Composition for regulating biological clock

Abstract

To provide food and drink and the like, containing an ingredient which is derived from a highly safe food eaten abundantly, effectively acts on the expression rhythm of clock genes, and can regulate biological clock.SOLUTION: There is provided a composition which comprises sudachitin as an active ingredient and regulates biological clock by enhancing amplitude of expression rhythm of clock gene Period 2. The composition regulates biological clock by being ingested or taken at a suitable time every day, and especially can prevent or improve fatigue feeling at the time of rising and during morning and daytime, weariness, drowsiness, loss of motivation, and decline in liveliness of daily life.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a composition for regulating the biological clock (circadian clock) that is effective in preventing or ameliorating various vague symptoms and diseases. [Background technology]

[0002] The internal body clock (circadian clock) is an important biological mechanism that life acquired during evolution to adapt to environmental changes accompanying the Earth's rotational period, and oscillates a circadian rhythm with a period of approximately 24 hours that is observed in various physiological phenomena including sleep-wakefulness and energy metabolism (see non-patent document 1).

[0003] The mammalian circadian clock has a hierarchical structure consisting of a master clock and a peripheral clock, the former of which is localized in a cell group called the suprachiasmatic nucleus of the hypothalamus, while the latter is distributed to individual cells that make up organs and tissues throughout the body. These clocks synchronize with various external environments such as light and food, and maintain the health of the individual by integrating the physiological functions of the entire body in time.

[0004] The chronic irregularity and nocturnal lifestyle caused by the light environment (artificial lighting) unique to modern society is thought to impair the function of the biological clock, causing various vague complaints and diseases, including sleep disorders and metabolic disorders. It has also been reported that the function of the biological clock decreases with age, and it is thought that the decrease in the function of the biological clock is also involved in various age-related diseases (see Non-Patent Documents 2 and 3).

[0005] Therefore, in modern society or in an aging society as described above, maintaining the normal function of the body clock by continuously adjusting it every day is expected to be an effective means of preventing or improving various vague symptoms and diseases.

[0006] The molecular mechanism by which the circadian clock oscillates to a rhythm with a 24-hour cycle is a time-delayed negative feedback loop of transcription and translation formed by a series of genes called clock genes. In mammals, the clock genes Period, Cryptochrome, Bmal1, and Clock are at the core of this mechanism.

[0007] In recent years, the establishment of molecular imaging technology for real-time monitoring of clock gene expression (Period2 or Bmal1) in cultured cells has led to high-throughput screening using large-scale synthetic compound libraries at several institutions (see Non-Patent Document 3). As a result, several compounds that act on the rhythm of clock gene expression and can regulate the biological clock have been obtained, and these are being developed as medical drugs.

[0008] However, in order to achieve the goal of regulating the biological clock by continuously influencing the rhythm of clock gene expression on a daily basis and maintaining its normal function over the long term, it is preferable to use safe food-derived ingredients that can be ingested daily rather than new compounds or pharmaceuticals.

[0009] Known foods or food-derived ingredients that can affect the rhythm of clock gene expression include, for example, cinnamon acids (see Patent Document 1), carnosine and anserine (see Patent Document 2), black ginger (see Patent Document 3), hesperetin and naringenin (see Patent Document 4), etc. However, there have been no reports yet of foods or food-derived ingredients that can normalize the function of the biological clock over the long term and prevent or improve sleep-wake disorders and energy metabolism disorders through continuous intake. [Prior art documents] [Non-patent literature]

[0010] [Non-Patent Document 1] "Chronobiology" edited by Fumiki Ebihara and Takashi Yoshimura, Kagaku Dojin Co., Ltd., 2102 [Non-Patent Document 2] "Science of Biological Clocks and Their Industrial Applications" edited by Shigenobu Shibata, CMC Publishing Co., Ltd., 2011 [Non-Patent Document 3] "Clinical Studies of Circadian Rhythm Sleep Disorders" Shigeru Chiba and Kenichi Homma (eds.), Shinko Medical Publishing Co., Ltd., 2003 [Non-Patent Document 4] Hirota T. et al., Chem Biol. 2009 Sep 25;16(9):921-7. [Non-Patent Document 5] Chen Z. et al., Cell MOL Life Sci. 2013 Aug;70(16):2985-98. [Patent documents]

