TWI451879B - Selected from the group consisting of D- alanine and D- hydroxy-proline, the above groups and D- alanine and proline salts of D- hydroxy consisting of one kind or two kinds of the compound for the production of laminin 332 the use of production accelerating composition - Google Patents
Selected from the group consisting of D- alanine and D- hydroxy-proline, the above groups and D- alanine and proline salts of D- hydroxy consisting of one kind or two kinds of the compound for the production of laminin 332 the use of production accelerating composition Download PDFInfo
- Publication number
- TWI451879B TWI451879B TW099116541A TW99116541A TWI451879B TW I451879 B TWI451879 B TW I451879B TW 099116541 A TW099116541 A TW 099116541A TW 99116541 A TW99116541 A TW 99116541A TW I451879 B TWI451879 B TW I451879B
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- Taiwan
- Prior art keywords
- alanine
- laminin
- hydroxyproline
- production
- cells
- Prior art date
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Classifications
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- A—HUMAN NECESSITIES
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- A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
- A21D2/24—Organic nitrogen compounds
- A21D2/245—Amino acids, nucleic acids
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
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- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/12—Fermented milk preparations; Treatment using microorganisms or enzymes
- A23C9/13—Fermented milk preparations; Treatment using microorganisms or enzymes using additives
- A23C9/1322—Inorganic compounds; Minerals, including organic salts thereof, oligo-elements; Amino-acids, peptides, protein-hydrolysates or derivatives; Nucleic acids or derivatives; Yeast extract or autolysate; Vitamins; Antibiotics; Bacteriocins
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
- A23G3/34—Sweetmeats, confectionery or marzipan; Processes for the preparation thereof
