Protective effects of polysaccharides on hepatic injury: A review

International Journal of Biological Macromolecules 141 (2019) 822–830

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International Journal of Biological Macromolecules journal homepage: http://www.elsevier.com/locate/ijbiomac

Review

Protective effects of polysaccharides on hepatic injury: A review Ye Yuan b, Lihe Che c, Chong Qi a, Zhaoli Meng a,⁎ a b c

Department of Translational Medicine Research Institute, First Hospital, Jilin University, Changchun, Jilin 130021, China Department of Medicine Laboratory, First Hospital, Jilin University, Changchun 130021, China Department of Infectious Disease, First Hospital, Jilin University, Changchun 130021, China

a r t i c l e

i n f o

Article history: Received 29 June 2019 Received in revised form 26 August 2019 Accepted 1 September 2019 Available online 02 September 2019 Keywords: Polysaccharides Hepatic injury Hepatoprotective activity

a b s t r a c t Chronic hepatic injury caused by hepatitis B and C virus (HBV and HCV) infection, high fat diet and alcohol intake has increased to be the critical promoter of hepatocellular carcinoma (HCC). These high risk factors set into motion a vicious cycle of hepatocyte death, inflammation and fibrosis that finally results in cirrhosis and HCC after several decades. However, the treatment options for HCC are very limited. Therefore, early treatment of liver injury may reduce the incidence and probability of HCC or delay the progression of HCC. Substantial ongoing research has focused on nontoxic biological macromolecules, mainly polysaccharides, which possess prominent efficacies on hepatoprotective activity. Based on these encouraging observations, a great deal of effort has been devoted to discovering novel polysaccharides for the development of effective therapeutics for hepatic injury. This review focuses on the protective effects of polysaccharides on liver injury, including hepatitis virus infection, nonalcoholic steatohepatitis, alcoholic liver disease and other hepatic injuries, and describes the underlying mechanisms. © 2019 Published by Elsevier B.V.

Contents 1. 2. 3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . Polysaccharide extraction and purification . . . . . . . . . . Protective effects of polysaccharides on hepatic injury . . . . 3.1. Polysaccharides and anti-HCC activity . . . . . . . . 3.2. Polysaccharides and NASH. . . . . . . . . . . . . . 3.3. Polysaccharides and anti-alcoholic liver disease activity 3.4. Polysaccharides and anti-liver fibrosis . . . . . . . . 3.5. Anti-HBV activity . . . . . . . . . . . . . . . . . . 3.6. Other hepatoprotective activities of polysaccharides . . 4. Conclusions and perspectives. . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . References. . . . . . . . . . . . . . . . . . . . . . . . . . .

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1. Introduction The liver, as the largest organ, plays an important role in metabolism, excretion, immunity and detoxification in the body [1].Once the liver is attacked by exogenous substances or their metabolites, these toxic substances will accumulate and cause liver injury. To date, alcohol consumption [2,3], nonalcoholic steatohepatitis (NASH) [4], and HBV [5,6] ⁎ Corresponding author. E-mail address: [email protected] (Z. Meng).

https://doi.org/10.1016/j.ijbiomac.2019.09.002 0141-8130/© 2019 Published by Elsevier B.V.

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822 823 824 824 824 825 827 827 828 828 829 829

and HCV infection [7] are considered the three major causes of liver injury [8]. Then, the chronic liver injury sets in motion a vicious cycle of hepatocyte cell apoptosis and death, inflammation, oxidative stress damage, and fibrosis that finally results in cirrhosis or hepatocellular carcinoma(HCC). The pathogenic mechanism underlying the development of HCC is unclear. Based on the existing data, the current hypothesis concerning the pathophysiology of HCC has been summarized (Fig. 1) [9,10]. HCC is highly refractory to therapeutic interventions. Even after surgical resection or ablation, 70% of patients experience tumor recurrence within 5 years [11]. It seems sensible to consider

Y. Yuan et al. / International Journal of Biological Macromolecules 141 (2019) 822–830

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Fig. 1. Chronic liver injury promotes HCC development. Chronic liver injury stimulates immune cells to release cytokines, increases the generation of ROS and DNA damage, activates HSCs to promote liver fibrosis, and finally results in cirrhosis and HCC.

preventing the development of HCC progression in patients at risk rather than treating the advanced-stage disease with limited health benefits. Thus, more researchers are devoting themselves to developing drugs to improve the liver after injury. Polysaccharides are polymeric carbohydrate molecules composed of long chains of monosaccharide units bound together by glycosidic linkages that upon hydrolysis gives the constituent monosaccharide or oligosaccharide [12]. Polysaccharides are widely present in plants, microorganisms, algae and animals [13–15] and have a broad spectrum of biological effects, such as antitumorigenic [16,17], antidiabetic [18], antibiotic [19], antioxidant [20], anticoagulant [21], and immunestimulatory activities [22,23]. Excluding these pharmacological activities, their hepatoprotective activities have recently aroused people's interest. Some polysaccharides could directly suppress the viability of HCC cells, and some polysaccharides can alleviate the hepatic injury caused by alcohol consumption, nonalcoholic steatohepatitis and viral hepatitis. Polysaccharides such as aconitum coreanum polysaccharide have been shown to exhibit significant HCC cytotoxicity in vivo [24]. Several other polysaccharides are able to function as immunomodulators to enhance the body's defense against liver injuries [25]. The first

