Immunopotentiating Activity of Fucoidans: History
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Eileen McGowan
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Size Chen
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Jerran Santos
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Haibin Yin
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Yiguang Lin

Fucoidans, discovered in 1913, are fucose-rich sulfated polysaccharides extracted mainly from brown seaweed. These versatile and nontoxic marine-origin heteropolysaccharides have a wide range of favorable biological activities, including antitumor, immunomodulatory, antiviral, antithrombotic, anticoagulant, antithrombotic, antioxidant, and lipid-lowering activities. In the early 1980s, fucoidans were first recognized for their role in supporting the immune response and later, in the 1990s, their effects on immune potentiation began to emerge. The understanding of the immunomodulatory effects of fucoidan has expanded significantly. The ability of fucoidan(s) to activate CTL-mediated cytotoxicity against cancer cells, strong antitumor property, and robust safety profile make fucoidans desirable for effective cancer immunotherapy.

  • fucoidan
  • seaweed
  • immunopotentiation
  • immunomodulatory

1. Introduction

Fucoidans were first isolated from the extracellular mucus matrix of brown macroalgae, class Phaeophycceae, species Fucus vesiculosus, Asophyllum nodosum, Laminaria digiata, and Laminaria saccharina, in 1913, by the Swedish professor Hareld Kylin at Uppsala University [1][2][3]. The name fucoidan was initially used as a general term referring to a variety of high-molecular weight sulfated polysaccharides derived from fibrillar cell walls and mucous matrices of diverse species of brown macroalgae [4]. Until relatively recently, the International Union of Pure and Applied Chemistry (IUPAC) based the fucoidan nomenclature on the generic sulfated fucan structure—a polysaccharide with a backbone structure based on sulfated L-fucose residues, with the main structure consisting of a minimum of 10 monosaccharides [5]. Hence, the names fucoidan, fucoidans, and sulfated fucans have been used synonymously in the literature, distinct from fucans and fucosans. 

The bioactivities of these versatile marine-origin heteropolysaccharides differ depending on the seaweed species and environmental growth conditions.Fucoidans are proving to be promising pharmaceutical agents, widely cited as exhibiting antitumor, immunomodulatory (mainly immunopotentiating), anti-inflammatory, and other pharmacological properties. Researchers aim to provide comprehensive information on the immunopotentiating activity of fucoidan and its immunomodulatory mechanisms, including the association between fucoidan and inflammatory cytokines and signaling pathways to emphasize the potential of fucoidans in modern cancer immunotherapies. 

2. Overview of Fucoidans

2.1. Structural Characteristics of Fucoidans

The structure and composition of fucoidans vary depending on the source [6], marine species [4][6][7][8][9][10][11][12], harvest season [13][14], and extraction methods [11][13][14]. When harvested from various sources and species at different times of the year, fucoidans have been shown to have distinct structural characteristics [4][6][8][9][10][11][12], and the compositional properties are often varied when derived using different extraction methods, which have been extensively reviewed in several species [4][6][8][9][10][11][12]. In particular, extraction methods and sources are the two critical factors that influence the proportions of monosaccharides contained within different fucoidan extracts [15][16][17], leading to the inducement of different immune activities. For example, previous studies have shown that fucoidan extracts from Ecklonia cava, Ascophyllum nodosum, Undaria pinnatifida, Laminaria japonica, and Fucus vesiculosus induced T cell activation [18], promoted T cell proliferation [19], dendritic cell (DC) maturation [20], macrophages [21], and activation of natural killer cells (NK), respectively. Although fucoidans have no universal structure, the fucoidan extracted from Fucus vesiculosus, known as bladderwrack, has the most straightforward and typical fucoidan chemical structure among all species of brown seaweed. Patankar et al. (1993) reported that fucoidan derived from Fucus vesiculosus has a base of repeating α

(1→3)-linked α-L-fucopyranose units with a substituted sulfate group at the C-4 position on the chain and fucose enabling branching points within the chain [11][22][23]. Subsequently, two additional structural models of fucoidan have been reported: (1) an alternated (1→4)-linked α-L-fucopyranose units [11][17][24][25]; (2) an alternated (1→3) and α

(1→4)-linked sulfated L-fucopyranose [11][25][26][27][28]. As previously mentioned, fucoidans are heteropolysaccharides that consist primarily of abundant L-fucose residues and sulfate groups, but they also contain traces of monomers, such as galactose, uronic acid, xylose, mannose, glucose, and glucuronic acid [2][11][24][27][28][29][30]. Previous characterization demonstrated variations in monosaccharide composition, molecular weight, types of glycosidic linkages, the presence of branching, and the degree of sulfation [15][29][31][32]. The importance of understanding these structural and compositional variations is that they can have varying impacts on therapeutic effects in cancer treatment and other inflammatory-based diseases.
The pharmacological effects of fucoidan vary with their molecular weight. Although the IUPAC definition of fucoidan is a minimum of 10 monosaccharides, fractional derivatives are commonly used to assess fucoidan bioactivity [33]. Fucoidans are usually classified as being either a low molecular weight fucoidan (LMWF) or high molecular weight fucoidan (HMWF), as the pharmacological effects of fucoidans vary with their molecular weight. Generally, LMWF refers to molecular weight < 10 kDa, while HMWF refers to a fucoidan with a molecular weight > 10,000 kDa, and medium molecular weight is 10–10,000 kDa [16][34]. However, other standards of classification are also used. For example, HMWF means a fucoidan with an average molecular weight of 300 kDa or more, while a fucoidan with an average MW < 300 kDa is considered LMWF [35].

