TW201834671A - 基因體穩定性增強劑 - Google Patents
基因體穩定性增強劑 Download PDFInfo
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- TW201834671A TW201834671A TW107108706A TW107108706A TW201834671A TW 201834671 A TW201834671 A TW 201834671A TW 107108706 A TW107108706 A TW 107108706A TW 107108706 A TW107108706 A TW 107108706A TW 201834671 A TW201834671 A TW 201834671A
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- royal jelly
- acid
- h2ax
- peptidase
- gnetin
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Abstract
本發明係提供一種基因體穩定性增強劑,其係含有選自酵素分解蜂王漿、買麻藤或其萃取物、及Gnetin C所成群中至少1種作為有效成分。
Description
本發明,係關於一種基因體穩定性增強劑。
大部分的正常細胞,一定次數的分裂後即停止增殖。靜止狀態的細胞,只要保持基因體穩定性,則可防止形質轉換。此靜止狀態,係在ARF/p53途徑的控制下,伴隨組織蛋白H2AX水平的降低而形成。同樣的增殖停止之細胞狀態,亦廣泛地被認為係構成正常保持恆定性之臟器的細胞。在H2AX水平降低之狀態,於細胞停止增殖的同時,造成DNA損傷的修復能力降低的狀態。因此,在增殖停止之細胞中,伴隨過剩的增殖刺激引起的DNA複製壓力誘導基因體不穩定性。另一方面,此種細胞,具有伴隨H2AX暫態誘導之修復能力之活化機制。
組織蛋白H2AX對DNA損傷修復因子的損傷部位之定位係重要的。若DNA發生雙股斷裂,其周邊的H2AX會被磷酸化。許多的DNA損傷修復因子,藉由與此被磷酸化的H2AX(稱作γ-H2AX)相互作用而定位於損傷部位。因此,藉由以免疫染色等檢測γ-H2AX,可作為DNA損傷的標記使用。
例如,非專利文獻1及2中,為了調查對白藜蘆醇類的癌 細胞之有效性,藉由檢測γ-H2AX來確認白藜蘆醇類誘導DNA損傷。生成癌細胞的DNA損傷之結果,即可得到細胞凋亡之誘導效果。
因此,非專利文獻1及2中記載被磷酸化之H2AX的檢測,並沒有探討H2AX自身的表現量。如前述,藉由使H2AX暫態誘導,活化DNA的修復能力並可增加基因體穩定性。
非專利文獻3中,揭露了以白藜蘆醇及蜂王漿的處理發現「增殖停止之正常細胞」中「伴隨H2AX暫態表現之DNA修復」。
非專利文獻4中,揭露了DNA修復相關的Factor X係藉由白藜蘆醇而暫態誘導。
亦有揭露富含蜂王漿及白藜蘆醇誘導體之倪藤,奏效於抗癌作用、抗老化作用、壽命延長作用等。(專利文獻1、2、及非專利文獻5-8)。
此外,基因修復機制之突變引起的疾病之色素性乾皮症、亨汀頓氏舞蹈症(Huntington's disease)、維爾納氏症候群(Werner syndrome)、布隆氏症候群(Bloom syndrome)、林奇氏症候群(Lynch syndrome)等,未發現有效的治療方法。
【專利文獻1】日本專利第5923699號公報
【專利文獻2】日本專利第5979810號公報
【非專利文獻1】Carsinogenesis (2011) 32(1):93-101
【非專利文獻2】Ann Hematol (2011) 90:173-183
【非專利文獻3】吉岡 研一,23-C-10致癌誘導壓力為起因,連動誘發「基因體不穩定性‧突變‧細胞形質轉換」的分子機制研究,網站<http://crdb.ncc.go.jp/search/DRTV050.action?rpno=012013007100000>
