key: cord-0982654-1io3a8cp
authors: Chen, Rui-rong; Li, Ya-jun; Chen, Jun-jia; Lu, Chuan-li
title: A review for natural polysaccharides with anti-pulmonary fibrosis properties, which may benefit to patients infected by 2019-nCoV
date: 2020-07-07
journal: Carbohydr Polym
DOI: 10.1016/j.carbpol.2020.116740
sha: 56058a5787e8267c38db9fba3f43beb4a2dcfde1
doc_id: 982654
cord_uid: 1io3a8cp

Pulmonary fibrosis (PF) is a lung disease with highly heterogeneous and mortality rate, but its therapeutic options are now still limited. Corona virus disease 2019 (COVID-19) has been characterized by WHO as a pandemic, and the global number of confirmed COVID-19 cases has been more than 8.0 million. It is strongly supported for that PF should be one of the major complications in COVID-19 patients by the evidences of epidemiology, viral immunology and current clinical researches. The anti-PF properties of naturally occurring polysaccharides have attracted increasing attention in last two decades, but is still lack of a comprehensively understanding. In present review, the resources, structural features, anti-PF activities, and underlying mechanisms of these polysaccharides are summarized and analyzed, which was expected to provide a scientific evidence supporting the application of polysaccharides for preventing or treating PF in COVID-19 patients.

but its therapeutic options are now still limited. Corona virus disease 2019 has been characterized by WHO as a pandemic, and the global number of confirmed COVID-19 cases has been more than 8.0 million. It is strongly supported for that PF should be one of the major complications in COVID-19 patients by the evidences of epidemiology, viral immunology and current clinical researches. The anti-PF properties of naturally occurring polysaccharides have attracted increasing attention in last two decades, but is still lack of a comprehensively understanding. In present review, the resources, structural features, anti-PF activities, and underlying mechanisms of these polysaccharides are summarized and analyzed, which was expected to provide a scientific evidence supporting the application of polysaccharides for preventing or treating PF in COVID-19 patients. 

Pulmonary fibrosis (PF) is a worldwide disease, along with progressive and permanent fibrotic "scar" in alveolus and bronchioles of the lung parenchyma (Jacob et al., 2018) , which could be induced by genetic susceptibility and various environmental risk factors including virus, bacteria, cigarette smoke, wood dust, stone dust etc. (Martinez et al., 2017; Richeldi, Collard, & Jones, 2017) . Interana and pirfenidone were approved by the USA Food and Drug Administration for suppressing the progression of pulmonary fibrosis (Raghu et al., 2015) . In clinical, glucocorticoid (Ozaki et al., burden for patient (Raimundo et al., 2016) . Therefore, it is still urgent developing new therapies and drugs for treating pulmonary fibrosis.

The transformation of epithelial into myofibroblasts and the amount of extracellular matrix (ECM) generated by fibroblasts are considered as crucial developmental milestones in pulmonary, wherein a pivotal fibrogenic cytokine TGF-β is aberrantly expressed, which in turn triggers epithelial-mesenchymal transition (EMT) process thereby enhancing ECM deposition mediated by both Smad dependent and independent pathways (Liu, Lu, Kang, Wang, & Wang, 2017; Bale, Venkatesh, Sunkoju, & Godugu, 2018) . Furthermore, some other mechanisms have been also found to be imperative in pulmonary fibrosis progression including inflammation, oxidative stress, deregulated ECM and EMT signaling (Liu, Lu, Kang, Wang, & Wang, 2017) .

Human coronaviruses were first described in the 1960s for patients with the common cold, which in the past two decades have caused severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), as well as COVID-19 now. A typical clinical feature associated with SARS is pulmonary fibrosis, which resulted in a high mortality and a low quality of life for recovered patients (Venkataraman & Frieman, 2017) . Several long-term follow-up studies have demonstrated that more than 20% of SARS survivors exhibited radiographic evidence of lung fibrotic changes (Hui et al., 2005; Xie et al., 2005) . Recently, a retrospective analysis on the pulmonary computed tomographic imaging of fifty patients with COVID-19 pneumonia also observed the formation of fibrotic stripes during their rehabilitation period (Xu et al., 2020) . It will be a high probability that pulmonary fibrosis is one of the major complications in COVID-19 patients. Therefore, there will be a huge need for effective and safety agents and therapeutic strategies for treating pulmonary fibrosis induced by COVID-19 .

diseases and improving health. In fact, many studies have been conducted to reveal the anti-pulmonary fibrosis activities and underlying mechanisms of naturally occurring polysaccharides from medicinal plants, seaweed, and edible fungi. However, to the best of our knowledge, a comprehensively understanding of these anti-pulmonary fibrosis natural polysaccharides is still limited.