2.2. Pharmacological Actions of Fucoidans

Fucoidans have been shown to exhibit a variety of beneficial pharmacological effects, including antitumor [36][37][38][39][40][41], anti-inflammatory [26][36][42], immunomodulatory [26][36] antioxidant [7][13][43], anticoagulant [36][44][45][46][47], antithrombotic [36][48][49], antiangiogenic [36][39][50][51][52][53][54], and antiviral [55][56][57][58][59][60].
The antitumor effects of fucoidans have been extensively investigated in vitro in various tumor cell lines, especially in lung and breast cancer cell lines [61][62][63], and in vivo in animal models [64]. The antitumor mechanisms of fucoidans in these tumor cells (e.g., A549, MCF-7) include cell cycle arrest at the sub-G1/G1 phase [65][66][67][68], caspase-dependent apoptosis [66][67][69], regulation of specific apoptotic proteins (e.g., poly [ADP-ribose] polymerase 1 (PARP1) [70][71][72], protein kinase RNA-like endoplasmic reticulum kinase (PERK), B-cell lymphoma 2 (Bcl-2) [70], BAX [70][73], and caspases -3, -8, and -9 [66][70][72]). Increasing evidence has shown that fucoidans are capable of exhibiting direct and indirect inhibitory effects on tumor cells by regulating several important signaling pathways, such as extracellular signal-regulated kinase 1/2 (ERK1/2) [39][70][74], phosphoinositide 3-kinase-Akt (PI3K/Akt) [70][74], p38 mitogen-activated protein kinase (p38 MAPK) [70], and mammalian target of rapamycin (mTOR) pathways [73][74].
In the in vitro study by Miyamoto et al. (2009) [66], they found that fucoidan (Cladosiphon okamuranus) was cytotoxic to MCF-7 cells and resulted in a significant increase in the number of apoptotic MCF-7 cell bodies, with condensation of chromatin and DNA fragmentation at the sub-G1 phase of the cell cycle [66]. They then demonstrated that cell cycle arrest at the sub-G1 phase was accompanied by activation of caspases (caspase 7, -8, -9) and PARP cleavage in fucoidan-treated MCF-7 cells at a concentration of 1000 μg/mL [66]. These results suggest that fucoidan (Cladosiphon okamuranus) induces apoptosis through activating specific caspases (e.g., caspase-7, -8, -9) and interacts with apoptotic proteins (e.g., PARP) to induce apoptosis in MCF-7 cells at a high concentration (e.g., 1000 μg/mL). In another in vitro study, Zhang et al. showed that fucoidan (Mozuku, Cladosiphon novaecaledoniae) caused an accumulation of apoptotic MCF-7 cells at the G1 phase of the cell cycle [65], and these apoptotic MCF-7 cells presented with shrunken nuclei and fragmented chromatin [65]. They found that fucoidan (Mozuku, Cladosiphon novaecaledoniae) was cytotoxic to MCF-7 cells and inhibited 60% of MCF-7 cell growth at a concentration of 820 μg/mL [65]. Banafa et al. showed, in vitro, that fucoidan (Fucus vesiculosus) could induce apoptosis in MCF-7 cells through inducing cell cycle arrest at the G1 phase by downregulating the expression levels of cyclin D1 and CDK-4 in MCF-7 cells [69]. They also revealed that fucoidan (Fucus vesiculosus) could induce apoptosis by downregulating the anti-apoptotic protein of Bcl-2 and upregulating the pro-apoptotic protein of Bax in fucoidan-treated MCF-7 cells [69]. In addition, they demonstrated that treatment with fucoidan (Fucus vesiculosus) could activate caspase-8 and increase cytochrome C release in MCF-7 cells [69], supporting the theory that a caspase-dependent pathway may lead to apoptotic protein cleavage, such as Bid cleavage [69]. Furthermore, a more recent in vitro study by Abudabbus et al. (2017) showed that commercial fucoidan (Fucus vesiculosus) caused cell cycle arrest at the sub-G1/G1 phase with activation of caspases 3, -7, and -9 [67]. Overall, these results suggest that the fucoidan (e.g., Cladosiphon novaecaledoniae, Fucus vesiculosus)-induced apoptosis involves the activation of caspases (caspase 3, -7, -8, -9) and cell cycle arrest at the G0/G1 phase in MCF-7 cells.
The molecular weight of fucoidan also influences its potential to induce apoptosis in MCF-7 and MDA-MB-231 cell lines. In a recent in vitro study conducted by Lu et al. (2018), they demonstrated that a LMWF from New Zealand Undaria pinnatifida was cytotoxic and exhibited maximum anti-proliferative effects in both MCF-7 and MDA-MB-231 cells at concentrations of 200 μg/mL and 300 μg/mL, respectively [75]. They also demonstrated that this LMWF (New Zealand Undaria pinnatifida) significantly increased the total caspase in MDA-MB-231 cells at a concentration of 300 μg/mL [75]. Notably, the concentration of fucoidan used in the study was much lower than in the previous studies by Zhang et al. (2013) [76], Miyamoto et al. (2009) [66], and Banafa et al. (2013) [69]. Therefore, these results suggest that the effective concentration of fucoidan used to induce apoptosis in breast cancer cell lines (MCF-7, MDA-MB-231) varies significantly.
Regardless of the species of fucoidan, all fucoidans tested inhibited A549 cell growth and proliferation by adjusting their concentrations in both in vitro and in vivo studies. An in vitro study conducted by Boo et al. (2011) showed that fucoidan (Undaria pinnatifida) significantly inhibited A549 cell growth leading to the accumulation of apoptotic A549 cell bodies at the sub-G1 phase of the cell cycle at a concentration of 200 μg/mL [70]. These apoptotic A549 cell bodies presented with chromatin condensation, membrane blebbing, and cell shrinkage [70]. Boo et al. (2011) also demonstrated that fucoidan (Undaria pinnatifida) could induce apoptosis by activating caspase-9, decreasing pro-caspase-3, and then inducing PARP cleavage in A549 cells at a concentration of 200 μg/mL [70]. Furthermore, they revealed that fucoidan-induced A549 cell apoptosis is also associated with downregulation of antiapoptotic Bcl-2 proteins and upregulation of pro-apoptotic BAX proteins at a concentration of 200 μg/mL [70]. In addition, they also demonstrated that fucoidan (Undaria pinnatifida) activated the ERK1/2 signaling pathway [70], whilst inhibiting the p38 MAPK and PI3K/Akt signaling pathways [70], suggesting that fucoidan (Undaria pinnatifida) induces apoptosis in A549 cells through regulating the MAPK-based signaling pathways (ERK1/2, p38 MAPK, and PI3K/Akt). In particular, this was the first in vitro study in which researchers confirmed that