marketing polysaccharide pharmaceutical, Lentinan for intravenous injection, was approved in Japan in 1986. Lentinan extracted from shiitake mushrooms has an action to enhance immune function, which is used to treat hepatitis B virus. Compared to the conventional or synthetic drugs that are used to treat liver disease, natural polysaccharides have attracted more attention due to their low bioavailability, low solubility and few side effects. We summarize the source, molecular weight, monosaccharide composition and structural features of polysaccharides with hepatoprotective activity. This review will provide inspiration for our researchers to design, research and develop polysaccharides. 2. Polysaccharide extraction and purification Hot water is the classical polysaccharide extraction method [26,27]. The scheme of extraction and purification of polysaccharides is shown in Fig. 2. Briefly, the raw materials, mycelium or fermentation broths, were first dried to a constant weight and ground into a powder, and then the powder was immersed in water with a designed extraction time, temperature and solid-liquid ratio. After a few hours, the mixture was centrifuged to remove the insoluble materials, and the supernatant

Fig. 2. The scheme of polysaccharide extraction and purification.

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or the fermentation broth was concentrated by low-molecular weight ultrafiltration centrifugal tube, and precipitated with enough 95% ethanol and maintained at 4 °C overnight. The crude polysaccharides can be obtained after centrifugation. The polysaccharide contents are determined by the phenol-sulfuric acid method using glucose as the standard [28]. To fully destroy the cell wall, acid-base and enzyme hydrolysis methods are often used in polysaccharide extraction [29]. However, the concentration of the acid or base should be controlled because some polysaccharides are easily hydrolyzed in the acid-base solution. In addition, various technologies have been used to improve the efficiency of extraction, such as microwaves and high-powered ultrasonic processing [30]. To obtain purified polysaccharide fragments, several purifying procedures have been used for crude polysaccharides. First, protein removal by the savage reagent and decolorization by H2O2 or macroporous resins can be applied to the crude extract [31,32]. Then, various chromatographic columns are used to separate the purified fragments, such as ion-exchange chromatography and gel chromatography. The purified solution is collected, dialyzed, concentrated, lyophilized and resuspended. Finally, various analytical methods and techniques are applied to evaluate the structure of the purified polysaccharide fragments. After acid hydrolysis, polysaccharides are subjected to high performance liquid chromatography (HPLC), Mass spectrometry (MS) or HPLC-MS to determine the monosaccharide composition [33]. The molecular weight could be determined by gel chromatography, HPLC or HPLC-MS. Fourier transform infrared spectroscopy (FT-IR) is an effective method which often is used to investigate functional groups such as C\\H, C_O,\\COO, C\\O\\C, O\\H and\\OCH3 [34]. Additionally, x-ray-diffraction (XRD) could analyze the symmetry and distance of helix [35], and scanning electron microscope (SEM) and atomic force electron microscope (AFM) are used to characterize the surface microstructure and optical properties of polysaccharide [36,37]. Nuclear magnetic resonance (NMR) could be applied to analyze the complicated polysaccharide information combined with periodate oxidation, Smith degradation and methylation analysis [38]. 3. Protective effects of polysaccharides on hepatic injury 3.1. Polysaccharides and anti-HCC activity HCC is one of the most common and fatal cancers worldwide. Although mortality associated with most types of cancer has steadily declined over the past 40 years, both the incidence and deaths due to HCC have substantially increased [39]. Novel and effective drugs for HCC are urgently needed. The development of natural polysaccharide drugs has been recognized as a new strategy to for HCC treatment. Many polysaccharides have displayed anti-HCC activity involving various mechanisms in vivo or in vitro. The common mechanisms identified were cell cycle arrest, depolarization of the mitochondrial membrane, activation of the death receptor and immunomodulation. APS from Astragalus membranaceus induced apoptosis of the H22 HCC cell line by upregulating the expression of Bcl-2, Bax, caspase-3 and caspase-8 and suppressing the metastatic capacity by decreasing the expression of Notch 1 [40]. LSP from Lepista sordida exerted antitumor effects on the HepG2 HCC cell line by inhibiting indoleamine 2,3-dioxygenase via the JAK-PKC-δ-STAT1 pathway [41]. PPPF from pumpkin fruit directly induces the apoptotic cell death of HepG2 cells via downregulation of the JAK2/STAT3 pathways [42].GLP from Ganoderma lucidum enhanced the radiosensitivity of HCC cells via regulation of the Akt signaling pathways [43]. EPS-1a, EPS-2a, EPS-3a, isolated from Streptococcus thermophiles CH9, exhibited antitumor activity against HepG2 cells by arresting the cell cycle in the G0/G1 phase [44]. LEP-2a from Lachnum YM130 treatment combined with cyclophosphamide caused a significant synergistic antitumor effect on H22 tumor-bearing mice through a Fas/FasL-mediated caspasedependent death and mitochondria apoptosis pathways, and LEP-2a

