Body clock regulator

Abstract

The present invention provides agents and other devices that can advance the phase of the circadian rhythm. [Solution] The body clock regulator contains bergamot oil, geranium oil, and cedarwood. It contains at least one of Virginia oil, citral, and β-caryophyllene. It contains an active ingredient that advances the phase of the expression rhythm of clock genes.

Description

Technical Field

[0001] The present disclosure relates to an internal clock regulator.

Background Art

[0002] It is known that the internal clock is controlled by regulating the expression of various clock genes (e.g., Per, Cry, Bmal, Clock, etc.) possessed by organisms. Specifically, for example in mammals, a complex of the BMAL1 protein, which is the product of the Bmal gene, and the CLOCK protein, which is the product of the Clock gene, activates the transcription of the Per gene and the Cry gene. Then, a complex of the PER protein and the CRY protein, which are the products of the Per gene and the Cry gene, suppresses the activation of transcription by BMAL1 and CLOCK, forming a feedback loop that oscillates with a 24-hour period. Such an internal clock includes a central clock in the suprachiasmatic nucleus of the hypothalamus in the brain and peripheral clocks present in various peripheral tissues. The expression of clock genes is controlled by a similar mechanism, and it is known that the clock genes also rhythmically beat in synchronization with the central clock in the peripheral clocks. In this way, the circadian rhythm formed by the feedback mechanism of clock genes regulates various biological activities such as the sleep-wake rhythm, the autonomic nervous system such as body temperature, the endocrine system such as blood hormone concentration, and the immune and metabolic systems. As a result, it is known that disruptions in the circadian rhythm can cause various psychosomatic symptoms such as sleep disorders related to falling asleep and waking up, lifestyle-related diseases including obesity and diabetes, and mental and neurological diseases including depression. in mammals, a complex of the BMAL1 protein, which is the product of the Bmal gene, and the CLOCK protein, which is the product of the Clock gene, activates the transcription of the Per gene and the Cry gene. Then, a complex of the PER protein and the CRY protein, which are the products of the Per gene and the Cry gene, suppresses the activation of transcription by BMAL1 and CLOCK, forming a feedback loop that oscillates with a 24-hour period. Such an internal clock includes a central clock in the suprachiasmatic nucleus of the hypothalamus in the brain and peripheral clocks present in various peripheral tissues. The expression of clock genes is controlled by a similar mechanism, and it is known that the clock genes also rhythmically beat in synchronization with the central clock in the peripheral clocks. In this way, the circadian rhythm formed by the feedback mechanism of clock genes regulates various biological activities such as the sleep-wake rhythm, the autonomic nervous system such as body temperature, the endocrine system such as blood hormone concentration, and the immune and metabolic systems. As a result, it is known that disruptions in the circadian rhythm can cause various psychosomatic symptoms such as sleep disorders related to falling asleep and waking up, lifestyle-related diseases including obesity and diabetes, and mental and neurological diseases including depression. 物であるCLOCKタンパク質との複合体が、Per遺伝子およびCry遺伝子の転写を 活性化する。そして、Per遺伝子およびCry遺伝子の産物であるPERタンパク質お よびCRYタンパク質の複合体が、BMAL1およびCLOCKによる転写の活性化を抑 制して、24時間周期で振動するフィードバックループが形成される。このような体内時 計には、脳の視床下部視交叉上核にある中枢時計と、末梢の様々な組織に存在する末梢時<000^017>計とがあり、同様の機構により時計遺伝子の発現制御が行われて、末梢時計においても中 枢時計と同調して時計遺伝子がリズムを刻むことが知られている。このようにして時計遺 伝子のフィードバック機構により形成される概日リズムは、睡眠·覚醒リズム、体温など の自律神経系、血中ホルモン濃度などの内分泌系、免疫·代謝系などの種々の生体活動を 調整している。その結果、概日リズムの乱れが、入眠および覚醒に係る睡眠障害や、肥満 や糖尿病を含む生活習慣病や、鬱病を含む精神神経疾患など、心身に係る種々の症状を引 き起こす要因になることが知られている。

[0003] To adjust such a circadian rhythm, techniques for regulating the expression of clock genes have been proposed For example, Patent Document 1 contains black ginger, Per2, Cry1, Bmal1 Furthermore, a composition for regulating circadian rhythms that promotes the expression of Clock is disclosed. Reference 2 contains lavender oil and eucalyptus oil as active ingredients, and clock genes Agents that promote the expression of the hyaluronic acid synthase gene are disclosed. Product 3 contains elemi oil and other active ingredients to induce the expression rhythm of the clock gene Bmal1. A circadian rhythm regulator that induces this is disclosed. Furthermore, Patent Document 4 discloses valerian oil. A circadian rhythm regulator containing an active ingredient that adjusts the circadian rhythm via inhalation stimulation has been disclosed. Furthermore, Patent Document 5 describes a method that includes sansho extract as an active ingredient and uses clock genes. A circadian rhythm regulator that induces the expression rhythm of Period has been disclosed. [Prior art documents] [Patent Documents]

[0004] [Patent Document 1] Japanese Patent Publication No. 2019-94357 [Patent Document 2] Japanese Patent Publication No. 2016-180007 [Patent Document 3] International Publication No. 2011 / 122040 [Patent Document 4] Japanese Patent Publication No. 2010-215561 [Patent Document 5] Patent No. 5868313 [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] Circadian rhythm disorders include jet lag syndrome, shift work sleep disorder, delayed sleep phase syndrome, and pre-sleep phase syndrome. Jet lag is one example of a known syndrome. The syndrome is caused by traveling long distances in a short time by aircraft, and shift work sleep. The disorder is caused by shift work with fluctuating working hours, and delayed sleep phase syndrome is a lifestyle issue. This can be caused by a shift towards a nocturnal lifestyle. Furthermore, especially in recent years, there are social constraints on weekday sleep. The difference between weekday and weekend sleep patterns (the difference in sleep / wake rhythms between weekdays and weekends) The problem of "social jet lag" caused by ( ) is becoming more pronounced. In other words, the discrepancy between the biological clock and the social clock (caused by social constraints such as work and school) As a result, the number of people complaining of various mental and physical symptoms such as sleep disorders, drowsiness, fatigue, and digestive symptoms is increasing. This is a contributing factor. Such social jet lag is a chronic phenomenon, and is caused by employment, etc. This continues throughout a period in which one is required to live according to a societal clock that does not align with one's own biological clock. Among the circadian rhythm disorders described above, at least one includes, for example, social jet lag. Circadian rhythm disorders in this area involve a discrepancy between the natural rhythm of the body's internal clock and the phases of sleep onset and wakefulness. Often, this is caused by a regression. Therefore, advancing the phase of the circadian rhythm is important. What was needed was the ability to perform the necessary skills. [Means for solving the problem]