fucoidan-induced apoptosis is associated with the regulation of apoptotic proteins (e.g., PARP, Bcl-2, Bax), signaling pathways (e.g., ERK1/2, p38 MAPK, PI3K/Akt), and specific caspases (e.g., caspase-9, pro-caspase-3) in A549 cells [70]. Similarly, an in vitro study by Hsu et al. (2017) demonstrated that commercial fucoidan (Fucus vesiculosus) induced cell cycle arrest at the sub-G1/G1 phases by upregulating p21 gene expressions in A549 cells at a concentration of 200 μg/mL and induced apoptosis by activating PARP proteins and caspase-3 in A549 cells at a concentration of 400 μg/mL [72]. They also reported that the commercial fucoidan (Fucus vesiculosus) could induce apoptosis through inducing an ER stress response by activating the PERK/ATF4/CHOP pathways [72]. These results suggest that fucoidan induces A549 cell apoptosis not only through regulating apoptotic proteins (e.g., PARP, Bcl-2, Bax), genes (e.g., p21) and caspases (e.g., caspase-9 and -3), but also by regulating extrinsic signaling pathways, such as the PERK/ATF4/CHOP pathways.
Furthermore, similar results were also obtained in in vitro studies by Lee et al. (2012) and Hsu et al. (2018) [71]. Lee et al. (2012) demonstrated that commercial fucoidan (Fucus vesiculosus) inhibited cell proliferation of A549 cells at a concentration of 400 μg/mL [74], and Hsu et al. (2018) demonstrated that fucoidan treatment could significantly inhibit A549 cells at concentrations of 200 and 400 μg/mL (IC50= 10 μM) [71]. Lee et al. (2012) found that commercial fucoidan (Fucus vesiculosus) could suppress MMP-2 activity, migration, and invasion of A549 cells at a concentration of 200 μg/mL, and also revealed that commercial fucoidan (Fucus vesiculosus) could inhibit MMP-2 expression, metastasis, and invasion by inhibiting phosphorylation levels of the ERK1/2 and PI3K-Akt-mTOR pathways and its downstream targets 4E-BP1 and p70S6K at a concentration of 200 μg/mL [74]. Thus, these results suggest that fucoidan inhibits the MMP-2 activity by regulating the ERK1/2 and/or PI3K-Akt pathways but may only partially involve the mTOR pathway. These results also indirectly indicate that commercial fucoidan (Fucus vesiculosus) inhibits A549 cell growth and proliferation by downregulating the PI3K-Akt-mTOR and ERK1/2 signaling pathways in a concentration range of 200–400 μg/mL. Furthermore, the in vitro study by Chen et al. (2021) also demonstrated that fucoidan inhibits A549 cell proliferation by decreasing the level of protein expression of p-mTOR and downstream proteins p-S6K, p-P70S6K, and p-4EBP1 in the mTOR pathway [73]. They also demonstrated that fucoidan induces apoptosis by reducing the expression levels of anti-apoptotic Bcl-2 proteins and increasing the expression levels of pro-apoptotic BAX proteins in A549 cells [73]. These results reinforce that fucoidan-induced apoptosis in A549 cells is associated with the balance of the Bcl-2/Bax ratio, and the regulation of the ERK1/2 and PI3K-Akt-mTOR pathways. Taken together, these results substantiate the theory that the balance of the apoptotic protein ratio and the activation of signaling pathways are essential for fucoidan to induce apoptosis in A549 tumor cells.
Some studies demonstrating the anti-inflammatory effects of fucoidans are presented here for discussion. In an in vitro study, Jeong et al. (2017) reported that fucoidan (Fucus vesiculosus) was non-cytotoxic to RAW264.7 murine macrophages at 100 μg/mL and attenuated the production of pro-inflammatory cytokines of TNF-α and IL-1β in RAW264.7 murine macrophages treated with liposaccharide (LPS) [77]. These results are consistent with the findings presented in a recent in vitro study where they showed that a particular fucoidan (Saccharina japonica) fraction (LJSF4) induced a strong inhibitory effect on the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 [78]. These results strengthen the argument that fucoidan, regardless of its species derivation, has the ability to induce anti-inflammatory effects in RAW264.7 macrophages. Furthermore, Lee et al. (2012) found that three Ecklonia cava fucoidan fractions (F1, F2, F3) were not toxic to the RAW 264.7 macrophages at a concentration of 12.5–100 μg/mL and could significantly inhibit NO production, iNOS, COX-2 mRNA expression level, and pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in LPS-treated RAW264.7 macrophages [79], where the F3 fraction had the highest inhibitory effects on NO production [79]. These results suggest that there may be an association between the inhibition of the iNOS/NO pathway and attenuation of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), but more studies are required to verify whether there is a connection between these two stimuli. Furthermore, the investigations by Fernando et al. (2017) also showed similar results; they found that the F2,4 fraction (Chnoospora minima fucoidan) was non-cytotoxic to LPS-treated RAW264.7 macrophages and exhibited a maximum inhibition in NO production, while the mRNA expression of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6) was decreased in LPS-treated RAW264.7 macrophages at a concentration of 50 μg/mL [80]. Sanjeewa et al. (2018) reported that the Sargassum horneri fucoidan f4 fraction (36.86% fuc and 18.47% sulfate contents) exhibited the maximum inhibitory effects on NO production and significantly inhibited the mRNA expression levels of the pro-inflammatory cytokines of TNF-α and the PEG2 enzyme in LPS-treated RAW264.7 murine macrophages without causing any toxicities [81], but only slightly inhibited IL-6 production [81]. They also demonstrated that the f4 fraction could dose-dependently inhibit the expression of the iNOS and COX-2 proteins [81], as well as inhibit the phosphorylation of IκB-α and p-I κB-α [81]. These results suggest that the Sargassum horneri fucoidan f4 fraction induces anti-inflammatory effects in LPS-treated RAW264.7 macrophages through the NF-κB pathway [81].
