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Review
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Biological activities and potential health benefits of polysaccharides from Poria cocos and their derivatives
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Yichun Sun ∗ Pharmaceutical College, Heilongjiang University of Chinese Medicine, Harbin 150040, PR China
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Article history: Received 12 November 2013 Received in revised form 18 March 2014 Accepted 7 April 2014 Available online xxx
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Keywords: Poria cocos Polysaccharides Biological activities
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Contents
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Poria cocos has a long history of medicinal use in Asian countries such as China, Japan, Korea and Thailand. It is a kind of edible and pharmaceutical mushroom. The chemical compositions of Poria cocos mainly include triterpenes, polysaccharides, steroids, amino acids, choline, histidine, etc. Great advances have been made in chemical and bioactive studies on Poria cocos polysaccharides (PCP) and their derivatives in recent decades. These PCP and their derivatives exhibit many beneficial biological activities including anticancer, anti-inflammatory, antioxidant and antiviral activities. Therefore, PCP and their derivatives have great potential for further development as therapy or adjuvant therapy for cancer, immune-modulatory and antiviral drugs. This paper presents an overview of biological activities and potential health benefits of PCP and their derivatives. © 2014 Published by Elsevier B.V.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological activities and potential health benefit effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Other biological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Edible and medicinal mushrooms are integral parts of natural medicines, and have been used for millennia to prevent or treat various diseases [1]. Poria cocos is a kind of edible and pharmaceutical mushroom. It is known for its name as Fu-ling in Chinese and grows under ground on the roots of pine trees [2]. In the wild, it grows much like the European truffle, but other genera, such as Citrus, Eucalyptus, or Quercus, and it can be parasited [3]. Poria cocos is commercially available and is popularly used in the formulation of nutraceuticals, tea supplements, cosmetics, and functional foods in Asia [4]. As reported previously, the chemical constituents of Poria cocos mainly include three principal groups of chemicals, the triterpenes, polysaccharides and steroids. Other minor compounds like
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amino acids, choline, histidine, and potassium salt, etc. have also been described [5–10]. Poria cocos is often present in Chinese herbal compound preparations and Kampo medicines such as Gui-Zhi-Fu-Ling tablet, Shan-Zha-Fu-Ling granules, Rikkunshi-to and Shikunshi-to, etc. It is used to treat chronic gastritis, edema, nephrosis, gastricatony, acute gastroenteric catarrh, dizziness, nausea, and emesis [11]. Since Poria cocos is commercially available and is popularly used in Asia, it is worthwhile to fully characterize its activities. Poria cocos polysaccharides (PCP) and their derivatives have been used in the adjuvant treatment for cancer and a number of medicinal and clinical researches in vivo and in vitro suggested that PCP and their derivatives showed an important role for human health [12]. Many different polysaccharides have been isolated from Poria cocos, the bioactive polysaccharides are shown in Table 1. This review focuses on polysaccharides derived from Poria cocos and presents an overview of their biological activities with potential health benefits. The bioactivities of PCP and their derivatives including
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2 Table 1 The bioactive polysaccharides from Poria cocos. Compound name
Monosaccharide composition
Structural features
Biological activities
References
The polysaccharide from Poria cocos Pi-PCM0
Rib:Ara:Xyl:Man:Glc:Gal in the ratio of 1.6:10.9:5.4:113:859:10.1 Ara:Xyl:Man:Gal:Glc in the ratio of 2.5:1.5:70.6:18.5:7.0 Fuc:Ara:Xyl:Man:Gal:Glc in the ratio of 10.9:1.0:2.8:23.6:36.5:25.2 Fuc:Man:Gal:Glc in the ratio of 1.9:29.6:38.9:29.7
-Glycosidic linkage
Anticancer and antioxidant Anticancer
[16]
Anticancer
[17]
Anticancer
[17]
Anticancer Anticancer
[6,17] [18,20]
Anticancer
[19]
Anticancer
[19]
Anticancer
[19]
Anticancer
[19]
Anticancer
[19,22]
Anticancer
[19,22]
Anticancer
[21]
Anticancer
[23]
Anti-inflammatory Anti-inflammatory and inhibit the formation of urinary llithiasis Anti-inflammatory Anti-inflammatory
[8] [24,31]
Antioxidant
[9]
Antioxidant and hepatoprotective effect Antioxidant
[28,32]
Inhibitory effect on the secretion of HBsAg and HBeAg on cultured HepG 2.2.15 cell line
[33]
Pi-PCM1 Pi-PCM2
Pi-PCM3-I PCS3-II
Glc
wc-PCM0 wc-PCM1
Fuc:Ara:Xyl:Man:Gal:Glc in the ratio of 4.1:3.0:2.5:61.7:15.0:13.7 Fuc:Man:Gal:Glc in the ratio of 10.5:24.5:27.5:37.5
wc-PCM2
Fuc:Man:Gal:Glc in the ratio of 3.4:12.5:13.4:70.7
ac-PCM2
Fuc:Man:Gal:Glc in the ratio of 0.8:19.1:29.7:51.4
ab-PCM3-I-S1–S5 ac-PCM3-I-S1–S5 CS-PCS3-II
Pi-PCM
PCSC Pachyman
PCPS PC-II
Man:Gal:Ara in the ratio of 92:6.2:1.3 Glc
Myo-inositol:Sorbitol:Fuc:Galactosamine:Gal:Glc:Man in the ratio of 6.2:3.1:44.4:3.9:1.6:0.9:16.5
Oxidized P. cocos polysaccharides CMP
Carboxymethylated P. cocos polysaccharides Carboxymethylpachymaram
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anticancer, anti-inflammatory, antioxidant and other biological activities were summarized.
