する植物であり、例えば、ペラゴニウム グラベオレンス（Pelargonium graveolens）、ラデュラ ゼラニウム（Pelargonium radula）、ペラルゴニウム ロゼム（Pelargonium roseum）、ペラルゴニウム カピタツム（Pelargonium capitatum）、ペラルゴニウム オドラティシマム（Pelargonium odoratissimum）、およびペラルゴニウムデンティクラタム（Pelargonium denticulatum）等が挙げられる。
Pelargonium plants are plants belonging to the genus Pelargonium genus, such as Pelargonium graveolens, Pelargonium radula, Pelargonium roseum, Pelargonium roseum (Pelargonium roseum), Pelargonium capitium Pelargonium odoratissimum), Pelargonium denticulatum, and the like.
本発明で使用されるペラルゴニウム属植物の抽出物は、ペラルゴニウム属植物の葉、茎または花、あるいはそれらを含む全草より、水蒸気蒸留または溶剤抽出により抽出して作成することができる。抽出に用いる溶剤としては、限定はされないが、例えば、水、アルコール、アセトン、酢酸エチル、石油エーテル等から選ばれる1種あるいは２種以上を使用することができ、好ましくは、石油エーテルが使用される。
The extract of the genus Pelargonium plant used in the present invention can be prepared by extracting from the leaves, stems or flowers of the genus Pelargonium plant, or whole plants containing them by steam distillation or solvent extraction. The solvent used for extraction is not limited, but for example, one or two or more selected from water, alcohol, acetone, ethyl acetate, petroleum ether, etc. can be used, and preferably petroleum ether is used. The
例えば、ペラルゴニウム属植物の全草を約一日放置後、水蒸気蒸留することによりオイルが得られる。
For example, the whole plant of the genus Pelargonium is allowed to stand for about a day and then steam distilled to obtain oil.
本発明のPeriod遺伝子発現調節剤は、ペラルゴニウム属に属する１種の植物の抽出物を用いても、あるいは２種以上の植物の抽出物を混合して用いてもよい。
The Period gene expression regulator of the present invention may be an extract of one plant belonging to the genus Pelargonium or a mixture of two or more plant extracts.
また、本発明の概日リズム調整剤は、Period遺伝子発現調節剤としての上記のペラルゴニウム属植物の抽出物の１種または２種以上を含む。
The circadian rhythm adjusting agent of the present invention includes one or more of the above-mentioned extracts of the genus Pelargonium as a Period gene expression adjusting agent.
本発明のPeriod遺伝子発現調節剤は、本発明の効果を損なわない限り、上記の必須成分に加えて任意の他の成分を含んでいてよい。また、単独で用いてもよいが、他のPeriod遺伝子の発現調節作用を有する薬剤等と組み合わせて使用してもよい。
The Period gene expression regulator of the present invention may contain any other component in addition to the above essential components as long as the effects of the present invention are not impaired. Moreover, although it may be used independently, you may use it in combination with the chemical | medical agent etc. which have the expression regulation effect of another Period gene.
本発明のPeriod遺伝子発現調節剤は、Period遺伝子が脳内ばかりでなく様々な末梢臓器でも発現していることより、投与方法については、特に限定しない。例えば、Period遺伝子の発現を促進するペラルゴニウム属植物の抽出物を配合した組成物を皮膚に適用した場合には、皮膚のPeriod遺伝子発現を調節して恒常性維持を促進し、健やかな肌状態を維持することが可能である。
The period gene expression-regulating agent of the present invention is not particularly limited in its administration method because the Period gene is expressed not only in the brain but also in various peripheral organs. For example, when a composition containing an extract of a pelargonium genus plant that promotes the expression of the Period gene is applied to the skin, it regulates the Period gene expression in the skin to promote homeostasis and maintain a healthy skin condition. It is possible to maintain.
本発明のPeriod遺伝子発現調節剤は、様々な対象物に含めることができ、その対象物の種類に応じて、上記の必須成分の他に、任意の構成要素をさらに含めることができる。
The Period gene expression regulator of the present invention can be included in various objects, and can further include an optional component in addition to the essential components described above, depending on the type of the object.
