What is fucoidan

Fucoidan is a group of high molecular weight, fucose-based polysaccharides largely made up of l-fucose and sulfate groups that is recognized as a key component of particular brown marine algae species such as Laminaria digitata, Ascophyllum nodosum and Fucus vesiculosus ¹ and more recently identified in seagrasses ². The total content of fucoidan may vary between 20 and 30 % of algae dry weight and it depends on the type of seaweed ³. Fucoidan occurs in all brown algae in different ratio and it is in the intercellular tissues and is considered to be a substance used by the weeds to protect themselves against the effects of drying out when exposed. There are two different forms of fucoidan such as F-fucoidan, which is >95 % composed of sulphated esters of fucose, and U-fucoidan, which is approximately 20 % glucuronic acid ³. The sulphated polysaccharide in fucoidan consists mainly of L-fucose units; at the same time it can also contain minor amounts of sugars such as galactose, mannose, xylose, or uronic acid and sometimes proteins. This is varying between different species ³. Fucoidan exhibits many biological activities which include anti-inflammatory, anticell proliferation, antiadhesion, antiviral, anticoagulant, antitumor and antiviral activities ³. Fucoidan is absorbed through the gut epithelium into the systemic circulation, although its oral bioavailability is low ⁴. The modest benefits of fucoidan appear to be indirect, due to modulation of the intestinal environment where it is a good source of fiberand acts as a microbiota-assessible carbohydrate, rather than the direct activities seen in cell culture studies ⁵. Consequently, benefits may depend on an intestinal environment/microbiome that is capable of utilizing the fucoidan. Most clinical studieswith evidence of benefits, albeit minor ones, were conducted in Japan, where fucoidan rich seaweed is a normal part of the diet, thus people there may already have microbiome more conducive to extracting benefits from fucoidan.

The brown seaweeds containing fucoidan are widely consumed as part of the normal diet in East Asia, particularly in Japan, China, and Korea ⁶. Wakame blades (Undaria pinnatifida) are green when cooked and have a subtly sweet flavor and satiny texture. The blades are normally cut into small pieces as they tend to expand during cooking. In Japan and Europe, wakame (Undaria pinnatifida) is consumed either dried or salted. It is mainly used in soups (particularly miso soup) and salads (tofu salad), or simply used as a side dish. These dishes are typically dressed with soy sauce and vinegar/rice vinegar. In addition, Goma wakame, also known as seaweed salad, is a popular side dish at American and European sushi restaurants. Literally translated, it means “sesame seaweed”, as sesame seeds and oil are usually included in the recipe.

The bioactive properties of fucoidan preparations have been assessed in a range of in vitro and animal models ⁷ and include demonstrated antimicrobial ⁸, antiviral ⁹ and anticancer ¹⁰ effects. While evidence from animal models suggests fucoidans may also possess immune-modulating effects ¹¹, the ability of fucoidan to act as potential modulators of mucosal health generally, and mucosal immune function appears underappreciated and requires further investigation given (i) the fucose-based structure of fucoidans, (ii) the role of fucose as a terminal sugar in human mucin glycoproteins ¹², and (iii) evidence from ex vivo tissue preparations suggesting fucose may regulate gut motility ¹³.

In clinical and animal studies, dietary fucoidan have been shown to increase innate immunity and decrease inflammation ¹⁴. In a clinical study, ingestion of fucoidan was shown to restore a marker of gut innate immunity (lysozyme) to normal levels in athletes ¹⁵. As a known selectin blockade agent, fucoidan has been shown to act as an anti-inflammatory ¹⁶. In addition, dietary fucoidan has been shown to attenuate pulmonary damage in a model of acute viral infection ¹⁷.

Currently, fucoidans are available for use in cosmetics, functional foods, dietary supplements and for inclusion in pet, livestock and aquaculture feed supplements ¹⁸. Fucoidan has been consumed for a long time in Japan, China, and Korea as part of whole seaweed, and it is used as nutraceuticals in Australia and the United States. The fucoidan materials are also used in cosmetics because their ability to absorb directly by the human skin with the following different effects includes whitening, preserving moisture, removing freckles ³. A fucoidan preparation called ‘Haikun Shenxi capsules’ was approved in China in 2003, and its clinical use as a therapeutic for chronic renal failure ¹⁹. There is now regulatory approval in the US and Europe for the use of fucoidan in supplements and cosmetics ⁷. There have been new developments in assay techniques for measuring fucoidan and establishing bioavailability. The first clinical trial on intravenous delivery of a radiolabelled fucoidan has now been reported ²⁰. This encouraging research focuses on the use of fucoidan to image thrombi and may become the first intravenous clinical application of fucoidan.