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2. Biological activities and potential health benefit effects
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2.1. Anticancer activity
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A polysaccharide mixture extracted from the mycelia of Poria cocos showed a strong antitumor effect against implanted sarcoma 180 (solid type) in mice [13]. PCP was evaluated for antitumor activity against several mouse tumors, PCP administered intraperitoneally increased somewhat the lifespan of mice inoculated intraperitoneally with IMC carcinoma and sarcoma 180, but were found to be inactive against intraperitoneally implanted L1210 leukemia, P388 leukemia and B16 melanoma [13–15].
Mannan
A heteropolysaccharide composed of -d-galactofuranan, (1 → 3)-␣-d-glucan and mannan. Linear (1 → 3)-␣-d-glucans Phosphorylated glucans with low degree of substitution ␣-(1 → 3)-d-Glucan bound with protein ␣-(1 → 3)-d-Glucan bound with protein ␣-(1 → 3)-d-Glucan bound with protein ␣-(1 → 3)-d-Glucan bound with protein Water-soluble ␣-d-glucan sulfated derivatives Water-soluble ␣-d-glucan sulfated derivatives Carboxymethylatedsulfated derivative -(1 → 3)-d-glucan Water-insoluble (1 → 3)-␣-d-glucan by phosphorylation Heteromannan [--d-Glc-(1 → 3)--d-Glc(1 → 3)]n (n = 180–200)
The repeating unit for the neutral 1,6-branched 1,3-␣-d-galactan Water-soluble (1 → 3)-d-polyglucuronic acid sodium salt Carboxymethylpachyman
Carboxymethylated -(1 → 3)-d-glucan
[17]
[25] [26]
[29]
Ke et al. investigated the effects of PCP on tumor cells growth in rats [16]. The results indicated that daily administrations of polysaccharides (100 and 200 mg/kg b.w.) for 7 weeks were effective in fully inhibiting tumor cells growth as detected in groups. Liver tumor weight was effectively reduced by the administration of polysaccharides in a dose dependent manner in rats of both the groups [16]. Huang et al. obtained three polysaccharides fractions from Poria cocos termed Pi-PCM0, Pi-PCM1 and Pi-PCM2, the water-soluble polysaccharides all exhibited strong antitumor activities against Sarcoma180 solid tumor implanted in BALB/c mice in vivo and against HL-60 tumor cell in vitro [17]. Chen et al. obtained polysaccharides mixture from Poria cocos termed PCS3-II, the original PCS3-II had no bioactivity, whereas the PCS3-II by phosphorylation exhibited anti-tumor activities in vitro and relatively strong inhibition ratios against S-180 in vivo [18]. It was revealed that the presence of phosphate group, relatively high molecular
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weight and relatively extended conformation could enhance the anti-tumor activities as a result of increasing the chance of binding with receptors on the immune cells [18]. 90 Yong et al. investigated the heteropolysaccharides from Poria 91 cocos mycelia cultured with wild strain in a medium contain92 ing corn steep liquor exhibited the highest antitumor activities 93 against Sarcoma 180 in vivo, and the heteropolysaccharides from 94 mycelium cultured in media with bran extract did not show sig95 nificant inhibition of tumor growth [19]. Wang et al. investigated 96 the water-insoluble native -glucan from Poria cocos showed no 97 antitumor activity either in vivo or in vitro, whereas its derivatives 98 exhibited good water solubility and manifest antitumor activities, 99 the sulfation and carboxymethylation significantly enhanced the 100 antitumor activities of the -glucan against Sarcoma 180 and gas101 tric carcinoma tumor cell in vivo and in vitro [20]. Considering 102 the molecular parameters and bioactivities, good water solubil103 ity, relatively high chain stiffness, and moderate molecular mass 104 of the derivatives in aqueous solution are shown to be beneficial 105 to enhancement of antitumor activity [20]. Huang et al. obtained 106 (1 → 3)-␣-d-glucan from Poria cocos mycelia which has good water 107 solubility, from immunohistochemical assays, it was concluded 108 that the sulfated derivative facilitated apoptosis in S-180 tumor cell 109 by up-regulation of Bax expression [6]. The sulfated derivative had 110 good therapeutic effect on tumor cell and the potential of clinical 111 application as a chemotherapeutic agent [6]. 112 Chen et al. obtained the water-soluble carboxymethylatedQ2 113 sulfated derivative which was synthesized successfully from 114 water-insoluble -glucan of Poria cocos termed CS-PCS3-II, this 115 in 0.15 M NaCl solution existed as extended flexible chain and 116 exhibited high inhibition ratio to S-180 tumor cell in vivo [21]. 117 Microscopic examination of tumor cells indicated sign of necrosis 118 and apoptosis in tumor cells treated with CS-PCS3-II, and enhance119 ment of immune ability of spleen [21]. Lin et al. also obtained 120 ␣-d-glucan derivatives that were satisfactorily synthesized from 121 water-insoluble (1 → 3)-␣-d-glucan from Poria cocos mycelia, the 122 sulfated derivatives exhibited higher in vivo and in vitro anti123 tumor activities against Sarcoma 180 than the natives [22]. The 124 moderate range of molecular mass from 2.0 × 104 to 40.0 × 104 , 125 relatively higher chain stiffness and good water solubility of the sul126 fated derivatives from the (1 → 3)-␣-d-glucan are beneficial to the 127 enhancement of the antitumor activities [22]. Huang et al. inves128 tigated the phosphated derivatives exhibited significantly in vivo 129 and in vitro anti-tumor activities against Sarcoma 180 tumor cell 130 compared with the unphosphated one [23]. 131 88 89
