Physiological functionalities and mechanisms of β-glucans

Trends in Food Science & Technology 88 (2019) 57–66

Contents lists available at ScienceDirect

Trends in Food Science & Technology journal homepage: www.elsevier.com/locate/tifs

Review

Physiological functionalities and mechanisms of β-glucans a,b,c

d

a,b,c

a,b,c

a,b,c

Junying Bai , Yikai Ren , Yan Li , Mingcong Fan , Haifeng Qian , Li Wang Gangcheng Wua,b,c, Hui Zhanga,b,c, Xiguang Qia,b,c, Meijuan Xue, Zhiming Raoe

T a,b,c,∗

,

a

State Key Laboratory of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, China School of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, China National Engineering Research Center for Functional Food, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, China d Department of Food Science, University of Guelph, 50 Stone Rd E, Guelph, Ontario, Canada e School of Biotechnology, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, China b c

A R T I C LE I N FO

A B S T R A C T

Keywords: β-Glucans Characteristics Modification Activities Mechanisms

Background: β-Glucans are polysaccharides constructed of glucose monomers linked by β-glucosidic bonds, which mainly exist in cereals (barley and oat), yeast and mushrooms. Some physiological functionalities of βglucans have been confirmed, consequently, their development and utilization in the biomedical, pharmaceutical, food, and cosmetic industries have received increasing interest. Foods and dietary supplements containing β-glucans are very popular. Scope and approach: This review summarizes recent findings regarding the physiological functionalities of βglucans and details the action mechanisms of β-glucans upon the present knowledge. The prospects for future research on these topics are also discussed. Key findings and conclusions: β-Glucans are effective in many aspects of human health, including cancer prevention, reducing glycemia and serum cholesterol, anti-inflammation, as well as improving immunity. The modification of β-glucans contributes to better solubility, viscosity and gelation, which can change the bioactivities of β-glucans. The action mechanisms of β-glucans and their derivatives are considered to be mainly mediated by some cytokines and hormones in subjects. Human health is supported by various mechanism researches. Although certain action mechanisms remain unclear, the clarification of how β-glucans exhibit biological effects is beneficial for our understanding of complicated biochemical reaction in living organisms.

1. Introduction β-Glucans are macromolecular polysaccharides consisted of D-glucose monomers linked through β-glycosidic bonds, which widely exist in plants and microorganisms (Du, Bian, & Xu, 2014). The most common β-glucans include cereal β-glucans, zymosan (MG), lentinan, schizophyllan (SPG), krestin (PSK), and betafectin (PGG). Different sources of β-glucans lead to different structures and physicochemical properties. Structural variations in side-chain length and distribution in β-glucans are mainly determined by the source and extraction method (Mantovani et al., 2008). However, the optimal extraction method depends on the structures and sources of β-glucans. β-Glucans are usually divided into soluble and insoluble forms, which correlate with the degree of polymerization (DP). β-Glucans with DPs higher than 100 are usually completely insoluble in water (Du et al., 2014). The applications of both soluble and insoluble β-glucans

cover most aspects of daily life. For example, β-glucans are used in beverages to adjust solution consistency owing to their thickening effect, and as food additives in milk, yogurt, and bread to decrease energy intake and reduce cholesterol (Sharafbafi, Tosh, Alexander, & Corredig, 2014; Barone Lumaga, Azzali, Fogliano, Scalfi, & Vitaglione, 2012). More importantly, β-glucans are used as functional ingredients to produce nutritional and healthy products. β-Glucans are also added into some medicine formulas to explore new pharmaceuticals with supplementary functions in the pharmaceutical industry. Furthermore, βglucans are applied in cosmetics because of their moisturizing, antiaging, and wound healing effects (Du et al., 2014). β-Glucans play important roles, particularly in healthy foods and pharmaceutical products, due to their widely known beneficial effects, including immunomodulation, antitumor activity, serum cholesterol and glucose reduction, and obesity prevention. The Food Marketing Institute (FMI) reported that health and dietary supplement products

∗ Corresponding author. State Key Laboratory of Food Science and Technology, School of Food Science and Technology, National Engineering Research Center for Functional Food, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122, China. E-mail address: [email protected] (L. Wang).

https://doi.org/10.1016/j.tifs.2019.03.023 Received 7 February 2018; Received in revised form 18 February 2019; Accepted 19 March 2019 Available online 22 March 2019 0924-2244/ © 2019 Published by Elsevier Ltd.

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containing β-glucans accounted for 33.7% of the global β-glucans market share in 2014. β-Glucans derived from cereals continue to dominate the total production. Yeast, another important source of βglucans, is thought to be the second largest source of β-glucans, followed by mushroom-derived β-glucans. Information regarding different aspects of β-glucans have been summarized previously, including their production and industrial applications (Zhu, Du, & Xu, 2016), characteristics (Zhu, Du, Bian, & Xu, 2015), and modification (Kagimura et al., 2015). In this review, the physiological functionalities and mechanisms of β-glucans are summarized, in addition to their modifications to prepare functional derivatives. Fig. 2. Structure of (1 → 3) β-glucans fragment with (1 → 6) branches.