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23G—COCOA; COCOA PRODUCTS, e.g. CHOCOLATE; SUBSTITUTES FOR COCOA OR COCOA PRODUCTS; CONFECTIONERY; CHEWING GUM; ICE-CREAM; PREPARATION THEREOF
- A23G3/00—Sweetmeats; Confectionery; Marzipan; Coated or filled products
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Description
本發明係關於一種包含選自由D-丙胺酸及D-羥基脯胺酸、與其衍生物及/或鹽所組成之群中之1種或2種以上的化合物之層黏連蛋白332產生促進組合物,以及包含投予上述化合物之步驟的抑制及/或改善皮膚損傷之方法。
已知層黏連蛋白為包含α鏈、β鏈及γ鏈之3條鏈蛋白質,以5種α鏈、3種β鏈及3種γ鏈之組合計至少存在15種異構物。其中,一般認為層黏連蛋白332(α3β3γ2,按以前的命名法為層黏連蛋白5)大量地存在於隔開表皮與真皮之基底膜中,並對皮膚之結構及功能發揮重要的作用(非專利文獻1)。層黏連蛋白332之基因剔除小鼠(knockout mouse)成為與表皮和真皮相分離而形成水泡的人類遺傳性疾病即交界型大皰性表皮松解症相同之表現型,顯示出著層黏連蛋白332係表皮與真皮之黏接所必需的(非專利文獻2)。又,若向於包埋人類纖維母細胞之膠原蛋白凝膠上培養角化細胞之皮膚等效模型中添加層黏連蛋白332之純化製劑,則會增強基底膜形成(非專利文獻3)。由表皮細胞產生之活化蛋白質分解酶胞漿素(plasmin)將層黏連蛋白332之α3次單元的胺基末端及羧基末端之肽、與β3次單元的胺基末端之肽切斷。酶切片段分別包含細胞之基質黏接分子之識別部位與7型膠原蛋白之結合部位。因此,被胞漿素消化之層黏連蛋白332與角質細胞之黏接能力減少。又,被胞漿素消化之層黏連蛋白332與7型膠原蛋白之親和性減退。因此,一般認為由紫外線照射及其以外之原因所引起之皮膚老化與由胞漿素引起之層黏連蛋白332消化、以及由此引起之基底膜的功能降低相關(非專利文獻4)。
因此,藉由促進層黏連蛋白332之產生,而有可能抑制及/或改善由紫外線照射以外之原因所引起之皮膚老化。關於促進層黏連蛋白332之產生的因子,近年來報告有HIF1(非專利文獻5)及Smad4(非專利文獻6)誘導α3次單元之基因的轉錄。然而,HIF1係對缺氧或機械刺激之類的環境刺激作出應答之轉錄調節因子,藉由好發炎性細胞激素亦進行上向調節。Smad4係與TGFβ之訊號傳遞有關之轉錄調節因子。該等因子均為大分子量之蛋白質,活性係藉由利用磷酸化等所進行之修飾或與其他次單元之締合狀態而調節,因此無法用於直接投予至生物體內,被送達至皮膚組織內之表皮細胞,而促進層黏連蛋白332之產生。又,由於上述因子之任一種均由廣泛之因子進行調節,除了促進層黏連蛋白332之產生以外,亦對炎症反應等生物體之功能產生較大影響,故無法於日常生活中安全地使用。
非專利文獻1:Sugawara等人、Exp Dermatol. 17(6),473-80(2008)
非專利文獻2:Aberdam等人、Nat. Genet. 6,299,(1994)
非專利文獻3:Amano,S.、SOFW J.、134:10(2008)
非專利文獻4:Amano,S.、J. Investig. Dermatol. Symp. Proc. 14:2-7(2009)
非專利文獻5:Fitsialos,G.等人、J. Cell Sci.、121:2992(2008)
非專利文獻6:Zboralski,D.等人、BMC Cancer,8:215(2008)
因此,必須開發一種可促進層黏連蛋白332之產生、且能夠用於日常生活中的穩定且安全之組合物。
本發明提供一種層黏連蛋白332產生促進組合物,其包含選自由D-丙胺酸及D-羥基脯胺酸、與其衍生物及/或鹽所組之成群中的1種或2種以上之化合物。
本發明之層黏連蛋白332產生促進組合物有時用於抑制及/或改善皮膚狀態。
於本發明之層黏連蛋白332產生促進組合物中,上述皮膚狀態包括光老化、皺紋、肌膚粗糙、細紋及乾燥,但並不限定於該等。
本發明之層黏連蛋白332產生促進組合物有時用作醫藥品。
本發明之層黏連蛋白332產生促進組合物有時用作皮膚外用劑。
本發明之層黏連蛋白332產生促進組合物有時用作食品。
本發明提供一種抑制及/或改善皮膚狀態之方法,其包括投予層黏連蛋白332產生促進組合物之步驟,該層黏連蛋白332產生促進組合物包含選自D-丙胺酸及D-羥基脯胺酸、其衍生物及/或鹽所組成之群中的1種或2種以上之化合物。
利用本發明之方法抑制及/或改善之皮膚狀態包括光老化、皺紋、肌膚粗糙、細紋及乾燥,但並不限定於該等。
於本發明之方法中,上述層黏連蛋白332產生促進組合物有時為醫藥品。
於本發明之方法中,上述層黏連蛋白332產生促進組合物有時為皮膚外用劑。
於本發明之方法中,上述層黏連蛋白332產生促進組合物有時為食品組合物。
