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食用菌活性成分的抗病毒作用研究进展

2021-01-06张相锋

食药用菌 2021年3期
关键词:流感病毒抗病毒乙型肝炎

张相锋

食用菌活性成分的抗病毒作用研究进展

张相锋

(伊犁师范大学微生物资源保护与开发利用重点实验室,新疆 伊宁 835000)

食用菌代谢产生的丰富生物活性物质,具有抗癌、抗菌、抗病毒、抗氧化和抗炎等作用。人类很多疾病的病原体是病毒。化学抗病毒药物的毒副作用及病毒对现有抗病毒药物的抗药性,要求我们开发更多安全性高的天然药物。通过综述食用菌中分离出的活性成分对人类免疫缺陷病毒、流感、乙型和丙型肝炎等病毒的作用效果研究进展,指出应对食用菌进行更深入的研究和开发,以获得更多天然、安全、有效的抗病毒药物。

食用菌;抗病毒;人类免疫缺陷病毒;流感病毒;肝炎病毒

食用菌含有丰富的蛋白质、人体必需氨基酸、维生素、矿物质元素、膳食纤维,以及大量有益于健康的活性物质,不含胆固醇,是一种世人公认的健康食品。食用菌在代谢过程产生的次生代谢物,如多肽、活性蛋白、萜类、多糖等,具有抗菌、消炎、抗病毒、抗肿瘤和调节免疫等效用。因此,食用菌既是营养食品,又是良好的药用资源。

在人类众多疾病中,有一部分是由病毒感染导致的,如常见的人类免疫缺陷病毒HIV(又称艾滋病病毒)、乙型肝炎病毒HBV、流感病毒等,对人类健康造成很大威胁。抗病毒药物能杀灭病毒、抑制病毒复制和传播的药物。目前临床上应用的抗病毒药物多为化学合成,且有一定的毒副作用。食用菌作为日常生活中食药功效兼备的大型真菌,在药物开发中具有非常高的安全优势。基于此,科学家们对食用菌活性代谢物进行了大量研究,发现其中很多成分对病毒有显著的抗性,在抗病毒方面有很高的应用价值,如凝集素、萜类物质、多糖等。以下对食用菌源活性成分在抗病毒方面的研究成果进行摘要综述。

1 对HIV的作用

HIV(Human Immunodeficiency Virus)是一种攻击人体免疫系统的病毒,它把人体免疫系统中最重要的CD4+T淋巴细胞作为主要攻击目标,通过大量破坏该细胞使人体丧失免疫功能,其症状又称为获得性免疫缺陷综合症(Acquired Immune Deficiency Syndrome,AIDS),即艾滋病。由于感染该病毒后死亡率非常高,是严重危害人类健康的病毒之一。HIV的入侵过程有两个关键步骤:一是病毒颗粒表面的包膜糖蛋白(Env)通过与免疫细胞表面的CD4分子、辅助受体互作,实现病毒与宿主细胞的融合[1];二是进入宿主细胞后,病毒利用自身的逆转录酶(Reverse transcriptase,RT)将RNA转变成DNA整合到宿主和基因组中实现真正的入侵。在HIV药物研发中,主要也以这两个环节作为切入点。

研究表明,一些食用菌的活性成分表现出较好的抗HIV活性,主要是对逆转录酶活性的抑制。如一种从大白口蘑()提取的低分子量漆酶(LAC),显著抑制HIV-1的RT活性[2];从猴头菇()[3]、灵芝()[4, 5]、鸡腿菇()[6]、紫丁香蘑()[7]、香菇()[4, 8]和杏鲍菇()[9]中分离到的漆酶同样具有RT活性;从斑玉蕈()中提取的Marmorin(一种核糖体抑制蛋白),也具有HIV-1 RT抑制活性[10];从榆黄蘑()[11]、大白菇()[12]、猴头菇[13]、多脂鳞伞()[14]、茶褐丝盖伞()[15]等食用菌中分离的凝集素具有显著的HIV-1 RT抑制活性;蛹虫草()的血凝素中发现具有HIV-1 RT抑制活性物质[16];虎乳芝()提取物也具有抗HIV-1 RT活性[17];从裂褶菌()中提取的溶血素[18],以及来自紫丁香蘑的金属蛋白酶[19]都表现有抗HIV-1 RT活性;一种新的杏鲍菇多糖肽复合物及其多肽对HIV-1 RT有抑制作用[20, 21];从元蘑()提取的一种新的核糖核酸酶也被证实有HIV-1 RT抑制活性[22]。