2. Origins and extraction methods

Stone, & Stanisich, 2005). β-Glucans from microorganisms usually have various biological activities. Fungal β-glucans have been reported to be effective on certain diseases, including cancer, various microbial infections, hypercholesterolemia, and diabetes (Luzio, Williams, Mcnamee, Edwards, & Kitahama, 1979).

2.1. Origins As previously mentioned, β-glucans are generally found as the main components of cell walls in cereals, fungi (including yeast and mushrooms), some bacteria, and seaweeds (Bacic & Stone, 1981, Bacic et al., 1981; Beresford & Stone, 1983; Buckeridge, Rayon, Urbanowicz, Tiné, & Carpita, 2004; Wood, Fulcher, & Stone, 1983). Naturally, β-glucans from cereals consist of β-(1 → 3) and (1 → 4) linkages (Tohamy, ElGhor, El-Nahas, & Noshy, 2003). However, β-glucans from fungi and bacteria consist of β-(1 → 3) and (1 → 6) linkages (Zhu et al., 2016). Cereals are the main source of β-glucans and dominate β-glucans production. β-Glucans contents are about 1% in wheat, 3–7% in oats, and 5–11% in barley (Skendi, Biliaderis, Lazaridou, & Izydorczyk, 2003). β-Glucans in cereals are linear homopolysaccharides of D-glucopyranosyl residues with β-(1 → 3) and β-(1 → 4) linkages (Fig. 1), and show structural variations in the ratios of trimers to tetramers and (1 → 3)-linkages to (1 → 4)-linkages (Lazaridou & Biliaderis, 2007; Zhu et al., 2016). Cereal β-glucans exhibit only partial solubility in water due to their structural diversity. For example, β-glucans containing blocks of adjacent β-(1 → 4) linkages can exhibit lower solubility via interchain aggregation (Vaikousi, Biliaderis, & Izydorczyk, 2004; Vårum & Smidsrød, 1988). Therefore, in addition to the physiological benefits of soluble dietary fiber, cereal β-glucans also show health effects typical of insoluble fiber, such as increased fecal bulk to relieve constipation and improve weight loss. In microorganisms, β-glucans consist of a linear central backbone of glucose residues linked via β-(1 → 3) linkages and often contain glucose side-chains of various sizes linked through β-(1 → 6) linkages. On average, β-(1 → 6) substitution occurs every two to three β-(1 → 3) main chain residues (Fig. 2). In general, β-glucans obtained from different sources have different constructions, but all appear to be righthanded triple helix structures stabilized by interchain hydrogen bonds (Brown & Gordon, 2005; Chihara, 2001, pp. 261–266). For fungi, βglucans contribute about half the mass of the cell walls (McIntosh,

2.2. Extraction methods Common methods for extracting β-glucans include hot water extraction, alkali extraction (Kao et al., 2012), enzyme extraction (Park, Ka, & Ryu, 2014), acidic extraction (Park et al., 2001) and other assisted extraction methods (ultrasound, microwave) (Chen et al., 2017; Hematian, Koocheki, & Elahi, 2017). Hot water extraction is a good method for extracting water-soluble β-glucans (Yan, Wang, & Wu, 2014). Water-insoluble β-glucans can be obtained by alkaline extraction, then isolated by centrifugation or fractional precipitation with ethanol, 2-propanol, and ammonium sulfate (Liu et al., 2014b; Smiderle et al., 2006; Wood, Siddiqui, & Paton, 1978). The extraction of β-glucans from cereals is mainly based on the isolation of proteins and starch. After dissolving β-glucans in hot water and alkaline solutions, the dissolved proteins are separated by isoelectric precipitation, and residual starch is isolated by repeated precipitation and enzymatic hydrolysis, affording purities of up to 99% (Westerlund, Andersson, & Åman, 1993; Wood et al., 1978, 1991). Crude β-glucans extract has been subjected to column chromatography and gel-filtration chromatography for further purification (Camelini et al., 2005; Kao et al., 2012; Kim, Kim, Choi, & Lee, 2005). 3. Physicochemical properties and modification 3.1. Physicochemical properties The nutritional and health functionalities of β-glucans are often related to their physicochemical properties. These properties, such as solubility, viscosity, and gelation, are determined by their molecular

Fig. 1. Structure of β-glucans fragment with (1 → 4) chains separated by (1 → 3) linkages. 58