Thus, in present review, the available information about these natural polysaccharides with anti-pulmonary fibrosis activities were collected by searching in the related topics of "pulmonary fibrosis" and "polysaccharides" in the databases of Scopus (http://www.scopus.com) and China National Knowledge Infrastructure (https://www.cnki.net). In addition, the resources, structural features, physiological activities, as well as underlying mechanisms of these polysaccharides were systematically summarized and analyzed, which was expected to provide a scientific evidence for the application of polysaccharides for preventing or treating pulmonary fibrosis in COVID-19 patients.

2.1 Transforming growth factor β1 (TGF-β1)-Smad2/3 axis TGF-β1 overproduction has been recognized as the most relevant element related to the progress of pulmonary fibrosis, which plays a crucial role in the induction of EMT, and stimulates differentiation, proliferation and migration of immature fibroblasts, as well as induces phenotypic conversion of fibroblasts into myofibroblasts (Walton, Johnson, & Harrison, 2017) . Smad2 and Smad3 are the main transcription factors for TGF-β1 signals, which are phosphorylated and translocated into the nucleus upon ligand binding (Fig.1 ).

DOP is a neutral heteropolysaccharides isolated from Dendrobium officinale, which consisted of Man and Glc (in a mole ration of 5.9:1) with an average molecular weight (Mw) at about 1.78×10 5 Da, and had a partial structure of O-acetylated glucomannan with β-D-configuration in pyranose sugar forms . It has been demonstrated that DOP could significantly attenuate bleomycin (BLM)-induced up-regulation of TGF-β1 expression and Smad2/3 phosphorylation in the rat lung J o u r n a l P r e -p r o o f tissues, and further suppress the transformation of rat type II alveolar epithelial cells into myofibroblasts (Fig. 1) .

Ginsan, a polysaccharide isolated from the roots of Panax ginseng with an average Mw of 1.5×10 6 Da, composed mainly of Glc and Gal (over 90%, w/w), and 5-8% Man and Ara (Lee, Chung, Lee, Kim, Hong, & Yun, 1997; Ahn et al., 2011) . In mouse lung fibroblasts (NIH/3T3 cells) or human lung fibroblasts (IMR-90 and WI-38 cells), ginsan could significantly reduce the phosphorylation of Smad2 and Smad3 induced by TGF-β via inhibiting induction of R-Smads but not inhibitory Smads (Smad6 or Smad7).

In addition, ginsan significantly reduced the phosphorylation of ERK and Akt induced by TGF-β, but did not affect the phosphorylation of either JNK or p38, which indicated that ginsan downregulated both Smad-dependent and independent signaling pathways induced by TGF-β. Furthermore, ginsan could obviously reduce the increases in protein expression of TGF-β receptors (TβRI and TβRII), and block the decrease in protein expression of TβRIII, a known coreceptor of TβRII (Ahn et al., 2011) (Fig. 1 ).

ERK signaling is another important mechanism implicated in the process of TGF- 

The differentiation antagonizing non-protein coding RNA (DANCR) is a newly identified long noncoding RNA (lncRNA) with pivotal roles in cell proliferation, migration, invasion, and stem cell differentiation, which was shown to promote EMT progression and invasion capability of malignant cells (Yang, Sun, Gao, Meng, & Yang, 2018 J o u r n a l P r e -p r o o f Huang, Xu, & Shang, 2012) . Treatment with total polysaccharide of Angelica sinensis (ASP) exhibited significant downregulatory effects on the expression of DANCR, which in turn represses AUF1-mediated FOXO3 translation to suppress the EMT and pulmonary fibrosis both in in vitro and in vivo (Qian, Cai, Qian, Wang, & Zhang, 2020) ( Fig. 2 ).

via DANCR/AUF-1/FOXO3 regulatory axis.

