Ganoderma and Health: Pharmacology and Clinical Application [1st ed. 2019] 978-981-32-9420-2, 978-981-32-9421-9

Table of contents :
Front Matter ....Pages i-viii
Immunomodulating Effect of Ganoderma (Lingzhi) and Possible Mechanism (Xin Wang, Zhibin Lin)....Pages 1-37
Antitumor Effect of Ganoderma (Lingzhi) Mediated by Immunological Mechanism and Its Clinical Application (Zhibin Lin, Lixin Sun)....Pages 39-77
Cellular and Molecular Mechanism of Ganoderma (Lingzhi) Against Tumor (Yu Sun, Lixin Sun)....Pages 79-118
Protective Effect of Ganoderma (Lingzhi) on Radiation and Chemotherapy (Lihua Chen, Abudumijiti Abulizi, Min Li)....Pages 119-142
Neuropharmacological Effect and Clinical Applications of Ganoderma (Lingzhi) (Xiangyu Cui, Yonghe Zhang)....Pages 143-157
Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Brain Injury (Yazhu Quan, Ang Ma, Baoxue Yang)....Pages 159-180
Protective Effect of Ganoderma (Lingzhi) on Cardiovascular System (Jia Meng, Baoxue Yang)....Pages 181-199
Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Diabetes (Qian Liu, Lu Tie)....Pages 201-215
Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Liver Injury (Zhiwei Qiu, Dandan Zhong, Baoxue Yang)....Pages 217-242
Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Renal Diseases and Clinical Applications (Xiaoqiang Geng, Dandan Zhong, Limin Su, Baoxue Yang)....Pages 243-262
Anti-osteoporosis Effect of Ganoderma (Lingzhi) by Inhibition of Osteoclastogenesis (Yajun Yang, Baoxue Yang)....Pages 263-269
Antioxidative and Free Radical Scavenging Activity of Ganoderma (Lingzhi) (Zhibin Lin, Aoyi Deng)....Pages 271-297
Anti-aging Effect of Ganoderma (Lingzhi) with Health and Fitness (Yan Pan, Zhibin Lin)....Pages 299-309
Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Skin Diseases and Care (Zhuming Yin, Baoxue Yang, Huiwen Ren)....Pages 311-321

Citation preview

Advances in Experimental Medicine and Biology 1182

Zhibin Lin Baoxue Yang Editors

Ganoderma and Health Pharmacology and Clinical Application

Advances in Experimental Medicine and Biology Volume 1182

Series Editors Wim E. Crusio, CNRS and University of Bordeaux UMR 5287, Institut de Neurosciences Cognitives et Intégratives d’Aquitaine, Pessac Cedex, France John D. Lambris, University of Pennsylvania, Philadelphia, PA, USA Nima Rezaei, Children’s Medical Center Hospital, Tehran University of Medical Sciences, Tehran, Iran

More information about this series at http://www.springer.com/series/5584

Zhibin Lin • Baoxue Yang Editors

Ganoderma and Health Pharmacology and Clinical Application

Editors Zhibin Lin Department of Pharmacology School of Basic Medical Sciences Peking University Beijing, China

Baoxue Yang Department of Pharmacology School of Basic Medical Sciences Peking University Beijing, China

ISSN 0065-2598     ISSN 2214-8019 (electronic) Advances in Experimental Medicine and Biology ISBN 978-981-32-9420-2    ISBN 978-981-32-9421-9 (eBook) https://doi.org/10.1007/978-981-32-9421-9 © Springer Nature Singapore Pte Ltd. 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore

