8 J Nutr Sci Vitaminol, 64, 8–17, 2018 Review b-Glucan in Foods and Its Physiological Functions Ayaka NAKASHIMA, Koji Y AMADA, Osamu IWATA, Ryota SUGIMOTO, Kohei ATSUJI, Taro OGAWA, Naoko ISHIBASHI-OHGO and Kengo SUZUKI* euglena Co., Ltd., Tokyo 108–0014, Japan (Received August 14, 2017) Summary b-Glucans are a class of polysaccharides consisting of D-glucose units that are polymerized primarily via the b-1,3 glycosidic bonds, in addition to the b-1,4 and/or b-1,6 bonds. They are present in various food products such as cereals, mushrooms, and seaweeds and are known for their numerous effects on the human body, depending on their struc- tures, which are diverse. The major physicochemical properties of b-glucans include their antioxidant property, which is responsible for the scavenging of reactive oxygen species, and their role as dietary fiber for preventing the absorption of cholesterol, for promoting eges- tion, and for producing short-chain fatty acids in the intestine. Dietary b-glucans also exert immunostimulatory and antitumor effects by activation of cells of the mucosal immune system via b-glucan receptors, such as dectin-1. In this review, we elaborate upon the diver- sity of the structures and functions of b-glucans present in food, along with discussing their proposed mechanisms of action. In addition to the traditional b-glucan–containing foods, recent progress in the commercial mass cultivation and supply of an algal species, Euglena gracilis, as a food material is briefly described. Mass production has enabled consumption of paramylon, a Euglena-specific novel b-glucan source. The biological effects of paramylon are discussed and compared with those of other b-glucans. Key Words b-glucan, food material, paramylon, food functionality b-Glucans as Food Constituents b-Glucan is a nonstarch polysaccharide that con- sists of D-glucose units linked via b glycosidic bonds. Typically, b-glucans do not include cellulose, which is formed only by b-1,4 glycosidic bonds. So-called b-glu- can is a polysaccharide formed mainly via b-1,3 glyco- sidic bonds, with varying numbers of b-1,4 and b-1,6 glycosidic bonds. The cell walls and aleurone layers of various organisms are made of these b-glucans. There- fore, human beings unintentionally consume b-glucans through their regular diet. The primary sources of dietary b-glucan for humans are cereal grains (espe- cially oats and barley), mushrooms, seaweeds, and yeast. The functions of b-glucan have been recognized for more than half a century. In pioneering studies, zymo- san, which was prepared from yeast cell walls, has been found to contain a high percentage of b-glucan (1) and has been reported to cause nonspecific activation of the immune system (2). On the basis of the accumulated knowledge related to b-glucan functions, lentinan and sonifilan prepared from mushrooms have been used as b-glucan-based medicines for their immunostimulatory effects (3, 4). Although the b-glucan–based medicines are administered via injections, oral administration of some b-glucans has been reported and has similar immunostimulatory effects. In addition, the dietary b-glucans present in cereals (such as oats and barley) have been demonstrated to reduce the level of serum cholesterol and to act as major dietary fiber prevent- ing obesity and metabolic disorders (5, 6). The reported functions of dietary b-glucan have encouraged the con- sumption of b-glucan–rich foods and the development of several functional foods that contain b-glucans. Types of b-Glucans b-Glucans extracted from different organisms pos- sess characteristic sizes; numbers of b-1,3, b-1,6, and b-1,4 glycosidic bonds; and b-1,6 branching patterns (Fig. 1, Table 1). Nonetheless, the size of a b-glucan also depends on the method of extraction and purifica- tion. The b-glucans present in cereals (such as oats and barley) include a mixture of b-1,3 and b-1,4 glycosidic bonds and show no b-1,6 branching (6, 7). On the other hand, the b-glucans present in other organisms contain fewer b-1,4 glycosidic bonds. The b-glucans present in edible mushrooms [such as Lentinus edodes (shiitake mushroom), Grifola