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2.2. Anti-inflammatory activity Lee et al. demonstrated that treatment with PCP significantly induces NO production and iNOS transcription through the activation of NF-B/Rel in the mouse macrophage line RAW 264.7[8]. These experiments demonstrated that PCP stimulates macrophages to produce NO through the induction of iNOS gene expression [8]. Tomohisa Hattori et al. investigated PCP was given to original-type anti-GBM nephritic rats for 10 days from the day of anti-GBM serum injection, the results showed that PCP prevented urinary protein excretion and the elevation of serum cholesterol content, which also reduced the degree of histopathological changes such as hypercellularity and adhesion as compared to the control group [24]. These results suggest that PCP was effective against original-type anti-GBM nephritis in rats and that the antinephritic mechanisms of pachyman may be partly due to the inhibitory action of this agent on C3 deposition in the glomeruli [24]. Jang et al. investigated the significantly higher concentration of PCP to reach the plateau of growth inhibition of treated U937 cells, as well as lower cytokines secretion after stimulation, showing that the immune response in male collegiate wrestlers to the
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polysaccharide fraction from Poria cocos were lessen by dehydration [25]. Lu et al. obtained polysaccharide from Poria cocos termed PC-II, PC-II showed no toxicity to human vascular endothelial cells (ECs), indicating the safety of the use of this fungus [26]. Experimental results indicated that the effect of PC-II on IP-10 expression was regulated at the translational and was not at the transcriptional level and thus it may participate in regulating inflammatory-related diseases [26]. Park et al. investigated the effects of a Korean traditional prescription, Geiji-Bokryung-Hwan (GBH) mainly consisting of herb of Poria cocos (Bokryung) on carrageenan-induced edema inflammation using female mice [27]. The results appeared in the carrageenan-induced model of inflammation in mice, the extracts significantly reduced paw edema both in the acute phase and in the chronic phase, as inhibition of edema was calculated relative to the mean edema of the vehicle-treated control group [27]. 2.3. Antioxidant activity Wang et al. investigated oxidation and the physiological properties of PCP and the resulting derivative [9]. The results demonstrated that water solubility, in vitro antioxidant activity of oxidized polysaccharides was enhanced by introducing carboxylate groups into the PCP structure, the oxidized polysaccharides would be positively expected to have several improved health benefits including reduction of cholesterol and blood pressure [9]. Ke et al. investigated polysaccharides effects on enhancing serum antioxidant enzymes activities in rats [16]. There was significant difference in serum antioxidant enzymes (SOD, CAT, GPx) activities between groups after 7 weeks of polysaccharides supplementation, in both the groups III and IV rats, polysaccharides supplementation significantly (p < 0.01) enhanced serum anti-oxidant enzymes activities [16]. Wang et al. investigated the effects of carboxymethylation of PCP on the structural and biological properties of the polysaccharides as a function of the degree of carboxymethylation, the degree of substitution (DS) of five carboxymethylated PCP, coded as CMP1/CMP2/CMP3/CMP4/CMP5, was determined to be 0.44–0.88 [28]. Experimental results showed that derivatives were effective in antioxidation in a dose dependent way, and the results proved that the carboxymethylation of PCP effectively enhanced their potential biological properties [28]. Wang et al. extracted the -(1-3)-d-glucan from the sclerotium of P. cocos and synthesized a carboxymethylated derivative [29]. Results revealed carboxymethylated polysaccharides increased solubility in vitro, antioxidant activity of carboxymethylated polysaccharides compared to the native sample was increased. [29]. 2.4. Other biological activities Chen et al. obtained polysaccharides mixture termed AE, and AE produced an increase Na+ and K+ excretion [30]. Chen et al. investigated the inhibiting effect of PCP on lithiasis formation of kidney [31]. Areas of calcium oxalate crystal in the kidneys of PCP group were significantly smaller than those in control group, PCP does inhibit the formation of urinary lithiasis [31]. Chen et al. investigated hepatoprotective effect of carboxymethylpachymaram (CMP), two groups of Swiss mice were respectively injected intraperitoneally with 100 mg CMP/kg d and 200 mg CMP/kg d continuing 5d, glutamic–pyruvic transaminase in serum were decreased by 27.32% and 41.03%, compared with the control group, P < 0.05 and P < 0.01 [32]. Swiss mice were injected intraperitoneally with 100 mg CMP/kg d continuing 4d before liver resection surgery, then injected intraperitoneally with 100 mg CMP/kg d continuing 3d after surgery, the results showed the degree of rat liver regeneration and regeneration of liver weight/body weight were
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increased by 73.29% and 18.95%, compared with the control group, P < 0.01 and P < 0.001 [32]. Duan et al. investigated the anti-HBV activity of carboxymethylpachymaram (CMP) on the culturing of HepG 2.2.15 cell line [33]. Concentrations of 20.0, 12.0, 6.0, 3.0, and 1.5 g/L of CMP were used to evaluate its toxicity to the cell line and the inhibition rates of the secretion of HBsAg and HBeAg in the cultured HepG 2.2.15 cell line, experiments showed that the mean half toxicity concentration of CMP for HepG 2.2.15 cell line was13.6 g/L and concentration for 50% inhibition of the secretion of HBsAg and HBeAg were 4.45 g/L, 5.61 g/L and TI were 3.06 and 2.42, therefore, CMP has good inhibitory effect on the secretion of HBsAg and HBeAg on cultured HepG 2.2.15 cell line [33].