本說明書中所謂D-丙胺酸及D-羥基脯胺酸之「鹽」,係指以不損及D-丙胺酸及D-羥基脯胺酸之層黏連蛋白332產生之促進效果為條件,而包括金屬鹽、胺鹽等之任一種鹽。上述金屬鹽有時包括鹼金屬鹽、鹼土金屬鹽等。上述胺鹽有時包括三乙基胺鹽、苄基胺鹽等。
本說明書中所謂D-丙胺酸及D-羥基脯胺酸之「衍生物」,係指以不損及D-丙胺酸及D-羥基脯胺酸之層黏連蛋白332產生之促進效果為條件,D-丙胺酸及D-羥基脯胺酸之分子於胺基、或羧基、或側鏈上與任一原子團進行共價鍵結而成者。上述任一原子團包括:N-苯基乙醯基、4,4'-二甲氧基三苯甲基(DMT)等之類的保護基,蛋白質、肽、糖、脂質、核酸等之類的生物體高分子,聚苯乙烯、聚乙烯(polyethylene)、聚乙烯(polyvinyl)、聚酯等之類的合成高分子,及酯基等之類的官能基,但並不限定於該等。上述酯基有時包括例如甲酯、乙酯以外之脂肪族酯、或芳香族酯。
胺基酸具有作為光學異構物的L-體及D-體,但天然蛋白質係L-胺基酸進行肽結合而成者,除了細菌之細胞壁等例外,其他僅利用L-胺基酸,故一般認為以人類為代表之哺乳類僅存在L-胺基酸,而僅利用L-胺基酸。(木野內忠稔等人、蛋白質核酸酶、50:453-460(2005)、Lehninger Principles of Biochemistry[上]第2版pp132-147(1993)廣川書店、Harper's‧Biochemistry原書22版pp21-30(1991)丸善)因此,先前於學術上產業上胺基酸均僅專用L-胺基酸。
作為例外地使用D-胺基酸之實例,有食品添加物之例,即在用作細菌所產生之抗生素之原料時,及在化學合成胺基酸時,為節省自等量獲得之L-胺基酸及D-胺基酸混合物中僅分離L-胺基酸之成本,而直接使用D-胺基酸製成DL-胺基酸混合物。但先前並無於產業上僅使用D-胺基酸來作為具有生理活性之物質的例子。
D-絲胺酸或D-天冬醯胺酸由於D體之比例較高,因此進行了比較性研究。D-絲胺酸局部存在於大腦、海馬區中,根據腦內之NMDA受體之調節因子而明確。認為D-天冬醯胺酸局部存在於睾丸或松果體中,表示參與了激素分泌之控制(日本專利特開2005-3558號公報)。然而,皮膚中之D-丙胺酸及D-羥基脯胺酸之生理作用仍不明確。
如以下實施例所示,至今仍未知D-丙胺酸及D-羥基脯胺酸增大層黏連蛋白332產生量之效果。因此,包含D-丙胺酸及/或D-羥基脯胺酸之本發明之層黏連蛋白332產生促進組合物為新穎發明。
近年來報告有,使ddY小鼠自由攝取10 mM之D-胺基酸水溶液2週後,於各器官中測定D-胺基酸濃度,結果於松果體中,每1腺松果體為3-1000 pmol,於腦組織中,每1克濕重量為2-500 nmol(Morikawa,A.等人、Amino Acids,32:13-20(2007))。基於此,算出以下說明之本發明之組合物中所含有的D-丙胺酸及D-羥基脯胺酸之一日攝取量之下限。
本發明之D-丙胺酸如以下實施例所示,對於培養人類表皮角化細胞於0.1 μM~1 μM之濃度下具有促進層黏連蛋白332產生之效果。因此,本發明之皮膚症狀改善劑、皮膚外用劑、及食品組合物中所含之D-丙胺酸量,以將該濃度範圍之D-丙胺酸送達至生物體皮膚組織之纖維母細胞為條件,任意含量均可。至於本發明之組合物為外用劑時之D-丙胺酸之含量,於本發明之組合物總量中為0.000015重量%至50重量%或可調配之最大重量濃度為止之範圍即可。即上述組合物為外用劑時之D-丙胺酸之含量理想的是0.00003重量%~30重量%,最理想的是0.0003重量%~3重量%。本發明之組合物為內服劑時之D-丙胺酸之含量為0.00001重量%~100重量%之範圍即可。本發明之組合物為內服劑時之D-丙胺酸的含量較理想的是0.00002重量%~80重量%,最理想的是0.0002重量%~60重量%。再者,本發明之組合物中所含之D-丙胺酸之一日攝取量之下限係每1 kg體重為0.01 ng,較好的是0.1 ng,更好的是1 ng。
本發明之D-羥基脯胺酸如以下實施例所示,對於培養人類表皮角化細胞於0.1 μM~1 μM之濃度下具有促進層黏連蛋白332產生之效果。因此,本發明之皮膚症狀改善劑、皮膚外用劑、食品組合物中所含之D-羥基脯胺酸量,以將該濃度範圍之D-羥基脯胺酸送達至生物體皮膚組織之纖維母細胞為條件,任意含量均可。至於本發明之組合物為外用劑時之D-羥基脯胺酸之含量,於本發明之組合物總量中為0.000015重量%至50重量%或可調配之最大重量濃度為止之範圍即可。即上述組合物為外用劑時之D-羥基脯胺酸之含量較理想的是0.00003重量%~30重量%,最理想的是0.0003重量%~3重量%。本發明之組合物為內服劑時之D-羥基脯胺酸之含量為0.00001重量%~100重量%之範圍即可。本發明之組合物為內服劑時之D-羥基脯胺酸之含量較理想的是0.00002重量%~80重量%,最理想的是0.0002重量%~60重量%。再者,本發明之組合物中所含之D-羥基脯胺酸之一日攝取量的下限係體重每1 kg為0.01 ng即可,較好的是0.1 ng,更好的是1 ng。
