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Several researches report that polysaccharides can be utilized for therapeutic purposes because of their several biological actions such as antioxidant, anticoagulant, antiviral, antidiabetic, antitumor, and immunostimulatory activities [100]. Medicinal polysaccharides also claimed as “biological response modifiers”, are that stimulate the immunological response to infection and disease [158].

The primary effect of polysaccharides was identified as enhancing and/or activating immune response [103]. Lo et al. proposed that arabinose, mannose, xylose, and galactose are the main monosaccharide components contributing to macrophage stimulating activity while being the most common monosaccharide component, glucose showed no clear role in the immunoactivity of polysaccharides [100]. The immunomodulating activity of polysaccharides comprises the activation of macrophages, dendritic cells, tumor-infiltrating lymphocytes, natural killer cells, lymphocyte activated killer cells, and several cytokines such as interferons, tumor necrosis factor, interleukins, and colony-stimulating factors [158]. For instance, glycan has been shown to promote macrophage functions, which include activating the phagocytic ability, enhancing the cytotoxic activity against the tumor cells, enhancing ROS and nitric oxide (NO) production, and promoting the synthesis and secretion of cytokines and chemokines [13]. In another study, in vivo administration of the exocellular polysaccharide of the algae, Porphyridium cruentum to mice has resulted in an increase of the macrophage population as well as in an increase of the acid phosphatase enzyme [159]. Natural polysaccharides from different sources have been found to activate macrophages mainly through the interaction with specific receptors on cells, called pattern recognition receptors (PRRs) including toll-like receptor 4 (TLR4), CD14, dectin-1, and mannose receptor. Receptor activation leads to the production of pro-inflammatory factors through the activation of downstream signaling [100]. In the field of cancer therapy, the potency of bioactive polysaccharides, such as polysaccharides derived from Basidiomycetes class of mushrooms (Krestin from Coriolus versicolor, lentinan from Lentinus edodes, schizophyllan from Schizophyllum commune) and some other botanical herbs (Astragalus membranaceus, Panax ginseng, Angelica sinensis, pectins, and modified citrus pectin), has been reported in preclinical models and claimed to diminish tumor growth and extend the patient’s life by triggering cell cycle arrest, apoptosis and, immune stimulation [158]. On the other hand, activation of immune response by polysaccharides may cause excessive inflammation which leads to sepsis and local or systemic inflammatory disorders. Thus, further studies are needed to investigate whether the pro- and anti-inflammatory factors induced by polysaccharides can ensure the homeostasis.

Heparin is a nontoxic, nonimmunogenic, and noninflammatory sulfated animal polysaccharide [160]. Biological functions of heparin, other than the clinical use as an anticoagulant, have been continuously discovered, such as it was shown that heparin can inhibit the proliferation of vascular smooth muscle cells, suppress delayed hypersensitivity, and stimulate the formation of the new blood vessel. Furthermore, due to its fibrin clot-dissolving and angiogenesis promoting actions, heparin is an effective polysaccharide in the wound healing process [161]. Heparin was suggested to modulate its biological functions through binding with the specific groups of proteins, such as binding with growth factors to enhance their activity [13]. Heparin sulfate is a structurally similar analog of heparin. This linear polysaccharide is found in cell surface or extracellular matrix and governs specific biological activities ranging from acting as a cell surface receptor, proliferation, differentiation, migration, and cancer metastasis to blood coagulation [162]. Even though heparin has been used for treating venous pulmonary embolism, thrombosis, and acute coronary syndrome, it can also activate blood proteins including platelet factor 4 that results in thrombocytopenia. To prevent the risks of potential bleeding and heparin-induced thrombocytopenia, earlier attempts involved depolymerization of heparin to obtain low molecular weight heparin. Today, ultra-low molecular weight heparin (AVE5026) with better pharmacological activities and tolerance in living systems are utilized in clinics [162–164].

In the human body, hyaluronic acid is found in various tissues, such as connective tissues, including eyes, joints, and skin, and fluids. Through binding its receptors, hyaluronic acid displays various biological activities such as modulation of cell functions including migration, adhesion, proliferation, and inflammation. In in vivo, hyaluronic acid has been shown to have chondroprotective effects. Exogenous hyaluronic acid can induce the synthesis of proteoglycan, regulate the functions of immune cells, and reduce the activity of proinflammatory cytokines. Additionally, it has a great water retention ability and thereby play a vital role in regulating tissue hydration and osmotic balance. Because of the high hygroscopicity, hyaluronic acid can significantly regulate the physical properties of the extracellular matrix [13, 165]. Researchers have made great progress in the science of hyaluronic acid-based applications; for example, the use of hyaluronic acid in some eye surgeries, such as the removal of the cataract, corneal transplantation, and repair of a detached retina has been approved by the Food and Drug Administration (FDA) [13]. FDA has also approved the use of hyaluronic acid fillers in the area of cosmetic surgery to reduce the appearance of fine lines and wrinkles, facial folds, and to create structure, framework, and to give volume to the face and lips [166]. However, hyaluronic acid can cause some side effects including delayed hypersensitivity and granulomatous reactions [167]. Therefore, the actions of hyaluronic acid and its derivatives have to be explored mechanistically and more clearly.

Nonetheless, obtaining the functional polysaccharides with high purity and characterizing the structure of them are challenges of naturally occurring polysaccharides to be used in clinics. To overcome the drawbacks including immunogenicity, polysaccharide-based ideal therapeutics with defined bioactivity, biocompatibility, required purity, and appropriate physicochemical properties are needed to be developed.