TW202143863A - 更年期症狀改善劑 - Google Patents
更年期症狀改善劑 Download PDFInfo
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- TW202143863A TW202143863A TW110113743A TW110113743A TW202143863A TW 202143863 A TW202143863 A TW 202143863A TW 110113743 A TW110113743 A TW 110113743A TW 110113743 A TW110113743 A TW 110113743A TW 202143863 A TW202143863 A TW 202143863A
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- Taiwan
- Prior art keywords
- rutinoside
- delphinidin
- cyanidin
- black currant
- symptoms
- Prior art date
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Abstract
本發明提供一種對更年期症狀之改善有用之更年期症狀改善劑。
本發明係一種更年期症狀改善劑,其以飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合作為有效成分。
Description
本發明係關於一種更年期症狀改善劑。
於女性更年期,作為不定主訴,出現全身倦怠感、頭暈、頭痛、失眠、上火、發熱、出汗、心悸、噁心、腹瀉、肩部酸痛、腰痛、頻尿等多種軀體主訴。其中,潮熱(上火、發熱)、出汗為更年期之特徵性症狀,可見於許多女性。
認為更年期之症狀係由隨著年齡增長而女性激素(雌激素)之分泌降低所引起的。因此,針對更年期症狀之一般性治療方法為激素補充療法(HRT)。於HRT中,投予雌激素或者雌激素與黃體素。
然而,據說更年期症狀不僅與雌激素之減少有關,而且與起因於工作或家庭環境等之社會、心理因素有著複雜聯繫。又,HRT被指出有增加乳腺癌或子宮內膜癌之發病率等負面作用,正在尋求更安全地改善更年期之不定主訴。
另一方面,黑醋栗(學名:Ribes nigrum)亦稱為黑穗醋栗、黑加侖,係分類為虎耳草科醋栗屬之植物,富含4種花青苷。黑醋栗花青苷中作為芸香糖苷體之飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷係黑醋栗花青苷之特徵性成分。據報導,黑醋栗花青苷具有血液流動改善作用,緩和肩部酸痛、全身倦怠感等(專利文獻1),具有雌激素作用(非專利文獻1)。
然而,並不明確黑醋栗花青苷是否有更年期症狀之改善作用。
(專利文獻1)國際公開第2001/01798號
(非專利文獻1)Molecules, 23(1), 74, 2018
本發明係關於以下之1)~7)者。 1)一種更年期症狀改善劑,其以飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合作為有效成分。 2)一種更年期症狀改善用食品,其以飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合作為有效成分。 3)一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之用途,其等用於製造更年期症狀改善劑。 4)一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之用途,其等用於製造更年期症狀改善用食品。 5)一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合,其等用於改善更年期症狀。 6)一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之非治療性用途,其等用於改善更年期症狀。 7)一種更年期症狀之改善方法,其係將飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合以有效量投予至需要其之對象或使需要其之對象攝取。
本發明係關於提供一種對更年期症狀之改善有用之更年期症狀改善劑。 [00109 本發明人發現飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷有改善潮熱(上火、發熱)、出汗等更年期症狀之效果。