Sanjeewa et al. (2017) demonstrated that a crude fucoidan extracted from Sargassum horneri had no cytotoxicity to RAW264.7 murine macrophages and exhibited a maximum suppressive effect on NO production in LPS-treated RAW264.7 murine macrophages [82]; it also reduced the secretion of pro-inflammatory cytokines TNF-α and IL-1β and downregulated the expression levels of iNOS and COX-2 proteins in RAW264.7 murine macrophages treated with LPS [82]. More importantly, they also showed that CCP fucoidan (Sargassum horneri) (100 μg/mL) induced anti-inflammatory effects in RAW264.7 murine macrophages treated with LPS by inhibiting the translocation of NF-κB p50 and p65 to the nucleus and downregulation of phosphorylation of p38 and ERK1/2 that was shown to increase with LPS stimulation in RAW264.7 macrophages [82].
Fucoidan has also been shown to act as a pro-inflammatory cytokine modulator in other types of cells, including mesenchymal stem cells (MSCs) [83], THP-1 monocytes [84], human peripheral blood mononuclear cells (PBMC) [85], porcine peripheral blood polymorphonuclear cells (PMN) [86], and human intestinal epithelial cells (Caco-2 cells) [87], indicating that fucoidan is capable of inducing anti-inflammatory effects in a broad range of cells. In an earlier in vitro study, Hwang et al. (2016) reported that LMWF (Sargassum hemiphyllum) induced anti-inflammatory effects in Caco-2 cells by downregulating LPS-induced TNF-α and IL-1β [87], which is in line with the findings from another in vitro study conducted by Ahmad et al. (2021) [85]; they demonstrated that fucoidan (Undaria pinnatifida) induced significant inhibitory effects on the pro-inflammatory cytokines of TNF-α and IL-6 in LPS-treated human PBMC cells [85]. However, the expression of IL-1β was only slightly reduced in the study [85], suggesting that fucoidan (Undaria pinnatifida) is less effective in reducing the expression of IL-1β in LPS-treated human PBMC cells as compared to the potency of the other two pro-inflammatory cytokines, namely TNF-α and IL-6. Furthermore, they also showed that fucoidan (Fucus vesiculosus) significantly inhibited three pro-inflammatory cytokines, namely TNF-α, IL-1β, and IL-6, in LPS-treated human PBMC [85]. Taken together, these results support the theory that Fucus vesiculosus fucoidan has a greater capability than Undaria pinnatifida fucoidan to exhibit inhibitory effects on pro-inflammatory cytokines, namely TNF-α, IL-1β, and IL-6, in LPS-treated human PBMC cells. It also indirectly indicates that Fucus vesiculosus fucoidan may have a greater cytotoxic level than Undaria pinnatifida fucoidan in LPS-treated human PBMC cells. Macrocystis pyrifera fucoidan and fractionated Macrocystis pyrifera fucoidan (5–30 kDa) also significantly inhibited pro-inflammatory cytokines TNF-α in LPS-treated THP-1 cells [85]. Furthermore, Kim et al. (2018) reported that fucoidan has a negative effect on inhibiting the production of TNF-α in PBMC [86]; this was found in the process of suppressing excessive phagocytosis of porcine peripheral blood PMN [86]. However, the mRNA expression level of TNF-α was reduced by adding fucoidan to LPS-stimulated PBMCs [86]. These results are in line with those reported in MSCs [83], they found that after coculture of MSCs treated with fucoidan with LPS-stimulated macrophages, the level of pro-inflammatory cytokines of TNF-α decreased, suggesting that MSCs treated with fucoidan are capable of inhibiting the production of TNF-α in LPS-stimulated macrophages. Another important in vitro study designed three fucoidan/chitosan nanoparticles for the topical delivery of methotrexate [84]. To assess the anti-inflammatory effect of this compound, Barbosa et al. (2019) characterized the fucoidan/chitosan (F/C) nanoparticles into three groups based on the weight ratio of fucoidan and chitosan, named 1F/1C, 3F/1C, and 5F/1C [84]. According to their findings, the 5F/1C nanoparticle contained a large amount of fucoidan and showed the highest inhibitory effects on the production of pro-inflammatory cytokines, namely TNF-α, IL-1, and IL-6, in human THP-1 monocytes [84], suggesting that the fucoidan content in the 5F/1C nanoparticle plays an important role in inducing anti-inflammatory effects in human THP-1 monocytes.
All these results further strengthen the concept that fucoidan may induce its anti-inflammatory effects by inhibiting pro-inflammatory cytokine secretion and mRNA expression levels of pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in LPS-stimulated immune cells including RAW264.7 murine macrophages [77][78][79][81][82][88], Caco-2 cells [87], THP-1 cells [85], human PBMC, porcine peripheral blood PMNs, and MSCs. More importantly, macrophages appear to play an essential role in the initial stages of the anti-inflammatory effects of fucoidan. However, Obluchinskaya et al. (2022) demonstrated that Fucus vesiculosus fucoidan extracts (FV1 and FV3) containing a high polyphenol content (135.9 PhE/g DW) induced a greater radical scavenging activity than four other seaweeds (Saccharina japonica, Fucus distichus, Fucus serratus, and Ascophyllum nodosum) [89], suggesting that the chemical composition in fucoidans may also influence its capability to induce anti-inflammatory effects.
Fucoidan antioxidant effects have been shown to prevent disruptions caused by the excessive accumulation of amyloid-β and reactive oxygen species (ROS) in the human body [90]. Several previous in vitro studies have demonstrated that fucoidans can act as ROS scavengers by removing free hydroxyl radicals and superoxide radicals [91][92]. The antithrombotic and anticoagulant effects of fucoidans are demonstrated primarily by prolonged activated partial thromboplastic time (APTT), prothrombin time (PT), and thrombin time (TT) [45], indicating that fucoidans can exhibit inhibitory effects on several intrinsic factors (e.g., II, V, VIII, IX, XI, XII) and extrinsic pathways to induce antithrombotic and anticoagulant effects in in vitro studies [47][90]. Fucoidans have also been shown to help relieve symptoms of various viral diseases, including severe acute respiratory syndrome coronavirus 2 (SRAS-CoV-2) [60], I-type influenza virus [58], human immunodeficiency virus 1 (HIV-1) [55], and herpes simplex virus (HSV) [57], by inhibiting virus attachment to host cells or directly inhibiting specific viral-related antigen productions. Fucoidans have also been shown to inhibit angiogenesis by regulating vascular endothelial growth factors (VEGF), fibroblast growth factor 2 (FGF-2), matrix metalloproteinases (MMPs), and chemokines (e.g., CXCL12) [52][90].