frondosa (maitake mush- room), and Schizophyllum commune (suehirotake mush- room)] consist of a linear b-1,3-glucan backbone with a single b-1,6-linked glucose unit present on two resi- dues up to every third residue of the backbone (8–11). In contrast, the b-glucan in zymosan, which is extracted from the cell wall of Saccharomyces cerevisiae, is a large molecule consisting of a linear b-1,3-glucan backbone with a 30-residue linear side chain (held together by b-1,3 glycosidic bonds) attached to the main chain via a b-1,6 glycosidic bond (12). The b-glucans present in * To whom correspondence should be addressed. E-mail: [email protected]
Transcript
8
J Nutr Sci Vitaminol, 64, 8–17, 2018
Review
b-Glucan in Foods and Its Physiological Functions
Ayaka Nakashima, Koji Yamada, Osamu Iwata, Ryota Sugimoto, Kohei Atsuji, Taro Ogawa, Naoko Ishibashi-Ohgo and Kengo Suzuki*
euglena Co., Ltd., Tokyo 108–0014, Japan
(Received August 14, 2017)
Summary b-Glucans are a class of polysaccharides consisting of d-glucose units that are polymerized primarily via the b-1,3 glycosidic bonds, in addition to the b-1,4 and/or b-1,6 bonds. They are present in various food products such as cereals, mushrooms, and seaweeds and are known for their numerous effects on the human body, depending on their struc-tures, which are diverse. The major physicochemical properties of b-glucans include their antioxidant property, which is responsible for the scavenging of reactive oxygen species, and their role as dietary fiber for preventing the absorption of cholesterol, for promoting eges-tion, and for producing short-chain fatty acids in the intestine. Dietary b-glucans also exert immunostimulatory and antitumor effects by activation of cells of the mucosal immune system via b-glucan receptors, such as dectin-1. In this review, we elaborate upon the diver-sity of the structures and functions of b-glucans present in food, along with discussing their proposed mechanisms of action. In addition to the traditional b-glucan–containing foods, recent progress in the commercial mass cultivation and supply of an algal species, Euglena gracilis, as a food material is briefly described. Mass production has enabled consumption of paramylon, a Euglena-specific novel b-glucan source. The biological effects of paramylon are discussed and compared with those of other b-glucans.Key Words b-glucan, food material, paramylon, food functionality
b-Glucans as Food Constituentsb-Glucan is a nonstarch polysaccharide that con-
sists of d-glucose units linked via b glycosidic bonds. Typically, b-glucans do not include cellulose, which is formed only by b-1,4 glycosidic bonds. So-called b-glu-can is a polysaccharide formed mainly via b-1,3 glyco-sidic bonds, with varying numbers of b-1,4 and b-1,6 glycosidic bonds. The cell walls and aleurone layers of various organisms are made of these b-glucans. There-fore, human beings unintentionally consume b-glucans through their regular diet. The primary sources of dietary b-glucan for humans are cereal grains (espe-cially oats and barley), mushrooms, seaweeds, and yeast.
The functions of b-glucan have been recognized for more than half a century. In pioneering studies, zymo-san, which was prepared from yeast cell walls, has been found to contain a high percentage of b-glucan (1) and has been reported to cause nonspecific activation of the immune system (2). On the basis of the accumulated knowledge related to b-glucan functions, lentinan and sonifilan prepared from mushrooms have been used as b-glucan-based medicines for their immunostimulatory effects (3, 4). Although the b-glucan–based medicines are administered via injections, oral administration of some b-glucans has been reported and has similar immunostimulatory effects. In addition, the dietary b-glucans present in cereals (such as oats and barley)
have been demonstrated to reduce the level of serum cholesterol and to act as major dietary fiber prevent-ing obesity and metabolic disorders (5, 6). The reported functions of dietary b-glucan have encouraged the con-sumption of b-glucan–rich foods and the development of several functional foods that contain b-glucans.