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Recent studies have provided evidence that PCP and their derivatives play a vital role in human health. Furthermore, the possibilities of designing new pharmaceuticals to treat or ameliorate diseases are promising. Therefore, it can be suggested that due to valuable biological functions with health beneficial effects, PCP and their derivatives have much potential as active ingredients for therapy or adjuvant therapy for cancer, immunomodulatory and antiviral drugs. But, until now, PCP and their derivatives on lymphocytes and macrophages functions of tumor immune response and molecular mechanisms of inhibition remains to be studied, if we can elucidate its mechanism of action, new research and development direction for cancer and immunological drugs was provided. Therefore, further researches need to be conducted in order to investigate their activity in human subjects. References [1] Y.Y. Zhao, J. Ethnopharmacol. 149 (2013) 35–48. [2] K.Y. Lee, H.J. You, H.G. Jeong, J.S. Kang, H.M. Kim, S.D. Rhee, Y.J. Jeon, Int. Immunopharmacol. 4 (2004) 1029–1038. [3] C.I. Esteban, Rev. Iberoam. Micol. 26 (2009) 103–107.
[4] X. Chen, Q. Tang, Y. Chen, W. Wang, S. Li, Carbohydr. Polym. 79 (2010) 409–413. [5] T. Akihisa, Y. Nakamura, H. Tokuda, E. Uchiyama, T. Suzuki, Y. Kimura, K. Q3 Uchikura, H. Nishino, J. Nat. Prod. 70 (2007) 948–953. [6] Q. Huang, L. Zhang, P.C.K. Cheung, X. Tan, Carbohydr. Polym. 64 (2006) 337–344. [7] J.H. Lee, Y.J. Lee, J.K. Shin, J.W. Nam, S.Y. Nah, S.H. Kim, J.H. Jeong, Y. Kim, M. Shin, M. Hong, E.K. Seo, H. Bae, Eur. J. Pharmacol. 615 (2009) 27–32. [8] K.Y. Lee, Y.J. Jeon, Int. Immunopharmacol. 3 (2003) 1353–1362. [9] Y. Wang, S. Liu, Z. Yang, Y. Zhu, Y. Wu, J. Huang, J. Mao, Carbohydr. Polym. 85 (2011) 798–802. [10] Y. Zheng, X.W. Yang, J. Asian Nat. Prod. Res. 10 (2008) 323–328. [11] M.M. Yuka Okui, A. Iizuka, Y. Komatsu, M. Okada, M. Maruno, A. Niijima, Jpn. J. Pharmacol. 72 (1996) 71–73. [12] J.L. Rios, Planta Med. 77 (2011) 681–691. [13] H. Kanayama, N. Adachi, Y. Fukai, I. Takeuchi, M. Togami, Yakugaku Zasshi 106 (1986) 199–205. [14] H. Kanayama, N. Adachi, M. Togami, Chem. Pharm. Bull. (Tokyo) 31 (1983) 1115–1118. [15] H. Kanayama, M. Togami, N. Adachi, Y. Fukai, T. Okumoto, Yakugaku Zasshi 106 (1986) 307–312. [16] K. RuiDian, L. ShunFa, C. Yi, J. ChuRong, S. QiaGuang, Carbohydr. Polym. 80 (2010) 31–34. [17] Q. Huang, Y. Jin, L. Zhang, P.C.K. Cheung, J.F. Kennedy, Carbohydr. Polym. 70 (2007) 324–333. [18] X. Chen, X. Xu, L. Zhang, F. Zeng, Carbohydr. Polym. 78 (2009) 581–587. [19] Y. Jin, L. Zhang, M. Zhang, L. Chen, P.C. Keung Cheung, V.E.C. Oi, Y. Lin, Carbohydr. Res. 338 (2003) 1517–1521. [20] Y. Wang, L. Zhang, Y. Li, X. Hou, F. Zeng, Carbohydr. Res. 339 (2004) 2567–2574. [21] X. Chen, L. Zhang, P.C. Cheung, Int. Immunopharmacol. 10 (2010) 398–405. [22] Y. Lin, L. Zhang, L. Chen, Y. Jin, F. Zeng, J. Jin, B. Wan, P.C. Cheung, Int. J. Biol. Macromol. 34 (2004) 289–294. [23] Q. Huang, L. Zhang, Carbohydr. Polym. 83 (2011) 1363–1369. [24] K.H. Tomohisa Hattori, T. Nagao, K. Furuta, M. Ito, Y. Suzuki, Jpn. J. Pharmacol. 59 (1992) 89–96. [25] K.M.-F. Jang Tsong-rong, C.-H. Chen, K.-C. Hsieh, W.-Y. Lai, Y.-Y. Chen, Chin. Med. J. (Engl.) 124 (2011) 530–536. [26] M.-K. Lu, J.-J. Cheng, C.-Y. Lin, C.-C. Chang, Food Chem. 118 (2010) 349–356. [27] W.H. Park, S.T. Joo, K.K. Park, Y.C. Chang, C.H. Kim, Immunopharmacol. Immunotoxicol. 26 (2004) 103–112. [28] Y. Wang, Q. Mo, Z. Li, H. Lai, J. Lou, S. Liu, J. Mao, Int. J. Biol. Macromol. 51 (2012) 1052–1056. [29] Y. Wang, Y. Yu, J. Mao, J. Agric. Food Chem. 57 (2009) 10913–10915. [30] Y.Y. Zhao, Y.L. Feng, X. Du, Z.H. Xi, X.L. Cheng, F. Wei, J. Ethnopharmacol. 144 (2012) 775–778. [31] L.C. Chen Yan, J. Zhang, Chin. J. Urol. 20 (1999) 114–115. [32] C. Chen, Edible Fungi (Suppl.) (2003) 46–47. [33] H.P. Duan, A.J. Hou, F.E. Lu, J.L. Huang, Chin. J. Exp. Clin. Virol. 19 (2005) 290–292.
