TWI701335B - 用於預防及/或改善急性肺損傷的蟬花菌絲體活性物質、其製備方法以及用途 - Google Patents
用於預防及/或改善急性肺損傷的蟬花菌絲體活性物質、其製備方法以及用途 Download PDFInfo
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Abstract
本發明提供一種用於預防及/或改善急性肺損傷的蟬花菌絲體活性物質,該活性物質的製備方法,包括下列步驟:(a)取一蟬花菌絲體(
Cordyceps Cicadaemycelia)於平板培養基上,於15至30℃的溫度下培養1至2周;(b)將步驟(a)培養後的蟬花菌絲體接種至一燒瓶內,於15至30℃、pH 2至6的環境培養3至14天;(c)將步驟(b)培養後的蟬花菌絲體接種於一發酵槽內,於15至30℃、pH 2至6的環境下攪拌培養3至21天,形成含有該蟬花菌絲體活性物質的一蟬花菌絲體發酵液。
Description
本發明關於一種蟬花菌絲體活性物質、其製備方法及用途。具體來說,關於一種用於預防及/或改善急性肺損傷的蟬花菌絲體活性物質,其製備方法,以及其在食品或醫藥品中的用途。
衛生福利部公布2017年十大死因中,其中第一大死因中惡性腫瘤中第一位的氣管、支氣管和肺癌、第三大死因肺炎、第七大死因慢性下呼吸道疾病,共四項國人十大死因與肺部發炎有著密不可分的相關性。
美國公告的十大死因中,也有三項與肺部發炎相關的疾病,包括肺與支氣管癌、慢性呼吸道疾病、流感與肺炎。更進一步統計分析發現,在美國平均每年每100,000人中就有79與59人發生急性肺損傷(acute lung injury,ALI)與急性呼吸窘迫症(acute respiratory distress syndrome,ARDS)。其中ALI/ARDS所造成的死亡率約為43%,造成美國每年約有75,000人死亡。由於空氣污染日趨嚴重與平均餘命逐年提高的情況下,推測在美國在未來25年內,ALI/ARDS的發生率將成長2倍以上。
ALI與更嚴重的ARDS為臨床常見的急性肺發炎的代表性疾
病,皆會引發呼吸衰節而導致死亡,並與許多呼吸道疾病相關。
造成ALI的危險因子分二大類,分別是直接型因子是指危險因子源自於肺臟,包括細菌或病毒引起感染性肺炎、大量吸入胃酸或異物、肺部挫傷等;間接型因子是指危險因子非源自於肺臟,包括敗血症、長期酒精與藥物濫用、輸入人工血漿等。其中,細菌感染為ALI主要的危險因子,革蘭氏陰性菌為其中一大類,其外套膜的主成分為內毒素,又名脂多醣(lipopolysaccride,LPS)。
由於ALI因機制複雜、病死率高,目前臨床上尚無確切有效的控制病死率的藥物。但常用的治療方法有機械通氣、β2腎上腺素受體刺激劑、抗凝、溶栓、表面活性劑及手術等。因此,研究有效治療ALI的方法仍是重要的發展方向。
蟬花(Cordyceps cicadae)又名蟲花、土蟬花、胡蟬和蟬蛹草等,指在土中蟬幼蟲被麥角菌科(Clavicipitaceae)蟲草屬(Cordyceps)真菌孢子寄生致死的帶菌屍體,在蟬體頭部長出菌絲形成的子座,外形似花蕾。在本草綱目、證類本草、中華藥海中,指出蟬花主治小兒夜啼、心悸、止瘧疾,並具散風熱、鎮驚等功效。經成分分析後發現天然蟬花子實體與冬蟲夏草相近。
近代藥理研究分析,發現蟬花具有免疫調節、抗氧化、抗發炎、神經保護、抗癌的生物活性。然而,目前尚未有蟬花對改善ALI的研究。
本發明提供一種蟬花菌絲體活性物質及其製備方法,其可用於製備具預防及/或改善急性肺損傷的組合物。相較於一般西藥及治療方法,本發明揭露的液態發酵蟬花菌絲體活性物質的製備方法更為安全、簡便,製成的蟬
花菌絲體活性物質更天然、安全,並可有效改善ALI。