【非專利文獻4】吉岡 研一、白川 仁,根據營養成分預防癌化‧老化效果及基因體穩定性控制機制之研究,網站<http://www.mishima-kaiun.or.jp/assist/docs/SJNo2-yoshioka,.pdf>
【非專利文獻5】日本藥理學雜誌(Folia pharmacol.Japon.)(1987) 89:73-80
【非專利文獻6】Cancer Medicine (2015) 4(11):1767-1780
【非專利文獻7】PLoS One (2011) 6(8):e23527
【非專利文獻8】Bioscience, Biotechnology, and Biochemistry (2015) 79(12):2044-2049
本發明之目的係提供一種基因體穩定性增強劑,其具有優異的基因體穩定性之增強作用。
本發明者們為了達成上述目的而反覆深入研究之結果,得到酵素分解蜂王漿誘導H2AX之作用比未酵素分解蜂王漿更高,並且,倪藤種子萃取物及Gnetin C誘導H2AX之作用比反式白藜蘆醇更高之知識。
本發明,係基於此等知識,更進一步反覆探討而完成,從而提供以下之基因體穩定性增強劑。
項1.一種基因體穩定性增強劑,其特徵係含有選自酵素分解蜂王漿、買麻藤或是其萃取物、及Gnetin C所成群中至少1種作為有效成分。
項2.如項1所記載之基因體穩定性增強劑,其中,其係化妝品、飲食品、醫藥品、或醫藥部外品。
項3.一種使基因體穩定性增強之方法,其特徵係包含選自酵素分解蜂王漿、買麻藤或其萃取物、及Gnetin C所成群中至少1種之有效量對於哺乳動物投餵之步驟。
項4.一種使用,其特徵係在基因體穩定性增強劑之製造中,使用選自酵素分解蜂王漿、買麻藤或其萃取物、及Gnetin C所成群中至少1種。
項5.如項4所記載之使用,其中,前述基因體穩定性增強劑係化妝品、飲食品、醫藥品、或醫藥部外品。
項6.一種基因體穩定性增強用組成物,其特徵係含有選自酵素分解蜂王漿、買麻藤或是其萃取物、及Gnetin C所成群中至少1種作為有效成分。
項7.如項6所記載之基因體穩定性增強用組成物,其中,其係化妝品、飲食品、醫藥品、或醫藥部外品。
酵素分解蜂王漿、買麻藤或是其萃取物、及Gnetin C具有優異的H2AX表現誘導作用,因此作為基因體穩定性增強劑的有效成分係有用的。
本發明的基因體穩定性增強劑具有優異的基因體穩定性增強作用,因此期待與基因體不穩定(基因修復機制之異常)關連的疾病:色素性乾皮症、亨汀頓氏舞蹈症、維爾納氏症候群、布隆氏症候群、林奇氏症候群等的發病預防及症狀減輕之效果。
【圖1】表示試驗例1中,就H2AX表現之西方墨點法解析之結果之照片(上),及表示H2AX表現量(相對值)之圖表(下)。左:未處理蜂王漿,右:酵素分解蜂王漿。
【圖2】表示試驗例2中,就H2AX表現之西方墨點法解析之結果之照片(上),及表示H2AX表現量(相對值)之圖表(下)。左:反式白藜蘆醇,右:倪藤。
【圖3】表示試驗例3中,就H2AX表現之西方墨點法解析之結果之照片(上),及表示H2AX表現量(相對值)之圖表(下)。左:反式白藜蘆醇,中:倪藤,右:Gnetin C。
【圖4】表示試驗例4中,Msh2之同型合子及異型合子基因剔除小鼠之生存率之圖表。◆:Msh2(-/-)一般的飼料n=11,■:Msh2(-/-)添加 0.3%倪藤種子萃取物的飼料n=8,▲:Msh2(+/-)一般的飼料n=10,×:Msh2(+/-)添加0.3%倪藤種子萃取物的飼料n=10
【圖5】表示試驗例5中,於Msh2之基因剔除小鼠的腸管形成的腫瘤數之圖表。+:倪藤種子萃取物投餵群,-:對照群。
以下,詳細說明本發明。
又,本說明書中「包含、含有(comprise)」,亦包含「本質上由...組成(essentially consist of)」之意義,及「由...組成(consist of)」之意義。
本發明的基因體穩定性增強劑,其特徵係含有選自酵素分解蜂王漿、買麻藤或其萃取物、及Gnetin C所成群中至少1種作為有效成分。
