TWI798936B - 猴頭菇菌絲體活性物質用於預防或治療視網膜病變之用途 - Google Patents
猴頭菇菌絲體活性物質用於預防或治療視網膜病變之用途 Download PDFInfo
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Abstract
本發明提供一種猴頭菇菌絲體活性物質之用途,其可用於製備預防或治療視網膜病變之組合物。所述猴頭菇菌絲體活性物質係以下列步驟製備而成:(a)取猴頭菇菌絲體於平板培養基上,於15-35℃之溫度下培養7-15天;(b)將步驟(a)培養後之猴頭菇菌絲體接種至燒瓶內,於15-35℃、pH 2-8之環境培養3-5天;(c)將步驟(b)培養後之猴頭菇菌絲體接種於發酵槽內,於15-35℃、pH 4.5-5.5之環境下攪拌培養7-15天,形成含有猴頭菇菌絲體活性物質之猴頭菇菌絲體發酵液。
Description
本發明關於一種猴頭菇菌絲體活性物質之用途,特別是指以猴頭菇菌絲體製備用以預防或治療視網膜病變的組合物。
老年性黃斑部病變(Age-related macular degeneration,AMD)是負責視力和色覺的視網膜黃斑部漸進退化性之疾病,主要是因中央視網膜感光接受器死亡所引起。位於感光層和脈絡膜之間的視網膜色素上皮(retinal pigment epithelium,RPE)細胞也與早期AMD的發病機制有關。如其名稱「老年性」所述,AMD的患病率隨著年齡的增長而逐漸增加,成為老年人失明的主要原因。
AMD的發病機制與許多因素有關,如代謝紊亂,免疫,炎症,活性氧物質(reactive oxygen species;ROS)等。近年的研究顯示ROS所造成的氧化壓力是AMD的主要致病因子。在過去的幾十年中,用來治療AMD的方法包括:(1)光凝固雷射(laserphotocoagulation)、(2)經瞳熱療雷射(transpupillary thermotherapy TTT)、(3)光動力療法(photodynamictherapy PDT)、(4)抗血管生成療法(antiangiogenic therapy)、(5)營養補充療法、(6)基因治療、(7)抗氧化劑
與(8)合併上述療法等,但手術療法具副作用,且術後失明率仍在增加。因此,開發具有較低毒性的新型治療劑對於AMD的預防或治療相當重要。
猴頭菇Hericium erinaceus(Bull.)Pers是一種珍貴的藥膳兼用真菌,主要分布於緯度較高的溫帶地區。《中國野菜食譜大全》認為其可治消化不良、胃潰瘍、胃炎、胃痛、胃脹及神經衰弱等病症,顯示猴頭菇除美味以外,具有胃部保護功能,可作為食藥兩用菇。1994年起Kawagishi從猴頭菇菌絲體分離純化多種猴頭素(A、B、C等),猴頭素可刺激老鼠星狀細胞,增加神經生長因子分泌量(NGF),而NGF可治療智力衰退、神經衰弱等疾病,故猴頭菇亦被認為可促進神經及大腦健康。然而,目前並無研究指出猴頭菇對視網膜病變具有療效。
本發明提供一種猴頭菇(Hericium erinaceus)菌絲體活性物質的用途,其係用於製備預防或治療視網膜病變之組合物。該猴頭菇菌絲體活性物質的製備方法包括下列步驟:(a)取一猴頭菇菌絲體於平板培養基上,於15-35℃之溫度下培養7-15天;(b)將步驟(a)培養後之猴頭菇菌絲體接種至一燒瓶內,於15-35℃、pH 2-8之環境培養3-5天;(c)將步驟(b)培養後之猴頭菇菌絲體接種於一發酵槽內,於15-35℃、pH 4.5-5.5之環境下攪拌培養7-15天,形成含有該猴頭菇菌絲體活性物質之一猴頭菇菌絲體發酵液。