The pathological progresses of pulmonary fibrosis are complex, but oxidative stress injury plays an important role (Cameli et al., 2020) . FYGL-1 is a neutral heteropolysaccharide isolated from Ganoderma lucidum, consisted of Gal, Rha and Glc (Pan et al., 2012) . Treatment with FYGL-1 (at 100 and 300 mg/kg for 28 days) led to a markedly reducing in the pulmonary index, inflammatory cell infiltration and collagen deposition in rats induced by BLM, which was associated with increased levels of glutathione, glutathione peroxidase, catalase and superoxide dismutase and decreased contents of malondialdehyde and hydroxyproline in the lung tissues (Chen et al., 2016) .

Pulmonary macrophages express several fibrotic mediators and play important roles in lung injury healing and fibrosis, which are currently classified into two phenotypes, classically activated macrophages (M1) with secretion of Th1-related cytokines (including TNF-α, IL-1β, and IL-6) and alternatively activated macrophages 

In present review, nine kinds of polysaccharides from plants were collected. The resources, structural features, and anti-pulmonary fibrosis activities of these polysaccharides were displayed in Table 1 .

The root of A. sinensis is a well-known traditional Chinese medicine, which has been used for thousands of years to prevent and treat various diseases. The polysaccharides have been proved as one of the major effective ingredients in A.

sinensis, and more than 30 kinds of polysaccharides have been identified from A.

sinensis, most of which were heteropolysaccharides (Jin, Zhao, Huang, Xu, & Shang, 2012) . Recently, Qian et al. (2020) have demonstrated that treatment with total polysaccharides from A. sinensis (ASP) significantly reversed BLM-induced collagen (Guo et al., 2016) . In addition, the PBS did not cause any side-effect in vivo with oral administration of 4000 mg/kg/day (He et al., 2017) . Ping Feng) also exhibited potential anti-pulmonary fibrosis activities in different in vitro and in vivo assays (Jiang, 2008; Xu et al., 2014; Gao, 2016) . In vivo: BLM-induced Sprague-Dawley rats;

In vitro: TGF-β1 induced alveolar type Ⅱ epithelial (RLE-6TN) cells.

In vivo, ASP administration suppressed the increasing of collagen deposition accompanying with restoring collagen-1 protein levels by inhibiting the DANCR/AUF1/FOXO3 pathway in BLM-induced PF model rats.

In vitro, ASP restored intercellular junction and spindle-like structure with downregulation of growth rate, migratory ability and α-SMA expression and upregulation of E-cadherin in RLE-6TN cells with TGF-β1 treatment.

Jin, Zhao, Huang, Xu, & Shang, 2012; Qian, Cai, Qian, Wang, & Zhang, 2020; Luo et al., 2017 RAP/Astragali radix Mw: 5.6~7600 kDa; Containing Glc, Rha, Gala, Ara, Xyl, Man, GlcA, Gala; Linkage: backbone 1,2,4-Rhap, α-1,4-Glcp, α-1,4-GalAp6Me, β-1,3,6-Galp with 1,2,4-Rhap, β-1,3,6-Galp, α-T-Araf, α-1,5-Araf at branching positions of O-4/O-2/O-3.

In vivo Astragalus polysaccharides administration inhibited inflammation of pulmonary alveoli and upregulated the serum level of IFN-γ with downregulated the serum levels of IL-4 and TNF-α in BLM-induced PF model rats. Li, et al., 2011; Yin et al., 2012 PBS/B. striata Mw: 401.3 kDa; Containing Man and Glc.

In vivo, administration of PBS improved pulmonary histomorphology and histopathology with inhibiting collagen deposition, decreased pulmonary index and hydroxyproline contents in BLM-induced PF model rats. Guo et al., 2016 DOP/D. officinale Mw: 178 kDa; Containing Man and Glc (5.9:1); Linkage: acetylated glucomannan with β-D configuration in pyranose.

In vitro: TGF-β1 induced rat type II alveolar epithelial cells.