[0006] This disclosure can be implemented in the following forms: (1) According to one embodiment of the present disclosure, a biological clock regulator is provided. This biological clock regulator is Bergamot oil, geranium oil, cedarwood Virginia oil, citral, It contains at least one of the following as an active ingredient: clock genes Adjust the body clock by advancing the phase of the expression rhythm. According to this form of body clock regulator, at least one of bergamot oil, geranium oil, cedar wood Virginia oil, citral, and β-caryophyllene is included as an active ingredient, thereby advancing the phase of the expression rhythm of the clock gene and adjusting the body clock. Therefore, it becomes possible to treat, improve, or prevent circadian rhythm disorders accompanied by a backward shift in the phase of the expression rhythm of the clock gene and symptoms associated with such circadian rhythm disorders. It becomes possible. (2) The body clock regulator in the above form may include at least one of bergamot oil, cedar wood Virginia oil, and citral as an active ingredient, and increase the amplitude of the expression rhythm of the clock gene. With such a configuration, by increasing the amplitude of the expression rhythm of the clock gene, it becomes possible to increase the amplitude of the circadian rhythm and make the circadian rhythm a strong rhythm with a clear cadence. Therefore, the body clock regulator can enhance the effect of treating, improving, or preventing circadian rhythm disorders and symptoms associated with circadian rhythm disorders. It becomes possible. [[ID=​​​​​​​​​​​​​(5) The above-mentioned forms of biological clock regulators are used for circadian rhythm disorders and symptoms associated with circadian rhythm disorders. It may also be used as a circadian rhythm regulator to treat, improve, or prevent the condition. For example, this could be caused by jet lag, delayed sleep phase syndrome, or social jet lag. Circadian rhythm disorders and associated symptoms (sleep disturbances, drowsiness, fatigue, digestion) It becomes possible to treat, improve, or prevent various mental and physical symptoms (such as organ symptoms). Yes. (6) According to another embodiment of the present disclosure, a circadian rhythm comprising the above-described circadian rhythm regulator. A transdermal formulation for the treatment of a disorder is provided. With this configuration, the body can be administered transdermally. By administering internal clock regulators into the body, circadian rhythm disorders and symptoms associated with circadian rhythm disorders are treated. This will make it possible to treat, improve, or prevent it. (7) According to yet another embodiment of the present disclosure, a circadian rhythm regulator comprising the above embodiment is provided. An oral formulation for the treatment of rhythm disorders is provided. With this configuration, oral administration is possible. This involves introducing a body clock regulator into the body to treat circadian rhythm disorders and those associated with them. It becomes possible to treat, improve, or prevent these symptoms. (8) A fragrance containing the above-described circadian rhythm regulator according to yet another embodiment of the present disclosure This is provided. With this configuration, the accumulation can be achieved by the simple method of installing an air freshener. By introducing a body clock regulator into the body without requiring any extreme intake, circadian rhythm disorders can be treated. This could make it possible to treat, improve, or prevent symptoms associated with circadian rhythm disorders. . (9) A bath additive containing the above-described circadian rhythm regulator according to yet another embodiment of the present disclosure. This is provided. With this configuration, bathing can be done in a simple way using bath salts. By introducing a body clock regulator into the body without requiring any active intake, the circadian rhythm... It is possible to treat, improve, or prevent symptoms associated with circadian rhythm disorders and other related conditions. It will become. (10) According to yet another embodiment of the present disclosure, an inhalation containing the above-described embodiment of the circadian rhythm regulator. The agent is provided. With this configuration, the body clock can be adjusted by inhaling the inhaled agent. The drug is introduced into the body to treat circadian rhythm disorders and symptoms associated with them. It becomes possible to improve or prevent the problem. (11) Food and beverages containing the above-described circadian rhythm regulator according to yet another embodiment of the present disclosure Products are provided. With this configuration, the body clock regulator is introduced into the body through the consumption of food and beverages. By incorporating it, circadian rhythm disorders and symptoms associated with circadian rhythm disorders can be treated, improved, and Rui can be prevented. (12) According to yet another embodiment of the present disclosure, a method for adjusting the biological clock is provided. The clock adjustment method involves, within the space where the subject experiencing circadian rhythm disorders is present, from (1) above (3) The circadian rhythm regulator described in any one of the items above is diffused to the subject and the circadian rhythm regulator is diffused to the subject Inhale the watch adjustment solution. According to this method of adjusting the body clock, a body clock adjusting agent is placed in the space where the subject is present. By dispersing the substance and having the target person inhale the body clock regulator, the act of actively taking the substance is stimulated. Without performing any other action, the body introduces a biological clock regulator into the body, which can lead to circadian rhythm disorders, or circadian rhythm disorders It becomes possible to treat, improve, or prevent the symptoms associated with it. This disclosure can be implemented in various forms other than those described above, for example, the expression rhythm of clock genes. Methods for adjusting the internal clock that advance the phase of the circadian rhythm, or methods for adjusting the internal clock that advance the phase of the circadian rhythm It can be implemented through legal means or other forms. [Brief explanation of the drawing]

[0007] [Figure 1] An explanatory diagram showing indicators for evaluating the effects of a test substance. [Figure 2] An explanatory diagram showing the luminescence rhythm when geranium oil is added. [Figure 3] An explanatory diagram showing the change in the phase of the peak when geranium oil is added. [Figure 4] An explanatory diagram showing the change in the relative expression level of Bmal1 when geranium oil is added. [Figure 5] An explanatory diagram showing the luminescence rhythm when bergamot oil is added. [Figure 6] An explanatory diagram showing the change in the phase of the peak when bergamot oil is added. [Figure 7] An explanatory diagram showing the change in amplitude due to the addition of bergamot oil. [Figure 8] An explanatory diagram showing the change in the relative expression level of Bmal1 when bergamot oil is added. [Figure 9] An explanatory diagram showing the change in the relative expression level of Per2 when bergamot oil is added. [Figure 10] An explanatory diagram showing the luminescence rhythm when cedarwood Virginia oil is added. [Figure 11] An explanatory diagram showing the change in peak phase when cedarwood Virginia oil is added. [Figure 12] An explanatory diagram showing the change in amplitude due to the addition of cedarwood Virginia oil. [Figure 13] An explanatory diagram showing the luminescence rhythm when β-caryophyllene is added. [Figure 14] An explanatory diagram showing the change in the phase of the peak when β-caryophyllene is added. [Figure 15] An explanatory diagram showing the luminescence rhythm when citral is added. [Figure 16] An explanatory diagram showing the change in the phase of the peak when citral is added. [Figure 17]An explanatory diagram showing the change in amplitude due to the addition of citral. [Figure 18] An explanatory diagram showing the luminescence rhythm when geraniol is added. [Figure 19] An explanatory diagram showing the luminescence rhythm when isomentone is added. [Figure 20] An explanatory diagram showing the luminescence rhythm when linalool is added. [Figure 21] An explanatory diagram showing the luminescence rhythm when d-limonene is added. [Figure 22] An explanatory diagram showing the luminescence rhythm when γ-terpinene is added. [Figure 23] An explanatory diagram showing the luminescence rhythm when α-cedrene is added. [Figure 24] An explanatory diagram showing the luminescence rhythm when lavender oil is added. [Figure 25] An explanatory diagram showing the luminescence rhythm when palmarosa oil is added. [Figure 26] An explanatory diagram showing the luminescence rhythm when rosemary oil is added. [Figure 27] An explanatory diagram showing the luminescence rhythm when ylang-ylang oil is added. [Figure 28] An explanatory diagram showing the luminescence rhythm when petitgrain oil is added. [Figure 29] An explanatory diagram showing the luminescence rhythm when eucalyptus oil is added. [Figure 30] An explanatory diagram showing the luminescence rhythm when cedarwood atlas oil is added. [Figure 31] An explanatory diagram showing the luminescence rhythm when caffeine is added. [Figure 32] An explanatory diagram showing the change in the phase of the peak when caffeine is added. [Figure 33] An explanatory diagram showing the change in amplitude due to caffeine addition. [Figure 34] An explanatory diagram showing the luminescence rhythm when bergamot oil and citral are added. [Figure 35] An explanatory diagram showing the change in peak phase when bergamot oil and citral are added. [Figure 36]An explanatory diagram showing the change in amplitude due to the addition of bergamot oil and citral. [Figure 37] An explanatory diagram showing the luminescence rhythm when bergamot oil and β-caryophyllene are added. [Figure 38] An explanatory diagram showing the change in amplitude due to the addition of bergamot oil and β-caryophyllene. [Figure 39] An explanatory diagram showing the luminescence rhythm when bergamot oil and caffeine are added. [Figure 40] An explanatory diagram showing the change in the phase of the peak when bergamot oil and caffeine are added. [Figure 41] An explanatory diagram showing the change in amplitude due to the addition of bergamot oil and caffeine. [Figure 42] An explanatory diagram showing the luminescence rhythm when citral and β-caryophyllene are added. [Figure 43] An explanatory diagram showing the change in the phase of the peaks when citral and β-caryophyllene are added. [Figure 44] An explanatory diagram showing the change in amplitude due to the addition of citral and β-caryophyllene. [Modes for carrying out the invention]

[0008] The biological clock regulator of this embodiment contains bergamot oil, geranium oil, and cedarwood. Virginia oil, citral, and at least one of β-caryophyllene This embodiment contains an active ingredient that acts as a biological clock regulator, advancing the phase of the circadian rhythm. The body clock regulators include bergamot oil, geranium oil, and cedarwood Virginia. One of the following is used as the active ingredient: oil, citral, or β-caryophyllene. It may also be included as such, and may contain a combination of several of the above-mentioned active ingredients. This is also good. Bergamot oil, geranium oil, cedarwood Virginia oil, citron Both lar and β-caryophyllene are readily available as commercial products.