藉由本發明之更年期症狀改善劑,能夠改善潮熱(上火、發熱)、出汗等更年期之症狀。
於本發明中,飛燕草素-3-芸香糖苷係於飛燕草素3位之羥基鍵結鼠李糖基-(α1→6)-葡萄糖而成之糖苷,具有以下結構。
於本發明中,矢車菊素-3-芸香糖苷係於矢車菊素3位之羥基鍵結鼠李糖基-(α1→6)-葡萄糖而成之糖苷,具有以下結構。
飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷可為鹽或溶劑合物,包含任一者。又,該等可分別單獨使用,亦可組合使用2種以上。其中,就易於獲得所需效果之方面而言,較佳為使用飛燕草素-3-芸香糖苷。 飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷可藉由化學合成,或者自含有該等之天然物、尤其是植物中提取、純化而獲取。又,試劑可使用市售者。由於在黑醋栗(學名:Ribes nigrum)中發現了飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷,因此較佳為使用源自黑醋栗提取物者。亦可使用黑醋栗提取物作為飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷。
黑醋栗之使用部位並無特別限定,可為整株植物、葉、莖、花、芽、蓓蕾、果皮、果實、根、根莖、種子等或該等之組合,但就富含黑醋栗花青苷之方面而言,較佳為使用果實或果皮。黑醋栗可生吃、乾燥或對其等進行處理而使用。作為處理,例如可例舉:切斷、破碎、磨碎、粉碎等。 提取方法可適當選擇,可為浸漬、煎出、浸出、回流提取、超臨界提取、超音波提取、微波提取等之任一者。
用於提取之溶劑可使用極性溶劑、非極性溶劑之任一者。作為溶劑之具體例,例如可例舉:水;一元、二元或多元醇類;丙酮、甲基乙基酮等酮類;乙酸甲酯、乙酸乙酯等酯類;二乙基醚、四氫呋喃等鏈狀或環狀之醚類;聚乙二醇等聚醚類;己烷等飽和或不飽和之烴類;苯、甲苯等芳香族烴類;二氯甲烷、氯仿、二氯乙烷、四氯化碳等鹵代烴類;吡啶類;二甲基亞碸;乙腈;二氧化碳、超臨界二氧化碳;油脂、蠟、其他油類;以及該等之混合物。較佳可例舉醇類及其水溶液,作為醇類,可例舉甲醇、乙醇、1,3-丁二醇、正丙醇、異丙醇、正丁醇、異丁醇、第二丁醇、第三丁醇等,較佳為乙醇及乙醇水溶液。
提取時之溶劑之使用量、提取條件只要為可進行充分提取之條件,則無特別限定,可進行適當調整。
黑醋栗提取物只要為符合食品或醫藥品上可容許之規格,包含黑醋栗花青苷且發揮本發明之效果者,則可為粗純化物。又,視需要,可藉由液液分配、固液分配、過濾膜、活性碳、合成吸附樹脂、離子交換樹脂、去除沈澱等公知技術實施惰性夾雜物之去除、除臭、脫色等處理。
又,亦可進而適當組合公知之分離純化方法來提高該等之純度。作為純化方法,可例舉:有機溶劑沈澱、離心分離、超濾膜、高效液相層析或管柱層析等。
黑醋栗提取物可直接使用,亦可以利用適當溶劑稀釋而得之稀釋液之形態使用,或者可為製成濃縮萃取物或乾燥粉末者、製備成糊狀者。又,亦可進行冷凍乾燥,於使用時藉由提取所通常使用之溶劑,例如水、乙醇、水-乙醇混合液等溶劑稀釋而使用。又,亦可內包於脂質體等之囊胞或微膠囊等中而使用。
至於黑醋栗提取物,以飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之合計量計,較佳為含有0.1質量%以上,更佳為含有10質量%以上。
如下述實施例所示,藉由飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之經口攝取,作為更年期症狀之潮熱及出汗得到改善。據報導黑醋栗花青苷具有雌激素作用(Molecules, 23(1), 74, 2018),但由於黑醋栗花青苷之雌激素作用為雌二醇之一千分之一左右之作用(Molecules, 23(1), 74, 2018),因此認為此次人類有效性試驗中所使用之黑醋栗花青苷具有激素補充療法(HRT)之十分之一左右之雌激素作用。因此,認為飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷改善更年期症狀而不取決於雌激素活性化。 另一方面,確認飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷具有抑制TRPV4之活性之作用,該作用係於TRPV4激動劑之存在下,於與藉由人類TRPV4基因轉殖而功能性表現TRPV4之轉形細胞(TRPV4表現細胞)接觸之情形時,抑制由TRPV4激動劑所引起之細胞內之陽離子(Ca2 +