played a crucial role in the enhancement of the immune response, inhibition of tumor angiogenesis and downregulation of survival-associated proteins [45]. The monosaccharide composition and molecular weight have been reported for most polysaccharides studied for their anti-HCC activity. CFv-PS is composed of fifteen monosaccharide units, and the simplest one, DOP, is composed of just two sugars. The molecular weights of these polysaccharides range from 10.7 to 1800 kDa. Among the polysaccharides we summarized, a number of polysaccharides displayed antiHCC activities against HepG2, H22 and Huh7 cells, and very few polysaccharides had anti-HCC tumor effects in tumor-bearing mice. Most of the published literature revolves around the screening of polysaccharides in HCC with minimal mechanistic insights. Additionally, there are very few reports showing the exact structure of the polysaccharides. There is an immense scope for further research on these anti-HCC polysaccharides directed towards the understanding of the oncogenic pathways that are modulated by them. Although these natural polysaccharides lack the potency that most conventional anti-HCC drugs possess, they still attract wide attention due to their few side effects. Table 1 summarizes the source, molecular weight, and monosaccharide composition of the various polysaccharides exhibiting anti-HCC activity. 3.2. Polysaccharides and NASH NASH is defined as diffuse fatty infiltration in the liver without alcoholic consumption, and it has been associated with obesity and hyperlipidemia [46,47]. Clinically, NASH is mainly characterized by increased levels of total cholesterol (TC), triglycerides (TG), and lowdensity lipoprotein cholesterol (LDL-C) along with a decrease in highdensity lipoprotein cholesterol (HDL-C) [48]. The imbalance of lipid metabolism caused by long-term high fat dietary intake results in NASH symptoms. In recent years, polysaccharides have gained much attention as sources of physiological functional food and drugs because of their anti-NASH activity. We summarized the polysaccharides with antiNASH activity in Table 2. Fungal polysaccharides from Morchella [49,50], Pleurotus eryngii [51–54], Lachnum [55–57], Termitomyces albuminosus [58], Ganoderma lucidum [59,60], Phellinus linteus [61] and Inonotus obliquus [62] displayed activity by lowering the injury caused by NASH. MPS, EnMPS (Morchella esculenta) [49] and CPMEP (Morchella angusticeps) [50] showed superior abilities to reduce hepatic lipid levels by monitoring the activities of the serum enzymes including alkaline phosphatase, (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase (AST); monitoring the serum lipid levels containing creatine kinase (CK), TC, HDL-C, LDL-C and lactate dehydrogenase (LDH); enhancing the hepatic antioxidant enzymes including free fatty acids, superoxide dismutase, SOD, catalase (CAT) and total antioxidant capacity (T-AOC); and decreasing lipid peroxidation including malondialdehyde (MDA) and myeloperoxidase (MPO). A series of polysaccharides, including En-MZPS [51], En-MSP, Ac-MSP, Al-MSP [52], PEPE [53] and Ac-MPS [54], isolated from Pleurotus eryngii showed potential effects on NASH. The carboxymethylated and sulfated polysaccharides CLEP and SLEP [55] and the extracellular polysaccharides LEP [56] and LEP-1b [57] extracted from Lachnum, significantly decreased the serum and liver lipid levels in a mouse model induced by a highfat diet. EIPS, AIPS and IPS [58] from Termitomyces albuminosus exhibited reduced hepatic lipid levels and prevented oxidative stress by improving serum enzymatic activities (ALT, AST and ALP), serum lipid levels (TC, TG, HDL-C, LDL-C and VLDL-C, VLDL-C), hepatic lipid levels (TC and TG), and antioxidant status (SOD, gammaglutamyltranspeptidase, GSH-Px, CAT, T-AOC, MDA and lipid peroxide, LPO). Liang and Wu found that GLP [59] extracted from Ganoderma lucidum significantly lowered liver tissue indexes, serum lipid accumulation and serum and small intestine oxidative stress in mice fed a highfat diet, and Zhong found that a Ganoderma lucidum polysaccharide

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Table 1 Polysaccharides that have exhibited anti-HCC activity. Name

Source

APS

Astragalus – membranaceus Lepista sordid – Pumpkin fruit – –

LSP PPPF GLP EPS-1a

EPS-2a EPS-3a LEP-2a APSs PAPS CFv-PS

PL GL AA GLPP

Ganoderm alucidum Streptococcus thermophilus\ CH9

Lachnum YM130 Astragalus membranaceus Periploca angustifolia Phormidim versicolor NCC466 P. linteus Ganoderma lucidum Auricularia auricula Ganoderma lucidum

DOP-40 Dendrobium DOP-50 officinale DOP-60 DOP-70 LJP Laminaria japonica W W1 W2 A A1 A2

MW Monosaccharide composition (kDa)

Effects

Ref.

