TWI805560B - Compositions for changing expression of clock genes - Google Patents

Compositions for changing expression of clock genes Download PDF

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TWI805560B
TWI805560B TW106134146A TW106134146A TWI805560B TW I805560 B TWI805560 B TW I805560B TW 106134146 A TW106134146 A TW 106134146A TW 106134146 A TW106134146 A TW 106134146A TW I805560 B TWI805560 B TW I805560B
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gene
bark
expression
water extract
clock
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TW201813656A (en
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渡邉卓巳
柴田重信
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日商康貝股份有限公司
學校法人早稻田大學
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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)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2200/00—Function of food ingredients
    • A23V2200/30—Foods, ingredients or supplements having a functional effect on health
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction

Abstract

本發明之目的在於提供一種用於使時鐘基因之表現變化，且藉由該表現變化而使晝夜節律變化之組合物，經過努力研究，結果明確得知合歡樹皮之水萃取物能夠使時鐘基因之表現量及相位變化。又發現，藉由經口投予合歡樹皮之水萃取物，受驗者午後睡意減少，而且清醒度、意志、情緒及集中力提升，清晨型傾向增強。The object of the present invention is to provide a composition for changing the expression of the clock gene, and changing the circadian rhythm through the expression change. After diligent research, it is clearly known that the water extract of the bark of Albizia Julibrissin can change the expression of the clock gene. Performance and phase changes. It was also found that by orally administering the water extract of the bark of Albizia Julibrissin, the subject's sleepiness decreased in the afternoon, and the degree of sobriety, will, mood and concentration were improved, and the morning tendency was enhanced.

Description

用於使時鐘基因之表現變化的組合物Compositions for changing the expression of clock genes

本發明係關於一種包含合歡樹皮之水萃取物作為有效成分的用於使時鐘基因之表現變化的組合物。又，本發明係關於一種包含該萃取物作為有效成分之用於使晝夜節律變化之組合物。The present invention relates to a composition for changing the expression of clock genes comprising the water extract of bark of Albizia Julibrissin as an active ingredient. Also, the present invention relates to a composition for changing circadian rhythm comprising the extract as an active ingredient.

地球上存在之大部分生物係根據外部環境(主要為明暗循環)以約24小時為週期而控制生理功能(睡眠清醒、體溫調節、攝食排泄、激素分泌等)，此種生物學之日夜變化被稱為「晝夜節律(Circadian rhythm)」。 近年來，因該晝夜節律異常而引起各種身心不適正成為社會問題。因生活環境及/或工作環境之變化等導致晝夜節律紊亂從而引起之問題較多，例如有因飛機等之移動引起之時差反應、因換班(交替工作)等不規則生活規律引起之睡眠障礙、因夜晚型生活(熬夜、夜班等)引起之睡眠清醒節律等失常。又，隨著年齡增長，調整晝夜節律之褪黑素等激素之分泌量降低，因此老年人於睡眠清醒、體溫調節等各種節律方面減弱。因晚年睡眠障礙等導致之QOL降低亦與近年來迅速高齡化互相作用，作為社會問題而令人擔憂。鑒於該現狀，期望能夠消除晝夜節律失常、減弱等、以及治療、改善上述睡眠障礙等之方法，但現狀為仍然未確立此種方法。 對於哺乳類而言，視交叉上核(SCN)成為晝夜節律之控制中心，該視交叉上核(SCN)係直徑僅為1毫米左右之小神經核，存在於從左右眼之視網膜延伸之視神經於腦內之視丘下部交叉而成之視神經交叉部位(視交叉)。而且，由SCN形成之晝夜節律係藉由稱為時鐘基因(Bmal1、Clock、Period、隱花色素(Cryptochrome)等)之基因群所形成。更具體而言，轉錄活化因子BMAL1及CLOCK蛋白質將Period及隱花色素基因之表現活化，由此轉錄轉譯之Period(PER1、PER2)及隱花色素(CRY1、CRY2)蛋白質與BMAL1及CLOCK蛋白質相互作用，由此形成抑制自身轉錄之負反饋。其後，PER及CRY蛋白質受到磷酸化及泛素化修飾後被蛋白酶體所分解，因此上述轉錄抑制被解除。然後，開始由BMAL1及CLOCK蛋白質引發之下一循環，該循環一週需要約24小時，此係晝夜節律形成之分子機理。 此種時鐘基因之反饋機制亦存在於肝臟或肌肉、肺、心臟等末梢組織、腦中之除SCN以外之組織中，已知藉由該機制於末梢組織等中亦形成晝夜節律。又，該節律係藉由作為控制中心之SCN經由各種組織而發出因神經及/或激素等所產生之信號而進行控制。 如此，晝夜節律係藉由時鐘基因之表現而進行控制。因此，業界正探索藉由使該表現變化，使晝夜節律變化，進而能夠治療因晝夜節律異常引起之睡眠障礙等的物質(專利文獻1～2)。 [先前技術文獻] [專利文獻] [專利文獻1]日本專利特開2008-266319號公報 [專利文獻2]日本專利特開2015-110564號公報Most organisms that exist on the earth control their physiological functions (sleeping, waking, body temperature regulation, feeding and excretion, hormone secretion, etc.) according to the external environment (mainly light and dark cycle) in a cycle of about 24 hours. This kind of biological day and night changes are called It is called "circadian rhythm". In recent years, various physical and mental discomforts caused by this circadian rhythm abnormality have become social problems. There are many problems caused by circadian rhythm disturbance due to changes in the living environment and/or working environment, such as jet lag caused by the movement of airplanes, sleep disorders caused by irregular life rules such as shifts (alternate work), Abnormal sleep-wake rhythm caused by night-type life (staying up late, night shift, etc.). In addition, as the age increases, the secretion of melatonin and other hormones that regulate the circadian rhythm decreases, so the elderly's sleep, waking, body temperature regulation and other rhythms are weakened. QOL decline due to sleep disturbances in old age also interacts with rapid aging in recent years, which is a concern as a social problem. In view of the current situation, methods for eliminating circadian rhythm disturbances, weakening, etc., and for treating and improving the above-mentioned sleep disorders are desired, but such methods have not yet been established. For mammals, the suprachiasmatic nucleus (SCN) becomes the control center of the circadian rhythm. The suprachiasmatic nucleus (SCN) is a small nerve nucleus with a diameter of only about 1 mm. It exists in the optic nerve extending from the retina of the left and right eyes. The optic chiasm (optic chiasm) formed by the crossing of the hypothalamus in the brain. Furthermore, the circadian rhythm formed by the SCN is formed by a group of genes called clock genes (Bmal1, Clock, Period, Cryptochrome, etc.). More specifically, the transcriptional activators BMAL1 and CLOCK proteins activate the expression of Period and cryptochrome genes, whereby the transcribed and translated Period (PER1, PER2) and cryptochrome (CRY1, CRY2) proteins interact with BMAL1 and CLOCK proteins function, thereby forming a negative feedback that inhibits its own transcription. Afterwards, the PER and CRY proteins are decomposed by the proteasome after undergoing phosphorylation and ubiquitination modification, so the above-mentioned transcriptional inhibition is released. Then, the next cycle initiated by BMAL1 and CLOCK proteins begins, and this cycle takes about 24 hours a week, which is the molecular mechanism of circadian rhythm formation. This feedback mechanism of clock genes also exists in peripheral tissues such as liver, muscle, lung, and heart, and tissues other than SCN in the brain, and it is known that circadian rhythm is also formed in peripheral tissues and the like by this mechanism. In addition, the rhythm is controlled by the SCN, which is a control center, sending signals generated by nerves and/or hormones through various tissues. Thus, circadian rhythm is controlled by the expression of clock genes. Therefore, the industry is searching for substances that can treat sleep disorders and the like caused by abnormal circadian rhythm by changing the expression and changing the circadian rhythm (Patent Documents 1 and 2). [Prior Art Document] [Patent Document] [Patent Document 1] Japanese Patent Laid-Open No. 2008-266319 [Patent Document 2] Japanese Patent Laid-Open No. 2015-110564

