食药用菌保健金字塔模型对增进人类福祉的作用（七）

张树庭 Solomon P. Wasser

（1.国际蕈菌生物技术服务中心，香港中文大学生物系，香港；2. 国际生物多样性与真菌生物技术中心，海法大学自然科学院进化研究所进化与环境生物学系，以色列，海法；乌克兰国家科学院国家科学院霍洛德内植物研究所，乌克兰，基辅）

食药用菌保健金字塔模型对增进人类福祉的作用（七）

张树庭1Solomon P. Wasser2

（1.国际蕈菌生物技术服务中心，香港中文大学生物系，香港；2. 国际生物多样性与真菌生物技术中心，海法大学自然科学院进化研究所进化与环境生物学系，以色列，海法；乌克兰国家科学院国家科学院霍洛德内植物研究所，乌克兰，基辅）

医药公司的药品研发需要新的天然产品来源。药用蕈菌就是一种最好的天然公共资源，它在较短的时间内即可收获并用于新药的研制。

下面详细地阐述蕈菌药品的发展过程。蕈菌生物活性代谢产物的药品发现途径包括以下基本步骤[14]。

8.1 蕈菌培养和生物质生产

首先，经选择的目标蕈菌菌株在固体培养基（琼脂-麦芽培养基或酵母-琼脂培养基）培养皿中作纯菌丝培养。不同蕈菌种类的菌丝体生长所需时间不同，主要取决于物种特性和培养条件，如基质营养成分、pH值、温度等。因此，根据研究的主要目的，应选择最佳生长条件，使目标菌株能够获得最高的生物量和生物活性物质。一般来说，在固体培养基上生长的蕈菌，其菌丝培养温度需维持在27 ℃，直至培养皿表面长满菌丝。当纯菌丝培养完成后，进入第二阶段，即获得菌丝生物质的液体发酵阶段。将新鲜的菌丝培养物切成小块接种于液体培养基（除不加琼脂外，其他营养成分相同）中，并置于旋转摇床上生长，直到菌丝球填满整个培养基。该培养阶段所需时间视不同种类蕈菌而异。为扩大生产量，需将得到的菌丝体匀浆接种到更大容器的液体培养基中，并置于摇床（或发酵罐）中培养。

8.2 生物提取

从蕈菌液体培养中获得的生物质需作干燥处理，并研磨成粉末。根据所提取蕈菌化合物的种类，需选择不同的有机溶剂。例如，要透过细胞膜萃取化合物，应选择不溶于水的溶剂，如乙酸乙酯。相反，若提取细胞表面化合物，则应选择溶于水的溶剂，如醇类。一般来说，最常见的用于生物质提取的有机溶剂有甲醇、乙醇、乙酸乙酯、乙醚、福尔马林等，或是其中某几种溶剂的组合。此外，由于培养液中含有丰富的蕈菌次生代谢活性物质，因此也可以用不溶于水的溶剂，如乙酸乙酯等从中萃取活性物质。

8.3 蕈菌萃取物的筛选

上面提到的蕈菌提取物的初步筛选分离可以采用多种不同的方法和检测分析技术。根据主要研究目标，需筛选出特定的癌细胞系。其中一种可能的方法是利用荧光素酶活性报告基因分析。携带在特异性启动子控制下的荧光素酶活性报告基因的转染细胞应该加以利用。在这种情况下，可采用分光光度计法测定提取物的活性，计算报告基因抑制率的百分比。另一种检测提取物对癌细胞存活率影响效果的方法是细胞增殖试验，用提取物处理细胞一段时间后，用台盼蓝染色剂排除法或MTT和XTT法测定活细胞的量。计算出代表提取物活性的癌细胞生长抑制率和IC50（抑制50％癌细胞生长的提取物浓度）。初步筛选试验至少需2次重复。

报告基因抑制率高于50％和癌细胞生长率低于50％的提取物，可被看作是有效的，应进行第二轮筛选，以确认其功效。第二轮筛选，可采用相同的方法，但需对初选获得的提取物作更多的浓度试验，以便更加精确地评估其效果。

8.4 选定提取物对靶标的影响

检测并记录与癌细胞的生长、增殖、转移、耐药性等相关的靶细胞蛋白水平，反映选定提取物的效果。接种癌细胞，用一定浓度的提取物对其进行处理、收集和裂解。采用蛋白质印迹（western blot）和酶联免疫吸附测定（ELISA）方法可检测出目标蛋白。特定基因的表达涉及肿瘤发生过程，也可用聚合酶链反应（PCR）检测靶基因的表达，用RT-PCR技术建立基因表达的大致水平，再用实时定量PCR技术测定该基因表达的准确水平。目标蛋白水平和靶基因水平的确立与蕈菌提取物的作用效果一致，可说明细胞内水平的特定作用机理。然后，选择对靶标有显著作用的、最有效的提取物作进一步的评估，并进行化学分离，以测定有效基团的化学起源。

8.5 选定提取物的化学分离

通过一个可使每种化合物分流成不同相态的系统将最有效的提取物分离为不同的化合物组分，能完成这一程序的系统是色谱仪。其中的阻滞系统可以是表面吸附剂，如二氧化硅、氧化铝、纤维素或木炭等能够可逆吸附的化合物。可用高效液相色谱法（HPLC），即一种分离蛋白质和其他分子的技术，或薄层色谱法（TLC）和离子交换色谱法进行化学分馏。这样可获得确切的化学组分含量，如蛋白质、多糖、脂类等。