)量之流入(參考例1)。 TRPV4(Transient receptor potential cation channel subfamily V member 4)係構成溫度感受性TRP通道之蛋白質之一。認為TRPV4作為感測器分子(sensor molecule)發揮功能,該感測器分子係於腎臟、肺、膀胱、心臟、皮膚、腦、消化道等廣泛之組織中表現,感知因滲透壓變化、溫度變化、血液流動而產生之剪應力、器官之容積變化等各種物理化學性刺激,並傳遞至細胞。 據報導,已知有TRPV4之活性抑制作用之綠原酸、咖啡酸、阿魏酸可改善自主神經功能及不定主訴(日本專利第6075830號、日本專利第5931633號、日本專利第4077149號),因此認為可藉由抑制TRPV4之活性而改善更年期女性之不定主訴。因此,推測飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷藉由抑制TRPV4之活性而改善更年期症狀。
因此,飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合可作為更年期症狀改善劑,可用於更年期症狀之改善,又,可用於製造更年期症狀改善劑。
此處,「用途」為於人類或非人類動物中之用途,且可為治療性用途,亦可為非治療性用途。所謂「非治療性」,為不包含醫療行為之概念,即,為不包含對人進行手術、治療或診斷之方法之概念,更具體而言,為不包含醫生或受到醫生指示者對人實施手術、治療或診斷之方法之概念。
日本婦產科學會將更年期症狀及更年期障礙定義如下,即「將閉經前後5年稱為更年期,該期間出現之各種各樣之症狀中,非器質性變化引起之症狀稱為更年期症狀,將該等症狀中妨礙日常生活之病情稱為更年期障礙」(女性醫學指南 更年期醫療編 2014年版,日本女性醫學學會編)。 作為更年期症狀,例如可例舉:頭暈、頭痛、失眠、上火、發熱、出汗、心悸、噁心、便秘、腹瀉、肩部酸痛、腰痛、關節痛、頻尿、皮膚或黏膜之乾燥、濕疹等。本說明書中之「更年期症狀改善」意指改善更年期症狀,較佳為潮熱、出汗之改善。 於本說明書中,所謂「潮熱」,指於更年期中突然感覺到之出現於頭部、胸部或全身之熱感(上火、發熱)。
所謂「改善」,指症狀或者狀態之好轉、症狀或者狀態之惡化之防止或者延遲、或症狀或者狀態之進展之逆轉、防止或者延遲。
本發明之更年期症狀改善劑其自身成為發揮改善更年期症狀之作用效果的人類或者動物用之醫藥品、準藥品、食品,或者可成為調配於該醫藥品、準藥品、食品中而使用之原材料或製劑。
該食品中,包含以更年期症狀之改善效果為概念,視需要表達其宗旨之功能性表達食品、特定保健用食品、補充品等。該等食品由於為功能表達得到容許之食品,因此可與通常之食品加以區別。
該醫藥品(亦包含準藥品在內)含有飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合作為用於改善更年期症狀之有效成分。進而,該醫藥品只要不失去該有效成分之功能,可視需要含有藥學上容許之載體、或其他有效成分、藥理成分等。
作為該醫藥品(亦包含準藥品在內)之劑型,例如可例舉:錠劑(包含咀嚼錠等)、膠囊劑、顆粒劑、散劑、口含劑等經口固形製劑;內服液劑、糖漿劑等經口液狀製劑;注射劑、栓劑、吸入藥、經皮吸收劑、外用劑等非經口投予製劑。較佳之投予形態為經口投予,
該等劑型之製劑係可將黑醋栗花青苷與藥學上容許之載體(例如賦形劑、黏合劑、增量劑、崩解劑、界面活性劑、潤滑劑、分散劑、緩衝劑、保存劑、調味劑、香料、被膜劑、稀釋劑等)、其他藥效成分等適當組合,按照慣例而製備。
該食品含有飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合作為用於改善更年期症狀之有效成分。食品之形態可為固形、半固形或液狀(例如飲料)。作為該食品之例,例如可例舉:清涼飲料、茶系飲料、咖啡飲品、果汁飲料、碳酸飲料、果凍狀飲料、似水飲料等飲料;果凍、威化餅、餅乾、麵包、麵條、香腸等食品飲料或營養品等各種食品;以及其等之原料。或者,該食品亦可為具有錠劑、膠囊、顆粒、粉末、液劑、糖漿等經口投予製劑形態之補充品。
該食品係可將飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合與任意食品材料、或者其他有效成分、或食品所容許之添加物(例如溶劑、軟化劑、油、乳化劑、防腐劑、酸味劑、甜味劑、苦味劑、pH值調整劑、穩定劑、著色劑、紫外線吸收劑、抗氧化劑、保濕劑、增黏劑、固定劑、分散劑、流動性改善劑、濕潤劑、香料、調味料、風味調整劑)等適當組合,按照慣例進行製備。