After DOP administration in BLM-induced PF model rats, the pulmonary index, hydroxyproline expression and serum TGFβ1 concentrations were lower, with the improvement of histopathology, morphology and the inhibition of neutrophildominant inflammation, expression on mRNA and protein of TGFβ1, Smad2, Smad3 and α-SMA protein expression. In vitro, DOP decreased the expression of α-SMA, Smad 2/3 protein, pSmad 2/3 protein and the Chen et al., 2018; He et al., 2016 synthesis of collagen 1 and fibronectin with increasing the expression of E-cadherin. BHP-1/L. Combined with bone marrow mesenchymal stem cells transplantation, BHP-1 decreased the pulmonary index and improved the pulmonary histopathology and collagen deposition with downregulating the protein expression of TNF-α and NF-κB in BLM-induced PF model mice. Luo et al., 2013; Hui et al., 2019; Hu, Jin, Yang, Li, Xin, & Qin, 2020 TPOB/O. In vitro: TGF-β1 induced human A549 cells.

In vitro, TPOB changed less in morphology and reduced hydroxyproline contents with upregulating the expression levels of E-cadherin and downregulating the expression levels of Vimenth, α-SMA and COL1 in humanA549 cells with TGF-β1 treatment. Hoffman et al., 2005; Yan et al., 2017 Ginsan/P. In vivo, TPRH administration improved pulmonary histopathological morphology, inflammation of pulmonary alveoli and proliferation and deposition of collagen fibrils with reducing the contents of hyaluronic acid and laminin in lung tissue of BLMinduced PF model rats.

In vivo combined small dose prednisone, TPRH administration alleviated alveolar inflammation, Su et al., 2016; Qiang, Wang, Li, Wang, & Li, 2018; Lei, Zhao, Wang, Yao, & Ding, 2008 Glcp-(1→ with α-L-Araf, α-L-Rhap, α-D-Glc at a branching position of O-6; backbone →6)α-D-Glcp-(1→ and →5)-α-L-Araf-(1→ with α-D-Glc, α-L-Araf-(1→2)-α-L-Rhap, α-L-Araf at branching positions of O-2/O-3. fibrosis degree and histopathology changes with downregulating the expression levels of collagen and TGF-β1 in BLM-induced PF model rats.

Ara, Rha, Xyl, Glc, Gal, and GalA in the mole ration of 1.00: 3.23: 0.26: 0.34: 0.84: 10.24

In vitro: TGF-β1 induced human lung carcinoma type Ⅱ epithelial (A549) cells.

In vitro, RSA improved morphological change, inhibited cell mortality, increased cell livability and downregulated the expression of fibronectin-EDA (Fn-EDA) with the inhibition of transformation to ectomesenchymal cells in A549 cells with TGF-β1 treatment.

Han, Liang, Zhang, Han, Gong, & Ma, 2002; Li, Gao, Zhao, & Hong, 2016 

MS80 is a marine-derived sulfated oligosaccharide (1→4 α-D-glucose) isolated from seaweed with the average Mw at 8×10 3 Da. MS80 showed a significant inhibitory effect against pulmonary fibrosis induced by BLM in Wistar rats without toxicity, with improving pathological settings and decreasing lung collagen contents through competitively inhibition of heparin/heparan sulfate-TGF-β1 interaction (Jiang & Guan, 2009 ). In addition, MS80 could arrest TGF-β1-induced HEPF cell proliferation, collagen deposition and matrix metalloproteinase activity (Jiang & Guan, 2009 ). LMWF, another sulfated polysaccharide extracted from brown seaweed, has also demonstrated to possess a significant inhibition of BLM-induced pulmonary fibrosis in C57BL/6 mice, as evidenced by improved lung histopathology and hydroxyproline content, attenuated the expression levels of TGF-β1 in BALF and lung tissue, and the lung EMT phenotype including the expression trends of E-cadherin, α-SMA and fibronectin (Wang, Zhang, Li, Zhang, Zhan, & Wang, 2019) . Furthermore, LMWF displayed no mutagenicity by either the bacterial reverse mutation or chromosomal aberration assays in vitro (at 5000 µg/mL), as well as no toxicological indications in vivo by repeated oral administration of LMWF (2000 mg/kg/day) for 28 days (Hwang, Yan, Lin, Li, & Lin, 2016) . In addition, LMWF could significantly inhibited the morphologic alterations and proliferation of A549 cells induced by TGF-β1, and attenuated TGF-β1-induced EMT phenotype such as less expression of E-cadherin and over expression of vimentin, α-SMA and fibronectin (Wang, Zhang, Li, Zhang, Zhan, & Wang, 2019) .

