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Chinese FDA Approved Fungal Glycan-Based Drugs: An Overview of Structures, Mechanisms and Clinical Related Studies

Zijing Zhou, Zhangrun Han, Yangyang Zeng, Meng Zhang, Yidi Cui, Lingling Xu and Lijuan Zhang*

School of Medicine and Pharmacy, Ocean University of China, Qingdao, China

*Corresponding Author:
Lijuan Zhang
Ocean University of China
5 Yushan Road, Qingdao, China
Tel: +86-532-82031615
E-mail: [email protected]

Received Date: June 06, 2014; Accepted Date: November 29, 2014; Published Date: December 06, 2014

Citation: Zhou Z, Han Z, Zeng Y, Zhang M, Cui Y, et al. (2014) Chinese FDA Approved Fungal Glycan-Based Drugs: An Overview of Structures, Mechanisms and Clinical Related Studies. Transl Med 4:141. doi:10.4172/2161-1025.1000141

Copyright: © 2014 Zhou Z, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Edible mushrooms have been used not only as food and nutraceuticals but also as important ingredients in traditional Chinese medicines for centuries. Pharmaceutical active components from different types of mushrooms have been extracted and studied by scientists all over the world during the past 50 years, and many biological functions, such as antitumor, immunomodulating, anti-oxidative, anti-inflammatory, and hypoglycemic activities, have been reported in peer reviewed English journals. Interestingly, the purified polysaccharides or glycans possess many reported functions of medicinal mushrooms, which make them potential drug candidates. However, glycans are a mixture of polysaccharides having variable numbers of monosaccharides, linkages, and molecular weight distributions as well as multiple biological functions that are hard to conceive as drugs by conventional standard in that a drug should have one structure and one function. On the other hand, multiple ingredients with multiple beneficial effects are essence of traditional Chinese medicines. Subsequently, glycans from different types of medicinal mushrooms are partially purified and trialed as oral and/or injectable drugs in China. Without serious safety concerns of mostly hot water extracted glycans from edible mushrooms and/or the cultured mycelium, eight of them are approved by Chinese Food and Drug Administration (SFDA) and used clinically in China since 1980s. This review article provides basic clinical information of the fungal glycan-based drugs in China and also summarizes structures, functions, and animal studies of fungal glycans conducted by scientists world-wide. Understanding glycan-based drugs at molecular biology level would be central for improving the clinical efficacy of current glycan-based drugs and for designing effective clinical trials of glycan-based drugs in future.

Keywords

Fungal glycan base; Chinese FDA; Mushrooms; Polysaccharides

Introduction

Polysaccharides or glycans are located at intracellular, cell membrane, and extracellular spaces serving energy storage, structure, signal transduction, and system regulatory purposes in all living organisms. Among them, animal glycans have been extensively studied at genetic levels. Knocking out a series genes responsible for biosynthesis or modifications of glycans in different animal model systems reveals that animal glycans are indispensable for cell division [1], for animal development [2], and for maintenance of proper immunity and homeostasis in adult animals [3]. For example, endothelial heparan sulfate deficiency impairs L-selectin- and chemokine-mediated neutrophil trafficking during inflammatory responses [4]. Moreover, life-saving drug heparin, one type of glycans purified from animal tissues, remains to be an un-replaceable anticoagulant drug in modern medicine after 78 years of clinical use [2]. Furthermore, 20 different kinds of animal glycan-based drugs have preceded through clinical trials and are used clinically world-wide not only as anticoagulant but also used together with other conventional drugs for cancer treatment with an annual sale over $7 billion dollars [5].These facts indicate glycan-based drugs are not different from other biological drugs either from views of modern molecular biology or from views of their clinical importance.

Like animal cells, fungi synthesize several different types of glycans located in intracellular, cell wall, and extracellular spaces. Moreover, fungi possess several unique glycans that are not made by animal cells, such as chitin, β - glucans, and heteroglycans. In addition, glycanpeptide, glycan-lipid, and glycan-protein complexes isolated from fungi also have potent biological activities. This review article provides basic information of eight fungal glycan-based drugs in China and also summarizes peer-reviewed literatures about structures and biological functions of the fungal glycans at cell- and animal levels along with clinical studies that have been conducted by scientists world-wide.