上述醫藥品、準藥品或食品中之飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之含量可根據其等之劑型或形態而不同。例如,於為食品或者經口投予製劑且為錠劑、顆粒劑、丸劑、散劑、橡膠劑等固形之情形時,以飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之合計量計,較佳為0.1質量%以上,更佳為0.5質量%以上,進而較佳為1質量%以上,進而較佳為5質量%以上,進而較佳為10質量%以上。
於為食品或者經口投予製劑且為液劑、糖漿劑、懸浮劑、乳劑、酏劑、凝膠劑等液體之情形時,以飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之合計量計,較佳為0.001質量%以上,更佳為0.005質量%以上,進而較佳為0.01質量%以上,進而較佳為0.05質量%以上。
飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之投予量及投予計劃可根據對象種類、體重、性別、年齡、狀態、或其他因素而由業者適當決定。
針對更年期症狀之激素補充療法之風險及效益複雜交織,適用於一部分女性之症狀管理,但也提示可能會增加嚴重疾病之風險(JAMA, 288(3), 321-333, 2002; JAMA, 310(13), 1353, 2013)。因此,於無類激素作用之表現之範圍內改善更年期之不定主訴變得重要起來。因此,作為飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之投予量,以飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之合計量計,就不表現激素作用之攝取濃度之觀點而言,例如對於1名成人(60 kg)而言,每天較佳為1 mg以上,更佳為10 mg以上,進而較佳為25 mg以上,又,較佳為150 mg以下,更佳為100 mg以下,進而較佳為50 mg以下。
作為飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之投予量,以飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之合計量計,對於1名成人(60 kg)而言,每天為1~150 mg,更佳為10~100 mg,進而較佳為25~50 mg。
於本發明中,較佳為例如分為1天1次、2次或3次以上,投予或攝取上述用量。投予或攝取期間並無特別限定,較佳為連續性,更佳為1週以上,進而較佳為2週以上。
投予或攝取之時點並無特別限定,較佳為早餐後及/或晚餐後至睡覺前之期間,於晚餐後至睡覺前之期間,更佳為希望睡眠時間之30分鐘~3小時之前,更佳為1小時~2小時之前。
作為投予或攝取本發明之更年期症狀改善劑之對象者,較佳為需要或期望改善更年期症狀之人類或非人類動物。更佳為使更年期症狀發現潮熱、出汗之人類或非人類動物攝取或對其投予之方法有效。該人類較佳為更年期之人類,更佳為更年期之女性。
關於上述實施方式,本發明進而揭示以下態樣。
<1>一種更年期症狀改善劑,其以飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合作為有效成分。 <2>一種更年期症狀改善用食品,其以飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合作為有效成分。
<3>一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之用途,其等用於製造更年期症狀改善劑。 <4>一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之用途,其等用於製造更年期症狀改善用食品。
<5>一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合,其等用於更年期症狀改善。 <6>一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之非治療性用途,其等用於改善更年期症狀。
<7>一種更年期症狀之改善方法,其係將飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合以有效量投予至需要其之對象或使需要其之對象攝取。
<8>於<1>至<7>中,更年期症狀較佳為頭暈、頭痛、失眠、上火、發熱、出汗、心悸、噁心、便秘、腹瀉、肩部酸痛、腰痛、關節痛、頻尿、皮膚或黏膜之乾燥、或濕疹,更佳為潮熱或出汗。
<9>於<1>至<8>中,飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷較佳為源自黑醋栗提取物。