[0009] (1) Bergamot oil Bergamot oil is an essential oil obtained from the bergamot plant (Citrus bergamia), a member of the citrus family. Bergamot oil mainly contains limonene, linalyl acetate, linalool, and β-pine. It contains γ-terpinene, β-myrcene, p-cymene, etc. Bergamot oil is It can be extracted from the peel of the bergamot fruit by pressing.

[0010] (2) Geranium oil Geranium oil is obtained from geranium (Pelargonium graveolens), a member of the Geraniaceae family. It is an essential oil. Geranium oil mainly contains citronellol, geraniol, and formic acid. It contains tronellyl, isomentone, linalool, geranyl formate, β-caryophyllene, etc. Geranium oil is extracted from geranium flowers and leaves using steam distillation. It is possible.

[0011] (3) Cedarwood Virginia Oil Cedarwood Virginia oil is made from cedarwood (Juniperus violaceus), a member of the cypress family. It is an essential oil obtained from cedarwood (Virginia). Cedarwood Virginia oil mainly contains α-septum. Drain, thujopsene, cedrol, β-cedrene, β-funebren, widrol, Cedarwood Virginia oil contains β-himacalene, β-caryophyllene, etc. It can be extracted from the wood of Virginia cedarwood by steam distillation.

[0012] (4) Citral Citral is a chain monoterpene aldehyde and has cis-trans isomers. Citral is a general term for lanial (trans(E) isomer) and neral (cis(Z) isomer). Essential oils of grass, lemon balm, lemon verbena, lemon myrtle, lemon, orange, etc. It is an ingredient. However, if the circadian clock regulator of this embodiment contains citral, Toral exists in forms different from essential oils, such as refined citral or synthetic citral. It is preferable that citral be included in circadian rhythm regulators.

[0013] (5) β-caryophyllene β-Caryophyllene is a bicyclic sesquiterpene found in ylang-ylang oil and lemon. Balm oil, rosemary oil, lavender oil, palmarosa oil, geranium It is a component of essential oils such as cedarwood oil and Virginia cedarwood oil. The biological clock of this embodiment If the adjusting agent contains β-caryophyllene, for example, geranium from the essential oils mentioned above. It is preferable that it be contained in the form of um oil or cedarwood Virginia oil. i. Also, if the circadian clock regulator of this embodiment contains β-caryophyllene, β- Caryophyllene exists in forms different from those of essential oils, for example, refined β-caryophyllene It is desirable that it be included in circadian rhythm regulators in the form of β-caryophyllene or synthetic β-caryophyllene. .

[0014] (6) Circadian rhythm regulators As previously mentioned, clock genes include various genes such as Per, Cry, Bmal, and Clock. The gene exists, and the circadian clock regulator of this embodiment advances the phase of the expression rhythm in clock genes. The child is not particularly limited. The biological clock regulator of this embodiment is the expression rhythm of the Bmal1 gene The phase of the rhythm is suitably advanced, but the circadian clock regulator of this embodiment advances the phase of the expression rhythm. The clock gene that triggers this is, for example, the BMAL1 protein, which is a product of the Bmal gene. This could be the Per gene or the Cry gene, whose transcription is activated. Circadian rhythm This is formed based on the transcriptional translation feedback loop of clock genes, therefore this implementation As mentioned above, the body clock regulator advances the phase of the expression rhythm of clock genes. This makes it possible to advance the phase of the entire circadian rhythm.

[0015] The biological clock regulator of this embodiment has the effect of shortening the period of the expression rhythm of clock genes. Physically, the circadian clock regulator of this embodiment, by administration of the circadian clock regulator, causes at least a time This advances the phase of the expression rhythm of clock genes, and as a result, shortens the period of the expression rhythm of clock genes. To shrink.

[0016] Furthermore, the circadian clock regulator of this embodiment contains, in addition to the active ingredients described above, any of the clock-related components. It may further include other components that advance the phase of the gene expression rhythm. For example, B Unlike the active ingredient of this embodiment described above, which advances the phase of the expression rhythm of the mal1 gene It encodes components such as the CLOCK protein, which forms a complex with the BMAL1 protein. Components that advance the phase of the Clock gene expression rhythm, and components that increase or decrease in the opposite direction to Bmal1. Components that advance the phase of the expression rhythm of Per and Cry genes expressed in the rhythm, The listed active ingredients may be combined to form a circadian rhythm regulator.

[0017] The biological clock regulator of this embodiment does not impair the effect of advancing the phase of the expression rhythm of clock genes. Unless otherwise specified, it may contain other ingredients in addition to the active ingredients described above. Other components contained in watch adjustment agents include, for example, excipients, fillers, diluents, solvents, and binding agents. Examples include mixtures, thickeners, emulsifiers, lubricants, buffers, surfactants, antioxidants, colorants, and fragrances. This can be done, and the appropriate choice can be made depending on the product form of the circadian rhythm regulator, as described later. stomach.

[0018] The circadian rhythm regulator of this embodiment can be used in various product forms, for example, for oral use. It can be a composition or a parenteral composition. It is taken into the body orally or parenterally. The active ingredients in the circadian rhythm regulator are absorbed into the bloodstream, for example, and supplied to cells in various parts of the body. It is supplied and acts.

[0019] When using the circadian rhythm regulator of this embodiment as an oral composition, the preparation of the oral composition Product forms include, for example, pharmaceuticals such as oral preparations, quasi-drugs, health foods and supplements, and It can be food and beverages, including beverages. The dosage form of the oral composition may be, for example, a tablet or a capsule. It can be prepared as a solid preparation such as granules, fine granules, or powder, or as a liquid preparation such as syrup or suspension. .

[0020] When the biological clock regulator of this embodiment is used as a parenteral composition, parenteral composition The product forms include, for example, transdermal formulations, nasal formulations, or pulmonary formulations (such as inhalation). It can be used as a pharmaceutical product. Furthermore, other product forms of parenteral compositions include cosmetics. Alternatively, the active ingredients of this embodiment can be used in general merchandise intended for ingesting into the body.

[0021] Among pharmaceuticals, transdermal and nasal administration formulations come in various forms, such as liquids, creams, and lotions. It can be an emulsifier, gel, or patch. Furthermore, the dosage form of a transpulmonary administration preparation may be, for example... Alternatively, it can be used as an inhalation formulation in which a circadian rhythm regulator is sprayed.

[0022] Cosmetic product forms include, for example, basic cosmetics such as creams and lotions, and makeup. Shampoo cosmetics, hair and scalp cosmetics, perfumes including eau de toilette, massage, etc. This can be a treatment agent used in this product, or a cleansing agent containing soap, etc. When using a circadian rhythm regulator in the form of a cosmetic product, the active ingredient in the circadian rhythm regulator should be used. It can be ingested transdermally and transpulmonaryly.

[0023] Examples of miscellaneous goods used to introduce active ingredients into the body include, for example, the active ingredients in circadian rhythm regulators. This refers to the active ingredients in fragrances, bath additives, and body clock regulators that are used by diffusing the ingredients into the air. It can be used as an inhalant by emitting or spraying it. (Fragrance) This refers to a form of use in which the circadian rhythm regulator is contained in a container, etc., and the active ingredient is gradually released into the air. In addition to fragrances, diffusers such as heated, ultrasonic, or nebulizer types are used. This includes fragrances that diffuse active ingredients into the air, as well as aromatherapy candles and incense. When using the internal clock regulator of this embodiment as a fragrance, bath additive, or inhalant, the body The active ingredients in the internal clock regulator can be ingested via the lungs. Furthermore, in this embodiment, When using a clock-regulating agent as a bath additive, the active ingredients in the internal clock-regulating agent are absorbed transdermally. It can be taken.