[發明所欲解決之問題] 本發明係鑒於上述先前技術所存在之課題而完成者，其目的在於提供一種用於使時鐘基因之表現變化，且藉由該表現變化而使晝夜節律變化之物質。 [解決問題之技術手段] 本發明者等人為了實現上述目的而反覆進行努力研究，結果發現，藉由向小鼠胚胎纖維母細胞中添加合歡樹皮之水萃取物，而能夠於該細胞之時鐘基因(Per2基因)之表現節律中抑制其振幅之過渡性減弱。進而，本發明者等人明確，上述萃取物根據投予細胞之時間點不同，既能夠使Per2基因表現節律之波峰(相位)濃度依賴性地前進，又能夠使其後退。 進而，對小鼠經口投予合歡樹皮之水萃取物，分析其末梢組織(肝臟)中之時鐘基因(Per1、Per2、Bmal1)之表現。結果本發明者等人發現，利用上述萃取物，末梢組織中時鐘基因之表現量及相位亦發生變化。 又，對人經口投予合歡樹皮之水萃取物，結果發現，如同反映上述萃取物使時鐘基因之表現變化之作用般，受驗者之清晨型傾向增強(入睡早，早起變得容易)，午後之睡意減少，活動性(清醒度、意志、情緒及集中力)提高，從而完成了本發明。 即，本發明提供以下者。 ＜1＞一種用於使時鐘基因之表現變化的組合物，其包含合歡樹皮之水萃取物作為有效成分。 ＜2＞如＜1＞所記載之組合物，其中時鐘基因係選自由Per1基因、Per2基因及Bmal1基因所組成之群中之至少一種基因。 ＜3＞如＜1＞或＜2＞所記載之組合物，其係用於使晝夜節律變化者。 [發明之效果] 根據本發明，能夠使時鐘基因之表現變化，又，能夠藉由該表現變化而使晝夜節律變化。進而，藉由該變化，能夠消除晝夜節律之異常，因此根據本發明，亦能夠治療、改善(緩和)或預防因該異常引起之疾病(晝夜節律障礙等)。[Problems to be Solved by the Invention] The present invention has been accomplished in view of the above-mentioned problems in the prior art, and its object is to provide a substance for changing the expression of clock genes and changing the circadian rhythm through the expression changes . [Technical means to solve the problem] The inventors of the present invention have made repeated efforts in research to achieve the above object, and found that by adding the water extract of bark of Albizia juliensis to mouse embryonic fibroblasts, the clock of the cells can be activated. Transitional weakening of the amplitude of the expression rhythm of the gene (Per2 gene). Furthermore, the inventors of the present invention have found that the above-mentioned extract can advance or retreat the peak (phase) of the expression rhythm of the Per2 gene in a concentration-dependent manner depending on the timing of administration to the cells. Furthermore, the aqueous extract of bark of Albizia juliensis was orally administered to mice, and the expression of clock genes (Per1, Per2, Bmal1) in the peripheral tissue (liver) was analyzed. As a result, the inventors of the present invention found that the expression level and phase of clock genes in peripheral tissues were also changed by using the above-mentioned extracts. In addition, the water extract of the bark of Albizia Julibrissin was orally administered to humans. As a result, it was found that, as reflected in the effect of the above-mentioned extract on the expression of the clock gene, the subject's morning type tendency was enhanced (early sleep, early waking becomes easier) , the drowsiness in the afternoon decreases, and the activity (awakeness, will, emotion and concentration) improves, thereby completing the present invention. That is, the present invention provides the following. <1> A composition for changing the expression of a clock gene, comprising an aqueous extract of bark of Albizia Julibrissin as an active ingredient. <2> The composition according to <1>, wherein the clock gene is at least one gene selected from the group consisting of Per1 gene, Per2 gene and Bmal1 gene. <3> The composition as described in <1> or <2>, which is used for changing the circadian rhythm. [Effects of the Invention] According to the present invention, it is possible to change the expression of clock genes, and also to change the circadian rhythm by changing the expression. Furthermore, the abnormality of the circadian rhythm can be eliminated by this change, and therefore, according to the present invention, diseases (circadian rhythm disorders, etc.) caused by the abnormality can also be treated, improved (alleviated), or prevented.

如下述實施例所示，本發明明確化了合歡樹皮之水萃取物能夠使時鐘基因之表現量及相位變化。又，上述萃取物能夠經由時鐘基因之表現變化而使由該基因控制之晝夜節律亦變化。因此，本發明提供包含合歡樹皮之水萃取物作為有效成分之用於使時鐘基因之表現變化的組合物。又，本發明提供包含該萃取物作為有效成分之用於使晝夜節律變化之組合物。合歡樹皮之水萃取物 首先，對在本發明之組合物中作為有效成分而包含之「合歡樹皮之水萃取物」進行說明。「合歡」係指屬於豆科合歡亞科之落葉喬木植物(Albizia julibrissin)。於將該合歡之樹皮供於下述萃取處理之情形時，可直接將樹皮供於萃取處理，但就進一步提高萃取效率之觀點而言，亦可於利用混合機、攪拌器、均化器、研缽、超音波破碎機等進行破碎後供於萃取處理。 於本發明中，作為萃取處理所使用之溶劑，可僅為水，亦可為水與其他溶劑之混合溶劑。作為本發明中用於萃取之水，並無特別限制，例如可列舉：蒸餾水、去離子水、RO水、超純水。又，作為與水混合之其他溶劑，並無特別限制，可列舉：乙醇、甲醇等醇類、丙二醇等多元醇類、乙酸甲酯等酯類。又，作為混合比率，亦無特別限制，較佳為水：其他溶劑＝90～50：10～50(體積比)。 萃取條件亦無特別限制，根據上述所使用之溶劑亦有所不同，例如於僅使用水之情形時，較佳為使用相對於1重量份之合歡樹皮為1～100重量份之水，於4～100℃之溫度下以10分鐘～7天進行萃取，更佳為使用相對於1重量份之合歡樹皮為5～20重量份之水，於70～100℃之溫度下以30分鐘～2小時進行萃取。又，就進一步提高萃取效率之觀點而言，可於萃取處理時一併進行加壓、攪拌、超音波處理等。進而，可於上述萃取處理後，藉由過濾或離心分離而將其與殘渣分離。 本發明之「合歡樹皮之水萃取物」亦可以萃取液之形態於本發明之組合物中使用，但亦可視需要藉由離子交換法、凝膠過濾法、膜分離法、電透析法、溶劑萃取法、減壓濃縮法、加熱處理法等而進行濃縮。 進而，「合歡樹皮之水萃取物」亦可視需要藉由實施噴霧乾燥、冷凍乾燥等處理使之乾燥而製成粉末。 又，就安全性之觀點而言，可對「合歡樹皮之水萃取物」實施殺菌處理。作為上述殺菌處理，可列舉：加熱殺菌、加壓殺菌、放射線殺菌、過濾除菌等。 又，如此而製備之「合歡樹皮之水萃取物」例如可直接作為本發明之組合物使用，亦可如下所述藉由與其他成分組合而作為本發明之組合物使用。用於使時鐘基因之表現或晝夜節律變化之組合物 其次，對本發明之組合物之態樣進行說明。如下述之實施例所示，上述之合歡樹皮之水萃取物具有藉由使時鐘基因之表現變化而使晝夜節律變化之活性。因此，以其作為有效成分之本發明之組合物可作為下述之用於晝夜節律障礙之治療、改善(緩和)或預防之藥物組合物、飲食品而使用。又，可作為用於使時鐘基因之表現變化之試劑、用於使晝夜節律變化之試劑而使用。 於本發明中，所謂「時鐘基因」，只要為具有控制晝夜節律(體內時鐘)之功能之基因即可，例如可列舉：Period基因(Per1、Per2、Per3等)、Bmal基因(亦稱為Arntl、Mop3、Tic、Jap3、Pasd3、bHLHe5之基因、Bmal1、Bmal2等)、隱花色素基因(Cry1、Cry2等)、Clock基因、Ror基因、Rev-erb基因、E4BP基因、GSK3β基因、CK1基因、Dec基因，於本發明中，較佳為Per1基因、Per2基因、Bmal1基因。 典型而言，人之Per1基因係編碼包含以RefSeq ID：NP_002607特定之胺基酸序列之蛋白質的基因(包含以RefSeq ID：NM_002616特定之核苷酸序列之基因)，人之Per2基因係編碼包含以RefSeq ID：NP_073728特定之胺基酸序列之蛋白質的基因(包含以RefSeq ID：NM_003894或NM_022817特定之核苷酸序列之基因)，人之Bmal1基因係編碼包含以RefSeq ID：NP_001025443、NP_001025444、NP_001169、NP_001284648或NP_001284651特定之胺基酸序列之蛋白質的基因(包含以RefSeq ID：NM_001030272、NM_001030273、NM_001178、NM_001297719或NM_001297722特定之核苷酸序列的基因)，小鼠之Per1基因係編碼包含以RefSeq ID：NP_001152839或NP_035195特定之胺基酸序列之蛋白質的基因(包含以RefSeq ID：NM_001159367或NM_011065特定之核苷酸序列之基因)，小鼠之Per2基因係編碼包含以RefSeq ID：NP_035196特定之胺基酸序列之蛋白質的基因(包含以RefSeq ID：NM_011066特定之核苷酸序列之基因)，小鼠之Bmal1基因係編碼包含以RefSeq ID：NP_001229977或NP_031515特定之胺基酸序列之蛋白質的基因(包含以RefSeq ID：NM_001243048或NM_007489特定之核苷酸序列之基因)。再者，於自然界(即非人工)核苷酸序列發生變化。因此，本發明所涉及之時鐘基因並不特定為作為典型例而列舉之上述序列，亦包括此種天然之突變體。 本發明中「時鐘基因之表現」不僅包括轉錄水平上之表現(作為mRNA之表現)，亦包括轉譯水平上之表現(作為蛋白質之表現)。又，「時鐘基因之表現之變化」除了時鐘基因之表現量之提升或減少以外，亦包括時鐘基因之表現節律(振幅、相位及週期長度中之至少一者)發生變化。 所謂「振幅」，如圖1所示係節律中從波峰至波谷之長度(振動之大小)，表示於時鐘基因之表現節律中時鐘基因於從該波峰至波峰、或從波谷至波谷之期間(一個週期)之表現量之幅度。已知於時鐘基因之表現節律及由其控制之晝夜節律中，隨著年齡增長，該等之振幅逐漸減弱。另一方面，如下述之實施例中所示，合歡之樹皮水萃取物能夠抑制該減弱。 所謂「相位」係一個週期之特定位置(例如波峰、波谷)。又，所謂「週期長度」，如圖1所示係節律中一個週期之長度(期間)，若為人，則原本(正常)為約24.3小時。如下述實施例所示，合歡樹皮水萃取物根據投予或攝取之時間點不同，而能夠使時鐘基因之表現節律及由其控制之晝夜節律之相位前進(於圖1中波形向左側位移)或後退(於圖1中波形向右側位移)，因此根據本發明，能夠將下述晝夜節律障礙等中偏離之相位調節至原本(正常)之相位。 如此，能夠利用合歡樹皮之水萃取物而消除時鐘基因之表現節律及由其控制之晝夜節律中之異常(振幅減弱或相位偏離等)，因此利用以上述萃取物作為有效成分之本發明之組合物能夠治療、改善(緩和)或預防由該異常引起之疾病(晝夜節律障礙等)。 作為晝夜節律障礙，例如可列舉睡眠相位前移綜合症(ASPS)、睡眠相位後移綜合症(DSPS)、非24小時睡眠清醒障礙、不規則型睡眠清醒障礙、時差反應(時區變化綜合症、飛行時差綜合症)、因換班引起之節律失常(交替工作)、因夜晚型生活(熬夜、夜班等)引起之生活節律失常、老年人之節律消失。進而，對於該等晝夜節律障礙所伴隨之失眠、身體不適、注意力缺失、意志力降低、皮膚粗糙等各症狀之治療、改善(緩和)或預防等，本發明之組合物亦有效。 又，如下述之實施例所示，即使為健康人，藉由攝取合歡樹皮之水萃取物，對象之清晨型傾向亦增強，午後睡意減少，活動性(清醒度、意志、情緒及集中力)提升。因此，本發明之組合物作為用於使生活節律(生活習慣)轉變成清晨型之組合物亦有用。再者，於本發明中，所謂「清晨型」係指早起、從上午起活動、晚上早入睡之生活節律(生活習慣)，例如可藉由清晨型-夜晚型問卷(MEQ；Morningness-Eveningness Questionnaire)進行評價(參照石原金由等人之「日語版清晨型-夜晚型(morningness-eveningness)問卷之調査結果」，心理學研究，1986年，第57卷，第87～91頁)。 本發明之組合物可根據公知之製劑學方法而製劑化。例如可製成膠囊劑、錠劑、丸劑、液劑、散劑、顆粒劑、細粒劑、膜包衣劑、丸粒劑(pellet agent)、口含劑、舌下劑、咀嚼劑、口頰錠、糊劑、糖漿劑、懸浮劑、酏劑、乳劑、塗敷劑、軟膏劑、硬膏劑、敷糊劑、透皮吸收型製劑、洗劑、吸入劑、氣霧劑、注射劑、栓劑等，經口或非經口地使用。然而，就對投予對象之負擔少之觀點而言，本發明之組合物較佳為作為經口用組合物而使用。 