<10>於<1>至<9>中,作為飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之投予量,以飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之合計量計,針對1名成人(60 kg)而言每天較佳為1 mg以上,更佳為10 mg以上,進而較佳為25 mg以上,又,較佳為150 mg以下,更佳為100 mg以下,進而較佳為50 mg以下,又,較佳為1~150 mg,更佳為10~100 mg,進而較佳為25~50 mg。
[實施例]
<實施例1 黑醋栗花青苷之純化> (1)黑醋栗提取物之粗分級
使用市售品之黑醋栗提取物(黑醋栗多酚AC10,黑醋栗花青苷總量11.8 wt%,Meiji Food Materia公司(股)製造),可分級為花青苷類及其他成分。以文獻(多酚:藥用植物及食品之功能性成分,CMC出版,250-251,2012)為參考,利用合成吸附樹脂進行分級。其結果,分級為含有花青苷類之組分(EtOH溶出分、判斷HPLC分析層析中之4個峰與其等對應,42.2 wt%)、及極性高於其之組分(H2
O溶出分,60.0 wt%)(參照圖1)。
(2)自EtOH組分進行花青苷之純化
由EtOH組分(含有花青苷類之組分)進行花青苷類之純化。以分析HPLC之條件為參考,利用ODS分取HPLC進行分級。其結果,分級為4種花青苷類純化組分及其他組分共計8種組分(Fr.E-1:14.9 wt%、Fr.E-2:1.91 wt%、Fr.E-3:1.91 wt%、Fr.E-4:6.41 wt%、Fr.E-5:1.10 wt%、Fr.E-6:4.65 wt%、Fr.E-7:0.44 wt%、Fr.E-8:6.27 wt%)(參照圖2)。
(3)純化花青苷類之鑑定
由於藉由分取HPLC分別對4個主要峰進行了分離純化,因此繼而進行其等之鑑定。與文獻(J Agric Food Chem, 50(11), 3228-3231, 2002)之HPLC分析層析進行比較,認為Fr.E-3為飛燕草素-3-葡萄糖苷(1、D3G)、Fr.E-4為飛燕草素-3-芸香糖苷(2、D3R)、Fr.E-5為矢車菊素-3-葡萄糖苷(3、C3G)、Fr.E-6為矢車菊素-3-芸香糖苷(4、C3R)之可能性較高。對此,測定各者之1
H、13
C-NMR,確認各訊號之歸屬及進行與文獻(J Sep Sci, 40(17), 3506-3512, 2017)之比較之結果如推測所示(參照圖3)。
<實施例2 黑醋栗提取物對更年期症狀之人類有效性試驗>
(1)對象者
40多歲~50多歲之健康女性17名,試驗開始時之對象者之平均年齡為51.5±1.4歲。
(2)試驗品之製作
以如下方式進行製作:將包含D3R及C3R之市售品之黑醋栗提取物(黑醋栗多酚AC10,黑醋栗花青苷總量11.8 wt%,D3R 5.4 wt%,C3R 3.8 wt%,Meiji Food Materia公司(股)製造)製成糖衣粒,且使每1粒糖衣粒之黑醋栗提取物成為100 mg。
(3)糖衣粒之攝取方法
於28天中,以1天2次(早餐後30分鐘以內、及睡覺60~30分鐘前)之頻率,將糖衣粒(2粒/次)與150 mL之礦泉水一起攝取。
(4)更年期症狀之評價方法
於含有黑醋栗提取物之糖衣粒之攝取前後,使用Kupperman更年期障礙指數對更年期症狀之程度進行評價。又,使用生活日誌對潮熱及出汗次數進行評價。再者,於試驗期間注意下述方面而進行試驗。
(注意事項)
(i)注意維持如平常之生活方式。
(ii)注意與平常相同之飲食習慣。
(iii)不改變運動習慣。
(iv)避免暴飲暴食或極端減食(節食)。
(v)不要開始攝取新的補充品。
(5)統計學檢定
所獲得之結果以平均值±標準誤差表示,含有黑醋栗提取物之糖衣粒之攝取前後之比較中使用Wilcoxon符號秩檢定。
於含有黑醋栗提取物之糖衣粒之攝取前後,Kupperman更年期障礙指數之合計分自23.7±1.9顯著地減少至17.6±2.0,並且Kupperman更年期障礙指數之重症度評價等級亦自2.8±0.2顯著地減少至1.9±0.2(P<0.05)。又,Kupperman更年期障礙指數之作為血管運動神經類症狀之「臉發燙(發熱)」、「容易出汗」之問題之得分,分別自6.8±0.8顯著地減少至4.5±0.7、自6.8±0.8顯著地減少至4.0±0.9(P<0.05)。
於含有黑醋栗提取物之糖衣粒之攝取前後,每天之潮熱產生次數自1.2±0.3(次)顯著地減少至0.5±0.3(次),並且每天之出汗次數亦自1.2±0.4(次)顯著地減少至0.6±0.3(次)(P<0.05)
根據以上結果,可知黑醋栗提取物具有減輕更年期症狀、尤其是潮熱及出汗之效果,藉由攝取黑醋栗提取物,能夠改善更年期症狀、尤其是潮熱及出汗。
<參考例1 TRPV4活性抑制作用之評價>