[0011] [Patent Document 1] Patent Publication No. 2016-204281 [Patent Document 2] Patent Publication No. 2015-110564 [Patent Document 3] Patent Publication 2016-210703 [Patent Document 4] Patent Publication No. 2008-266319 Summary of the Invention [Problem to be solved by the invention]

[0012] The objective of the present invention is to provide foods, beverages, etc. that contain as active ingredients components that are derived from foods that are widely consumed and are highly safe, and that can effectively act on the rhythm of clock gene expression and regulate the biological clock. [Means for solving the problem]

[0013] Means for Solving the Problems The present inventors conducted extensive research to solve the above problems and discovered that sudachitin has an effect of enhancing the amplitude of the expression rhythm of the clock gene Period2, thereby completing the present invention.

[0014] That is, the aspects of the present invention are as follows. (1) A composition having the effect of enhancing the amplitude of the expression rhythm of the clock gene Period2, characterized by containing sudachitin as an active ingredient. (2) A composition for regulating the biological clock, characterized by containing sudachitin as an active ingredient. (3) A composition described in (1) or (2), which has the effect of regulating at least one of the phase, period, or amplitude of the clock gene expression rhythm. (4) The composition according to any one of (1) to (3), which has the effect of preventing or improving fatigue, lethargy, sleepiness, loss of motivation, or loss of rhythm in daily life upon waking, in the morning, or during the day. Effect of the Invention

[0015] The present invention makes it possible to provide foods and the like that prevent or improve various vague complaints and diseases caused by a decrease in the function of the biological clock, such as sleep-related complaints such as difficulty falling asleep, waking up in the middle of the night, early awakening, and difficulty sleeping soundly, as well as difficulty waking up after sleeping. It is also now possible to provide foods and the like that prevent or improve fatigue, lethargy, sleepiness, loss of motivation, or a loss of rhythm in one's daily life upon waking, in the morning, or during the day. It has also become possible to provide foods that prevent or improve morning complaints such as a depressed mood and reduced motivation and enthusiasm upon waking up. It is also now possible to provide foods that prevent or improve various vague symptoms and diseases caused by a decline in the function of the biological clock, such as jet lag and social jet lag, cognitive memory disorders, mood disorders, lifestyle-related diseases, gastrointestinal dysfunction including loss of appetite and constipation, skin dysfunction including rough skin and wrinkles, urinary dysfunction including frequent urination and nocturia, cancer, and aging. [Brief description of the drawings]

[0016] [Figure 1] 1 is a graph showing the effect of sudachitin on the amplitude of the expression rhythm of the clock gene Period2.

[0017] [Diagram 2]1 is a graph showing the effect of continuous oral administration of sudachi peel extract on the nocturnal spontaneous locomotor activity of mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] The composition of the present invention is characterized by containing sudachitin as an active ingredient.

[0019] Sudachitin is a component specific to Sudachi that exists in the skin of Sudachi, and is a type of polymethoxyflavone. Sudachitin includes its pharmaceutically acceptable salt. In addition, the embodiment of the composition of the present invention may be a Sudachi skin extract containing Sudachitin.

[0020] The effective dosage of Sudachitin varies depending on age and other factors, but is generally 1 mg to 1000 mg per day for adults, preferably 1 mg to 50 mg, and more preferably 1 mg to 10 mg.

[0021] Furthermore, within the effective dosage range, the method of use and dosage can be appropriately set depending on the mode of use and the state of the user's biological clock.

[0022] The biological clock adjustment effect refers to adjusting at least one of the phase, period, and amplitude of the clock gene expression rhythm or behavioral rhythm (see Non-Patent Document 5). A preferred embodiment of adjusting the phase of the biological clock is to advance the phase of a delayed biological clock. A preferred embodiment of adjusting the period of the biological clock is to shorten the period of an extended clock gene expression rhythm. A preferred embodiment of adjusting the amplitude of the biological clock is to enhance the amplitude of an attenuated clock gene expression rhythm.