Eight Fungal Glycans-Based Drugs Approved By Chinese Food and Drug Administration (SFDA)

According to published reports, water-soluble glycans are the most active pharmacological components tested in over 300 kinds of glycans extracted from either plants or fungi [6]. Thus, all eight glycans-based drugs approved by SFDA are hot water extracted glycans either from edible mushrooms and/or from cultured mycelium. Table 1 summaries the basic information of the 8 drugs including imagine of the medicinal mushrooms, starting materials for glycans extraction, type of drugs approved, specified glycan contents, drug number granted by SFDA, clinical indications, and published clinical studies [7-65].

Imagine Specie Source Drug type Glycan content SFDA drug number Clinical applications Ref.
equation
Ref. [160]
Ganoderma lucidum Spores Injection Ganoderma lucidum glycans
no less than 90%
H20003510 Improving endurance of cyclists Dyslipidemia Facial paralysis [7]
[8]
[9]
equation
Ref.[161]
Ganoderma Sinensis Fruiting body Tablet Ganoderma Sinensis glycan
no less than 83%
Z22022112 Mushroom poisoning Leukopenia [10]
[11]
equation
Ref.[160]
Lentinus edodes Fruiting body Capsule Lentinan Z20080579 Artificial urticaria [12]
Gastrointestinal cancers [13-18]
Tablet Lentinan
no less than 40%
Z20026215
Primary liver cancer Hepatitis Malignant
pleural effusion HIV-positive
[19]
[20,21]
[22-27]
[28]
injection Lentinan
no less than 85%
H20067183
equation
Ref.[161]
Polyporus unbellatus Fruiting body Capsule no less than 40% Z10970134 Hepatitis B Reduce the recurrence of bladder cancer [29-33]
[33]
Injection Polyporus glycan
no less than 90%
Z32021229
equation
Ref.[161]
Polystictus Versicolor Culture of mycelium Capsule Krestin (PSK)
glycans no less than 35%
H31022501 Acute nonlymphocytic leukemia Colorectal cancer Gastric cancer Lung cancer Primary liver cancer Hepatitis Hyperlipidemia [34]
[35,36]
[37-40]
[41]
[42-44]
[45-50]
[51]
Dropping
pills
Krestin(PSK)
glycans no less than 38%
Z20090728
equation
Ref.[161]
Poria cocos Culture of Mycelium Injection Pachymaran
no less than 84%
H20003510 Chronic pulmonary edema Insomnia Alopecia Schizophrenia [52]
[53]
[54]
[55]
equation
Ref.[160]
Grifola frondosa Culture of mycelium Capsule Maitake glycans
no less than 40%
B20020023 Antitumor Impaired Glucose Tolerance
Polycystic ovary syndrome
[56,162]
[58]
[59]
equation
Ref. [163]
Tremella fuciformis Berk Fruiting body Capsule Tremella glycan
no less than 60%
Z22022048 Mycoplasma pneumonia
Chronic active hepatitis
Antidiabetics
Cancer patients with leukopenia
[60]
[61]
[62]
[63-65]

Table 1: Eight fungal glycan based-drugs.

As shown in Table 1, glycan contents of the eight approved drugs range from 30% to 93%. There are no specifications about monosaccharide compositions, glycan structures, molecular weight, or biological activity for these approved drugs due to inherent structural diversity of glycans. Taking Ganoderma lucidum glycans as an example, 16 different types of glycans with different monosaccharide compositions, different glycan linkages, and different molecular weight have been purified and identified by applying additional purification schemes when hot water extracted glycans are used as starting materials (Table 2). Therefore, these drugs are not “pure” or a single type of glycans.