蜂王漿,係混合蜜蜂中日齡3~12天之工蜂由下咽頭腺及大顎腺所分泌之分泌物而製成之乳白色的膠狀物質。蜂王漿中主要的生理活性成分,列舉例如:以蜂王漿所特有之10-羥基癸烯酸(以下,以「癸烯酸」記載)等之有機酸類為首、蛋白質、脂質、醣類、維生素B群、葉酸、菸鹼酸、泛酸等之維生素類、各種礦物質類等。此蜂王漿之生理活性及藥理作用,已知有抗菌作用、免疫增強作用、抗抑鬱作用、抗腫瘤作用、抗炎症作用、血流量增加作用等。此外,亦據悉可降低抗癌劑之副作用及放射線傷害時之延命效果。
酵素分解蜂王漿之製造所使用之蜂王漿,無特別限制,可 使用:生蜂王漿、乾燥生蜂王漿並粉末化之蜂王漿粉末、或藉由水或含水乙醇等萃取生蜂王漿等。
蜂王漿之產地,無特別限制,可為日本、中國、巴西、歐洲各國、大洋洲各國、美國等之任一者。
本發明作為對象之酵素分解蜂王漿,係以蛋白質分解酵素處理蜂王漿者。理想為低過敏原化酵素分解蜂王漿,其係藉由肽酶處理抑制起因於蜂王漿所含有之蛋白質導致的過敏反應。因此,本發明之酵素分解蜂王漿,除了蜂王漿中所含有之蛋白質的肽酶分解物之外,亦可包含前述癸烯酸等之有機酸類、脂質、醣類、維生素類、及各種礦物質類。
用於將蜂王漿酵素分解之酵素,可適當列舉肽酶。所使用之肽酶,若具有內肽酶作用及外肽酶作用之至少一種即可,但至少具有內肽酶作用者為佳,具有此等兩種之作用者更佳。
本發明之酵素分解蜂王漿,理想為水解蜂王漿所含有之蛋白質從而低過敏原化者。因此,使用至少具有內肽酶作用之肽酶(內肽酶),較佳係使用具有內肽酶作用及外肽酶作用之兩者的肽酶,水解蜂王漿為佳。於此,具有內肽酶作用及外肽酶作用之兩者的肽酶,可單獨使用同時具有此等兩種作用之肽酶,又,亦可組合使用具有內肽酶作用之肽酶(內肽酶)及具有外肽酶作用之肽酶(外肽酶)。
可用於本發明之內肽酶,只要係至少具有內肽酶活性之蛋白質分解酵素,即可為任何東西。可廣泛例示如:動物來源(例如:胰蛋白酶、胰凝乳蛋白酶等)、植物來源(例如:木瓜蛋白酶等)、或微生物來源(例如:乳酸菌、酵母菌、黴菌、枯草桿菌、放線菌等)之內肽酶。
外肽酶,只要係至少具有外肽酶活性之蛋白質分解酵素,即可為任何東西。可例示如:羧肽酶、胺肽酶、或微生物來源(例如:乳酸菌、麴黴屬菌、根黴屬菌等)之外肽酶、或亦兼具內肽酶活性之胰酶、胃蛋白酶等。
然而於肽酶中,存在實質上僅具有外肽酶作用之外肽酶、實質上僅具有內肽酶作用之內肽酶、以及具有外肽酶作用及內肽酶作用之兩者的肽酶。此等之中,具有外肽酶作用及內肽酶作用之兩者的酵素,在內肽酶作用強大時,可作為「內肽酶」使用;在外肽酶作用強大時,可作為「外肽酶」使用;在外肽酶作用與內肽酶作用相等或幾乎相等時,可作為同時具有內肽酶作用及外肽酶作用之肽酶使用。
此種肽酶之中,具有外肽酶作用之酵素之佳例,可列舉例如:米麴菌(Aspergillus orizae)產生肽酶(商品名:Umamizyme G、Promod 192P、Promod 194P、Sumizyme FLAP)、醬油麴黴菌(Aspergillus sojae)產生肽酶(商品名:Sternzyme B15024)、麴黴屬產生肽酶(商品名:Kokulase P)、米根黴菌(Rhizopus oryzae)產生肽酶(商品名:Peptidase R)等。
此外,具有內肽酶作用之肽酶之佳例,可列舉例如:枯草桿菌(Bacillus subtilis)產生肽酶(商品名:Orientase 22BF、Nukureishin)、地衣芽孢桿菌(Bacillus licheniformis)產生肽酶(商品名:Alcalase)、嗜熱脂肪芽孢桿菌(Bacillus stearothermophilus)產生肽酶(商品名:Protease S)、液化澱粉芽孢桿菌(Bacillus amyloliquefaciens)產生肽酶(商品名:Neutrase)、芽孢桿菌屬產生肽酶(商品名:Protamex)等。