本發明之組合物中除了D-丙胺酸及D-羥基脯胺酸、D-丙胺酸及D-羥基脯胺酸之鹽、及/或於生物體內因藥物代謝酶及其他因素而可釋放出D-丙胺酸之衍生物以外,以不損及D-丙胺酸及D-羥基脯胺酸之層黏連蛋白332產生之促進效果為條件,有時還包含1種或2種以上藥學上容許之添加物。上述添加物包括:稀釋劑及膨脹劑、結合劑及黏接劑、潤滑劑、流動促進劑、塑化劑、崩解劑、載體溶劑、緩衝劑、著色料、香料、甜味料、防腐劑及穩定化劑、吸附劑、業者所知之其他醫藥品添加劑,但並不限定於該等。
本發明之組合物亦可僅使用作為有效成分的D-丙胺酸及D-羥基脯胺酸、D-丙胺酸及D-羥基脯胺酸之鹽、及/或於生物體內因藥物代謝酶及其他因素而可釋放出D-丙胺酸及D-羥基脯胺酸的衍生物而加以製備,但通常於不損及本發明之效果的範圍內,視需要可適當調配用於包括準藥品之化妝品或醫藥品等皮膚外用劑等之其他成分。作為上述其他成分(任意調配成分),例如可列舉:油分、界面活性劑、粉末、色材、水、醇類、增黏劑、螯合劑、矽酮類、抗氧化劑、紫外線吸收劑、保濕劑、香料、各種藥效成分、防腐劑、pH值調整劑、中和劑等。
至於本發明之用於抑制及/或改善皮膚狀態之層黏連蛋白332產生促進組合物(以下稱為「皮膚狀態改善劑」)之劑型,若為包括例如軟膏、霜劑、乳液、洗劑、敷劑、凝膠劑、貼劑等外用劑,例如粉末、顆粒、軟膠囊、片劑等經口劑,例如經鼻噴霧等經鼻劑,及注射劑之用於先前的準藥品組合物及醫藥品組合物中者,則所有者均可。
至於本發明之皮膚外用劑之劑型,若為包括例如軟膏、霜劑、乳液、洗劑、敷劑、凝膠劑、貼劑等之用於先前的皮膚外用劑者,則所有者均可。
本發明之食品組合物中除了D-丙胺酸及D-羥基脯胺酸、D-丙胺酸及D-羥基脯胺酸之鹽、及/或於生物體內因藥物代謝酶及其他因素而可釋放出D-丙胺酸及D-羥基脯胺酸之衍生物外,以不損及D-丙胺酸及D-羥基脯胺酸之層黏連蛋白332產生之促進效果為條件,有時還包含調味料、著色料、保存料及其他容許作為食品之成分。
本發明之食品組合物若為例如糖果、曲奇(cookie)、味噌、法式沙拉醬、蛋黃醬、法式麵包、醬油、酸乳酪、香松、調味料‧納豆佐料汁、納豆、未過濾黑醋等用於先前之食品組合物者,則任意者均可,但並不限定於上述例示。
以下所說明之本發明之實施例僅以例示為目的,並不限定本發明之技術範圍。本發明之技術範圍僅由申請專利範圍之記載來限定。
本說明書中所提及之所有文獻藉由引用而將其整體併入本說明書中。
1. 藉由添加丙胺酸及羥基脯胺酸而促進層黏連蛋白332產生
1-1. 材料與方法
(1) 細胞
細胞係使用來自人類表皮細胞之HaCaT細胞(H. Hans等人、Experimental Cell Research 239:399(1998))、以及來自人類角化細胞之KC細胞(三光純藥股份有效公司、製造商:LONZA Walkersville Inc.)。將上述細胞以每1孔4×104
個之方式播種於24孔板中,使用於細胞培養用培養基(D-MEM(1 g/L葡萄糖)、和光純藥)中添加有0.1%之BSA的培養基(以下稱為「通常培養基」),於37℃、5% CO2
及飽和水蒸氣環境下培養24小時。
(2) 丙胺酸及羥基脯胺酸之添加
其後,上述細胞係於將L-或D-丙胺酸1 μM、或者L-及D-丙胺酸一起各0.5 μM、或者L-或D-羥基脯胺酸1 μM、或者L-及D-羥基脯胺酸一起各0.5 μM添加於上述通常培養基中而獲得之培養基中替換培養24小時。使用未添加丙胺酸及羥基脯胺酸之上述通常培養基作為陰性對照。本實施例中所使用之D-羥基脯胺酸為4-順-D-羥基脯胺酸。
(3) 層黏連蛋白332產生量之定量
於培養結束後回收培養基,以3000 rpm離心分離5分鐘,使用ELISA(enzyme linked immunosorbent assay,酵素結合免疫吸附分析)法(Amano,S.等人、J. Immunol. Methods、224:161(1999))測定上清液中之層黏連蛋白332濃度。上述ELISA法係使用針對層黏連蛋白5之α3鏈的單株抗體即BM165、以及針對層黏連蛋白5之β3鏈的單株抗體即6F12之生物素化偶聯物(conjugate)的三明治ELISA法,藉由辣根過氧化物酶(horseradish peroxidase)標記抗生蛋白D(Vector Labs公司、目錄編號A-2004)而檢測。使用PBS作為對照。
(4) 活細胞數之定量
於培養基回收後,用PBS清洗細胞,添加alamarBlue(商標、Biosource、Biosource International)使最終濃度達到10%。2小時後,依據Ahmed S. A.等人、(J. Immunol Method. 170,211-224(1994))及製造者之說明書,以激發波長544 nm、螢光波長590 nm測定alamarBlue液之螢光強度。
1-2. 結果