於該等製劑化中，可與藥理學上或作為飲食品而容許之載體進行適當組合，上述載體具體而言為滅菌水或生理食鹽水、植物油、溶劑、基劑、乳化劑、懸浮劑、界面活性劑、穩定劑、香味劑、芳香劑、賦形劑、媒劑、防腐劑、結合劑、稀釋劑、等張化劑、止痛劑、增量劑、崩解劑、緩衝劑、包衣劑、潤滑劑、著色劑、甜味劑、增稠劑、矯味矯臭劑、助溶劑或其他添加劑等。 又，於將本發明之組合物用作飲食品之情形時，該飲食品例如可為健康食品、功能性食品、特定保健用食品、功能性標示食品、營養輔助食品、病人用食品、食品添加物或動物用飼料。本發明之飲食品除了可作為如上所述之組合物而攝取以外，亦可作為各種飲食品而攝取。作為飲食品之具體例，可列舉食用油、沙拉醬、美乃滋、人造黃油等包含油分之製品；湯類、乳飲料、清涼飲料、茶飲料、酒精飲料、飲劑、果凍狀飲料、功能性飲料等液狀食品；飯類、麵條類、麵包類等含碳水化合物之食品；火腿、香腸等畜產加工食品；魚糕、乾貨、鹹魚等水產加工食品；鹹菜等蔬菜加工食品；果凍、活菌發酵乳等半固體狀食品；味噌、醱酵飲料等醱酵食品；西式點心類、日式點心類、糖果類、口香糖類、軟糖、冷凍點心、冰點心等各種點心類；咖喱、澆汁、中式湯等蒸煮製品；速食湯、速食味噌汁等速食食品或微波爐食品等。進而亦可列舉製備為粉末、顆粒、錠劑、膠囊劑、液狀、糊狀或果凍狀之健康飲食品。 本發明之組合物可以任何生物為對象而使用，尤其較佳為用於包括人在內之動物。作為除人以外之動物，並無特別限制，可以各種家畜、家禽、寵物、實驗用動物等為對象。具體而言，可列舉豬、牛、馬、綿羊、山羊、雞、野鴨、鴕鳥、鴨、狗、貓、兔、倉鼠、小鼠、大鼠、猴，但不限定於此。 本發明中之飲食品之製造可採用該技術領域公知之製造技術而實施。於該飲食品中，亦可添加對晝夜節律障礙等之改善或預防有效之一種或兩種以上成分或者其他功能性食品。又，亦可藉由與發揮出該改善等以外之功能的其他成分或其他功能性食品加以組合，而製成多功能性之飲食品。 於投予或攝取本發明之組合物之情形時，其投予量或攝取量係根據對象之年齡、體重、症狀、健康狀態、組合物之種類(藥品、飲食品等)等而適當選擇，於以人(成人)為對象之情形時，較佳為1天1次或分數次投予合歡樹皮之水萃取物10～1000 mg，更佳為投予50～200 mg。又，作為本發明之組合物之投予等之時間點，根據晝夜節律如何偏離(前進或後退)而異，較佳為上午、更佳為上午7～10點之間，進而較佳為上午8～9點之間。進而，較理想為將本發明之組合物持續(至少連續3天，更佳為連續10天以上)投予等。 本發明之組合物製品(藥品、飲食品、試劑)或其說明書可附上用於使時鐘基因之表現變化、及/或使晝夜節律變化之主旨之標示。此處所謂「對製品或說明書附上標示」係指於製品本身、容器、包裝等上附上標示，或者於公開製品信息之說明書、附加文件、宣傳品、其他印刷物等上附上標示。 又，本發明亦提供以如此將本發明之藥物組合物投予至對象(例如罹患晝夜節律障礙者)為特徵之伴有對象之晝夜節律變化的疾病之治療或預防之方法。 [實施例] 以下，基於實施例更具體地說明本發明，但本發明並不限定於以下之實施例。 (實施例1) ＜合歡樹皮之水萃取物之製備＞ 於合歡之樹皮(Young Forest股份有限公司製造)中加入其10倍重量之蒸餾水，於高壓釜(100℃，60分鐘)中進行處理。使所獲得之萃取物通過不鏽鋼網(網眼：150 μm，Tokyo Screen股份有限公司製造，網篩，製品號：635-54-18-41)。使所獲得之濾液進而通過193號濾紙(ADVANTEC公司製造)，進行合計2次之過濾處理後，利用旋轉蒸發器(東京理化器械股份有限公司製造，N-1300型)濃縮至固形物成分成為5%。繼而，將所獲得之濃縮液與糊精(三和澱粉工業股份有限公司製造，Sun Deck)加以混合，供於加熱殺菌處理(90℃，60分鐘)後，利用冷凍乾燥機(AGC Techno Glass股份有限公司製造，FRD-82M)而製成乾燥粉末。 再者，如此而獲得之乾燥粉末中合歡樹皮之水萃取物與糊精之比率為1：3。合歡樹皮之水萃取物於吸濕性方面較高而物性容易發生變化(結塊)，因而如上所述加入有糊精作為賦形劑。又，乾燥粉末中合歡樹皮之水萃取物為供於萃取處理之合歡樹皮之6～8質量%。 (實施例2) ＜細胞增敏試驗＞ 將PER2：：LUC MEF(小鼠胚胎纖維母細胞)利用包含10%之胎牛血清(FBS)、0.1 mM之D-螢光素鈉鹽之DMEM(Dulbecco改良Eagle培養基)進行維持培養。然後，以成為200 nM之方式將地塞米松添加至上述培養基中，並培養2小時後，換成不含地塞米松之上述培養基進行培養。繼而，添加地塞米松，於2.4天後±2小時之間，以成為50 μg/ml、100 μg/ml之方式向培養基中添加包含如上所述製備之合歡樹皮之水萃取物之乾燥粉末，並培養30分鐘後，換成不含合歡樹皮水萃取物之上述培養基繼續進行培養。又，進行地塞米松處理後，細胞係於設定為37℃、5%CO2 且設置為Lumi循環(LumiCycle32，Actimetrics)之孵育箱內培養5.5天，並分析PER2基因之表現節律。將所獲得之結果示於圖2。 再者，PER2：：LUC MEF係從Per2：：螢光素酶敲入小鼠所分離之胚胎纖維母細胞。又，對於該小鼠，由於將螢火蟲螢光素酶基因導入至Per2基因下游，故而能夠以螢光素-螢光素酶反應之發光節律而追蹤Per2基因之表現節律(參照Narishige S.等，Br J Pharmacol.，2014年12月，第171卷，第24號，第5858～5869頁)。 又，作為合成腎上腺皮質激素(合成糖皮質激素)之地塞米松亦作為末梢臟器(細胞)之晝夜節律同步因子而發揮作用，因此為了重設各細胞中之時鐘基因之表現循環而使其同步，如上所述將其添加至PER2：：LUC MEF中。 進而，於Per2基因之表現節律(發光節律)分析中，進行Lumi循環中之測量資料(RAW資料)減去24小時之移動平均值之平滑化處理，其後進行以2小時之移動平均值進行平滑化之平滑化處理，算出該波形資料之發光值之峰值(參照Hayasaka N.等人，Endocrinology，2007年，第148卷，第7號，第3316～3326頁；Ohta H.等人，PLoS ONE，2008年，3：e2601)。又，對圖2所示之波峰2及波峰3之值之變化進行分析。將其結果示於表1。 [表1]

Figure 106134146-A0304-0001
(實施例3) ＜對小鼠之投予試驗＞ 如圖3所示，對於7週齡雌性ICR小鼠，將合歡樹皮之水萃取物(將如上述所製備之乾燥粉末1 mg或者10 mg溶解於蒸餾水中而成之溶液)或蒸餾水，於ZT4(12：00)之時間點用口喂管強制性經口投予3天。然後，於投予最後一天之ZT5.5解剖該等小鼠，摘取肝臟。繼而，從所摘取之肝臟中萃取總RNA，逆轉錄為cDNA後，藉由實時PCR對Per1、Per2及Bmal1基因之表現量進行分析。將所獲得之結果示於圖4～6。 (實施例4) ＜對人之投予試驗＞ 於下述條件下使人每天攝取合歡樹皮之水萃取物，攝取10天，供於睡眠檢查(對於睡眠檢查法，請參照松浦雅人編纂，「睡眠檢查學之基礎與臨床」，新興醫學出版社股份有限公司，2009年8月10日發行，第149～155頁)。 受驗者：29～49歲，健康者(男性5名、女性4名、合計9名) 攝取：將如上述所製備之乾燥粉末100 mg加入至膠囊(Hiruherf Research股份有限公司製造，明膠膠囊)中，將所獲得者於上午8：30～9：00之間與水一起經口攝取10天。 睡眠檢查：於攝取合歡樹皮之水萃取物之前一天及第10天之13～16點之時間點，進行下述KSS及VAS，評價睡意。又，於攝取合歡樹皮之水萃取物攝取之前一天及第10天，根據下述MEQ而調查清晨型-夜晚型之傾向。關西學院大學式嗜睡量表 (KSS ： Kwansei-Gakuin sleeping scale) KSS係以斯坦福嗜睡量表為參考而製成日語版之睡意問卷，由22項構成。對每項附有0～7分之量度值，數字越大，表示睡意越強。算出所選擇之項(可多選)之平均量度值作為睡意得分(參照石原金由等人之「睡眠之量度及其實驗研究)」，心理學研究、1982年，第52卷，第362～365頁)。將所獲得之結果(合計9名受驗者之平均值)示於圖8。視覺模擬評價量表 (VAS ： Visual analog scale) 藉由視覺模擬評價量表(VAS)對受驗者之主觀睡眠進行評價。更具體而言，預先於100 mm直線之左右兩端記下「完全不睏」、「非常睏」等單詞，令受驗者於認為與目前狀態接近之位置畫垂直線之方法。以毫米單位測定從0之點到垂直線之距離，該數值為睡意得分。得分每1 mm設為1分，採用0～100分之得分。此次除清醒度以外亦對意志、情緒、感覺、身體疲勞、集中力、食慾、自信度合計8個項目進行調查。將所獲得之結果(合計9名受驗者之平均值)示於圖9～12。清晨型 - 夜晚型問卷 (MEQ ： Morningness-Eveningness Questionnaire) MEQ係研究睡眠-清醒節律之個體差異、生活方式之節律意向之問卷，由19項問題構成。根據對各項之回答而給出得分，其總得分越高，評價越傾向於清晨型(參照石原金由等人之「日語版清晨型-夜晚型問卷之調查結果」，心理學研究，1986年，第57卷，第87～91頁)。將所獲得之結果示於圖13。再者，對於MEQ，亦準備在晚飯時攝取合歡樹皮之水萃取物而代替在上午(8：30～9：00)攝取之受驗者，使其接受該檢查。將所獲得之結果(合計9名受驗者之平均值)示於圖14。 由圖2所示之結果明確，藉由向小鼠胚胎纖維母細胞中添加合歡樹皮之水萃取物，於該細胞時鐘基因(Per2基因)之表現節律中抑制了其振幅之過渡性減弱(維持了Per2之基因表現水平)。進而，由表1所示之結果亦明確，於將合歡樹皮之水萃取物於Per2表現節律之遞減過程中添加至細胞中之情形時，Per2表現節律之波峰(相位)濃度依賴性地前進。另一方面，雖然未圖示，但明確於將合歡樹皮之水萃取物於Per2表現節律之遞增過程中添加至細胞中之情形時，Per2達節律之波峰(相位)濃度依賴性地後退。 因此，根據投予時間點不同，能使相位向前後之任一方向移動，因此明確合歡樹皮之水萃取物能夠用於調節時鐘基因之表現量及相位。 又，如圖4及5所示，將合歡樹皮之水萃取物對小鼠經口投予，結果末梢組織(肝臟)中之Per1基因及Per2基因之表現量依賴於投予量而減少。另一方面，如圖6所示，藉由投予合歡樹皮之水萃取物，末梢組織中之Bmal1基因之表現量增加。 再者，於哺乳動物體內，BMAL1蛋白質與CLOCK蛋白質形成異型二聚體而促進Period基因(Per1、Per2)之轉錄。又，另一方面，PER蛋白質與CRYPTOCHROME蛋白質形成異型二聚體而抑制BMAL1蛋白質及CLOCK蛋白質之活性。而且，晝夜節律因此種反饋迴路而得到調節，又，已知Period基因與Bmal1基因之表現節律大致偏差12小時。因此，認為圖4～6中所示之時鐘基因(Per1及Per2、與Bmal1)之表現量之變化不一致反映了於表現節律中Per1及Per2、與Bmal1處於逆相關係。 進而，參考小鼠(不投予合歡樹皮之水萃取物)體內ZT0～24之每3小時Per1基因表現量之變化(參照圖7)，於合歡樹皮之水萃取物投予小鼠體內ZT5.5之Per1基因表現量減少，由此提示Per1基因表現節律之相位後退。 由以上小鼠體內之結果明確，藉由經口攝取合歡樹皮之水萃取物，能夠用於末梢組織之時鐘基因之表現量及相位之調節。 又，如圖8～12所示，將合歡樹皮之水萃取物對人經口投予之結果明確，利用該萃取物，午後之睡意得到改善(KSS得分減少)，又，清醒度、意志、情緒、集中力方面亦有意義地得到改善(VAS得分增加)。 進而，如圖13所示，將合歡樹皮之水萃取物上午對人經口投予之結果明確，清晨型傾向增強(MEQ得分增加)。另一方面，如圖14所示，即使將合歡樹皮之水萃取物於午後(晚餐時)投予，亦未見MEQ得分之有意義變化。 如上所述，藉由經口投予合歡樹皮之水萃取物，午後睡意減少，又，清醒度、意志、情緒及集中力提升，清晨型傾向增強。據此得出如下推論，藉由攝取該萃取物，時鐘基因之表現節律發生變化，進而晝夜節律發生變化，結果變得入睡早，易早起，並且午後睡意減少，另一方面，活動性提高。 [產業上之可利用性] 如以上說明般，根據本發明，能夠使時鐘基因之表現變化，又，藉由該表現變化能夠使晝夜節律變化。又，藉由發生上述變化，能夠消除晝夜節律之異常，因此本發明之組合物作為用於因該異常引起之疾病(晝夜節律障礙等)之治療、改善(緩和)或預防之藥品、食品等有用。進而，本發明之組合物作為用於使時鐘基因之表現變化，且藉由該表現變化而使晝夜節律變化之試劑亦有用。As shown in the following examples, the present invention clarifies that the water extract of the bark of Albizia Julibrissin can change the expression level and phase of clock genes. In addition, the above-mentioned extract can change the circadian rhythm controlled by the clock gene through the expression change of the clock gene. Therefore, the present invention provides a composition for changing the expression of clock genes comprising the water extract of the bark of Albizia Julibrissin as an active ingredient. Also, the present invention provides a composition for changing circadian rhythm comprising the extract as an active ingredient. Water Extract of Bark of Albizia Julibrissin First, the "water extract of bark of Albizia Julibrissin" contained as an active ingredient in the composition of the present invention will be described. "Albizia julibrissin" refers to a deciduous tree plant (Albizia julibrissin) belonging to the subfamily Fabaceae Albizia julibrissin. When the bark of Albizia juliensis is subjected to the following extraction treatment, the bark can be directly used for the extraction treatment, but from the viewpoint of further improving the extraction efficiency, it can also be used in the process of using a mixer, agitator, homogenizer, Mortar, ultrasonic crusher, etc. are used for extraction after crushing. In the present invention, the solvent used in the extraction treatment may be water alone, or a mixed solvent of water and other solvents. The water used for extraction in the present invention is