進一步,具有外肽酶作用及內肽酶作用之兩者的肽酶,特 別係鹼性肽酶之佳例,可列舉例如:灰色鏈黴菌(Streptomyces griseus)產生肽酶(商品名:Actinase AS)、米麴菌(Aspergillus orizae)產生肽酶(商品名:Protease A、Flavourzyme)、蜂蜜黴菌(Aspergillus melleus)產生肽酶(商品名:Protease P)等。根據使用此等肽酶之酵素處理,具有下述優點:以一階段酵素處理可將蛋白質低分子化,故操作簡便之同時,亦可防止蜂王漿所含有之有用成分之生理活性的消失及大幅降低。
對於蜂王漿之肽酶的使用量,根據使用蜂王漿濃度、酵素滴定度、反應溫度及反應時間各有差異,但一般來說,肽酶以蜂王漿所含有之蛋白質每1克50~10000作用單位之比例使用為佳。又,此時,向蜂王漿內添加肽酶,可一次添加,亦可分成少量添加。
肽酶處理時蜂王漿之pH值,對應於使用酵素之最佳pH值,係pH2~12,較佳係pH7.5~10,更佳係選自pH7.8~9之範圍。具體而言,於前述蜂王漿內添加肽酶前,根據使用酵素之種類,透過酸、鹼劑、或緩衝劑之添加可調整期望之pH值,使其為pH2~12,較佳係pH7.5~10,更佳係pH7.8~9之範圍內。此種情形,可各別例示,如酸:鹽酸、硫酸、硝酸、磷酸、醋酸等;鹼劑:氫氧化鈉、氫氧化鉀、碳酸鉀等;此外,緩衝劑:磷酸緩衝劑、檸檬酸緩衝劑等。
肽酶處理之溫度,無特別限制,可提供實用之範圍,包含肽酶作用,較佳係內肽酶作用,更佳係出現內肽酶作用及外肽酶作用之兩種作用之最佳溫度範圍,亦即,通常選自30~70℃之範圍。溫度比肽酶之最佳溫度(約40~50℃為佳)低溫或高溫,例如,藉由維持在50~60℃之範圍,可防止於肽酶處理步驟中之腐敗。肽酶處理之時間,係取決於使用酵 素之種類、及反應溫度、pH值等之反應條件,並無特別限定。
又,蜂王漿,係以原樣、或係溶解於水或分散之狀態,可提供蛋白質分解酵素處理。此等為乾燥形態之情形,以溶解於水之狀態可提供蛋白質分解酵素處理為佳。
肽酶處理之停止,係藉由去活化或除去肽酶來進行。去活化操作係可藉由加熱處理(例如,於85℃下15分鐘等)來進行。
本發明中酵素分解蜂王漿,只要係至少如前述以肽酶處理後之蜂王漿即可,不只肽酶處理,亦包含與其他酵素組合處理,例如,肽酶處理與醣分解酵素處理後之蜂王漿。
本發明中酵素分解蜂王漿,亦可使用將酵素分解後之蜂王漿乾燥及粉末化者。乾燥方法,可使用一般食品加工所採用之習知的方法,如:通風乾燥、陽光乾燥等之自然乾燥;透過電等加熱乾燥之強制乾燥、流動層乾燥、噴霧乾燥、高頻乾燥、冷凍乾燥等,較佳係冷凍乾燥。為了粉末化之粉碎方法,可使用習知的方法進行,如:使用粉碎機(輾磨機)(例如:針磨機、錘磨機、球磨機、噴射磨機、輥磨機、膠體磨機等)粉碎之方法等。
買麻藤(別名倪藤,學名Gnetum gnemon L.,英文名Gnemon tree,印度尼西亞名Melinjo、Belinjo)係買麻藤科的植物,於東南亞栽培。
本發明中,買麻藤的使用部位無特別限制,可列舉果實(或種子)、花、葉等,較佳為種子。又,買麻藤亦可使用加工物,其加工方式可列舉乾燥、加熱乾燥、切斷、粉碎等。
本說明書中,所謂買麻藤種子係指由種皮、薄皮、及胚/胚乳(內乳)所成者。買麻藤種子的形狀及形態,只要可得到本發明之效果,皆可使用任何形狀及形態,以長徑:約1.3~2.3cm、短徑:約0.6~1.3cm,花生狀之形狀者為佳。買麻藤種子,只要包含買麻藤種子之形態者,即可於本發明使用,可列舉例如,買麻藤種子上具有果皮之形態之買麻藤果實。
本發明之買麻藤種子,亦包含加工物,此種買麻藤種子之加工物,可列舉:(藉由陽光曬乾等)乾燥狀態者、加熱乾燥狀態者等。又,買麻藤種子,可使用未經切斷及粉碎之保持原形的狀態者,以及經切片及粉碎之買麻藤種子之加工物。本發明中,亦可使用買麻藤種子的胚/胚乳(內乳)、或僅有種皮的買麻藤種子之加工物。
本發明中,理想係使用買麻藤種子之萃取物,此萃取物之製造方法,無特別限制,例如:可使用藉由將買麻藤種子浸漬於浸漬液之萃取方法(例如:日本特開2013-82701號公報所記載之方法)等來進行。