桦褐孔菌()中的一种水溶性高分子量木质素对HIV-1蛋白酶有抑制作用[23]。从姬菇()中提取的泛素样蛋白酶和从灵芝中分离出的羊毛脂烷型三萜类化合物显示出对HIV-1蛋白酶的抑制活性[24, 25]。虎乳芝醇提物和水提物对HIV-1蛋白酶有显著的抑制活性[17]。香菇菌丝体中的多羧化水溶性木质素具有抗HIV活性,它能够抑制HIV感染的小鼠体内类似于人类T4细胞的HIV抗原表达过程[26]。

2 对肝炎病毒的作用

肝炎病毒是一类以侵害肝脏引起病变的古老病毒。主要分为:甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、丁型肝炎病毒(HDV)、戊型肝炎病毒(HEV)等。其中甲肝、乙肝和丙肝3种病毒比较常见。甲肝病毒为单正链线性RNA病毒,主要通过粪口途径传播,易在人群中爆发,但危害小、易治疗、可预防、可自愈。乙型肝炎病毒为不完全双链DNA病毒,主要通过密切接触和血液进行传播,是所有肝炎病毒中致病力最强、危害最大、最难治疗的,目前主要通过接种疫苗等途径进行预防。丙型肝炎病毒为+ssRNA病毒,主要通过血液及其相关制品进行传播,危害性仅次于乙型肝炎病毒。

甲型肝炎病毒虽然易爆发,但一般可以自愈,所以少有人研究。对于肝炎病毒的预防和治疗的研究主要集中在乙型肝炎病毒和丙型肝炎病毒。一项对乙型肝炎患者使用姬松茸()提取物12个月的临床研究结果,患者肝功能均恢复正常[27]。灵芝多糖组分和三萜类化合物对乙肝病毒有一定的抑制作用[28]。从灰树花()中提取的D-组分与人干扰素α-2b联合使用对乙型肝炎病毒有更好的抑制作用[29]。平菇()凝集素能够通过激活TLR6信号通路克服转基因小鼠对HBV的耐受性[30],其作为乙肝病毒DNA疫苗的佐剂,能增强免疫应答[31]。用高效液相色谱技术从灵芝中分离出的6种有机酸中,有3种对乙型肝炎病毒抗原分泌具抑制作用[32]。茯苓()多糖II作为佐剂与乙肝疫苗联合使用时,能增强免疫反应[33]。樟芝()多糖能有效抑制HBV抗原[34]。茶树菇()和斑玉蕈水提物可以抑制宿主细胞中人HBV抗原的表达[35]。自香菇中分离纯化出一种抗病毒蛋白YP46-46,对HBV表面抗原有抑制作用[36]。香菇多糖在体外也具有显著的HBV抑制活性[37]。猪苓()多糖单独使用或与其他药物联合用于预防和治疗乙型肝炎患者,有非常好的疗效[38]。从灵芝中提取的灵芝酸可抑制HepG2215细胞中HBV的复制[39]。

香菇菌丝提取物可抑制HCV进入细胞[40]。姬松茸提取物对治疗慢性丙型肝炎,显示出明显效果[41]。从平菇中纯化的LAC可阻止HCV进入外周血细胞和肝癌细胞[42]。双孢蘑菇()水酶提取物在体外对HCV 蛋白酶NS3有抑制作用[43]。网盖红褶伞()中分离的化合物罗丹汀(Rhodatin音译)对HCV有较强的抑制作用[44]。在HCV感染的huh7.5细胞中,蛹虫草提取物可降低HCV核心蛋白或NS3蛋白的表达,从而表现出对HCV的抑制作用[45]。

3 对流感病毒的作用

流感病毒是人类健康的最大威胁之一。全球每年感染流感病毒的病例在6亿~12亿,重症病例死亡率为8%~10%。根据流感病毒核蛋白(NP)和基质蛋白(MP)抗原性可分为甲(A)、乙(B)、丙(C)三类,最容易在人群中造成大流行的是甲(A)型流感病毒,这是一种-ssRNA病毒,是目前人类研究的主要对象。

裂蹄木层孔菌()菌丝提取物作为佐剂可以提高疫苗对变异的H5N1高致病流感病毒交叉感染的保护作用[46]。抗流感病毒蘑菇中的硒、锌和镁等微量元素可能通过刺激宿主的固有免疫反应来预防流感[47]。软异薄孔菌()、粗糙拟迷孔菌()、拟皱皮菌()、彩绒革盖菌()、偏肿栓孔菌()、苦白蹄()、桦褶孔菌()的提取物对人类H3N2和高致病性禽流感H5N1病毒有显著的抗性[48]。盖鲍氏针层孔菌()乙醇提取物中的多酚类物质能非竞争性地抑制H1N1、H5N1和H3N2神经氨酸酶活性,并减少病毒诱导的细胞病变(CPE)数量[49]。香菇菌丝体固体培养提取物通过直接作用于病毒生长和促进宿主先天免疫而具有抗流感病毒活性[50]。裂蹄木层孔菌水提取物对甲型和乙型流感病毒有效,包括2009年大流行性H1N1、人H3N2、禽H9N2和奥司他韦耐药H1N1病毒[51]。Tetiana等研究发现,被研究的10种食用菌菌丝提取物都能抑制流感病毒H1N1在MDCK细胞中的繁殖[52]。从相邻小孔菌()甲醇提取物中分离出的4种神经氨酸酶抑制剂,对流感病毒有特异的抑制性[53]。来自香菇、茯苓()、生姜、陈皮的混合多糖(MPs)可通过激活体液和细胞免疫来提高H1N1病毒感染疫苗小鼠的免疫效果和减轻肺部炎症[54]。皱盖罗鳞伞()中纯化出一种10 425 Da的蛋白,对甲型流感病毒有抑制作用[55];纯化出的另一种分子量为28 KD的抗病毒蛋白,具有抗甲型流感病毒活性[56]。