–

Showed cytotoxicity to the H22 HCC cell line

[40]

– –

[41] [42]

–

Showed antitumor effects in HepG2 cells Inhibited the growth of HepG2 cells via the induction of apoptosis Enhanced the radiosensitivity of HCC cells

1800

Sor:Man = 30.18:69.82

Showed anti-HepG2 activity

[44]

1060 1050 1310

Ara:Xyl:Sor:Man:Glc = 1.11:0.55:15.05:57.09:23.39 Fuc:Rib:Rha:Ara:Xyl:Sor:Glc:Gal = 1.07:0.63:0.59:0.35:0.41:2.03:63.93:36.07 –

Showed antitumor effects in H22 tumor-bearing mice Showed cytotoxicity of H22 cells

[45]

–

– –

Ara:Pyr:Man:Fru:Gal:Dul:L-Ini:L-Glc:M-Ino:Nos:Tre:Sac:Mal:Sor:Raf = Induced a cytotoxic effect on HepG2 cells 0.06:0.12:8.65:2.32:6.42:3.12:10.32:8.76:9.08:0.13:21.05:23.65:0.84:0.63:0.04% Ara:Xyl:Rib:Rha:Gcl:NAc:Gal:Glc:Man:GlcA:Sac = Showed cytotoxic effects on HepG2 cells, exhibited 2.41:1.58:2.18:6.23:7.04:28.21:26.04:3.02:5.07:0.86 hepatoprotective properties against Cd-induced hepatotoxicity – Suppressed the proliferation of HepG2 cells –

–

–

–

–

999 657 243 50.3 –

D-Man/D-Glc = 6.32 ± 0.15:1 D-Man/D-Glc = 8.67 ± 0.16:1 D-Man/D-Glc = 8.34 ± 0.13:1 D-Man/D-Glc = 8.82 ± 0.05 –

10.7 18.2 60.6 16.9 41.9 67.5

L-Ara:LRha:Dxyl:DGal:DGlc = 5.1:19.5:3.6:7.5:64.3% L-Ara:LRha:Dxyl:DGal:DGlc = 20.4:14.2:3.5:9.1:52.8% L-Ara:LRha:Dxyl:DGal:DGlc = 0.6:20.2:75.7:0.7:2.8 L-Ara:LRha:Dxyl:DGal:DGlc = 11.8:37.3:3.8:11.6:35.4 L-Ara:LRha:Dxyl:DGal:DGlc = 7.7:45.0:3.3:10.5:33.5 L-Ara:LRha:Dxyl:DGal:DGlc = 15.8:26.7:2.2:5.9:49.5

63.79

peptide (GLPP) [60] had a therapeutic effect on NASH. PLP [61] from Phellinus linteus ameliorated high-fat high-fructose diet-induced insulin resistance in mice. UIOPS (Inonotus obliquus) polysaccharides have protective effects against H2O2-induced oxidative damage in hepatic L02 cells, suggesting the potential for anti-NAFLD [63]. Furthermore, plant polysaccharides such as CPP-2 from Cyclocarya paliurus [64] leaves and CP-1 from Cichorium intybus [65] showed significant anti-NASH activity. CPP-2 [64] treatment could improve blood lipid levels (TG, TC, HDL-C and LDL-C), liver lipid levels (TC and TG) and antioxidant status (SOD, T-AOC, GSH-PX, MDA and LPO). CP-1 [65] significantly increased the serum levels of SOD and HDL-C and decreased the levels of ALT, AST, TG, TC, LDL-C, ALP, LDH and MDA in NAFLD rats via AMPK activation. Chinese medicine polysaccharides, such as APS [66] from Astragalus membranaceus and LBP [67] from Lycium barbarum, both showed beneficial effects on NASH. APS [66] significantly reduced hepatic triglyceride levels in metabolically stressed APPswe/PS1De9 mice. LBP [67] significantly ameliorated NASHinduced injuries, including increased serum ALT and AST levels, hepatic oxidative stress, fibrosis, inflammation, and apoptosis, by suppressing the NLRP3/6 inflammatory pathway and NF-κB activation. Based on these data, we can conclude that the hepatoprotective activity of polysaccharides against NASH was mainly attributed to their antioxidant activity. Polysaccharides decrease serum and liver lipid levels, improve the activities of antioxidant enzymes and ameliorate the histopathological status of hepatic tissues. The molecular weight of these polysaccharides range from only 1.35 kDa to 2676 kDa, and they

[43]

[93] [94] [95]

[96]

Reduced the accumulation of lipid droplets and the content of TG in HepG2 cells and primary hepatocytes induced by oleic acid and palmitic acid Showed anti-HepG2 cell activity

[60]

Showed anti-H22 cell activity.

[98]

Showed inhibitory effects on Huh7 cells

[99]

[97]

are composed of 4–6 sugars. Among these polysaccharides, the structures of CPMEP and LEP-1b are clear. The main chain of CPMEP is composed of (1 → 4)-α-D-glucose, (1 → 6)-α-D-galactose, (1 → 2)-α-Dmannose and (1 → 5)-α-D-arabinose, and its branched chain is composed of (1 → 2 → 6)-β-D-galactose. LEP-1b consists of β-1, 3-D-pyran glucose residues, every five glucose residues constitutes a repeat unit, and each repeat unit contains a branched chain (two D-pyran glucose residues linked by a β-1, 3-linkage), which is linked at C6 of the backbone chain by a β-1, 6-linkage. 3.3. Polysaccharides and anti-alcoholic liver disease activity Excessive alcoholic consumption leads to a series of clinical symptoms and morphological characteristics of apoptosis, such as steatohepatitis, hepatic fibrosis, cirrhosis and hepatocellular carcinoma [68]. Hence, the development of novel agents for the treatment of liver injury induced by alcohol has drawn increasing attention. In the development of alcoholic liver disease (ALD), many types of innate cells, such as natural killer cells, natural killer T cells, Kupffer cells, macrophages and adaptive cells, including T cells and B cells, are enriched in the liver and function in the physiology and pathology of the liver. These cells play important roles in the pathogenesis of alcoholic liver disease in humans and mice [69]. Interestingly, polysaccharides are considered natural biological macromolecules with immunoregulatory activity that may improve ALD. Furthermore, the oxidative metabolites of ethanol, such as acetaldehyde and reactive

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Table 2 Polysaccharides that have exhibited anti-nonalcoholic steatohepatitis activity. Name

Source

MW (kDa)

Monosaccharide composition

Effects

Ref.