Source Extraction method Backbone Major monosaccharide Mw Ref.
Fruiting bodies Hot-water extraction.
Ethanol fractionation, DEAE-cellulose and gel chromatography
β-Arabinoxyloglucan,
α-Arabinoxyloglucan
Glucose, xylose, arabinose 4×104 [164]
Fruiting bodies Hot water and alkali extraction Water-soluble
heteroglycans
Glucose,Galactose,
Mannose,Arabinose,
Xylose, Fucose
[165]
Water-insoluble β-glucan Glucose
Culture of mycelium Branched β-glucan Glucose [165]
Fruiting bodies Alkali-extraction
at 25°C and 65°C.
Linear α-glucan Glucose [166]
Spores Hot-water extraction.
DEAE-cellulose and
Sephacryl S-200HR
β-Glucan Glucose 1×104 [130]
Fruiting bodies Hot-water extraction.
DEAE-cellulose and
gel-filtration
chromatography
α-Heteroglycans
β-Heteroglycans
Glucose,Galactose,
Rhamnose
8.3×103 [131]
β-Glucan Glucose 6.3×104
β-Heteroglycan Glucose, Mannose 2.0×105
Extracellular DEAE-Sephacel and
Sephadex G200
α-Galactose Galactose,Mannose,
Glucose,Arabinose,
Rhamnose
2.2×104 [167]
Fruiting bodies Hot-water extraction
DEAE-Sepharose Fast-Flow and SephacrylS-300
α-Galactose,
α-Glucose
Galactose,
Glucose, Fucose
1.2×104 [168, 169]
Fruiting bodies Ultra-filtration, DEAE- Sepharose Fast-Flowand Sephacryl S-300 α-Galactose,
β-Glucose
Galactose,Glucose,
Fucose
[170]
Fruiting bodies Hot-water extraction
DEAE-cellulose-32 and
Sephacryl S-200h
β-Glucan Glucose 5.2×103 [171]
Heteroglycans Glucose,Galactose,
Mannose
1.54×104
Fruiting bodies Hot-water extraction
DEAE Sepharose Fast-Flow and Sepharose CL-6B
α-Galactose, Galactose,Glucose,
Fucose
1.12×104 [172]
β-Glucose
Fruiting bodies Ultrasound/microwave assisted extraction
DEAE Sepharose Fast Flow and Sephacryl S-500
β-Glucose Glucose, Galactose 2.5×106 [173]
Spores Hot-water extraction, graded ethanol precipitation, DEAE-cellulose and Sephacryl S-300 β-Glucan Glucose 10.3×104 [174]

Table 2: Different glycans isolated from Ganoderma lucidum.

Β - Glucans are glycans that contain only glucose as structural components and are linked with β - glycosidic bonds. β - glucans are the simplest and the most studied fungal glycans. The biologically active fungal β - glucans are those comprising β (1,3) linked-glucose with side-chains of glucose with β (1,6) linkage. As shown in Table 2, the six β - glucans purified from Ganoderma lucidum are either water soluble or insoluble with molecular weight ranged from 5.2 x 103 to 1.0 x 105 Da.Therefore, β - glucans are not pure glycans. β -glucans can bind to six identified receptors on cell surface of immune cells (Figure 1) [66-73]. The β - glucan and receptor interactions can activate multiple signaling transduction pathways directly or indirectly through macrophages, monocytes, dendritic cells, natural killer cells, B-cells, T-cells and neutrophils. β -Glucans also stimulate the release of cytokines, such as tumor necrosis factor (TNF-α) and several interleukins.

translational-medicine-glucans-membrane-immune

Figure 1: Receptors for β-glucans. β -glucans can bind to several membrane receptors on the immune cell surface, such as toll-like recepters 2/6 (TLR2/6), Dectin-1, Fc receptor (FcR), lactosylceramide (LacCer), scavenge receptor (Sc), and complement receptor 3 (CR3). Subsequently, multiple signaling pathways are activated and merged onto important immune regulatory pathways, such as NF- κ B.

Activating the immune cells explain the immunomodulating and antitumor activities of β - glucans. However, not only fungi but also bacteria, plants, and algae synthesize biological active β - glucans. Moreover when present in animal blood circulation, tissues, or organs, most foreign glycans are recognized as sign of bacterium or fungus invasions through a series of receptors on immune cells including those receptors that bind to β - glucans. Most of glycans also have antiinflammatory properties that could not be explained by the glycan/ receptor signal transduction mechanism. Moreover, anti-oxidative and hypoglycemic properties are also common to all biological active glycans. As shown in Table 1, the drug indications of the 8 fungal glycan-based drugs are very different, which suggests the unique glycan compositions, but not the β - glucans alone, might contribute to the observed pharmaceutical effects of the fungal glycan-based drugs. Being not pure might be a reasonable character for glycan-based drugs since glycans produced by nature are never pure even for the simplest β -glucans (see different characteristics of six β -glucans purified from Ganoderma lucidum listed in Table 2. We will briefly review the structure, function, clinical uses, and animal studies (summarized in Table 3) of the 8 fungal glycans and the glycan-based drugs in the next section.