例えば、皮膚外用剤に配合する場合、その剤形（例えば、液剤、粉末剤、顆粒剤、エアゾール剤、固形剤、ジェル剤、パッチ剤、坐剤等）や、製品形態（例えば化粧料、医薬品、医薬部外品等）に応じて、通常そのような皮膚外用剤に含まれる任意の成分を、本発明のPeriod遺伝子発現調節剤と共に含んでいてよい。皮膚外用剤は、皮膚（頭皮、頭髪、爪も含む）に対して適用する組成物全般を包括する概念であり、例えば、基礎化粧料、メーキャップ化粧料、毛髪化粧料、皮膚もしくは毛髪洗浄料等の化粧料や、軟膏剤、パッチ剤、坐剤、歯磨等の種々の医薬品ないし医薬部外品等を含む。その剤形も特に限定されず、例えば、水溶液系、可溶化系、乳化系、油液系、ゲル系、ペースト系、軟膏系、エアゾール系、水－油２層系、水－油－粉末３層など、任意の剤型を含む。皮膚外用剤が化粧料である場合、例えば、香水、オードトワレ、オーデコロン、クリーム、乳液類、化粧水、ファンデーション類、粉白粉、口紅、石鹸、シャンプー・リンス類、ボディーシャンプー、ボディーリンス、ボディーパウダー類、浴剤類等が挙げられる。
For example, when blended into an external preparation for skin, its dosage form (eg, liquid, powder, granule, aerosol, solid, gel, patch, suppository, etc.) or product form (eg, cosmetics, pharmaceuticals) Depending on the quasi-drug, etc., any component usually contained in such an external preparation for skin may be included together with the Period gene expression regulator of the present invention. The topical skin preparation is a concept that encompasses all compositions applied to the skin (including the scalp, hair, and nails). For example, basic cosmetics, makeup cosmetics, hair cosmetics, skin or hair cleansing agents, etc. Cosmetics, ointments, patches, suppositories, various drugs such as dentifrices and quasi drugs. The dosage form is not particularly limited. For example, an aqueous solution system, a solubilization system, an emulsification system, an oil liquid system, a gel system, a paste system, an ointment system, an aerosol system, a water-oil two-layer system, a water-oil-powder 3 Includes any dosage form, such as a layer. When the skin external preparation is a cosmetic, for example, perfume, eau de toilette, eau de cologne, cream, milky lotion, lotion, foundations, powdered white powder, lipstick, soap, shampoo / rinse, body shampoo, body rinse, body powder And bath agents.
また、例えば、散剤、顆粒、錠剤、カプセル剤等様々な形態のサプリメント（栄養補助食品）、菓子、飲料等の任意の食品、医薬等に、本発明のPeriod発現調節剤を含めてもよい。
Further, for example, the Period expression regulator of the present invention may be included in various forms of supplements (nutritional supplements) such as powders, granules, tablets and capsules, confectionery, beverages and other foods, medicines and the like.
対象物中における本発明のPeriod遺伝子発現調節剤の配合量は、対象物の種類等によって適宜選択することができ、本願発明の効果を発揮できる限り限定されないが、皮膚外用剤に配合する場合、有効成分であるペラルゴニウム属植物の抽出物の配合量は通常、皮膚外用剤全質量に対して０．０１～１０００ｐｐｍであり、より好ましくは、０．１～１００ｐｐｍである。
The blending amount of the Period gene expression regulator of the present invention in the subject can be appropriately selected depending on the type of the subject, etc., and is not limited as long as the effects of the present invention can be exhibited, but when blended in a skin external preparation, The compounding amount of the extract of the genus Pelargonium as an active ingredient is usually 0.01 to 1000 ppm, more preferably 0.1 to 100 ppm, based on the total mass of the external preparation for skin.
尚、本発明の使用態様を例示したが、これらに限定されるものではなく、本発明の効果を達成できる限り、任意の態様で用いることができる。また、本発明のPeriod遺伝子発現調節剤の他に、具体的な態様に応じて、他の任意の薬剤等を本発明の効果を損なわない限り、配合することができる。
In addition, although the usage aspect of this invention was illustrated, it is not limited to these, As long as the effect of this invention can be achieved, it can be used in arbitrary aspects. In addition to the Period gene expression regulator of the present invention, other arbitrary drugs and the like can be added according to specific embodiments as long as the effects of the present invention are not impaired.
本発明のPeriod遺伝子発現調節剤やそれを配合した対象物の具体的な適用は、Period遺伝子発現の調節に関連するものであれば特に限定されないが、例えば、皮膚に適用した場合には、肌の保湿や柔軟性向上、しわの予防または改善、肌荒れなどの皮膚諸症状の予防、改善または治療等に適用できる。
The specific application of the Period gene expression regulator of the present invention and the object containing the same is not particularly limited as long as it relates to the regulation of Period gene expression. For example, when applied to the skin, It can be applied to moisturizing, improving flexibility, preventing or improving wrinkles, preventing, improving or treating various skin symptoms such as rough skin.
