Radioprotective effects and mechanisms of animal, plant and microbial polysaccharides

Journal Pre-proof Radioprotective effects and mechanisms of animal, plant and microbial polysaccharides

Wenjie Wang, Changhu Xue, Xiangzhao Mao PII:

S0141-8130(20)30876-X

DOI:

https://doi.org/10.1016/j.ijbiomac.2020.02.203

Reference:

BIOMAC 14820

To appear in:

International Journal of Biological Macromolecules

Received date:

28 January 2020

Revised date:

14 February 2020

Accepted date:

18 February 2020

Please cite this article as: W. Wang, C. Xue and X. Mao, Radioprotective effects and mechanisms of animal, plant and microbial polysaccharides, International Journal of Biological Macromolecules(2020), https://doi.org/10.1016/j.ijbiomac.2020.02.203

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© 2020 Published by Elsevier.

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Radioprotective effects and mechanisms of animal, plant and microbial polysaccharides Wenjie Wanga, Changhu Xuea,b,*, Xiangzhao Maoa.b,*

a

College of Food Science and Engineering, Ocean University of China, Qingdao

b

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266003, China Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for

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Marine Science and Technology, Qingdao 266200, China

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Corresponding Author

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*Professor Xiangzhao Mao and Changhu Xue: Tel.: +86-532-82032660 and

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[email protected].

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+86-532-82032468; Fax: +86-532-82032272; E-mail: [email protected] and

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Abstract Ionizing radiation is increasingly used to successfully diagnose many human health problems, but ionizing radiation may cause damage to organs/tissues in the living organisms such as the spleen, liver, skin, and brain. Many radiation protective agents have been discovered, with the deepening of radiation research. Unfortunately,

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these protective agents have many side effects, which cause drug resistance, nausea,

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vomiting, osteoporosis, etc.. The polysaccharides extracted from natural sources are

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widely available and low in toxicity. In vivo and in vitro experiments have

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demonstrated that polysaccharides have anti-radiation activity through anti-oxidation, immune regulation, protection of hematopoietic system and protection against DNA

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damage. Recently, some studies have shown that polysaccharides were resistant to

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radiation. In the review, the anti-radiation activities of polysaccharides from different

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sources are summarized, and the anti-radiation mechanisms are discussed as well. It can be used to develop more effective anti-radiation management drugs. Keywords: Polysaccharide; Ionizing radiation; Anti-radiation; Mechanism

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1. Introduction Ionizing radiation is widely used in medical imaging diagnosis, radiotherapy, radiation sterilization of food raw materials and equipment, which has promoted the development of the medical and food industries [1-3]. While promoting the development of the industry, radiation also brings some negative effects that cannot

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be ignored, such as radiation from electronic equipment, sunlight, and radiation

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radiotherapy [4]. Ionizing radiation can generate electromagnetic waves of various

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ions to attack the the body and cause damage such as decreased immunity, skin

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redness, cancer and so on. If the body is exposed to ionizing radiation for a long time, it may cause serious damage to normal tissues and organs, leading to the occurrence

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of diseases [5-7]. The damage mechanism is divided into three types as shown in Fig.

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1: direct damage, indirect damage, and bystander effect. The key target of direct

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damage is DNA, which can result in DNA single-strand and double-strand breaks [8-9]. Indirect damage is considered to be the main cause of radiation damage. Indirect damage means that ionizing radiation causes ionization of water molecules to generate free radicals, induce apoptosis, and dyfunction, and cause damage to organs and tissues [10]. The bystander effect means that the irradiated cells transmit signals to adjacent or distant unirradiated cells, resulting in unirradiated cells exhibiting various biological dysfunctions, including chromosomal aberrations and micronuclei [11]. Therefore, radiation can cause damage to various systems of the human body, such as damage to the hematopoietic system, nervous system, lung tissue, and other tissues [12-14]. The emergence of radioprotectants has mitigated

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radiation damage, and amifostine and glucocorticoids had proven to be the most effective radiation protection product against radiation-induced lung injury [15-16]. These substances mainly play a beneficial role in resisting radiation damage to healthy organisms, repairing damaged cells, and scavenging free radicals. However, most synthetic radioprotectants have toxic side effects, causing nausea, vomiting,

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diarrhea, hypotension, and adverse symptoms such as nephrotoxicity and neurotoxicity, which cannot be taken for a long time [17-18]. Therefore, it is very

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necessary to develop safety radiation protection agents.

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Polysaccharide is a polymer composed of 10 or more monosaccharides linked by glycosidic bonds, which is widely found in animals, plants and microorganisms

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[19]. It is an important component of living organisms and is closely related to many

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life activities. More than 300 polysaccharides have been isolated from natural

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products such as plants, bacteria, fungi, and attention has been paid to the structure and biological functions of polysaccharides with the development of biochemical technology [20-21]. It has been reported that polysaccharides have various physiological activities and functions such as anti-oxidation, anti-radiation, inhibition of tumor, immune regulation, and blood sugar lowering, and polysaccharide has no toxic and side effects on body tissue cells [22-24]. Therefore, polysaccharides have the potential of replacing anti-radiation drugs. The accumulated evidence indicates that the anti-radiation mechanism of polysaccharides is mainly achieved by scavenging free radicals, enhancing immunity, exerting immunomodulatory effects, reducing radiation damage to hematopoietic system,

