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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.

      6.2.3 Cosmetics

The knowledge of skin biology enables the identification of active ingredients which are essential for healthy skin and crucial for the maintenance of its barrier function and integrality. Polysaccharides are known with their protective effects on the skin; therefore, the development of cosmetic formulations with these ingredients can enhance the efficacy of the formulations [168].

      In cosmetics, applications of polysaccharides range from peelings with candy sugar crystals up to cleansing products. Polysaccharides used in cosmetics can be categorized as functional and active polysaccharides. Functional polysaccharides can be used in the formulation technology such as gelling agent, film former, thickener, conditioner, suspending agent, and emulsifier while active polysaccharides are used in the cosmetics because of their ability in forming hydrogel structure with moisturizing effect [169]. In the gelling masks, that are spread on the skin in liquid form and then removed after they have solidified into a rubbery substance, the main ingredient is alginic acid. Agar, a mixture of agarose and agaropectin, is used as a consistency and bonding agent. Food-grade carrageenan is an entirely safe and appropriate ingredient for toothpaste, like furcelleran. Chitosan is used for hair conditioning purposes in shampoos and hair gels and used in toothpaste and mouthwashes as a bacteria-inhibiting component. It can also be used in skincare products as a cationic filming agent. Glucan has skin-protecting and tightening features and it is used for the skincare after peeling and laser treatments, after shaving as well as an additive for body lotions. Carboxymethyl cellulose, which is also called sodium cellulose glycolate, is obtained by chemical modification of cellulose. It forms water-soluble sodium salts with thickening properties and the salts can be used in cleansing and washing products as highly effective carriers for dirt particles. Dextrins can retain perfumes and can be used for the slow release of the perfume [168, 170]. Hyaluronic acid is also widely used in cosmetic practice. As an injectable dermal filler, it is preferred by most anti-aging, esthetic and plastic specialists. For instance, hyaluronic acid is used for skin regeneration, wrinkle-treatment, and wound healing as an effective, non-invasive, non-surgical alternative due to its enormous ability to bind water and easiness of implantation [67]. Similar to hyaluronic acid, xanthan has gentle skin-smoothing properties and moisturizing characteristics [170].

      The data obtained from clinical studies have been shown that polysaccharide-based formulations prevent transepidermal water loss and protect the skin barrier function. Thus, natural polysaccharides are suitable to be used in cosmetic formulations effective in skin protection and maintenance of structural integrity of the skin. Besides, natural polysaccharides can interact with other ingredients in a formulation, such as active substances, surfactants, and salts. The only drawback of many of these natural polymers is that their composition may vary depending on their geographical origin and the manufacturing process that can result in differences in chemical purity and quality which can lead to skin reactions [168]. Therefore, careful analysis of the chemical properties of polysaccharides and their by-products are extremely important for cosmetic production.

      6.2.4 Foods and Food Ingredients

      Although polysaccharides originating from plants (e.g., starch and guar gum), microorganisms (e.g., xanthan), algae (e.g., alginates and carrageenans), and animals (e.g., glycogen and chitin) are frequently used in food, most of the polysaccharides used as food ingredients are plant-derived. For example, gum arabic is obtained from the sap of

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