2.3. Pharmacokinetics of Fucoidans

The absorption of fucoidans is dependent on their source and structure. Several studies have investigated fucoidan absorption using the ELISA method and suggested that the molecular weight of a fucoidan may influence its absorption and excretion [93]. However, this observation is not entirely consistent with those obtained from other relevant in vivo and human clinical studies [94][95][96][97][98][99][100][101]. They suggested that the dosage, species, and structure of a fucoidan would also contribute to the variation in absorption and elimination [94][95][96][97][98]. Zhao et al. reported that oral administered LMWF (Laminaria japonica) reached the highest concentration in rat plasma at 15 h [94], which was faster than LMWF (Laminaria japonica, MW = 35 kDa) at the same oral dose [94]. The results suggest that the molecular weight of fucoidan below 10 kDa with a high oral dose would help to increase the absorbed amount of fucoidan in a relatively short timeframe (15 h vs. 25 h). It also indicated that the molecular weight of fucoidan ranging from 10–40 kDa has a long absorption time in rat plasma. Others showed that oral administration of LMWF (Laminaria japonica) in rat plasma reached the Cmax in under 2 h [95][96], which has a shorter absorption time after oral administration. When Zhao et al. (2016) used a higher oral dose of fucoidan (oral dose = 400 mg/kg and 800 mg/kg) in rats, the time to take to reach Cmax was much longer. Thus, the oral dose of LMWF could also be a critical factor affecting the pharmacokinetics of fucoidan in rats. Furthermore, Pozharitskaya et al. demonstrated that the fucoidan concentration (Fucus vesiculosus), in the plasma of rats reached a maximum level (0.125 μg/g) at 4 h after intragastric administration. These results were not entirely consistent with those obtained from human clinical studies. A human study showed that the plasma concentration of fucoidan (Cladosiphon okamuranus, molecular weight = 66 kDa, dose = 1 g) reached the maximum level in 7 out of 10 samples (serum: up to 100 ng/mL) at 6 h after 1 g of fucoidan administered to healthy volunteers, and only one sample reached the highest concentration (approximately 62 ng/mL) at 9 h [97]. These results indicate that the human intestinal absorption rate of fucoidan varies between individuals. They also found that the concentration of fucoidan was elevated in urine (up to 1000 ng/mL) after oral administration [97], but the molecular weight of fucoidan was reduced to 1.8–3.1 kDa in urine [97]. These results indicate that orally administered LMWF has a higher absorption and elimination rate than intragastrical administered HMWF, suggesting that the molecular weight of fucoidan could be a critical factor influencing the pharmacokinetics of fucoidan in the body. Fucoidan species is less likely to be a factor affecting the pharmacokinetics of fucoidan, suggesting that LMWF from Fucus vesiculosus or Cladosiphon okamuranus is capable of being developed and used for therapeutic purposes.
The pharmacokinetics of fucoidan is also influenced by the route of administration. A LMWF (Laminaria japonica,) reached the Cmax (110.53 μg/mL) in 5 min after I.V. injection [99], but oral administered LMWF (Laminaria japonica,) was detected at 2 h after intragastric administration [99]. Similar results were also obtained from a recent study by Bai et al. (2020); they demonstrated that the fluorescein isothiocyanate labeled (FITC) fucoidan (Fucus vesiculosus, MW = 107.8 kDa, I.V. injection dose = 50 mg/kg) reached the Cmax (66.37 μg/g) in mouse plasma at 30 min and was not detectable in the blood after 4 h [101]. They also showed that FITC fucoidan could circulate to other organs in mice, such as the lung (Cmax = 110.92 μg/g at 4 h), liver (Cmax = 284.7 μg/g at 0.5 h), spleen (Cmax = 77.79 μg/g at 6 h), and kidney (Cmax= 1092.31 μg/g at 4 h) [101]. Data on pharmacokinetics in humans is still limited.

2.4. Biomedical Usages of Fucoidans

Fucoidans are important pharmaceutical candidates in cancer therapy because of their high nutritional and biomedical value. Fucoidans have been classified as a dietary supplement that is generally recognized as safe by the FDA and is recognized as a safe food ingredient [28][102][103]. Prior to becoming an FDA-approved food supplement in 2017 and commercially available on the market, seaweed has been widely used as a functional food and as an established ingredient in local cuisine in several Asian countries, including China, Japan, and Korea [38]. During the 16th to 18th centuries, seaweed was discovered to have medicinal benefits in the treatment of goiter, psoriasis, asthma, several thyroid deficiencies, and skin diseases in China, France, and the United States [104]. In addition, fucoidan derived from Fucus vesiculosus has been used in a variety of combination products in European countries, including (1) homeopathic medical products in Austria; (2) laxatives in Belgium and Poland; (3) an authorized iodine supplement in Denmark; (4) an adjuvant in slimming diets in France, Spain, and the United Kingdom, and (5) as a traditional herbal remedy to treat obesity and rheumatic pain in the United Kingdom [104]. Fucoidan, as a nutritional supplement, is administered primarily through oral tablets and liquid administration. On the other hand, fucoidan is currently used as an ingredient in cosmetic and nutraceutical products.

3. Immunopotentiating Effects of Fucoidans

Fucoidan was first observed to support the immune response in the early 1980s [105]. The effect of fucoidans on immune potentiation emerged in the 1990s [106][107]. Over the past two decades, research into the immunomodulatory (immunopotentiating) effects of fucoidans has expanded significantly.