根據本發明的一實施例,提供用於製備改善ALI的蟬花菌絲體活性物質的製備方法,其係包括下列步驟:(a)取蟬花菌絲體(Cordyceps Cicadae mycelia)於平板培養基上,於15至30℃的溫度下培養1至2周;(b)將步驟(a)培養後的蟬花菌絲體接種至燒瓶內,於15至30℃、pH 2至6的環境培養3至14天;(c)將步驟(b)培養後的蟬花菌絲體接種於發酵槽內,於15至30℃、pH 2至6的環境下攪拌培養3至21天,形成含有蟬花菌絲體活性物質的蟬花菌絲體發酵液。
一實施例中,製備蟬花菌絲體活性物質的方法更包括步驟(d):將蟬花菌絲體發酵液冷凍乾燥後磨粉,形成含有該蟬花菌絲體活性物質的一蟬花菌絲體凍乾粉。
一實施例中,步驟(c)中的發酵槽進一步通入一氣體,此氣體包括空氣、氧氣、二氧化碳、氦氣或其組合,發酵槽的槽壓為0.5至1.0kg/cm2且通氣速率為0.01至1.5VVM。
本發明之另一實施態樣係提供一種蟬花菌絲體活性物質,其係以上述製備方法製造而成。
本發明之又一實施態樣係提供一種用於預防及/或改善急性肺損傷的組合物,其係包含上述的蟬花菌絲體活性物質,以及藥學上可接受的載劑、賦形劑、稀釋劑或輔劑。
本發明之再一實施態樣係提供一種上述蟬花菌絲體活性物質的用途,其係用於製備預防及/或改善急性肺損傷的組合物。
一實施例中,所述改善急性肺損傷係指肺部發炎的病理症狀減緩。
一實施例中,所述肺部發炎病理減緩係指肺泡的結構由破壞或融合趨向完整。
一實施例中,所述改善急性肺損傷係指蛋白質滲出反應降低。
一實施例中,所述改善急性肺損傷係指發炎細胞浸潤程度降低。
一實施例中,所述發炎細胞係指白血球、吞噬細胞及/或嗜中性白血球。
為使本發明的上述及其它方面更為清楚易懂,下文特舉實施例,並配合所附圖式詳細說明。
圖1繪示蟬花菌絲體凍乾粉經由腹腔注射,再利用內毒素經由鼻腔吸入誘發急性肺發炎模式中,可有效改善ALI的病理變化。
圖2繪示蟬花菌絲體凍乾粉經由腹腔注射,再利用內毒素經由鼻腔吸入誘發急性肺發炎模式中,可有效改善ALI的肺泡微血管障壁破壞。
圖3繪示蟬花菌絲體凍乾粉經由腹腔注射,再利用內毒素經由鼻腔吸入誘發急性肺發炎模式中,可有效改善ALI的白血球浸潤(A)、吞噬細胞(B)、嗜中性白血球(PMN)(C)。
圖4繪示蟬花菌絲體凍乾粉經由口服投予,再利用內毒素經由鼻腔吸入誘發急性肺發炎模式中可有效改善ALI的病理變化。
圖5繪示蟬花菌絲體凍乾粉經由口服投予,再利用內毒素經由
鼻腔吸入誘發急性肺發炎模式中,可有效改善ALI的肺泡微血管障壁破壞。
圖6繪示蟬花菌絲體凍乾粉經由口服投予,再利用內毒素經由鼻腔吸入誘發急性肺發炎模式中,可有效改善ALI的白血球浸潤(A)、吞噬細胞(B)、嗜中性白血球(PMN)(C)。
本發明的實施例所用的蟬花(Cordyceps cicadae)菌絲體係由採集而得的台灣野生蟬花子實體經分離而得其菌絲體,並繼代保存於平板培養基上。經台灣食品工業發展研究所做鑑定其基因序列後,證實為蟬花(Cordyceps cicadae),此菌株已公開寄存於財團法人食品工業發展研究所的生物資源研究中心(BCRC),其寄存編號為MU30106。但本發明所述的蟬花菌絲體活性物質之來源不限於由此菌種所得。
(1)平板培養:將蟬花菌絲體接種於平板上,於15至30℃下培養1至2周(本實施例中,係於25℃下培養7天)。平板培養基的成份可包含馬鈴薯糊精培養基(Potato Dextrose Agar,PDA)、碳源及氮源,並無特別限制。
(2)燒瓶培養:刮取(1)平板上的菌絲體接種於燒瓶中,並以15至30℃、pH 2至6及轉速110至130rpm的條件震盪培養3至14天(本實施例中,於25℃、pH 5、轉速120rpm的下震盪培養7天)。此震盪培養係以下表1所示的培養基進行培養。
上述培養基配方中,綜合性碳氮源可選自穀類(如:麥粉)或豆類(如:黃豆粉、綠豆粉、大豆粉、肉桂粉等);醣類可為葡萄糖、果糖、麥芽糖、蔗糖等;無機鹽類可為硫酸鎂、磷酸氫二鉀、磷酸二氫鉀、硫酸鐵等。特別說明的是,表1培養基配方僅為其中一種範例,使用時成份可依需求調整,或搭配市售培養基使用,並無特別限制。