Types of b-Glucansb-Glucans extracted from different organisms pos-
sess characteristic sizes; numbers of b-1,3, b-1,6, and b-1,4 glycosidic bonds; and b-1,6 branching patterns (Fig. 1, Table 1). Nonetheless, the size of a b-glucan also depends on the method of extraction and purifica-tion. The b-glucans present in cereals (such as oats and barley) include a mixture of b-1,3 and b-1,4 glycosidic bonds and show no b-1,6 branching (6, 7). On the other hand, the b-glucans present in other organisms contain fewer b-1,4 glycosidic bonds. The b-glucans present in edible mushrooms [such as Lentinus edodes (shiitake mushroom), Grifola frondosa (maitake mush-room), and Schizophyllum commune (suehirotake mush-room)] consist of a linear b-1,3-glucan backbone with a single b-1,6-linked glucose unit present on two resi-dues up to every third residue of the backbone (8–11). In contrast, the b-glucan in zymosan, which is extracted from the cell wall of Saccharomyces cerevisiae, is a large molecule consisting of a linear b-1,3-glucan backbone with a 30-residue linear side chain (held together by b-1,3 glycosidic bonds) attached to the main chain via a b-1,6 glycosidic bond (12). The b-glucans present in
* To whom correspondence should be addressed.E-mail: [email protected]
b-Glucan-Containing Foods 9
Fig.
1.
Rep
rese
nta
tive
stru
ctu
res
of b
-glu
can
s ex
trac
ted
from
cer
eals
, mu
shro
oms,
yea
st, s
eaw
eeds
, bac
teri
a, a
nd
Eug
lena
. (A
) A c
erea
l b-g
luca
n c
onsi
stin
g of
con
secu
tive
b-1
,3 a
nd
b-1
,4
glyc
osid
ic b
onds
wit
hou
t b
-1,6
bra
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ing.
(B
) A
mu
shro
om b
-glu
can
con
sist
ing
of a
lin
ear
b-1
,3-g
luca
n c
hai
n w
ith
sin
gle
b-1
,6-l
inke
d gl
uco
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nit
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tach
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o th
e ba
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(C
) A
ye
ast b
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ext
ract
ed a
s a
larg
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olec
ule
sh
owin
g a
hig
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bra
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ed s
tru
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re. I
t con
tain
s on
ly b
-1,6
gly
cosi
dic
bon
ds in
the
b-1
,3-g
luca
n c
hai
n. (
D) A
sea
wee
d b
-glu
can
com
pose
d of
b-1
,3-g
luca
n c
hai
ns
wit
h b
-1,6
bra
nch
ing.
Som
e se
awee
d b
-glu
can
s ar
e ch
arac
teri
zed
by th
e pr
esen
ce o
f m
ann
itol
at t
he
end
of th
e b
-1,3
-ch
ain
. (E)
Bac
teri
al a
nd
Eug
lena
’s b
-glu
can
s co
nsi
stin
g of
lin
ear
b-1
,3-g
luca
n c
hai
ns
wit
hou
t bra
nch
ing.
Nakashima A et al.10
seaweeds such as Laminaria digitate, Saccharina longi-cruris, and Durvillaea antarctica are reported to consist of a b-1,3-glucan backbone too, with a small percent-age of b-1,6 glycosidic bonds in the backbone, and b-1,6-glucan side chain branching (13–15). The b-glu-cans extracted from seaweeds are relatively smaller in size compared to the b-glucans of other organisms and include a monosaccharide other than glucose (like man-nitol) at the end of the chain.
Among various b-glucans, including those men-tioned above, the b-glucan with the simplest structure is the linear and unbranched b-1,3-glucan curdlan, which is extracted from the bacterium Agrobacterium biobar (16). Although the organisms containing cur-dlan are not edible, purified curdlan serves as a thick-ening agent for food products. Nonetheless, the recent commercialization of Euglena gracilis production has provided an alternate source of linear and unbranched
Fig. 2. Microscopic images of (A) Euglena gracilis cells and (B) paramylon granules. Scale bars represent the size indicated in the figures.