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enhancing DNA damage repair ability, and inhibiting cell apoptosis. The anti-radiation effect of polysaccharides from Hohenbuehelia serotina is achieved by effectively increasing the activity of superoxide dismutase (SOD) and catalase (CAT) and reducing the level of malondialdehyde (MDA) in splenocytes after irradiation [25]. Rheum polysaccharide antagonizes the immunosuppression of γ-rays by

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increasing spleen index, thymus index, macrophage phagocytic ability, lymphocyte proliferation ability, and NK cell activity [26]. Aloe polysaccharide can improve the

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increase of micronucleus of bone marrow polychromatic erythrocytes caused by

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ionizing radiation, decrease of peripheral blood leukocyte level and decrease of bone

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marrow cells [27]. The barley β-glucan anti-radiation activity is attributed to its

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ability to effectively prevent a decrease in apoptosis of cells, an increase in survival

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fraction and a decrease in DNA strand breakage [28]. Hence, the anti-radiation mechanism of polysaccharides mainly protects radiation by eliminating free radicals,

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immune regulation, and apoptosis [25, 28-29]. However, few papers have reviewed the anti-radiation properties of natural polysaccharides and their anti-radiation mechanisms. Therefore, the focus of this paper is on the anti-radiation effects and anti-radiation

mechanisms

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polysaccharides

from

animals,

plants,

and

microorganisms, and the future research directions of polysaccharide anti-radiation. 2. Different sources of polysaccharide and their anti-radiation effect Polysaccharide, is a chain polymer formed by dehydration of aldose or ketose to form glycosidic bonds and linked by linear or branched glycosidic bonds [30-31]. Polysaccharide is not only a structural support and energy storage material of cells,

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but also one of the basic substances involved in the metabolism of living organisms [32]. It is involved in the recognition and regulation between among cells, the carrying and transmission of cellular biological information, immune response and protein transfer. Therefore, the biological activities of polysaccharides are getting more and more attention [33-36]. Generally, natural polysaccharides can be

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classified into animal polysaccharides, plant polysaccharides, and microbial polysaccharides [35, 37]. According to reports, polysaccharides derived from animal

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plants and microorganisms have good biological activity and application space

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[38-40]. The biological activity of polysaccharides is not only affected by the source,

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but also closely related to the structure of the polysaccharides. Cumulative

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experiments showed that polysaccharides from animal, plant, and microbial have

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anti-radiation activity (Natural polysaccharides with anti-radiation activity over the past 10 years are listed in Table 1). Such as sea cucumber polysaccharides [41-42],

[44].

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Mesona blumes polysaccharides [43], and Hohenbuehelia serotine polysaccharides

2.1 Animal polysaccharides

Animal polysaccharides mainly include glycosaminoglycans and chitosan, which have anti-oxidant, anti-inflammatory, antibacterial, anti-ultraviolet and other biological activities, so they can be used in drug development and biomedical fields [33-36]. Among them, the presence of uronic acid and sulfuric acid groups were closely related to the anti-radiation of animal polysaccharides. For example, Sipunculus nudus polysaccharide (SNP) and Chondroitin sulfate have effective

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anti-radiation properties. 2.1.1 SNP Sipunculus nudus is a worm animal door, commonly known as sand worm, also known as "animal ginseng". Li et al. (2016) used 1% NaOH for alkaline hydrolysis and trichloroacetic acid for deproteinization to obtain polysaccharides of

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Sipunculus nudus [45]. SNP was purified from DEAE-cellulose 52 and Sephacryl

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S-300 chromatography. The SNP is an acidic heteropolysaccharide composed of

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mannose, rhamnose, galacturonic acid, glucose, arabinose, and fucose. Researches

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show that SNP has various favorable bioactivities and remarkable anti-radiation

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effect. Li et al. (2016) also constructed a 137Cs-γ ray (4.0 Gy) injury model of Balb/c mice, and found that SNP can significantly increase the number of red blood cells

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(RBC), white blood cells (WBC), and platelets in peripheral blood (PLB), increase

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the spleen and testicular organ index. It also can significantly increase bone marrow DNA content, bone marrow hematopoietic stem cell content, reduce micronucleus rate, and cell death of bone marrow phagocytes. In addition, SNP can effectively protect the crypt cell in intestinal and gastric mucosa against irradiation, and decrease the apoptosis rate in crypt cells measured by TUNEL staining. These results indicate that SPN has significant radiation resistance. Song et al. (2010) found similar evidence that the antioxidant activity of polysaccharide in bryopsisplumosa is directly related to glucuronic acid content or the molecular weight of the polysaccharide [46]. Therefore, the effective radiation resistance of SNP may be closely related to the uronic acid. In addition, Cui and other studies found that

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compared with the irradiated model group, the beagle dogs of SNP were better protected, and the activity of antioxidant enzymes was also significantly improved, which shown that the anti-radiation effect of SNP was very significant [47]. SNP combined with

WR-2721, rh IL-11 and rh G-CSF can be used to treat diseases

caused by malformed radiation damage, protect immune and hematopoietic systems,

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protect various organs of radiation damage, etc [29].

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2.1.2 Chondroitin sulfate

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Chondroitin sulfate is a class of glycosaminoglycans widely found in tissues

and

animals

[48-49].