上述浸漬液,可使用水、有機溶劑或含水有機溶劑。有機溶劑,可與水自由地混合者為佳,其可列舉:甲醇、乙醇、1-丙醇、2-丙醇、1-丁醇、2-丁醇、2-甲基-1-丙醇、2-甲基-2-丙醇、1-戊醇、2-戊醇、3-戊醇等之碳數1~5之低級醇;二乙醚等醚類;乙酸甲酯、乙酸乙酯等酯類;丙酮等酮類;醋酸、冰醋酸、丙酸等有機酸。有機溶劑以低級醇為佳。
進行浸漬時浸漬液的溫度,根據買麻藤種子及浸漬液的量等而可適宜設定,例如:10~50℃,較佳為20~40℃。進行浸漬的時間, 根據買麻藤種子及浸漬液的量等而可適宜設定,較佳為3日以上,更佳為3日~7日。
回收之浸漬液,可以直接使用,亦可依照需求,藉由超濾、分子篩層析法(凝膠過濾)、吸附層析法、離子交換層析法、親和層析法、高效液相層析法(HPLC)、透析法、此等組合等進行精煉。
買麻藤種子之萃取物,亦可採取固形物之任何狀態,其係除去回收之浸漬液(包含視需要進一步精煉者)、濃縮該浸漬液之濃縮液、及藉由進行冷凍乾燥、噴霧乾燥等之該浸漬液之溶劑。於此,浸漬液的濃縮、冷凍乾燥及噴霧乾燥可依據常法進行。本發明的買麻藤種子之萃取物之形態,以粉末狀為佳。
Gnetin C為下述化學式所示之多酚的一種。
Gnetin C,係不論自製品或市售品皆可使用。於此自製Gnetin C之方法,無特別限制,可列舉從含Gnetin C之植物萃取之方法、使微生物產生之方法(例如參照Adil E Bala et al.,“Antifungal activity of resveratrol oligomers from Cyphostemma crotalarioides”,Pesticide Science,Vol.55,Issue 2,Pages 206-208等)、及化學合成方法。
含Gnetin C之植物,無特別限制,較佳可列舉屬於買麻藤 科之植物(Ibrahim Iliya et al.,“Stilbenoids from the stem of Gnetum latifolium(Gnetaceae)”,Phytochemistry,2002 Dec;61(8):959-61;Ibrahim Iliya et al.,“Dimeric Stilbenes from Stem Lianas of Gnetum Africanum”,HeteroCycles,VOL.57;NO.6;PAGE.1057-1062(2002))。
具體來說,可例示為屬於買麻藤科之Gnetum latifolium、Gnetum Africanum及Gnetum gnemon(買麻藤),而以買麻藤為佳。關於所使用植物之部位只要係包含許多Gnetin C之部位,無特別限制為果實(或是種子)、花、葉等部位,而以果實(或是種子)為佳,果實之胚乳更佳。
於此從植物萃取Gnetin C之情形,其方法無特別限制,例如,前述之萃取方法可使用日本特開2013-82701號公報記載之萃取方法等。Gnetin C可使用未經分離或精煉之狀態者(粗萃取物),及經離析或精煉者任一種。精煉方法可使用前述之方法。
又,精煉不需要進行到純度100%。本發明所使用之Gnetin C,純度一般為50質量%以上即可,而以80質量%以上為佳,90質量%以上更佳。
此外,用微生物產生Gnetin C之情形,或藉由化學合成取得之情形,以實施與上述同樣的精煉處理為佳。
本發明之Gnetin C,包含游離狀態或鹽之狀態二種。鹽可列舉例如鈉鹽、鉀鹽、鎂鹽、鈣鹽、鋁鹽等之無機鹼之鹽;甲胺、乙胺、乙醇胺等之有機鹼之鹽;離胺酸、鳥胺酸、精胺酸等之鹼性胺基酸之鹽及銨鹽。該鹽亦可為酸加成鹽,相關之鹽可具體列舉鹽酸、氫溴酸、氫碘酸、硫酸、硝酸、磷酸等之礦酸;甲酸、醋酸、丙酸、草酸、丙二酸、琥 珀酸、富馬酸、馬來酸、乳酸、蘋果酸、酒石酸、檸檬酸、甲磺酸、乙磺酸等之有機酸;天門冬胺酸、麩胺酸等之酸性胺基酸之酸加成鹽。此外,本發明之Gnetin C亦包括其水合物、溶劑化物、多晶型等。
