TWI528959B - 氧化丁香烯用以製造時鐘基因之表現促進劑的用途 - Google Patents
氧化丁香烯用以製造時鐘基因之表現促進劑的用途 Download PDFInfo
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Description
本發明係關於一種時鐘基因之表現調節劑、以及含有其之晝夜節律調整劑。
地球上之幾乎所有生物之體內均具有以約24小時為週期進行自發性波動之「生物時鐘」。一般認為生物時鐘會引起晝夜節律(circadian rhythm)之生物學之晝夜變化，支配以生物之睡-醒週期為首之體溫、血壓、激素分泌、代謝、進而心身之活動、飲食等各種生物現象(活動)之晝夜變化。近年來，指出晝夜節律紊亂係睡眠障礙、皮膚疾病、生活習慣病、進而憂鬱症等精神神經疾病等各種心身之症狀或疾病之主要發病原因。
如圖1所示，生物時鐘係由含有稱為「時鐘基因(clock gene)」之基因簇的節律產生系統所控制，於哺乳類之情形時，藉由促進/抑制CLOCK、BMAL1、PERIOD、CRYPTOCHROME之4種編碼成為核心之蛋白質的基因之轉錄而形成之回饋迴路(feedback loop)成為時鐘分子機構之核心(core)，該回饋迴路刻畫約24小時之節律而形成晝夜節律。
現已明確，時鐘基因係作為轉錄因子而直接控制其他基因之表現節律，進而經由激素分泌之調節等而間接控制大量基因之晝夜表現，若生物體內之時鐘基因之表現節律發生紊亂，則生物器官之機能或內分泌系會出現損傷，而引
起以高血壓等生活習慣病為首之各種疾病(非專利文獻1)。例如，有報告稱肥胖者於時鐘基因之表現方面存在異常，又，亦報告有與憂鬱症或癌症等之相關性。進而，亦已知時鐘基因係調節皮膚之各種生理機能之晝夜節律，有報告稱於使用正常人類皮膚纖維母細胞之實驗中，I型膠原基因於與時鐘基因Period2相同之表現圖譜中係具有晝夜節律而進行表現(非專利文獻2)。
現已明確，晝夜節律之制禦中樞(中樞時鐘)雖然存在於下視丘之視叉上核，但於肝臟、腎臟、皮膚等末梢組織中亦表現時鐘基因，由相同之系統形成晝夜節律。末梢之時鐘基因之表現係由來自視叉上核之訊號調節其之表現，進而亦已知糖皮質素、兒茶酚胺、血管緊張素II等之訊號刺激因子係直接控制末梢組織或細胞之時鐘基因之表現而形成生理節律。近年來，目前係於皮膚纖維母細胞等培養細胞中添加糖皮質素、腺苷酸環化酶活化劑(forskolin)或血清等刺激因子使表現節律同步而於活體外誘導時鐘基因表現之晝夜節律，並將其表現作為指標來評價晝夜節律(非專利文獻3~5)。
進而，有報告稱於使用此種人類皮膚纖維母細胞之評價系中，扁柏萃取物、綠藻萃取物等生藥及杜松子油、薰衣草油等精油可調節Bmal時鐘基因之表現，又，山金車萃取物、萍蓬草萃取物等生藥及杜松子油、香柏油等精油可調節Period時鐘基因之表現(專利文獻1及2)。
如上所述，藉由調節時鐘基因之表現，可調整由此控制
之生物之各種行為節律或生理機能之晝夜節律，業界強烈期望開發出可應用於廣泛用途且有效地調節時鐘基因之表現之新型藥劑。
[專利文獻1]國際公開第2011/122040號說明書
[專利文獻2]國際公開第2011/122041號說明書
[非專利文獻1]Hastings M., O'Neill JS., and Maywood ES., (2007) Circadian clocks: regulators of endocrine and metabolic rhythms. Journal of Endocrinology, 195; 187-198
[非專利文獻2]泉香津代等人、具有晝夜節律之皮膚生理基因之探索、日本分子生物學會第32次年會主旨2P-0009
[非專利文獻3]Okamura H., (2004) Clock genes in cell clocks: Roles, Actions, and Mysteries. Journal of Biological Rhythms, 19 (5); 388-399