Contents

1 Immunomodulating Effect of Ganoderma (Lingzhi) and Possible Mechanism.......................................................................... 1 Xin Wang and Zhibin Lin 2 Antitumor Effect of Ganoderma (Lingzhi) Mediated by Immunological Mechanism and Its Clinical Application................ 39 Zhibin Lin and Lixin Sun 3 Cellular and Molecular Mechanism of Ganoderma (Lingzhi) Against Tumor.......................................................................................... 79 Yu Sun and Lixin Sun 4 Protective Effect of Ganoderma (Lingzhi) on Radiation and Chemotherapy................................................................................... 119 Lihua Chen, Abudumijiti Abulizi, and Min Li 5 Neuropharmacological Effect and Clinical Applications of Ganoderma (Lingzhi)........................................................................... 143 Xiangyu Cui and Yonghe Zhang 6 Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Brain Injury........................................................................................ 159 Yazhu Quan, Ang Ma, and Baoxue Yang 7 Protective Effect of Ganoderma (Lingzhi) on Cardiovascular System....................................................................................................... 181 Jia Meng and Baoxue Yang 8 Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Diabetes................................................................................................ 201 Qian Liu and Lu Tie

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Contents

9 Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Liver Injury......................................................................................... 217 Zhiwei Qiu, Dandan Zhong, and Baoxue Yang 10 Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Renal Diseases and Clinical Applications......................................... 243 Xiaoqiang Geng, Dandan Zhong, Limin Su, and Baoxue Yang 11 Anti-osteoporosis Effect of Ganoderma (Lingzhi) by Inhibition of Osteoclastogenesis................................................................................ 263 Yajun Yang and Baoxue Yang 12 Antioxidative and Free Radical Scavenging Activity of Ganoderma (Lingzhi)........................................................................... 271 Zhibin Lin and Aoyi Deng 13 Anti-aging Effect of Ganoderma (Lingzhi) with Health and Fitness................................................................................................ 299 Yan Pan and Zhibin Lin 14 Preventive and Therapeutic Effect of Ganoderma (Lingzhi) on Skin Diseases and Care...................................................................... 311 Zhuming Yin, Baoxue Yang, and Huiwen Ren

Contributors

Abudumijiti  Abulizi  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Lihua  Chen  Department of Medicine Clinical Laboratory, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China Xiangyu  Cui  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Aoyi Deng  The School of Health Humanities, Peking University, Beijing, China Xiaoqiang Geng  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Min Li  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Zhibin  Lin  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Qian Liu  State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, China Ang Ma  State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Jia Meng  State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Yan Pan  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China vii

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Contributors

Zhiwei Qiu  State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Yazhu Quan  State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Huiwen  Ren  Department of Pharmacology and Tianjin Key Laboratory of Inflammation Biology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, China Limin Su  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Lixin  Sun  Affiliated Hospital of Chengde Medical University, Chengde, Hebei, China Yu  Sun  Affiliated Hospital of Chengde Medical University, Chengde, Hebei, China Lu  Tie  State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Beijing Key Laboratory of Tumor Systems Biology, Peking University, Beijing, China Xin  Wang  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Baoxue  Yang  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Yajun  Yang  Department of Pharmacology, School of Pharmacy, Guangdong Medical University, Zhanjiang, Guangdong, China Zhuming  Yin  Department of Breast Oncoplastic Surgery, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer (Tianjin), Sino-Russian Joint Research Center for Oncoplastic Breast Surgery, Key Laboratory of Breast Cancer Prevention and Therapy, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China Yonghe Zhang  Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China Dandan  Zhong  State Key Laboratory of Natural and Biomimetic Drugs, Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China

Chapter 1

Immunomodulating Effect of Ganoderma (Lingzhi) and Possible Mechanism Xin Wang and Zhibin Lin

