食藥用菌保健金字塔模型對增進人類福祉的作用（七）

張樹庭 Solomon P. Wasser

（1.國際蕈菌生物技術服務中心，香港中文大學生物系，香港；2. 國際生物多樣性與真菌生物技術中心，海法大學自然科學院進化研究所進化與環境生物學系，以色列，海法；烏克蘭國家科學院國家科學院霍洛德內植物研究所，烏克蘭，基輔）

食藥用菌保健金字塔模型對增進人類福祉的作用（七）

張樹庭1Solomon P. Wasser2

（1.國際蕈菌生物技術服務中心，香港中文大學生物系，香港；2. 國際生物多樣性與真菌生物技術中心，海法大學自然科學院進化研究所進化與環境生物學系，以色列，海法；烏克蘭國家科學院國家科學院霍洛德內植物研究所，烏克蘭，基輔）

醫藥公司的藥品研發需要新的天然產品來源。藥用蕈菌就是一種最好的天然公共資源，它在較短的時間內即可收獲并用于新藥的研制。

下面詳細地闡述蕈菌藥品的發展過程。蕈菌生物活性代謝產物的藥品發現途徑包括以下基本步驟[14]。

8.1 蕈菌培養和生物質生產

首先，經選擇的目標蕈菌菌株在固體培養基（瓊脂-麥芽培養基或酵母-瓊脂培養基）培養皿中作純菌絲培養。不同蕈菌種類的菌絲體生長所需時間不同，主要取決于物種特性和培養條件，如基質營養成分、pH值、溫度等。因此，根據研究的主要目的，應選擇最佳生長條件，使目標菌株能夠獲得最高的生物量和生物活性物質。一般來說，在固體培養基上生長的蕈菌，其菌絲培養溫度需維持在27 ℃，直至培養皿表面長滿菌絲。當純菌絲培養完成后，進入第二階段，即獲得菌絲生物質的液體發酵階段。將新鮮的菌絲培養物切成小塊接種于液體培養基（除不加瓊脂外，其他營養成分相同）中，并置于旋轉搖床上生長，直到菌絲球填滿整個培養基。該培養階段所需時間視不同種類蕈菌而異。為擴大生產量，需將得到的菌絲體勻漿接種到更大容器的液體培養基中，并置于搖床（或發酵罐）中培養。

8.2 生物提取

從蕈菌液體培養中獲得的生物質需作干燥處理，并研磨成粉末。根據所提取蕈菌化合物的種類，需選擇不同的有機溶劑。例如，要透過細胞膜萃取化合物，應選擇不溶于水的溶劑，如乙酸乙酯。相反，若提取細胞表面化合物，則應選擇溶于水的溶劑，如醇類。一般來說，最常見的用于生物質提取的有機溶劑有甲醇、乙醇、乙酸乙酯、乙醚、福爾馬林等，或是其中某幾種溶劑的組合。此外，由于培養液中含有豐富的蕈菌次生代謝活性物質，因此也可以用不溶于水的溶劑，如乙酸乙酯等從中萃取活性物質。

8.3 蕈菌萃取物的篩選

上面提到的蕈菌提取物的初步篩選分離可以采用多種不同的方法和檢測分析技術。根據主要研究目標，需篩選出特定的癌細胞系。其中一種可能的方法是利用熒光素酶活性報告基因分析。攜帶在特異性啟動子控制下的熒光素酶活性報告基因的轉染細胞應該加以利用。在這種情況下，可采用分光光度計法測定提取物的活性，計算報告基因抑制率的百分比。另一種檢測提取物對癌細胞存活率影響效果的方法是細胞增殖試驗，用提取物處理細胞一段時間后，用臺盼藍染色劑排除法或MTT和XTT法測定活細胞的量。計算出代表提取物活性的癌細胞生長抑制率和IC50（抑制50％癌細胞生長的提取物濃度）。初步篩選試驗至少需2次重復。