It

consisting

of

D-glucuronic

acid

and

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humans

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such as cartilage, muscle bonds, ligaments, corneas, and blood vessel walls of

N-acetyl-D-aminogalactose linked by 1,3 glycosidic bond, and the relative molecular

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weight is generally 25-30 kDa. According to the position of sulfate group on

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galactose, it is mainly divided into chondroitin sulfate A (CS-A) and chondroitin sulfate C (CS-C) [50-51]. Xie et al. (2013) explored the protective effect of CS-A on mice with X-ray irradiation injury. The determination of white blood cells and bone marrow DNA content after exposure to X-rays in mice [52]. The results showed that CS-A can antagonize the decrease of white blood cell count and increase the DNA content of mouse bone marrow after irradiation. CS-A has protective effect on radiation injury in mice, especially in DNA damage [53]. 2.2 Plant polysaccharide Polysaccharides extracted from plants have received increasing attention due

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to their biodegradability, sustainability, lower processing costs, and low toxicity [21, 37]. Interestingly, polysaccharides can effectively regulate the body's immune system. Therefore, there is great potential for plant polysaccharides to be used in the development of disease treatment drugs [38-39]. It has been reported that plant polysaccharides containing acetylmannan, laberinogalactan, galactomannan or

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sulfated fucoidan had anti-radiation activity, including Aloe, Astragalus, Angelica,

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and Brown alga polysaccharide.

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2.2.1 Aloe polysaccharide (AP)

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Aloe is a perennial plant belonging to the family liliaceae. Its expanded green

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leaves are composed of mesophyll (gel) and thick epidermis (skin). It has been widely used in folk medicine, functional foods, and cosmetics. So far, a variety of

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biologically active substances from aloe have been extensively studied such as

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carbohydrates, soluble sugars, organic acids, proteins, vitamins, minerals, and amino acids [54-55]. Among these functional chemicals, carbohydrates account for more than 60% of dry matter, and they are found to be acetylmannan, glucomannan or pectin polysaccharides [56-57]. Interestingly, some studies have shown that the beneficial effects of Aloe plants depend to a large extent on the chemical properties of these polysaccharides, particularly molecular weight and acetylation patterns. Kumar's research results shown that the main polysaccharide acetylated mannan in aloe gel had a significant protective effect on radiation. Aloe acetylated mannan protects irradiated mice by regulating the immune system and inducing the proliferation of hematopoietic cells in WBI mice. Also, Aloe acetylated mannan is

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non-toxic at high doses [58]. Hence, Aloe acetylated mannan has the potential to be developed as an anti-radiation agent. In addition, AP has a certain radiation protection effect on non-malignant cells [59]. AP has a protective effect on X-ray-irradiated non-malignant cells and help to alleviate cell cycle disturbances caused by X-rays.

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2.2.2 Astragalus polysaccharides (ASP)

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Astragalus belongs to the family of legumes and is a perennial herb. It is also a

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traditional Chinese herbal medicine with a long history of application. Astragalus

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has a variety of biological activities, such as anti-tumor, anti-viral, anti-bacterial and

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immune promotion [60-61]. Polysaccharides are relatively high levels of active substances in Astragalus. ASP has many good health care effects, such as improving

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blood circulation and immune function [38-39]. The structure of APS was analyzed

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and found that different concentrations of ethanol precipitated ASP with different molecular weights. The ethanol concentration is the higher that the molecular weight of ASP is the smaller. The molecular weights of the four ASPs were 257.7 kDa, 40.1 kDa, 15.3 kDa, and 3.2 kDa, respectively. Analysis of monosaccharide composition showed that ASP1 consisted only of glucose and ASP2 consisted of arabinose. ASP3 consists of rhamnose, glucose, galactose, and arabinose, and ASP4 consists of galactose and arabinose. The results of immunological biological activity assay showed that both ASP2 and ASP3 could effectively stimulate the proliferation of normal spleen lymphocytes in vitro. The results of this study indicate that ASP are composed of arabinose with a molecular weight between 15.2 kDa and 40.1 kDa and

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have significant immunological activity [62-63]. Cumulative studies have shown that radiation can damage the immune system, so radiation resistance and immunity are closely related. Liu et al. (2014) found that 200 mg/kg of ASP can significantly alleviate IR-induced liver and lung injury. Therefore, ASP can effectively treat mouse damage caused by 60Co γ-irradiation (5Gy, single dose) [64].

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2.2.3 Angelica polysaccharides (ALP)

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As one of the traditional Chinese herbal medicines, Angelica is widely used in

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the treatment of various diseases, for example, treatment of cardiovascular disease,

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anemia, and gynecological diseases [65-66]. Cumulative studies have shown that

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polysaccharides from angelica have various biological activities, including antioxidants, anti-tumor, immunomodulatory activities and hematopoietic agents

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[67-68]. Recently, studies have reported that angelica polysaccharides have

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anti-radiation activity. Zhao et al. (2012) found that two novel homogenous polysaccharides ALP-1a and ALP-3a from Angelica, which can increase the thymus and spleen index, and increase the number of RBC and WBC in peripheral blood, and the number of bone marrow cells in irradiated mice also can increase. Therefore, ALP has a radiation protection effect [69]. Sun et al. (2007) also explored the anti-radiation activity of ALP. The results showed that ALP can promote the antioxidant capacity of cells after irradiation, protect the integrity of cell membrane structure, and reduce DNA damage. ALP has certain anti-radiation function and has good protective effect on mice with radiation injury [70]. ALP generally has a molecular weight between 20 kDa and 65 kDa and mainly composed of galactose,

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arabinose, and glucose. Sun et al. (2005) analyzed the polysaccharides of ALP, indicating that is a pectin polysaccharide composed of uronic acid, galactose, arabinose, glucose, rhamnose, and mannose [71]. Arabinogalactan, galactomannan and pectin polysaccharides from plants have been shown to have antioxidant and immunomodulatory activities [72]. Therefore, the significant anti-radiation activity

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of ALP may be attributed to the presence of arabinose, mannose, and galactose in

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pectin polysaccharides.