(3)發酵槽培養:將(2)中燒瓶培養的菌絲體接種於發酵槽內,以15至30℃、槽壓0.5至1.0kg/cm2、pH 2至6及攪拌速度50至150rpm條件下,以0.1至1.5VVM的通氣速率培養3至21天,形成一蟬花菌絲體發酵液(本實施例中,係在25℃、槽壓0.5kg/cm2、pH 5,攪拌速度80rpm及1.0VVM(空氣)的條件下培養14天),即得蟬花菌絲體發酵液。發酵槽培養使用的培養基可與步驟(2)燒瓶培養使用的培養基相同、亦可另外配置適當培養基(本實施例以相同於步驟(2)之培養基培養)。此蟬花菌絲體發酵液內即含本發明的蟬花菌絲體活性物質。蟬花菌絲體發酵液可進一步藉由冷凍乾燥步驟製備為蟬花菌絲體發酵液凍乾粉。於本實施例中,100L的蟬花菌絲體發酵液可製得約3kg凍乾粉。
蟬花菌絲體活性物質的態樣可被包含於蟬花菌絲體發酵液
(菌絲體與澄清液)、發酵液凍乾粉、以及凍乾粉回溶於溶劑的型態或其他劑型。在一較佳實例中,該回溶凍乾粉的溶劑為水、乙醇或其組合。在一較佳實例中,作為該回溶凍乾粉的溶劑的水與乙醇的比例為1:1。以下實施例二中,係以蟬花菌絲體發酵液凍乾粉作為蟬花菌絲體活性物質態樣進行後續相關實驗分析。
細菌感染為ALI主要的危險因子,革蘭氏陰性菌為其中一大類,其外套膜的主成分為內毒素,又名脂多醣(lipopolysaccride,LPS)。在許多致病源中LPS是廣泛被接受造成肺部急性發炎最佳的誘發物,也是最接近臨床上急性發炎的模式。因此,若能抑制LPS造成的肺部發炎、免疫調解作用及機制,即能達到改善ALI的效果。目前已有實驗利用內毒素誘發的ALI疾病動物模式。可參照Yunhe Fu et al.(2017),Protective effect of TM6 on LPS-induced acute lung injury in mice,SCIENTIFIC REPORTS,7:572.。根據此篇論文中利用LPS建立老鼠的急性肺部發炎模式,在鼻腔內引入(intranasally,i.n.)LPS 50μg/20μL造成急性肺損傷,後續進行肺部病理、肺泡沖洗液總細胞數、蛋白質濃度及各種細胞激素的變化分析,用以評估合成肽例如:細胞可滲透衍生自TIR結構域的誘導胜肽(cell-permeable TIR domain-derived decoy peptide)對ALI的改善結果。本實驗中亦以LPS建立老鼠的急性肺部發炎模式,進行肺部病理、肺泡沖洗液總細胞數、蛋白質濃度及各種細胞激素的變化分析,評估蟬花菌絲體活性物質對ALI的改善結果。
運用BALB/c小鼠進行動物實驗,依施予途徑分為腹腔注射及口服兩大組,每大組再依施予物質不同,分為不施予任何物質的控制組(Control組)、僅施予LPS作為負對照組(LPS組)、施予LPS也施予蟬花菌絲
體活性物質凍乾粉組(CC mycelia組)、施予LPS也施予地塞米松(Dexamethasone)作為正對照組(DEX組),共計8組如下表2。每組6隻小鼠,共48隻小鼠。
針對施予途徑為腹腔注射的組別,內毒素組(LPS)利用鼻腔吸入施予20μl,LPS濃度為每隻小鼠50μg,24小時後犠牲小鼠取其檢體進
行後述分析。CC mycelia組首先將蟬花菌絲體凍乾粉回溶於水與乙醇以比例1:1配製的溶劑中,經超音波震盪以均質化,並確認無沉澱後,作為要施予的樣品。利用腹腔注射(i.p.)施予小鼠50μl的蟬花樣品,30分鐘後經鼻腔投予內毒素(LPS),施予與犧牲的方法同上。DEX組將DEX溶於生理食鹽水(saline)中,利用腹腔注射(i.p.)施予小鼠50μl,30分鐘後經鼻腔投予內毒素(LPS),施予與犧牲的方法同上。