The inhibitory effects of FSH has been reported against radiation pneumonitis and relative lung fibrosis in C57BL/6 mice treated by irradiated (10 Gy/shot) (Yu et al., 2018) , which indicated that administration of FSH significantly attenuated the increasing in pro-collagen 1α deposition, neutrophil (over expression levels of Ly6G In vivo: BLM-induced male C57BL/6 mice; In vitro: TGF-β1 induced A549 cells.

After LMWF administration in BLM-induced PF model mice, lung fibrotic histopathology and lung hydroxyproline content was significantly improved, levels of TGF-β1 expression (in BALF and lung tissue) and the lung EMT phenotype (the expression trends of E-cadherin, α-SMA and fibronectin) was attenuated, as well as ERK signaling was downregulated.

In vitro TGF-β1-induced A549 cells, LMWF significantly inhibited the cell morphologic alterations and proliferation, attenuated EMT phenotype (less expression of E-cadherin and over expression of vimentin, α-SMA and fibronectin mRNA), and downregulated the over expression of p-ERK1/2 induced by TGF-β1. Cui et al., 2016; Wang, Zhang, Li, Zhang, Zhan, & Wang, 2019 S. hemiphyllum/ FSH Mw: 0.8kDa; Containing rich L-fucose and sulfated ester groups with some D-xylose, D-galactose, Dmannose, glucuronic acid and a mixture of fatty acid methyl esters.

In vivo: radiotherapy (10 Gy/shot)-induced pneumonitis and lung fibrosis in C57BL/6 mice.

Fucoidan administration attenuated the increasing of pro-collagen 1α deposition, neutrophil (over expression levels of Ly6G mRNA) and macrophages (over expression levels of F4/80 mRNA) infiltration in lung tissues, reduced cytokine expression (TIMP-1, CXCL1, MCP-1, MIP-2, IL-1Ra, TREM-1, SDF-1/CXCL12 and IL-16) in the pleural fluid induced by radiation in mice. Yu et al., 2018; Zheng, Li, Liu, Yuan, & Lu, 2001 A kind of seaweed/ MS80 Mw: 8 kDa; Backbone →4)-α-D-Glcp-(1→ with sulfated residues and hydroxymethylated group.

In vivo: BLM-induced pathogen-free adult Wistar rats;

In vitro: TGF-β1 induced HEPF cells.

After MS80 administration in BLM-induced PF model rats, there were some improvements in morphology and increasing hydroxyproline content of lung tissue. In vitro, MS80 inhibited the combining capacity of TGF-β1 with heparin examined by surface plasm on resonance and the proliferation, collagen deposition and matrix metalloproteinase activity of HEPF cells with TGF-β1 or BALF. Jiang & Guan, 2009 

Four kinds of natural polysaccharides from fungi were collected in the present review. The resources, structural features, and anti-pulmonary fibrosis activities of these polysaccharides were displayed in Table 3 .

Polysaccharides from Cordyceps (polysaccharide content > 64%, average Mw < 2×10 5 Da) exhibited a significant inhibition of pingyangmycin-induced pulmonary fibrosis in mice, which could increase the IL-1RA levels, and reduce the hydroxyproline content and fibrosis area (Hu, Yang, Bai, & Fu, 2019) . FYGL-1, a neutral heteropolysaccharide isolated from G. lucidum, showed the similar inhibitory effect on BLM-induced pulmonary fibrosis in rats, which could suppress the pulmonary index, inflammatory cell infiltration and collagen deposition, as well as ameliorate the oxidative stress in the lung tissue, such as upregulating the levels of glutathione, glutathione peroxidase, catalase, superoxide dismutase (SOD) and downregulating the levels of malondialdehyde (MDA) (Chen et al., 2016) . Galp (Cai et al., 2018) . At the doses of 0-300 µg/mL, FMP-1 exhibited a potential antipulmonary fibrosis activity in H2O2-induced human alveolar epithelial A549 cells, without no inhibitory effect on cells' proliferation, which could attenuate H2O2-induced cytochrome c and Caspase-3 release to prevent cell apoptosis via inhibition of MDA J o u r n a l P r e -p r o o f and ROS levels, and enhancement the enzymatic activities of SOD and total antioxidant capacity . In addition, the high degree of branching, low molecular weight and favorable structures (e.g. 1,4-linked Glcp, 1,6-linked Galp and 1.6-linked Manp) are supposed to play an essential role in excellent antioxidant activities (Cai et al., 2018) . In vivo, cordyceps polysaccharide increased the IL-1RA levels, decreased the hydroxyproline content and shrank the fibrosis area in pingyangmycin-induced PF model mice. In vivo: BLM-induced male mice (C57BL/6).