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2.2.4 Brown alga polysaccharide

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Brown algae are a higher group of algae plants, which multicellular bodies,

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and generally include kelp, wakame, small kelp and so on [73-74]. Current research indicates that there are three types of brown algae polysaccharides: (1) sodium

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alginate, which is the sodium salt of alginic acid, also known as alginate, which is a

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block copolymer composed of α-1,4-L-guluronic acid and β-1,4-D-mannuronic acid as a monomer. (2) Brown algae polysaccharide, also known as laminaria polysaccharide, seaweed sulfate polysaccharide, mainly composed of glucose molecules. (3) Fucoidan, the main component is a polymer of fucoidan α-L-fucose-4-sulfate, and also contains different proportions of galactose, xylose, glucuronic acid and a small amount of protein [75-76]. Malyarenko et al. (2019) found that polysaccharides from brown algae have radioprotective effects. Fucoidan is a sulfated polysaccharide purified from brown algae. In addition to its effective antioxidant and antitumor activity, it can also improve the radiation resistance caused by 8Gy in a dose-dependent manner (1, 10 and 100 μg/mL) [6, 77]. The sulfated

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polysaccharide fucoidan has a protective effect by radiation [78]. It also enhances cell viability and immunomodulatory activity and contributes to the development of new radiation protection products. 2.3 Microbial polysaccharides Polysaccharides derived from microorganisms are also a major type of

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polysaccharides. Microbial polysaccharides have good biological activity, gelation

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and biocompatibility [33]. In addition, the production cycle of microorganisms is

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short, and the restrictions of seasons and regions will not affect the growth of

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microorganisms [40]. Hence, it has a very broad development prospect. Studies

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showed that the presence of β-D-glucan was the key to the excellent biological activity of microbial polysaccharides. Both radiation-resistant Auricularia auricula

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and Hohenbuehelia serotina polysaccharides (HSP) contain β-D-glucan.

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2.3.1 Auricularia auricula polysaccharide (AAP) Auricularia auricula is a homologous bacteria and food, not only nutritious, but also has a variety of biological activities. According to reports in the literature, Auricularia auricula has anti-radiation, anti-tumor, anti-oxidation, blood lipid reduction, and enhanced immunity [79-80]. Polysaccharides have attracted more and more attention as the main substance in Auricularia auricula. Sone et al. (1978) isolated β-D-glucan and acidic heteropolysaccharides from the fruiting bodies of Auricularia auricula-judae. Soluble Auricularia auricula β-D-glucan has significant antitumor activity. The acidic heteropolysaccharides are mainly composed of glucose,

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mannose, xylose, and glucuronic acid [81]. The Auricularia auricula acidic polysaccharide plays an effective role in blood coagulation, platelet aggregation and thrombus formation. Bai et al. (2014) extracted the polysaccharide of AAP. It is a heteropolysaccharide with average molecular weights of 3.30 × 102 kDa, which is composed of mannose and glucose, in addition to a small amount of xylose and

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galactose. In addition, Bai et al. (2014) experimented with oxidative damage induced by radiation in cells and mice. It is found that the complex of AAP and grape seed

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procyanidins (GSP) can significantly increase the viability of splenocytes and the

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proliferative capacity of splenocytes. Therefore, AAP and GSP can synergistically

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enhance the immune activity of the body and have a synergistic radiation protection

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effect on spleen cells. Moreover, the combination of AAP and GSP can inhibit the 60

Co-γ radiation, and

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stagnation of spleen cells in G0/G1 mice induced by

synergistically protect against apoptosis induced by 60Co-γ radiation [82]. Ding et al.

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(2019) found that pinecones of pinus koraiensis (PPPK) protected biological macromolecules and hematopoietic system function by regulating the activity of immune organs and lymphocytes. Therefore, it exhibits anti-radiation activity. PPPK can exhibit synergistic effects when combined with AAP. The combination of PPPK and AAP can be used as a very promising radiation protectant as a new combination of natural ingredients [83]. 2.3.2 HSP Hohenbuehelia serotina is a kind of mushroom with rich nutrients and high edible value. As a medicinal fungus, Hohenbuehelia serotina can enhance the body's

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immunity and have defenses against diseases such as leg pain, inflammation, numbness and so on. Some data analysis showed that polysaccharide is the main active ingredient of Hohenbuehelia serotine [84-86]. Cumulative studies have shown that HSP can be used as a natural radiation protectant to protect against radiation damage. Wang et al. (2019) found that HSP has a protective effect on 60Co-γ-induced

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splenocyte apoptosis. In addition, HSP significantly enhances the function of the antioxidant system and protects DNA from radiation damage [25]. Furthermore, HSP

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can block endogenous mitochondrial cell apoptosis induced by

60

Co-γ in mouse

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spleen cells [87]. The radiation protection of polysaccharide is closely related to its

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structural characteristics. Li et al. (2017) characterize the structure of HSP that the

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average molecular weight was 8.09 kDa, and the composed of glucose, mannose,

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galactose and arabinose, and the molar ratio was 28:16:4:11. HSP are semi-crystalline materials with a multi-branched structure. It is shown that the main

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chain of HSP contains →3,6)-α-D-Glcp-(1→, which is branched by C-3 of →2)-α-L-Arap-(1→, C-3 of α-D-Manp-(1→ and C-6 of→6)-β-D-Galp-(1→), respectively. Polysaccharides containing (1→3) and (1→6) linked residues have significant

biological

activities

including

anti-oxidation,

anti-tumor,

immunomodulation and anti-radiation [88]. 2.4 Relationship between polysaccharide structure and activity The structure-activity relationship of the polysaccharide refers to the relationship between the structure of the polysaccharide and its biological activity. The current research on the structure-activity relationship of polysaccharides mainly