以下、実施例を挙げて本発明を具体的に説明するが、本発明は下記の実施例に限定されるものではない。尚、培養細胞として、皮膚線維芽細胞、上皮細胞、内皮細胞、色素細胞、脂肪細胞、神経細胞など各種細胞を用いることができるが、本実施例ではヒト皮膚線維芽細胞を用いて評価を行なった。また、ヒトでは、Period遺伝子としてPeriod1、Period2およびPeriod3の３種類の存在が知られているが、本実施例では代表としてPeriod1の発現を測定した。
Hereinafter, the present invention will be specifically described with reference to examples, but the present invention is not limited to the following examples. As cultured cells, various cells such as dermal fibroblasts, epithelial cells, endothelial cells, pigment cells, fat cells and nerve cells can be used. In this example, human skin fibroblasts are used for evaluation. It was. In humans, three types of Period genes, Period1, Period2, and Period3, are known. In this example, the expression of Period1 was measured as a representative.
培養ヒト皮膚線維芽細胞における時計遺伝子発現リズムの検討
培養ヒト皮膚線維芽細胞の系で時計遺伝子の発現パターンを確認するため、コルチゾールを刺激薬剤として用いて、Period1およびBmal1の発現量を経時的に測定した。培養細胞では通常、個々の細胞がばらばらのタイミングでリズムを刻んでいるが、コルチゾールやフォルスコリンのようなシグナル刺激因子で刺激することにより、時計遺伝子発現リズムを同調させて概日リズムを誘導することができる。 Examination of clock gene expression rhythms in cultured human skin fibroblasts To confirm the expression pattern of clock genes in cultured human skin fibroblasts, the expression levels of Period1 and Bmal1 were measured over time using cortisol as a stimulant. It was measured. In cultured cells, individual cells usually divide rhythms at different timings, but by stimulating with a signal stimulating factor such as cortisol or forskolin, the clock gene expression rhythm is synchronized to induce circadian rhythms. be able to.
培養ヒト皮膚線維芽細胞の系で時計遺伝子の発現パターンを確認するため、コルチゾールを刺激薬剤として用いて、Period1およびBmal1の発現量を経時的に測定した。培養細胞では通常、個々の細胞がばらばらのタイミングでリズムを刻んでいるが、コルチゾールやフォルスコリンのようなシグナル刺激因子で刺激することにより、時計遺伝子発現リズムを同調させて概日リズムを誘導することができる。 Examination of clock gene expression rhythms in cultured human skin fibroblasts To confirm the expression pattern of clock genes in cultured human skin fibroblasts, the expression levels of Period1 and Bmal1 were measured over time using cortisol as a stimulant. It was measured. In cultured cells, individual cells usually divide rhythms at different timings, but by stimulating with a signal stimulating factor such as cortisol or forskolin, the clock gene expression rhythm is synchronized to induce circadian rhythms. be able to.
培養ヒト皮膚線維芽細胞は、正常成人皮膚由来線維芽細胞を購入し（Cell
Application, Inc）、実験に用いた。10%FBS、20mM HEPES、 Glutamax、抗菌剤を添加したDMEM培地に播種し、37℃、5%CO2にて培養した。培養６日目に、50ng/mlのコルチゾールを含む培地に交換し、交換直後を0時間とし、経時的に細胞をサンプリングした。採取した細胞から、市販のRNA抽出キットを使用してRNAを抽出し、市販のPCRプライマー（Perfect Real Time Primer、タカラバイオ社）を用い、RT-PCR法により、Period1およびBmal1遺伝子の発現量を測定した。同様に、ハウスキーピング遺伝子であるRPLP0の発現量を定量して内部標準として用い、RPLP0の発現量に対する目的遺伝子の相対的発現量を算出した。 For cultured human skin fibroblasts, purchase normal adult skin-derived fibroblasts (Cell
Application, Inc), used for experiments. The cells were inoculated in DMEM medium supplemented with 10% FBS, 20 mM HEPES, Glutamax, and an antibacterial agent, and cultured at 37 ° C. and 5% CO 2 . On the 6th day of culture, the medium was replaced with a medium containing 50 ng / ml of cortisol, and the cells were sampled over time, with 0 hour immediately after the replacement. RNA is extracted from the collected cells using a commercially available RNA extraction kit, and the expression levels of Period1 and Bmal1 genes are determined by RT-PCR using a commercially available PCR primer (Perfect Real Time Primer, Takara Bio Inc.). It was measured. Similarly, the expression level of the housekeeping gene RPLP0 was quantified and used as an internal standard, and the relative expression level of the target gene relative to the expression level of RPLP0 was calculated.
