NJ025-601

Structure and Bioactivity of Acidic Polysaccharides from Natural Resources 

Toshihiko Toida*

Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1, Inohana, Chuoh-ku, Chiba 263-8675, Japan

Corresondence to: Toshihiko Toida, toida@faculty.chiba-u.jp

Received: June 11, 2025; Accepted: July 22, 2025; Published: July 26, 2025

NATPRO J. 2025, 2, 13-24 

https://doi.org/10.23177/NJ025.601 

Copyright ©  The Asian Society of Natural Products

Abstract

Interest in naturally occurring polysaccharides has steadily increased over the past two decades. These compounds have found applications in a variety of fields, including nutraceuticals, cosmetics, pharmaceuticals, and biomedicine. As studies of the structure-activity relationships (SAR) of glycans have progressed, the biological significance and functions of natural polysaccharides have become clearer. This progress has been fueled by significant advancements in enabling technologies, including various isolation and purification methods, chemical reactions that elucidate structures, and analytical tools such as nuclear magnetic resonance (NMR) and mass spectrometry (MS). Recent technological advances have revealed that some polysaccharides have irregular functional group patterns or branched sugar units within regular structures. This review will focus on the SAR of some acidic polysaccharides in the context of pharmaceuticals and nutraceuticals, and new concepts regarding the biological functions of polysaccharides as matrikines, with a particular focus on chondroitin sulfate.

Keywords

acidic polysaccharides, glycosaminoglycans; structure-activity relationship (SAR); nutraceutical; pharmaceutical

1. Introduction

The interest in polysaccharides of natural origin has steadily increased over the past two decades [1-4]. There have been many excellent review papers on naturally occurring polysaccharides already published, and the author would strongly encourage the readers to refer to them [5-8]. The potential applications for these compounds are expanding across various fields, including food supplements, cosmetics, pharmaceuticals, and biomedical uses [9-11]. The exploration of new sources of bioactive polysaccharides from diverse origins is well documented in recent literature [12-15].　Polysaccharides, which represent the third major class of biopolymers (carbohydrates), play a crucial role in various biological processes, including the immune system [16-19], blood coagulation [20], fertilization [21], and pathogenesis prevention [22]. As research on the structure-activity relationship (SAR) of carbohydrate chains has progressed, the significance and biological functions of polysaccharides derived from natural products have become increasingly apparent [23,24]. The technologies supporting these studies have also advanced significantly, encompassing various separation and purification techniques, structure-determining reactions, and analytical instruments such as nuclear magnetic resonance (NMR) and mass spectrometry (MS). Recent technological developments have demonstrated that some polysaccharides exhibit irregular functional group sequences or branched saccharides within their otherwise regular structures [25-27]. It is a time-consuming, labor-intensive, and technically demanding task to elucidate the necessity of the structure for the activity among these many factors, the elucidation of the necessity will provide important information on the mechanism of activity. Unfortunately, there are currently no techniques that can accurately determine the molecular weight of polysaccharides, particularly acid polysaccharides. Although techniques such as viscometry, gel permeation high-performance liquid chromatography (HPLC), and light scattering techniques are currently used for convenience, this remains a major challenge in the field of analytical science [25, 26].

Based on elucidating the necessity, we are able to obtain important information on the mechanism of activity expression. Furthermore, even though polysaccharides are rare as natural products, it may be possible to obtain large amounts of similar active polysaccharides by modifying polysaccharides such as amylose and chitin, which are inexpensive and abundant, using the knowledge obtained through these studies. If the time comes when polysaccharides can be synthesized cheaply and with a wide range of structures, it may be possible to develop polysaccharide drugs whose potency and duration of activity can be freely controlled based on the knowledge obtained. In recent years, several polysaccharides have been progressively introduced into clinical trials and have attained pharmaceutical status, allowing for the modulation of potency and duration of activity based on the knowledge acquired [28,29].

Polysaccharides were first used as medicines in Sweden during World War II with the development of the plasma bulking agent dextran [30]. Nowadays polysaccharides are used in a growing number of actual medical applications, including the antithrombotic agent heparin [31,32], the antitumor agent lentinan [33,34], and the knee osteoarthritis treatment hyaluronan [35]. There is no doubt that polysaccharide-based medicines will continue to expand in the future. So far, numerous review articles have reported on biological activities of polysaccharides. The aim of this paper is to focus on acidic polysaccharides in the field of pharmaceuticals and functional foods (nutraceuticals).