8.6 确证活性馏分（化合物）的作用机理和效果

对提取物化学分馏后获得的所有馏分进行靶标作用效果的评估，以筛选出含有最有效物质的馏分。评估方法可采用蛋白质印迹、ELISA、细胞增殖分析、PCR、RT-PCR、real-time PCR等技术。再次测定对目标蛋白质有积极影响的有效蕈菌馏分，以确定其特定的作用机理。

8.7 动物试验

对那些在体外试验中具有预期效果的馏分作进一步的动物试验，以检测其活体试验效果。常用于试验的有大鼠和裸小鼠（即用于接受人类或其他动物肿瘤或移植细胞的小鼠）。肿瘤细胞将被皮下注射入实验动物体内并培养一段时间。有效蕈菌馏分（化合物）将被注入该肿瘤动物体内，定期检测其肿瘤细胞生长和转移的情况。当该动物死亡后，将肿瘤取出，用含有蕈菌化合物的培养液处理，以测定其对肿瘤细胞的直接效应。

对在动物活体试验中显示出显著抗癌活性的馏分进行进一步化学分析，以确定目标生物活性化合物的精确化学结构。利用药物化学（分子的化学修饰）方法，以获得更好和更有效的化合物。这一化合物将成为一种潜在的候选药物。

8.8 临床前药物开发

候选药物经过配方预制及制定，以及代谢、毒性、生物药效率和其他药理学性质的测试，传统上这些工作多采用动物试验，而今越来越多的是在离体模型试验中完成。如果可以获得预期效果，并通过产品稳定性测定，那么就可以将该候选药物用于试制生产。

8.9 临床药物开发

最终的药物开发包括以下几个阶段。首先，制造的候选药物需要通过申请临床试验的批准。之后的临床试验分为三个阶段：（1）在志愿者中测试药物的安全性；（2）找出对患者有疗效的佐证，估算适合的剂量；（3）准确评估候选药物的临床应用价值。这些阶段包含了系统而大量的试验记录，用以获得候选药物的市场准入许可[14]。

9 结束语

食用和药用蕈菌作为潜在的人类食品和医药产品开发的重要来源，前景广阔。因此，人类应尽一切努力最大限度地利用农业废弃物资源来生产蕈菌。当前我们应齐心协力地致力于蕈菌栽培技术的研究和开发。同时，我们应给各国政府和国际组织，以及各产业界一个提醒：在蕈菌产业基础之上开展的研究和开发不是一项奢侈的投资，而是一个国家的必备产业。尽管在蕈菌种植中还存在许多问题，但是我们可以预见，蕈菌的利用具有更加重要和积极的效应，尤其是作为一种稳定的蛋白质来源，既可以丰富人类的饮食，又可用作膳食补充剂，提高人体免疫功能。这对欠发达国家尤为重要，因为与大多数发达国家相比，这些国家的蛋白质和医疗保健机制较为缺乏。毫无疑问，无论是城市还是农村，都可以从这项技术中获利，能够以最小的成本、最大限度地提高单位面积的蕈菌产量，从而利用农业废弃物获得一个新的生产蛋白质食品的廉价来源；同时开启了蕈菌生物技术加工的旅程，为人类提供可促进健康的膳食补充剂产品。

过去20年的研究和生产利用的进展表明，蕈菌对人类食物和医疗保健体系都具有重要的作用。现代医学可能也有无法解决的问题，蕈菌膳食补充剂有望成为一种有效缓解和预防疾病的产品。疾病的预防很重要，不仅可提高社会和经济效益，而且有利于保持/提高生命质量和人类的尊严。希望我们微弱的呼吁是对全球蕈菌产业提出的挑战，并能对积极实施引起良好的关注和思考。

蕈菌衍生物产品既不是营养保健品（食品/功能性食品），也不是药品，这是因为其中大部分产品的有效成分不是常规药物治疗中所定义的单一的化合物。因此，它们可被列入膳食补充剂或介于食品和药品之间的传统药物。

一些关于药用蕈菌衍生物研究的报告称，药用蕈菌产品如灵芝、冬虫夏草等，对所有的疾病有疗效。我们认为这有些言过其实。实际上，无论是常规的还是传统的医学，没有一种已知的治疗方式可以在任何人和任何疾病上通用。

我们不应该假设蕈菌衍生物产品可以替代现代医学。但是我们可以肯定，通常蕈菌衍生物是一种特殊类型，既可以提高患者的总体幸福感，也可以配合现代医学，起到辅助治疗的作用。

如前所述，蕈菌被用作保健食品、滋补品和药品（药物和植物性药物）。定期摄入蕈菌产品和蕈菌衍生物产品，可以使身体更健康、舒适和快乐。

蕈菌中含有丰富的药用成分，尤其是硒（抗氧化剂）的含量高，硒可以使人更显年轻和长寿。本文主要传递蕈菌生产和使用的科学、经济、健康和环保等价值。

我们已经讨论了在世界的不同国家和地区，包括美国、欧盟、加拿大、澳大利亚、新西兰、日本和中国大陆等，对引进和管理从药用蕈菌中获得的膳食补充剂所涉及的立法和监管问题，以及世界卫生组织的指导方针。大部分关注的还是烹饪用的药用蕈菌的安全性和多样性。当前，市场上药用蕈菌膳食补充剂产品的类型非常多样，但是用以保证其质量的标准规范却很少。必须进行透彻分析研究、提高品质、规范管理，才能增加和维持消费者的信任，促使国家相关管理部门建立对当前和未来蕈菌市场的监管体系。我们希望现有的和未来的法规与标准，能够继续为质量稳定的药用蕈菌产品的市场供应提供保障，希望研发最好、最先进的生物技术，以获得稳定、安全的蕈菌产品。

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