[0024] The amount of the aforementioned active ingredient contained in the circadian clock regulator of this embodiment is related to the clock genes. While not particularly limited as long as a phase-advancing effect on the expression rhythm is obtained, the composition is that of a biological clock regulator. The proportion to the whole substance should preferably be 0.00001% by mass or more, and 0.000 It is more desirable that the amount be 1% by mass or more. The amount of such active ingredients is, for example, body The efficiency of absorption into the body is determined by the manner in which the active ingredient of the internal clock regulator is administered (ingested), The appropriate dosage should be set considering the effects of the active ingredients on skin, mucous membranes, etc., as described above. For example, when diluting the active ingredient with a carrier oil and using it in an oil treatment... The concentration of the active ingredient should preferably be 1% or less relative to the carrier oil. When used by diffusing into a space such as inside, the concentration of the diffused active ingredient must be 0.01 ppb. It is desirable to aim for a concentration of approximately 100 ppm.

[0025] According to the biological clock regulator of this embodiment configured as described above, bergamot oil, Geranium oil, cedarwood Virginia oil, citral, and β-caryophyll By including at least one of the following as an active ingredient, the expression rhythm of clock genes is The phase can be advanced. Therefore, the internal clock regulator of this embodiment can advance the circadian rhythm It can be used to advance the phase of the rhythm, and to correct the phase that has been delayed due to circadian rhythm disorders, etc. This makes it possible to bring it closer to the desired (original) phase. Therefore, in this embodiment, Clock adjustment agents are used for conditions such as jet lag, delayed sleep phase syndrome, and social jet lag. Circadian rhythm disorders caused by circadian rhythm disorders, and symptoms associated with circadian rhythm disorders (sleep disturbances, drowsiness, fatigue) To treat, improve, or prevent various psychosomatic symptoms (such as digestive symptoms). It can be used.

[0026] The circadian rhythm regulator of this embodiment is bergamot oil and fern, which are among the active ingredients described above. - Wood Virginia oil and at least one of citral as active ingredients If included, in addition to the effect of advancing the phase of the expression rhythm of the clock genes mentioned above, the clock This can increase the amplitude of the gene expression rhythm. Therefore, the active ingredient and and a small amount of bergamot oil, cedarwood, Virginia oil, and citral. The biological clock regulator of this embodiment, which includes at least one of these, increases the amplitude of the circadian rhythm. It can be used in the following applications. In particular, both bergamot oil and citral are used as active ingredients. When included, an additive effect can be obtained regarding the amplitude enhancement effect. Amplitude increase As a result, the circadian rhythm becomes a distinct and strong rhythm. Therefore, in this embodiment, the body Clock adjustment agents treat, improve, or alleviate circadian rhythm disorders and associated symptoms. This can enhance the preventive effects mentioned above. Also, for example, in the elderly, generally, circadian rhythm It is known that the amplitude of the rhythm tends to decrease, resulting in a loss of emphasis. Therefore, a small amount of bergamot oil, cedarwood Virginia oil, and citral. By using the circadian clock regulator of this embodiment, which contains at least one active ingredient, elderly It is possible to improve various disorders caused by a decline in the ability to maintain circadian rhythms in the following cases. It will become.

[0027] Furthermore, the active ingredients contained in the circadian rhythm regulator of this embodiment are bergamot oil and geranium. Um oil, cedarwood Virginia oil, citral, and β-caryophyllene are These are all volatile aromatic components. Therefore, the internal clock regulator of this embodiment is used for circadian rhythm The substance is diffused into the space where individuals experiencing circadian rhythm disorders are present, and the individuals inhale the circadian rhythm regulator. By introducing this, it becomes possible to easily administer circadian rhythm regulators to the subjects. In other words, the space where the target person is present is filled with the above-mentioned active ingredients to promote well-being. By creating a space, it becomes possible to avoid special actions such as actively taking medication or other substances. This naturally helps regulate the body's internal clock rhythm. [Examples]

[0028] <Method for evaluating the effect of test substances on circadian rhythms> Using a system with mouse embryonic fibroblasts, bergamot oil, geranium oil, Various coatings containing cedarwood Virginia oil, citral, and β-caryophyllene The effects of the test substance (essential oil or essential oil components, etc.) on circadian rhythms were evaluated. Specifically, A reporter gene is placed downstream of the promoter of the clock gene Bmal1 or Per2. Emerald Luc (Eluc), a luciferase derived from the click beetle *Emerald Luc* Genetically modified mouse embryonic fibroblasts were used as evaluation cells. The evaluation cells were heated at 37°C. Under a 5% CO2 atmosphere, 10% FBS and 100 U / mL Penicil D-MEM medium containing lin / Streptomycin (High glucose) They were cultured in the following containers. Next, the above evaluation cells were placed in 96-well plates and 24-well plates. Alternatively, sow seeds in a 35mm dish and treat with 100nM dexamethasone for 2 hours after 24 hours. Therefore, the circadian rhythm cycle of the evaluation cells was reset and synchronized. After that, the plate Alternatively, the above medium in the dish may be replaced with a medium containing 400 μM D-Luciferin (luminescence). Substitute the substrate-containing medium and use the culture-equipped luminometer (Kronos) as the measuring device. The above evaluation cells were placed in HT or Kronos Dio (manufactured by ATTO Corporation) and time elapsed The luminescence (expression level of the reporter gene) was measured. After the start of measurement, the luminescence value reached its peak. The timing was checked. Three hours after the luminescence value reached its peak, 0.3% DMSO (dimethyl The test substance, diluted in a sulfoxide solution, was added to a luminescent substrate at various concentrations. The culture medium was replaced with a culture medium containing the active ingredient, and the plate or dish was returned to the measuring device to resume measurement. At the same time as the medium is changed to one containing the test substance, 0.3% DM without the test substance is added. Evaluation cells that had been cultured in a luminescent substrate-containing medium supplemented with SO solution were used as the control. Based on the acquired data, the period and amplitude of the measured luminescence intensity were compared with the control, and the subject The effects of the substance were evaluated.

[0029] Figure 1 is an explanatory diagram showing indicators for evaluating the effects of the test substance. In Figure 1, time is shown on the horizontal axis. The vertical axis shows the luminescence intensity, which represents the expression level. Figure 1 shows trend removal (de-trending). This schematically represents the fluctuations in the expression level of the reporter gene (expression rhythm). A reporter gene integrated downstream of a gene promoter controls the expression of the aforementioned clock gene. It is expressed according to a rhythm. The peak of the expression rhythm occurs immediately after the culture medium containing the test substance is changed. Starting with the first peak, we call them peak1, peak2, peak3, and so on. The length between cycles, or the length of one period, is indicated as the "period length," which is approximately 24 hours. Furthermore, the magnitude of the fluctuation in the amount of light emitted (expression level of clock genes) in one cycle (the relevant cycle) The difference between the beginning peak and the bottom is called the "amplitude." For example, between peak1 and peak2. The amplitude in the period is called amplitude 1, and the amplitude in the period between peak2 and peak3 is called amplitude 1. This is called width 2. In Figure 1, the magnitude of amplitude 1 is shown by a double-headed arrow. Also, the expression rhythm The change in the "phase" is determined by the timing (time) at which each peak appears in the expression rhythm. We evaluated the case where the waveform shifts to the left along the time axis in the expression rhythm shown in Figure 1. When the phase shifts forward, it is called "phase advance," and when the waveform shifts to the right, it is called "phase retreat." .

[0030] <Method for analyzing the relative expression levels of clock genes> The evaluation cells are used in the same manner as described above in "Method for evaluating the effect of test substances on circadian rhythms". To evaluate these cells, they were seeded in a 6-well plate and, after 24 hours, 100 nM dexamethoxazole was administered. The cells were treated with Zon for two hours to reset and synchronize the circadian rhythm cycle of the evaluation cells. Afterward, the culture medium in the plate is replaced with the luminescent substrate-containing medium described above, and the culture function described above is applied. The evaluation cells were placed inside the measuring device. Then, 3 hours after the luminescence value reached its peak, 0 The test substance was diluted with 0.3% DMSO (dimethyl sulfoxide) solution to various concentrations. The culture medium was replaced with one containing a luminescent substrate added to sea urchin, and cultivation was continued. From the time of adding the test substance, 0.4 Cells were collected after 8, 12, 16, 20, and 24 hours, and FastGene RNA Ba Using the SiC Kit (manufactured by Genetics Japan), at each of the above recovery timings RNA was extracted from 3 wells each. Using 300 ng of extracted RNA, PrimeS cript(registered trademark) RTMaster Mix (Perfect Real Tim e) The reverse transcription reaction was carried out using (manufactured by Takara Bio Inc.). Subsequently, Power SY BR Green PCR Master Mix (Thermo Fisher Sc Using ientific (manufactured by ientific), quantitative PCR (qPCR; quantitative The relative expression levels of Bmal1 or Per2 were analyzed by PCR. At the same time as changing to a culture medium containing the substance, replace the 0.3% DMSO solution that does not contain the test substance. The evaluation cells, which had been replaced with a culture medium containing the added luminescent substrate, were used as a control, and similarly... We performed an analysis of the following.