2. Natural Polysaccharides with Carboxyl Groups

Due to their negative charge, the carboxyl and sulfate groups present in polysaccharide chains can interact with various proteins and metal ions in vivo [36]. They often act as mimics of glycosaminoglycans, such as heparin and hyaluronic acid, that are originally found in vivo; however, they may also exhibit unique physiological effects. Therefore, elucidating the functional significance of acidic polysaccharides derived from natural products is important for understanding the molecular basis of polysaccharide biological activity. Interestingly, polysaccharides containing carboxyl groups are widely distributed in nature. This section outlines polysaccharides exhibiting biological activity.

2.1. Alginate

Alginate is a well-known polysaccharide due to its ability to form a characteristic gel [37]. Alginate is a polyuronic acid composed of linear chains of D-mannuronic acid and L-guluronic acid in varying proportions. (Figure 1) Alginate is primarily derived from marine brown algae such as Sargassum, Macrocystis pyrifera, and Laminaria japonica. Additionally, some microorganisms are also capable of alginate synthesis, for example, Pseudomonas and Azotobacter [37]. Structurally, alginate is a polysaccharide consisting of β-D-mannuronic acid (M) and α-L-guluronic acid (G) residues. It has long been established that the compositional ratios of these two uronic acids differ significantly based on factors such as species, genus, growth location, and tissue type [37].

Sodium alginate has been utilized in various fields, including the medicinal, pharmaceutical and food industries, for its gelling, stiffening and stabilizing properties [38]. There are several reports of oligosaccharides prepared from alginate that exhibit a variety of biological activities, including anti-allergy properties through the suppression of IgE [39,40], anti-hypertensive activity [41], an ability to enhance the growth of human endothelial cells and keratinocytes [42], and an ability to induce cytokine production in a mouse macrophage cell line [43]. The proportion and sequential arrangement of the uronic residues such as mannuronic acid (ManA) and guluronic acid (GulA) vary based on the algal species from which the alginate is prepared. This composition, ManA/GulA (M/G) ratio and alginate molecular weight are responsible for its biological and physico-chemical properties [37,44].

Calcium alginate gel is widely utilized in the food industry for products such as ice cream, confectionery jellies, meat sauces, syrups, and various other applications [45]. The consistency of the gel can be easily adjusted by modifying the amount and type of salt, pH, chelating agents, and other factors [37]. 

2.2 Pectin

Pectin is a high-molecular-weight, biocompatible, nontoxic, and anionic natural polysaccharide extracted from the cell walls of higher plants [46,47]. It primarily consists of three structurally well-characterized polysaccharide motifs: homogalacturonan (HG), rhamnogalacturonan I (RG I), and rhamnogalacturonan II（RG II）(Figure 2) [46,47]. HG serves as the backbone chain of the pectin molecule, comprising α-1,4-linked D-galacturonic acid units. RG I is found in the highly branched region and contains a significant number of neutral sugars, such as arabinose, galactose, and mannose, which act as side chains of α-1,2-linked residues of l-rhamnopyranose. RG II is a branched pectic domain that features an HG backbone and is a highly conserved yet widespread structure [46,47].

Pectin is recognized as a functional ingredient, gelling/thickening agent, and stabilizer in the food industry due to its ability to form aqueous gels [48]. It has been widely used in jams, jellies, fruit preparations, fruit drink concentrates, fruit juices, desserts, and fermented dairy products [49]. Furthermore, its excellent gelling properties, good biocompatibility, nontoxicity, and biodegradability make pectin an attractive novel biopolymer material for applications in the pharmaceutical industry, health promotion, and cosmetics [50].