Glycans Models Effects Ref.
Ganoderma lucidum glycans Mouse Enhance phagocytosis and cytotoxicity of macrophages [125]
Mouse Enhance Lymphokine-activated killer cells [125]
Mouse Increase cytotoxic T lymphocyte cytotoxicity and NK activity [134-136]
Mouse Stimulate spleen-cell proliferation and cytokine generation [134,137,138]
Mouse Reduce tumor weight [134]
Mouse Exert antitumor effect on solid tumor induced by Ehrlich’s ascites carcinoma cells [128]
Nude Mouse Reduce Human lung carcinoma xenograft size [140]
Mouse Induce tumor apoptosis and enhance immunological effect [141]
Mouse Enhance scavenging abilities on reactive oxygen species [175]
Rat Reduce ROS production and increase the activity of Manganese superoxide dismutase (Mn-SOD) [142]
Mouse Increase insulin levels and decrease blood glucose [143,144]
Rat Decrease total cholesterol (TC) [143,144]
Mouse Reduce serum triglyceride (TG) [143]
Mouse NO production [139]
Ganoderma sinensis glycan Mouse Enhance levels of IL-2, IL-3, IL-4, interferon γ, TNF α, and IL-2R [112]
Lentinan Mouse Inhibite growth of Sarcoma [78]
Mouse Increase production of cytokine in immune cells [79,80]
Nude Mouse Trigger delayed-type hypersensitivity response against tumor-associated antigens [81]
Chicken Enhance serum antibody titer and promote lymphocyte proliferation [82]
Rat Improve bactericidal ability of peritoneal and alveolar macrophages [83]
Mouse Enhance sensitivity of colon 26 tumor to cis-diamminedichloroplatinum (II) and decrease glutataione transferase expression [84]
Pig Induce high level of alveolar macrophage activation [85]
Mouse Induce TNF-α secretion of murine macrophages [86]
Rat Induce long-term potentiation in the rat dentate gyrus [87]
Mouse Induction of cytotoxic peritoneal exudate cells [176]
Mouse Stimulate the expression of cytokines [88]
Polyporus glycan Mouse Enhance TNF- α , IL-1b, and NO production [177]
Rat Prevente the progression of renal injury and the subsequent renal fibrosis in Aristolochic acid nephropathy [178]
Rat Inhibit bladder carcinogenesis, which may be associated with upregulation of GSTPi and NQO1 in the bladder [179]
Rat Down-regulate AQP2, and down-regulate AQP2 by down-regulating V(2)R [180]
Krestin Rat Suppress metastasis induced by hepatic I/R [100]
Rat Inhibit bone Metastasis of Breast Cancer [101]
Rat Improve GALT inhibition caused by TPN [102]
Pachymaran Mouse Increase thymus and spleen indices, lysozyme, catalase , superoxidase dismutase activities, and total antioxidant capacity. Decrease xanthine oxidase activity and malondialdehyde levels. [118]
Rat Decrease MDA and increase GSH levels in serum cervical of rats with cervical cancer [119]
Rat Increase SOD, CAT, GPx, and GR activities in serum and cervical of rats with cervical cancer [119]
Mouse Enhance antitumor activities [120]
Mouse Increase macrophage activities and PFC, SRFC, DTH, IL-2 , IFN-γ, TNF-α, TCGF levels [121-123]
Maitake glycan Mouse Activate macrophage and induce of IL-1, IL-6 and TNF-a secretion [181]
Mouse Lower plasma cholesterol level [152]
Mouse Activate natural killer and dendritic cells and enhance antitumor immunity [147]
Mouse Protective effect of pancreatic β-cells exerted by decreasing levels of oxidative stress and NO synthesis [148]
Mouse Induce systemic tumor-antigen specific T cell response, increase infiltration of activated T cells into tumor and decrease number of tumor-caused immunosuppressive cells [149]
Rat Significantly lower systolic blood pressure (SBP) in diabetic Sprague-Dawley rats [150]
Rat Inhibite LPS-induced upregulation of NF-κB activation and the production of IL-1β, TNF-α, iNOS, ICAM-1, and COX-2 [151]
Tremella glycan Mouse Have radiation protection properties [154]
Mouse Increase plasma insulin level and the activities of hepatic hexokinase and glucose-6-phosphatase dehydrogenase, and decrease hepatic glucose-6-phosphatase level [155]
Rat Improve cognitive function via regulation of the CREB signaling pathway and cholinergic system in the hippocampus [156,157]
Rat Increase cholinergic activity [158]
Rat Increase fecal neutral steroids, total bile acids excretion, and SCFA productions [159]

Table 3: Animal studies of biological effects of Fungal glycans.

Structural and Functional Studies of Fungal Glycans

Lentinan from Lentinus edodes

Lentinan is a name given to β - glucans purified from Lentinus edodes. The antitumor property of lentinan was first reported by Chihara et al in 1970 [74]. Sasaki and Takasuka demonstrated that the primary structure of lentinan has β - (1-3)-glucose backbone with many (1-6)- β - glucose branches [75].