Table 1. A summary of physicochemical properties of representative b-glucans present in food products.
Category General name SpeciesName of the
glucanGlycosidic bond(s)
Example of size
Solubility Reference
Higher plant Oats Avena sativa —b-1,3 and b-1,4 glyco-
sidic bonds without branching
1.6 MDa, 1.1 MDa
Soluble 7)
Higher plant BarleyHordeum
vulgare— 49 MDa Soluble 6)
MushroomMaitake mushroom
Grifola frondosa Grifolan
b-1,3 bonds present in the main chain with b-1,6-linked single glucose units
1 Size of b-glucan in the MT-2 fraction.2 Estimated by the polymerization degree of glucose.
b-Glucan-Containing Foods 11
b-1,3-glucan. Euglena, which is a genus comprising photosynthetic flagellates living in fresh and brackish water, is known to accumulate b-1,3-glucan in its body as a carbohydrate source (Fig. 2). Paramylon, i.e., crys-tallized b-glucan from Euglena, has characteristic fea-tures such as the presence of unbranched b-1,3-glucan (17, 18), highly crystalline structure with a triple-helix conformation (19, 20), and unique saccharide compo-sition (exclusively consisting of glucose) (21). Owing to its crystalline structure, paramylon typically exists in the form of insoluble granules that are 2–3 mm in size. The granules can be easily obtained by centrifugation from cells disrupted by sonication and subsequently can be purified by denaturing the proteins with a suitable detergent (22). These features differentiate paramylon from other b-glucans in that systematic analysis of its functions is possible.
The types and strength of physiological functions of b-glucans depend on their structure, such as composi-tion of the glucan backbone, types and frequency of side chains, size of the molecule, solubility, and three-dimensional conformation. b-Glucans show viscosity in an aqueous solution and thus function as dietary fiber by adsorbing unnecessary materials in the gut and helping to egest them (23). They also scavenge reactive oxygen species (ROS) in the gut, thereby exerting an antioxidant activity (24). These activities are common for all b-glucans although they vary depending on the physicochemical properties of each b-glucan species. In addition, the structure of the b-1,3-glucan backbone and b-1,6 branching at appropriate sites enhance the immunostimulatory effect of b-glucans by promoting their interaction with specific receptors (25, 26).
Dectin-1, a C-type lectinlike pattern recognition receptor present on the surface of leukocytes, is known
as the primary receptor for b-glucans (27). The triple-helix structure formed by the b-1,3-glucan backbone is specifically recognized by dectin-1. Additionally, the branches located on the surface of the helix further mod-ulate this recognition (28, 29). An assay of the binding of recombinant dectin-1 to various b-glucans indicates a wide range of binding affinity (IC50, half maximal inhibitory concentration, as 2.6 mm to 2.2 pm), depend-ing on the size and branching patterns of b-glucans (30). The interaction of dectin-1 with cereal b-glucan, which includes both b-1,3 and b-1,4 glycosidic bonds, has been confirmed; however, the binding affinity is weaker than that for b-1,3-glucan (31). Another impor-tant b-glucan receptor is complement receptor 3 (CR3), which is a heterodimeric transmembrane glycoprotein found on leukocytes (32). CR3 is known for respond-ing to small soluble b-glucan molecules although it is also activated by insoluble b-glucan to some extent (33, 34). In addition, b-glucans are reported to interact with such receptors as langerin (35), lactosylceramide (36), and L-ficolin (37), thereby regulating their respective downstream signaling pathways (25). The receptor-mediated effects of b-glucans are well characterized for the b-glucan extracts of mushrooms and yeast that serve as medicines. The b-glucan present in mushrooms has considerable receptor-mediated effects. b-Glucans extracted from other organisms exert the same effects probably to a lesser extent (5, 6, 38). The differences in these receptor-mediated functions of b-glucans seem to depend on their intestinal uptake efficiency and affinity for their receptor(s).