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3.2.1. Chemical modification Sulfated polysaccharides are found throughout nature. Water-insoluble polysaccharides show little bioactivity, while their water-soluble sulfated derivatives exhibit high antitumor and antiviral activities (Zhang, Lu, Zhang, Qin, & Zhang, 2010; Liu, 2014; Shi, Nie, Chen, Liu, & Tao, 2007; Yamamoto et al., 2013; Bo, Muschin, Kanamoto, Nakashima, & Yoshida, 2013). The sulfation of β-glucans could increase their water solubility for use in various foods and drugs to improve texture (Jindal et al., 2013). Furthermore, many reports have noted that sulfated β-glucans, in most cases, take on health benefits, including antimicrobial, antithrombotic, antiherpetic (Liu, Wan, Shi, & Lu, 2011), anticoagulant (Lu, Mo, Guo, & Zhang, 2012; Mestechkina & Shcherbukhin, 2010), and immunomodulation effects (Vetvicka, Vetvickova, Frank, & Yvin, 2008; Zhang et al., 2010). Sulfated natural glucan from Phellinus ribis shows antiangiogenic activity, which plays an important role in the growth, metastasis, and prognosis of malignant solid tumors (Liu et al., 2018). Similarly, Tao et al. (2006) reported that sulfated derivatives exhibited relatively higher in-vitro antitumor activities against human hepatic cancer cell line HepG2 compared with native water-soluble hyper-branched β-glucan. The introduction of sulfate groups was the main factor in enhancing this antitumor activity. The carboxymethylation of β-glucans is recognized as a promising chemical modification owing to the improved health effects compared with unmodified β-glucans. Carboxymethylated β-glucan from yeast (CM-G) was reported to positively modulate vascular function, mainly in NO-dependent responses, with CM-G being more selective than native β-glucan for adenosine diphosphate-induced platelet aggregation (Bezerra et al., 2017). Analogously, carboxymethylated glucan extracted from Saccharomyces cerevisiae induced vasodilation mediated by the NOS/NO/SCG pathway and showed negative inotropic effects in rats (Paixão Vieira et al., 2017). The data of Chen, Siu, et al. (2014) and Chen, Zhang, et al. (2014) indicated that the type of substituent and the degree of substitution played a decisive role in the bioactivities of the βglucan derivatives. Furthermore, Kogan et al. (2005) reported the radical scavenging activity of carboxymethylated β-glucan in vivo in the adjuvant arthritis model, which showed the potential for possible medicinal applications of this glucan derivative in arthritis treatment. β-Glucan modifications involving oxidation and chemical degradation have also been reported. For example, oat-derived β-glucans were subjected to chemical modification via 2,2,6,6-tetramethyl-1-piperidine oxoammonium ion-mediated oxidation, in which C6 primary hydroxyl groups were selectively oxidized to carboxyl groups. The water solubility of oat β-glucan increased with oxidation, with oxidized oat βglucan showing potential as an active cholesterol-lowering ingredient (Park, Bae, Lee, & Lee, 2009). Low-MW soluble yeast glucan that has undergone acid degradation (ad-sBBG-low) can modulate immunity by

features (Ahmad, Anjum, Zahoor, Nawaz, & Dilshad, 2012), including molecular weight (MW) and structure. Different temperature and concentration also result in diverse physiological functionalities (Mantovani et al., 2008). For example, ultrasound-degraded β-glucan from a medicinal fungus showed an excellent moisture absorption capability comparable to chitosan and urea (Chen et al., 2014). The structural characteristics of β-glucans, especially the ratios of β(1 → 3) to β-(1 → 4) linkages or β-(1 → 3) to β-(1 → 6) linkages, are important determinants of viscosity and solubility (Skendi et al., 2003). In general, the viscosity is directly controlled by the MW and concentration in solution (Wood, Beer, & Butler, 2000). Oat β-glucan with high MW exhibits high viscosity that restricts its applications. Furthermore, soluble β-glucans seem more beneficial for human health than insoluble β-glucans, because the latter often exert health effects only as a dietary fiber. Meanwhile, the textural properties and melting profiles of β-glucans gels can be manipulated by adjusting the ratios of MW fractions (Brummer et al., 2014). Rheological properties can help to identify the particle sizes of β-glucans (Ahmad, Mustafa, & Man, 2015). β-Glucans extracted from oats, wheat, and barley, have different MWs, which are affected by the structural features and degree of polymerization, with the opposite trend between polydispersity index and viscosity. Molecular weight is responsible for the observed behavior (Zhao et al., 2014), with high-MW cereal β-glucans predominantly showing viscous flow behaviors, while gelation can be observed, particularly in solutions of lower MW materials (Böhm & Kulicke, 1999; Doublier & Wood, 1995). It seems that β-glucans with similar MWs from different origins possess similar flow viscosity behaviors, but completely different gelation properties, with a higher proportion of (1 → 3)-linked cellotriose units in a structure leading to more rapid gelation for cereal β-glucans. 3.2. Modification In general, water solubility, chain conformation, and the introduction of suitable ionic groups with the appropriate degree of substitution can change the bioactivities of polysaccharides (Tao, Zhang, & Cheung, 2006). β-Glucans can be modified by physical and chemical crosslinking reactions to improve their bioavailability and obtain various derivatives with potential industrial or medicinal applications (Table 1) (Ahmad et al., 2015; Synytsya & Novak, 2013). Several common modification methods have been applied to β-glucans, including chemical methods, such as sulfation, carboxymethylation, and oxidation, and physical methods, such as radiation, microwaves, and heating. Modifications of β-glucans often influence their MW, polymerization, solubility, viscosity, and gelation, which changes their nutrition value (Raveendran, Yoshida, Maekawa, & Kumar, 2013). Table 1 Modifications of β-glucans and physiological functions of the products. Type

Method

Object

Sources

Functions

References

Chemical modification

Sulfation

(1 → 3) (1 → 6)-β-D-glucan

Russula virescens

Antitumor

Sulfation Carboxymethylation Carboxymethylation carboxymethylation-sulfation Acetylation Phosphorylation