not particularly limited, and examples thereof include distilled water, deionized water, RO water, and ultrapure water. Moreover, it does not specifically limit as another solvent mixed with water, Alcohols, such as ethanol and methanol, Polyhydric alcohols, such as propylene glycol, Esters, such as methyl acetate, are mentioned. Moreover, although it does not specifically limit as a mixing ratio, Water:other solvent=90-50:10-50 (volume ratio) is preferable. The extraction conditions are not particularly limited, and the solvents used above are also different. For example, when only water is used, it is better to use 1 to 100 parts by weight of water relative to 1 part by weight of Albizia juliensis bark. Extract at a temperature of ~100°C for 10 minutes to 7 days, more preferably use 5 to 20 parts by weight of water relative to 1 part by weight of Albizia Julibrissin bark, and extract at a temperature of 70 to 100°C for 30 minutes to 2 hours Do the extraction. In addition, from the viewpoint of further improving the extraction efficiency, pressurization, stirring, ultrasonic treatment, etc. may be performed together with the extraction treatment. Furthermore, after the above-mentioned extraction treatment, it can be separated from the residue by filtration or centrifugation. The "water extract of Albizia julienne bark" of the present invention can also be used in the composition of the present invention in the form of an extract, but it can also be used in the composition of the present invention by ion exchange method, gel filtration method, membrane separation method, electrodialysis method, solvent Extraction method, vacuum concentration method, heat treatment method, etc. to concentrate. Furthermore, the "water extract of bark of Albizia juliensis" can also be made into a powder by subjecting it to treatment such as spray drying and freeze drying, if necessary. Also, from the viewpoint of safety, the "water extract of bark of Albizia Julibrissin" can be sterilized. Examples of the above-mentioned sterilization treatment include heat sterilization, pressure sterilization, radiation sterilization, filtration sterilization, and the like. Moreover, the "water extract of the bark of Albizia Julibrissin" thus prepared can be used as the composition of the present invention as it is, for example, or can be used as the composition of the present invention by combining with other components as described below. Composition for Changing Expression of Clock Gene or Circadian Rhythm Next, an aspect of the composition of the present invention will be described. As shown in the following examples, the above-mentioned water extract of bark of Albizia juliensis has the activity of changing the circadian rhythm by changing the expression of clock genes. Therefore, the composition of the present invention containing it as an active ingredient can be used as a pharmaceutical composition, food or drink for the treatment, improvement (alleviation) or prevention of circadian rhythm disorder described below. Also, it can be used as a reagent for changing the expression of clock genes or a reagent for changing the circadian rhythm. In the present invention, so-called " clock gene ", as long as it is the gene that has the function of controlling circadian rhythm (body clock), for example can enumerate: Period gene (Per1, Per2, Per3 etc.), Bmal gene (also known as Arnt1 , Mop3, Tic, Jap3, Pasd3, bHLHe5 genes, Bmal1, Bmal2, etc.), cryptochrome genes (Cry1, Cry2, etc.), Clock gene, Ror gene, Rev-erb gene, E4BP gene, GSK3β gene, CK1 gene, Dec gene, in the present invention, is preferably Per1 gene, Per2 gene, Bmal1 gene. Typically, the human Per1 gene encodes a protein gene (comprising a nucleotide sequence specific to RefSeq ID: NM_002616) comprising the amino acid sequence specified by RefSeq ID: NP_002607, and the human Per2 gene encodes a protein comprising The gene of the protein with the amino acid sequence specified by RefSeq ID: NP_073728 (including the gene with the nucleotide sequence specified by RefSeq ID: NM_003894 or NM_022817), the human Bmal1 gene encoding contains the gene with RefSeq ID: NP_001025443, NP_001025444, NP_001169 , NP_001284648 or NP_001284651 specific amino acid sequence of the protein gene (comprising the gene of the nucleotide sequence specific to RefSeq ID: NM_001030272, NM_001030273, NM_001178, NM_001297719 or NM_001297722), the Per1 gene coding of the mouse comprises: RefSeq ID : NP_001152839 or NP_035195 specific amino acid sequence protein gene (comprising the gene of the nucleotide sequence specified by RefSeq ID: NM_001159367 or NM_011065), the Per2 gene of the mouse is coded and contains the amine group specified by RefSeq ID: NP_035196 The gene of the protein of the amino acid sequence (comprising the gene of the specific nucleotide sequence with RefSeq ID: NM_011066), the Bmal1 gene of the mouse is the gene encoding the protein comprising the specific amino acid sequence of RefSeq ID: NP_001229977 or NP_031515 (comprising Genes with nucleotide sequences specified by RefSeq ID: NM_001243048 or NM_007489). Furthermore, there are variations in the nucleotide sequence in nature (ie, non-artificial). Therefore, the clock gene involved in the present invention is not specifically the above-mentioned sequence listed as a typical example, but also includes such natural mutants. The "expression of clock gene" in the present invention includes not only the expression at the transcriptional level (expression as mRNA), but also the expression at the translational level (expression as protein). In addition, "changes in the expression of clock genes" include changes in the expression rhythm (at least one of amplitude, phase, and cycle length) of clock genes in addition to the increase or decrease in the expression level of clock genes. The so-called "amplitude", as shown in Figure 1, is the length from the peak to the trough in the rhythm (the size of the vibration), which means that the clock gene is in the period from the peak to the peak or from the trough to the trough in the expression rhythm of the clock gene ( A period) of the magnitude of the performance. It is known that in the expression rhythms of clock genes and the circadian rhythms controlled by them, the amplitudes of these gradually decrease with age. On the other hand, as shown in the following examples, the bark water extract of Albizia Julibrissin can inhibit this attenuation. The so-called "phase" refers to a specific position of a cycle (eg peak, trough). Also, the so-called "period length" refers to the length (period) of one cycle in the rhythm as shown in Fig. 1, which is originally (normally) about 24.3 hours for a human. As shown in the following examples, the bark water extract of Albizia juliensis can advance the expression rhythm of the clock gene and the phase of the circadian rhythm controlled by it according