Functions of Dietary b-GlucansFor understanding the correlation between b-glucan
structure and function, the biological effects of dietary
Fig. 3. Schematic representation of the mechanisms of recognition of pathogens and b-glucans in the gut. Both b-glucan particles and pathogens have b-glucan residues on their surface. Both presumably pass through the epithelial lumen by active transport mediated by M cells in Peyer’s patches; however, some soluble b-glucans may also be absorbed like other nutrients. b-Glucans act on receptors expressed on leukocytes, such as macrophages and dendritic cells.
Nakashima A et al.12
b-glucans have been evaluated after their purification. The differences in the b-glucan preparation proce-dures under specific experimental conditions result in observation of a limited range of effects. Thus, the real potential of foods containing b-glucans is not necessar-ily restricted to the reported effects. In addition, owing to the difficulties with preparing highly pure and stan-dardized b-glucans, careful evaluation excluding the effects of contaminants is required for elucidation of the true effects of dietary b-glucans. Various effects on the human body after consumption of dietary b-glucans have been reported, including a reduction in the cho-lesterol level, prevention of diabetes, regulation of the gut microflora, antioxidant activities, antitumor effects, and immunostimulation. Some important effects are discussed below.a) Immunostimulation
The immune system is a framework for defending the body against bacterial and viral infections (and other invaders). The age-related reduction in immunological function is referred to as immunosenescence, which results in the increased susceptibility to infections in the elderly. One of the primary causes of immunosenes-cence is the age-related decline of T-cell function and involution of the thymus (39, 40). Ingestion of b-glucan exerts a stimulatory effect on immune homeostasis via the b-glucan receptor present in the mucosal immune system and contributes to the prevention of age-related diseases (41). This effect has been reported for almost all b-glucan–containing foods although the effect size may vary (5, 33, 38, 42).
The immunostimulatory effect of b-glucans is medi-ated by innate immunity intended for the defense against pathogens (43). Upon ingestion, b-glucans affect the mucosal immune system in the gastrointes-tinal tract (Fig. 3). The uptake of microorganisms from the intestinal lumen is undertaken by the M cells of Pey-er’s patches in the small intestine. Subsequently, these cells present the antigen (or the microorganism itself) at their basal surfaces to immune cells such as macro-phages and dendritic cells (44). To identify the patho-gens, the receptors specific for pathogens’ cell wall are enriched on the surface of immune cells. Several pattern recognition receptors target b-glucans that are present in the cell wall of microorganisms. In addition to act-ing as a stimulatory signal on cell surface receptors, the microorganisms that pass through the intestinal lumen are phagocytosed by macrophages and have additional immunostimulatory effects. Microparticles that include insoluble b-glucan and range in size from 1 to 2 mm show strong immunostimulatory effects (45), probably because of being recognized as pathogens. Although it is not clear how b-glucans pass through the epithelial cell lining, some epithelial cells such as M cells may actively absorb b-glucans (like other antigens). The difference in the immunostimulatory effects of insoluble and soluble b-glucans suggests that they act via different molecular mechanisms (33). Moreover, purified b-glucans, such as lentinan, which are generally administered via injec-tion, have a considerably smaller immunostimulatory
effect after oral administration (46), thereby indicating that b-glucans also act differently depending on their route of administration.