[非專利文獻4]Balsalobre A., Damiola F., and Schibler U., (1998) A serum shock induces circadian gene expression in mammalian tissue culture cells. Cell, 93; 929-937
[非專利文獻5]Yagita K., Tamanini F., van der Horst G., and Okamura H., (2001) Molecular mechanisms of the biological clock in cultures fibroblasts. Science, 292; 278-281
本發明鑒於如上述之情況，其目的在於提供一種可調節時鐘基因之表現之新型藥劑。
本發明者發現：於培養細胞中，氧化丁香烯、以及苯甲酸甲酯(Methyl Benzoate)衍生物可促進Bmal、Period等時鐘基因之表現，從而完成本發明。
本發明之時鐘基因表現調節劑係以選自由氧化丁香烯、及具有下述結構式之化合物所組成之群中之1種以上作為有效成分，
(X為CH3、NH2或NHCH3)。
該等特定之化合物可調節時鐘基因之表現至今完全不為人知。
本發明之時鐘基因表現調節劑並無限定，係調節例如Bmal基因(Bmal1、Bmal2)、Period基因(Period1、Period2、Period3)、Clock基因、隱花色素(Cryptochrome)基因、白蛋白D位點結合蛋白質(Dbp，albumin site D-binding protein)基因、E4BP4基因、Npas2基因、Rev-erb基因之表現，其中調節生物時鐘之核心基因之Bmal、
Period、Clock及/或隱花色素基因、尤其是Bmal及Period基因之表現。
於本發明中，所謂基因表現調節，除促進基因之表現以外，亦包括調節基因之表現節律(相位或週期)。
本發明之晝夜節律調整劑含有上述時鐘基因表現調節劑。如上所述，時鐘基因可藉由直接或間接地控制生物器官之機能或與內分泌系相關之各種基因之晝夜表現，而調節作為生物時鐘之核心基因之Bmal、Period等時鐘基因之表現，從而調整由其控制之生物之各種行為節律或生理機能之晝夜節律。
本發明之時鐘基因表現調節劑可於醫藥、準藥品、化粧料、食品、雜貨、衣料等各種態樣中使用，可有效地調節時鐘基因之表現而改善由晝夜節律之不調引起之各種心身之症狀或疾病。
本發明之時鐘基因表現調節劑係以氧化丁香烯或上述苯甲酸甲酯(Methyl Benzoate)衍生物作為有效成分。該等化合物均為已知之化合物，以下簡單地進行說明。
氧化丁香烯((1R,4R,6R,10S)-4,12,12-三甲基-9-亞甲基-5-氧雜三環[8.2.0.04,6]十二烷)係分子量為220.35之無色液體或無色晶體，可藉由於乙酸鈉之存在下，使用過乙酸於0~5度下將丁香烯或異丁香烯環氧化而獲得。已知其於天然中存在於苦配巴油、丁香油(glove bud oil)、薰衣草油
等中。
又，本發明所使用之苯甲酸甲酯衍生物的2-甲基苯甲酸甲酯係分子量為150.18之無色液體。2-胺基苯甲酸甲酯係分子量為151.17之液體，可藉由於甲醇120份中添加鄰胺基苯甲酸80份，於40度以下緩慢添加濃硫酸100份，並於75~83度下結束反應，於回收甲醇後添加至碳酸鈉110份、水240份之溶液中進行中和並水洗後，藉由蒸餾進行純化而獲得。亦有由鄰硝基甲苯之合成法。已知在天然中存在於橙花、伊蘭花精油等中。已知2-甲胺基苯甲酸甲酯係分子量為165.2之無色液體，在天然中存在於橙子之果皮、紅橘油等中。
本發明之時鐘基因表現調節劑含有上述化合物之1種或2種以上。於本發明中，上述化合物可為源自天然者，亦可為合成者。
本發明之時鐘基因表現調節劑可單獨使用，亦可與其他具有時鐘基因之表現調節作用之藥劑組合使用。
進而，本發明之時鐘基因表現調節劑及晝夜節律調整劑可單獨使用該等，亦可包含於各種對象物中。根據其對象物之種類，除上述必須成分以外，亦可進而含有任意構成要素。
例如於對象物為皮膚外用劑之情形時，亦可根據其劑形(例如液劑、粉末劑、顆粒劑、氣溶膠劑、固形劑、凝膠劑、貼劑、栓劑等)，或製品形態(例如化粧料、醫藥品、準藥品等)，而一併含有通常此種皮膚外用劑中所含有之