Application, Inc）、実験に用いた。10%FBS、20mM HEPES、 Glutamax、抗菌剤を添加したDMEM培地に播種し、37℃、5%CO2にて培養した。培養６日目に、50ng/mlのコルチゾールを含む培地に交換し、交換直後を0時間とし、経時的に細胞をサンプリングした。採取した細胞から、市販のRNA抽出キットを使用してRNAを抽出し、市販のPCRプライマー（Perfect Real Time Primer、タカラバイオ社）を用い、RT-PCR法により、Period1およびBmal1遺伝子の発現量を測定した。同様に、ハウスキーピング遺伝子であるRPLP0の発現量を定量して内部標準として用い、RPLP0の発現量に対する目的遺伝子の相対的発現量を算出した。 For cultured human skin fibroblasts, purchase normal adult skin-derived fibroblasts (Cell
Application, Inc), used for experiments. The cells were inoculated in DMEM medium supplemented with 10% FBS, 20 mM HEPES, Glutamax, and an antibacterial agent, and cultured at 37 ° C. and 5% CO 2 . On the 6th day of culture, the medium was replaced with a medium containing 50 ng / ml of cortisol, and the cells were sampled over time, with 0 hour immediately after the replacement. RNA is extracted from the collected cells using a commercially available RNA extraction kit, and the expression levels of Period1 and Bmal1 genes are determined by RT-PCR using a commercially available PCR primer (Perfect Real Time Primer, Takara Bio Inc.). It was measured. Similarly, the expression level of the housekeeping gene RPLP0 was quantified and used as an internal standard, and the relative expression level of the target gene relative to the expression level of RPLP0 was calculated.
結果を図１に示す。Period1とBmal1は、逆位相で概日リズムを刻んで発現しており、Period1は、添加２時間後に高く、１６時間後に低い、発現パターンを示していた。そこで以下の実験では、刺激の２時間後および１６時間後の遺伝子発現量を指標として、試験物質のPeriod1遺伝子の発現に対する効果について評価した。
The results are shown in FIG. Period1 and Bmal1 were expressed with circadian rhythms in opposite phases, and Period1 showed an expression pattern that was high 2 hours after addition and low after 16 hours. Therefore, in the following experiment, the effect of the test substance on the expression of Period1 gene was evaluated using the gene expression level after 2 hours and 16 hours after stimulation as an index.
ペラルゴニウム属植物の抽出物による時計遺伝子発現調節効果の評価
上記と同様の方法により、正常成人皮膚由来線維芽細胞（Cell Application, Inc）を播種し、培養６日目に、各濃度のペラルゴニウム属植物の抽出物（ゼラニウム油、香栄興業社製）を培地中25ppmまたは50ppm含む試験用培地に交換し、交換直後を０時間とし、２時間後および１６時間後に細胞をサンプリングした。採取した細胞から、市販のRNA抽出キットを使用してRNAを抽出し、市販のPCRプライマー（Perfect Real Time Primer、タカラバイオ社）を用い、RT-PCR法によりPeriod１遺伝子の発現量を測定した。また、同様に、ハウスキーピング遺伝子であるRPLP0の発現量を定量して内部標準として用い、RPLP0の発現量に対する目的遺伝子の相対的発現量を算出した。得られた値について、Dunnettの多重比較検定を行い、コントロール（試験物質の添加なし）と比較して片側５％の危険率で有意差があるものを効果有りと判定した。 Evaluation of clock gene expression regulation effect by extract of pelargonium genus plant Normal adult skin-derived fibroblasts (Cell Application, Inc) were seeded by the same method as described above, and pelargonium genus plant at each concentration was cultured on the 6th day of culture. The extract (Geranium oil, manufactured by Koei Kogyo Co., Ltd.) was replaced with a test medium containing 25 ppm or 50 ppm in the medium, and immediately after the replacement, the cells were sampled after 2 hours and 16 hours. RNA was extracted from the collected cells using a commercially available RNA extraction kit, and the expression level of Period1 gene was measured by RT-PCR using a commercially available PCR primer (Perfect Real Time Primer, Takara Bio Inc.). Similarly, the expression level of the housekeeping gene RPLP0 was quantified and used as an internal standard, and the relative expression level of the target gene relative to the expression level of RPLP0 was calculated. Dunnett's multiple comparison test was performed on the obtained values, and those having a significant difference in the risk rate of 5% on one side compared with the control (no addition of the test substance) were judged to be effective.