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Contents lists available at ScienceDirect
International Journal of Biological Macromolecules journal homepage: www.elsevier.com/locate/ijbiomac
Review
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Biological activities and potential health benefits of polysaccharides from Poria cocos and their derivatives
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Yichun Sun ∗ Pharmaceutical College, Heilongjiang University of Chinese Medicine, Harbin 150040, PR China
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Article history: Received 12 November 2013 Received in revised form 18 March 2014 Accepted 7 April 2014 Available online xxx
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Keywords: Poria cocos Polysaccharides Biological activities
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3.
Poria cocos has a long history of medicinal use in Asian countries such as China, Japan, Korea and Thailand. It is a kind of edible and pharmaceutical mushroom. The chemical compositions of Poria cocos mainly include triterpenes, polysaccharides, steroids, amino acids, choline, histidine, etc. Great advances have been made in chemical and bioactive studies on Poria cocos polysaccharides (PCP) and their derivatives in recent decades. These PCP and their derivatives exhibit many beneficial biological activities including anticancer, anti-inflammatory, antioxidant and antiviral activities. Therefore, PCP and their derivatives have great potential for further development as therapy or adjuvant therapy for cancer, immune-modulatory and antiviral drugs. This paper presents an overview of biological activities and potential health benefits of PCP and their derivatives. © 2014 Published by Elsevier B.V.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Biological activities and potential health benefit effects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.1. Anticancer activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.2. Anti-inflammatory activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.3. Antioxidant activity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2.4. Other biological activities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Edible and medicinal mushrooms are integral parts of natural medicines, and have been used for millennia to prevent or treat various diseases [1]. Poria cocos is a kind of edible and pharmaceutical mushroom. It is known for its name as Fu-ling in Chinese and grows under ground on the roots of pine trees [2]. In the wild, it grows much like the European truffle, but other genera, such as Citrus, Eucalyptus, or Quercus, and it can be parasited [3]. Poria cocos is commercially available and is popularly used in the formulation of nutraceuticals, tea supplements, cosmetics, and functional foods in Asia [4]. As reported previously, the chemical constituents of Poria cocos mainly include three principal groups of chemicals, the triterpenes, polysaccharides and steroids. Other minor compounds like
∗ Tel.: +86 13984196797. E-mail address: [email protected]