MPS

Morchella esculenta

24.1

Rha:Xyl:Man:Glc:Gal = 4.90:16.82:16.40:54.42:74.5% Rha:Xyl:Man:Gal = 2.19:33.89:17.37:46.55% D-Ara:D-Man:D-Glc:D-Gla = 1:2.37:4.79:3.09 Ara:Man:Gal:Glc = 15.62:13.20:14.11:57.07%

Hepatic lipid levels ↓, serum lipid levels ↓, hepatic antioxidant enzymes ↑, lipid peroxidation ↓

[49]

Cholesterol-lowering ability in rats↑

[50]

ALT, AST and ALP ↓, serum lipid levels (TC, TG, HDL-C, LDL-C and VLDL-C) ↓, antioxidant enzymatic (SOD, GSH-Px, CAT, T-AOC) activity ↑ in hyperlipidemic mice

[51]

1.35 2.11 2.26 –

Gal: Glc = 3.51:2.04 Ara: Xyl:Glc = 1.50:3.40:1.54 Rib:Ara:Xyl = 1.50:3.53:1.63 –

Organ enzymatic activities ↑, lipid peroxide contents in the liver ↓

[52]

Prevented excessive lipid formation in the liver tissue in a high-fat-load mouse model

[53]

271.2

Ara:Man:Gal:Glc = 10.7:23.2:13.4:52.7%

Oxidative stress (TG, TC, TCLDL-C) ↓, SOD, GSH-Px, CAT and T-AOC activity ↑, MDA and LPO contents in high-fat diet-induced hypertriglyceridemic mice ↓

[54]

1.68 – –

Man: Gal = 16.3:1.0 – –

Decreased the TG and TC concentrations in high-fat diet and low-dose streptozotocin mouse model by activation of AMPK Attenuated liver injury induced by Pb

[55]

40.2

Glc

[57]

–

Showed strong lipid lowering and liver protecting effects on mice with hyperlipidemic fatty livers Prevented oxidative stress by improving serum enzyme activities(ALT, AST and ALP), serum lipid levels (TC, TG, HDL-C, LDL-C and VLDL-C), hepatic lipid levels (TC and TG) and antioxidant status (SOD, GSH-Px, CAT, T-AOC, MDA and LPO)

[58]

13.7

Rha:Ara:Man:Gal:Glc = 4.54:6.93:13.78:19.46:55.219% Xly:Man:Gal:Glc = 1.81:13.71:3751:46.96% Rha:Ara:Xyl:Man:Gal:Glc = 2.36:5.93:1.74:15.56:25.99:45.42% Glc:Gal = 3.72:1 Reduced the levels of TG, TC, and low-density lipoprotein cholesterol and liver weight

–

–

Attenuated the oxidative damage induced by H2O2 in hepatic L02 cells

[63]

Protected against high-fat diet-induced hyperlipidemia and non-alcoholic fatty liver disease CP-1 significantly attenuated the high-fat diet induced alcoholic fatty liver disease via AMPK activity Reduced hepatic triglycerides induced by metabolic stress

[64]

Ameliorated NASH-induced injuries, including ALT, AST, hepatic oxidative stress, fibrosis, inflammation, and apoptosis

[67]

EnMPS

23.4

CPMEP

43.6

Morchella angusticeps En-MZPS Pleurotus eryngii var. tuoliensis En-MSP Pleurotus Ac-MSP eryngii Al-MSP PEPE Pleurotus eryngii Ac-MPS Pleurotus eryngii var. tuoliensis LEP Lachnum SLEP YM240 LEP Lachnum YM281 LEP-1b Lachnum YM281 EIPS Termitomyces albuminosus AIPS

UIOPS CPP-2 CP-1 APS LBP

– –

IPS GLP

–

Ganoderma lucidum Inonotus obliquus Cyclocarya paliurus Cichorium intybus L. Astragalus membranaceus Lycium barbarum

307, 3.7

Rha:Man:Glc:Gal = 1.00:0.78:3.22:0.45 8.5 Sor:Glc:Fru:Glucitol = 1.00:5.58:13.97:10.32 0.86–2676.00 Fuc:Myo-inositol:Fru:Sor:Glc = 1:1.4:2.1:13.7:91.5 – –

oxygen species (ROS), play a predominant role in the clinical and pathological spectrum of ALD [70]. The antioxidant activity of polysaccharides may account for the amelioration of ALD. Many polysaccharides have displayed anti-ALD activity. ALPS [71] showed a strong antioxidant and anti-inflammatory ability and markedly low serum enzymatic activities, hepatic and serum lipid levels, and low hepatic lipid peroxidation levels. Moreover, ALPS improved the alcohol metabolism system. IMPP [72], AcMPS and EnMPS [73] from Pleurotus geesteranus could improve the hepatic parameters of MPO, TC, ALT, AST and ALP, HDL-C, LDL-C and VLDL-C, decrease inflammatory cytokines including TNF-α, IL-1β and IL-6, inhibit the activities