The effects of fucoidan on microbiome is an emerging area of focus. Global concern regarding the increase of drug-resistant superbugs and the lack of new antibiotics for treating human and animal diseases has led to a call for new approaches. In agriculture, there is an urgent need to develop strategies to replace antibiotics for food-producing animals, especially poultry and livestock. In human health, there is increasing awareness of a connection between the microbiome and disease conditions. Fucoidans have bacteria-inhibiting qualities against the ulcer-causing Helicobacter pylori ²¹ and modulate the growth and biofilm-forming properties of other types of bacteria ²². Additional antiviral activity and the anti-inflammatory nature of fucoidans ¹⁸ make them suitable for a wide range of digestive tract applications. In particular, fucoidan can attenuate inflammation generated by lipopolysaccharides produced by Gram-negative bacteria ²³. New research demonstrates activity against norovirus, for which there are no current treatments ²⁴. Perhaps much of the biological activity ascribed to fucoidans may be due their effects on modulating microbiome and inflammation from the oral cavity and throughout the length of the gut ⁷.

However, no fucoidan has been declared as a drug ¹⁴. The reason is that the structural diversity of fucoidan is extremely large. Fucoidan represents the family of fucose-containing homo- and heteropolysaccharides from polysaccharides with a high content of uronic acids and low fucose and sulfate contents, for example, from Hizikia fusiforme alga, for practically pure α-L-fucans with the main component of polysaccharide-fucose (brown alga Fucus evanescens). Except for fucose, these polysaccharides can contain minor amounts of other monosaccharides (galactose, mannose, xylose, glucose) and also sulfates, uronic acids, acetyl groups, and protein ²⁵. In particular, fucoidan from Fucus evanescens has a similar l-fucosyl backbone of alternating α (1→4) and α (1→3) l-fucosyls with sulphate substitution at C2. An additional sulphate may occupy position 4 in some of the α (1→3)-linked fucosyls, and the remaining hydroxyl groups may be randomly acetylated ²⁶.

Fucoidan chemical structure

Fucoidan is made up of l-fucose, sulfate groups and one or more small proportions of xylose, mannose, galactose, rhamnose, arabinose, glucose, glucuronic acid and acetyl groups in a variety of brown algae ²⁷. In a number of studies, researchers have also used galactofucan to represent a kind of fucoidan. Galactofucan is known as a monosaccharide and the composition of the monosaccharide is galactose accompanied by fucose, similar to rhamnofucan (rhamnose and fucose) and rhamnogalactofucan (rhamnose, galactose and fucose). In addition to the structure of fucoidan, there is also a variation amongst different seaweed types. Nevertheless, fucoidan normally has two types of homofucose (Figure 2). One type (I) encompasses repeated (1→3)-l-fucopyranose, and the other type (II) encompasses alternating and repeated (1→3)- and (1→4)-l-fucopyranose ²⁸.

By a way of illustration, most of the fucoidans sourced from species belonging to the Fucales have an alternating linkage of (1→3)-α-l-fucose and (1→4)-α-l-fucose ²⁹. Structures of Ascophyllum nodosum fucoidan ³⁰ and Fucus vesiculosus fucoidan show a resemblance of one another, the difference is only significant based on sulfate patterns and the presence of glucuronic acid. A number of Fucales species, such as Fucus serratus, Fucus distichus and Pelvetia canaliculate, present similar fucoidan backbone, but show more diversity in the branching and the presence of different monosaccharides ³¹. However, exceptions do exist, for instance, fucoidans from the Bifurcaria bifucardia and Himanthalia elongate do not follow or ascribe to such a structural feature ³². Hence, identifying the structure of fucoidan based on the species they belong to presents a challenge.