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amino acids, choline, histidine, and potassium salt, etc. have also been described [5–10]. Poria cocos is often present in Chinese herbal compound preparations and Kampo medicines such as Gui-Zhi-Fu-Ling tablet, Shan-Zha-Fu-Ling granules, Rikkunshi-to and Shikunshi-to, etc. It is used to treat chronic gastritis, edema, nephrosis, gastricatony, acute gastroenteric catarrh, dizziness, nausea, and emesis [11]. Since Poria cocos is commercially available and is popularly used in Asia, it is worthwhile to fully characterize its activities. Poria cocos polysaccharides (PCP) and their derivatives have been used in the adjuvant treatment for cancer and a number of medicinal and clinical researches in vivo and in vitro suggested that PCP and their derivatives showed an important role for human health [12]. Many different polysaccharides have been isolated from Poria cocos, the bioactive polysaccharides are shown in Table 1. This review focuses on polysaccharides derived from Poria cocos and presents an overview of their biological activities with potential health benefits. The bioactivities of PCP and their derivatives including
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2 Table 1 The bioactive polysaccharides from Poria cocos. Compound name
Monosaccharide composition
Structural features
Biological activities
References
The polysaccharide from Poria cocos Pi-PCM0
Rib:Ara:Xyl:Man:Glc:Gal in the ratio of 1.6:10.9:5.4:113:859:10.1 Ara:Xyl:Man:Gal:Glc in the ratio of 2.5:1.5:70.6:18.5:7.0 Fuc:Ara:Xyl:Man:Gal:Glc in the ratio of 10.9:1.0:2.8:23.6:36.5:25.2 Fuc:Man:Gal:Glc in the ratio of 1.9:29.6:38.9:29.7
-Glycosidic linkage
Anticancer and antioxidant Anticancer
[16]
Anticancer
[17]
Anticancer
[17]
Anticancer Anticancer
[6,17] [18,20]
Anticancer
[19]
Anticancer
[19]
Anticancer
[19]
Anticancer
[19]
Anticancer
[19,22]
Anticancer
[19,22]
Anticancer
[21]
Anticancer
[23]
Anti-inflammatory Anti-inflammatory and inhibit the formation of urinary llithiasis Anti-inflammatory Anti-inflammatory
[8] [24,31]
Antioxidant
[9]
Antioxidant and hepatoprotective effect Antioxidant
[28,32]
Inhibitory effect on the secretion of HBsAg and HBeAg on cultured HepG 2.2.15 cell line
[33]
Pi-PCM1 Pi-PCM2
Pi-PCM3-I PCS3-II
Glc
wc-PCM0 wc-PCM1
Fuc:Ara:Xyl:Man:Gal:Glc in the ratio of 4.1:3.0:2.5:61.7:15.0:13.7 Fuc:Man:Gal:Glc in the ratio of 10.5:24.5:27.5:37.5
wc-PCM2
Fuc:Man:Gal:Glc in the ratio of 3.4:12.5:13.4:70.7
ac-PCM2
Fuc:Man:Gal:Glc in the ratio of 0.8:19.1:29.7:51.4
ab-PCM3-I-S1–S5 ac-PCM3-I-S1–S5 CS-PCS3-II
Pi-PCM
PCSC Pachyman
PCPS PC-II
Man:Gal:Ara in the ratio of 92:6.2:1.3 Glc
Myo-inositol:Sorbitol:Fuc:Galactosamine:Gal:Glc:Man in the ratio of 6.2:3.1:44.4:3.9:1.6:0.9:16.5
Oxidized P. cocos polysaccharides CMP
Carboxymethylated P. cocos polysaccharides Carboxymethylpachymaram
60 61
anticancer, anti-inflammatory, antioxidant and other biological activities were summarized.
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2. Biological activities and potential health benefit effects
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2.1. Anticancer activity
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A polysaccharide mixture extracted from the mycelia of Poria cocos showed a strong antitumor effect against implanted sarcoma 180 (solid type) in mice [13]. PCP was evaluated for antitumor activity against several mouse tumors, PCP administered intraperitoneally increased somewhat the lifespan of mice inoculated intraperitoneally with IMC carcinoma and sarcoma 180, but were found to be inactive against intraperitoneally implanted L1210 leukemia, P388 leukemia and B16 melanoma [13–15].