上記と同様の方法により、正常成人皮膚由来線維芽細胞（Cell Application, Inc）を播種し、培養６日目に、各濃度のペラルゴニウム属植物の抽出物（ゼラニウム油、香栄興業社製）を培地中25ppmまたは50ppm含む試験用培地に交換し、交換直後を０時間とし、２時間後および１６時間後に細胞をサンプリングした。採取した細胞から、市販のRNA抽出キットを使用してRNAを抽出し、市販のPCRプライマー（Perfect Real Time Primer、タカラバイオ社）を用い、RT-PCR法によりPeriod１遺伝子の発現量を測定した。また、同様に、ハウスキーピング遺伝子であるRPLP0の発現量を定量して内部標準として用い、RPLP0の発現量に対する目的遺伝子の相対的発現量を算出した。得られた値について、Dunnettの多重比較検定を行い、コントロール（試験物質の添加なし）と比較して片側５％の危険率で有意差があるものを効果有りと判定した。 Evaluation of clock gene expression regulation effect by extract of pelargonium genus plant Normal adult skin-derived fibroblasts (Cell Application, Inc) were seeded by the same method as described above, and pelargonium genus plant at each concentration was cultured on the 6th day of culture. The extract (Geranium oil, manufactured by Koei Kogyo Co., Ltd.) was replaced with a test medium containing 25 ppm or 50 ppm in the medium, and immediately after the replacement, the cells were sampled after 2 hours and 16 hours. RNA was extracted from the collected cells using a commercially available RNA extraction kit, and the expression level of Period1 gene was measured by RT-PCR using a commercially available PCR primer (Perfect Real Time Primer, Takara Bio Inc.). Similarly, the expression level of the housekeeping gene RPLP0 was quantified and used as an internal standard, and the relative expression level of the target gene relative to the expression level of RPLP0 was calculated. Dunnett's multiple comparison test was performed on the obtained values, and those having a significant difference in the risk rate of 5% on one side compared with the control (no addition of the test substance) were judged to be effective.
図２に結果を示す。25ppmおよび50ppmのいずれの濃度においても、ペラルゴニウム属植物の抽出物は、刺激２時間後のPeriod1遺伝子の発現を有意に高めた。
Figure 2 shows the results. At both concentrations of 25 ppm and 50 ppm, the pelargonium plant extract significantly increased the expression of the Period1 gene 2 hours after stimulation.
上記の結果から、ペラルゴニウム属植物の抽出物が、Period遺伝子の発現を促進し得ることが示された。
From the above results, it was shown that the extract of the genus Pelargonium plant can promote the expression of the Period gene.
(配合例)
以下、本発明のPeriod発現調節剤の配合例を示すが、本発明の実施は以下に限定されるものではない。配合量は全て製品全量に対する質量％で表す。 (Formulation example)
Hereinafter, although the formulation example of the Period expression regulator of this invention is shown, implementation of this invention is not limited to the following. All compounding amounts are expressed in mass% with respect to the total amount of the product.
以下、本発明のPeriod発現調節剤の配合例を示すが、本発明の実施は以下に限定されるものではない。配合量は全て製品全量に対する質量％で表す。 (Formulation example)
Hereinafter, although the formulation example of the Period expression regulator of this invention is shown, implementation of this invention is not limited to the following. All compounding amounts are expressed in mass% with respect to the total amount of the product.