Abstract  Ganoderma (Lingzhi) has been used for a long time in China to prevent and treat various diseases. Accumulated studies have demonstrated that the Ganoderma modulates immune function both in vivo and in vitro. The immunomodulating effects of Ganoderma were extensive, including promoting the innate immune function, humoral immunity, and cellular immunity. In particular, G. lucidum polysaccharides may affect immune cells and immune-related cells including B and T lymphocytes, dendritic cells, macrophages, and natural killer cells, with the promotion of immune organ growth, cytokine release, and other immune regulatory functions. Furthermore, cellular and molecular immunomodulatory mechanisms, possible receptors involved, and triggered signaling pathways have also been summarized. However, whole animal experiments are still needed to further establish the mechanism of the immunomodulating effects by Ganoderma. Importantly, evidence-based clinical trials are also needed. Keywords  Ganoderma · Polysaccharides · Immunomodulatory effects · Macrophages · Cytokines It has been deeply investigated and well recognized that the variety of pharmacological activities of Ganoderma (Lingzhi) and its active components including polysaccharides were mainly through its extensive immunomodulatory effects. A number of studies have demonstrated the immunomodulating effects both in vivo and in vitro, including promoting the proliferation, differentiation, and function of antigen-presenting cells (APC) such as dendritic cells, enhancing the phagocytic function of mononuclear macrophages and natural killer (NK) cells, and enhancing humoral and cellular immunity, such as promoting immunoglobulin production, promoting T and B lymphocyte proliferative responses, and promoting cytokine production. Ganoderma can restore immune dysfunction induced by various causes X. Wang · Z. Lin (*) Department of Pharmacology, School of Basic Medical Sciences, Peking University, Beijing, China e-mail: [email protected]; [email protected] © Springer Nature Singapore Pte Ltd. 2019 Z. Lin, B. Yang (eds.), Ganoderma and Health, Advances in Experimental Medicine and Biology 1182, https://doi.org/10.1007/978-981-32-9421-9_1

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[1]. The immunomodulatory effect of Lingzhi is one of the potential mechanisms of “Fuzheng Guben (supporting the healthy energy, strengthening and consolidating body resistance),” which is one of the major principles in the therapeutics of traditional Chinese medicine [2–4]. This review provides a comprehensive summary of the cellular and molecular mechanisms of immunomodulation by Ganoderma on the basis of our research and highlights recent advances delineating immunobiological mechanisms that have been made toward integrating immunomodulatory therapies in the clinic.

1.1  Ganoderma Enhances Innate Immune Function Innate immunity, also known as natural immunity or non-specific immunity, is a series of defense mechanisms that not only responds quickly to various invading pathogenic microorganisms but also plays an important role in the initiation and effect processes of specific immunity. Studies have found that a variety of innate immune cells such as natural killer (NK) cells, dendritic cells (DCs), and macrophages can regulate the innate immune response. Enhancing the body’s non-specific immunity is of great significance to improve the overall immune function of the body.

1.1.1  G  anoderma Promote Maturation and Function of Dendritic Cells Dendritic cells (DCs) are the most powerful professional antigen-presenting cells (APCs) in the body. DCs are the initiator of immune response and play a unique role in the induction of immune response. Mature DCs can activate the initial T cells effectively. Cao and Lin (2002) firstly established the culture of murine bone marrow-derived DC in vitro and further explored whether G. lucidum polysaccharides (Gl-PS) have regulatory effects on maturation and function of DC. The results showed that Gl-PS at the concentration of 0.8, 3.2, and 12.8 μg/mL upregulated the co-expression of I-A/I-E and CDl1c molecules on DC surface and promoted mRNA expression and protein secretion of IL-12 p40 unit, which indicated that Gl-PS could promote the maturation of DC in the presence of 1 mg/mL lipopolysaccharide (LPS). On the other hand, the upregulation of co-expression of I-A/I-E and CD11c on the DC surface also indicated the mechanism by which Gl-PS promotes the maturation of DC may be related to its effect on I-A/I-E expression. Further results confirmed that Gl-PS could promote the proliferation of one-way MLC induced by DC, indicating the modulating effects of Gl-PS on innate immune response primed by mature DC. These data demonstrate that Gl-PS promotes not only the maturation of ­cultured