Another important fact that deserves mentioning is that the structure of fucoidan is also highly dependent on the harvest season. This is based on the Undaria pinnafida fucoidan, which exhibited distinct characteristics and bioactivity, especially when harvested during different seasons ³³. In addition, it should be indicated that the purification method also plays a critical role in the structure of fucoidan. To such an extent that new purification methods have led to the revelation that the fucoidan structure is comprised of multiple fractions ³⁴. An investigation reported that the structure of crude fucoidan sourced from Ascophyllum nodosum showed a predominant repetition of [→(3)-α-l-Fuc(2SO3−) − (1→4)-α-Fuc(2,3diSO3−)-(1)]n ³⁵. However, from the same species, a purified fraction comprised of primarily α-(1→3)-fucosyl residues with a sparse linkage of α-(1→4) and was found to be highly branched ³⁶. Therefore, the employment of different extraction methods results in distinct structures. For example, a report states that one species produced two distinct fucoidan structures, particularly galactofuctans and uronofucoidans ³⁷. Hence, it should be emphasized that purification techniques are one of the determining factors towards the structure and the associated bioactivities.

Figure 1. Fucoidan chemical structure

Footnote: Structure of fucoidan from Fucus evanescens.

Figure 2. Chemical structure of fucoidan

Footnotes: Type I and type II of common backbone chains in brown seaweed fucoidan. R can be fucopyranose, glucuronic acid and sulfate groups, while the location of galactose, mannose, xylose, rhamnose, arabinose and glucose in several kinds of seaweed species remains unknown.

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Fucoidan sources

Fucoidan is a sulfated polysaccharide which can be found amongst a number of marine sources, including sea cucumbers ³⁸ or brown algae ³⁹. A great number of algae and invertebrates have been ascertained for their fucoidan contents inclusive of Fucus vesiculosus, Sargassum stenophyllum, Chorda filum, Ascophyllum nodosum, Dictyota menstrualis, Fucus evanescens, Fucus serratus, Fucus distichus, Caulerpa racemosa, Hizikia fusiforme, Padina gymnospora, Kjellmaniella crassifolia, Analipus japonicus and Laminaria hyperborea shown in Figure 3. In these sources, different types of fucoidan can be obtained and the methods of extraction employed are different, especially when they are reported in different studies ¹.

Fucoidan is usually extracted from the sporophyll of Undaria pinnatifida ⁴⁰. However, a key difference between fucoidan from Undaria pinnatifida and those from of other brown seaweed species such as Fucus vesiculosus lies in the composition of monosaccharides that form the backbone of the polysaccharide molecule ⁴¹. Fucoidan from Undaria pinnatifida is sulfated galactofucan ⁴². In contrast, fucoidan isolated from the vast majority of other brown seaweeds mainly consists of sulfated fucose ⁴². Literature shows that sulfate content, monosaccharide composition, and structural conformation of fucoidan affect its biological activity ⁴³. As such, it is suggested that fucoidan from Undaria pinnatifida with different monosaccharide composition and structural conformation, would possess a wide range of biological activities, which offers itself as an attractive functional ingredient of health products ⁴⁴.

The brown seaweed species Undaria pinnatifida is native to the cold temperate seas of China, Japan, and Korea, and has been introduced in many other places including the Europe Atlantic, French Mediterranean, Australia, and New Zealand ⁶. It is regarded as a highly invasive species with a high tolerance for light, temperature, and salinity ⁴⁵. It is also highly fertile with high growth rate and large reproductive output, releasing spores all year round ⁴⁶. It is farmed extensively in Japan, Korea, and Japan and as such, it is an abundant source from which fucoidan could be extracted and used.

Figure 3. Sources of fucoidan

Footnotes: 1. Fucus vesiculosus, 2. Laminaria digitata, 3. Fucus evanescens, 4. Fucus serratus, 5. Ascophyllum nodosum, 6. Pelvetia canaliculata, 7. Cladosiphon okamuranus, 8. Sargassum fusiforme, 9. Laminaria japonica, 10. Sargassum horneri, 11. Nemacystus decipiens, 12. Padina gymnospora, 13. Laminaria hyperborea.