to the timing of administration or ingestion (the waveform shifts to the left in Figure 1 ) or backward (the waveform is shifted to the right in FIG. 1 ), so according to the present invention, the deviated phase in the following circadian rhythm disorders and the like can be adjusted to the original (normal) phase. In this way, the water extract of the bark of Albizia Julibrissin can be used to eliminate the abnormality (amplitude weakening or phase deviation, etc.) in the expression rhythm of the clock gene and the circadian rhythm controlled by it, so the combination of the present invention using the above-mentioned extract as an active ingredient The drug can treat, improve (alleviate) or prevent diseases caused by the abnormality (circadian rhythm disorder, etc.). Examples of circadian rhythm disorders include advanced sleep phase syndrome (ASPS), delayed sleep phase syndrome (DSPS), non-24-hour sleep-wake disorder, irregular sleep-wake disorder, jet lag (time zone shift syndrome, jet lag syndrome), arrhythmia caused by shift change (alternate work), arrhythmia caused by night life (staying up late, night shift, etc.), rhythm disappearance in the elderly. Furthermore, the composition of the present invention is also effective for the treatment, improvement (alleviation) or prevention of symptoms such as insomnia, physical discomfort, loss of concentration, decreased willpower, rough skin, etc. associated with these circadian rhythm disorders. In addition, as shown in the following examples, even healthy people, by ingesting the water extract of Albizia juliensis bark, the subject's morning tendency is also enhanced, the sleepiness in the afternoon is reduced, and the activity (awakeness, will, mood and concentration) promote. Therefore, the composition of the present invention is also useful as a composition for converting a life rhythm (lifestyle) into a morning type. Furthermore, in the present invention, the so-called "morning type" refers to the life rhythm (lifestyle habits) of getting up early, getting active in the morning, and falling asleep early in the evening. ) for evaluation (refer to Ishihara Kinyuki et al. "Japanese version of morningness-eveningness (morningness-eveningness) questionnaire survey results", Psychological Research, 1986, Vol. 57, pp. 87-91). The composition of the present invention can be formulated according to known pharmaceutical methods. For example, it can be made into capsules, lozenges, pills, liquids, powders, granules, fine granules, film-coated agents, pellet agents, buccal agents, sublingual agents, chewable agents, buccal agents, etc. Tablets, pastes, syrups, suspensions, elixirs, emulsions, coatings, ointments, plasters, pastes, transdermal preparations, lotions, inhalants, aerosols, injections, suppositories, etc. , for oral or parenteral use. However, the composition of the present invention is preferably used as an oral composition from the viewpoint of less burden on the subject to be administered. In these formulations, it can be appropriately combined with a carrier that is acceptable pharmacologically or as a food or drink. Specifically, the above-mentioned carrier is sterilized water or physiological saline, vegetable oil, solvent, base, emulsifier, suspending agent, Surfactants, Stabilizers, Fragrances, Fragrances, Excipients, Vehicles, Preservatives, Binders, Diluents, Isotonic Agents, Analgesics, Bulking Agents, Disintegrants, Buffers, Coatings additives, lubricants, coloring agents, sweeteners, thickeners, flavoring agents, solubilizers or other additives, etc. Also, when the composition of the present invention is used as a food or drink, the food or drink may be, for example, a health food, a functional food, a food for specific health use, a food with a functional label, a nutritional supplement, a food for patients, or a food additive. food or animal feed. The food-drinks of this invention can be ingested as various food-drinks other than the composition mentioned above. Specific examples of food and beverages include oil-containing products such as edible oil, salad dressing, mayonnaise, and margarine; soups, milk drinks, soft drinks, tea drinks, alcoholic drinks, drinks, jelly drinks, functional Liquid foods such as beverages; Carbohydrate-containing foods such as rice, noodles, and bread; processed livestock foods such as ham and sausages; processed aquatic foods such as fish cakes, dried goods, and salted fish; processed vegetable foods such as pickles; Semi-solid foods such as fermented milk; fermented foods such as miso and fermented beverages; Western-style confectionery, Japanese-style confectionery, candy, chewing gum, soft candy, frozen dessert, iced dessert and other snacks; curry, pouring Instant soup, instant soup, instant miso juice and other instant food or microwave food, etc. Further, health food and drink prepared in the form of powder, granule, lozenge, capsule, liquid, paste or jelly can also be mentioned. The composition of the present invention can be used for any living beings, and is particularly preferably used for animals including humans. Animals other than humans are not particularly limited, and various domestic animals, poultry, pets, experimental animals, and the like can be used as objects. Specifically, pigs, cows, horses, sheep, goats, chickens, wild ducks, ostriches, ducks, dogs, cats, rabbits, hamsters, mice, rats, and monkeys are exemplified, but not limited thereto. The food and beverages in the present invention can be produced using known production techniques in the technical field. One or two or more components effective in improving or preventing circadian rhythm disorders, etc., or other functional foods may be added to the food or drink. Moreover, it is also possible to prepare a multifunctional food and drink by combining it with other components exhibiting functions other than the improvement, or other functional foods. When administering or ingesting the composition of the present invention, the dosage or intake is appropriately selected according to the subject's age, body weight, symptoms, health status, type of composition (drugs, food and drink, etc.), In the case of humans (adults), it is preferable to administer 10-1000 mg of the water extract of bark of Albizia Julibrissin once a day or in divided doses, more preferably 50-200 mg. Also, the timing for administering the composition of the present invention depends on how the circadian rhythm deviates (forward or backward), but it is preferably in the morning, more preferably between 7 and 10 am, and still more preferably in the morning Between 8 and 9 o'clock. Furthermore, it is preferable to administer the composition of the present invention continuously (at least 3 consecutive days, more preferably 10 consecutive days or more). Composition products (drugs, food and beverages, reagents) of the present invention or their