(1 → 3) (1 → 3) (1 → 3) (1 → 3) (1 → 3) (1 → 3)

(1 → 6)-β-D-glucan (1 → 6)-β-D-glucan (1 → 6)-β-D-glucan (1 → 6)-β-D-glucan (1 → 4)-β-D-glucan (1 → 6)-β-D-glucan

Improving immunity Antioxidation Anti-tumor Immunoactivity Increasing bile acid binding capacity immunostimulating activity

Acid degradation Microwave Drying Ultrasound-degradation

(1 → 3) (1 → 3) (1 → 3) (1 → 3)

(1 → 6)-β-D-glucan (1 → 4)-β-D-glucan (1 → 4)-β-D-glucan (1 → 6)-β-D-glucan

Immune modulating Antioxidation enhancing Immunoactivity Moisturizing

Ishimoto et al. (2018) Ahmad et al. (2016) Liepins et al. (2015) Chen, Siu, et al. (2014)

Gamma irradiation Gamma irradiation

(1 → 3) (1 → 6)-β-D-glucan (1 → 3) (1 → 4)-β-D-glucan

Yeast Lasiodiplodia theobromae Pleurotus tuber-regium Poria cocos Oat yeast Saccharomyces cerevisiae Yeast Hordeum vulgare L Brewer's yeast Cordyceps sinensis CsHK1 Yeast Avena sativa

Sun, He, Liang, Zhou, and Niu (2009) Wang et al. (2016) Kagimura et al. (2015) Zhang, 2004 Wang et al. (2015) de Souza et al. (2015) Shi, Shi, and Li (2014)

Plant growth promoter Antioxidation, anticancer, hypoglycemic activity

Luan le & Uyen, 2014 Hussain, Rather, and Suradkar (2018)

Physical modification

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binding to dectin-1 (an innate immunity receptor of β-glucan), resulting in antagonistic activity against reactive oxygen production and cytokine synthesis by macrophages (Ishimoto et al., 2017).

secretion of proinflammatory cytokines TNF, IL-1β, IL-6, and IL-12, and anti-inflammatory cytokine IL-10. Receptors that recognize β-glucans include dectin-1, CR3, TLR4 and TLR2, scavenger receptors, and lactosylceramide (LacCer) (Kiron et al., 2016). Mechanistically, dectin-1 is the main receptor for β-glucans in macrophages, dendritic cells, and neutrophils (Fuller et al., 2012; Minato, Laan, Ohara, & van Die, 2016; Wu, Shi, Wang, & Wang, 2016). Dectin-1 induces various immune responses upon β-glucan recognition, including phagocytosis, respiratory burst, the production of numerous cytokines and chemokines, and arachidonic acid metabolite production (Drummond & Brown, 2011; Jellmayer et al., 2017). However, research has shown that dectin-1 is not involved in β-glucan-mediated protection against bacterial infection (Marakalala et al., 2013). β-1,3-Glucan recognition protein 3 (βGRP3) also plays a key role in the immune recognition and signaling pathway of insect innate immunity by activating the prophenoloxidase system in response to bacterial infection (Wu et al., 2018). Furthermore, some findings suggest that β-glucan induces an increase in cortisol, which has been proposed as an important mechanism for improving innate immune response in matrinxã (Franco Montoya, Martins, Gimbo, Zanuzzo, & Urbinati, 2017).

3.2.2. Physical modification Among physical modifications of β-glucans, gamma irradiation has been shown to lead to the formation of low-MW β-glucan from barley with enhanced antioxidant and antiproliferative activities against human cancer cell lines Colo-205, T47D, and MCF7 (Shah et al., 2015). Low-MW oat β-glucan degraded by gamma irradiation also showed modified biological activities. Gamma-irradiated oat β-glucan had higher cytotoxicity against colo-205 and MCF7 cancer cells compared with T47D cells, with no cytotoxicity observed against normal cell lines at all concentrations tested (Hussain et al., 2018). Microwave modification changed the structural and physicochemical properties of βglucan from barley, which enhanced its antioxidant potential. Structural elucidation showed that scission of the polymeric chain and glycosidic linkages of β-glucan had occurred (Ahmad, Gani, Shah, Gani, & Masoodi, 2016). Solubilized yeast β-glucan (hd-sBBG) heated at 135 °C for several hours exhibited antagonistic activity toward reactive oxygen production and cytokine synthesis in macrophages, providing an important procedure for producing immunomodulating soluble yeast βglucan (Ishimoto et al., 2017).