本發明之基因體穩定性增強劑中之酵素處理蜂王漿之含量,無特別限制,而以0.01質量%或w/v%以上為佳,以1.4~100質量%或w/v%更佳,以30~65質量%或w/v%進一步更佳。
本發明之基因體穩定性增強劑中之買麻藤或其萃取物之含量,無特別限制,而以0.01質量%或w/v%以上為佳,以0.03~100質量%或w/v%更佳,以30~65質量%或w/v%進一步更佳。
本發明之基因體穩定性增強劑中之Gnetin C之含量,無特別限制,而以0.001質量%或w/v%以上為佳,以0.01~100質量%或w/v%更佳,以1~40質量%或w/v%進一步更佳。
本發明之基因體穩定性增強劑,其意義包含:化妝品、飲食品(特別係以保健、維持健康、增進等為目的之飲食品(例如:健康食品、機能性食品、營養組成物(nutritional composition)、營養補助食品、補充劑、保健用食品、特定保健用食品、營養機能食品、機能性表現食品))、醫藥部外品及醫藥品(特別係口服藥物)。此外,本發明之基因體穩定性增強劑,其意義亦包含:賦予基因體穩定性增強作用之添加劑。
上述之化妝品,除了上述之有效成分以外,因應必要可適當配合一般化妝品所使用之成分,例如:美白劑、保濕劑、抗氧化劑、油性成分、紫外線吸收劑、界面活性劑、增稠劑、酒精類、粉末成分、色材、水性成分、水、各種皮膚營養劑等。
化妝品,即包含所有適用於動物(包括人類)的皮膚、黏膜、體毛、頭髮、頭皮、指甲、牙齒、臉皮、嘴唇等之化妝品。
化妝品之劑型,可採用廣泛之劑型,如水溶液系、可溶化系、乳化系、粉末系、油液系、凝膠系、軟膏系、噴霧系、水-油雙層系、水-油-粉末3層系等。
化妝品之用途為任意,例如,若為基礎化妝品,可列舉:洗面乳、化妝水、乳液、乳霜、凝膠、精華液、美容液、泥膜、面膜等;若為彩妝化妝品,可列舉:粉底、口紅、腮紅、眼影、眼線、睫毛膏等;若為指甲化妝料,可列舉:指甲油、底層護甲油、表層護甲油、去光水等;其他,可列舉:洗面乳、(膏狀或液體)牙膏、漱口水、按摩用劑、清潔用劑、鬚後水、鬚前水、剃鬚膏、沐浴露、肥皂、洗髮精、潤絲精、護髮乳、頭髮造型品、養髮劑、生髮劑、止汗劑、入浴劑等。
上述之飲食品,除了上述之有效成分之外,因應必要可配合如:賦形劑、光澤劑、礦物質類、維生素類、黃酮類、醌類、多酚類、胺基酸、核酸、必需脂肪酸、清涼劑、黏合劑、甜味劑、崩解劑、潤滑劑、著色劑、香料、穩定劑、防腐劑、緩釋調整劑、界面活性劑、溶解劑、潤濕劑等。
飲食品,即包含所有為動物(包括人類)可攝取之飲食品。飲食品之種類,無特別限制,可列舉例如:飲料類(如咖啡、果汁、茶飲料之清涼飲料、含乳飲料、乳酸菌飲料、優格飲料、碳酸飲料、如日本酒、洋酒、水果酒之酒等);抹醬類(卡士達醬等);糊膏類(水果糊等);西點類(巧克力、甜甜圈、餡餅、泡芙、口香糖、果凍、糖果、餅乾、蛋糕、布丁 等);日式糕點(大福、麻糬、日式饅頭、卡斯特拉、餡蜜、羊羹等);冰點心類(冰淇淋、冰棒、雪酪等);食品類(咖哩、牛丼、雜燴粥、味噌湯、湯、肉醬、義大利麵、漬物、果醬等);調味料類(沙拉醬、香鬆、增味劑、湯塊等)等。
關於使用補充劑時之劑量單位形式並無特別限定,可適宜選擇,可列舉例如:錠劑(例如素錠、糖衣錠、膜衣錠、咀嚼錠、口服錠等)、膠囊劑、顆粒劑、液劑、散劑、糖漿、糊膏、飲劑等。
飲食品之攝取量,係可因應攝取者之體重、年齡、性別、症狀等各種條件而適當設定。
上述之醫藥品,可僅使用上述之有效成分,亦可與維生素、生藥等日本藥典記載之其他醫藥成分混合使用。
本發明之基因體穩定性增強劑,作為醫藥品調製之情形,可將上述之有效成分與醫藥品中容許之無毒性載體、稀釋劑或賦形劑,一同調製片劑(包括素錠、糖衣錠、發泡錠、膜衣錠、咀嚼錠、口服劑等)、膠囊劑、丸劑、粉末劑(散劑)、細粒劑、顆粒劑、液劑、懸濁液、乳濁液、糖漿、糊膏等之型態,成為可口服之製劑。
醫藥品之劑量,係可因應患者之體重、年齡、性別、症狀等各種條件而適當決定。
此外,本發明之醫藥品及化妝品,亦包含醫藥部外品在內。
以上說明的本發明之基因體穩定性增強劑,係適用於包括人類之哺乳動物者。