instructions may be marked with the purpose of changing the expression of clock genes and/or changing the circadian rhythm. The so-called "attaching a label to the product or instruction manual" here refers to attaching a label to the product itself, container, packaging, etc., or attaching a label to the instruction manual, attached documents, promotional materials, or other printed materials that disclose product information. Furthermore, the present invention also provides a method for treating or preventing a disease involving a change in the circadian rhythm of the subject, which is characterized by administering the pharmaceutical composition of the present invention to a subject (for example, a person suffering from a circadian rhythm disorder). EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, this invention is not limited to a following Example. (Example 1) <Preparation of water extract from bark of Albizia Julibrissin> Add 10 times the weight of distilled water to the bark of Albizia juliensis (manufactured by Young Forest Co., Ltd.), and process in an autoclave (100°C, 60 minutes). The obtained extract was passed through a stainless steel mesh (mesh: 150 μm, manufactured by Tokyo Screen Co., Ltd., mesh screen, product number: 635-54-18-41). The obtained filtrate was further passed through No. 193 filter paper (manufactured by ADVANTEC Co., Ltd.), and after a total of 2 filtration treatments, it was concentrated by a rotary evaporator (manufactured by Tokyo Physical and Chemical Instrument Co., Ltd., N-1300 type) until the solid content became 5 %. Then, the obtained concentrated solution was mixed with dextrin (manufactured by Sanhe Starch Industry Co., Ltd., Sun Deck), and after heat sterilization (90°C, 60 minutes), it was dried using a freeze dryer (AGC Techno Glass Co., Ltd. Co., Ltd., FRD-82M) and made into dry powder. Furthermore, the ratio of the water extract of Albizia Julibrissin bark to dextrin in the dry powder thus obtained is 1:3. The water extract of Albizia Julibrissin bark has high hygroscopicity and is prone to change (caking) in physical properties, so dextrin is added as an excipient as mentioned above. Also, the water extract of the bark of Albizia Julibrissin in the dry powder is 6-8% by mass of the bark of Albizia Julibis for extraction treatment. (Example 2) <Cell Sensitization Test> PER2::LUC MEFs (mouse embryonic fibroblasts) were used in DMEM containing 10% fetal bovine serum (FBS), 0.1 mM D-luciferin sodium salt ( Dulbecco's modified Eagle's medium) for maintenance. Then, 200 nM of dexamethasone was added to the above-mentioned medium, and after culturing for 2 hours, the culture medium was replaced with the above-mentioned medium not containing dexamethasone. Next, dexamethasone was added, and 2.4 days later ± 2 hours, the dry powder containing the water extract of the bark of Albizia Julibrissin prepared as described above was added to the medium in such a manner that it became 50 μg/ml and 100 μg/ml, And after cultivating for 30 minutes, change to the above-mentioned medium that does not contain the bark water extract of Albizia Julibrissin to continue culturing. In addition, after dexamethasone treatment, the cell line was cultured for 5.5 days in an incubator set at 37°C, 5% CO 2 and set to Lumi Cycle (LumiCycle32, Actimetrics), and the expression rhythm of the PER2 gene was analyzed. The obtained results are shown in FIG. 2 . Furthermore, PER2::LUC MEFs are embryonic fibroblasts isolated from Per2::luciferase knock-in mice. In addition, since the firefly luciferase gene was introduced downstream of the Per2 gene in this mouse, the expression rhythm of the Per2 gene could be tracked with the luminescence rhythm of the luciferin-luciferase reaction (see Narishige S. et al., Br J Pharmacol., December 2014, Vol. 171, No. 24, pp. 5858-5869). In addition, dexamethasone, which is a synthetic adrenocortical hormone (synthetic glucocorticoid), also functions as a circadian rhythm synchronization factor of peripheral organs (cells), so it is used to reset the expression cycle of clock genes in each cell. Sync, add it to the PER2::LUC MEF as above. Furthermore, in the analysis of the expression rhythm (luminescence rhythm) of the Per2 gene, the measurement data (RAW data) in the Lumi cycle were smoothed by subtracting the 24-hour moving average, and then the 2-hour moving average was performed. The smoothing process of smoothing calculates the peak value of the luminescence value of the waveform data (refer to people such as Hayasaka N., Endocrinology, 2007, volume 148, number 7, pages 3316-3326; people such as Ohta H., PLoS ONE, 2008, 3:e2601). Moreover, the change of the value of the peak 2 and the peak 3 shown in FIG. 2 was analyzed. The results are shown in Table 1. [Table 1]
Figure 106134146-A0304-0001
 (Example 3) <Administration test on mice> As shown in Fig. 3, to 7-week-old female ICR mice, the aqueous extract of the bark of Albizia Julibrissin (1 mg or 10 mg of the dry powder prepared as above Dissolved in distilled water) or distilled water, at the time point of ZT4 (12:00), orally administered for 3 days with an oral feeding tube. Then, on the last day of ZT5.5 administration, these mice were dissected, and the liver was removed. Then, total RNA was extracted from the excised liver, reverse-transcribed into cDNA, and the expression levels of Per1, Per2 and Bmal1 genes were analyzed by real-time PCR. The obtained results are shown in FIGS. 4 to 6 . (Example 4) <Administration test on humans> Under the following conditions, people ingested the water extract of Albizia juliensis bark every day for 10 days, and used it for sleep examination (for the sleep examination method, please refer to the edited by Masato Matsuura, " The basics and clinical practice of sleep examination", Xinxing Medical Publishing House Co., Ltd., issued on August 10, 2009, pp. 149-155). Subjects: 29-49 years old, healthy subjects (5 males, 4 females, 9 in total) Ingestion: Add 100 mg of the dry powder prepared above to capsules (manufactured by Hiruherf Research Co., Ltd., gelatin capsules) In this method, the obtained product was orally ingested with water for 10 days between 8:30 and 9:00 am. Sleep test: The following KSS and VAS were performed at the time point of 13-16 o'clock on the day before ingesting the water extract of the bark of Albizia Julibrissin and on the 10th day to evaluate sleepiness. Moreover, the morning type-evening type tendency was investigated according to the following MEQ on the day before and the 10th day before the ingestion of the water extract of the bark of Albizia Julibrissin. Kansai Gakuin University-style Sleepiness Scale (KSS : Kwansei-Gakuin sleeping scale) KSS is a Japanese version of sleepiness questionnaire made with the Stanford Sleepiness Scale as a reference, consisting of 22 items. Each item has a scale value from 0 to 7 points, the