任意成分與上述時鐘基因表現調節劑。皮膚外用劑之概念包括應用於皮膚(亦包括頭皮、頭髮、指甲)之全部組合物，例如包括基礎化粧料、彩粧化粧料、毛髮化粧料、皮膚或毛髮清洗料等化粧料，或軟膏劑、貼劑、栓劑、牙膏等各種醫藥品或準藥品等。其劑形亦無特別限定，例如包括水溶液系、可溶化系、乳化系、油液系、凝膠系、貼敷系、軟膏系、氣溶膠系、水-油雙層系、水-油-粉末三層等任意劑型。於皮膚外用劑為化粧料之情形時，例如可列舉：香水、淡香水、古龍水、乳霜、乳液類、化粧水、粉底類、蜜粉、口紅、肥皂、洗髮精/潤絲精類、沐浴乳、保濕沐浴乳、爽身粉類、浴劑類等。
又，本發明之時鐘基因表現調節劑亦可包含於例如芳香劑、除臭劑、香薰蠟燭、薰香、文具、錢包、包、鞋子等任意雜貨類，或例如內衣、西裝、帽子、長襪、短襪等任意衣類，或者例如散劑、顆粒、錠劑、膠囊劑等各種形態之補充品(營養補充食品)、點心、飲料等任意食品等中，又，亦可於吸入醫藥品或空間散佈劑之類的吸入製品中使用。
再者，雖然例示了本發明之時鐘基因表現調節劑之使用態樣，但並不限定於該等，只要可實現本發明之效果，則可以任意態樣使用。又，除本發明之時鐘基因表現調節劑以外，只要無損本發明之效果，則可根據具體態樣調配其他具有晝夜節律調整作用之藥劑。
對象物中之本發明之時鐘基因表現調節劑之調配量可根
據所使用之化合物之種類或形態、對象物等而適宜選擇，並無特別限定，例如相對於對象物之總質量，適宜為0.00001~100質量%，更適宜為0.0001~50質量%，進而適宜為0.0001~20質量%。
再者，本發明之時鐘基因表現調節劑或晝夜節律調整劑或調配有其之對象物之具體應用只要與晝夜節律之調整相關，則無特別限定。例如可應用於如下各症狀之預防、改善或治療等：時差症候群、輪班工作症候群、睡眠週期延遲症候群、非24小時睡-醒週期症候群、具有晝夜節律睡眠損傷之憂鬱狀態等，進而該等晝夜節律損傷所併發之失眠、身體機能不調、注意力缺乏、意志減退、皮膚粗糙等。
以下，列舉實施例具體地說明本發明，但本發明並不限定於下述實施例。再者，作為培養細胞，可使用皮膚纖維母細胞、上皮細胞、內皮細胞、色素細胞、脂肪細胞、神經細胞等各種細胞，本實施例係使用人類皮膚纖維母細胞進行評價。由於時鐘基因之核心系統於任一生物種及細胞種中為共通，故而認為於人類皮膚纖維母細胞中之評價結果亦可反映於其他生物種及細胞種。又，已知時鐘基因存在Brnal、Period、Clock、隱花色素、白蛋白D位點結合蛋白質(Dbp)、E4BP4、Npas2、Rev-erb等，但本實施例係測定與核心系統相關之Bmal及Period之表現作為代表例。再者，已知Bmal存在Bmal1及Bmal2，又，Period存在Per1、
Per2、Per3，認為相同基因簇會顯示相同之行為而分別以bmal1及Per1為代表例。下述實施例係測定人類Bmal1(hBmal1)及人類Per1(hPer1)之表現。又，下述所使用之試驗物質係使用所購買之市售品。
確認利用使用培養人類皮膚纖維母細胞之系，可誘導時鐘基因表現之晝夜節律。
培養人類皮膚纖維母細胞係購買正常成人皮膚由來纖維母細胞(Cell Application,Inc)而用於實驗。將該培養人類皮膚纖維母細胞接種至添加有10% FBS、20 mM之HEPES、Glutamax、抗菌劑之DMEM培養基中，於37℃、5% CO2下進行培養。於培養第6天，添加腎上腺皮質素50 ng/ml並處理2小時後，隨時間經過對細胞進行取樣。使用市售之RNA萃取試劑套組，自細胞萃取RNA，使用市售之PCR(Polymerase Chain Reaction，聚合酶鏈反應)引子(Perfect Real Time Primer，TAKARA BIO公司)，藉由RT-PCR法測定hBmal1及hPer1基因之表現量。又，同樣地，定量作為管家基因之RPLP0之表現量並算出目標基因相對於RPLP0之表現量的相對表現量。
一般認為，於生物體內腎上腺皮質素等糖皮質素與末梢組織等之生物時鐘之調節相關，早上起床時腎上腺皮質素之血中濃度上升而重設生物時鐘。於培養細胞中，通常各個細胞係於分散之時間點刻畫節律，但藉由利用如腎上腺
皮質素之類的訊號刺激因子進行刺激，可使時鐘基因表現節律同步而誘導晝夜節律。