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murine bone marrow-derived DC in vitro but also the immune response initiation induced by DC [5]. Further data show that Gl-PS are able to promote the cytotoxicity of specific cytotoxic T lymphocyte (CTL) induced by Gl-PS-treated DC pulsed with P815 tumor cell lysates during the stage of antigen presentation, with the mechanism mainly through interferon (IFN)-γ and granzyme B pathways [6]. Lin et al. (2005, 2006) investigated the effects of the polysaccharide component with a branched (1  →  6)-β-D-glucan moiety of G. lucidum (PS-G) on human monocyte-­derived DC.  Treatment of DC with PS-G (10  μg/mL) resulted in the enhanced cell surface expression of CD80, CD86, CD83, CD40, CD54, and human leukocyte antigen (HLA)-DR, as well as the enhanced mRNA expression and production of IL-12 p70, IL-12 p40, and IL-10, while the capacity for endocytosis was suppressed in DC.  In addition, treatment of DC with PS-G resulted in enhanced T-cell stimulatory capacity and increased T-cell secretion of IFN-γ and IL-10 [7, 8]. Chan et al. (2007) demonstrated that extracts from different parts of G. lucidum can also stimulate the maturation of monocyte-derived DC cells. The crude/pure polysaccharide of G. lucidum mycelium (1, 10, 100 μg/mL) could induce proliferation of human peripheral blood mononuclear cells (PBMC) in a dose- and time-­ dependent manner; upregulate cell surface and costimulatory molecules HLA-DR, CD40, CD80, and CD86; promote the functional maturation of DC cells; and secrete IL-12, IL-12 p70, and IL-10. The results of homologous (allogenic) mixed lymphocyte experiment showed that DC treated with purified G. lucidum mycelium polysaccharide promoted T-cell proliferation. Contrarily, DC treated with purified G. lucidum spore polysaccharide inhibited T-cell proliferation. The contents of IL-10 and TGF-β in supernatants of DC/T mixed cells treated with G. lucidum spore polysaccharide did not change significantly [9]. Another study confirmed that combination of GLPS and GMCSF/IL-4 induces the transformation of THP-1 cells into typical DC cells, while GLPS alone can only induce the proliferation of THP-1 and U937 cells. In addition, when THP-1 was converted to DC, the expression of HLA-DR, CD40, CD80, and CD86 increased significantly, and the ability of antigen uptake also increased. However, its ability to induce allogeneic T-cell proliferation is weak [10]. Zhao et al. (2010) investigated the immunomodulation activities of G. lucidum polysaccharide (GLP) by way of regulating the enteric mucosal immune response. Mouse peripheral blood mononuclear cells (PBMCs), intestinal epithelial lymphocytes (IEL), and Peyerʼs patches lymphocytes (PPL), respectively, were co-­ incubated with different concentrations of GLP (250, 125, 62.5, 31.25  μg/mL) under stimulation of ConA (4 μg/mL). The MTT assay suggests that GLP can stimulate the proliferation of PBMC and enteric mucosal lymphocytes. ELISA and RT-PCR assay reveal that GLP obviously increased the production of IL-2 and IL-10, as well as TNF-α and IL-10 mRNA expression in PBMC, IEL, and PPL induced by ConA [11]. To investigate and analyze the effects of G. lucidum polysaccharides (GLPs) on cell phenotype and functional maturation of murine DCs, Meng et al. (2011) use conventional scanning electronic microscopy (SEM) and transmitted electron