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Fucoidan supplement

In recent years, fucoidan extracts have attained regulatory approvals in a number of global jurisdictions for use in foods and dietary supplements. In particular, fucoidan extracts from Undaria pinnatifida and Fucus vesiculosus were filed as ‘Generally Recognised as Safe’ (GRAS) with the US FDA by the Australian manufacturer, Marinova ⁴⁷. The FDA had no further questions in relation to the two GRAS determinations, which permit daily consumption of high-concentration fucoidan extracts from Undaria pinnatifida or Fucus vesiculosus at rates of up to 250 mg/day ⁷.

In the European Union, the same fucoidan extracts from Undaria pinnatifida and Fucus vesiculosus were assessed by the European Commission and found to be substantially equivalent to the parental seaweeds from which they are extracted, and hence were approved as novel foods under the Commission Implementing Regulation (EU) 2017/2470 of 20 December 2017, for consumption up to 250 mg/day ⁷.

In Canada and Australia, the respective agencies have approved a number of listed medicines containing fucoidan extracts. In Australia, fucoidan has been approved in a species-specific context for both Undaria pinnatifida and Fucus vesiculosus. They are recognised as listable components of their parental herbal (seaweed) source ⁷.

Fucoidan health benefits

The first clinical trial on intravenous delivery of a radiolabelled fucoidan has now been reported ²⁰. The ability of fucoidan to bind to p-selectin groups on platelets assists in the imaging of blood flow-limiting thrombi. This application may become the first non-oral clinical application of fucoidan.

Reports of orally delivered clinical use of fucoidan have increased in the last few years. A recent paper outlines the use of fucoidan from Saccharina japonica to address kidney disease in China ⁴⁸. This traditional Chinese medicine formulation shows promise for use in other parts of the world and is supported by studies in the literature detailing the use of fucoidan to treat kidney disease in a variety of animal models. Mesenchymal stem cells are a class of cells that show promise in regenerating diseased organs ⁴⁹. Currently, the damage caused to mesenchymal stem cells by uremic toxins makes kidney mesenchymal stem cell transplantation unfeasible. However, fucoidan from Fucus vesiculosus reversed senescence caused by the uremic toxin p-cresol, indicating a potential support for both resident and transplanted mesenchymal stem cells ⁵⁰.

Following on from an animal study showing inhibition of inflammation in ethanol-induced gastritis ⁵¹, a clinical study in young Chinese men showed a substantial—and no doubt welcome— decrease in gastritis (cause undisclosed) after ingestion of a blend of fucoidan and wheat peptides ⁵².

Additional studies have demonstrated fucoidan utility in reducing inflammation in cancer patients ⁵³. No interactions or adverse effects were observed with the commonly used hormone therapies tamoxifen and letrozole in breast cancer patients. Reductions in joint pain were also noted following co-administration of fucoidan from Undaria pinnatifida ⁵⁴.

Fucoidan exerts anti-inflammatory effects by reducing the production of proinflammatory cytokines ⁵⁵. Orally administered fucoidan reduces the levels of proinflammatory cytokines, including interleukin 1β (IL-1β) and IL-6, in patients with advanced cancer ⁵⁶. Similarly, orally administered fucoidan has been shown to reduce radiation-induced pneumonitis and lung fibrosis in a mouse model ⁵⁷. Orally administered fucoidan also exerts antithrombotic effects by inducing biosynthesis of prostacyclin ⁵⁸. The crude extract of the brown seaweed Cladosiphon okamuranus (mozuku) consistently exerted antithrombotic effects in rats after 8 weeks of oral administration, likely through the fucoidan in the extract ⁵⁹. Another study shows that low-molecular-weight fucoidan prepared in the laboratory has greater antithrombotic activity and oral bioavailability than middle-molecular-weight fucoidan ⁶⁰.