4 展 望

很多食用菌在其子实体、菌丝体和发酵液中都含有种类繁多的生物活性物质[57]。这些食用菌大多可药食兼用,基于安全性考虑,其所含的天然活性物质可作为抗病毒药物在临床中大力开发应用。化学抗病毒药品毒副作用很大,而且在使用过程中,病毒由于变异会产生抗药性。而天然抗病毒药物不但疗效显著,而且安全性高。因此,人类越来越迫切地需要用天然抗病毒药物来替代化学药物。Li等总结了治疗新型冠状病毒肺炎COVID-19的潜在药物,其中包括RdRp的核苷类抑制剂、HCV抑制药物、蛋白酶抑制剂、凝集素类、免疫调节类药物[58]。这些药物的类似物在食用菌中广泛存在。我国采用一些独特的中药方剂对COVID-19的预防和治疗效果足以证明这一点。

人类应用药食用真菌历史比较悠久,但是多集中在食用和栽培方面,对于其在医药方面的应用研究还比较少。虽然我们分离到了一些具有相应活性的化学组分,但是对这些组分的作用机制还缺乏深刻认识,尤其是高纯度单组分及单组分复配的疗效和机制还没有进一步的研究。虽然上述提到的很多食用菌的活性成分对多种病毒有抗性,但是我们应该进一步筛选出针对一种病毒的专一高效的食用菌种类和组分,做到治疗的精准性、高效性。已知世界上蕈菌的种类大约有15万~16万种,而我们目前认识到的不足10%,有大量的可被开发利用的菌类等待我们去挖掘[59]。

面对肆虐的病毒,开发更多有效的天然抗病毒药物显得非常重要。大量研究成果已充分证实,食用菌是天然抗病毒药物开发的宝库。多数病毒是通过人类的粘膜层入侵人体的[61]。食用菌活性成分能够通过人体的粘膜层发挥防护和清除入侵病毒的作用[60]。这些活性成分通过诱导人体粘膜层的Th1cell,活化其中的Nkcell及细胞毒性Tcell和Tγδcell,其中Tγδcell担负着非常重要的角色。它一方面能够发挥非特异性免疫的作用诱导和趋化白细胞去吞食入侵的病原体及受病原体侵染的细胞;另一方面起到呈递抗原的作用,诱导Bcell向浆细胞分化,产生相应的抗体,启动特异性的体液免疫[62]。COVID-19是通过人的呼吸道黏膜感染人体的。Francesco D P等指出,虽然香菇活性物质针对COVID-19的疗效尚未进行具体评估,但基于其在病毒感染中的保护作用,可以尝试将其用于预防由人类致病性冠状病毒(包括COVID-19)引起的疾病[62],以发挥食用菌活性物质在预防和治疗COVID-19中的积极作用。

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Research progress on antiviral effect of active ingredients from mushrooms

Zhang Xiangfeng

( Key Lab. of Microbial Res. Protect. & Devel., Yili Normal Uni., Yining, Xinjiang 835000, China)

Edible mushrooms are rich in bioactive substances, which have anticancer, antibacterial, antiviral, antioxidant and anti-inflammatory effects. Many human diseases are caused by viruses. The side effects of chemical antiviral drugs and the resistance of viruses to existing antiviral drugs require us to develop more natural drugs with high safety. The active components isolated from mushrooms have a significant inhibitory effect on human immunodeficiency virus, influenza, hepatitis B, and hepatitis C virus. To obtain more natural, safe, and effective antiviral drugs, we should conduct more in-depth research on mushrooms.

mushroom; antiviral; human immunodeficiency virus; influenza virus; hepatitis virus

S646

A

2095-0934(2021)03-189-07

微生物资源保护与开发利用重点实验室开放课题(YLUKLM202002)

张相锋,男,副教授,主要从事微生物多样性及开发利用研究工作。E-mail:759737497@ qq.com。

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