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microscopy (TEM) for the morphology of and intracellular lysosomes inside the DCs. Under SEM, the DC treated with 300 μg/mL GLP for 24 h shows more protrusions and rougher surface in morphology, which indicates matured DC to trigger T-cell response. Under TEM, the number of lysosomes inside the DC treated with GLP reduced significantly with gradual maturation compared with those in the untreated DC. Other assays included cellular immunohistochemistry for phagocytosis by the DCs, flow cytometry (FCM) for analyzing key surface molecule alteration, bio-assay for the activity of acid phosphatases (ACP), and ELISA for the production of pro-inflammatory cytokine IL-12. It was found that GLP induced phenotypic maturation, as evidenced by increased expression of key surface markers and receptors such as CD86, CD40, and MHC II.  Functional experiments showed the downregulation of ACP inside the DCs, which occurs when phagocytosis of DCs decreased, and antigen presentation increased with maturation. GLP increased the production of IL-12, which would work as an intensified signal to activating CD4+ T-cell response. These data reveal that GLPs exert positive modulation to DCs, markedly enhance DC maturation and function, as well as have a marked enhancement in the DC-CD4+ T-cell pathway [12]. Lv et al. (2016) use high content imaging system to quantify the immunostimulation ability of one major fraction of G. lucidum polysaccharide, GLPII. GLPII-­ treated (40 μg/mL) Raw264.7 cells for 24 h significantly increased cell metabolic activity and changed the morphology of Raw264.7 cells toward dendritic-like cells (DC) (Fig. 1.1). Within 24 h, the sizes of cells became larger with extended dendritic pseudopods compared to untreated group. Cell irregularity increases quickly within 0–10 h and then gradually reached a plateau after 30 h. Raw264.7 cell differentiation by GLPII was also in a concentration-dependent manner; at the same time, the 30 h plateau increased with the concentration. It indicated that polysaccharides may induce a strong metabolic activity during cell differentiation instead of cell proliferation. Flow cytometry was used to examine phenotypic changes on Raw264.7 cells by polysaccharides. Typical phenotypic maturation surface markers involved MHCII, CD40, CD80, and CD86. After treatment with different concentrations of GLPII, all these cell surface markers showed a dose-dependent upregulation [13]. Another work from the same research group (Zhu et al. 2016) compared polysaccharides isolated from Ganoderma lucidum (GLP) with other herbs to determine the immunoactivities on innate immune response, applying bone marrow-derived DC.  DCs incubated with salt eluent of GLP 45  μg/mL for 24  h showed similar immuno-potentiation ability on DC maturation through the increased expression of CD40, MHCII, CD80, and CD86 compared to 0.1 μg/mL LPS, elongated protrusion (Fig. 1.2), and increased level of nitric oxide (NO). Interestingly, blockage of NO by an iNOS inhibitor (S-methylisothiourea sulfate, SMT) significantly decreased

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Fig. 1.1  Morphology changes of Raw264.7 cells by GLPII.  Cells were treated with culture medium, 40 μg/mL GLPII and 0.1 μg/mL LPS (positive control). Transmission electron microscopy of non-treated (left) and 40 μg/mL GLPII-treated Raw264.7 cells (right). (Reproduced with permission from Ref. 13)

Fig. 1.2  Morphological changes of DC by GLP. Cells were treated with culture medium or 45 μg/ mL GLP and imaged by (a) optical microscopy, (b) scanning electron microscopy, and (c) transmission electron microscopy. (Reproduced with permission from Ref. 14)

CD40/MHCII but not CD80/CD86 expression induced by GLP, indicating that NO was partially involved in DC maturation. Immature DCs keep the capability to capture antigens, while after maturation, DCs start to process and present antigen. The phagocytic ability expressed by FITC-dextran uptake in cells evaluated by flow cytometry reduced significantly in GLP-treated DC compared to the non-treated

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Fig. 1.3  Endocytosis of GLP-FITC that can be blocked by endocytic inhibitors. (a) Endocytosis revealed by confocal microscopy. Cells were incubated with 180  μg/mL GLP-FITC for 24  h. Differential interference contrast (DIC) showed the morphology of DC with elongated dendrites. GLP-FITC was found to distribute in the cells as a punctate pattern (green). Hoechst staining represents the cell nuclei (blue). (b) Inhibition of GLP-FITC endocytosis. Endocytic inhibitors sodium azide (0.65 mg/mL), nocodazole (10 μg/mL), and brefeldin A (10 μg/mL) were added with 180 μg/ mL GLP-FITC for 1 h. Cells were collected and washed and analyzed by flow cytometry and normalized to GLP-FITC-treated sample. ∗0.01