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includes sugar unit, types of glycosidic chains and the backbone, conformation of chain, and the molecular weight. (1) Different types of polysaccharides had different composition of main chain sugar units, and their biological activities were different. Dextran was a basic structural unit of many animal, plant, and microbial polysaccharides, such as AAP and barley polysaccharides. Both of AAP and barley

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polysaccharides had anti-radiation functions [28, 81]. The composition of other types of sugar units also affected the biological activity of polysaccharides. SNP is an acid

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heteropolysaccharide composed of mannose, rhamnose, galacturonic acid, glucose,

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arabinose, and fucose, and it also had anti-radiation properties [41]. (2) The type of

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glycosidic bond referred to the connection mode of adjacent glycosyl groups on the

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main chain of the polysaccharide. Most dextran polysaccharides with outstanding

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biological activity were linked by (1→3) glycosidic bonds. For example, Tremella fuciformis polysaccharide with (1→3) glucan as the main chain had anti-radiation

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and immune regulation activities. Other glycosidic bond types were also resistant to radiation. For example, HSP containing (1→3) and (1→6) linking residues had antioxidant, antitumor, immunomodulatory, and anti-radiation activities [88-89]. (3) Polysaccharide activity was not only affected by sugar units and glycosidic bonds. Different main chain configurations also led to differences in biological activity. For dextran,

α-glucans

were

generally

inactive,

and

most

radiation-active

polysaccharides all had the backbone structure of (1→3)-β-D-glucan, such as Mushroom polysaccharide and AAP [84-86]. (4) Many studies showed that the specific spatial conformation of polysaccharides was necessary for its biological

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activity. Polysaccharides with strong biological activity usually had regular spatial conformations. (5) Studies have shown that the radiation resistance of polysaccharides was related to the molecular weight. ASP with molecular weights ranging from 10 to 50 kD showed strong immune activity [62-63]. ALP had a molecular weight in the range of 20 kDa to 65 kDa, which had effective

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3. Anti-radiation mechanism of polysaccharide

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anti-radiation activity [70-71].

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Natural polysaccharides show good anti-radiation properties and are closely

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related to the biological activities of polysaccharides such as anti-oxidation, immune

lP

regulation and prevention of apoptosis [25-26]. Studies have shown that the anti-radiation mechanism of polysaccharides is mainly achieved through improve

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oxidative damage, regulate the immune system, regulation of apoptosis, protect DNA

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and hematopoietic systems [28-29]. 3.1 Improve oxidative damage

The production of reactive oxygen species (ROS) in the body is dynamically regulated by the oxidation-reduction system and maintained at a normal level, under normal physiological conditions. Oxidative stress refers to an imbalance between oxidation and antioxidation in the body and is a pathological condition, which means that reactive oxygen species (ROS) are overproduced under conditions in which elimination is reduced [89-90]. Ionizing radiation induces the body to continuously generate reactive oxygen free radicals, which makes the balance between oxidation

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and antioxidant capacity of the body imbalance, leading to oxidative stress in the body. Oxidative stress is considered to be one of the important mechanisms of radiation leading to the pathogenesis of the body. The excessive ROS can consume a large amount of antioxidant enzymes in the body that producing more free radicals, peroxides, etc., which attack the biological macromolecules in the body [91]. Hence,

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lipid peroxidation, protein and nucleic acid damage are generated, and changes in important antioxidant enzymes shuch as SOD, CAT and GSH-Px [92]. In addition,

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non-enzymatic antioxidants are also important substances against free radicals, and

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refer to small molecular compounds with antioxidant effects, including intracellular

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synthesis of GSH, ceruloplasmin, vitamin E and so on [93].

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According to reports, polysaccharides can block or slow down the progress of

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lipid peroxidation by capturing ROS, thereby achieving a direct clearance of ROS. In

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addition, polysaccharides can complex with the metal ions necessary to produce ROS, and play an indirect clearance effect on ROS. On the other hand, polysaccharides can play an antioxidant role by increasing the activity of antioxidant enzymes such as SOD and GSH-Px [90-92]. Therefore, polysaccharides have antioxidant capacity and are effective in scavenging free radicals to protect the body from radiation damage (Fig. 2). The synergistic effect of AAP and GSP on radiation is mainly attributed to the scavenging effects of AAP and GSP on ABTS+·, O2-·, DPPH·, and OH· free radicals [82]. The polysaccharide from the Lactobacillus plantarum-fermented Ishige okamurae has a protective effect on on zebrafish induced by γ-ray radiation because the polysaccharide has a highly efficient hydroxyl

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radical-scavenging and 1,1-diphenyl-2-picrylhydrazyl activities [94]. The mice pretreated with ASP significantly decreased the levels of alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and NF-κB. ASP-treated mice of IR-induced showed the decrease in catalase and glutathione activities, superoxide dismutase and attenuation of the IR-induced increase in thiobarbituric acid reactive

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substance. The molecular mechanism associated with the protective effect of ASP on radiation-induced damage in mice may involve inhibition of radiation-induced

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oxidative stress [64]. The composite polysaccharides of Tricholoma matsutake and

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Lentinus edodes had protective effects on mice irradiated by γ-rays. The activities of