In vivo, POL improved histopathological changes, reduced collagen deposition and the accumulation of macrophages (inhibiting the expression levels of NOS2, CXCL10/IP10, MARCO and ST2), downregulated the expression levels of proinflammatory and pro-fibrogenic factors (TNF-α, IL-1β, IL-6, OSM,IL-10, IL-13, α-SMA, MCP-1 and TGF-β1) and inhibited MDA production with promoting SOD level in BLM-induced PF model mice.

Zhou et al., 2020)

In present review, the structural features, physiological activities, and underlying mechanisms of 16 kinds of natural polysaccharides from plant, algae and fungi were systematically summarized and analyzed. The anti-pulmonary fibrosis activities of natural polysaccharides such as ASP, BHP-1, ginsan, TPRH, MS80, LMWF, and FYGL-1, have been demonstrated in different in vivo and in vitro assays, which can significantly ameliorate the pulmonary index, histopathological changes, and collagen deposition in rats or mice induced by BLM. And the main mechanisms of the antipulmonary fibrosis activities of these polysaccharides were targeting the TGFβ/Smad2/3 and DANCER/AUF-1/FOXO3 regulatory axis, and reducing the recruitment of macrophages and neutrophil. Furthermore, the sources of these polysaccharides are most edible materials, and the safety of ginsan, PBS and LMWF have been demonstrated in different in vivo and in vitro assays. Therefore, these polysaccharides maybe considerate as the safety and effective alternative agents for preventing or treating pulmonary fibrosis in COVID-19 patients.

The inhibitory effect of Ginsan on TGF-beta mediated fibrotic process

An adaptogen: withaferin A ameliorates in vitro and in vivo pulmonary fibrosis by modulating the interplay of fibrotic, matricelluar proteins, and cytokines

The use of prednisone (Meticorten) in respiratory disease. II. Pulmonary emphysema and pulmonary fibrosis

Structural characterization, in vitro and in vivo antioxidant activities of a heteropolysaccharide from the fruiting bodies of Morchella esculenta

Drug treatment of idiopathic pulmonary fibrosis systematic review and network metaanalysis

Oxidant/antioxidant disequilibrium in idiopathic pulmonary fibrosis pathogenesis

Polysaccharides from Dendrobium officinale inhibit bleomycininduced pulmonary fibrosis via the TGF beta 1-Smad2/3 axis

Protective roles of polysaccharides from Ganoderma lucidum on bleomycininduced pulmonary fibrosis in rats

A 14-week randomized, placebo-controlled, double-blind clinic trail to evaluate the efficacy and safety of gineng polysaccharide (Y-75)

Polysaccharides from Laminaria japonica: Structural characteristics and antioxidant activity

Study on Gua Lou Xie Bai Decoction for inhibiting pulmonary fibrosis

Inhibitory effect of Bletilla striata extracts on bleomycin-induced pulmonary fibrosis in rats

Purification and composition analysis of a polysaccharide RSA from Rhodiola sachalinensis A

Structural characterization and immunomodulating activity ofpolysaccharide from Dendrobium officinale

Bletilla striata: Medicinal uses, phytochemistry and pharmacological activities

Structural analysis of xyloglucans in the primary cell walls of plants in the subclass Asteridae

Effect of Cordyceps polysaccharide on pingyangmycin induced pulmonary fibrosis in mice

The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors

Structural characterization, antioxidant and antibacterial activities of two heteropolysaccharides purified from bulbs of Lilium davidii var. unicolor Cotton

Toxicological evaluation of low molecular weight fucoidan in vitro and in vivo

Likelihood of pulmonary hypertension in patients with idiopathic pulmonary fibrosis and emphysema

The effects and mechanism study of TCM-based Fei KangLing (FKL) on pulmonary interstital fibrosis