Pectin is capable of forming a wide range of derivatives due to its unique structure which includes numerous hydroxyl and carboxyl groups distributed along the backbone, as well as a variety of neutral sugars present as side chains [51,52]. By creating pectin derivatives, properties such as solubility, hydrophobicity, physicochemical characteristics, and biological functions can be modified, leading to the development of new functional properties [53]. Thanks to the efforts of numerous research groups, pectin modification has been accomplished using techniques such as substitution (including amidation, thiolation, and sulfation), chain elongation (through cross-linking and grafting), and depolymerization (via acid or enzymatic hydrolysis, β-elimination, and mechanical degradation) [54].

3．Naturally Sulfated Polysaccharides

To identify sulfated polysaccharides purified from natural products, NMR spectroscopy is a useful and powerful tool [27]. For example, the presence of a distinct sulfate group is determined by the low-field shift of the sugar ring proton signal due to substitution of sulfate groups. A separate review article on detailed structural analysis methods for sulfated polysaccharides using NMR spectroscopy will be published in the near future. The polysaccharides containing sulfate groups are generally recognized for their anticoagulant and anti-viral activities [55-57]. Additionally, these sulfated polysaccharides may act as “mimic of glycosaminoglycans” such as endogenous heparin and chondroitin sulfate found in our body. In contrast, some polysaccharides with carboxyl groups have also been evaluated for their biological activity described above.  However, the results indicated that neither alginate nor pectin exhibited any anticoagulant activity [58], and pectin was also ineffective against viral infection [59]. This suggests that, despite containing acidic functional groups with differing dissociation constants, these polysaccharides do not necessarily exhibit comparable physiological activities. In this section, recent progress of biological activities of sulfated polysaccharides as natural products are described.

3.1 Carrageenan

Carrageenan is a highly viscous sulfated polysaccharide derived from red algae, such as hornworts and certain species of seaweed (Figure 3) [60]. Among these polysaccharides, the fraction that precipitates in dilute potassium chloride solution is referred to as κ-carrageenan, while the fraction remaining in the supernatant is known as λ-carrageenan, a classification proposed in 1953 [61]. Currently, carrageenan is fractionated into more than seven distinct types, each with a determined chemical structure [62,63]. The most representative type, κ-carrageenan, is a linear polysaccharide composed of alternating D-galactose and 3,6-anhydro-D-galactose units, particularly those with a sulfate group attached at the 4-position of the D-galactose residue. The other types are considered part of the structural heterogeneity of carrageenan and are classified based on their differences in gel formation [60,62,63].

The relationship between gel-forming ability and structure of carrageenan was clarified relatively early, and it was found that the greater the presence of 3,6-anhydrosugar residues and fewer sulfate groups enhance gel forming ability, while a lower concentration of anhydro sugars and a higher concentration of sulfate groups result in more viscous solutions [64]. Although carrageenan is not currently utilized as a drug, several pharmacological activities have been reported [64]. Notably, anticoagulant activity is one of the most frequently investigated pharmacological properties of polysaccharides containing sulfate groups, and this activity has been measured for an extended period [65]. The consistent finding across various studies is that the anticoagulant activity of λ-carrageenan is significantly higher than that of κ- and ι-type carrageenan [65]. This suggests that there is a structural element within the λ-fraction that exhibits high activity, regardless of the algal species involved. On the other hand, the use of κ- and ι-carrageenan in pharmaceuticals, cosmeceuticals and nutraceuticals is not yet satisfactory [65]. This area will require future developments in structural and biological activity research.

3.2 Fucoidan

Fucoidan is the generic name for polysaccharides in which fucose is the main component [66]. The glycosidic linkages of fucose residues are α-(1-2) or α-(1-3). Other known sugar residues include galactose, mannose, xylose, and glucuronic acid (Figure 4) [67-69]. Partial hydroxyl groups of saccharides are acetylated, and uronic acids other than glucuronic acid have also been identified as components. The sulfate groups characteristic of fucoidan can be randomly substituted at the C2, C3, or C4 positions of L-fucopyranosyl residues. Fucoidan has a broad molecular weight distribution ranging approximately 100-1600 kilodaltons (kDa) [67-69]. A review of the literature indicates that the basic structure of fucoidan varies considerably from species to species. The diversity in fucoidan's sugar composition also makes it difficult to classify and predict its structure based on algal orders. Furthermore, compositional data may differ depending on the extraction method employed. Based on complexity of fucoidan structure, there is few applications for fucoidan in medical and pharmaceutical fields, except usage of fucoidan in nutraceutical as anti-inflammatory ingredients described below. In 1962, Bernardi et al. published a series of comprehensive studies on the anticoagulant activity of fucoidan. In addition to its anticoagulant properties, fucoidan has been reported to have other physiological activities, including promoting the binding of human sperm to the transparent body [72] and inhibiting cancer metastasis [73].