Letinan-based drugs are available as capsules, tablets, and injections in China. The published clinical reports indicate that these drugs have been used for treating urticaria [12], gastrointestinal cancers [13-18], primary liver cancers [19], hepatitis [20,21], malignant pleural effusion [22-27], and HIV [28].

In 1985, lentinan is approved as an adjuvant for stomach cancer therapy in Japan. The lentinan activates immune cells [76], promotes the T- and B-lymphocyte proliferation, and enhances the activities of NK cells. The lentinan also plays multiple roles in inducing α-interferon production and leukocyte infiltration into tumor tissues [77]. The biological activities of lentinan have been studied by using mouse-,rat-, chicken-, and pig-based animal models [76,78-88]. These animal studies confirm that lentinan stimulate the productions of different cytokines and have antitumor and immunomodulating properties.

Polyporus glycan

Polyporus glycan is extracted from the sclerotium of Polyporus umbellatus. The major component of polyporus glycan is a β - glucan with a (1-3)- β -glucose backbone and (1-6)- β -glucose side chains with a molecular weight of approximately 1.6×105 Da [89].

Polyporus glycans have been commercially available as an immunomodulating drug since 1990. Based on published reports, the polyporus glycan-based capsules are effective in treating hepatitis B [29-33,90,91] and the polyporus glycan-based injections reduce the recurrence of bladder cancer [33]. Polyporus glycan boosts the immune system and have anti-parasite properties [92,93]. It is also used in treating leukemia and liver cancers [94,95]. Study has also shown that Polyporus glycans are effective in protecting liver from certain toxins [95]. Polyporus glycans are also used together with chemotherapy drugs to treat primary lung cancer, liver cancer, cervical cancer, nasopharyngeal carcinoma, esophageal cancer and leukemia.

Polysaccharide-K (PSK) or krestin

PSK or Krestin is a protein bound glycan isolated from cultured mycelium of Polystictus Versicolor. Glucose is the major monosaccharide found in PSK. PSK also contains arabinose, rhamnose, fucose, galactose, mannose, and xylose [96]. The glycans in PSK is highly branched. The molecular weight of PSK is around 1 × 105 Da and the protein component is covalently linked to the β-1,6 glucose side chain.

PSK-based drugs are available as capsules and dropping pills in China. The published clinical reports indicate that these drugs have been used for treating acute nonlymphocytic leukemia [34], colorectal cancers [35,36], gastric cancers [37-40], lung cancer [41], primary liver cancer [42-44], hepatitis[45-50], and hyperlipidemia [51].

PSK has increased the survival time of cancer patients in randomized, control studies, with stomach cancer (meta-analysis of 8,009 patients) [97], colorectal cancer (randomized, controlled study of 448 patients) [98], but PSK has produced mixed results with liver cancer [99]. Rat-based animal studies confirmed the anti-metastasis properties of PSK [100-102].

Three mechanisms are proposed to explain the clinical effectiveness of PSK in suppressing cancer relapse [103]. First, PSK improves host immune-competence by inhibiting the production and also by neutralizing immunosuppressive substances that are increased in cancer. Second, PSK activates immune cells such as lymphocytes, either directly or by regulating the production of various cytokines. Third, PSK acts directly on cancer cells. In addition, the effects of PSK on the production of various cytokines and nitric oxide (NO) have also been reported [104,105].

Ganoderma Sinensis glycans

Ganoderma sinensis glycans are purified from fruiting body of Ganoderma Sinensis. The major bioactive Ganoderma sinensis glycans are α/β -glucans, glycan-protein complex and water-soluble heteroglycans with different combinations of glucose, mannose, galactose, xylose, fucose as well as arabinose. The molecular weight of the glycans ranges from 103 to 106 Da [106].

Ganoderma sinensis glycan-based drugs are available as capsules. Published reports indicated the drug is used for neutralizing mushroom poisoning [10] and stimulate leukocytes productions in leukopenia patients [11] . Further studies showed that Ganoderma sinensis glycans enhance the immune responses in patients with advanced-stage cancer [107,108]. Ganoderma sinensis glycans also have potent antioxidant activities [109-111]. Mouse-based animal studies indicate that Ganoderma sinensis glycans enhance the levels of a variety of citokines [112].

Pachymaran

Pachymaran is a name giving to a heteroglycan isolated from Poria Cocos. Pachymaran consists of glucose, galactose, and mannose. It exhibits antitumor activities both in vitro and in vivo [113,114]. β-Glucan extracted from Poria Cocos is water-insoluble and has no antitumor activity, whereas its phosphorylated water soluble derivatives exhibits strong anti-S-180 tumor activities [115].