(1) KC活細胞數之定量
圖1表示研究添加丙胺酸對KC細胞增殖的影響之實驗結果。各實驗條件之誤差棒表示相同條件下重複3次之實驗結果的測定值之標準偏差。
於KC細胞中,陰性對照之alamarBlue(商標)之螢光強度之相對值(以下相同)為50。利用添加1 μM之L-丙胺酸之培養基、添加1 μM之D-丙胺酸之培養基、添加各0.5 μM之L-及D-丙胺酸之培養基進行培養的KC細胞之螢光強度,分別為40、45及50。於KC細胞中,與陰性對照相比,利用添加丙胺酸之培養基進行培養的細胞之alamarBlue(商標)之螢光強度於Tukey-Kramer檢驗中並無顯著差異。因此,表示L-及D-丙胺酸對KC細胞並無細胞毒性。
(2) KC細胞之層黏連蛋白332產生
圖2中表示研究添加丙胺酸對KC細胞中產生層黏連蛋白332之效果之實驗結果。圖2之圖表的縱軸表示與各孔之培養上清液中之層黏連蛋白332濃度成比例的ELISA測定之吸光度除以與各孔之細胞數成比例的alamarBlue(商標)之螢光強度所得之商(以下稱為「單位細胞數量之層黏連蛋白332濃度之相對值」)。各實驗條件之誤差棒表示於相同條件下重複3次之實驗結果的計算值之標準偏差。又,星號(**)表示於Tukey-Kramer檢驗中p未達1%。
單位細胞數量之層黏連蛋白332濃度之相對值於陰性對照中為0.35。利用添加1 μM之L-丙胺酸之培養基、添加1 μM之D-丙胺酸之培養基、添加各0.5 μM之L-及D-丙胺酸之培養基進行培養的KC細胞之單位細胞數量之層黏連蛋白332濃度的相對值分別為0.40、0.50及0.45。於添加1 μM之D-丙胺酸與陰性對照之間,於Tukey-Kramer檢驗中p未達1%,有顯著差異。因此證明藉由添加D-丙胺酸而促進KC細胞中之層黏連蛋白332產生。
(3) HaCaT活細胞數之定量
圖3及圖4表示研究添加丙胺酸及羥基脯胺酸對HaCaT細胞增殖之影響之實驗結果。以下所謂D-羥基脯胺酸(D-Hyp),係指4-順-D-羥基脯胺酸。各實驗條件之誤差棒表示於相同條件下重複3次之實驗結果的測定值之標準偏差。
於HaCaT細胞中,陰性對照之alamarBlue(商標)之螢光強度為300。利用添加1 μM之L-丙胺酸之培養基、添加1 μM之D-丙胺酸之培養基、添加各0.5 μM之L-及D-丙胺酸之培養基進行培養的HaCaT細胞之螢光強度均為250(圖3)。利用添加1 μM之L-羥基脯胺酸之培養基、添加1 μM之D-羥基脯胺酸之培養基、添加各0.5 μM之L-及D-羥基脯胺酸之培養基進行培養的HaCaT細胞之螢光強度均為280(圖4)。HaCaT細胞中,與陰性對照相比,利用添加丙胺酸及D-羥基脯胺酸之培養基進行培養的細胞之alamarBlue(商標)之螢光強度於Tukey-Kramer檢驗中無顯著差異。因此,表示L-及D-丙胺酸、與L-及D-羥基脯胺酸對HaCaT細胞亦無細胞毒性。
(4) 藉由添加丙胺酸之HaCaT細胞之層黏連蛋白332之產生
圖5中表示研究添加丙胺酸對HaCaT細胞中產生層黏連蛋白332之效果之實驗結果。圖5之圖表的縱軸表示各孔之培養上清液中單位細胞數量之層黏連蛋白332濃度的相對值。各實驗條件之誤差棒表示於相同條件下重複3次之實驗結果的計算值之標準偏差。又,星號(**)表示於Scheffe's F-檢驗中p未達1%,星號(*)表示p未達5%。
單位細胞數量之層黏連蛋白332濃度之相對值於陰性對照中為0.04。利用添加1 μM之L-丙胺酸之培養基、添加1 μM之D-丙胺酸之培養基、添加各0.5 μM之L-及D-丙胺酸之培養基進行培養的HaCaT細胞之單位細胞數量之層黏連蛋白332濃度的相對值分別為0.07、0.11及0.10。於添加1 μM之D-丙胺酸與陰性對照之間,於Scheffe's F-檢驗中p未達1%,於混合添加各0.5 μM之D-丙胺酸及L-丙胺酸與陰性對照之間,於Scheffe's F-檢驗中p未達5%,於1 μM之D-丙胺酸與1 μM之L-丙胺酸之間,於Scheffe's F-檢驗中p未達5%,均有顯著差異。因此,證明與KC細胞同樣,在HaCaT細胞中亦藉由添加D-丙胺酸而促進層黏連蛋白332產生。
(5) 藉由添加羥基脯胺酸之HaCaT細胞之層黏連蛋白332之產生
圖6中表示研究添加羥基脯胺酸對HaCaT細胞中產生層黏連蛋白332之效果之實驗結果。圖6之圖表的縱軸表示各孔之培養上清液中單位細胞數量之層黏連蛋白332濃度的相對值。各實驗條件之誤差棒表示於相同條件下重複3次之實驗結果的計算值之標準偏差。
單位細胞數量之層黏連蛋白332濃度的相對值於陰性對照中為0.04。利用添加1 μM之L-羥基脯胺酸之培養基、添加1 μM之D-羥基脯胺酸之培養基、添加各0.5 μM之L-及D-羥基脯胺酸之培養基進行培養的HaCaT細胞之單位細胞數量的層黏連蛋白332濃度之相對值分別為0.05、0.065及0.06。
2. 藉由添加各種胺基酸之層黏連蛋白332產生量之比較
2-1. 材料與方法