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SOD, CAT, and GSH-Px in serum were significantly increased, and the content of

lP

MDA was significantly decreased [95]. In addition, Hohenbuehelia serotina neutral 60

Co-γ radiation damage. The

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polysaccharide (NTHSP) has a protective effect on

protective mechanism is mainly achieved by increasing the activity of GSH-Px by

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NTHSP and increasing the content of GSH and ceruloplasmin in plasma after 6 Gy irradiation [10]. Radiation could cause oxidative stress and led to pathological changes in the body. The important mechanism of polysaccharides against radiation was to improve oxidative damage. 3.2 Regulate the immune system

Immune system can resist the invasion of pathogens, remove foreign bodies and pathogens, and maintain the balance of the body. The system is mainly composed of immune organs (spleen, thymus, bone marrow, lymph nodes, etc.), immune cells (lymphocytes, macrophages, granulocytes, etc.), and immune

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molecules (TNF, IFN, IL, etc.) with immune surveillance, immune self-stabilization, and immune defense [96]. The spleen is the largest lymphoid organ in the human body, which has the functions of hematopoiesis, clearing aging blood cells, and regulating immune function. The body will respond to the spleen after antigen stimulation, and produce various immune cells and immune molecules to clear the

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antigen and protect the body. T lymphocytes develop and mature in the thymus, so the thymus is closely related to the immune system. It not only promotes the

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production of T lymphocytes, but also secretes a variety of hormones, such as thymin,

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which can promote the recovery of T lymphocytes in immunodeficiency patients.

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The spleen and thymus are extremely sensitive to ionizing radiation [48, 97].

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Ionizing radiation can cause a significant decrease in the volume of the spleen and

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lymphocytes.

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thymus, morphological and functional abnormalities, and significant reduction of

Cumulative studies have shown that most natural polysaccharides have immunomodulatory effects and can be used as effective immunomodulators [98-100]. Therefore, polysaccharides can repair damage caused by radiation by regulating the body's immune response. According to reports, the immunomodulatory effects of active polysaccharides are currently recognized as one of the mechanisms of anti-radiation. Exopolysaccharides from Lactobacillus plantarum N14 have the function of enhancing the phagocytic ability of macrophages, promoting the release of cytokines and improving the immune surveillance function of the body, thereby providing radiation protection [94]. The complex polysaccharide can significantly

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improve the spleen index, thymus index, and spleen lymphocyte proliferation ability of the mice after irradiation. The data indicates that acemannan has the ability to protect mice from radiation-induced death through immune regulation [58]. According to the current literatures, the immunomodulation of polysaccharides against radiation is mainly through the following three signaling pathways (Fig. 3).

of

3.2.1 MAPK signal pathway

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MAPK is a highly conserved silk/threonine protein kinase that can be activated

-p

by extracellular stimuli. MAPK family members in mammalian cells are mainly

re

extracellular signal-regulated kinase (ERK), c-Jun NH2-terminal kinase (JNK) and

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p38 mitogen-activated protein kinase (p38 MAPK). The MAPK signal transduction pathway is a signaling cascade composed of a grade 3 kinase. In unstimulated cells,

na

MAPK continues to remain in a state of rest. MAPK (including ERK, p38, JNK) is

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activated, and the phosphorylated transcription factor produced by the activated MAPK enters the nucleus to regulate the transcription of related genes when the cells are stimulated [71, 101]. Studies have shown that acemannan polysaccharide can decrease radiation-induced NO levels in mice and reduce IL-6 expression after irradiation. Acetylated mannan treatment prevents radiation damage resulting in increased survival by upregulating the immune system [58]. Moreover, Malyarenko et al. (2019) have demonstrated that sulfated laminarin reduces the radiation resistance

of melanoma cells

by down-regulating MAPK activity.

And

polysaccharides promote cell proliferation and colony formation and can significantly inhibit cancer cell migration. In addition, neutral water-soluble

Journal Pre-proof β-D-glucans of brown algae to realize anti-radiation activity via the ERK1/2 signal pathway. Data from western blot analysis showed that polysaccharide pretreatment increased phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in SK-MEL-28 cells [6]. Therefore, polysaccharides can protect the body from radiation damage by regulating the MAPK signal pathway.

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3.2.2 PI3K/Akt signal pathway

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The PI3K pathway is a multifunctional signaling pathway associated with cell

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defense, proliferation, and apoptosis. Liu et al. (2019) revealed that S.

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cerevisiae-derived-beta-D-glucan and high linear-energy-transfer carbon ion

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irradiated mice are associated with enhanced PI3K/Akt signaling pathway [102]. Up-regulated differentially expressed genes (DEGs) primarily activate PI3K-Akt,

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Focal adhesion and extracellular matrix (ECM) receptor interaction pathways, and

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most of the DEGs annotated in Focal adhesion and ECM-receptor interaction pathway overlapped in PI3K-Akt pathway. It has been reported that the PI3K-Akt pathway regulates nuclear factor erythrocyte-2-related factor-2 (Nrf-2), and crosstalk between the PI3K-Akt and Nrf-2 pathways protects cells from inflammation and oxidative damage. S. cerevisiae-derived-beta-D-glucan reduced ROS and MDA levels and improved carbon monoxide-induced bone marrow mononuclear cells injury by activating the PI3K-Akt pathway. In addition, rutin as a natural radioprotectant can resist γ-radiation-induced brain damage by activating the PI3K-Akt signaling pathway and reducing ROS interference [103].