Mannan
A heteropolysaccharide composed of -d-galactofuranan, (1 → 3)-␣-d-glucan and mannan. Linear (1 → 3)-␣-d-glucans Phosphorylated glucans with low degree of substitution ␣-(1 → 3)-d-Glucan bound with protein ␣-(1 → 3)-d-Glucan bound with protein ␣-(1 → 3)-d-Glucan bound with protein ␣-(1 → 3)-d-Glucan bound with protein Water-soluble ␣-d-glucan sulfated derivatives Water-soluble ␣-d-glucan sulfated derivatives Carboxymethylatedsulfated derivative -(1 → 3)-d-glucan Water-insoluble (1 → 3)-␣-d-glucan by phosphorylation Heteromannan [--d-Glc-(1 → 3)--d-Glc(1 → 3)]n (n = 180–200)
The repeating unit for the neutral 1,6-branched 1,3-␣-d-galactan Water-soluble (1 → 3)-d-polyglucuronic acid sodium salt Carboxymethylpachyman
Carboxymethylated -(1 → 3)-d-glucan
[17]
[25] [26]
[29]
Ke et al. investigated the effects of PCP on tumor cells growth in rats [16]. The results indicated that daily administrations of polysaccharides (100 and 200 mg/kg b.w.) for 7 weeks were effective in fully inhibiting tumor cells growth as detected in groups. Liver tumor weight was effectively reduced by the administration of polysaccharides in a dose dependent manner in rats of both the groups [16]. Huang et al. obtained three polysaccharides fractions from Poria cocos termed Pi-PCM0, Pi-PCM1 and Pi-PCM2, the water-soluble polysaccharides all exhibited strong antitumor activities against Sarcoma180 solid tumor implanted in BALB/c mice in vivo and against HL-60 tumor cell in vitro [17]. Chen et al. obtained polysaccharides mixture from Poria cocos termed PCS3-II, the original PCS3-II had no bioactivity, whereas the PCS3-II by phosphorylation exhibited anti-tumor activities in vitro and relatively strong inhibition ratios against S-180 in vivo [18]. It was revealed that the presence of phosphate group, relatively high molecular
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weight and relatively extended conformation could enhance the anti-tumor activities as a result of increasing the chance of binding with receptors on the immune cells [18]. 90 Yong et al. investigated the heteropolysaccharides from Poria 91 cocos mycelia cultured with wild strain in a medium contain92 ing corn steep liquor exhibited the highest antitumor activities 93 against Sarcoma 180 in vivo, and the heteropolysaccharides from 94 mycelium cultured in media with bran extract did not show sig95 nificant inhibition of tumor growth [19]. Wang et al. investigated 96 the water-insoluble native -glucan from Poria cocos showed no 97 antitumor activity either in vivo or in vitro, whereas its derivatives 98 exhibited good water solubility and manifest antitumor activities, 99 the sulfation and carboxymethylation significantly enhanced the 100 antitumor activities of the -glucan against Sarcoma 180 and gas101 tric carcinoma tumor cell in vivo and in vitro [20]. Considering 102 the molecular parameters and bioactivities, good water solubil103 ity, relatively high chain stiffness, and moderate molecular mass 104 of the derivatives in aqueous solution are shown to be beneficial 105 to enhancement of antitumor activity [20]. Huang et al. obtained 106 (1 → 3)-␣-d-glucan from Poria cocos mycelia which has good water 107 solubility, from immunohistochemical assays, it was concluded 108 that the sulfated derivative facilitated apoptosis in S-180 tumor cell 109 by up-regulation of Bax expression [6]. The sulfated derivative had 110 good therapeutic effect on tumor cell and the potential of clinical 111 application as a chemotherapeutic agent [6]. 112 Chen et al. obtained the water-soluble carboxymethylatedQ2 113 sulfated derivative which was synthesized successfully from 114 water-insoluble -glucan of Poria cocos termed CS-PCS3-II, this 115 in 0.15 M NaCl solution existed as extended flexible chain and 116 exhibited high inhibition ratio to S-180 tumor cell in vivo [21]. 117 Microscopic examination of tumor cells indicated sign of necrosis 118 and apoptosis in tumor cells treated with CS-PCS3-II, and enhance119 ment of immune ability of spleen [21]. Lin et al. also obtained 120 ␣-d-glucan derivatives that were satisfactorily synthesized from 121 water-insoluble (1 → 3)-␣-d-glucan from Poria cocos mycelia, the 122 sulfated derivatives exhibited higher in vivo and in vitro anti123 tumor activities against Sarcoma 180 than the natives [22]. The 124 moderate range of molecular mass from 2.0 × 104 to 40.0 × 104 , 125 relatively higher chain stiffness and good water solubility of the sul126 fated derivatives from the (1 → 3)-␣-d-glucan are beneficial to the 127 enhancement of the antitumor activities [22]. Huang et al. inves128 tigated the phosphated derivatives exhibited significantly in vivo 129 and in vitro anti-tumor activities against Sarcoma 180 tumor cell 130 compared with the unphosphated one [23]. 131 88 89
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2.2. Anti-inflammatory activity Lee et al. demonstrated that treatment with PCP significantly induces NO production and iNOS transcription through the activation of NF-B/Rel in the mouse macrophage line RAW 264.7[8]. These experiments demonstrated that PCP stimulates macrophages to produce NO through the induction of iNOS gene expression [8]. Tomohisa Hattori et al. investigated PCP was given to original-type anti-GBM nephritic rats for 10 days from the day of anti-GBM serum injection, the results showed that PCP prevented urinary protein excretion and the elevation of serum cholesterol content, which also reduced the degree of histopathological changes such as hypercellularity and adhesion as compared to the control group [24]. These results suggest that PCP was effective against original-type anti-GBM nephritis in rats and that the antinephritic mechanisms of pachyman may be partly due to the inhibitory action of this agent on C3 deposition in the glomeruli [24]. Jang et al. investigated the significantly higher concentration of PCP to reach the plateau of growth inhibition of treated U937 cells, as well as lower cytokines secretion after stimulation, showing that the immune response in male collegiate wrestlers to the