4.2. Antitumor effect β-Glucans have long been considered as a potential antitumor agent. For example, β-glucan from yeast has exerted antitumor effects without toxicity in normal mouse cells (Mo et al., 2017). (1 → 3,1 → 6)-β-DGlucans produced by Diaporthe sp. endophytes show antiproliferative activity against human breast carcinoma (MCF-7) and hepatocellular carcinoma (HepG2-C3A) cells (Orlandelli et al., 2017). Lentinan, a typical β-(1 → 3,1 → 6)-glucan isolated from Lentinus edodes, was able to induce apoptosis of S180 cells via mitochondrial pathways (Zhang et al., 2015). The strong antitumor properties of a new low-MW βglucan from oats might be due to β-glucan-induced strong expression of caspase-12 in Me45 and A431 cancer cell lines (Choromanska et al., 2015). Proapoptotic properties of (1 → 3) (1 → 4)-β-D-glucan from Avena sativa have been reported against human melanoma HTB140 cells in vitro. Oat β-D-glucan caused a concentration-dependent increase in caspase-3/7 activation and the appearance of phosphatidylserine on the external surface of cellular membranes, where it was bound to annexin V-FITC, demonstrating the induction of apoptosis. Intracellular ATP levels decreased with decreasing mitochondrial potential, which suggested a mitochondrial pathway for apoptosis. Cell cycle analysis showed increases in the number of apoptotic cells and cells in the G1 phase, and a decrease in the number of cells in G2/M (Parzonko, Makarewicz-Wujec, Jaszewska, Harasym, & KozlowskaWojciechowska, 2015). The antiproliferative action of β-glucan appears to be involved in the repression of genes related to the G1 phase of the cell cycle and possibly the interaction of β-glucan with the CCR5 receptor (Malini et al., 2015). The antitumor effect exerted by (1 → 3) (1 → 6)-β-D-glucan from Saccharomyces cerevisiae may be attributed to the immunostimulating properties and apoptosis-inducing features of the polysaccharide (Mo et al., 2017). β-Glucan has been shown to inhibit the activity of legumain, with the observed inhibitory effect involving legumain internalization into macrophages induced by the dectin-1 receptor. Particulate β-glucans were more potent TNF-α inducing agents than partly water-soluble β-glucans and water-soluble β-glucans in RAW 264.7 macrophages (Berven et al., 2015). β-Glucan from Baker's yeast (BBG) interacted with CR3 and TLR2 on the surface of macrophage-like RAW264.7 cells, and initiated activation of RAW264.7 cells, as characterized by significant production of TNF-α and monocyte chemoattractant protein 1 (MCP-1). Furthermore, nuclear factor kappa B p65 (NF-κB p65), c-Jun N-terminal kinase (JNK), and extracellular signalregulated kinase (ERK) activation by BBG has been observed, confirming the stimulation of RAW264.7 cells by BBG (Zheng et al., 2016). Imprime PGG is a soluble yeast β-(1 → 3) (1 → 6)-glucan that has been

4. Physiological functionalities and action mechanisms Typical (1 → 3) (1 → 4)-β-glucans from cereals have received the most attention due to their remarkable effects, including reducing blood glucose and cholesterol for obesity and cardiovascular disease (CVD). In contrast, (1 → 3) (1 → 6)-β-glucans from microorganisms tend to show better antitumor, anti-inflammation, and antiviral activities against immune system diseases. 4.1. Immunomodulation β-Glucans have received increasing attention owing to their notable immunomodulation effects. The immunomodulation activity of Aureobasidium pullulans-produced β-glucans is expressed indirectly through activation of small intestinal immunity (Aoki et al., 2015). A water-soluble β-glucan from edible mushroom Entoloma lividoalbum exhibited macrophage, splenocyte, and thymocyte stimulation as an immunostimulating agent (Maity et al., 2015). (1 → 3) (1 → 6)-β-DGlucan extract from pathogenic oomycete Pythium insidiosum directly induced significant and specific Th17 cellular immune response and increased immune protein IgG concentrations (Chethan et al., 2017). Dietary yeast β-glucan enhanced immunity by increasing the immunoglobulin concentration and stimulating alkaline phosphatase (ALP) (Ma et al., 2015). In vitro, β-D-glucan extract significantly promoted spleen lymphocyte proliferation and a significant increase in IL2, IL-6, IL-10, TNF-α, and IL-17A production (Jellmayer et al., 2017; Tondolo et al., 2017). Glucans from the mycelia and fruit body of Pleurotus ostreatus show immunological functions via lymphocyte proliferation, macrophage activation (NO production, reactive oxygen species generation, phagocytosis, TNF-α production), and macrophage and NK cell-mediated cytotoxicity (Devi, Behera, Mishra, & Maiti, 2015; Dulal et al., 2016; Na, Je, & Seok, 2018). β-(1 → 3) (1 → 6)-Glucan induced macrophage activation via the TLR4/NF-κB signaling pathway led to the up-regulation of NO, IL-1β, IL-6, and TNF-α production, and mRNA expression levels of iNOS, IL-1β, IL-6, and TNF-α in RAW264.7 cells macrophages. Also, the binding of DIP (a polysaccharide from Dictyophora indusiata) to target cells and cytokine production could be markedly inhibited by anti-TLR4 monoclonal antibodies (Deng et al., 2016). Furthermore, as immunomodulators, β-(1 → 3) (1 → 6)-glucans have the capacity to activate human dendritic cells (DCs) by triggering multiple signaling pathways, including the up-regulation of maturation markers and 60

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successfully administered intravenously. It has a novel β-glucan PAMP (pathogen-associated molecular pattern) that binds to and activates innate immune effector cells, triggering a cascade of immunoactivation events to orchestrate a coordinated anticancer immune attack. Preclinically, imprime PGG improves the antitumor efficacy of tumor-targeting, anti-angiogenic, and immune checkpoint inhibitor (CPI) antibodies (Bose et al., 2016). Although mechanisms related to the antiproliferative activity of βglucans are not yet fully understood, the presence of a (1 → 3)-β-glucopyranose main chain substituted at O-6 positions by β-glucopyranose seems to be required for inhibitory activity, because branches may favor more effective interactions with cell receptors in tumor cells, playing an important role in the induction of cell death (Pires, Ruthes, Cadena, & Iacomini, 2017; Ruthes, Smiderle, & Iacomini, 2015).