本發明之基因體穩定性增強劑含有有效成分之酵素分解蜂王漿、買麻藤或其萃取物、及Gnetin C,係如後述實施例所示,與未酵素分解蜂王漿及反式白藜蘆醇相比,誘導H2AX作用較高。因此,本發明之基因體穩定性增強劑,具有優異的H2AX表現誘導作用,而可以預想於優異的基因體穩定性增強作用奏效。
本發明的基因體穩定性增強劑具有優異的基因體穩定性增強作用,因此為了預防基因體不穩定(基因修復機制之異常)關連的疾病:色素性乾皮症、亨汀頓氏舞蹈症、維爾納氏症候群、布隆氏症候群、林奇氏症候群(遺傳性非瘜肉大腸癌)等的發病、症狀減輕及治療而可適當使用。
以下,藉由實施例進一步詳細說明本發明。惟,本發明並非限定為此等實施例。
材料
蜂王漿之酵素分解物,係根據日本專利第3994120號公報之實施例1調製。為使酵素分解蜂王漿及蜂王漿之冷凍乾燥粉末之最終濃度達到100μg/mL,將其溶解於添加10% FBS之α-MEM培養基,並過濾滅菌。
倪藤種子萃取物,係根據日本特開2009-013123號公報之段落[0024]之記載,將倪藤的乾燥果實之破碎物於室溫下浸漬於含水乙醇,將所得之萃取液減壓濃縮,得到含63.2質量%固形物成分之倪藤種子萃取物。
Gnetin C,係將上述所得之倪藤種子萃取物2.5g以管柱層析法(凝膠的種類:Cosmosil 75C18-PREP(Nacalai Tesque公司製)、管柱尺寸:φ3×26.5cm),使用甲醇含量為10容量%、25容量%、40容量%、80容量%及100容量%之含水甲醇作為沖提液,依次逐步溶出(流出各沖提液600mL、每100mL分取)。所得之各成分以下述條件之HPLC確認後,確認出Gnetin C係以滯留時間33.5分(1容量%醋酸及含有80容量%甲醇之含水甲醇溶出分離物)溶出。
<HPLC條件>
管柱:東曹(TOSOH)製TSKgel ODS-100V、5μm、4.6×150mm移動相:A液:含有1.0容量%醋酸之水、B液:含有1.0容量%醋酸之甲醇
梯度條件:0分→10分:A:B=65:35(v/v)→63:37(v/v)、10分→20分:A:B=63:37(v/v)→56:44(v/v)、20分→40分:A:B=48:52(v/v)
檢測波長:320nm
流速:0.8mL/min
將上述分離物濃縮後,以下述條件之中壓管柱層析法依次溶出。
<中壓管柱層析法條件>
凝膠種類:矽膠、Daisogel IR-60-40/63-W
管柱尺寸:φ2×7.48cm
檢測波長:320nm
移動相:A液:甲醇、B液:氯仿
梯度條件:0分→2分:A:B=11:89(v/v)、2分→8分:A:B=11:89(v/v)→18:82(v/v)、8分→12分:A:B=18:82(v/v)、12分→14分:A:B=21:79(v/v)、14分→20分:A:B=21:79(v/v)→29:71(v/v)、20分→24分:A:B=29:71(v/v)、24分→30分:A:B=29:71(v/v)→36:64(v/v)、30分→34分:36:64(v/v)
流速:60ml/min
溶出液以各60mL分裝,將檢測波長:320nm顯示之第29支至第30支吸收波峰之分離物以蒸餾器濃縮,從而獲得Gnetin C(35.2mg、純度97%)。
反式白藜蘆醇係由Sigma-Aldrich公司取得。
試驗例1
正常細胞之增殖停止係因伴隨H2AX(向DNA損傷修復因子群之DNA損傷部位之聚集誘導為必須)水平之降低而誘導,同時DNA修復能力亦降低。基因體不穩定性,在此背景下增殖刺激所引起之誘導變得明確。於是,解析了酵素分解蜂王漿(酵素處理RJ)及蜂王漿(未處理RJ)之對H2AX表現的影響。
將MEF(mouse embryo fibroblast)細胞於含有添加25μg/ml之酵素處理RJ或未處理RJ之10% FCS(fetal calf serum)的DMEM培養基中,在37℃、5% CO2條件下,以3T3法培養。回收培養0、3、6、12、24小時之細胞,用H2AX抗體(Bethyl Laboratories,Inc.)及β-actin抗體(AC-74,Sigma-Aldrich)進行西方墨點法解析。