[56]

[59]

[65] [66]

of hepatic adenosine dehydrogenase and aldehyde dehydrogenase, enhance the activities of the antioxidant enzymes SOD, GSH-Px, CAT and T-AOC, and reduce MDA and LPO contents in acute alcoholic liver disease. Both AcMPS and EnMPS are β-pyranoside polysaccharides with (1 → 3) and (1 → 6) linkages. H-SMPS and E-SMPS [74], isolated from Laetiporus sulphureus, exhibited hepatoprotective effects against ALD by improving liver function, increasing antioxidant status and reducing lipid peroxidation. SCAP [75], from the well-known traditional Chinese medicine Schisandra chinensis, significantly reduced serial AST and ALT in livers and HepG2 cells injured by ethanol, decreased TG levels in liver tissue, improved hepatopathological changes, decreased MDA

Table 3 Polysaccharides that have exhibited antialcoholic liver disease activity. Name

Source

MW Monosaccharide composition (kDa)

Effects

GP

Allium sativum L. Pleurotus geesteranus

10

Fru:Gal:Gal-A = 307:25:32

–

Fuc:Ara:Xyl:Man:Gal:Glc = 9.07:3.09:1.49:2.05:2.04:3.00 L-Rha:D-Rib:L-Ara:D-Glc:D-Man:D-Gal = 47.31:12.93:11.07:12.81:8.77:7.11% Rha:Xyl:Man:Gal = 43.34:8.98:9.78:37.9 – – GlaA:Glc:Gal:Ara:Rha:Man = 53.6:30.19:7.25:4.3:3.68:1.36%

Hepatoprotective effects against ALF in mice through modulation of lipid peroxidation and [62] oxidative stress, regulation of TGF-β1, TNF-α and decorin signaling pathways Showed anti-inflammatory effects against alcoholic liver disease by improving the [72] antioxidant status and anti-inflammatory activities Lipid accumulation ↓, oxidative stress ↓, inflammatory symptoms ↑ in alcoholic liver disease [73] (ALD) mice

IMPP AcMPS

34.9

EnMPS H-SMPS Laetiporus E-SMPS sulphureus SCAP

36.7 – – –

Ref.

Hepatoprotective effects against alcohol-induced alcoholic liver disease

[74]

Showed protective effects on ethanol-induced liver injury in mice and cells

[75]

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Table 4 Polysaccharides that have exhibited anti-liver fibrosis activity. Name

Source

MW Monosaccharide composition (kDa)

Effects

Ref.

Phellinus linteus LBPs Lycium barbarum MZPS-1 Pleurotus MZPS-2 djamor MZPS-3

–

–

[61]

–

–

Protected against TAA-induced liver fibrosis via regulation of the oxidative stress pathway, heat shock pathways and metabolic pathways from amino acids and nucleic acids Alleviated effects of LBPs on CCl4-induced liver fibrosis in Wistar rats

4.6 13.3 13.9

MZPS FPS

18.7 –

Man:Glc:Gal = 62.18:38.90:18.93% Man:Glc:Gal:=46.44:22.22:31.34% Rha:Xyl:Glc:Gal = 62.16:15.6:9.84:12.4% Rha:Man:Glc = 45.09:43.88:11.03% Glc:Man:Gal:Fuc:Ara:Glc A = 70.30:8.70:12,88:0.79:5.04:1.57% Man:Rib:Glc:Gal:Xyl = 4.07:4.54:3.07:1:2.21

PLP

FVP

Agaricus bisporus Flammulina velutipes

–

[79]

AST, ALT, MDA and LPO ↓, remarkably increased the levels of TC, TG and ALB ↑, the activities of SOD, [80] GSH-Px, CAT and T-AOC ↑ inCCl4-induced liver injury mice

Hepatoprotective effects against CCl4-induced liver damage partially through the downregulation [81] of the TGF-β1/Smad signaling pathway Showed the hepatoprotective effects of FVP on CCl4-induced acute liver injury in rats by decreasing [82] AST and ALT

levels, and decreased the SOD activity in serum, liver tissue and HepG2 cells by inhibiting the upregulation of the protein cytochrome P4502E1. Garlic polysaccharide, GP [62], isolated from Allium sativum L., significantly decreased serum ALT, AST, MDA, TC, TG and LDL-C levels, increased SOD, GSH-Px and GSH levels, and decreased the levels of TGFβ1 and TNF-α. MPCC [76] (Coprinus comatus) significantly attenuated hepatic and serum lipid levels, obviously enhanced antioxidant enzyme activities, markedly improved the alcohol metabolism system and inflammatory response, and mitigated alcohol-induced liver injury histopathologically. Table 3 summarizes the source, molecular weight, and monosaccharide composition of the various polysaccharides exhibiting anti- ALD activity.