マッサージ用ジェル
（１）エリスリトール ２．０
（２）カフェイン ５．０
（３）オウバク抽出物 ３．０
（４）グリセリン ５０．０
（５）カルボキシビニルポリマー ０．４
（６）ポリエチレングリコール４００ ３０．０
（７）エデト３ナトリウム ０．１
（８）ポリオキシエチレン（１０）メチルポリシロキサン共重合体
２．０
（９）スクワラン １．０
（１０）水酸化カリウム ０．１５
（１１）ペラルゴニウム属植物の抽出物 １．０
Massage Gel (1) Erythritol 2.0
(2) Caffeine 5.0
(3) Oat extract 3.0
(4) Glycerin 50.0
(5) Carboxyvinyl polymer 0.4
(6) Polyethylene glycol 400 30.0
(7) edet trisodium 0.1
(8) Polyoxyethylene (10) methylpolysiloxane copolymer 2.0
(9) Squalane 1.0
(10) Potassium hydroxide 0.15
(11) Pelargonium plant extract 1.0
（１）エリスリトール ２．０
（２）カフェイン ５．０
（３）オウバク抽出物 ３．０
（４）グリセリン ５０．０
（５）カルボキシビニルポリマー ０．４
（６）ポリエチレングリコール４００ ３０．０
（７）エデト３ナトリウム ０．１
（８）ポリオキシエチレン（１０）メチルポリシロキサン共重合体
２．０
（９）スクワラン １．０
（１０）水酸化カリウム ０．１５
（１１）ペラルゴニウム属植物の抽出物 １．０
Massage Gel (1) Erythritol 2.0
(2) Caffeine 5.0
(3) Oat extract 3.0
(4) Glycerin 50.0
(5) Carboxyvinyl polymer 0.4
(6) Polyethylene glycol 400 30.0
(7) edet trisodium 0.1
(8) Polyoxyethylene (10) methylpolysiloxane copolymer 2.0
(9) Squalane 1.0
(10) Potassium hydroxide 0.15
(11) Pelargonium plant extract 1.0
マッサージクリーム
（１）固形パラフィン ５．０
（２）ミツロウ １０．０
（３）ワセリン １５．０
（４）流動パラフィン ４１．０
（５）１．３－ブチレングリコール ４．０
（６）モノステアリン酸グリセリン ２．０
（７）ＰＯＥ（２０）ソルビタンモノラウリン酸エステル ２．０
（８）ホウ砂 ０．２
（９）カフェイン ２．０
（１０）防腐剤 適量
（１１）酸化防止剤 適量
（１２）ペラルゴニウム属植物の抽出物 １．０
（１３）精製水 残余
Massage cream (1) Solid paraffin 5.0
(2) Beeswax 10.0
(3) Vaseline 15.0
(4) Liquid paraffin 41.0
(5) 1.3-butylene glycol 4.0
(6) Glycerol monostearate 2.0
(7) POE (20) sorbitan monolaurate 2.0
(8) Borax 0.2
(9) Caffeine 2.0
(10) Preservative appropriate amount (11) Antioxidant appropriate amount (12) Pelargonium plant extract 1.0
(13) Purified water residue
（１）固形パラフィン ５．０
（２）ミツロウ １０．０
（３）ワセリン １５．０
（４）流動パラフィン ４１．０
（５）１．３－ブチレングリコール ４．０
（６）モノステアリン酸グリセリン ２．０
（７）ＰＯＥ（２０）ソルビタンモノラウリン酸エステル ２．０
（８）ホウ砂 ０．２
（９）カフェイン ２．０
（１０）防腐剤 適量
（１１）酸化防止剤 適量
（１２）ペラルゴニウム属植物の抽出物 １．０
（１３）精製水 残余
Massage cream (1) Solid paraffin 5.0
(2) Beeswax 10.0
(3) Vaseline 15.0
(4) Liquid paraffin 41.0
(5) 1.3-butylene glycol 4.0
(6) Glycerol monostearate 2.0
(7) POE (20) sorbitan monolaurate 2.0
(8) Borax 0.2
(9) Caffeine 2.0
(10) Preservative appropriate amount (11) Antioxidant appropriate amount (12) Pelargonium plant extract 1.0
(13) Purified water residue
顆粒
（１）スクラロース ０．１
（２）ペラルゴニウム属植物の抽出物 ０．１
（３）香味料 ５．０
（４）賦形剤（セオラス） １０．０
（５）マルチトール 残余
Granule (1) Sucralose 0.1
(2) Pelargonium plant extract 0.1
(3) Flavoring 5.0
(4) Excipient (Theolus) 10.0
(5) Maltitol residual
（１）スクラロース ０．１
（２）ペラルゴニウム属植物の抽出物 ０．１
（３）香味料 ５．０
（４）賦形剤（セオラス） １０．０
（５）マルチトール 残余
Granule (1) Sucralose 0.1
(2) Pelargonium plant extract 0.1
(3) Flavoring 5.0