The anti-inflammatory activity of fucoidan has garnered significant attention with studies highlighting its immunomodulatory potential [74-76]. Research indicates that low-molecular-weight fucoidan exhibits anti-inflammatory properties, while high-molecular-weight fucoidan demonstrates immunomodulatory effects [77,78]. However, this phenomenon is not consistent; both low- and high-molecular-weight fucoidan from certain species show anti-inflammatory effects [79]. Fucoidan isolated from Undaria pinnatifida significantly increased the levels of natural killer cells, neutrophils, and pro-inflammatory cytokines in the body while downregulating apoptosis [80]. Fucoidan from Fucus vesiculosus also enhanced dendritic cell maturation, Th1 immune responses, and cytotoxic T-cell activation, as well as increased antibody production following exposure to antigens [81]. Furthermore, fucoidan purified from Fucus evanescens, Laminaria cichorioides, and Laminaria japonica has been shown to activate the immune system [82]. Makarenkova et al. demonstrated that the interaction between fucoidan and Toll-like receptors (TLRs) enhances the production of cytokines and chemokines [83]. These findings suggest that fucoidan binds to TLRs, thereby enhancing NF-κB signaling, which results in the production of cytokines and inflammatory responses [83]. Hayashi et al. reported that natural killer cells and activated T cells were stimulated by treatment with fucoidan isolated from Undaria pinnatifida [84]. Additionally, this treatment increased the production of pro-inflammatory cytokines in a herpes simplex virus (HSV-1)-infected mouse model [84]. Notably, Nagamine et al. evaluated the immunomodulatory activity of fucoidan in clinical trials [85]. This study reported the effects of fucoidan purified from C. okamuranus on the activation of natural killer cells in cancer survivors. The findings suggested that a dose of 3 g of fucoidan was safe for patients and that the recurrence of tumors significantly decreased [85].

4. Glycosaminoglycans

Glycosaminoglycans (GAGs) of proteoglycan molecules are complex polysaccharides that are widely distributed in animal connective tissues and body fluids [86], and as far as this author knows, there have been no reports of glycosaminoglycans existing in the plant kingdom so far. A significant number of proteoglycans have been identified, and their diversity has increased, revealing their involvement in various cellular activities in vivo [87]. The chemical structure of GAGs is highly intricate. The fundamental framework consists of a repeating linear disaccharide structure made up of uronic acid and hexosamine, most of which undergo various modifications during biosynthesis [87]. The major modifications include: (1) the conversion of uronic acid at position 5 (glucuronic acid to iduronic acid), (2) sulfation of the sugar hydroxyl group (O-sulfation), and (3) sulfation of the amino group (N-sulfation). Naturally, this structural heterogeneity complicates structural analysis and has been a source of concern for researchers for many years. Recently, advanced separation techniques such as high-performance liquid chromatography (HPLC) and electrophoresis, along with instrumental analysis methods like nuclear magnetic resonance (NMR), glycan-specific degrading enzymes, and antibodies, have been developed, establishing a solid foundation for the structural analysis of GAGs [88-90].

Glycosaminoglycans (GAGs), like the polysaccharides, possess numerous sulfate and carboxyl groups within their elongated structures. As a result, they exhibit a strong overall negative charge. These polymers demonstrate significant water retention, cation retention properties, and high viscoelasticity [89]. It is easy to envision that GAGs exert both physical and chemical effects on various environments and biological systems in vivo, thereby facilitating their physiological activities [91,92]. This topic is particularly intriguing. We will provide a brief overview of the known physiological and pharmacological activities of heparin/heparinoids, hyaluronan and chondroitin sulfate as representative examples of GAGs. 