Abdel-Aal, Ames, Duss, & Tosh, 2014; Jenkins et al., 1978; Regand, Chowdhury, Tosh, Wolever, & Wood, 2011; Wood et al., 1994; Östman, Rossi, Larsson, Brighenti, & Björck, 2006). The interaction of β-glucans with intestinal mucus has been proposed as another potential mechanism for cereal β-glucans in regulating postprandial blood glucose and insulin levels (Mackie et al., 2016). However, data on blood glucose response has shown that the important role of the aforementioned mechanisms in the reduction of postprandial glycemic response by βglucan is a result of coil overlap (Rieder, Knutsen, & Ballance, 2017; Tosh, 2013). Evidence suggests that oat β-glucan particles, as part of the cell wall, exist in a network-like native structure that might encapsulate proteins and starch to form a complex matrix within the cell wall. This matrix could decrease enzyme accessibility, leading to reduced starch digestion and a decreased postprandial glycemic response (Zhang, Luo, & Zhang, 2017). The high viscosity of β-glucan from oats (OBG) may also play a crucial role as a physical barrier to glucose uptake in normally absorptive gut epithelial cells IEC-6 by affecting the expression of intestinal glucose transport protein 1 (SGLT1) and transporter 2 (GLUT2) (Abbasi, Purslow, Tosh, & Bakovic, 2016). β-D-Glucans have also been shown to elicit an increase in insulin secretion and a decline in insulin resistance owing to the high viscosity of the solution markedly repairing and improving the integrity of pancreatic islet β-cell and tissue structures (Liu et al., 2016). Furthermore, the reduction of glucose or insulin levels by β-glucans is influenced by levels of gut peptides, such as YY and ghrelin. Gut peptides can affect gut hormones, which seemingly play an important role in glucose homeostasis (Baldassano et al., 2017; Pradhan, Samson, & Sun, 2013).

4.3. Anti-inflammation Although orally delivered β-glucans have been shown to aggravate intestinal inflammation induced by dextran sulfate sodium (DSS) at the level of the mucosa (Heinsbroek et al., 2015), β-glucans have more positive anti-inflammatory effects. For example, yeast β-glucan improves DSS-induced changes in mucosal inflammatory lesions and the intestinal barrier by inhibiting the expression of inflammatory mediators and enhancing the expression of tight junction proteins associated with intestinal permeability (Han, Fan, Yao, Yang, & Han, 2017). The suppression of the macrophage-mediated phagocytosis of apoptotic cells by soluble β-glucan is attributed to the failure of PKC-βII translocation by β-glucan (Sekiguchi et al., 2016). β-Glucan immune receptors dectin-1 and CR3 specifically induce an Akt/PI3 K-dependent anti-inflammatory IL-1Ra (Proinflammatory agent (IL-1) receptor antagonist (IL-1Ra)) response upon recognition of C. albicans. (Smeekens et al., 2015). In contrast, β-glucan from oats (purity approx. 75%) with a low MW led to the reduction of enteritis groups in rats, mainly due to the increased antioxidative defense (Suchecka et al., 2015). β-Glucans with high MWs directly activate leukocytes and modulate the production of proinflammatory cytokines and chemokines, while those with low MWs activate leukocytes via the stimulation of nuclear transcription factors (Brown & Gordon, 2003). Yeast-glucans increased gene expression of Cath-2, AvBD-4, and AvBD-10 in the early infection stage, and Cath-1, Cath-2, and AvBD-1 in the later infection stage in the gut, while decreasing AvBD-10 and LEAP-2 mRNA levels in the later infection stage, which improved perfringens-induced necrotic enteritis in broiler birds (Tian, Shao, Wang, & Guo, 2016). It is reported that receptors (TLR2, TLR4, dectin-1, CR3) and hormone (YY) all play roles in immunomodulation, antitumor, and antiinflammation activities (Baldassano, Accardi, & Vasto, 2017; Chen & Seviour, 2007). Although some hypotheses regarding relationships among different action mechanisms have been proposed, they have not been confirmed. Therefore, the role of β-glucans in the whole immune system remains unclear.