[0031] <Evaluation Results> [Geranium oil] Figure 2 shows the luminescence rhythm when geranium oil is added as the test substance (Bmal1 This is an explanatory diagram showing the gene expression rhythm. Figure 2 shows geranium added to a culture medium containing a luminescent substrate. When the um oil concentration was 100 μg / mL, and when it was 20 μg / mL, and the control The results for this are shown. As shown in Figure 2, geranium oil was used as the test substance. If present, the phase advanced in a concentration-dependent manner.

[0032] Figure 3 shows the results from Figure 2 when the geranium oil concentration is 100 μg / mL. Regarding the comparison of each peak (peak1, peak2, peak3) with the control: This is an explanatory diagram showing the amount of phase change. In Figure 3, the vertical axis shows the phase change compared to the control. This shows the phase advance; the larger the absolute value of the negative value, the greater the phase advance. Figure 3 As shown, the addition of geranium oil advanced the phase by up to approximately 3.7 hours.

[0033] Figure 4 shows the relative changes in the Bmal1 gene when geranium oil is added as the test substance. This is an explanatory diagram showing the changes in expression levels. Figure 4 shows the timing of Bm addition of the test substance. The relative expression levels of Bmal1 at each time interval are shown, with the expression level of al1 set to 1.0. As shown in Figure 4, when geranium oil is used as the test substance, geranium The phase of the Bmal1 gene expression rhythm advanced in a concentration-dependent manner with Um oil. Specifically In the control group, Bmal1 expression levels peaked after 16 hours, whereas in the control group, 10 When geranium oil was added at a concentration of 0 μg / mL, the development of Bmal1 occurred after 4 hours. When the current amount reaches its peak and geranium oil is added at a concentration of 20 μg / mL, 8 The expression level of Bmal1 peaked after a certain period of time.

[0034] [Bergamot oil] Figure 5 shows the luminescence rhythm (Bmal1) when bergamot oil is added as the test substance. This is an explanatory diagram showing the gene expression rhythm. Figure 5 shows the bell added to the culture medium containing the luminescent substrate. When the gamot oil concentration is 100 μg / mL, 10 μg / mL, and 1 μg / The results for mL and the control are shown. When bergamot oil is used, the phase advances in a concentration-dependent manner, and the amplitude... It increased.

[0035] Figure 6 shows the results from Figure 5, specifically for a bergamot oil concentration of 100 μg / mL. For the combined results, each peak (peak1, peak2, peak3) is compared to the control. This is an explanatory diagram showing the amount of phase change in the same manner as in Figure 3. As shown in Figure 6, Bergamot The addition of the oil advanced the phase by up to approximately 2.7 hours.

[0036] Figure 7 shows the results from Figure 5, specifically for a bergamot oil concentration of 100 μg / mL. Regarding the results, the diagram below shows the comparison of the magnitudes of amplitude 1 and amplitude 2 with the control. Yes. As shown in Figure 7, both amplitude 1 and amplitude 2 are due to the addition of bergamot oil. The amplitude increased by more than double. Thus, by adding bergamot oil... Furthermore, it was confirmed that the expression rhythm of Bmal1 is a distinct and strong rhythm.

[0037] Figure 8 shows the phase of the Bmal1 gene when bergamot oil was added as the test substance. This is an explanatory diagram showing the change in expression levels relative to the timing of the addition of the test substance. Figure 8 shows B The relative expression levels of Bmal1 at each time interval are shown, with the expression level of mal1 set to 1.0. As shown in Figure 8, when bergamot oil is used as the test substance, B The phase of the expression rhythm of the mal1 gene advanced. Specifically, in the control group, it was 12:00. While Bmal1 expression levels peaked after a short interval, at a concentration of 100 μg / mL, bergamot When cotton oil was added, the expression level of Bmal1 peaked after 4 hours.

[0038] Figure 9 shows the relative changes in the Per2 gene when bergamot oil is added as the test substance. This is an explanatory diagram showing the changes in expression levels. Figure 9 shows the timing of Pe's addition to the test substance. The relative expression levels of Per2 at each time point are shown, with the expression level of r2 set to 1.0. As shown in Figure 9, when bergamot oil is used as the test substance, Per2 The phase of the gene expression rhythm advanced. Specifically, in the control group, P was released after 16 hours. While er2 expression levels hit their lowest point, bergamot oil at a concentration of 100 μg / mL When the substance was added, the expression level of Per2 hit its lowest point after 12 hours.

[0039] [Cedarwood Virginia Oil] Figure 10 shows the luminescence rhythm when cedarwood Virginia oil is added as the test substance. This is an explanatory diagram showing the expression rhythm of the Bmal1 gene. Figure 10 shows a culture medium containing a luminescent substrate. When the concentration of cedarwood Virginia oil added is 100 μg / mL, and the control The results for the test material are shown. As shown in Figure 10, the test material was cedarwood bark. When using engineer oil, the phase advanced and the amplitude increased.

[0040] Figure 11 shows the results shown in Figure 10, with a cedarwood Virginia oil concentration of 100. For the case of μg / mL, each peak (peak1, peak2) was compared to the control. This is an explanatory diagram showing the amount of phase change of ) in the same manner as in Figure 3. As shown in Figure 11, cedar The addition of wood Virginia oil advanced the phase by up to approximately one hour.

[0041] Figure 12 shows the case where the cedarwood Virginia oil concentration is 100 μg / mL as shown in Figure 10. Regarding the results, the diagram below shows the comparison of the magnitudes of amplitude 1 and amplitude 2 with the control. Yes. As shown in Figure 12, the amplitude of the addition of cedarwood Virginia oil is It grew up to 1.6 times larger. Thus, by adding cedarwood Virginia oil... It was confirmed that the expression rhythm of Bmal1 is a distinct and strong rhythm.

[0042] [β-caryophyllene] Figure 13 shows the luminescence rhythm (Bmal) when β-caryophyllene is added as the test substance. This is an explanatory diagram showing the expression rhythm of one gene. Figure 13 shows the addition of a luminescent substrate to a culture medium. When the concentration of β-caryophyllene was 500 μM, and when it was 100 μM, and the control was... The results are shown below. As shown in Figure 13, β-caryophyllene was used as the test substance. When used, the phase advanced in a concentration-dependent manner.

[0043] Figure 14 shows the results based on Figure 13, where the β-caryophyllene concentration is 500 μM. For both the combined and 100 μM cases, each peak was compared to the control. 1. This is an explanatory diagram showing the phase change of peak 2) in the same manner as in Figure 3. As shown in Figure 14. Thus, the addition of β-caryophyllene causes the phase to advance in a concentration-dependent manner, resulting in β-caryophyllene. By setting the ylene concentration to 500 μM, the phase advanced by up to approximately 2.3 hours.

[0044] [Citral] Figure 15 shows the luminescence rhythm (Bmal1 gene) when citral is added as the test substance. This is an explanatory diagram showing the expression rhythm of [the substance]. Figure 15 shows [the substance] added to a culture medium containing a luminescent substrate. The results for a concentration of 100 μM and for the control are shown in Figure 15. Therefore, when citral is used as the test substance, the phase advances and the amplitude increases. That's impressive.

[0045] Figure 16 shows the results when the citral concentration is 100 μM, based on the results shown in Figure 15. Then, the phase of each peak (peak1, peak2, peak3) compared to the control. This is an explanatory diagram showing the amount of change in the same manner as in Figure 3. As shown in Figure 16, citral is added. This causes the phase to advance, and by setting the citral concentration to 100 μM, the phase reaches its maximum. We advanced for about four hours.