3.1. Overall Effects of Fucoidans on the Immune System

Fucoidans have now been shown to have immunopotentiating effects on both the adaptive and innate immune response. The immunopotentiating effects of fucoidan have been identified in studies using T cells [108][109][110], macrophages [21][108][111], DC (DCs) [110][112], and natural killer cells (NK) [57][110][113][114]. Toll-like receptors (TLRs) and scavenger receptor type A (SR-A) receptors are the two critical controllers in fucoidan-activated DCs [20][115][116]. Pro-inflammatory cytokines, such as TNF-α, IFN-γ, and interleukin 6 (IL-6), have been proposed as a mechanism to regulate fucoidan-activated macrophages and NK cells to induce antitumor immunity dependent on dose and molecular weight [20][117][118].

3.2. Immunological Effect of Fucoidans on T Cells

Fucoidan immunomodulatory effects are preferentially studied using T cells, particularly when investigating its antitumor immunity. However, studies investigating the direct effect of fucoidans on T cells are relatively limited. So far, there has been no study examining the effect of fucoidan on CAR-T cells.
Fucoidan antitumor immune responses have been studied in both in vivo and in vitro models [26][112][116][119]. When co-cultured CD8+ T cells and human breast cancer cells (MCF-7) were used to investigate the immune response of fucoidan, it was discovered that the number of CD8+ T cells and interferon-γ (IFN-γ) was doubled in the fucoidan-treated group compared to the control [120]. However, when NY-ESO-1-specific CD8+ T cells were stimulated by fucoidan (Fucus vesiculosus)-treated DCs, interferon-γ (IFN-γ) secretion was higher than in the CD8+ T cells group [120], suggesting that fucoidan can activate NY-ESO-1-specific CD8 + T cells by increasing IFN-γ production. Similar results were also obtained from a separate study, which demonstrated that fucoidan promotes both CD4+ and CD8+ T cell responses by upregulating the pro-inflammatory cytokines of Th1 and Tc1 cells, namely IFN-γ and TNF-α [112]. However, because this immune response depends on IL-12 production, fucoidan may be able to enhance Th1 and Tc1 immune responses if it increases IL-12 production in the presence of Th1 and Tc1 cells.
Yang et al. demonstrated that fucoidans from Ascophyllum nodosum and Fucus vesiculosus directly promote T cell proliferation and activation through upregulating IFN-γ and TNF-α secretion in CD8+ T cell populations [19]. Furthermore, gene set enrichment analysis (GSEA) revealed that some representative genes within the JAK/STAT pathway were increased in the fucoidan treatment group, including IL-3, IL-6, IL-13, IL-14, IL-24a, CSF2, and CD70 indicating that fucoidan improves CD8+ T cell activation and proliferation via the JAK/STAT pathway [19]. More importantly, they found that the T cell receptor (TCR) complex played a critical role in promoting the activation and proliferation of CD8+ T cells and that it interacted with the TCR/CD3 complex to enhance T cell activation [19], which has a significant advantage in the discovery of new molecular mechanisms of fucoidan-induced immunomodulatory effects. These results are partially consistent with another study in which the treatment with intranasal fucoidan (Ecklonia cava) treatment increased the level of IFN-γ and TNF-α in mLN CD8 and CD4 T cells in both C57BL/6 and BALB/c mice [18].
Fucoidan can also induce indirect immune responses in T cells. LMWF (Undaria pinnatifida) has been shown to induce indirect immune responses in CD4+ and CD8+ T cells through DCs [20], as DCs treated with LMWF activated T cells and significantly increased CD4+ and CD8+ T cell proliferation, indicating that DCs treated with LMWF play a critical role in T cell activation and proliferation.

3.3. Immunological Effect of Fucoidan on Dendritic Cells

In early studies, DCs were considered to be a potential target for the immunomodulatory capacity of fucoidan [115]. The DCs are critical mediator cells that interact with fucoidan to activate pattern recognition receptors (PRR), resulting in T cell priming and acquired immunity [121]. Toll-like receptors (TLRs) and scavenger receptors (SRs) have emerged as critical regulators that can interact with DC and fucoidan to influence innate and adaptive immunity [112][121][122]. Fucoidan can activate DC maturation by increasing specific surface molecules, such as CD40, CD86, MHC class I and class II, or cytokines, including IL-12 [112], TNF-α[116] and IFN-γ, in the host [115].

3.3.1. Fucoidan Activates the Maturation of DCs via Toll-like Receptors

The TLRs are essential receptors for initiating DCs and triggering primary immune responses and are typically involved in the recognition of potential pathogens and the activation of DCs [121]. Activation of TLRs can alter the ability of DCs to interact with T cells by regulating three types of signals delivered by DC to promote T cell expansion and differentiation into effectors: (1) antigen-specific signal 1; (2) co-stimulatory ‘signal 2′ proteins, such as CD40, CD80, and CD 86; (3) cytokines, such as TNF-α and INF-γ [121][123]. As previously reported, LMWF from Undaria pinnatifida stimulated the maturation of DCs by activating the toll-like receptor 4 (TLR4), and its downstream MAPK and NF-κB signaling pathways markedly increasing the expression of CD40, CD86, MHC I, and MHC II molecules [20].
Another LMWF fucoidan (Ecklonia cava) has also been shown to promote similar activation of DCs by increasing the levels of CD40, CD80, CD86, and MHC class I and II molecules in fucoidan-treated mice, upregulating the production of several pro-inflammatory cytokines, such as IL-6, IL-12, and TNF-α [114].
Fucoidan (Fucus vesiculosus) also contributed to activation of the maturation of human monocyte-derived DCs [115], as well as the upregulation of the expression of co-stimulatory molecules of DCs, promoting the secretion of cytokines, namely TNF-α, IL-12 and IFN-γ[115].
It is worth noting that different sources of fucoidan used in the above studies could lead to the activation of DCs, implying that the actual source of fucoidan may not be a critical factor. One common feature of LMWFs was that in all experiments they were shown to be endotoxin-free, which differ from HMWFs that potentially were contaminated with endotoxin.