西方墨點法解析之結果,及使用ImageJ(Rasband,W.S., ImageJ,U.S.National Institutes of Health,Bethesda,Maryland,USA,http://imagej.nih.gov/ij/,1997-2016.)將西方墨點法解析之結果數值化之圖表如圖1所示。酵素分解RJ及未處理RJ處理,皆發現H2AX暫態表現之誘導。條帶8比起條帶2,H2AX表現量為2.1倍量。此結果顯示,酵素分解RJ之H2AX的暫態表現誘導能力為未處理RJ之2.1倍量。
試驗例2
使用與試驗1相同方法,解析倪藤及反式白藜蘆醇之對H2AX表現之影響。又,本次為添加0.26、0.52、1.0、2.1w/v%之倪藤種子萃取物或反式白藜蘆醇至培養基,回收培養1小時之細胞。
西方墨點法解析之結果,及將西方墨點法解析之結果數值化之圖表如圖2所示。其結果,倪藤及反式白藜蘆醇,皆發現H2AX暫態表現之誘導。條帶9比起條帶4,H2AX表現量為2.7倍量。此結果顯示,倪藤之H2AX的暫態表現誘導能力為反式白藜蘆醇之2.7倍。
試驗例3
使用與試驗1相同方法,解析反式白藜蘆醇、倪藤及Gnetin C之對H2AX表現之影響。又,本次為添加2.5μM(0.52μg/ml)之反式白藜蘆醇、0.52μg/ml之倪藤種子萃取物、或2.5μM之Gnetin C至培養基,回收培養0、1.5、3、6、12、24小時之細胞。
西方墨點法解析之結果,及使用ImageJ(Rasband,W.S.,ImageJ,U.S.National Institutes of Health,Bethesda,Maryland,USA,http://imagej.nih.gov/ij/,1997-2016.)將西方墨點法解析之結果數值化之圖表如圖3所示。其結果,反式白藜蘆醇、倪藤及Gnetin C,皆發現H2AX暫 態表現之誘導。倪藤(條帶4)及Gnetin C(條帶4)之H2AX的表現量分別比反式白藜蘆醇(條帶3)高1.9倍、1.8倍。此結果顯示,倪藤及Gnetin C之H2AX的暫態表現誘導能力為反式白藜蘆醇之1.9倍、1.8倍。
試驗例4
為了檢證倪藤對生物體之基因體穩定性增強效果,使用欠缺錯配修復因子之Msh2-KO小鼠{產生基因體不穩定性之一類之微衛星不穩定性(MSI)的林奇氏症候群模型}進行實驗。已知此小鼠從月齡10個月左右開始,經過大約半年左右之期間即會死去。
結果由圖4所示。比較投餵有H2AX之暫態表現誘導能力之倪藤種子萃取物0.3質量%(360mg/kg體重/日)群(■)及給予一般飼料群(◆)之結果,相對於食用一般飼料群,半數以上經過20週即死亡,食用含有倪藤種子萃取物之飼料群,此期間無確認到小鼠死亡。
此為明確顯示基因修復機能之低下時,藉由具有H2AX暫態表現之誘導活性之「基因體穩定性增強劑」會出現「延長壽命之效果」。
試驗例5
檢證倪藤的攝取是否會發揮預防的效果。投餵8-12週齡之Msh2-KO小鼠0.03w/v%的倪藤種子萃取物(36mg/kg體重/日)群,或對於對照群之投餵滅菌水之小鼠給予含有致癌劑之溴酸鉀(0.02%)之水或飲料水。24週後,計算腸管內形成之腫瘤數,比較倪藤群及對照群。欠缺錯配修復因子之Msh2-KO小鼠易生成基因體不穩定,且藉由化學致癌物質之BrKO3容易於消化管中形成腫瘤。
結果如圖5所示。投餵倪藤種子萃取物群,觀察到抑制明確的致癌等級之效果。此現象顯示,即使是易生成基因體不穩定性之體質,藉由預防性攝取倪藤種子萃取物,可防止癌症發病。
Claims (2)
- 一種基因體穩定性增強劑,其特徵係含有選自酵素分解蜂王漿、買麻藤或是其萃取物、及Gnetin C所成群中至少1種作為有效成分。
- 如申請專利範圍第1項所記載之基因體穩定性增強劑,其中,其係化妝品、飲食品、醫藥品、或醫藥部外品。
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