larger the number, the stronger the sleepiness. Calculate the average measurement value of the selected items (multiple choices) as the sleepiness score (refer to Ishihara Kaneyuki et al. "Sleep Measurement and Experimental Research)", Psychological Research, 1982, Vol. 52, No. 362- 365 pages). The obtained results (the average value of 9 test subjects in total) are shown in FIG. 8 . Visual analog scale (VAS : Visual analog scale) evaluates the subject's subjective sleep by using the visual analog scale (VAS). More specifically, words such as "not sleepy at all" and "very sleepy" were recorded on the left and right ends of a 100 mm straight line in advance, and the subjects were asked to draw a vertical line at a position they thought was close to the current state. The distance from the point 0 to the vertical line is measured in millimeters, and this value is the sleepiness score. The score is set as 1 point per 1 mm, and the score is from 0 to 100 points. In addition to sobriety, 8 items including will, emotion, feeling, physical fatigue, concentration, appetite, and self-confidence were also investigated. The obtained results (average values of 9 test subjects in total) are shown in FIGS. 9 to 12 . Morningness - Eveningness Questionnaire (MEQ : Morningness-Eveningness Questionnaire) MEQ is a questionnaire for studying individual differences in sleep-wake rhythm and rhythm intention of lifestyle, consisting of 19 questions. Scores are given based on the answers to each item, and the higher the total score, the more inclined the evaluation is to the morning type (refer to Ishihara Kinyu et al. "Japanese version of the morning type-evening type questionnaire survey results", Psychological Research, 1986 , Vol. 57, pp. 87-91). The obtained results are shown in FIG. 13 . Furthermore, regarding MEQ, subjects who ingested the water extract of the bark of Albizia juliensis at dinner instead of ingesting in the morning (8:30 to 9:00) were also prepared to be subjected to the examination. The obtained results (the average value of nine subjects in total) are shown in FIG. 14 . From the results shown in Figure 2, it is clear that by adding the water extract of Albizia julienne bark to the mouse embryonic fibroblasts, the transitional weakening of the amplitude of the cell clock gene (Per2 gene) was suppressed (maintained). gene expression level of Per2). Furthermore, it is also clear from the results shown in Table 1 that when the water extract of the bark of Albizia juliensis is added to the cells during the decreasing process of the Per2 expression rhythm, the peak (phase) of the Per2 expression rhythm advances in a concentration-dependent manner. On the other hand, although not shown, it is clear that when the water extract of the bark of Albizia juliensis was added to the cells during the increase of the Per2 expression rhythm, the peak (phase) of the Per2 expression rhythm retreated in a concentration-dependent manner. Therefore, depending on the time point of administration, the phase can be shifted in either direction forward or backward. Therefore, it is clear that the water extract of bark of Albizia juliensis can be used to regulate the expression level and phase of clock genes. Also, as shown in FIGS. 4 and 5 , when the water extract of Albizia juliensis bark was orally administered to mice, the expression levels of Per1 and Per2 genes in peripheral tissues (liver) decreased depending on the dose. On the other hand, as shown in FIG. 6 , the expression level of the Bmal1 gene in the peripheral tissue was increased by administering the water extract of the bark of Albizia Julibrissin. Furthermore, in mammals, BMAL1 protein and CLOCK protein form heterodimers to promote the transcription of Period genes (Per1, Per2). On the other hand, PER protein and CRYPTOCHROME protein form a heterodimer to inhibit the activities of BMAL1 protein and CLOCK protein. Furthermore, the circadian rhythm is regulated by such a feedback loop, and it is known that the expression rhythms of the Period gene and the Bmal1 gene deviate by approximately 12 hours. Therefore, it is considered that the inconsistency in the expression changes of the clock genes (Per1 and Per2, and Bmal1) shown in Figures 4 to 6 reflects that Per1, Per2, and Bmal1 are in an inverse relationship in the expression rhythm. Furthermore, referring to the change of Per1 gene expression level of ZT0-24 per 3 hours in the mice (not administered with the water extract of the bark of Albizia Julibrissin), ZT5. The expression level of Per1 gene in 5 decreased, which suggested that the phase of Per1 gene expression rhythm was backward. From the above results in mice, it is clear that oral intake of the water extract of bark of Albizia juliensis can be used to regulate the expression level and phase of clock genes in peripheral tissues. Also, as shown in Figures 8 to 12, the results of oral administration of the water extract of the bark of Albizia juliensis to humans are clear. Using the extract, the drowsiness in the afternoon is improved (the KSS score is reduced), and the degree of sobriety, willpower, Mood, concentration also improved meaningfully (increased VAS score). Furthermore, as shown in FIG. 13 , the results of oral administration of the water extract of bark of Albizia juliensis to human beings in the morning were clear, and the morning type tendency was enhanced (MEQ score increased). On the other hand, as shown in FIG. 14 , even when the water extract of Albizia juliensis bark was administered in the afternoon (dinner), no significant change in the MEQ score was observed. As mentioned above, by orally administering the water extract of the bark of Albizia juliensis, the drowsiness in the afternoon is reduced, and the degree of sobriety, willpower, mood and concentration are improved, and the tendency of morning type is enhanced. Based on this, it is inferred that the expression rhythm of the clock gene changes by taking the extract, and then the circadian rhythm changes. As a result, it becomes easier to fall asleep early, wake up early, and reduce sleepiness in the afternoon. On the other hand, the activity increases. [Industrial Applicability] As described above, according to the present invention, it is possible to change the expression of clock genes, and also to change the circadian rhythm by the change in expression. In addition, the abnormality of the circadian rhythm can be eliminated by the occurrence of the above-mentioned changes, so the composition of the present invention is used as a medicine, food, etc. for the treatment, improvement (alleviation) or prevention of diseases (circadian rhythm disorders, etc.) caused by the abnormality. it works. Furthermore, the composition of the present invention is also useful as an agent for changing the expression of clock genes and changing the circadian rhythm by changing the expression.