(4) Excipient (Theolus) 10.0
(5) Maltitol residual
錠剤（チュアブルタイプ）
（１）イノシトール １１．０
（２）マルチトール ２１．０
（３）スクロース ０．５
（４）鮭白子抽出物（ＤＮＡ Ｎａ） ０．１
（５）酵母抽出物 ０．１
（６）ペラルゴニウム属植物の抽出物 ０．１
（７）香味料 ５．０
（８）賦形剤 残余
Tablet (chewable type)
(1) Inositol 11.0
(2) Maltitol 21.0
(3) Sucrose 0.5
(4) White coconut extract (DNA Na) 0.1
(5) Yeast extract 0.1
(6) Pelargonium plant extract 0.1
(7) Flavoring 5.0
(8) Excipient residue
（１）イノシトール １１．０
（２）マルチトール ２１．０
（３）スクロース ０．５
（４）鮭白子抽出物（ＤＮＡ Ｎａ） ０．１
（５）酵母抽出物 ０．１
（６）ペラルゴニウム属植物の抽出物 ０．１
（７）香味料 ５．０
（８）賦形剤 残余
Tablet (chewable type)
(1) Inositol 11.0
(2) Maltitol 21.0
(3) Sucrose 0.5
(4) White coconut extract (DNA Na) 0.1
(5) Yeast extract 0.1
(6) Pelargonium plant extract 0.1
(7) Flavoring 5.0
(8) Excipient residue
タブレット
（１）潤沢剤（ショ糖脂肪酸エステル等） １．０
（２）アラビアガム水溶液（５％） ２．０
（３）酸味料 １．０
（４）着色料 適量
（５）ペラルゴニウム属植物の抽出物 ０．１
（６）糖質（粉糖またはソルビトール等） 残余
Tablet (1) Lubricant (sucrose fatty acid ester, etc.) 1.0
(2) Gum arabic aqueous solution (5%) 2.0
(3) Acidulant 1.0
(4) Coloring agent appropriate amount (5) Pelargonium plant extract 0.1
(6) Carbohydrate (such as powdered sugar or sorbitol)
（１）潤沢剤（ショ糖脂肪酸エステル等） １．０
（２）アラビアガム水溶液（５％） ２．０
（３）酸味料 １．０
（４）着色料 適量
（５）ペラルゴニウム属植物の抽出物 ０．１
（６）糖質（粉糖またはソルビトール等） 残余
Tablet (1) Lubricant (sucrose fatty acid ester, etc.) 1.0
(2) Gum arabic aqueous solution (5%) 2.0
(3) Acidulant 1.0
(4) Coloring agent appropriate amount (5) Pelargonium plant extract 0.1
(6) Carbohydrate (such as powdered sugar or sorbitol)
キャンディー
（１）砂糖 ５０．０
（２）水飴 ４７．９５
（３）有機酸 ２．０
（４）ペラルゴニウム属植物の抽出物 ０．０５
Candy (1) Sugar 50.0
(2) Minamata 47.95
(3) Organic acid 2.0
(4) Pelargonium plant extract 0.05
（１）砂糖 ５０．０
（２）水飴 ４７．９５
（３）有機酸 ２．０
（４）ペラルゴニウム属植物の抽出物 ０．０５
Candy (1) Sugar 50.0
(2) Minamata 47.95
(3) Organic acid 2.0
(4) Pelargonium plant extract 0.05
ガム
（１）砂糖 ４３．０
（２）ガムベース ３０．９５
（３）グルコース １０．０
（４）水飴 １６．０
（５）ペラルゴニウム属植物の抽出物 ０．０５
Gum (1) Sugar 43.0
(2) Gum base 30.95
(3) Glucose 10.0
(4) Minamata 16.0
(5) Pelargonium plant extract 0.05
（１）砂糖 ４３．０
（２）ガムベース ３０．９５
（３）グルコース １０．０
（４）水飴 １６．０
（５）ペラルゴニウム属植物の抽出物 ０．０５
Gum (1) Sugar 43.0
(2) Gum base 30.95
(3) Glucose 10.0
(4) Minamata 16.0
(5) Pelargonium plant extract 0.05
これら配合例の製品は、それぞれの製品形態の典型的な使用態様における使用テストにより、Period遺伝子の発現を促進して、生体の概日リズムを調整することができる。
The products of these combination examples can adjust the circadian rhythm of the living body by promoting the expression of the Period gene by the use test in the typical usage mode of each product form.
Claims (4)
- ペラルゴニウム属植物の抽出物を有効成分として含有する、Period遺伝子発現調節剤。 A Period gene expression regulator comprising an extract of a genus Pelargonium as an active ingredient.