4.5. Reducing serum cholesterol levels for coronary heart disease (CHD) Reducing cholesterol levels is well known to significantly reduce the risk of coronary heart disease (CHD) (Andersson, Svedberg, Lindholm, Oste, & Hellstrand, 2010; Bae, Lee, Kim, & Lee, 2009). This is just one reason for β-glucans preventing CHD. The detailed mechanism for reducing serum cholesterol levels is not yet defined, but several hypotheses have been proposed. The current lead hypothesis for cholesterol-lowering effects in blood is through limited reabsorption and enhanced excretion of bile salts by binding to viscous β-glucan in the small intestine (Gunness et al., 2012, 2016). Restricting reabsorption of bile acid (BA) results in reduced blood total cholesterol (TC) and lowdensity lipoprotein cholesterol (LDL-C), which is strongly dependent on the amount and type of dietary fiber in the diet (Ghaffarzadegan, Zhong, Fak Hallenius, & Nyman, 2018). Reducing the mass transfer of bile and lipids through the intestinal mucus layer might be one factor enabling this decrease in bile reabsorption and prolonged postprandial lipid absorption (Mackie et al., 2016). β-Glucans also resulted in beneficial reprofiling of secondary BAs (Gunness et al., 2017). However, dietary hull-less barley β-glucan (HBG) reduces the concentration of plasma LDL cholesterol by promoting the excretion of fecal lipids and regulating the activities of 3-hydroxy-3-methyl glutaryl-coenzyme A (HMG-CoA) reductase and cholesterol 7-a hydroxylase (CYP7A1) in hypercholesterolemic hamsters (Tong et al., 2015). Rats fed with oat-based diets showed significantly higher levels of acetate and butyrate in the colon content (Hu, Xing, & Zhen, 2013). Importantly, acetate and butyrate have been suggested to inhibit cholesterol synthesis, which may contribute to the cholesterol-lowering effect of oat bran in humans and animals (Hara, Haga, Aoyama, & Kiriyama, 1999). The positive action of β-glucan is likely to involve complex processes and interactions with the food matrix. The biological activities are not only affected by the intrinsic functionality of the β-glucan (or other components), but also the physical form in which it is delivered for digestion (Grundy et al., 2017). Further research is needed to establish how supplemental β-glucans produce beneficial effects for the development of atherosclerosis in humans.

4.4. Regulating postprandial blood glucose and insulin levels for diabetes Cereal β-glucans have received much attention because they can regulate postprandial blood glucose and insulin levels, which is beneficial for diabetes prevention. A study has shown that even low levels of oat β-glucan significantly decreased both glycaemia and insulin (Ekström, Henningsson Bok, Sjöö, & Östman, 2017). After a metaanalysis of randomized controlled trials, the beneficial effect of βglucan from barley on postprandial glycaemia in the healthy human population was observed (AbuMweis, Thandapilly, Storsley, & Ames, 2016). Although one study has indicated the relationship between the decrease in plasma glucose and the dose of cereal β-glucans (Cavallero, Empilli, Brighenti, & Stanca, 2002), much evidence has shown that the viscosity of β-glucans should be the primary factor responsible for lowering glycemic, insulinemic, and LDL-cholesterol levels (Gamel, 61

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mucosa, stimulating water and mucous secretion in the large intestine. Secondly, gel-forming soluble fiber (such as psyllium) has a high waterholding capacity that resists dehydration. Both the above mechanisms require fiber to resist fermentation and remain relatively intact throughout the large intestine (meaning that fiber must be present in the stool). Besides, both mechanisms lead to increased stool water content, resulting in bulky, soft, and easily passed stools (McRorie & McKeown, 2017).

4.6. Lowering fat for obesity Obesity has been suggested to be related to the high intake of fat and low intake of fiber. β-Glucans from plants, as a dietary fiber, play an important role in preventing high-fat-diet-induced obesity and serum biochemical indicators associated with obesity, fatty liver, and adipocyte size (Hu et al., 2015). The intake of high β-glucan barley has been shown to lead to significant and safe reductions in visceral fat obesity (Aoe et al., 2017). Interaction mechanisms reported for dietary fiber in preventing obesity mainly include: (i) Dietary fiber decreasing the energy intake and increasing the viscosity of intestinal content, which delays the gastric emptying rate and causes extended satiety after meals (Drzikova, Dongowski, Gebhardt, & Habel, 2005); (ii) dietary fiber affecting microflora and subsequent products in the colon, as increasing acetate and butyrate contents through fermentation play a direct role in suppressing central appetite and obesity (Frost et al., 2014; Lin et al., 2012); and (iii) dietary fiber increasing short-chain fatty acids (SCFAs) in the large intestine, which might promote the release of the anorectic gut hormones PYY and GLP-1, leading to reduced food intake (Lin et al., 2012). Some studies have shown a relationship between gene regulation and fat decrease. Over 300 genes have been shown to reduce body fat when inactivated, while inactivation of more than 100 genes has been shown to increase fat storage (Ashrafi et al., 2003). For example, Prowashonupana barley riched in β-glucan reduced intestinal fat deposition (IFD) in a C. elegans model system, which appeared to be primarily mediated by sir-2.1, daf-16, and daf-16/daf-2 (Gao et al., 2015).