一實施例中,製備該猴頭菇菌絲體活性物質的步驟更包括步驟(d):將該猴頭菇菌絲體發酵液冷凍乾燥後磨粉,形成含有該猴頭菇菌絲體活性物質之一猴頭菇菌絲體凍乾粉。
一實施例中,製備該猴頭菇菌絲體活性物質的步驟更包括步驟(e):將該猴頭菇菌絲體凍乾粉以一溶劑萃取,形成含有該猴頭菇菌絲體活性物質之一猴頭菇菌絲體萃取液。
一實施例中,製備該猴頭菇菌絲體活性物質的步驟更包括步驟(f):將該猴頭菇菌絲體萃取液乾燥,以獲得該猴頭菇菌絲體活性物質。
一實施例中,在步驟(e)中的溶劑為乙醇,且該猴頭菇菌絲體凍乾粉以乙醇重複萃取二次。
一實施例中,步驟(b)之燒瓶培養為震盪培養,且轉速為10-250rpm。
一實施例中,該視網膜病變為黃斑部病變。
一實施例中,步驟(c)中該發酵槽係進一步通入一氣體,該氣體包括空氣、氧氣、二氧化碳、氦氣或其組合,該發酵槽的槽壓為0.5-2.0kg/cm2且通氣速率為0.5-1VVM。
一實施例中,該組合物為醫藥組合物,且該醫藥組合物進一步包含藥學上可接受之載劑、賦形劑、稀釋劑或輔劑。
一實施例中,該組合物為食品添加劑。
一實施例中,該組合物的施用方式為口服。
為使本發明之上述及其他方面更為清楚,下文特舉實施例,並配合所附圖式進行說明。
圖1為各組小鼠的光學斷層掃描(Optical Coherence Tomography)圖;圖2為圖1的視網膜厚度測量結果;圖3(A)為各組小鼠眼睛的蘇木精&伊紅染色(H&E stain)照片,圖3(B)為圖3(A)的紅色虛線框放大圖;圖4(A)為圖3(A)的內核層INL厚度測量結果,圖4(B)為圖3(A)的外核層ONL厚度測量結果。
猴頭菇菌絲體來源
本發明之實施例所用之猴頭菇(Hericium erinaceus)菌種,購自於台灣財團法人食品工業研究所,寄存編號為BCRC 35669。該菌株係可由BCRC之官方網站(https://catalog.bcrc.firdi.org.tw/)直接購得,為公眾可輕易取得之菌株。但本發明所述之猴頭菇活性物質不限於由此菌種所得。
菌絲體液體培養
將猴頭菇菌絲體接種於平板培養基上,於適當溫度15-35℃(較佳為25℃)下培養7-15天,刮取菌絲接種於燒瓶內。在15-35℃(較佳為25℃),pH 2-8(較佳為pH 4-7,更佳為pH 5.5),震盪速率100-250rpm的條件下培養3-5天,然後將燒瓶培養物接種於發酵槽培養基(同燒瓶培養基)內,在15-35℃(較佳為25℃),槽壓0.5-2.0kg/cm2,pH 4.5-5.5,10-150rpm攪拌速度或不攪拌(air lift)情況,以0.5-1VVM通氣速率通入空氣,或空氣、氧氣、二氧化碳、氮氣及上述氣體之混合物(較佳者為空氣),培養時間為7-15天內,即得猴頭菇菌絲體發酵
液。此發酵液包括菌絲體與澄清液。前述培養條件僅為例示,使用者可視情況調整。
其中該綜合性碳氮源可為穀類(如:麥粉類)或豆類(如:黃豆粉、綠豆粉、大豆粉等)。該無機鹽類可為硫酸鎂、磷酸氫二鉀、磷酸二氫鉀、硫酸鐵等。該醣類可為葡萄糖、果糖、麥芽糖、蔗糖等。特別說明的是,本發明使用的培養基並不限制為上述成份或比例,使用者可視實際情況進行調整。