Fucoidan extracted from Fucus vesiculosus has been known as an alpha-glucosidase inhibitor that is able to treat diabetes ⁶¹. Among other studies, fucoidan was mentioned to have an ability to attenuate diabetic retinopathy through inhibiting vascular endothelial growth factor (VEGF) signaling ⁶². Additionally, a report of a low molecular-weight fucoidan was noted to provide protection against diabetic associated symptoms in Goto-Kakizaki rats ⁶³. Fucoidan also improves glucose tolerance by modulating AMP-activated protein kinase (AMPK) signaling and GLUT4 activity ⁶⁴. Some studies mention that fucoidan from the sea cucumber Pearsonothuria graeffei with a molecular weight of 310 kDa can be used as a form of functional food to treat metabolic syndromes ⁶⁵. Fucoidan from the sea cucumber Pearsonothuria graeffei enabled weight reduction in high fat diet-fed mice, it also reduced hyperlipidemia, and protected the liver from steatosis. Concurrently, fucoidan from the sea cucumber Pearsonothuria graeffei reduced the serum inflammatory cytokines combined with reduced macrophage infiltration into adipose tissue. Furthermore, it was declared that the treatment effect for metabolic syndrome was primarily related to the 4-O-sulfated structure of fucoidan, since it was identified as a tetrasaccharide repeating unit with a backbone of [→3Fuc (2S, 4S) α1→3Fucα1→3Fuc(4S) α1→3Fucα1→]n.

Fucoidan administration improved taste sensitivity in diabetics ⁶⁶, whilst a study on obese, but non-diabetic, subjects using a fucoidan-polyphenol complex from Fucus vesiculosus showed no effects on glucose or insulin resistance ⁶⁷.

Fucoidan is recognized as a prebiotic to regulate the intestinal ecosystem or microbiome ⁶⁸. Fucoidan promotes the growth of beneficial bacteria which represents a mechanism inhibiting the development of metabolic syndromes ⁶⁹. A report by Parnell et al. ⁷⁰ showed that prebiotics containing fucoidan can regulate blood glucose and metabolism by providing a beneficial environment for the growth stimulation of probiotics. Cheng et al. ⁷¹ also demonstrated that Sargassum fusiforme fucoidan could modify gut microbiota during the alleviation of streptozotocin-induced hyperglycemia in mice. The yield of Sargassum fusiforme fucoidan was 6.02%., with sulfate content up to 14.55% and the average molecular weight of 205.8 kDa. This study was done with diabetic mice where after a 6-week administration, Sargassum fusiforme fucoidan impressively decreased the fasting blood glucose, diet and water intake. Additionally, Sargassum fusiforme fucoidan attenuated the pathological changes in the heart and liver tissues, hence, improving liver function. Also, Sargassum fusiforme fucoidan suppressed oxidative stress in streptozotocin-induced diabetic mice which are manifestations associated with metabolic syndromes. Concurrently, Sargassum fusiforme fucoidan significantly altered the gut microbiota in diabetic mice, what was noted is Sargassum fusiforme fucoidan decreased the relative abundances of the diabetes-related intestinal bacteria, which might be the potential mechanism for relieving the symptoms of diabetes ⁷¹.

A clinical topical study using a cream containing 4% fucoidan was found to be effective for treating oral herpes ⁷². This topical application is supported by a substantial body of research indicating excellent inhibitory activity against herpes viruses ⁷³.

Fucoidan has also been shown to have antiviral activity against influenza A virus ⁷⁴, hepatitis B virus ⁷⁵, canine distemper virus ⁷⁶ and human immunodeficiency virus (HIV), mainly in vitro ⁷⁷. One study in human volunteers showed that serum/plasma concentrations of fucoidan following oral ingestion of a Cladosiphon okamuranus (mozuku) extract were sufficient to exert anti-HIV activity ⁷⁸. Furthermore, a more recent study by Kwon et al ⁷⁹ showed fucoidan extracted from Saccharina japonica (kombu) to have strong antiviral activity against Covid-19 (SARS-CoV-2) in vitro. The activity of fucoidan against SARS-CoV-2 was even greater than that of remdesivir. Thus, fucoidan in dietary brown seaweeds might exert antiviral effects against SARS-CoV-2, at least within the intestine.

Fucoidan and cancer

Observational studies indicate that daily intake of seaweed (30 g fresh or 2 g dried) is associated with overall reduced disease risk ⁸⁰ and some types of cancer, including breast cancer ⁸¹. However, there is no clear evidence that this association is mediated by the anti-cancer effects of fucoidan.