(Table 4). LBPs from Lycium barbarum alleviated the CCl4-induced oxidative injury and inflammatory response [79]. Phellinus linteus polysaccharide (PLP) extracts showed remarkable hepatoprotective activity against thioacetamide (TAA)-induced liver fibrosis via regulation of the oxidative stress pathway, heat shock pathway and metabolic pathways [61]. MZPS-3 isolated from Pleurotus djamor significantly decreased the levels of AST, ALT, MDA and LPO and prominently restored the activities of SOD, GSH-Px, CAT and T-AOC in serum/liver homogenate against CCl4-induced injuries [80]. FPS from Agaricus bisporus significantly alleviated CCl4-induced liver injury partly through the downregulation of the TGF-β1/Smad signaling pathway [81]. FVP from Flammulina velutipes showed a hepatoprotective effect on acute liver injury induced by CCl4 by decreasing AST and ALT levels, enhancing antioxidant effects and attenuating pathological injury [82].

3.4. Polysaccharides and anti-liver fibrosis 3.5. Anti-HBV activity Hepatic fibrosis has been recognized as a reversible wound-healing response to a variety of chronic stimuli [77]. The etiologies of hepatic fibrosis include alcohol abuse, viral infection, persistent exposure to chemicals and drugs, etc. Additionally, a persistent inflammatory response will promote the activation of hepatic stellate cells (HSCs) and eventually aggravate hepatic fibrosis [78]. Many polysaccharides can alleviate liver fibrosis, which is mainly attributed to their inflammatory regulation and antioxidant activities

Hepatitis B infection is one of the three major HCC risk factors besides a high fat diet and alcohol intake. Presently, effective therapeutic strategies include vaccines, interferon, and nucleoside analogs. However, these drugs possess many restrictions, such as low efficacy, inadequate intake, side effects and resistance. As shown in Table 5, FVP1 and SFP both displayed anti-HBV activities. FVP1 from Flammulina velutipes possesses significant hepatitis B

Table 5 Polysaccharides that have exhibited anti-HBV and other activities. Name

Source

FVP1

MW Monosaccharide composition (kDa)

Effects

Ref.

54.78

Showed significantly anti-HBV activity and immune activity

[83]

Exerted significant hepatoprotective and anti-HBV roles

[84]

Exerted potential hepatoprotective effects against APAP-induced liver injury

[86]

Hepatoprotective against APAP-induced liver injury in mice Alleviated APAP-induced hepatotoxicity

[87] [88]

Possessed hepatoprotective effects against T. gondii-induced liver injury by the TLRs/NF-κB and Nrf2/HO-1 pathways Enhanced the antioxidant activity in the livers of cyclophosphamide-treated mice

[89]

Attenuated dextran sodium sulfate-induced hepatic pathological damage, liver parameters, infiltration of macrophages, cytokine levels, DMA levels and increased antioxidant enzyme activities Attenuated concanavalin A-induced liver injury through its anti-inflammatory and antioxidant actions in mice

[91]

Flammulina velutipes SFP-100-A Sophora SFP-100-B flavescens

– –

SFP-100-C

–

DOP

8.5

Dendrobium officinale PCP Poria cocos SP Seabuckthorn berry IOP Inonotus obliquus Se-GFP-22 Se-enriched Grifola frondosa DOPS Dendrobium officinal ASP

Angelica sinensis

– –

Man:Glc:Gal: = 7.74:70.41:16.38% Ara:Glc:Gla = 1.00:9.12:0.26 Ara:Glc:Gla:GalA = 1.00:0.85:0.35:0.43 Ara:Glc:Gla:GlcA:GlaA = 1.00:0.33:0.45:0.56:14.37 –

4130

– Man:Ara:Glc:Gal:Rha = 2.02:1.02:4:24:1:9.22 Man: Rha:Glc:Gal:Xyl:Ara = 2.2:1.1:11.8:2.8:2.7:1.0 Man:Glc:Gla = 3.3:23.3:1

–

–

72.9

–

42.0

[90]

[92]

828

Y. Yuan et al. / International Journal of Biological Macromolecules 141 (2019) 822–830

Fig. 3. Mechanisms of polysaccharide protection of liver injury.

surface antibody (anti-HBV) activity through the reduction of the expression of hepatitis B surface antigen (HBsAg), hepatitis B antigen (HBeAg) and hepatitis B virus (HBV) DNA replication [83]. SFP-100, SFP-100-A and SFP-100-C remarkably inhibited the secretion of HBsAg and HBeAg by HepG22.2.15 cells [84]. These findings suggest a novel role for the polysaccharide used for the treatment of immunemediated liver disease in the future.