報告基因抑制率高于50％和癌細胞生長率低于50％的提取物，可被看作是有效的，應進行第二輪篩選，以確認其功效。第二輪篩選，可采用相同的方法，但需對初選獲得的提取物作更多的濃度試驗，以便更加精確地評估其效果。

8.4 選定提取物對靶標的影響

檢測并記錄與癌細胞的生長、增殖、轉移、耐藥性等相關的靶細胞蛋白水平，反映選定提取物的效果。接種癌細胞，用一定濃度的提取物對其進行處理、收集和裂解。采用蛋白質印跡（western blot）和酶聯免疫吸附測定（ELISA）方法可檢測出目標蛋白。特定基因的表達涉及腫瘤發生過程，也可用聚合酶鏈反應（PCR）檢測靶基因的表達，用RT-PCR技術建立基因表達的大致水平，再用實時定量PCR技術測定該基因表達的準確水平。目標蛋白水平和靶基因水平的確立與蕈菌提取物的作用效果一致，可說明細胞內水平的特定作用機理。然后，選擇對靶標有顯著作用的、最有效的提取物作進一步的評估，并進行化學分離，以測定有效基團的化學起源。

8.5 選定提取物的化學分離

通過一個可使每種化合物分流成不同相態的系統將最有效的提取物分離為不同的化合物組分，能完成這一程序的系統是色譜儀。其中的阻滯系統可以是表面吸附劑，如二氧化硅、氧化鋁、纖維素或木炭等能夠可逆吸附的化合物?？捎酶咝б合嗌V法（HPLC），即一種分離蛋白質和其他分子的技術，或薄層色譜法（TLC）和離子交換色譜法進行化學分餾。這樣可獲得確切的化學組分含量，如蛋白質、多糖、脂類等。

8.6 確證活性餾分（化合物）的作用機理和效果

對提取物化學分餾后獲得的所有餾分進行靶標作用效果的評估，以篩選出含有最有效物質的餾分。評估方法可采用蛋白質印跡、ELISA、細胞增殖分析、PCR、RT-PCR、real-time PCR等技術。再次測定對目標蛋白質有積極影響的有效蕈菌餾分，以確定其特定的作用機理。

8.7 動物試驗

對那些在體外試驗中具有預期效果的餾分作進一步的動物試驗，以檢測其活體試驗效果。常用于試驗的有大鼠和裸小鼠（即用于接受人類或其他動物腫瘤或移植細胞的小鼠）。腫瘤細胞將被皮下注射入實驗動物體內并培養一段時間。有效蕈菌餾分（化合物）將被注入該腫瘤動物體內，定期檢測其腫瘤細胞生長和轉移的情況。當該動物死亡后，將腫瘤取出，用含有蕈菌化合物的培養液處理，以測定其對腫瘤細胞的直接效應。

對在動物活體試驗中顯示出顯著抗癌活性的餾分進行進一步化學分析，以確定目標生物活性化合物的精確化學結構。利用藥物化學（分子的化學修飾）方法，以獲得更好和更有效的化合物。這一化合物將成為一種潛在的候選藥物。

8.8 臨床前藥物開發

候選藥物經過配方預制及制定，以及代謝、毒性、生物藥效率和其他藥理學性質的測試，傳統上這些工作多采用動物試驗，而今越來越多的是在離體模型試驗中完成。如果可以獲得預期效果，并通過產品穩定性測定，那么就可以將該候選藥物用于試制生產。

8.9 臨床藥物開發

最終的藥物開發包括以下幾個階段。首先，制造的候選藥物需要通過申請臨床試驗的批準。之后的臨床試驗分為三個階段：（1）在志愿者中測試藥物的安全性；（2）找出對患者有療效的佐證，估算適合的劑量；（3）準確評估候選藥物的臨床應用價值。這些階段包含了系統而大量的試驗記錄，用以獲得候選藥物的市場準入許可[14]。