Pachymaran used for making the glycan-based injection drugs in China is isolated from mycelium of Poria Cocos. It is used for treating chronic pulmonary edema [52], insomnia [53], alopecia [54], and schizophrenia [55]. It prevents tumor metastasis through its immunomodulatory activities [116,117]. Mouse- and rat-based animal studies showed that pachymaran has potent antioxidative and antitumor activities [118-123].

Ganoderma Lucidum glycans

Ganoderma Lucidium glycans are composed of different variety of glycans as shown in Table 2. Ganoderma Lucidium glycan-based drugs are purified form spores and available as injections. Published reports indicated the drug improves endurance of cyclists [7] and helps patients with dyslipidemia conditions [8]. Interestingly, when combined with glucocorticoid, the drug cures facial paralysis in patients [9].

Mouse and rat-based animal studies showed Ganoderma Lucidium glycans activate different immune cells and stimulate chemokine and cytokine production [108,124-139]. Ganoderma Lucidium glycans also have antitumor [128,140,141], anti-oxidative [124,142], antidiabetic [143,144], and hypolipidemic [143,144] activities.

Maitake glycans

Grifola Frondosa is also called maitake. A bioactive β - glucan fraction termed D-fraction was isolated from both mycelia and fruiting body of Grifola Frondosa by Japanes mycologists in 1984. Grifolanis of maitake glycans is a glycan-protein complex, which is called Wu Rong D-fraction in China. Its glycans mainly consist of glucose along with xylose, fucose, galactose, and mannose. The ratio of protein to glycan in Grifolanis is 7:3. The average molecular weight of Grifolanis is greater than 1x 106 Da. Only Wu Rong D-fraction have antitumor activities [145].

Grifola Frondosa glycans used for drug production is isolated from cultured mycelium. The glycan-based drugs are available as capsules. Published reports indicated the drug is used for cancer treatment [56,57], impaired glucose tolerance conditions [58], and for treating polycystic ovary syndrome [59]. Grifola Frondosa glycans have also been used for cosmetic and other biological purposes [146].

Mouse and rat-based animal studies showed Grifola Frondosa glycans activate different types of immune cells [147] and regulate chemokine and cytokine productions [147-151]. Grifola Frondosa glycans also have antitumor [147], anti-oxidative [148], hypocholesterol [152], and hypo-systolic blood pressure [150] activities.

Tremella glycan

Tremella glycans are isolated from fruiting body of Tremella fuciformis. The most representative glycans in Tremella fuciformis is acidic heteroglucan where α - mannan constituteits the backbone with β - (1,2) xylose, β - (1,2) glucuronic acid, and minor amount of fucose on the side chains. Other glycans include several neutral heteroglycans comprising of xylose, mannose, and galactose.

Tremella glycan-based drugs are available as capsules in China. The drug is used clinically in treating mycoplasma caused pneumonia [60], chronic active hepatitis [61], diabetic [62], leukopenia [63-65] conditions. The drug also promotes neural cell growth and improves memory [153].

Mouse-based animal studies showed tremella glycans have radiation protection properties [154]. Tremella glycans increase plasma insulin level and the activities of hepatic hexokinase and glucose-6-phosphatase dehydrogenase and decrease hepatic glucose-6-phosphatase level [155]. Interestingly, tremella glycans improve cognitive functions through multiple distinctive mechanisms in rats [156-159].

Future Perspectives

There are multiple issues needed to be addressed before fungal glycan-based drugs are accepted by governments and clinicians worldwide, such as how to comprehend the pharmacodynamics of fungal glycan-based drugs at molecular level, how to standardize quality, composition, purity of the highly dispersed glycan molecules, and how to perform reliable pharmacokinetic studies. Compared to conventional small molecule- and protein-based drugs, the advantages of glycan-based drugs are their broad spectrum of therapeutic properties, relatively low toxicity, less drug-resistant issues, and relatively low costs. The disadvantages of glycan-based drugs are the inherited heterogeneity of their structures and functions, lack of tools to do proper structure analyses, and difficulty in establishing structure and function relationships. Thus, developing reliable biological assays and novel structural characterization tools might be critical in understanding the information encoded in the fungal glycans and to perform reliable pharmacokinetic and pharmacodynamic studies.

Acknowledgement

This work was supported by Natural Science Foundation of China (Grant No. 91129706). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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