[0023] The composition of the present invention can enhance the amplitude of the expression rhythm of the clock gene Period2 in particular, thereby exerting an effect of adjusting at least one of the phase, period, and amplitude of the clock gene expression rhythm, thereby adjusting the biological clock.

[0024] By ingesting or taking the composition of the present invention at the appropriate time every day, it is possible to adjust the body clock and prevent or improve fatigue, lethargy, drowsiness, loss of motivation, and loss of rhythm in one's daily life, particularly upon waking, in the morning, and during the day.

[0025] The composition of the present invention may contain other active ingredients in a qualitative and quantitative range that does not impair the effect of the composition. In addition, the composition may be provided as an oral preparation such as a solid preparation or an oral liquid preparation, or as a parenteral preparation such as an external preparation, by adding known additives. Furthermore, when the composition is provided as an oral preparation, it may be provided as a medicine, a quasi-drug, or a food product, but in consideration of the ease of daily intake and administration, the convenience of storage, etc., it is most preferable to provide an oral solid preparation as a food product.

[0026] The present invention will be described in more detail below with reference to examples. EXAMPLES

[0027] Test Example 1 <Test Method> The effect of sudachitin on the amplitude of clock gene expression rhythm was evaluated by a reporter assay (see Non-Patent Document 3). The specific protocol is as follows. (1) A reporter plasmid (pSLG-Per2) containing the promoter region (-280 / +48) of the Period2 gene was introduced into NIH-3T3 mouse fibroblast cells to produce a stable Per2-Luc reporter gene expression line. After culturing the line for three days, the line was treated with 100 nM dexamethasone for two hours to synchronize the rhythm. (2) After synchronization, the culture medium was replaced with a medium containing 150 μM luciferin, and a sudachitin solution was added to a final concentration of 1 to 30 μM. (3) After the addition of sudachitin solution, the luminescence of luciferase was measured continuously for three days using a luminometer equipped with a CO2 incubator (Chronos Dio AB-2550). (4) As a control, DMSO, the matrix of the sample solution, was added at the same concentration (0.1%) as the sample.

[0028] <Result> Addition of sudachitin enhanced the amplitude of the Period2 gene expression rhythm compared to the control (see FIG. 1).

[0029] Test Example 2 <Test Method> The effect of Sudachi peel extract (containing 9.2% Sudachitin) on the nocturnal spontaneous locomotor activity of mice was evaluated. The specific protocol is as follows. (1) Six-week-old male C57BL / J mice were acclimated to a normal light-dark environment (light period 7:00-19:00, dark period 19:00-7:00), and then the control group was forcefully orally administered 0.5% carboxymethylcellulose solution as a vehicle, and the sudachi peel extract group was forcefully orally administered 1.09 g / kg of sudachi peel extract powder at a dose of 10 mL / kg every day at 13:00 for 14 consecutive days. (2) During the experimental period, the amount of spontaneous motor activity of each individual was measured using an infrared sensor, and the amount of spontaneous motor activity at night was calculated.

[0030] <Result> Administration of sudachi peel extract was found to have an effect of increasing nocturnal spontaneous locomotor activity, i.e., enhancing the amplitude of spontaneous locomotor activity rhythm, compared to the control group (see Figure 2). [Industrial Applicability]

[0031] By providing a composition that enhances the amplitude of the expression rhythm of the clock gene Period2 and regulates the biological clock, it is expected that this will contribute to the promotion of people's health through the prevention or amelioration of various vague symptoms and diseases, and will also promote the healthy development of the pharmaceutical, food, and other industries.

Claims

1. An oral composition for enhancing the amplitude of the expression rhythm of the clock gene Period2, characterized by containing sudachitin as an active ingredient.

2. An oral composition for adjusting the biological clock, which contains sudachitin as an active ingredient and has the effect of enhancing the amplitude of the expression rhythm of the clock gene Period2.

3. The oral composition according to claim 1 or 2, which has the effect of adjusting at least one of the phase, period or amplitude of the clock gene expression rhythm.

4. The oral composition according to any one of claims 1 to 3, which has the effect of preventing or improving fatigue, lethargy, sleepiness, loss of motivation, or loss of rhythm in one's daily life upon waking, in the morning, or during the day.

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