[0046] Figure 17 shows the results shown in Figure 15, but for a citral concentration of 100 μM. This is an explanatory diagram showing the results of comparing the magnitudes of amplitude 1 and amplitude 2 with the control. Figure 1 As shown in 7, the addition of citral increased the amplitude by up to 1.4 times. Thus, the addition of citral results in a more distinct and strong Bmal1 expression rhythm. It was confirmed that it creates a rhythm.

[0047] [Geranium oil components] Figure 18 shows the luminescence rhythm when geraniol is added as the test substance (Bmal1 gene). This is an explanatory diagram showing the expression rhythm of the offspring. Figure 18 shows geranium added to a culture medium containing a luminescent substrate. The results were obtained for ol concentrations of 100 μM, 10 μM, and 1 μM, and for control The results regarding geraniol concentration and geraniol are shown. As shown in Figure 18, Regardless of whether geraniol was added or not, there was no significant difference in the expression rhythm of Bmal1. No phase change was observed due to the addition.

[0048] Figure 19 shows the luminescence rhythm when isomenthone is added as the test substance (Bmal1 gene). This is an explanatory diagram showing the expression rhythm of the offspring. Figure 19 shows the ragworm added to a culture medium containing a luminescent substrate. The results for when the concentration of tonone was 100 μM, when it was 10 μM, and for the control were compared. This is shown. As shown in Figure 19, the concentration of isomenthone and whether or not isomenthone is added vary. However, there was no significant difference in the expression rhythm of Bmal1, and the addition of isomentone did not alter the phase. No transformation was observed.

[0049] Figure 20 shows the luminescence rhythm (Bmal1 gene) when linalool is added as the test substance. This is an explanatory diagram showing the expression rhythm of [the substance]. Figure 20 shows the [expression rhythm] of [the substance] added to the luminescent substrate-containing medium. When the concentration of the solution is 100 μM, 10 μM, and 1 μM, and the control is... The results show that, as shown in Figure 20, in the expression rhythm of Bmal1, lina No phase change was observed due to the addition of the roll.

[0050] The geraniol, isomentone, and linalool mentioned above are found in geranium oil. It is a compound that is also found in geranium oil. Regarding tronellil and geranyl formate, when added to the cells being evaluated as test substances... When the luminescence rhythm was examined, no phase change due to the addition of the substance was observed (data not shown). Thus, among the components of geranium oil, other than β-caryophyllene shown in Figure 13... Therefore, no phase advance effect on the expression rhythm of Bmal1 was observed. (See Figure 2) In the example using geranium oil, the geranium oil added to the culture medium containing the luminescent substrate When the concentration is 100 μg / mL, the concentration of β-caryophyllene is approximately 6.6 μM.

[0051] [Ingredients of bergamot oil] Figure 21 shows the luminescence rhythm when d-limonene is added as the test substance (Bmal1 gene). This is an explanatory diagram showing the expression rhythm of the offspring. Figure 21 shows d-Lycoplasma added to a culture medium containing a luminescent substrate. The results were obtained for monene concentrations of 100 μM, 10 μM, and 1 μM, and for the control group. The results for the following are shown. As shown in Figure 21, the d-limonene concentration and d-limonene Regardless of whether d-limonene was added or not, there was no significant difference in the expression rhythm of Bmal1. No phase change was observed due to the addition.

[0052] Figure 22 shows the luminescence rhythm when γ-terpinene is added as the test substance (Bmal1 This is an explanatory diagram showing the gene expression rhythm. Figure 22 shows γ- added to the luminescent substrate-containing culture medium. When the terpinene concentration is 100 μM, 10 μM, and 1 μM, the control The results for the γ-terpinene concentration and γ-terpinene are shown. As shown in Figure 22, the γ-terpinene concentration and γ-terpinene Regardless of whether pinene was added or not, there was no significant difference in the expression rhythm of Bmal1, and γ-ter No phase change was observed due to the addition of pinene.

[0053] The d-limonene and γ-terpinene mentioned above are compounds found in bergamot oil. Furthermore, regarding linalool, another component of bergamot oil, as shown in Figure 20. As shown above, no effect was observed in advancing the phase of the Bmal1 expression rhythm. , and other components of bergamot oil, such as β-pinene, β-myrcene, and p-cyanthide. Regarding men, when the luminescence rhythm was examined after adding it to the evaluation cells as a test substance, No phase change was observed due to the addition (data not shown). Thus, bergamot In any of the major components contained in the oil, the phase advancement effect of the Bmal1 expression rhythm is observed. No results were observed. When bergamot oil was used as the test substance, the expression rhythm was not observed. Although it shows a phase-advancing effect, when each component of bergamot oil is used as the test substance... Since it does not exhibit a phase-advancing effect, for example, multiple components in bergamot oil combine It is thought that a phase-forward effect may occur when they are combined. Alternatively, Other trace components in bergamot oil, distinct from the components mentioned above, contribute to phase advancement. It is thought that an effect may occur. Furthermore, among the components of bergamot oil, acetic acid... Since linalyl is broken down into acetic acid and linalool in the body, no component evaluation was performed.

[0054] [Ingredients of Cedarwood Virginia Oil] Figure 23 shows the luminescence rhythm when α-cedrene is added as the test substance (Bmal1 gene). This is an explanatory diagram showing the expression rhythm of the offspring. Figure 23 shows α-sequester added to a culture medium containing a luminescent substrate. Figure 23 shows the results for a drain concentration of 100 μM and for the control group. As shown, a slight phase advance was observed with the addition of α-cedrene, but α- No amplitude enhancement effect was observed with the addition of cedrene. Among the components of the oil, β-caryophyllene is also pre-phase, as shown in Figures 13 and 14. A transient response was observed, but no amplitude enhancement effect was found.

[0055] [Essential oils containing β-caryophyllene] Figure 24 shows the luminescence rhythm (Bmal1) when lavender oil is added as the test substance. This is an explanatory diagram showing the gene expression rhythm. Figure 24 shows the reaction of a luminescent substrate added to a culture medium. When the vendor oil concentration is 100 μg / mL, 10 μg / mL, and 1 μg / The results for mL and the control are shown. Regardless of the concentration of dara oil or the presence or absence of lavender oil, the expression rhythm of Bmal1 There was no significant difference, and no phase change was observed due to the addition of lavender oil.

[0056] Figure 25 shows the luminescence rhythm when palmarosa oil is added as the test substance (Bmal This is an explanatory diagram showing the expression rhythm of one gene. Figure 25 shows the addition of a luminescent substrate to a culture medium. When the concentration of palmarosa oil is 100 μg / mL, when it is 10 μg / mL, and when it is 1 μ The results for the g / mL case and the control are shown. As shown in Figure 25, Regardless of the concentration of lumarosa oil or whether palmarosa oil is added, the development of Bmal1 There was no significant difference in the current rhythm, and no phase change was observed due to the addition of palmarosa oil. .

[0057] Figure 26 shows the luminescence rhythm (Bmal) when rosemary oil is added as the test substance. This is an explanatory diagram showing the expression rhythm of one gene. Figure 26 shows the addition of a luminescent substrate to a culture medium. When the rosemary oil concentration is 100 μg / mL, and when it is 10 μg / mL, and 1 μ The results for the g / mL case and the control are shown. Regardless of the rosemary oil concentration or whether rosemary oil is added, the development of Bmal1 There was no significant difference in the current rhythm, and no phase change was observed due to the addition of rosemary oil. .

[0058] Figure 27 shows the luminescence rhythm (Bmal) when ylang-ylang oil is added as the test substance. This is an explanatory diagram showing the expression rhythm of one gene. Figure 27 shows the addition of a luminescent substrate to a culture medium. The results for a ylang-ylang oil concentration of 1 μg / mL and for the control group are shown. As shown in Figure 27, there is a significant difference in the expression rhythm of Bmal1 between the control and the Bmal1 expression rhythm. There was no change in phase due to the addition of ylang-ylang oil. When the concentration of ylang-ylang oil added to the culture medium is 100 μg / mL and 10 μ Cytotoxicity was observed at g / mL concentrations.