3
polysaccharide fraction from Poria cocos were lessen by dehydration [25]. Lu et al. obtained polysaccharide from Poria cocos termed PC-II, PC-II showed no toxicity to human vascular endothelial cells (ECs), indicating the safety of the use of this fungus [26]. Experimental results indicated that the effect of PC-II on IP-10 expression was regulated at the translational and was not at the transcriptional level and thus it may participate in regulating inflammatory-related diseases [26]. Park et al. investigated the effects of a Korean traditional prescription, Geiji-Bokryung-Hwan (GBH) mainly consisting of herb of Poria cocos (Bokryung) on carrageenan-induced edema inflammation using female mice [27]. The results appeared in the carrageenan-induced model of inflammation in mice, the extracts significantly reduced paw edema both in the acute phase and in the chronic phase, as inhibition of edema was calculated relative to the mean edema of the vehicle-treated control group [27]. 2.3. Antioxidant activity Wang et al. investigated oxidation and the physiological properties of PCP and the resulting derivative [9]. The results demonstrated that water solubility, in vitro antioxidant activity of oxidized polysaccharides was enhanced by introducing carboxylate groups into the PCP structure, the oxidized polysaccharides would be positively expected to have several improved health benefits including reduction of cholesterol and blood pressure [9]. Ke et al. investigated polysaccharides effects on enhancing serum antioxidant enzymes activities in rats [16]. There was significant difference in serum antioxidant enzymes (SOD, CAT, GPx) activities between groups after 7 weeks of polysaccharides supplementation, in both the groups III and IV rats, polysaccharides supplementation significantly (p < 0.01) enhanced serum anti-oxidant enzymes activities [16]. Wang et al. investigated the effects of carboxymethylation of PCP on the structural and biological properties of the polysaccharides as a function of the degree of carboxymethylation, the degree of substitution (DS) of five carboxymethylated PCP, coded as CMP1/CMP2/CMP3/CMP4/CMP5, was determined to be 0.44–0.88 [28]. Experimental results showed that derivatives were effective in antioxidation in a dose dependent way, and the results proved that the carboxymethylation of PCP effectively enhanced their potential biological properties [28]. Wang et al. extracted the -(1-3)-d-glucan from the sclerotium of P. cocos and synthesized a carboxymethylated derivative [29]. Results revealed carboxymethylated polysaccharides increased solubility in vitro, antioxidant activity of carboxymethylated polysaccharides compared to the native sample was increased. [29]. 2.4. Other biological activities Chen et al. obtained polysaccharides mixture termed AE, and AE produced an increase Na+ and K+ excretion [30]. Chen et al. investigated the inhibiting effect of PCP on lithiasis formation of kidney [31]. Areas of calcium oxalate crystal in the kidneys of PCP group were significantly smaller than those in control group, PCP does inhibit the formation of urinary lithiasis [31]. Chen et al. investigated hepatoprotective effect of carboxymethylpachymaram (CMP), two groups of Swiss mice were respectively injected intraperitoneally with 100 mg CMP/kg d and 200 mg CMP/kg d continuing 5d, glutamic–pyruvic transaminase in serum were decreased by 27.32% and 41.03%, compared with the control group, P < 0.05 and P < 0.01 [32]. Swiss mice were injected intraperitoneally with 100 mg CMP/kg d continuing 4d before liver resection surgery, then injected intraperitoneally with 100 mg CMP/kg d continuing 3d after surgery, the results showed the degree of rat liver regeneration and regeneration of liver weight/body weight were
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increased by 73.29% and 18.95%, compared with the control group, P < 0.01 and P < 0.001 [32]. Duan et al. investigated the anti-HBV activity of carboxymethylpachymaram (CMP) on the culturing of HepG 2.2.15 cell line [33]. Concentrations of 20.0, 12.0, 6.0, 3.0, and 1.5 g/L of CMP were used to evaluate its toxicity to the cell line and the inhibition rates of the secretion of HBsAg and HBeAg in the cultured HepG 2.2.15 cell line, experiments showed that the mean half toxicity concentration of CMP for HepG 2.2.15 cell line was13.6 g/L and concentration for 50% inhibition of the secretion of HBsAg and HBeAg were 4.45 g/L, 5.61 g/L and TI were 3.06 and 2.42, therefore, CMP has good inhibitory effect on the secretion of HBsAg and HBeAg on cultured HepG 2.2.15 cell line [33].
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3. Concluding remarks
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Recent studies have provided evidence that PCP and their derivatives play a vital role in human health. Furthermore, the possibilities of designing new pharmaceuticals to treat or ameliorate diseases are promising. Therefore, it can be suggested that due to valuable biological functions with health beneficial effects, PCP and their derivatives have much potential as active ingredients for therapy or adjuvant therapy for cancer, immunomodulatory and antiviral drugs. But, until now, PCP and their derivatives on lymphocytes and macrophages functions of tumor immune response and molecular mechanisms of inhibition remains to be studied, if we can elucidate its mechanism of action, new research and development direction for cancer and immunological drugs was provided. Therefore, further researches need to be conducted in order to investigate their activity in human subjects. References [1] Y.Y. Zhao, J. Ethnopharmacol. 149 (2013) 35–48. [2] K.Y. Lee, H.J. You, H.G. Jeong, J.S. Kang, H.M. Kim, S.D. Rhee, Y.J. Jeon, Int. Immunopharmacol. 4 (2004) 1029–1038. [3] C.I. Esteban, Rev. Iberoam. Micol. 26 (2009) 103–107.
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