(1)人類TRPV4基因表現載體之製作
對自源自人類十二指腸之細胞(Hutu-80細胞,自American Type Culture Collection購入)提取之totalRNA進行反轉錄,將所獲得之cDNA作為模板,使用參考公開之人類TRPV4基因序列而合成之包含下述所示之鹼基序列所表示之寡核苷酸的引子組,於下述條件下進行聚合酶鏈反應(PCR)。
<引子組>
正向引子:5'-CACCATGGCGGATTCCAGCGAAGGCCC-3'(序列編號1)
反向引子:5'-CTAGAGCGGGGCGTCATCAGTCC-3'(序列編號2)
<PCR條件>
a)PCR溶液組成
cDNA(模板(Template)) 15 μL
5×PrimeStar GXL 緩衝液(Buffer) 10 μL
dNTPs混合物(mixture)(2.5 mM) 4 μL
PrimeStar GXL DNA聚合酶(Polymerase)(塔卡拉生物) 1 μL
正向引子(Forward Primer)(10 μM) 1 μL
反向引子(Reverse Primer)(10 μM) 1 μL
水(Water) 18 μL
b)溫度及循環條件
95℃ 2 min
↓
98℃ 10 sec 33週期
70℃ 2 min
使用高純度PCR產物純化套組(High Pure PCR Product Purification Kit)(羅氏公司製造)對所獲得之PCR產物進行純化。使用純化之PCR產物、及pcDNA3.1 Directional TOPO表現套組(Invitrogen公司製造),製作人類TRPV4基因表現載體。
(2)人類TRPV4表現細胞之製作
使用包含10%胎牛血清之DMEM/F12培養基(Invitrogen公司製造),進行源自人類宮頸癌之細胞株(HeLa細胞,自American Type Culture Collection購入)之培養。將HeLa細胞以2×105
個細胞/皿接種於10 cm細胞培養用皿中。培養2天後,使用TransIT-HeLaMONSTER轉染套組(Mirus公司製造)將上述(1)中製作之人類TRPV4基因表現用載體(7.7 μg)轉染於細胞,培養1天。
藉由Detachin(Genlantis公司製造)將細胞剝離,於96孔光學底板(Nunc公司製造)上,以2.0×104
個細胞/90 μL/孔之細胞密度播種於包含10%胎牛血清之DMEM/F12培養基中,進而培養1天。
(3)細胞內鈣離子流入活性之測定
細胞內鈣離子流入活性之測定係使用Calcium Kit II-fluo 4(商品名,DOJINDO)進行。將含有Fluo4-AM之加樣緩衝液(Loading buffer)以90 μL/孔添加於上述(2)中所製作之人類TRPV4表現細胞中,於37℃下培育1小時。其後,於37℃下使用螢光讀板儀(FDSS/µCELL 藥物開發篩選支持系統C13299,Hamamatsu Photonics公司製造)以每2秒測定一次螢光強度(激發波長:488 nm,螢光波長:524 nm)。於測定開始30秒後,藉由測定套組之稀釋緩衝液分別稀釋作為TRPV4激動劑之GSK1016790a(Sigma公司製造)及作為檢體之上述製造例中所製備之黑醋栗提取物、或D3R、C3R、D3G、C3G,添加20 μL/孔之該等混合溶液(於即將添加之前混合),300秒前每2秒測定一次螢光強度變化。再者,添加GSK1016790a以使其最終濃度成為10 nm,基於黑醋栗提取物中之含有率設定各花青苷之評價濃度。
檢體之TRPV4活性係將作為TRPV4激動劑之GSK1016790a之處理之鈣離子流入率設為100%,藉由下式而算出。
(算式)
鈣離子流入率(%)=[(F300/F0)-(F300C2/F0C2)]/[(F300C1/F0C1)-(F300C2/F0C2)]×100
F300:測定開始300秒後之添加有GSK1016790a及檢體之孔之螢光強度
F300C1:測定開始300秒後之添加有GSK1016790a及溶劑之孔之螢光強度
F300C2:測定開始300秒後之僅添加有溶劑之孔之螢光強度
F0:剛開始測定後之與F300相同之孔之螢光強度
F0C1:剛開始測定後之與F300C1相同之孔之螢光強度
F0C2:剛開始測定後之僅添加有溶劑之孔之螢光強度
將添加有檢體之情形時之鈣離子流入率與添加GSK1016790a+溶劑時進行比較,使用Dunnett's test進行檢定。將添加黑醋栗提取物、或D3R、C3R、D3G、C3G之情形時之結果以平均值±標準誤差之形式示於表中(表中,將GSK1016790a,黑醋栗提取物,黑醋栗提取物之乙醇組分,黑醋栗提取物之水組分,及D3R、C3R、D3G、C3G這4種之混合物(D3R:45.6 wt%、C3R:33.0 wt%、D3G:13.6 wt%、C3G:7.8 wt%)分別略記為GSK、CaE、EtOH、H2