圖1係表示時鐘基因之表現節律、或由該表現節律所控制之晝夜節律之概略的波形圖。 圖2係表示添加有合歡樹皮之水萃取物(50 μg/ml或100 μg/ml)、或作為對照之蒸餾水(DW)的小鼠胚胎纖維母細胞中之Per2基因之表現節律的波形圖。圖中之橫軸表示為了重設各細胞中之Per2基因等時鐘基因之表現循環使其同步而於培養基中添加地塞米松之後之天數。 圖3係表示對小鼠投予合歡樹皮之水萃取物之試驗之日程的概略圖。 圖4係表示經口投予有合歡樹皮之水萃取物(1 mg或10 mg)或作為對照(cont.)之蒸餾水的小鼠體內之Per1基因之表現量的圖。 圖5係表示經口投予有合歡樹皮之水萃取物(1 mg或10 mg)或作為對照(cont.)之蒸餾水之小鼠體內之Per2基因之表現量的圖。 圖6係表示經口投予有合歡樹皮之水萃取物(1 mg或10 mg)或作為對照(cont.)之蒸餾水之小鼠體內之Bmal1基因之表現量的圖。 圖7係表示小鼠體內之Per1基因之表現量之經時變化的圖。其中，縱軸係作為以Gapdh基因之表現量為基準之相對值而表示Per1基因之表現量者。橫軸表示明暗條件下之時刻(以光照期開始時間(ZT：Zeitgeber Time)作為ZT0)。 圖8係表示上午攝取合歡樹皮之水萃取物的人接受睡眠檢查(關西學院大學式嗜睡量表，KSS)之結果之圖。 圖9係表示於上午攝取合歡樹皮之水萃取物的人接受睡眠檢查(視覺模擬評價量表，VAS)之結果(清醒度)之圖。 圖10係表示於上午攝取合歡樹皮之水萃取物的人接受睡眠檢查(視覺模擬評價量表，VAS)之結果(意志)之圖。 圖11係表示於上午攝取合歡樹皮之水萃取物的人接受睡眠檢查(視覺模擬評價量表，VAS)之結果(情緒)之圖。 圖12係表示於上午攝取合歡樹皮之水萃取物的人接受睡眠檢查(視覺模擬評價量表，VAS)之結果(集中力)之圖。 圖13係表示於上午攝取合歡樹皮之水萃取物的人接受睡眠檢查(清晨型-夜晚型問卷，MEQ)之結果之圖。 圖14係表示於晚餐時攝取合歡樹皮之水萃取物的人接受睡眠檢查(清晨型-夜晚型問卷，MEQ)之結果之圖。Fig. 1 is a waveform diagram schematically showing the expression rhythm of clock genes or the circadian rhythm controlled by the expression rhythm. Fig. 2 is a waveform diagram showing the expression rhythm of Per2 gene in mouse embryonic fibroblasts added with water extract of Albizia juliensis bark (50 μg/ml or 100 μg/ml), or distilled water (DW) as a control. The horizontal axis in the figure represents the number of days after dexamethasone was added to the medium in order to reset and synchronize the expression cycle of the isoclock gene of the Per2 gene in each cell. Fig. 3 is a schematic diagram showing the schedule of a test in which mice were administered an aqueous extract of bark of Albizia juliensis. Fig. 4 is a graph showing the expression level of Per1 gene in mice orally administered with water extract of bark of Albizia Julibrissinus (1 mg or 10 mg) or distilled water as a control (cont.). Fig. 5 is a graph showing the expression level of Per2 gene in mice orally administered with water extract of bark of Albizia juliensis (1 mg or 10 mg) or distilled water as a control (cont.). Fig. 6 is a graph showing the expression level of Bmal1 gene in mice orally administered with water extract of bark of Albizia juliensis (1 mg or 10 mg) or distilled water as a control (cont.). Fig. 7 is a graph showing changes over time in the expression level of the Per1 gene in mice. Wherein, the vertical axis represents the expression level of the Per1 gene as a relative value based on the expression level of the Gapdh gene. The horizontal axis represents the time under light and dark conditions (ZT0 is defined as the photoperiod start time (ZT: Zeitgeber Time)). Fig. 8 is a graph showing the results of a sleep test (Kansai Gakuin University Sleepiness Scale, KSS) of people who ingested the water extract of the bark of Albizia Julibrissin in the morning. Fig. 9 is a graph showing the results (awakeness) of a sleep test (Visual Analogue Scale, VAS) of people who ingested the water extract of the bark of Albizia Julibrissin in the morning. Fig. 10 is a graph showing the results (volition) of a sleep test (Visual Analogue Scale, VAS) of people who ingested the water extract of the bark of Albizia Julibrissin in the morning. Fig. 11 is a graph showing the results (mood) of sleep examination (Visual Analogue Scale, VAS) of people who ingested the water extract of the bark of Albizia Julibrissin in the morning. Fig. 12 is a graph showing the results (concentration) of a sleep test (Visual Analogue Scale, VAS) of people who ingested the water extract of Albizia Julibrissin bark in the morning. Fig. 13 is a graph showing the results of sleep examination (Morning-Evening Questionnaire, MEQ) of people who ingested the water extract of the bark of Albizia Julibrissin in the morning. Fig. 14 is a graph showing the results of sleep examination (morning-evening questionnaire, MEQ) of people who ingested the water extract of Albizia juliensis bark at dinner.

Claims (6)

一種合歡樹皮之水萃取物之用途，其係用以製造用於使哺乳類之時鐘基因之表現節律之相位前進或後退的組合物，該合歡樹皮之水萃取物係於70~100℃之溫度下以水進行萃取者。 A use of the water extract of the bark of Albizia Julibrissin, which is used to manufacture a composition for advancing or regressing the phase of the expression rhythm of the clock gene of mammals, the water extract of the bark of Albizia Julibrissin is kept at a temperature of 70-100°C Extracted with water. 一種合歡樹皮之水萃取物之用途，其係用以製造用於抑制哺乳類之時鐘基因之表現量之振幅減弱的組合物，該合歡樹皮之水萃取物係於70~100℃之溫度下以水進行萃取者。 A use of the water extract of the bark of Albizia Julibrissin, which is used to manufacture a composition for suppressing the amplitude reduction of the expression of clock genes in mammals. The extractor. 如請求項1或2之用途，其中上述時鐘基因係選自由Per1基因、Per2基因及Bmal1基因所組成之群中之至少一種基因。 The use of claim 1 or 2, wherein the clock gene is at least one gene selected from the group consisting of Per1 gene, Per2 gene and Bmal1 gene. 如請求項1或2之用途，其中上述組合物係用於使晝夜節律之相位前進或後退之組合物。 The use according to claim 1 or 2, wherein the above-mentioned composition is a composition for advancing or regressing the phase of circadian rhythm. 如請求項1或2之用途，其中上述組合物係用於治療、改善或預防晝夜節律障礙及伴隨晝夜節律障礙之症狀之組合物。 The use according to Claim 1 or 2, wherein the above-mentioned composition is a composition for treating, improving or preventing circadian rhythm disorder and symptoms associated with circadian rhythm disorder. 如請求項1或2之用途，其中上述水萃取物係以合歡樹皮加入10倍重量之水，並於100℃、60分鐘之條件下之高壓釜中所獲得之萃取成分。 The use of claim 1 or 2, wherein the above-mentioned water extract is the extract obtained by adding 10 times the weight of water to the bark of Albizia Julibrissin, and obtaining it in an autoclave at 100°C for 60 minutes.
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