3.3.2. Fucoidans Activate the Maturation of DCs via Scavenger Receptor Type A (SR-A)

Fucoidans inhibited SR-A in DCs by significantly increasing the binding of NY-ESO-1 to DCs. The DCs treated with fucoidan (species data not shown) exhibited a more mature phenotype than the DCs without fucoidan treatment [120]. This result indicates that SR-A is a critical factor that may influence DC maturation. Fucoidan (Fucus evanescens) was shown to indirectly induce human peripheral blood dendritic cell maturation (PBDC) and increase TNF-α production [116]. Therefore, fucoidan (Fucus evanescens)-medicated DC maturation can be blocked if fucoidan is pretreated with a TNF-α-neutralizing antibody [116]. Furthermore, a consistent result was obtained in a later in vivo study, in which they not only demonstrated that fucoidan (Fucus vesiculosus) could induce maturation in mouse DCs and induce upregulation of TNF-α, but also showed that fucoidan (Fucus vesiculosus) increased the production of IL-6 and IL-12 in spleen DCs [112]. These findings imply that fucoidan is a viable candidate for induced antitumor immune responses by regulating the levels of IFN-γ, TNF-α, or other specific interleukins, such as IL-6 and IL-12 levels.

3.4. Immunological Effect of Fucoidan on Macrophages

The immunomodulatory effect of fucoidan via macrophages is strongly associated with the production of pro- and anti-inflammatory cytokines, such as interleukin 6 (IL-6) [21][117], TNF-α [21][111][117], nitric oxide (NO) [111][124], and inducible nitric oxide synthase (iNOS) [111][117][125].
In the innate and adaptive immune systems of mammals, macrophages are the first line of defense against pathogens and tumors [117]. Macrophages have been shown to interact with fucoidan to inhibit tumor initiation, progression, and metastasis within the malignant tumor microenvironment (TME) [118][126]. A recent study demonstrated that LMWF from Undaria pinnatifida markedly increased the number of macrophages in splenocytes with elevated levels of IL-6 secretion [20], implying that fucoidan-mediated IL-6 secretion may play an essential role in macrophage activation.
Fucoidan has been shown to induce immunomodulatory effects after being treated with M2 macrophages by suppressing cytokines (IL-6 and TNF-α), and downregulating CCL22 chemokine by inhibiting p65-NF-κB phosphorylation [117][118]. However, different results were found in a different study where they demonstrated that LMWF-treated RAW264.7 macrophages increased the expression of pro-inflammatory mediators of IL-6 and TNF-α [117], as well as enhancing NO and iNOS production [117]. Furthermore, LMWF also activated the NF-κB signaling pathway by upregulating the phosphorylation of lκB-α and p65, and upregulated the MAPK signaling pathway by inducing phosphorylation of p38 [117]. Increased NO production in macrophages could be through the p38 MAPK and NF-κB signaling pathway [124]. A fractionated fucoidan (Nizamuddinia zanardiinii) named as F3, could activate RAW264.7 macrophages by increasing the expression of cytokine mRNA (iNOS, NO, TNF-α, IIL-1β, and IL-6) and proteins that regulate the MAPK and NF-κB signaling pathway, such as p-NF-κB, p-JNK, p-ERK, and p-p38 proteins [111]. In summary, these results show that fucoidan activates RAW264.7 macrophages by upregulating the inflammatory cytokine, MAPK, and NF-κB signaling pathways.
Furthermore, fucoidan (Laminaria japonica) has been used to promote the differentiation of RAW264.7 macrophages from M0 to M1 phenotype macrophages [21]. Differentiation of RAW264.7n macrophages to M1 macrophages occurs via increasing the pro-inflammatory cytokines of IL-6, TNF-α, and NO [21]. Fucoidan compounds KCA (Kjellmaniiella crassifolia, Astragalus polysaccharide, and Codonopsis pilosula) and UCA (Undaria pinnatifida, Astragalus polysaccharide, and Codonopsis pilosula) may increase macrophage proliferation by increasing GM-CSF and TNF-α at concentrations below 200 μm/mL (KCA: 50–100 μm/mL; UCA: 25–200 μm/mL) [127]. However, when the concentrations of fucoidan compounds were above 200 μm/mL, fucoidan killed the RAW264.7 macrophages. Surprisingly, fucoidan from a few sources (for example, Kjellmaniiella crassifolia and Undaria pinnatifida fucoidan) showed different effects, such as inhibiting the growth of macrophages opposed to cell death [127].