發酵液乾燥
此猴頭菇菌絲體發酵液可進一步藉由乾燥步驟製備為凍乾粉等其他劑型。乾燥方法包括但不限於:噴霧乾燥、熱風乾燥、滾筒乾燥、冷凍乾燥或其他方式。
凍乾粉萃取-乙醇萃取
取猴頭菇菌絲體凍乾粉加入25倍體積之乙醇進行第1次萃取,利用超音波震盪萃取1小時,取懸浮液進行離心。離心後取上清液,將殘渣重複上述萃取步驟,以乙醇進行第二次萃取。第二次萃取獲得的上清液與第一次萃取的上清液混合,經減壓濃縮,得膏狀的猴頭菇菌絲體乙醇萃取物,其中包含猴頭菇菌絲體活性物質。重複萃取兩次的原因係為了獲得較高的產率。
上述猴頭菇菌絲體發酵液、猴頭菇菌絲體凍乾粉、猴頭菇菌絲體乙醇萃取物皆含有本發明之猴頭菇菌絲體活性物質。以下根據上述方法製備猴頭菇菌絲體活性物質,並進行生物實驗評估其功效。
菌株:本發明之實施例所用之猴頭菇(Hericium erinaceus)菌種係購自於財團法人食品工業研究所,寄存編號為BCRC 35669。
平板培養:將菌絲體接種於平板培養基上,培養基為馬鈴薯糊精培養基(Potato Dextrose Agar,PDA),於25℃下培養7天。
燒瓶培養:刮取平板上之菌絲接種於燒瓶內,用下列培養基配方,在25℃,pH 5.0下,於震盪機上以轉速120rpm震盪培養5天;
發酵槽培養:培養基同上,將燒瓶培養物接種於發酵槽培養基內,在25℃,槽壓1.0kg/cm2,pH 5.0下,50rpm攪拌速度,以1.0VVM通氣速率通入空氣,培養12天,得猴頭菇菌絲體發酵液。該猴頭菇菌絲體發酵液經冷凍乾燥可得猴頭菇菌絲體凍乾粉。
萃取物製備:將猴頭菇菌絲體凍乾粉加入為凍乾粉25倍重量的95 v/v%乙醇進行第一次萃取,接著利用超音波震盪以震盪速率120rpm萃取一
小時,取懸浮液進行離心,離心後取上清液。將第一次萃取之殘渣重複上述萃取步驟以85v/v%乙醇進行第二次萃取。兩次萃取離心得到的上清液混合,經減壓濃縮,得膏狀的猴頭菇菌絲體乙醇萃取物(簡稱醇萃物)。
結果:20公噸發酵槽培養完畢之猴頭菇菌絲體發酵液經冷凍乾燥後,可得約320公斤凍乾粉,再經二次萃取步驟,可得約20公斤乙醇萃取物。以下生物實驗係以猴頭菇菌絲體乙醇萃物進行。
視網膜病變小鼠動物模式之建立
碘酸鈉(Sodium iodate,NaIO3)為一種穩定的氧化劑,已被證明是一種誘導視網膜變性的有效方法。碘酸鈉引起的視網膜變性與視網膜色素上皮細胞(RPE)的區域性喪失相關,同時也會出現區域性萎縮的一些形態學特徵。已有許多研究利用不同的哺乳動物之物種證實了NaIO3對生物視網膜具有毒性,包括綿羊、兔子、大鼠和小鼠。上述的研究指出在視網膜中,NaIO3主要標靶為RPE細胞,可誘導其死亡,如壞死(necrosis)、細胞凋亡(apoptosis)或細胞自噬(autophagy),其次是脈絡膜毛細血管萎縮(choriocapillaris atrophy)和全視網膜變性(panretinal degeneration)。
近年來,研究學者以低劑量NaIO3(15-35mg/kg)來誘導小鼠產生老年性黃斑部病變(Age-related macular degeneration,AMD)模型,發現其與視功能下降以及局部性RPE流失和外部視網膜損傷有關,與乾性AMD的共同發病機制極為相似,因此近年來大多以此模式來探討RPE再生及AMD的預防。