Dectin-1, which is expressed on the surface of mac-rophages and dendritic cells, is reported to serve as the primary receptor for b-glucans, which consequently have immunostimulatory effects (27). Depending on the recognition of b-glucan by dectin-1, those cells phago-cytize particles displaying b-glucan on their surface as well as the pathogens that include b-glucan in their cell wall (47). In parallel with the phagocytosis, dectin-1 induces secretion of proinflammatory cytokines (48, 49) via the activation of tyrosine kinase Syk and a tran-scription factor, nuclear factor kB, which is responsible for multiple immune reactions (33). Insoluble b-glucan preferentially binds to dectin-1, whereas water-soluble b-glucans bind to another receptor, CR3, and thus trig-ger an immune reaction (33). Meanwhile, micronized and water-soluble b-glucans are probably also absorbed by the small intestine following ingestion, reach as far as the circulatory system, and increase the expression levels of dectin-1 and a Toll-like receptor 2 (TLR2), which together with dectin-1 recognizes b-glucan in gut-associated lymphoid tissue (50). Thus, it seems that b-glucans are absorbed in the body and act in different ways to elicit an immune reaction depending on their structure.b) Immune regulation of the T helper 1 (Th1)/Th2 balance
The importance of balanced immune homeostasis has been recognized in recent years because excessive immune responses can lead to autoimmune diseases or allergies (51). One example of immune homeostasis is the balance between Th1 cells of cell-mediated immu-nity and Th2 cells of humoral immunity (52). The Th1- and Th2-mediated immune reactions suppress each other for immunological homeostasis. Atopic dermatitis represents an example of allergic reactions caused by an imbalance between Th1 and Th2 cells. An alteration of the immunological equilibrium in the Th2 direction is responsible for the symptoms of atopic dermatitis and other allergies (53). Meanwhile, excessive activation of the immune system mediated by Th1 cells together with that of Th17 cells causes autoimmune diseases, such as rheumatoid arthritis (54). Ingestion of b-glucans primarily activates Th1 and Th17 cells (55), thereby resulting in the suppression of activity of Th2 cells. This phenomenon shifts the Th1/Th2 response equilibrium in the Th1 direction and alleviates the symptoms of allergic diseases (56). This action is basically triggered by the immunostimulatory effect of b-glucans, sug-gesting that all b-glucan–containing foods possessing immunostimulatory effects also have this activity.c) Cholesterol-lowering property
The cholesterol-lowering property of the dietary b-glucan of cereals, such as oats and barley, has been known for several decades and has been verified clini-cally by prescription of dietary b-glucan to patients with high levels of serum cholesterol (5, 6). The lowering of cholesterol levels does not affect high-density lipopro-tein (HDL) cholesterol; however, it affects low-density
b-Glucan-Containing Foods 13
lipoprotein (LDL) cholesterol, which is an important marker of the risk of cardiovascular diseases (57, 58). This means that consumption of dietary b-glucans pres-ent in cereals lowers the risk of cardiovascular diseases. For example, consumption of bread formulated with oat b-glucan significantly lowers LDL-cholesterol lev-els (59). Because the cholesterol-lowering property has only been reported for the b-glucans derived from cere-als, the effects of other b-glucan-containing foods on cholesterol levels are uncertain at present.
The reduction in cholesterol levels by b-glucan is primarily due to its ability to act as dietary fiber and to entrap the bile acid micelles containing fats. This activ-ity disrupts the interaction of the micelles with lumi-nal membrane transporters present on the intestinal epithelium, thereby increasing the fecal output of fat, bile acids, and cholesterol (23). Next, to compensate for the decrease in the bile acid level, the expression of 7a-hydroxylase (an enzyme involved in the synthesis of bile acids) is upregulated (60, 61). Accordingly, the hepatic cholesterol level also decreases and is restored by LDL-cholesterol from serum. In addition, the delayed absorption effect due to the high viscosity of b-glucans from cereals may lower postprandial glucose levels and prevent diabetes (62).d) Fermentation effects of b-glucan in the colon