4.1 Heparin and Heparinoids

In 1916, McLean isolated a substance from bovine liver tissue that disrupted blood clotting, which Howell subsequently named heparin [31,32,93]. Heparin is found exclusively in a proteoglycan known as cell glycine and is predominantly extracted from the granules of mast cells, as well as from the liver, lungs, and small intestine [94].　The structure of heparin has been extensively studied due to its potent anticoagulant activity [31,32,93]. The generalized structure is represented as (4IdoAα1→4GlcNAcα1→)n, where approximately 80% of the constituent　glucosamine residues are N-sulfated. The administration of heparin into the blood stream significantly the complex formation of complexes thrombin, a serine protease, and its inhibitor, anti-thrombin (AT) within blood coagulation cascade, thereby inhibiting blood coagulation (Figure 5) [95]. Extensive subsequent studies employing heparinolytic methods showed the smallest heparin fragment that capable of binding AT identified by Lindahl's group in 1982 as a pentasaccharide [96]. Notably, series of synthetic studies conducted by van Boeckel demonstrated the sulfate group at position 3 on the glucosamine residue in this pentasaccharide is absolutely essential for its activity (Figure 5) [97]. 

Heparin was the first glycosaminoglycan discovered by humans [31,32].　All heparin-like glycosaminoglycans isolated from animal tissues, as well as all polysaccharides found in nature that exhibit the biological activity of heparin, are called heparinoids. Heparin, produced only by mast cells, is the most sulfated glycosaminoglycan and serves as an essential anticoagulant in modern medicine [31,32,93]. Heparin inhibits thrombin production and activity, releases tissue factor pathway inhibitors, and exhibits anti-inflammatory, antiviral, anti-angiogenic, antitumor, and antimetastatic properties through its high-affinity interactions with various proteins in the bloodstream [31,32,93]. The diverse pharmacological actions of heparin depend on its glycan sequence and degree of sulfation. Conversely, heparinoids with a lower degree of sulfation have been shown to exhibit more physiological functions than heparin [98]. Because heparin is associated with severe side effects, such as bleeding, heparin-induced thrombocytopenia, and thrombosis, heparinoids with a low degree of sulfation are expected to serve as an alternative for patients who cannot use heparin. However, the origin and structure of heparinoids must first be confirmed. 

Crude heparin, which is isolated from animal tissues, contains approximately 50 percent heparin and less than 50 percent heparan sulfate and dermatan sulfate. [98].　The less sulfated glycosaminoglycans, which are usually discarded during heparin production, are chemically degraded and developed into the clinical drug danaparoid [100, 101]. The more highly sulfated glycosaminoglycans are also chemically degraded and used as the clinical drug sulodexides [102, 103]. Clinical studies have shown that these danaparoids and sulodexides have different pharmacological activities than heparin, and further development is expected.

Due to the "Heparin Crisis" caused by contamination of chemically modified chondroitin sulfate in 2007-2008, the global project of the chemo-enzymatic synthesis of heparin is in progress [104].

4.2 Hyaluronan

Hyaluronan (hyaluronic acid) is a linear, high-molecular-weight glycosaminoglycan composed of alternating units of N-acetylglucosamine and glucuronic acid (Figure 6). It is abundant in the vitreous humor of the eye, ligaments, skin, chicken combs, and synovial fluid [105]. Unlike other glycosaminoglycans (GAGs), hyaluronan does not contain sulfate groups, and a core protein has not been identified. One gram of hyaluronan is so hydrophilic that it can retain up to 6 liters of water, existing as a gel-like substance in vivo [105]. Due to this property, hyaluronan has already been utilized in clinical practice for the treatment of knee osteoarthritis, shoulder periarthritis, and as an ingredient in eye drops [106].

It is currently being utilized as a skin wound dressing and as a drug delivery system (DDS) [107]. When considering the pharmacological activity of hyaluronan in the future, it is crucial to recognize that this substance is not a singular component in tissue wounds, tumor growth, or infiltration. If we can elucidate the role of hyaluronan in these physiological phenomena, we may be able to develop new drugs based on this polysaccharide.