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3.2.3 Membrane immunoglobulin (mIg) complex receptor-mediated signaling pathway The mIg receptor is the most important receptor on the surface of B lymphocytes and is a characteristic surface marker of B lymphocytes. It can form a mIg complex receptor with CD79b, recognize antigen and regulate B lymphocytes

of

[104-105]. The DNA damage caused by ionizing radiation is the most important

ro

factor in cell death, which leads to a decrease in the number of splenocytes and

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lymphocytes in the bone marrow [106]. Sulfur-containing polysaccharides can

re

induce the proliferation of spleen lymphocytes, differentiate them into IgM secreting plasma cells, and increase the expression of mIg [107]. This may be the main reason

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3.3 Regulation of apoptosis

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for the radioprotective effect of brown algae sulfated polysaccharides [78].

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Apoptosis can be mediated by a variety of pathways, including the mitochondrial pathway, the endoplasmic reticulum-mediated pathway, and the death receptor-mediated pathway, which has been reported to be involved in oxidative imbalance [108]. Ionizing radiation will cause a large amount of active oxygen in the body, and excess active oxygen will cause the body to be in an oxidative imbalance status [109]. And the previous literature has shown that free radicals generated by ionizing radiation act on mitochondria, leading to a decrease in mitochondrial membrane

potential,

increase

membrane

permeability,

and

initiation

of

mitochondrial apoptotic pathways, leading to apoptosis as shown in Fig. 4 (Wang et

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al., 2019) [25, 110-111]. Members of the Bcl-2 family, cytochrome c, and caspase-3 are critical factors in the mitochondrial pathway of apoptosis. Bcl-2 inhibits cell apoptosis by preventing the release of cytochrome c into the cytoplasm. Apoptosis causes cytochrome c to be released through the mitochondrial outer membrane, and in the cytoplasm, it binds to apoptotic protein activating factor to form an oligomer,

of

which leads to caspase-3 activation and further activates other downstream caspases. The radioprotectant can inhibit the apoptosis through the mitochondrial pathway

-p

ro

[112-113].

Hu et al. found that Potentilla anserine polysaccharide-treated cells at

re

concentrations of 50, 100, 200, or 400 μg/mL reduced the number of apoptotic cells

lP

in a dose-dependent manner [8]. Bing et al. found that acidic polysaccharide of

na

Panax ginseng (APG) can increase epithelial cell regeneration, and APG

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pretreatment of jejunal cells can reduce radiation-induced jejunal cell apoptosis. In addition, APG can increase the expression levels of anti-apoptotic proteins (Bcl-2 and Bcl-xs/L) and at the same time significantly reduce the expression levels of pro-apoptotic proteins (p53, Bax, cytochrome C, and caspase-3) [114]. Barley β-glucan is effective in preventing apoptosis and protecting HepG2 cells from radiation [28]. Li et al. (2015) studied the protective effect of neutral Hohenbuehelia serotina polysaccharides (NTHSP) on

60

Co-γ ray radiation (6 Gy) with SPF

Kunming male rats. It was found that NTHSP can significantly inhibit the expression of Bax protein and promote the expression of Bcl-2 protein. It inhibits the release of cytochrome c and promotes the expression of caspase-3, thereby blocking the

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mitochondrial apoptosis pathway of mouse spleen cells. It shows that NTHSP is a natural radiation protectant [87]. In addition, Wang et al. systematically studied the radiation protection of the endoplasmic reticulum (ER) apoptotic pathway of NTHSP. NTHSP inhibits γ-radiation-induced apoptosis of splenocytes by mediating ER apoptosis pathway. NTHSP inactivates the apoptotic executor caspase-3 by blocking

of

cytochrome c released from the mitochondria to the cytoplasm. Furthermore, NTHSP also prevents apoptosis by reducing the expression of caspase-12, which is activated

ro

by calcium loss from ER [25]. NTHSP has good potential as a natural radiation

re

-p

protectant for human body against radiation damage.

lP

3.4 Protect DNA and hematopoietic systems

So far, the results of the study have indicated that DNA and hematopoietic

na

system damage repair capabilities are two important mechanisms for polysaccharides

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to resist radiation [87, 115]. Ionizing radiation can degrade DNA macromolecules and also can cause damage to nucleotides and their components. The common DNA radiation damage includes base damage, glycosyl-phosphate damage and strand breaks, pyrimidine dimer formation, and DNA-protein cross-links. Experiments have shown that DNA single-strand breaks can be repaired quickly in mammals. The reconnection of single-strand breaks is dependent on the original DNA ligase in the irradiated cells, with not or rarely affected by certain nucleic acid and protein synthesis inhibitors. Double-strand breaks are also capable of reconnection, and the reconnection of double-strand breaks is accomplished by two processes of ligation and recombination. At present, researchers are paying attention to DNA strand breaks,

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especially double-strand breaks. Because this is closely related to cell survival, chromosomal aberrations, micronuclei, and gene mutations. Chromosome is a complex of DNA and protein that is very sensitive to ionizing radiation. Chromosomal aberrations are a good indicator of cell populations reflecting ionizing radiation damage. Ionizing radiation can stimulate the ionization of water in cells and

of

produce a large amount of active oxygen. The powerful oxidizing power can damage the DNA of cells. It also causes the double-strand and single-strand breaks of the

ro

double helix of the biological cell DNA, which in turn causes the chromosome to

-p

rupture and eventually forms chromosomal aberrations. Studies have reported that

re

radioprotective substances protect against DNA damage by inhibiting the occurrence

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of DNA double-strand breaks, enhancing DNA repair related genes and related

na

proteins. Polyphenolic glycoconjugates from medical plants of Rosaceae/Asteraceae family have shown that significantly reduce DNA damage when applied after