O、MIX)。
[表1]
細胞內Ca2+ 上升率(%) | |
GSK 10 nm+溶劑 | 100.0±1.6 |
GSK 10 nm+CaE 10 μg/mL | 75.9±1.0(P<0.01) |
GSK 10 nm+CaE 100 μg/mL | 72.7±2.8(P<0.001) |
GSK 10 nm+EtOH 4.2 μg/mL | 74.4±1.9(P<0.001) |
GSK 10 nm+EtOH 42 μg/mL | 73.0±2.1(P<0.001) |
GSK 10 nm+H2 O 6 μg/mL | 97.8±3.7 |
GSK 10 nm+H2 O 60 μg/mL | 99.4±7.2 |
n=3,平均值±SE | |
細胞內Ca2+ 上升率(%) | |
GSK 10 nm+溶劑 | 100.0±1.6 |
GSK 10 nm+MIX 1 μg/mL | 70.9±4.1(P<0.001) |
GSK 10 nm+MIX 10 μg/mL | 69.8±3.0(P<0.001) |
GSK 10 nm+D3R 0.46 μg/mL | 89.5±2.0 |
GSK 10 nm+D3R 4.6 μg/mL | 78.8±1.2(P<0.01) |
GSK 10 nm+C3R 0.35 μg/mL | 95.3±4.2 |
GSK 10 nm+C3R 3.5 μg/mL | 86.6±5.1(P=0.07) |
GSK 10 nm+D3G 0.14 μg/mL | 101.4±2.7 |
GSK 10 nm+D3G 1.4 μg/mL | 100.4±3.2 |
GSK 10 nm+C3G 0.05 μg/mL | 94.4±3.1 |
GSK 10 nm+C3G 0.5 μg/mL | 101.5±4.1 |
n=3,平均值±SE |
根據表1,黑醋栗提取物及黑醋栗提取物之乙醇組分使鈣離子流入顯著地降低。又,作為乙醇組分之主要成分的D3R、C3R、D3G、C3G這4種之混合物(MIX)使鈣離子流入顯著地降低,尤其是D3R使鈣離子流入顯著地降低,C3R表現出降低鈣離子流入之傾向。
根據以上之結果,藉由應用黑醋栗提取物或D3R、C3R,TRPV4活性得到抑制。此表示黑醋栗提取物或D3R、C3R對TRPV4活性之抑制有效。
進而,表示具有抑制TRPV4活性之作用之黑醋栗提取物或D3R、C3R對更年期症狀之改善有效。
圖1係表示黑醋栗花青苷純化之流程之圖。 圖2係黑醋栗花青苷之分取HPLC(high performance liquid chromatography,高效液相層析法)之層析圖。 圖3係Fr.E-3~-6之1
H、13
C-NMR譜。
Claims (9)
- 一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之用途,其等用於製造更年期症狀改善劑。
- 一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之用途,其等用於製造更年期症狀改善用食品。
- 如請求項1或2之用途,其中更年期症狀為潮熱、出汗。
- 如請求項1或2之用途,其中飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷源自黑醋栗提取物。
- 如請求項1或2之用途,其中以飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之合計量計,對1名成人(60 kg)每天投予或使其攝取1~150 mg之量的飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合。
- 一種飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合之非治療性用途,其等用於改善更年期症狀。
- 如請求項6之非治療性用途,其中更年期症狀為潮熱、出汗。
- 如請求項6或7之非治療性用途,其中飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷源自黑醋栗提取物。
- 如請求項6或7之非治療性用途,其中以飛燕草素-3-芸香糖苷及矢車菊素-3-芸香糖苷之合計量計,對1名成人(60 kg)每天投予或使其攝取1~150 mg之量的飛燕草素-3-芸香糖苷、矢車菊素-3-芸香糖苷或其組合。
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