9 結束語

食用和藥用蕈菌作為潛在的人類食品和醫藥產品開發的重要來源，前景廣闊。因此，人類應盡一切努力最大限度地利用農業廢棄物資源來生產蕈菌。當前我們應齊心協力地致力于蕈菌栽培技術的研究和開發。同時，我們應給各國政府和國際組織，以及各產業界一個提醒：在蕈菌產業基礎之上開展的研究和開發不是一項奢侈的投資，而是一個國家的必備產業。盡管在蕈菌種植中還存在許多問題，但是我們可以預見，蕈菌的利用具有更加重要和積極的效應，尤其是作為一種穩定的蛋白質來源，既可以豐富人類的飲食，又可用作膳食補充劑，提高人體免疫功能。這對欠發達國家尤為重要，因為與大多數發達國家相比，這些國家的蛋白質和醫療保健機制較為缺乏。毫無疑問，無論是城市還是農村，都可以從這項技術中獲利，能夠以最小的成本、最大限度地提高單位面積的蕈菌產量，從而利用農業廢棄物獲得一個新的生產蛋白質食品的廉價來源；同時開啟了蕈菌生物技術加工的旅程，為人類提供可促進健康的膳食補充劑產品。

過去20年的研究和生產利用的進展表明，蕈菌對人類食物和醫療保健體系都具有重要的作用。現代醫學可能也有無法解決的問題，蕈菌膳食補充劑有望成為一種有效緩解和預防疾病的產品。疾病的預防很重要，不僅可提高社會和經濟效益，而且有利于保持/提高生命質量和人類的尊嚴。希望我們微弱的呼吁是對全球蕈菌產業提出的挑戰，并能對積極實施引起良好的關注和思考。

蕈菌衍生物產品既不是營養保健品（食品/功能性食品），也不是藥品，這是因為其中大部分產品的有效成分不是常規藥物治療中所定義的單一的化合物。因此，它們可被列入膳食補充劑或介于食品和藥品之間的傳統藥物。

一些關于藥用蕈菌衍生物研究的報告稱，藥用蕈菌產品如靈芝、冬蟲夏草等，對所有的疾病有療效。我們認為這有些言過其實。實際上，無論是常規的還是傳統的醫學，沒有一種已知的治療方式可以在任何人和任何疾病上通用。

我們不應該假設蕈菌衍生物產品可以替代現代醫學。但是我們可以肯定，通常蕈菌衍生物是一種特殊類型，既可以提高患者的總體幸福感，也可以配合現代醫學，起到輔助治療的作用。

如前所述，蕈菌被用作保健食品、滋補品和藥品（藥物和植物性藥物）。定期攝入蕈菌產品和蕈菌衍生物產品，可以使身體更健康、舒適和快樂。

蕈菌中含有豐富的藥用成分，尤其是硒（抗氧化劑）的含量高，硒可以使人更顯年輕和長壽。本文主要傳遞蕈菌生產和使用的科學、經濟、健康和環保等價值。

我們已經討論了在世界的不同國家和地區，包括美國、歐盟、加拿大、澳大利亞、新西蘭、日本和中國大陸等，對引進和管理從藥用蕈菌中獲得的膳食補充劑所涉及的立法和監管問題，以及世界衛生組織的指導方針。大部分關注的還是烹飪用的藥用蕈菌的安全性和多樣性。當前，市場上藥用蕈菌膳食補充劑產品的類型非常多樣，但是用以保證其質量的標準規范卻很少。必須進行透徹分析研究、提高品質、規范管理，才能增加和維持消費者的信任，促使國家相關管理部門建立對當前和未來蕈菌市場的監管體系。我們希望現有的和未來的法規與標準，能夠繼續為質量穩定的藥用蕈菌產品的市場供應提供保障，希望研發最好、最先進的生物技術，以獲得穩定、安全的蕈菌產品。

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