細胞係使用HaCaT細胞,以與實施例1相同之方式進行培養。其後,上述細胞係於將10 nM、100 nM及1000 nM之L-或D-丙胺酸、或者L-或D-羥基脯胺酸、或者L-或D-天冬醯胺酸、或者L-或D-天冬醯胺、或者L-或D-脯胺酸、或者L-或D-絲胺酸的胺基酸添加於通常培養基中而獲得之培養基中替換培養24小時。使用未添加上述胺基酸之上述通常培養基作為陰性對照。本實施例中所使用之D-羥基脯胺酸為4-順-D-羥基脯胺酸。層黏連蛋白332產生量以與實施例1相同之方式進行測定。再者,以下實驗中,藉由添加胺基酸所致之細胞毒性在任何濃度下均未發現,因此於各實驗條件下對細胞之層黏連蛋白332產生量進行比較。
2-2. 結果
(1) 添加丙胺酸
圖7中表示研究添加各種濃度之丙胺酸對HaCaT細胞中產生層黏連蛋白332之效果之實驗結果。圖7之圖表的縱軸表示各孔之培養上清液中之層黏連蛋白332濃度(ng/mL)。各實驗條件之誤差棒係於相同條件下重複4次之實驗結果的計算值之標準偏差。
層黏連蛋白332濃度於陰性對照中為1.7 ng/mL。利用10 nM、100 nM及1000 nM之添加L-丙胺酸之培養基及添加D-丙胺酸之培養基進行培養的HaCaT細胞之層黏連蛋白332濃度分別為1.7 ng/mL及1.7 ng/mL、2.3 ng/mL及3.4 ng/mL、2.8 ng/mL及4.8 ng/mL。由以上結果表明,D-丙胺酸係以100 ng/mL以上之濃度促進層黏連蛋白332產生。
(2) 添加羥基脯胺酸
圖8中表示研究添加各種濃度之羥基脯胺酸對HaCaT細胞中產生層黏連蛋白332之效果之實驗結果。圖8之圖表的縱軸表示各孔之培養上清液中之層黏連蛋白332濃度(ng/mL)。各實驗條件之誤差棒表示於相同條件下重複4次之實驗結果的計算值之標準偏差。
層黏連蛋白332濃度於陰性對照中為1.5 ng/mL。利用10 nM、100 nM及1000 nM之添加L-羥基脯胺酸之培養基及添加D-羥基脯胺酸之培養基進行培養的HaCaT細胞之層黏連蛋白332濃度分別為1.5 ng/mL及1.5 ng/mL、2.3 ng/mL及3.3 ng/mL、2.7 ng/mL及4.4 ng/mL。由以上結果表明,D-羥基脯胺酸係以100 ng/mL以上之濃度促進層黏連蛋白332產生。
(3) 添加天冬醯胺酸
圖9中表示研究添加各種濃度之天冬醯胺酸對HaCaT細胞中產生層黏連蛋白332之效果之實驗結果。圖9之圖表的縱軸表示各孔之培養上清液中之層黏連蛋白332度(ng/mL)。各實驗條件之誤差棒表示於相同條件下重複4次之實驗結果的計算值之標準偏差。
層黏連蛋白332濃度於陰性對照中為1.7 ng/mL。利用10 nM、100 nM及1000 nM之添加L-天冬醯胺酸之培養基及添加D-天冬醯胺酸之培養基進行培養的HaCaT細胞之層黏連蛋白332濃度分別為1.8 ng/mL及1.9 ng/mL、1.8 ng/mL及1.9 ng/mL、2.0 ng/mL及1.7 ng/mL。由以上結果表明,L-及D-天冬醯胺酸並不促進層黏連蛋白332產生。
(4) 添加天冬醯胺
圖10中表示研究添加各種濃度之天冬醯胺對HaCaT細胞中產生層黏連蛋白332之效果之實驗結果。圖10之圖表的縱軸表示各孔之培養上清液中之層黏連蛋白332濃度(ng/mL)。各實驗條件之誤差棒表示於相同條件下重複4次之實驗結果的計算值之標準偏差。
層黏連蛋白332濃度於陰性對照中為1.5 ng/mL。利用10 nM、100 nM及1000 nM之添加L-天冬醯胺之培養基及添加D-天冬醯胺之培養基進行培養的HaCaT細胞之層黏連蛋白332濃度分別為1.6 ng/mL及1.5 ng/mL、1.5 ng/mL及1.5 ng/mL、1.6 ng/mL及1.5 ng/mL。由以上結果表明,L-及D-天冬醯胺並不促進層黏連蛋白332產生。
(5) 添加脯胺酸
圖11中表示研究添加各種濃度之脯胺酸對HaCaT細胞中產生層黏連蛋白332之效果之實驗結果。圖11之圖表的縱軸表示各孔之培養上清液中之層黏連蛋白332濃度(ng/mL)。各實驗條件之誤差棒表示於相同條件下重複4次之實驗結果的計算值之標準偏差。
層黏連蛋白332濃度於陰性對照中為1.8 ng/mL。利用10 nM、100 nM及1000 nM之添加L-脯胺酸之培養基及添加D-脯胺酸之培養基進行培養的HaCaT細胞之層黏連蛋白332濃度分別為1.8 ng/mL及2.0 ng/mL、1.9 ng/mL及1.9 ng/mL、1.9 ng/mL及1.9 ng/mL。由以上結果表明,L-及D-脯胺酸並不促進層黏連蛋白332產生。
(6) 添加絲胺酸
圖12中表示研究添加各種濃度之絲胺酸對HaCaT細胞中產生層黏連蛋白332之效果之實驗結果。圖12之圖表的縱軸表示各孔之培養上清液中之層黏連蛋白332濃度(ng/mL)。各實驗條件之誤差棒表示於相同條件下重複4次之實驗結果的計算值之標準偏差。