針對施予途徑為口服的組別,內毒素組(LPS)利用鼻腔吸入施予20μl,LPS濃度為每隻小鼠50μg,24小時後犠牲小鼠取其檢體進行後述分析。CC mycelia組首先將蟬花菌絲體凍乾粉回溶於水與乙醇以比例1:1配製的溶劑中,經超音波震盪以均質化,並確認無沉澱後,作為要施予的樣品。利用口服管餵施予小鼠200μl的蟬花樣品三天,每天一次,三天後經鼻腔投予內毒素(LPS),施予與犧牲的方法同上。DEX組將DEX溶於生理食鹽水(saline)中,利用口服管餵施予小鼠200μl三天,每天一次,三天後經鼻腔投予內毒素(LPS),施予與犧牲的方法同上。
肺組織病理形態觀察:取未進行肺泡灌洗的小鼠右肺,立即以福馬林液固定,並製成石蠟切片,再以蘇木精-伊紅染色(hematoxylin and eosin stain、H&E stain)的常規方法染色,於光學顯微鏡下觀察其病理組織學變化。
氣管肺泡灌洗術(Bronchoalveolar lavage,BAL):小鼠的左肺用1ml PBS經氣管插管灌洗三次,將支氣管肺泡腔中的內含物沖出以取得沖洗液(BAL fluid,BALF)。沖洗液離心後,沉澱出來的細胞的部分進行血球分類與計數;上清液的部分,則利用布拉德福蛋白質定量法(Bradford protein assay)進行蛋白質濃度。
白血球計數與種類分析:利用流式細胞儀分析:為靈敏度高
且人為誤差小的分析方法,將血液與BALF檢體利用白血球的表面具有專一性抗原的特性,進行白血球分型,包括有(1)分析BALF中細胞總數;(2)白血球(CD45)總數;(3)吞噬細胞(CD45+/CD11b+)總數;(4)嗜中性球(CD45+/Ly6G+)總數;(5)巨噬細胞[(CD45+/CD11b+)-(CD45+/Ly6G+)]總數。
統計方法:實驗數據皆以Mean±standard deviation(SD)表示,統計以one-way ANOVA進行分析,並以LSD事後檢定比較各組差異,分析結果若p小於0.05,視為具有統計上的顯著意義。
腹腔注射的結果如圖1顯示蟬花菌絲體凍乾粉可有效改善肺部發炎病理變化。Control組未見明顯改變,肺泡結構多數保持完整。LPS組肺組織病變明顯,肺泡結構破壞、融合,而CC mycelia組及DEX組小鼠肺部病情情況明顯減輕。
於腹腔注射後分析內毒素誘發肺部發炎所導致的蛋白質滲出反應,發現蟬花菌絲體活性物質凍乾粉可有效降低蛋白質滲出反應如圖2及下表3。# P<0.05與對照組比較,*P<0.05與LPS組比較。
於腹腔注射後分析內毒素誘發肺部發炎所導致的(A)白血球(CD45)、(B)吞噬細胞(CD45+/CD11b+)、及(C)嗜中性球(CD45+/Ly6G+)浸潤反應,發現蟬花菌絲體活性物質凍乾粉可有效改善白血球、吞噬細胞及嗜中性白血球(PMN)浸潤如圖3(A至C)及下表4至6。#P<0.05與control組比較;* P<0.05與LPS組比較。
經由口服的結果如圖4顯示蟬花菌絲體活性物質凍乾粉可有效改善肺部發炎病理變化。Control組未見明顯改變,肺泡結構多數保持完整。LPS組肺組織病變明顯,肺泡結構破壞、融合,而CC mycelia組及DEX組小鼠肺部病情情況明顯減輕。
於口服投予後分析內毒素誘發肺部發炎所導致的蛋白質滲出反應,發現蟬花菌絲體活性物質凍乾粉可有效降低蛋白質滲出反應如圖5及下表7。# P<0.05與對照組比較,*P<0.05與LPS組比較。
於口服投予後分析內毒素誘發肺部發炎所導致的(A)白血球(CD45)、(B)吞噬細胞(CD45+/CD11b+)、及(C)嗜中性球(CD45+/Ly6G+)浸潤反應,發現蟬花菌絲體活性物質凍乾粉可有效改善白血球、吞噬細胞及嗜中性白血球(PMN)浸潤如圖6(A至C)及下表8至10。#P<0.05與control組比較;* P<0.05與LPS組比較。
本發明的蟬花菌絲體活性物質經上述實驗,已證實具有改善ALI的作用。
本發明提供一組合物,其包含蟬花菌絲體活性物質,以製備為醫藥組合物,亦可作為保健營養食品。