4.9. Antioxidant and antibacterial activities Low-MW oat β-glucan has been shown to transfer hydrogen from molecules that can act as free radical quenchers under physiological conditions. This property can be associated with the suppression of oxidative stress in the spleen, especially for rats with induced gut inflammation (Błaszczyk et al., 2015). Similarly, (1 → 3,1 → 6)-β-Dglucan produced by Botryosphaeria rhodina exerts antioxidant scavenging activities, with the precise mechanism thought to be related to the activity of anomeric hydrogen in molecules that can act as free-radical quenchers (Giese et al., 2015). Antibacterial and antiviral effects of β-glucans are achieved by simulating the immune system. For example, the antibacterial effect of βglucans from Coriolus versicolor (CVP) is probably caused by the activation of innate immune cells, especially macrophages. Macrophages activated by CVP can phagocytize and kill bacteria, probably due to the production of NO and iNOS (Shi et al., 2016). 4.10. Other functionalities and mechanisms

4.7. Reducing blood pressure In addition to the activities discussed above, β-glucans can also promote health in other important ways, such as liver protection, radioprotection, and improving cognitive impairment. β-Glucan can attenuate scopolamine-induced cognitive impairment by enhancing the central cholinergic tone via inhibition of the acetylcholinesterase (AChE) enzyme, and can be considered as an economic therapeutic option for cognitive ailments associated with a decline in cholinergic neurotransmission (Haider, Inam, Khan, HifzaMahmood, & Abbas, 2016). Cytoprotective and genoprotective effects of β-glucans against aflatoxin B1-induced DNA damage in broiler chicken lymphocytes have been reported (Zimmermann et al., 2015). Slamenová (2003) also reported the protective effect of β-glucan against oxidative DNA lesions in V79 hamster lung cells. Furthermore, the in vivo efficacy showed that the inclusion of soluble β-(1 → 3) (1 → 6)-glucan in Carbopol increased epithelialization and wound contraction in db/db mice (Grip, Engstad, Skjaeveland, Skalko-Basnet, & Holsaeter, 2017). Daily oral β-(1 → 3) (1 → 6)-glucan may protect against upper respiratory tract infections (URTIs) and reduce the duration of URTI symptoms in older individuals once infected (Fuller et al., 2017). An in vivo test showed that a watersoluble glucan (GLSWA-I) could significantly promote dinitrochlorobenzene (DNCB)-induced delayed-type ear swelling in mice (Wang et al., 2017). Water-insoluble β-D-glucans isolated from aqueous and alkaline extracts of mushroom-forming ascomycete Cookeina tricholoma with similar MWs showed that only (1 → 6)-linked β-D-glucopyranose side chains (ICW-Ct and IHW-Ct) significantly inhibited neurogenic pain (Moreno et al., 2016).

β-Glucans have been shown to possess blood pressure lowering effects in some studies. The action mechanism of β-glucans proposed for lowering the blood pressure is supposedly strongly related to its viscosity properties. There are multiple possible reasons for the observed reduction. Firstly, the intake of β-glucans prompts weight to decrease due to their viscosity effect, which is suggested to be associated with a decrease in blood pressure (Charlton et al., 2012; Chutkan, Fahey, Wright, & McRorie, 2012; Khan et al., 2018). Secondly, insulin resistance, an important indicator of hypertension (Montero, 2013), has been demonstrated to be related to the viscosity of β-glucans (Wong & Jenkins, 2007). Thirdly, the intake of highly viscous fiber can affect renal sodium reabsorption and transmembrane ion transport, which undoubtedly lowers the blood pressure (Schulman & Zhou, 2009; Zhou, Schulman, & Raij, 2010). Therefore, there might be close links among blood glucose, insulin level, serum cholesterol level, blood pressure, and body fat. These various reactions in humans are closely related, with even a small change in any factor perhaps affecting all others. The viscosity of βglucans, acetate and butyrate by fermentation, and gut peptides have been suggested to play vital and all-purpose roles in all stated changes listed above. 4.8. Improving prominent human gut flora and laxative effect The degradation of β-glucans in the human gut depends on the resident microbiota. Microbial utilization of complex polysaccharides is a major driving force in shaping the composition of human gut microbiota. Molecular insight into human gut metagenomes shows that syntenic mixed-linkage β-(1 → 3)/β-(1 → 4)-glucan utilization locus (MLGUL) serves as a genetic marker for MLG catabolism across commensal gut bacteria (Tamura et al., 2017). The acceleration of intestinal peristalsis by gut microorganisms is usually regarded as an important mechanism of the laxative effect. Furthermore, the mechanisms driving the laxative effect have been reported to manifest in two other ways. Firstly, large/coarse insoluble fiber particles (such as wheat bran) mechanically irritate the gut

5. Conclusion and perspective FMI survey data showed that the global β-glucans market was valued at 307.8 million dollars in 2016. Markets and Markets predicted that, in 2022, the global β-glucans market would be up to 476.5 million dollars, which indicates the enormous development potential in application of β-glucans. In this review, we summarized the physiological functionalities of normal β-glucans and modified β-glucans. The underlying mechanisms in activities of β-glucans were also discussed, with the aim to enhance understanding of how β-glucans can be better 62

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applied clinically, safely and effectively. A variety of biological activities of β-glucans have been presented, but potential action mechanisms have not been clarified, because some proposed mechanisms are still based on assumptions. Future research should be focused on exploring the deep interaction mechanisms between β-glucans and different subjects, and links among different mechanisms. This would be beneficial for understanding changes caused by β-glucans in humans and animals. This would be also helpful for development and application of β-glucans from different sources. In food and medicine manufacture, the impact of single component often tends to be limited. Therefore, the exploitation of products showing synergistic effects with β-glucans should also receive attention.

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