層黏連蛋白332濃度於陰性對照為1.7 ng/mL。利用10 nM、100 nM及1000 nM之添加L-絲胺酸之培養基及添加D-絲胺酸之培養基進行培養的HaCaT細胞之層黏連蛋白332濃度分別為1.8 ng/mL及1.8 ng/mL、1.9 ng/mL及1.8 ng/mL、1.9 ng/mL及1.8 ng/mL。由以上結果表明,L-及D-絲胺酸並不促進層黏連蛋白332產生。
結論
根據實施例1及2之實驗結果,層黏連蛋白332產生促進效果於D-丙胺酸及D-羥基脯胺酸中得到確認,而於天冬醯胺酸、天冬醯胺、脯胺酸及絲胺酸中並未發現。因此顯示出,D-丙胺酸及D-羥基脯胺酸會促進對於基底膜之結構及功能發揮重要作用的層黏連蛋白332之產生,藉此可抑制及/或改善皮膚狀態。
基於本發明,以下表示包含D-丙胺酸及/或D-羥基脯胺酸之乳液製劑、貼劑、片劑、軟膠囊、顆粒、飲料、糖果、曲奇、味噌、法式沙拉醬、蛋黃醬、法式麵包、醬油、酸乳酪、香松、調味料‧納豆佐料汁、納豆、未過濾黑醋、霜劑、身體用潤膚霜、凝膠劑、撕除式面膜(peel off mask)、含浸式面膜、乳液、化妝水及氣溶劑之調配例。該等調配例係以例示為目的而列舉者,且並非旨在限定本發明之技術範圍。
調配例1(乳液製劑)
調配例2(貼劑)
調配例3(片劑)
調配例4(片劑)
調配例5(軟膠囊)
調配例6(軟膠囊)
調配例7(顆粒)
調配例8(飲料)
調配例9(糖果)
調配例10(曲奇)
調配例10(曲奇)之製造方法
一面攪拌黃油一面緩慢添加精製細砂糖,添加雞蛋及香料、以及D-丙胺酸或D-羥基脯胺酸並加以攪拌。充分混合後,添加均勻地過篩之低筋麵粉並低速攪拌,以塊狀置於冷庫中。其後,進行成型並於170℃下焙燒15分鐘而製成曲奇。
調配例11(味噌)
調配例11(味噌)之製造方法
將米曲與鹽充分地混合。將洗淨之大豆於3倍量之水中浸泡一晚後去除水,一面添加新的水一面煮,再倒入笸籮中。收集煮汁(種水),以達到10% w/v之方式溶解D-丙胺酸或D-羥基脯胺酸。將煮熟之豆立即磨碎,添加混有鹽之米曲,一面補充上述溶解有D-丙胺酸或D-羥基脯胺酸之種水,一面均勻地混合至黏土程度之硬度。將搓成團子狀者以無間隙之方式緊密地塞入桶之各個角落,使表面平整並用保鮮膜覆蓋密封。3個月後更換容器,使表面平整並用保鮮膜覆蓋。再者,可使用大量產生D-丙胺酸或D-羥基脯胺酸之米曲來代替將D-丙胺酸或D-羥基脯胺酸添加至種水中。為獲得上述米曲,可藉由日本專利特開2008-185558中記載之方法,對D-丙胺酸或D-羥基脯胺酸進行定量而挑選。又,亦可於市售之味噌中添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽。
調配例12(法式沙拉醬)
調配例12(法式沙拉醬)之製造方法
於醋中添加氯化鈉、及D-丙胺酸或D-羥基脯胺酸後,充分地攪拌溶解。添加沙拉油並充分地攪拌再添加胡椒。
調配例13(蛋黃醬)
調配例13(蛋黃醬)之製造方法
於蛋黃(室溫)中添加醋、氯化鈉及胡椒、以及D-丙胺酸或D-羥基脯胺酸,利用起泡器充分地攪拌。一點一點地添加沙拉油並繼續攪拌而製成乳化液。最後添加砂糖並加以攪拌。
調配例14(法式麵包)
調配例14(法式麵包)之製造方法
於溫水中投入砂糖1 g及乾酵母使之預備醱酵。將高筋麵粉、低筋麵粉、氯化鈉、砂糖5 g、以及D-丙胺酸或D-羥基脯胺酸投入盆中,向其中投入經預備醱酵之酵母。充分捏和後製成球狀於30℃下使之進行一次醱酵。將麵團再次捏和後加以醒置,其後整形為適當之形狀,使用電子醱酵機使之進行最終醱酵。切開並於220℃之烘箱中焙燒30分鐘。
調配例15(醬油)
調配例15(醬油)之製造方法
於市售之醬油中添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽並充分地攪拌。又,可使用大量產生D-丙胺酸或D-羥基脯胺酸之曲代替添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽而釀造醬油。為獲得上述曲,可藉由日本專利特開2008-185558中記載之方法對D-丙胺酸或D-羥基脯胺酸進行定量而挑選。
調配例16(酸乳酪)
調配例16(酸乳酪)之製造方法
於40℃~45℃下使之醱酵。可使用其他市售之種菌,亦可於市售之酸乳酪中添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽。又,亦可使用大量產生D-丙胺酸或D-羥基脯胺酸之菌來代替添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽。為獲得上述菌,可藉由日本專利特開2008-185558中記載之方法,對D-丙胺酸或D-羥基脯胺酸進行定量而挑選。
調配例17(香松)
調配例18(調味料‧納豆佐料汁)
調配例19(納豆)
調配例19(納豆)之製造方法