3.6. Other hepatoprotective activities of polysaccharides Acetaminophen (APAP) is a drug used for managing pain and fever; however, overdose accounts for acute liver failure and liver disease [85]. Recently, the effects of polysaccharides on APAP-induced hepatotoxicity and the underlying mechanisms involved were investigated. DOP from Dendrobium officinale significantly alleviated hepatic injury by decreasing the ALT and AST contents in the serum and the ROS, MDA and MPO contents in the liver, as well as increasing the GSH, CAT and T-AOC contents in the liver, which was achieved by suppressing oxidative stress and activating the Nrf2-Keap1 signaling pathway [86]. Poria cocos polysaccharide (PCP) exerted pharmacological bioeffects against APAPinduced liver injury in mice by suppressing the inflammatory response and apoptosis in the liver [87]. SP from sea buckthorn significantly suppressed APAP-induced JNK phosphorylation, increased the ratio of Bcl2/Bax, and activated the Nrf-2/HO-1-SOD-2 signaling pathway [88]. Additionally, polysaccharides have shown various hepatoprotective activities by immunoregulatory functions. IOP from Inonotus obliquus showed hepatoprotective effects against T. gondii-induced liver injury in mice in part due to its anti-inflammatory activity through the inhibition of the TLRs/NF-κB pathway and the activation of the Nrf2/HO-1 pathway [89]. Se-GFP-22 from Se-enriched G. frondosa could enhance antioxidant activity by evaluating the GSH-Px, SOD, CAT, and MDA levels in the liver of cyclophosphamide-treated mice and strongly stimulate the release of cytokines (IL-2, IFN-γ) and NO production by upregulating JNK, ERK and p38 in the MAPK signaling pathway [90]. DOPS from Dendrobium officinale can downregulate the TNF-α signaling pathway and activate the Nrf-2 signaling pathway, suggesting that DOPS may be an effective therapeutic reagent to attenuate secondary liver injury in acute colitis immunosuppression [91]. Another polysaccharide, ASP (Angelica sinensis polysaccharide), attenuated caspase 3dependent apoptosis by caspase-8- and JNK-mediated pathways and inhibited the activation of the IL-6/STAT3 and NF-κB signaling pathways

in mice with concanavalin A (Con A)-induced liver damage [92]. The features of the polysaccharide were shown in Table 5.

4. Conclusions and perspectives Liver cirrhosis is the terminal stage of chronic liver injury and a distinct risk factor for developing HCC. Early intervention at the stage of liver injury is very sensible for the prevention of HCC. Inflammation, oxidative stress, apoptosis and cell death are all involved in liver injury. Since polysaccharides have diverse biological activities, such as antioxidative, immunoregulatory and antitumor activities, they are very effective in alleviating liver injury. Polysaccharides from a variety of sources, such as plants, fungi and Chinese herbs, have displayed hepatoprotective activities against HCC, NASH, ALD, liver fibrosis and HBV. Therefore, polysaccharides are recognized as potential natural compounds for the treatment of liver injury. In this study, we summarized the current findings regarding the polysaccharides with hepatoprotective activity and describe the underlying mechanisms (Fig. 3). In general, the possible mechanisms of action by which polysaccharides exert their hepatoprotective activity are mainly divided into the following three directions. (1) They inhibit the viability of HCC cells by directly activating apoptosis proteins, such as Bcl-2, Bax, caspase3, and caspase 8, and they can also activate the JAK/ STAT, Notch and Akt pathways that are widely involved in cell proliferation, differentiation, apoptosis and inflammation. (2) Polysaccharides can ameliorate the hepatic and serum index through oxidative stress response pathways in NASH or ALD mouse models, such as the Nrf2/HO-1 pathway. (3) Polysaccharides can balance the inflammatory response by regulating immune cell populations and cytokine levels through multiple inflammatory pathways in NASH, ALD, liver fibrosis models and other drug-induced liver injury models. To better determine the effects of polysaccharides on liver injury, their structure should be fully analyzed. Polysaccharide structural features that have been related to their activity are the monosaccharide and glycosidic-linkage compositions, conformation, molecular weight, function groups, and branching characteristics. These structural features may have different relevances depending on the type of polysaccharide, and their combination may impact the resulting hepatoprotective activities in different ways. More experiments are required to further elucidate their mechanisms of action and the relationship between the hepatoprotective activity and structure.

Y. Yuan et al. / International Journal of Biological Macromolecules 141 (2019) 822–830

Declaration of competing interest There are no conflicts of interest. Acknowledgments This work was supported by the Project of Transformation of Science and Technology Achievements from the First Hospital of Jilin University (NO. JDYYZH-1902041) and the International Science and Technology Cooperation Project from Department of Science and Technology from Jilin province (20180414064GH). References [1] H.B. El-Serag, N. Engl. J. Med. 365 (2011) 1118–1127. [2] D. Fuster, J.H. Samet, N. Engl. J. Med. 379 (2018) 1251–1261. [3] N. Ganne-Carrié, C. Chaffaut, V. Bourcier, I. Archambeaud, J.-M. Perarnau, F. Oberti, D. Roulot, C. Moreno, A. Louvet, T. Dao, R. Moirand, O. Goria, E. Nguyen-Khac, N. Carbonell, T. Antonini, S. Pol, V. de Ledinghen, V. Ozenne, J. Henrion, J.-M. Péron, A. Tran, G. Perlemuter, X. Amiot, J.-P. Zarski, M. Beaugrand, S. Chevret, J. Hepatol. 69 (2018) 1274–1283. [4] Q.M. Anstee, C.P. Day, Nat. Rev. Gastroenterol. Hepatol. 10 (2013) 645–655. [5] Y. Wei, Y. Wei, Z. 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