該組合物進一步包含添加劑。在一較佳的實施態樣中,該添加劑可為賦型劑、防腐劑、稀釋劑、填充劑、吸收促進劑、甜味劑、潤滑劑、黏稠劑、或其組合。該賦型劑可選自檸檬酸鈉、碳酸鈣、磷酸鈣、蔗糖或其組合。該防腐劑可延長醫藥組合物的儲藏期限,例如苯甲醇、對羥基苯甲酸(parabens)、二氧化矽或其組合。該稀釋劑可選自水、乙醇、丙二醇、甘油或其組合。該填充劑可選自乳糖、高分子量聚乙二醇或其組合。該吸收促進劑可選自二甲基亞碸(DMSO)、月桂氮卓酮、丙二醇、甘油、聚乙二醇或其組合。該甜味劑可選自安塞甜(Aeesulfame K)、阿斯巴甜(aspartame)、糖精(saccharin)、三氯蔗糖/蔗糖素(sucralose)、紐甜(neotame)或其組合。該潤滑劑可選自硬脂酸鎂或阿拉伯膠。該黏稠劑可為玉米澱粉。除上述所列舉的添加劑以外,在不影響組合物的醫藥效果前提下,可依需求選用適合的其他添加劑。
該組合物於醫藥領域中可開發為不同商品。在一較佳實施態樣中,該組合物為一藥品、飼料、飲料、營養補充品、乳製品、食品或保健食品。
該組合物可根據受施予者之需要,而採用不同形態。在一較佳實施態樣中,該組合物的形態為粉劑、錠劑、造粒、栓劑、微膠囊、安瓶(ampoule/ampule)、液劑噴劑或塞劑。
本發明的組合物可使用於動物或是人類。在不影響效果的前提下,該組合物可製為任何藥物型態,並根據藥物型態以適用的途徑施予該動物或人類。
本發明的蟬花菌絲體活性物質若應用於食品用途,則以下組合物1的態樣作為例示性實例。
組合物1:取蟬花菌絲體活性物質凍乾粉(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。
本發明的蟬花菌絲體活性物質若以液體劑型應用於醫藥用途,則以下組合物2的態樣作為例示性實例。
組合物2:取蟬花菌絲體活性物質凍乾粉(20wt%)與作為甜味劑的蔗糖素(8wt%)、作為潤滑劑的阿拉伯膠(7wt%)、作為賦型劑的蔗糖(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。
雖然本發明已用實施例揭露如上,然其並非用以限制本發明。本領域的通常知識者,於參酌以上教示後,當能對上述實施例的內容進行適當修改,而仍然能達到本案所主張的功效。因此,本發明的保護範圍應以其後所附的申請專利範圍為準。
Claims (9)
- 一種蟬花菌絲體(Cordyceps Cicadae mycelia)活性物質的用途,其係用於製備預防及/或改善急性肺損傷的藥物。
- 如申請專利範圍第1項所述的用途,其中所述改善急性肺損傷係指肺部發炎的病理症狀減緩。
- 如申請專利範圍第2項所述的用途,其中所述肺部發炎病理減緩係指肺泡的結構由破壞或融合趨向完整。
- 如申請專利範圍第1項所述的用途,其中所述改善急性肺損傷係指蛋白質滲出反應降低。
- 如申請專利範圍第1項所述的用途,其中所述改善急性肺損傷係指發炎細胞浸潤程度降低。
- 如申請專利範圍第5項所述的用途,其中所述發炎細胞係指白血球、吞噬細胞及/或嗜中性白血球。
- 如申請專利範圍第1項所述的用途,其中蟬花菌絲體活性物質的製備方法,其包括下列步驟:(a)取一蟬花菌絲體於平板培養基上,於15至30℃的溫度下培養1至2周;(b)將步驟(a)培養後的蟬花菌絲體接種至一燒瓶內,於15至30℃、pH 2至6的環境培養3至14天;(c)將步驟(b)培養後的蟬花菌絲體接種於一發酵槽內,於15至30℃、pH 2至6的環境下攪拌培養3至21天,形成含有該蟬花菌絲體活性物質的一蟬花菌絲體發酵液。
- 如申請專利範圍第7項所述的用途,其中更包括步驟(d):將該蟬花菌絲體發酵液冷凍乾燥後磨粉,形成含有該蟬花菌絲體活性物質的一蟬花菌絲體凍乾粉。
- 如申請專利範圍第7項所述的用途,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至1.0kg/cm2且通氣速率為0.01至1.5VVM。
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