Soluble b-glucans, especially those present in cere-als, are fermented by the microorganisms residing in the colon and are converted to short-chain fatty acids (SCFAs) such as acetic acid, propionic acid, and butyric acid (63). The SCFAs produced in the colon have various effects, such as immunomodulation (64), mediation of apoptosis of colon cancer cells (65), and prevention of obesity (66). As an example, the prevention of obesity is accomplished by regulation of energy metabolism and prevention of excess lipid accumulation in adipose tis-sue via SCFA receptor GPR43 (66). Besides, SCFAs sup-press the growth of harmful bacteria such as Clostrid-ium spp. and pathogenic coliforms and thereby maintain a healthy gut microflora (67).e) Antioxidant activity
Cereals are known to exert antioxidant activities by scavenging ROS. In particular, the ROS-scavenging abil-ity of oats and barley mainly derives from their abun-dant b-glucans, which are known to scavenge ROS as effectively as other polysaccharides do (5, 6). The b-glu-can extracted from barley shows a significantly higher antioxidant activity as compared to b-glucan from oats and black yeast, indicating that the structure and com-position of b-glucans also influence their antioxidant activity (24). Meanwhile, the ROS-scavenging activity of b-glucan–containing foods other than cereals may be low because they include lesser amounts of b-glu-can, and its abundance is important for this action. The antioxidant effects of ingested cereal b-glucan possibly prevent the damage to the gut that is caused by ROS generated there. In addition to the reports on the physi-cal ability of b-glucan to scavenge ROS, several stud-ies on rats as a model organism have revealed that the antioxidant activity of orally administered b-glucan is
also directed against oxidative stress induced even in the internal organs such as kidneys and the liver (68, 69). These reports imply that b-glucan also exerts the anti-oxidant effect by either of the following mechanisms: b-glucan incorporated into the circulatory system scavenges ROS there, or b-glucan stimulates the innate antioxidant system via specific receptors in the mucosal immune system and the subsequent cytokine release.f) Antitumor activity
The medicinally important b-glucans—lentinan, gri-folan, and schizophyllan glucan (SPG), which are puri-fied from shiitake mushrooms, maitake mushrooms, and Schizophyllum, respectively—are used as antitu-mor drugs (3, 4). The antitumor effects are attained via intravenous administration (70). Nevertheless, oral administration of the recently developed superfine dis-persed lentinan has shown significant effects on hepa-tocellular and pancreatic cancers (71, 72). This finding suggests that eating mushroom fruiting bodies itself may have potential antitumor effects. The antitumor activity of b-glucans via the b-glucan receptors is pri-marily mediated by an increase in the tumor immunity, which enhances the killing of iC3b-opsonized tumor cells (33). Consistent with this observation, the antitu-mor activities of other b-glucans, which are known for their immunostimulatory effects, have been reported as well (5, 33, 73). In addition to their effect on tumor immunity, the antitumor activity against colon cancer may be attributed to other factors such as induction of egestion of a carcinogen in the gut, regulation of the gut microflora, and scavenging of ROS, as mentioned in subsections (c), (d), and (e), respectively.
Paramylon as a Functional Ingredient of FoodDue to the establishment of commercial mass cultiva-
tion of E. gracilis in 2005, a reliable and economically feasible supply of purified paramylon and the algal pow-der containing large amounts of paramylon is now pos-sible (74). Because paramylon has a crystalline struc-ture composed of b-1,3-glucan chains, it presumably has effects on the human body that are similar to those of other b-glucans. Thus, it can serve as a substitute or supplement for b-glucan–based applications. To evalu-ate the effects of ingestion of paramylon compared to that of other b-glucans, a series of experiments have been conducted.
To determine whether paramylon has an antioxidant activity, its effects on oxidative liver damage induced by carbon tetrachloride have been examined in rats (75). It was observed that the carbon tetrachloride–induced damage is suppressed after 3 d of oral preadministra-tion of paramylon, indicating that paramylon has an antioxidant activity. The effects of oral administration of paramylon on oxidative liver damage suggest that it also possibly prevents oxidation-induced damage to other organs by a mechanism similar to that of other b-glucans (68, 69).