4.3 Chondroitin Sulfate

Chondroitin sulfate (hereinafter abbreviated as CS) is a natural acidic polysaccharide (Figure 7) derived from animal sources that is permitted as a designated food additive [108]. It is recognized for its diverse applications as a raw material in pharmaceuticals, health foods, and cosmetics [109]. Generally, CS has been reported to have pain-relieving effects for knee osteoarthritis [110]. The U.S. Department of Health (NIH) published a final report assessing the therapeutic efficacy of oral sodium CS and glucosamine sulfate over a five-year period for osteoarthritis treatment [111]. Despite the findings not meeting expectations, sales of these products have continued to rise, coinciding with restrictions on the use of raw materials from cattle and pigs due to concerns over mad cow disease, as well as limitations on the capture of sharks and whales [112]. CS chains specifically containing sulfation patterns are also known to exhibit anticoagulant activity, including chondroitin sulfates D, E, and K [113], as well as the recently discovered branched fucosyl glycosaminoglycan DHG (Figure 7) [114]. In light of these circumstances, a study was conducted in which products marketed as health foods were randomly selected and analyzed for the quality of CS they contained, utilizing an analytical method developed by the authors. The results indicate that products of questionable origin and quality are indeed being distributed in the market [108]. There are many controversial reports on the effect of chondroitin sulfate as a functional food on osteoarthritis. However, this discrepancy might be explained if we assume that chondroitin sulfate, which has the same structure as the chondroitin sulfate found in our bodies (disaccharide composition), acts as a matrikine in vivo and acts in tissue regeneration (Table 1, Figure 8). For example, the major disaccharide unit is CS-C disaccharide in fish cartilage such as sharks and rays, whereas it is CS-A disaccharide in bovine and porcine cartilage. Also, CS-C disaccharide is predominant in human cartilage resembling in fish CS. This similarity may be important for the biological activity of chondroitin sulfate as a matrikine, which will be described below.

Matrikines are generally defined as degradants of the extracellular matrix produced in response to tissue damage and inflammation induced in vivo [115]. Specifically, they are recognized as peptides generated by matrix metalloproteinases. These degradation products are known to promote cytokine production by immune cells, thereby facilitating tissue regeneration and repair. However, glycosaminoglycan chains, which are also degradation products of proteoglycans in the extracellular matrix, have also been shown to act as matrikines by stimulating cytokine production by immune cells [116]. Based on these results, this review reaffirms the action of sugar chains, especially chondroitin sulfate, as a matrikine and proposes the concept shown in Figure 8.

Recently, chondroitin sulfate proteoglycans (CSPGs), particularly intact aggrecan, have been considered as an alternative nutraceutical material to CS polysaccharides, with several papers reporting on biological effects observed for CSPG isolated from the salmon nasal cartilage [117]. For instance, our group has already reported a method for the preparation of a new CSPG and type II collagen complex using the salmon nasal cartilage [118]. Here, the stronger affinity of CSPG compared to CS polysaccharide chain for L-selectin on the cell surface of immune cells could also be identified [118]. This observation strongly suggests that both CSPG and CS polysaccharide may act as matrikines for tissue remodeling and healing of damages of connective tissues (Figure 8) [110]. Furthermore, the role of the prepared CSPG as a nutraceutical as well as its associated role in various biological and functional activities during the treatment of several disorders related to aging was investigated [119]. Very recently, the presence of CSPG in bony fish has been published [120], and it may be a promising source for the preparation of CS/CSPG as a health food ingredient. Although the CSPG isolated from salmon nasal cartilage as a nutraceutical is only commercially available, it must be becoming more popular material as a nutraceutical in global market.

5. Conclusion

In this review, we introduce natural acidic polysaccharides, particularly those exhibiting significant bioactivity. Additionally, we propose a new hypothesis for the functional role of nutraceutical chondroitin sulfate as a matrikine (Figure 8). The ongoing research focused on it will be addressed in a separate article in the near future.

Acknowledgement

The author would like to thank Hayata Iritani and Tatsuya Wada (Nihon Pharmaceutical Co. Ltd.) for providing beautiful figures (HI) and for careful reading the text (HI & TW).

Conflict of Interest

The author of this review, Dr. Toshihiko Toida is an independent researcher who serves as a paid consultant for Nihon Pharmaceutical Co. Ltd., a company that manufactures polysaccharide-based health products discussed in this review. This relationship is disclosed in the interest of transparency.

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