[0059] The above-mentioned lavender oil, palmarosa oil, rosemary oil, and ylang Ylang oil is an essential oil that contains β-caryophyllene. Regarding other essential oils, such as lemon balm oil, when it was added to the cells being evaluated as a test substance... When the luminescence rhythm was examined, no phase change due to the addition was observed (data shown). (In this way, among essential oils containing β-caryophyllene, geranium oil shown in Figure 2 Aside from the above, no phase-advancing effect on the expression rhythm of Bmal1 was observed. β-Carioff When filene is used as the test substance, it shows a phase advance effect on the expression rhythm, but β-ka When essential oils containing lyoflene are used as test substances, the position is different from that of geranium oil. Since they do not exhibit a phase-advancing effect, for example, the above essential oils other than geranium oil are β-potassium It is thought that this may contain components that inhibit the above-mentioned effects of ofphyllene.

[0060] [Essential oils containing citral] Figure 28 shows the luminescence rhythm (Bmal1) when petitgrain oil is added as the test substance. This is an explanatory diagram showing the gene expression rhythm. Figure 28 shows the addition of a luminescent substrate to a culture medium. When the tigrain oil concentration is 100 μg / mL, 10 μg / mL, and 1 μg / The results for mL and the control are shown. Regardless of the concentration of len oil or the presence or absence of petitgrain oil, the expression rhythm of Bmal1 There was no significant difference, and no phase change was observed due to the addition of petitgrain oil.

[0061] The petitgrain oil mentioned above is an essential oil containing citral. Regarding other essential oils, such as lemon balm oil, when added to the cells being evaluated as a test substance... When the luminescence rhythm was examined, no phase change due to the addition was observed (data not shown). Thus, in essential oils containing citral, the phase-advancing effect on the expression rhythm of Bmal1 is Not observed. When citral was used as the test substance, the phase-advancing effect of the expression rhythm was observed. Although it shows results, when essential oils containing citral are used as the test substance, a phase-advancing effect is observed. Since it does not show, for example, essential oils containing citral, as described above, do not exhibit the above effects of citral. It is thought that it may contain components that inhibit fruit growth.

[0062] [Examples of other essential oils] Figure 29 shows the luminescence rhythm when eucalyptus oil is added as the test substance (Bmal1 This is an explanatory diagram showing the gene expression rhythm. Figure 29 shows the luminescent substrate added to the culture medium. The results for potassium oil concentrations of 100 μg / mL, 10 μg / mL, and 1 μg / mL. The results for the case and the control are shown. As shown in Figure 29, Eucalyptus Regardless of the yl concentration or the presence or absence of eucalyptus oil addition, the Bmal1 expression rhythm is clearly evident. There was no difference, and no phase change was observed due to the addition of eucalyptus oil.

[0063] The eucalyptus oil mentioned above and the lavender oil shown in Figure 24 are, for example, conventional oils as previously described. Technical reference 2 demonstrates the effect of promoting the expression of clock genes such as the Bmal1 gene. However, eucalyptus oil and other oils that have been reported to have a circadian rhythm gene expression-promoting effect have been reported. Even lavender oil has the effect of altering the phase of the Bmal1 gene expression rhythm. It was not approved.

[0064] Figure 30 shows the results when cedarwood atlas (Atlas cedar) oil was added as the test substance. This is an explanatory diagram showing the luminescence rhythm (Bmal1 gene expression rhythm). In Figure 30, When the concentration of cedarwood atlas oil added to the culture medium containing the luminescent substrate is 10 μg / mL The results for 1 μg / mL and the control are shown in Figure 30. The urchin depends on the cedarwood atlas oil concentration and whether or not cedarwood atlas oil is added. There was no significant difference in the expression rhythm of Bmal1, and the addition of cedarwood atlas oil... No phase change was observed due to the addition. The concentration of cedarwood atlas oil was 100 μg. Cytotoxicity was observed at g / mL levels. *Antica* is a plant belonging to the pine family, and is in a different family from cedarwood (Virginia cedarwood).

[0065] [Examples of components that exhibit phase-back effect] Figure 31 shows the luminescence rhythm (Bmal1 gene) when caffeine is added as the test substance. This is an explanatory diagram showing the expression rhythm of caffeine added to a culture medium containing a luminescent substrate. The results for concentrations of 1 mM, 0.3 mM, and the control group are shown. As shown in Figure 31, the addition of caffeine resulted in a phase-recession effect on the peak. Furthermore, an amplitude enhancement effect was observed.

[0066] Figure 32 shows the results for caffeine concentrations of 0.3 mM and 1 mM, based on the results shown in Figure 31. For each case of M, compare each peak (peak1, peak1) with the control. 2) This is an explanatory diagram showing the amount of phase change in the same manner as in Figure 3. As shown in Figure 32, the cuff It was confirmed that the addition of the chain caused a phase shift.

[0067] Figure 33 shows the results shown in Figure 31, with the magnitudes of amplitude 1 and amplitude 2 controlled. This is an explanatory diagram showing the results of the comparison. As shown in Figure 33, either amplitude 1 or amplitude 2 However, the addition of caffeine increased the amplitude from approximately twice to more than twice.

[0068] [Combination of bergamot oil and citral] Figure 34 shows the test substances: bergamot oil, citral, and bergamot Luminescence rhythm when a mixture of oil and citral is added (Bmal1 gene) This is an explanatory diagram showing the expression rhythm of the offspring. Figure 34 shows the berga added to the culture medium containing the luminescent substrate. When the concentration of motte oil is 100 μg / mL and the concentration of citral is 100 μM And, bergamot oil with a concentration of 100 μg / mL and citral with a concentration of 100 μM The results for the combined use and the control group are shown in Figure 34. When using sea urchin, bergamot oil, and citral in combination as test substances. The amplitude increased as the phase advanced.

[0069] Figure 35 shows the peaks for each test substance shown in Figure 34, compared to the control. Explanation showing the phase changes of (peak1, peak2, peak3) in the same manner as in Figure 3. This is a diagram. As shown in Figure 35, the test substances are bergamot oil, citral, and In addition, when using a combination of bergamot oil and citral However, a phase-forward effect was observed. However, in the case of the phase-forward effect, bergamot oil No additive effect was observed when combining ru and citral.

[0070] Figure 36 shows the magnitudes of amplitude 1 and amplitude 2 for each test substance shown in Figure 34. This is an explanatory diagram showing the results compared with the control. As shown in Figure 36, the test substance was: Bergamot oil, citral, and a combination of bergamot oil and citral Regardless of which of the above was used, an amplitude enhancement effect was observed. At this time, Bell Combining gamot oil and citral increases the amplitude by up to 2.7 times. The effect increased, and an additive effect was observed when combining bergamot oil and citral. It was done.

[0071] [Combination of bergamot oil and β-caryophyllene] Figure 37 shows the test substances: bergamot oil, β-caryophyllene, and bell Luminescence rhythm when a mixture of gamot oil and β-caryophyllene is added. This is an explanatory diagram showing the expression rhythm of the Bmal1 gene. Figure 37 shows a culture medium containing a luminescent substrate. When the concentration of bergamot oil added is 100 μg / mL, and β-caryophyllene When the concentration is 100 μM, and when the concentration of bergamot oil is 100 μg / mL and the concentration is 1 When used in combination with 00 μM β-caryophyllene, and the control... The results are shown. As shown in Figure 37, bergamot oil and β- were used as test substances. When using caryophyllene in combination, bergamot oil is used as the test substance. Similar to cases where β-caryophyllene is used as the test substance, a phase-forward effect occurs. It was approved.

[0072] Figure 38 shows the magnitudes of amplitude 1 and amplitude 2 for each test substance shown in Figure 37. This is an explanatory diagram showing the results compared with control. As shown in Figure 38, the test substance was: Bergamot oil, β-caryophyllene, and bergamot oil and β-caryophyllene Regardless of which combination of ferens was used, an amplitude enhancement effect was observed. Here, of bergamot oil and β-caryophyllene, bergamot oil alone It has an amplitude-enhancing effect, but when bergamot oil and β-caryophyllene are combined... The amplitude enhancement effect of the combination was comparable to that of bergamot oil alone.