於市售之納豆中添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽並充分地攪拌。又,可使用大量產生D-丙胺酸或D-羥基脯胺酸之菌來代替添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽而製作納豆。為獲得上述菌,可藉由日本專利特開2008-185558中記載之方法,對D-丙胺酸或D-羥基脯胺酸進行定量而挑選。
調配例20(未過濾黑醋)
調配例20(未過濾黑醋)之製造方法
於市售之未過濾黑醋中添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽並充分地攪拌。可使用大量產生D-丙胺酸或D-羥基脯胺酸之菌來代替添加D-丙胺酸或D-羥基脯胺酸、或者該等之鹽而製作醋、黑醋、酒糟。為獲得上述菌,可藉由日本專利特開2008-185558中記載之方法,對D-丙胺酸或D-羥基脯胺酸進行定量而挑選。
調配例21(霜劑)
調配例22(身體用潤膚霜)
調配例23(凝膠劑)
調配例24(撕除式面膜)
調配例25(含浸式面膜)
調配例26(乳液)
調配例27(乳液)
調配例28(化妝水)
調配例29(化妝水)
調配例30(氣溶脲外用劑原液)
調配例31(氣溶脲噴射劑)
調配例31(氣溶脲噴射劑)之填充方法
將氣溶脲外用劑原液及二甲醚填充至內面特氟綸(Teflon)(註冊商標)塗佈處理耐壓氣溶鋁罐中,而製備氣溶劑。
圖1係表示D-丙胺酸對KC細胞之影響之圖表;
圖2係表示D-丙胺酸對KC細胞中產生層黏連蛋白332之效果之圖表;
圖3係表示D-丙胺酸對HaCaT細胞之影響之圖表;
圖4係表示D-羥基脯胺酸對HaCaT細胞之影響之圖表;
圖5係表示D-丙胺酸對HaCaT細胞中產生層黏連蛋白332之效果之圖表;
圖6係表示D-羥基脯胺酸對HaCaT細胞中產生層黏連蛋白332之效果之圖表;
圖7係表示各種濃度之D-丙胺酸對HaCaT細胞中產生層黏連蛋白332之效果之圖表;
圖8係表示各種濃度之D-羥基脯胺酸對HaCaT細胞中產生層黏連蛋白332之效果之圖表;
圖9係表示各種濃度之D-天冬醯胺酸對HaCaT細胞中產生層黏連蛋白332之效果之圖表;
圖10係表示各種濃度之D-天冬醯胺對HaCaT細胞中產生層黏連蛋白332之效果之圖表;
圖11係表示各種濃度之D-脯胺酸對HaCaT細胞中產生層黏連蛋白332之效果之圖表;及
圖12係表示各種濃度之D-絲胺酸對HaCaT細胞中產生層黏連蛋白332之效果之圖表。
(無元件符號說明)
Claims (6)
- 一種選自由D-丙胺酸及D-羥基脯胺酸、與D-丙胺酸及D-羥基脯胺酸之鹽所組成之群中的1種或2種以上之化合物的用途,其特徵在於:其係用於製造層黏連蛋白332產生促進組合物者。
- 如請求項1之用途,其中上述層黏連蛋白332產生促進組合物係用於抑制及/或改善皮膚狀態。
- 如請求項2之用途,其中上述皮膚狀態選自由光老化、皺紋、肌膚粗糙、細紋及乾燥所組成之群。
- 如請求項1至3中任一項之用途,其中上述層黏連蛋白332產生促進組合物係用作醫藥品。
- 如請求項1至3中任一項之用途,其中上述層黏連蛋白332產生促進組合物係用作皮膚外用劑。
- 如請求項1至3中任一項之用途,其中上述層黏連蛋白332產生促進組合物係用作食品。
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2010
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Also Published As
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EP2484355A1 (en) | 2012-08-08 |
EP2484355B1 (en) | 2015-07-08 |
TW201110997A (en) | 2011-04-01 |
RU2012114586A (ru) | 2013-11-10 |
EP2484355A4 (en) | 2013-04-03 |
KR20120080178A (ko) | 2012-07-16 |
US8586622B2 (en) | 2013-11-19 |
JP6023428B2 (ja) | 2016-11-09 |
BR112012007611A2 (pt) | 2016-08-23 |
ES2544268T3 (es) | 2015-08-28 |
AU2010302036A1 (en) | 2012-04-19 |
CN102939083A (zh) | 2013-02-20 |
JPWO2011040082A1 (ja) | 2013-02-21 |
RU2581916C2 (ru) | 2016-04-20 |
US20120184593A1 (en) | 2012-07-19 |
WO2011040082A1 (ja) | 2011-04-07 |
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