3.5. Immunological Effect of Fucoidan on NK Cells

The NK cells are innate lymphoid cells that are essentially derived from common lymphoid progenitors [128]. The broad range of cytokines (e.g., IFN-γ, perforin, granzyme B) [110][114][128], and activating (e.g., NKp30, FasL) and inhibitory receptors (e.g., killer inhibitory receptor, KIR) located on the cell surface [128][129] allow them to interact with other immune cells or biomolecules which allow them to recognize tumor cells and then induce antitumor effects [128][130]. Furthermore, NK cells have also been described as DC promoters and T cell response regulators [130], suggesting that NK cells can enhance and maximize the antitumor effects of other immune cells in TME [128]. Ale et al. showed that intraperitoneally administered fucoidan (Fucus vesiculosus, 50 mg/kg) increased NK cell proliferation in C57BL/6 mice [113]. Fucoidan from Fucus vesiculosus and Undaria pinnatifida could significantly increase NK cells (NK1.1+CD3−) proliferation. Fucoidan from other sources (Fucus vesiculosus, Undaria pinnatifida, Ascophyllum nodosum, Macrocystis pyrifera) could activate NK cells (CD3−NK1.1+) via increasing killer cell lectin-like receptor and IFN-γ [110]. Furthermore, Zhang et al. (2019) further demonstrated that intraperitoneal administration of fucoidan (Macrocystis pyrifera, 50 mg/kg) in C57BL/6 mice could activate and increase NK cell proliferation of NK cells (NK1.1+CD3−) via increasing IFN-γ production and CD69 expression [131], suggesting that fucoidan activates NK cells through secreted cytokines (e.g., IFN-γ) and killer activating receptors (e.g., KLRG1). Exceptionally, CD3−NK1.1+ NK cells activated by all fucoidans from Fucus vesiculosus, Undaria pinnatifida, Ascophyllum nodosum, and Macrocystis pyrifera induced cytotoxic activity against YAC-1 cells [110]. Importantly, both Zhang et al. (2015) and Zhang et al. (2019) showed that fucoidan (Macrocystis pyrifera, 50 mg/kg)-activated CD3−NK1.1+ NK cells induced the highest cytotoxicity in mouse lymphoma YAC-1 cells [110][131], which suggest that fucoidan-activated CD3−NK1.1+ NK cells could induce antitumor effects, regardless of the fucoidan species. Consistent results were demonstrated in a recent study by Zhang et al. (2021); they showed that intraperitoneal administration of fucoidan (Ecklonia cava) in C57BL/6 mice induced the strongest CD3−NK1.1+ NK cell proliferation through increased CD69 expression and IFN-γ levels among the five fucoidans (Fucus vesiculosus, Undaria pinnatifida, Ascophyllum nodosum, Macrocystis pyrifera, and Ecklonia cava) at a concentration of 50 mg/kg [114][114]. Fucoidan (Ecklonia cava)-treated NK cells also induced strong antitumor effects in YAC-1 cells by significantly upregulating the expression of TRAIL, perforin, and granzyme B on the surface of fucoidan (Ecklonia cava)-treated NK cells [114]. Furthermore, an in vivo study by An et al. (2022) demonstrated that fucoidan (Laminaria japonica) could promote CD3−NK1.1+NK cells proliferation via increasing CD69 at a higher concentration of 100 mg/kg and killing targeted cells by secreting IFN-γ, perforin, and granzyme B at a lower concentration of 50 mg/kg [132]. Two other immunological mediators were also involved in the activation and cytotoxicity of fucoidan-mediated NK cells against other tumor cells in vitro, the death ligand FasL and the activating receptor NKp30 [129]. These data suggest that fucoidan would increase NK cells proliferation via increasing CD69 expression and IFN-γ levels and would induce cytotoxic effects of CD3−NK1.1+ NK cells in YAC-1 cells by upregulating surface markers, including perforin, granzyme B, NKp30, FasL, TRAIL, and KLRG1. Thus, cytotoxic mediators of IFN-γ, namely perforin and granzyme B, play a critical role for fucoidan in the promotion and activation of NK cells in mice.
Fucoidans could also induce cytotoxicity and the activation of NK cells in cyclophosphamide (CP)-treated immunosuppressed mice. It was reported that fucoidan (Undaria pinnatifida, 50 mg/kg, 100 mg/kg, 150 mg/kg) induced cytotoxicity against YAC-1 cells and increased NK1.1+NK cells proliferation in CP-treated immunosuppressed mice [133], but it is unknown whether fucoidan secreted IFN-γ or promoted CD69 expression on the surface of NK1.1+NK cells [133]. The HMWF (Undaria pinnatifida) markedly increased the proliferation of NK-92MI cells in the concentration range of 62.5 to 2000 μg/mL and induced a high cytotoxicity of NK-92MI cells against YAC-1 cells in CP-treated immunosuppressed mice by releasing granzyme B [35]. These results suggest that fucoidan could promote NK cell proliferation and activation by releasing granzyme B in CP-treated immunosuppressed mice. Oral administration of fucoidans (Cladosiphon okamuranus, HMWF: 110–138 kDa, LMWF: 6.5–40 kDa) has significantly increased the proliferation of NK cells in the spleen and reduced tumor weight in mice with tumors in the colon 26 [134], suggesting that fucoidan induces antitumor immunity effects by mediating NK cell activity [134].
It is noteworthy that it was previously suggested that “fucoidan-mediated NK cell activation depends on DC maturation” by showing that fucoidan (Ecklonia cava) was unable to increase CD69, IFN-γ, perforin, and granzyme B levels in NK cells after splenocytes depleted CD11c+DCs [114][132]. However, uronic acid levels in fucoidans (Fucus vesiculosus, Undaria pinnatifida, Ascophyllum nodosum, Macrocystis pyrifera, and Ecklonia cava) have also been suggested to influence the immunological effects of fucoidan in NK cells [114]. Thus, further investigations are required to determine whether the depletion of DCs or the levels of uronic acid influence fucoidan to activate NK cells.

3.6. Factors Influencing Fucoidan-Activated Immune Cells

The dosage and molecular weight of fucoidan play a critical role in modulating the effect on macrophages. Indeed, LMWF fucoidan (Undaria pinnatifida) significantly enhances macrophage proliferation (CD11b +) and NK cells (CD3-CD19-CD49b+) by upregulating IL-6 secretion [20]. Furthermore, LMWF can restore cyclophosphamide (CTX)-induced immunosuppression without causing toxic effects. This natural multifunctional molecule is capable of alleviating CTX toxicity and acts as an immunomodulator in vivo [20]. These findings lay the basis for future studies to determine whether this optimal dose is appropriate for testing Fucus vesiculosus fucoidan using other immune cells, such as CD4+ and CD8+ T cells. Importantly, their findings establish the foundation for future researchers to select appropriate dose ranges that can be used in human clinical studies to examine their antitumor immunity in cancer patients and a suitable route of administration. However, it remains controversial whether the molecular weight of fucoidan influences its immune modulation effects on macrophages [127].
Furthermore, HMWF is also important in inducing immunomodulatory effects on macrophages. To determine whether molecular weight could be a factor that influences fucoidan to induce immunomodulatory effects on macrophages, Jiang et al. reported that HMWF-treated spleen cells, which include macrophages, enhanced the production of IFN-γ and NO production compared to LMWF treatment [135], suggesting that HMWF is more capable than LMWF of stimulating IFN-γ and NO production, increasing macrophage viability. However, increased NO production may be the result of contaminated HMWF used in the study; concern has been raised about endotoxin contamination in HMWF used in studies [117]. To overcome this concern, it is suggested that endotoxin-free LMWF is a better choice for future studies to investigate its immunomodulatory effects of fucoidan [20].

This entry is adapted from the peer-reviewed paper 10.3390/md21020128

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