MS80, a novel sulfated oligosaccharide, inhibits pulmonary fibrosis by targeting TGF-beta 1 both in vitro and in vivo

Isolation, structure and bioactivities of the polysaccharides from Angelica sinensis (Oliv.) Diels: A review

The use of mushroom glucans and proteoglycans in cancer treatment

Activation of multiple effector pathway of immune system by the antineoplastic immunostimulator acidic polysaccharide ginsan isolated from Panax ginseng

An experimental observation of pulmonary fibrosis in rats and its transforming growth factor beta1 treated by total hedysarum polybotyssaccharide

Effects of Astragalus polysaccharides on level of cytokines and pathological structure of lung tissue in rat model of pulmoanry fibrosis

Polysaccharide FMP-1 from Morchella esculenta attenuates cellular oxidative damage in human alveolar epithelial A549 cells through PI3K/AKT/Nrf2/HO-1 pathway

Study on rhodiola polysaccharide against pulmonary fibrosis

Pirfenidone attenuates bleomycin-induced pulmonary fibrosis in mice by regulating Nrf2/Bach1 equilibrium

Effects of Angelica polysaccharides and angelica small molecules on expression of α-SMA, CTGF in human embryonic lung fibroblast cells induced by TGF-β1

Effect of lily polysaccharides combined with BMSCs transplantation on expression of TNF-alpha and NF-kappaB in bleomycin-induced pulmonary fibrosis mice

Idiopathic pulmonary fibrosis

Pulmonary fibrosis in systemic sclerosis: is treatment with cyclophosphamide more effective than placebo?

Bioactive algal-derived polysaccharides: multi-functionalization, therapeutic potential and biomedical applications

Glucocorticoid receptors in bronchoalveolar cells from patients with idiopathic pulmonary fibrosis

Structure characterization of a novel neutral polysaccharide isolated from Ganoderma lucidum fruiting bodies

Angelica Sinensis polysaccharide suppresses epithelial-mesenchymal transition and pulmonary fibrosis via a DANCR/AUF-1/FOXO3 regulatory axis

Structure and activity of Hedysari radix polysaccharides and its derivatives

An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis an update of the 2011 clinical practice guideline

Clinical and economic burden of idiopathic pulmonary fibrosis: a retrospective cohort study

Idiopathic pulmonary fibrosis

Bioactivities, isolation and purification methods of polysaccharides from natural products: A review

Effects of active ingredients in Radix hedysari on collagen area, hyaluronic acid and laminin of lung tissues in rats with pulmonary interstitial fibrosis

Structure and biological activities of the polysaccharides from the leaves, roots and fruits of Panax ginseng CA Meyer: An overview

The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis

Targeting TGF-beta mediated SMAD signaling for the prevention of fibrosis

Use of fucoidan to treat renal diseases: a review of 15 years of clinic studies

Advances in the research of mechanism of pulmonary fibrosis induced by Corona Virus Disease

Lowmolecular-weight fucoidan attenuates bleomycin-induced pulmonary fibrosis: possible role in inhibiting TGF-beta 1-induced epithelial-mesenchymal transition through ERK pathway

Dynamic changes of serum SARS-Coronavirus IgG, pulmonary function and radiography in patients recovering from SARS after hospital discharge

Total polysaccharide of Yu Ping Feng protects against bleomycin-induced pulmonary fibrosis via inhibiting transforming growth factor-beta 1-mediated type I collagen abnormal deposition in rats

Clinical and computed tomographic imaging features of novel coronavirus pneumonia caused by SARS-CoV-2

Inhibitory effect of Basil polysaccharide on TGF-beta-induced epithelialmesenchymal transition of A549 cells

Long non-coding RNA DANCR facilitates glioma malignancy by sponging miR-33a-5p

Separation, structure characterization, conformation and immunomodulating effect of a hyperbranched heteroglycan from Radix astragali

Fucoidan inhibits radiation-Induced pneumonitis and lung fibrosis by reducing inflammatory cytokine expression in lung tissues

Basil polysaccharides: a review on extraction, bioactivities and pharmacological applications

Sulfoglycolipid from the marine brown alga Sargassum hemiphyllum

This work was financed by the National Natural Science Foundation of China (No.

2019GDASYL-0103039).

The authors declare that they have no conflict of interests.J o u r n a l P r e -p r o o f