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irradiation, indicating that they have a regulatory effect on the DNA repair pathway [116]. Hohenbuehelia serotina polysaccharides have a significant protective effect on ionizing radiation-induced DNA apoptosis [117]. Moreover, Li et al. showed that neutral Hohenbuehelia serotina polysaccharide can effectively increase the amount of bone marrow DNA and reduce the rate of chromosome aberration and micronucleus in mouse bone marrow [87]. In addition, PPPK and APP complexes can significantly improve bone marrow DNA content and monocyte phagocytic activity, while reducing bone marrow micronucleus rate and chromosome aberration rate. It shows that the composite has effective radiation protection [83]. Ghavami et

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al. found that barley beta-glucan can alleviate DNA damage in human liver cancer HepG2 cells and improve cell cycle progression to protect human liver cancer HepG2 cells from radiation damage [28]. The protective effect of polysaccharides on radiation-induced damage to the hematopoietic system is critical to the body [58]. The hematopoietic system is the

of

most sensitive tissue of ionizing radiation, and ionizing radiation can inhibit and

ro

destroy the function of the hematopoietic system. After the hematopoietic system is

-p

damaged, the number of blood cells such as white blood cells and platelets in the

re

body is significantly reduced. As a result, the body is highly susceptible to infection by bacteria, viruses, and other pathogens. The body also has symptoms such as

lP

anemia and bleeding, due to the large reduction in blood cell. Studies have shown

na

that polysaccharides can reduce the damage of radiation to the hematopoietic system.

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Jiang et al. reported that Astragalus polysaccharide can significantly increase the levels of white blood cells and platelets in mice induced by radiation. It was found by morphological examination of bone marrow that Astragalus polysaccharide can significantly increase the number of hematopoietic stem/progenitor cells and megakaryocytes [118]. Sipunculus nudus L. polysaccharide combined with SNP, WR-2721, rhIL-11, and rhG-CSF synergistically restored white blood cells, red blood cells, platelet count and hemoglobin levels in irradiated mice [29]. The beta-D-glucan derived from Saccharomyces cerevisiae regulates the proliferation and differentiation of hematopoietic cells and directly or indirectly regulates the proliferation of hematopoietic stem/progenitor cells [115]. Hassan et al. studied the

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protective effect of Alcaligenes xylosoxidans MSA3 polysaccharides (AXEPS) on ɤ-irradiation (5Gy) in male rats. They found that AXEPS can counteract the decrease in peripheral blood levels caused by radiation [119]. In addition, the Mesona blumes polysaccharide has been found to prevent a reduction in the number of blood cells caused by radiation [43]. It can be seen that the protective effect of polysaccharides

of

on DNA and hematopoietic system is closely related to the anti-radiation of

ro

polysaccharides.

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4. Conclusions and prospects

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Polysaccharides have become more and more important in human health and

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human nutrition as a functional ingredient in animals, plants and microorganisms. In this review, we summarize the simple structure and anti-radiation activity of

na

polysaccharides from animals/plants and microorganisms. Studies have shown that

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different types of polysaccharides play an important role in regulating the body's anti-radiation function. Both the molecular weight and monosaccharide composition of a polysaccharide affect its radiation resistance. Low or high molecular weight is not conducive to the functional activity of polysaccharides. The molecular weight of polysaccharides between 10 KDa and 100 KDa may exhibit more effective anti-radiation properties. Generally, polysaccharides containing uronic acid, arabinose, mannan, or dextran have better radiation resistance. In addition, acetylated mannan and sulfated polysaccharides showed more significant radiation resistance. Polysaccharides have an effective anti-radiation effect due to that polysaccharides can prevent oxidative damage, regulate the immune system, prevent apoptosis, and

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protect DNA and hematopoietic systems. Polysaccharides can be regulated in one or more ways to prevent radiation damage. Some in vitro and in vivo studies have shown that anti-radiation of polysaccharides is promising, but in order to better apply to health products, pharmaceuticals and cosmetics, the relationship between anti-radiation and its

of

polysaccharide structure needs to be established. Polysaccharides modified by

ro

acetylation and sulfation show good anti-radiation activity, but the mechanism by

-p

which they exert their anti-radiation activity remains to be studied. Compared with

re

terrestrial polysaccharides, marine large algae polysaccharide resources are generally considered to be less toxic and more active. However, the current research on the

lP

anti-radiation effect of marine polysaccharide resources and derivatives has not been

na

fully studied. At present, the research on the anti-radiation activity of natural

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polysaccharides is still limited to surface research, and its anti-radiation mechanism needs to be further clarified. And the application of polysaccharides in the medical field is limited to a small range. Therefore, it is an active research field in the next few years.

Acknowledgement This work was supported by the National Natural Science Foundation of China (31922072), China Agriculture Research System (CARS-48), Fundamental Research Funds for the Central Universities (201941002), Taishan Scholar Project of Shandong Province (tsqn201812020).

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Heliantnus tuberosus L. polysaccharide Mesona blumes polysaccharide

Laminaria japonica polysaccharide Alga polysaccharide Schizandrae polysaccharide Rosaceae and Asteraceae families polysaccharide Acanthopanax senticosus polysaccharide Haberlea rhodopensis polysaccharide Tinospora cordifolia Root polysaccharide Panax ginseng polysaccharide Pectin polysaccharide Soybean Meal polysaccharide Purple Sweet Potato Polysaccharide

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Figure 1

Figure 2

Figure 3

Figure 4