將測定hBmal1及hPer1之結果示於圖2。確認藉由利用腎上腺皮質素進行刺激，該等均刻畫約24小時週期之晝夜節律而獲得表現。
由上述結果可見，於培養人類皮膚纖維母細胞評價系中，時鐘基因係藉由利用腎上腺皮質素之刺激而刻畫晝夜節律。由於期望於表現量較高之時間帶內之評價，故而hBmal1係將刺激之16小時後、hPer1係將刺激之2小時後之基因表現量作為指標，對試驗物質之時鐘基因表現調節效果進行評價。
藉由與上述相同之方法，接種源自正常成人皮膚之纖維母細胞(Cell Application,Inc)，於培養第6天以成為50 ppm之方式添加各藥劑，於2小時後及16小時後對細胞進行取樣。再者，作為對照，添加相同質量之乙醇代替試驗物質。使用市售之RNA萃取試劑套組，自細胞萃取RNA，使用市售之PCR引子(Perfect Real Time Primer，TAKARA BIO公司)，藉由RT-PCR法測定hBmal1及hPer1基因之表現量。又，相同地，定量作為管家基因之RPLP0之表現量並用作內部標準，算出目標基因相對於RPLP0之表現量之相對表現量。針對所獲得之值，進行Dunnett之多重比較檢定，與對照進行比較，將於單側5%之顯著水準下具有顯著差異者判定為有效。
圖3A表示添加試驗物質16小時後之hBmal1基因之相對表現量，圖3B表示添加試驗物質2小時後之hPer1基因之相對表現量。
又，將16小時後之hBmal1基因及2小時後之hPer1基因之相對表現量示於下述表1。
氧化丁香烯、2-甲基苯甲酸甲酯、2-甲胺基苯甲酸甲酯及胺基苯甲酸甲酯(Methyl anthranilate，鄰胺基苯甲酸甲酯)與對照相比顯著地同時提高hBmal1基因及hPer1基因之表現量，提示該等化合物可調節時鐘基因表現。
以下，揭示本發明之時鐘基因表現調節劑之調配例，但本發明之實施並不限定於以下內容。再者，以下調配量均以相對於製品總量之質量%表示。
於銅銨纖維素溶液(纖維素濃度10重量%、銨濃度7重量%、銅濃度3.6重量%)中，以相對於纖維素重量為0.1~20重量%之範圍內添加、混和內包有本發明之時鐘基因表現調節劑之微膠囊(粒徑50 μm以下，化合物於微膠囊中所佔之比率為50重量%)後，依據通常之濕式紡絲方法進行紡絲，經過精煉步驟、乾燥步驟，獲得芳香性纖維。
該等調配例之製品藉由各製品形態之典型使用態樣之使用試驗，可調節時鐘基因基因之表現而調整生物之晝夜節
律。
圖1係表示利用時鐘基因之晝夜節律產生系統之核心迴路部分的概略圖。
圖2係表示於培養人類皮膚纖維母細胞中利用腎上腺皮質素之時鐘基因表現之晝夜節律之誘導的圖表。
圖3A係表示於培養人類皮膚纖維母細胞中利用試驗物質之時鐘基因Bmal1之表現調節的圖表。
圖3B係表示於培養人類皮膚纖維母細胞中利用試驗物質之時鐘基因Per1之表現調節的圖表。
Claims (3)
- 一種氧化丁香烯之用途，其係用於製造時鐘基因表現促進劑。
- 如請求項1之用途，其中上述時鐘基因為Bmal或Period。
- 如請求項1或2之用途，其中上述時鐘基因表現調節劑係用於製造晝夜節律調整劑。
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| WO2019036870A1 (zh) * | 2017-08-21 | 2019-02-28 | 深圳市博奥康生物科技有限公司 | 一种人arntl基因高表达载体的构建方法及应用 |
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| JP2013184921A (ja) | 2013-09-19 |
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| US20140057979A1 (en) | 2014-02-27 |
| US20130237716A1 (en) | 2013-09-12 |
| TW201336492A (zh) | 2013-09-16 |
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