- 前記ペラルゴニウム属植物が、ペラゴニウム グラベオレンス（Pelargonium graveolens）、ラデュラ ゼラニウム（Pelargonium radula）、ペラルゴニウム ロゼム（Pelargonium roseum）、ペラルゴニウム カピタツム（Pelargonium capitatum）、ペラルゴニウム オドラティシマム（Pelargonium odoratissimum）、およびペラルゴニウム デンティクラタム（Pelargonium denticulatum）から選択される１種または２種以上であることを特徴とする、請求項１記載のPeriod遺伝子発現調節剤。 The Pelargonium genus Pelargonium peliteum (Pelargonium graveolens), Pelargonium it pelticum (Pelargonium peltium) (Pelargonium peltium (Pelargonium pelitum) The Period gene expression regulator according to claim 1, wherein the Period gene expression regulator is one or more selected from the group consisting of:
- Period遺伝子が、Period1、 Period2または Period3であることを特徴とする請求項１または２記載のPeriod遺伝子発現調節剤。 The Period gene expression regulator according to claim 1 or 2, wherein the Period gene is Period1, Period2, or Period3.
- 請求項１から３いずれか１項記載のPeriod遺伝子発現調節剤を含む概日リズム調整剤。 The circadian rhythm regulator containing the Period gene expression regulator of any one of Claim 1 to 3.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2012-212574 | 2012-09-26 | ||
| JP2012212574A JP2014065682A (en) | 2012-09-26 | 2012-09-26 | Expression modulator for clock gene period |
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| Publication Number | Publication Date |
|---|---|
| WO2014050003A1 true WO2014050003A1 (en) | 2014-04-03 |
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|---|---|---|---|
| PCT/JP2013/005410 WO2014050003A1 (en) | 2012-09-26 | 2013-09-12 | Expression modulator for clock gene period |
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| Country | Link |
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| JP (1) | JP2014065682A (en) |
| TW (1) | TW201424744A (en) |
| WO (1) | WO2014050003A1 (en) |
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| WO2024106205A1 (en) * | 2022-11-16 | 2024-05-23 | 株式会社豊田中央研究所 | Biological clock regulator |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003119490A (en) * | 2001-08-08 | 2003-04-23 | Shiseido Co Ltd | Psychosedative perfume composition |
| JP2005023044A (en) * | 2003-07-04 | 2005-01-27 | Nitto Yakuhin Kogyo Kk | Aromatic agent |
| JP2005187432A (en) * | 2003-12-26 | 2005-07-14 | Shiseido Co Ltd | Fat accumulation suppressing composition |
| JP2008156276A (en) * | 2006-12-22 | 2008-07-10 | Lion Corp | Mental fatigue-improving agent for woman |
-
2012
- 2012-09-26 JP JP2012212574A patent/JP2014065682A/en active Pending
-
2013
- 2013-09-12 WO PCT/JP2013/005410 patent/WO2014050003A1/en active Application Filing
- 2013-09-25 TW TW102134601A patent/TW201424744A/en unknown
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2003119490A (en) * | 2001-08-08 | 2003-04-23 | Shiseido Co Ltd | Psychosedative perfume composition |
| JP2005023044A (en) * | 2003-07-04 | 2005-01-27 | Nitto Yakuhin Kogyo Kk | Aromatic agent |
| JP2005187432A (en) * | 2003-12-26 | 2005-07-14 | Shiseido Co Ltd | Fat accumulation suppressing composition |
| JP2008156276A (en) * | 2006-12-22 | 2008-07-10 | Lion Corp | Mental fatigue-improving agent for woman |
Non-Patent Citations (4)
| Title |
|---|
| GOZU Y ET AL.: "SCENT REDUCES THE DELETERIOUS EFFECT OF SLEEP INTERRUPTION ON CIRCADIAN RHYTHM AND SKIN CONDITIONS", SLEEP BIOL RHYTHM, vol. 9, no. 4, October 2011 (2011-10-01), pages 410 * |
| JIRO IMANISHI: "Kaori ni yoru Utsu Jotai Oyobi Fuankan no Keigen", AROMA RES, vol. 9, no. 2, 2008, pages 169 - 175 * |
| RYOICHI KOMAKI ET AL.: "5-alkyl-2(3H)-furanones no Melanin Seisei Yokusei Koka", FRAGRANCE JOURNAL, vol. 33, no. 5, 2005, pages 43 - 49 * |
| SHIBATA S: "Circadian Clock Gene Expression and Brain Function.", ACTA HISTOCHEM CYTOCHEM, vol. 32, no. 6, 1999, pages 501 * |
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| JP2014065682A (en) | 2014-04-17 |
| TW201424744A (en) | 2014-07-01 |
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