[0073] [The combination of bergamot oil and caffeine] Figure 39 shows the results for bergamot oil and bergamot oil and cough as test substances. The luminescence rhythm (expression rhythm of the Bmal1 gene) when a mixture of chains is added. This is an explanatory diagram showing (M). Figure 39 shows bergamot oil added to a culture medium containing a luminescent substrate. When the concentration is 100 μg / mL, and when the concentration of bergamot oil is 100 μg / mL and When used in combination with caffeine at a concentration of 0.3 mM, and regarding the control group... It shows the result.

[0074] Figure 40 shows the peaks for each test substance compared to the control, as shown in Figure 39. Explanation showing the phase changes of (peak1, peak2, peak3) in the same manner as in Figure 3. This is a diagram. As shown in Figure 32, caffeine exhibits a phase-back effect, but a phase-forward effect. By combining the bergamot oil shown with caffeine, the phase receding of caffeine is achieved. It was confirmed that the effect was suppressed, resulting in an overall phase-advancing effect.

[0075] Figure 41 shows the magnitudes of amplitude 1 and amplitude 2 for each test substance shown in Figure 39. This is an explanatory diagram showing the results compared with control. As shown in Figure 41, bergamot oil Lu alone exhibits an amplitude-enhancing effect, and caffeine also exhibits an amplitude-enhancing effect alone (see Figure 33). And, as shown in Figure 41, when bergamot oil and caffeine are combined... At an amplitude of 1, the amplitude enhancement effect was higher compared to bergamot oil alone, but other In terms of amplitude, the amplitude enhancement effect was comparable to that of bergamot oil alone. Thus, Even when combining test substances that exhibit amplitude enhancement effects, it is not necessarily true that the amplitude enhancement effect is obtained additively. It was confirmed that this was not the case.

[0076] [Combination of citral and β-caryophyllene] Figure 42 shows citral, β-caryophyllene, and citral as test substances. Luminescence rhythm when a mixture of β-caryophyllene is added (Bmal1 gene) This is an explanatory diagram showing the expression rhythm of the offspring. Figure 42 shows Citra added to a culture medium containing a luminescent substrate. When the concentration of the ethanol is 100 μM, and when the concentration of β-caryophyllene is 100 μM, Combining citral at a concentration of 100 μM with β-caryophyllene at a concentration of 100 μM The results for the case where the method was used and the control group are shown.

[0077] Figure 43 shows the peaks for each test substance shown in Figure 42, compared to the control. Explanation showing the phase changes of (peak1, peak2, peak3) in the same manner as in Figure 3. It is a figure. As shown in FIG. 43, as the test substance, citral, β-caryophyllene, and in any case where either a combination of citral and β-caryophyllene is used, even then, a phase advance effect was observed. However, in the phase advance effect, an additive effect by combining citral and β- caryophyllene was not observed.

[0078] FIG. 44 is an explanatory diagram showing the results of comparing the magnitudes of amplitude 1 and amplitude 2 for each of the test substances shown in FIG. 42 with a control. As shown in FIG. 44, when citral was used as the test substance, and in any case where a combination of citral and β-caryophyllene was used, an amplitude enhancement effect was observed. Here, among citral and β-caryophyllene, citral has an amplitude enhancement effect alone, but the amplitude enhancement effect when citral and β- caryophyllene are combined is of the same degree as the amplitude enhancement effect when citral is alone. caryophyllene, citral alone has an amplitude enhancement effect, but the amplitude enhancement effect when citral and β- caryophyllene are combined is of the same degree as the amplitude enhancement effect when citral is alone. was.

[0079] This disclosure is not limited to the above-described embodiments and the like, and can be realized in various configurations without departing from the gist thereof. For example, the technical features in the embodiments corresponding to the technical features in each form described in the column of the summary of the invention can be appropriately replaced or combined in order to solve some or all of the above-described problems, or in order to achieve some or all of the above-described effects. Further, if the technical feature is not described as essential in this specification, it can be appropriately deleted. The technical features in the embodiments corresponding to the technical features in each form described in the column of the summary of the invention can, for example, solve some or all of the above problems, or achieve some or all of the above effects, and can be appropriately replaced or combined as needed. Also, if the technical feature is not described as essential in this specification, it can be appropriately deleted. in order to achieve some or all of the above effects, it is possible to appropriately replace or combine them. Further, if the technical feature is not described as essential in this specification, it can be appropriately deleted. is not described as essential in this specification, it can be appropriately deleted.

[0080] This disclosure can also be realized in the following forms. [Application Example 1] A body clock regulator, Bergamot oil, geranium oil, cedarwood Virginia oil, citral It contains at least one of the following as an active ingredient: The body clock is adjusted by advancing the phase of the expression rhythm of clock genes. A medication for regulating the body clock. [Application Example 2] The biological clock regulator described in Application Example 1, Bergamot oil, cedarwood Virginia oil, and a small amount of citral It contains at least one as an active ingredient, This increases the amplitude of the expression rhythm of the aforementioned clock gene. A medication for regulating the body clock. [Application Example 3] The circadian rhythm regulator described in Application Example 2, Contains both bergamot oil and citral as active ingredients. A medication for regulating the body clock. [Application Example 4] A biological clock regulator according to any one or two of the application examples 1 to 3, A biological clock regulator that advances the phase of the circadian rhythm. [Application Example 5] A biological clock regulator described in any one of the application examples 1 to 4, To treat, improve, or prevent circadian rhythm disorders and associated symptoms A medication to regulate the body clock. [Application Example 6] A circadian rhythm disorder containing a biological clock regulator described in any one of the application examples 1 to 5. A transdermal preparation for the treatment of harm. [Application Example 7] A circadian rhythm disorder containing a biological clock regulator described in any one of the application examples 1 to 5. Oral formulation for the treatment of harm. [Application Example 8] An air freshener containing a biological clock regulator as described in any one of the application examples 1 to 5. [Application Example 9] A bath additive containing a biological clock regulator as described in any one of the application examples 1 to 5. [Application Example 10] An inhalant containing a biological clock regulator as described in any one of the examples 1 to 4. [Application Example 11] Food and beverages containing a biological clock regulator as described in any one of the examples 1 to 5. [Application Example 12] A method for adjusting the body clock, Within the space where a subject experiencing circadian rhythm disorders is present, one of the following application examples 1 to 5 applies: The circadian rhythm regulator described in paragraph 1 is diffused, and the subject is allowed to inhale the circadian rhythm regulator. ru Methods for adjusting your internal body clock.

Claims

1. It is a body clock regulator, Bergamot oil, geranium oil, cedarwood Virginia oil, citral It contains at least one of the following as an active ingredient: The body clock is adjusted by advancing the phase of the expression rhythm of clock genes. A medication for regulating the body clock.

2. A biological clock regulator according to claim 1, Bergamot oil, cedarwood Virginia oil, and a small amount of citral It contains at least one as an active ingredient, This increases the amplitude of the expression rhythm of the aforementioned clock gene. A medication for regulating the body clock.

3. A biological clock regulator according to claim 2, Contains both bergamot oil and citral as active ingredients. A medication for regulating the body clock.

4. A biological clock regulator according to any one of claims 1 to 3, A biological clock regulator that advances the phase of the circadian rhythm.

5. A biological clock regulator according to any one of claims 1 to 3, To treat, improve, or prevent circadian rhythm disorders and associated symptoms A medication to regulate the body clock.

6. A circadian rhythm disorder comprising the internal clock regulator described in any one of claims 1 to 3. A transdermal preparation for the treatment of harm.

7. A circadian rhythm disorder comprising the internal clock regulator described in any one of claims 1 to 3. Oral formulation for the treatment of harm.

8. A fragrance containing the circadian rhythm regulator described in any one of claims 1 to 3.

9. A bath additive containing the circadian rhythm regulator described in any one of claims 1 to 3.

10. An inhalant containing a biological clock regulator according to any one of claims 1 to 3.

11. Food and beverages containing the circadian rhythm regulator described in any one of claims 1 to 3.

12. A method for adjusting the body clock, In a space where a subject experiencing circadian rhythm disorders is present, any of claims 1 to 3 The circadian rhythm regulator described in paragraph 1 is diffused, and the subject is allowed to inhale the circadian rhythm regulator. ru Methods for adjusting your internal body clock.

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