本實施例使用40mg/kg劑量NaIO3誘發小鼠產生AMD,藉此評估猴頭菇菌絲體活性物質對於視網膜病變(特別是黃斑部病變)的預防及治療效果。
實驗動物:品系Balb/c雄性小鼠購自台灣國家實驗動物中心,年齡約6-8周,體重約26.21±1.76g克。小鼠飼養於中山醫學大學實驗動物中心,提供正常潔淨飼料及飲水,飼養環境為12小時照光及12小時黑暗之循環光照,溫度控制在20±2℃,濕度控制在50±5%。
餵食劑量與實驗步驟
本試驗共進行21天,試驗進行前將小鼠分為4組,每組6隻:
(1)空白對照組(Mock):以靜脈注射(i.v.)磷酸鹽緩衝生理鹽水(PBS)100μL後,並以每日口餵方式給予PBS 200μL。
(2)負對照組:以靜脈注射(i.v.)給予碘酸鈉NaIO3 40mg/kg,誘發AMD,並以每日口餵方式給予PBS 200μL。
(3)猴頭菇乙醇萃取物組(實驗組):先以每日口餵方式給予實施例一製得的猴頭菇乙醇萃取物100mg/kg 14天後,再以靜脈注射給予碘酸鈉NaIO3 40mg/kg誘發AMD,之後再每日餵食猴頭菇乙醇萃取物100mg/kg 7天。
各組小鼠在實驗21天後犧牲進行視網膜損傷程度檢測及相關指標分析。
視網膜損傷程度檢測及相關指標分析
1.眼底影像偵測
使用Phoenix-Micro IV眼底影像偵測系統,可檢測光學眼底鏡、螢光眼底造影以及視網膜斷層掃描儀,並以此依據評估小鼠視網膜組織完整性與平滑度改變。圖1為各組小鼠注射碘酸鈉第7天後的光學斷層掃描(Optical Coherence Tomography)圖。
對圖1小鼠以視神經為中心,鼻側與顳側300μm~600μm的範圍(黃線示意處)進行6次厚度(紅線範圍)測量後,計算其平均值,可得小鼠的視網膜厚度,其結果列為圖2。
請參圖1的光學斷層掃描圖,Mock組紅線標記部分可看出視網膜結構完整。至於單獨施打碘酸鈉的小鼠組別(NaIO3)的視網膜排列較不規則、鬆散,且組織間的排序較不平滑、界線較為模糊,有明顯視網膜扭曲的情形發生。而經由猴頭菇菌絲體萃取物預先處理的小鼠組別(HE)與單獨施打碘酸鈉的小鼠組別(NaIO3)相比,視網膜排列不規則與模糊的情形有明顯較少的現象。
圖2視網膜厚度測量的結果則顯示(其中*號標記表示與單獨加入NaIO3組別相比,p<0.05,有顯著差異),與空白對照組(Mock)相比,單獨施打碘酸鈉的小鼠組別(NaIO3)在接受碘酸鈉注射7天後,視網膜厚度有明顯變薄情形。而經由猴頭菇菌絲體萃取物(HE)預先處理預先處理的小鼠組別與單獨施打碘酸鈉的小鼠組別(NaIO3)相比,雖然厚度仍有變薄,但仍有顯著回升。
據此,可得知本發明實施例的猴頭菇菌絲體萃取物可減緩碘酸鈉NaIO3所誘導之小鼠視網膜扭曲與變薄,進而改善AMD的情形。
2.組織病理分析(H&E stainine)
將各組小鼠於注射碘酸鈉第7天後進行犧牲採血,眼睛做組織切片後,以蘇木精和伊紅染色,區別RPE的結構與型態,其照片如圖3(A)所示。圖3(B)為圖3(A)的紅色虛線框放大圖,用以觀察內核層(Inner nuclear layer,INL)與外核層(Outer nuclear layer,ONL)厚度,以及觀察發炎細胞的數量。