The dectin-1–mediated immunostimulatory effect of paramylon in animal disease models has been reported too. For example, oral administration of paramylon to
Nakashima A et al.14
the rainbow trout has been found to be effective against the enteric redmouth infection, a bacterial disease of salmonid fishes (76). In addition, paramylon enhances antibody responses in mice against sheep red blood cells by inducing the production of cytokines IL-1 and IL-6, which were primarily released by macrophages (77). A similar beneficial effect of paramylon has been demonstrated in a mouse model of atopic dermatitis (78). In contrast to the immunomodulatory effect of the shiitake mushroom-derived b-glucan lentinan via shifting the Th1/Th2 response equilibrium toward the Th1 response (79), paramylon suppresses both Th1 and Th2 cell responses in a mouse model of atopic derma-titis (78). This finding suggests that paramylon has an additional function as compared to the other b-glucans. The structural differences between paramylon and the other b-glucans may be responsible for varying levels of receptor activation and specificity. Given that oral administration of paramylon also exerts an immuno-stimulatory effect in healthy human subjects (80), it is capable of adequately regulating immune responses.
The antitumor activity of paramylon has been evalu-ated by testing the suppression of colon cancer aberrant crypt foci (ACF; precancerous lesions that form before colon polyps and are detected at the earliest stage of colon cancer) in mice. After paramylon treatment, ACF formation mediated by administration of the chemi-cal carcinogen 1,2-dimethylhydrazine is suppressed by 59% (81), indicating that paramylon exerts an antitu-mor activity. Just like dietary b-glucans present in cere-als, paramylon has an anti-ACF preventive effect that is potentially mediated by a combination of tumor immu-nity enhancement, antioxidation, and egestion activities (5, 6). Due to the unique crystalline structure of par-amylon granules purified from E. gracilis, they cannot be hydrolyzed by any b-1,3-glucanases (82). This char-acteristic feature differentiates paramylon from other b-glucans. In the absence of intestinal fermentation of paramylon, it is expected to have long-lasting effects. Furthermore, the hydrolysis resistance of paramylon may be partly responsible for its effects on the intes-tine as a dietary fiber. This phenomenon increases the fecal weight and shortens the intestinal residence time for contents of the digestive tract (83). Additionally, it adsorbs harmful carcinogens and promotes their excre-tion (81), thereby possibly preventing colon cancer.
The effects of paramylon are similar to those of other dietary b-glucans. This observation suggests that par-amylon also functions by being transported across the epithelial cells, is recognized by macrophages via recep-tor dectin-1, and induces a Th1 cell response. The size of a paramylon molecule is typically 2–3 mm (Fig. 2B), which is similar to the size of pathogenic bacteria. This observation suggests that paramylon is potentially transported across the epithelial cells via the same mechanism as that for pathogenic bacteria. The crys-talline structure of paramylon consists of triple helices (19, 20), which are recognized by b-glucan receptor dectin-1, implying that paramylon presumably activates dectin-1. In agreement with the above data, paramylon
directly binds to recombinant dectin-1 (84) and upregu-lates proinflammatory factors such as NO, TNF-a, IL-6, and COX-2 (80). Although studies have suggested that the number and size of b-1,6 branches on the b-1,3 backbone are important for the function of b-glucan (25, 26), paramylon, despite limited branching, shows functional diversity. This phenomenon indicates that paramylon derived from Euglena may serve as a useful food ingredient to provide benefits similar to those of other dietary b-glucans.
ConclusionThe physiological functions of dietary b-glucan can
be subdivided into two groups depending on whether specific receptors are involved or not. Functions that do not depend on specific receptors include the ROS-scav-enging activity (antioxidant activity) resulting from the physicochemical properties of b-glucan and the ability to lower the level of serum cholesterol and to improve the intestinal bacterial flora as dietary fiber. Such func-tions are reported mainly for cereal b-glucans. Mean-while, specific receptors such as dectin-1 and CR-3 are involved in immunoregulatory functions and the anti-tumor activity, which are well known for mushroom b-glucans. In addition, relatively strong immunomod-ulatory and antitumor effects have been reported for Euglena paramylon, which was recently validated as a functional food ingredient.
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