INL及ONL層厚度測試皆是以視神經為中心,在其鼻側與顳側300μm~600μm進行6次厚度(圖3(B)黃線標記)測量後,計算其平均值,其結果分別列於圖4(A)與圖4(B),其中*號標記表示與單獨加入NaIO3組別相比,p<0.05,有顯著差異。
與空白對照組(Mock)相比,單獨施打碘酸鈉的小鼠組別(NaIO3)在接受碘酸鈉注射7天後,視網膜ONL與INL層厚度皆有變薄的情形。而經由猴
頭菇菌絲體萃取物(HE)預先處理的小鼠組別與單獨施打碘酸鈉的小鼠組別(NaIO3)相比,可顯著減緩碘酸鈉誘導之小鼠視網膜ONL與INL層厚度變薄。
據此,可得知本發明實施例的猴頭菇菌絲體萃取物可減緩碘酸鈉(NaIO3)誘導之小鼠視網膜內核層與外核層變薄,進而改善AMD的情形。
本實施例之猴頭菇菌絲體活性物質若應用於醫藥用途,則以下組合物1之態樣作為例示性實例。
組合物1:取實施例一之猴頭菇菌絲體活性物質的凍乾粉或水萃物(20wt%),與作為潤滑劑的硬脂酸鎂(8wt%)、作為防腐劑的二氧化矽(7wt%)充分混合,並溶於純水(65wt%)中,存放於4℃備用。前述wt%係指各成分佔組合物總重之比例。
不過,雖然實施例二中的猴頭菇菌絲體活性物質係以口服方式餵食小鼠,但實際應用上亦可採用如滴劑、栓劑等其他方式。
本揭露之菌種若以液體劑型應用於食品用途,則以下組合物2之態樣作為例示性實例。
組合物2:取實施例一之猴頭菇菌絲體活性物質的凍乾粉或水萃物(20wt%),與作為防腐劑之苯乙醇(8wt%)、作為稀釋劑之甘油(7wt%)、作為稀釋劑之蔗糖(10wt%)充分混合,並溶於純水(55wt%)中,存放於4℃備用。前述wt%係指各成分佔組合物總重之比例。
Claims (7)
- 一種猴頭菇(Hericium erinaceus)菌絲體活性物質用於製備預防或治療老年性黃斑部病變之組合物的用途,其中該猴頭菇菌絲體活性物質的製備方法包括下列步驟:(a)取一猴頭菇菌絲體於平板培養基上,於15-35℃之溫度下培養7-15天;(b)將步驟(a)培養後之猴頭菇菌絲體接種至一燒瓶內,於15-35℃、pH 2-8之環境培養3-5天;(c)將步驟(b)培養後之猴頭菇菌絲體接種於一發酵槽內,於15-35℃、pH 4.5-5.5之環境下攪拌培養7-15天,形成含有該猴頭菇菌絲體活性物質之一猴頭菇菌絲體發酵液;(d)將該猴頭菇菌絲體發酵液冷凍乾燥後磨粉,形成含有該猴頭菇菌絲體活性物質之一猴頭菇菌絲體凍乾粉;(e)將該猴頭菇菌絲體凍乾粉以一溶劑萃取,形成含有該猴頭菇菌絲體活性物質之一猴頭菇菌絲體萃取液;及(f)將該猴頭菇菌絲體萃取液乾燥,以獲得該猴頭菇菌絲體活性物質。
- 如請求項1所述之用途,其中在步驟(e)中,該溶劑為乙醇,且該猴頭菇菌絲體凍乾粉以乙醇重複萃取二次。
- 如請求項1所述之用途,其中步驟(b)之燒瓶培養為震盪培養,且轉速為10-250rpm。
- 如請求項1所述之用途,其中步驟(c)中該發酵槽進一步通入一氣體,該氣體包括空氣、氧氣、二氧化碳、氦氣或其組合,該發酵槽的槽壓為0.5-2.0kg/cm2且通氣速率為0.5-1VVM。
- 如請求項1所述之用途,其中該組合物為醫藥組合物,該醫藥組合物進一步包含藥學上可接受之載劑、賦形劑、稀釋劑或輔劑。
- 如請求項1所述之用途,其中該組合物為食品添加劑。
- 如請求項1所述之用途,其中該組合物的施用方式包括口服、滴劑及栓劑。
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