The anti-cancer properties of fucoidan have been extensively studied in test tube and animal models, however, there have only been a few small clinical trials testing fucoidan supplementation in cancer patients, and the benefits have been minimal. Bioactive polysaccharides are attractive anti-tumor agents because they typically do not act on tumor cells directly, but rather, induce changes in the host’s immune system tumor microenvironment that reduces the viability of tumor cells ⁸². Since the polysaccharides themselves are not directly cytotoxic, they do not pose a risk to the viability of healthy host cells. Fucoidan shows anti-tumor effects against a variety of cell cancer lines in cell culture and xenograft models, though the anti-cancer effects are highly dependent on sulfate content. In cancer cell lines, fucoidan can induce apoptosis primarily through inhibition of P13K/Akt or ERK1/2 signaling ⁸³. Due to fucoidan low oral bioavailability, its anti-cancer potency in vivois greatly diminished, and has primarily been tested for its ability to be used as an adjunct to traditional anti-cancer therapies. The clinical trials conducted thus far suggest that fucoidan may be beneficial for cancer patients receiving chemotherapy in terms of reducing side effects/improving tolerability of the chemotherapy. In advanced colorectal cancer patients (n=20, average age 70) undergoing chemotherapy [5-fluorouracil/leucovorin (FOLFOX) or 5-fluorouracil/leucovorin (FOLFIRI)], fucoidan (4.05 g/day in 150 ml from Cladosiphon okamuranus[Okinawamozuku], Marine Products Kimuraya Co., Ltd.) for 6 months reduced chemotherapy-associated fatigue (incidence 10% with fucoidan vs. 60% in controls) ⁸⁴. The fucoidan treated patients were able to tolerate more cycles of chemotherapy (19.9 vs 10.8), and this resulted in a trend toward longer survival in this cohort. Critically, a separate open-label trial in breast cancer patients (n=20) found that fucoidan treatment (500 mg 2x daily Maritech extract from Undaria pinnatifida, Marinova) had no significant effects on the pharmacokinetics of the chemotherapeutic agents letrozole, tamoxifen, or their active metabolites ⁸⁵, suggesting that fucoidan does not negatively interfere with the efficacy of the chemotherapeutics. In an open-label trial in advanced cancer patients with metastases (n=20), fucoidan (4 g/day in 400 ml extracted from Cladosiphon novae-caledoniae kylin [Mozuku], Power Fucoidan, Daiichi Sangyo) for at least 4 weeks was associated with a stabilization of quality of life scores and a reduction of proinflammatory cytokines (1L-1β, IL-6, TNFα). The reduction in IL-1βwithin the first two weeks was a prognostic factor for survival (Hazard ratio, HR: 0.08) ⁸⁶. A double-blind, controlled RCT in metastatic colorectal cancer patients undergoing chemotherapy (n=54) found that fucoidan (4 g powder, molecular weight 0.8 kDa, from Sargassum hemiphyllum, Hi-Q Marine Biotech) for 6 months improved the disease control rate (92.8% vs 69.2%), but had no significant effects on overall response rate or survival ⁸⁷.

These studies suggest that fucoidan supplementation is not harmful, and may improve treatment tolerability or survival in some cancer patients, but has minimal to no direct anti-cancer potency.

Fucoidan appears to act both directly on cancer cells and indirectly, by increasing immune clearance of cancer cells and preventing metastasis. For example, tumour metastasis and cachexia were attenuated via the inhibition of vascular endothelial growth factor (VEGF) and matrix metalloproteases in a Lewis lung cancer tumour model mice given oral fucoidan ⁸⁸.

Fucoidan acts independently as checkpoint modulators and may serve as alternative complementary agents for the treatment of cancers with high PD-L1 expression ⁸⁹. Apoptosis or cell cycle arrest appears as a common feature of fucoidan bioactivity directly on cancer cells. Uterine cancer cell lines were inhibited by fucoidans derived from Undaria pinnatifida, whilst normal cells were unaffected ⁹⁰. Lower molecular weight fractions of Undaria fucoidan were highly effective inhibitors of human prostate cancer cells, when delivered orally in a xenografted mouse model ⁹¹. Head and neck cancers, which may be caused by human papilloma viruses (HPV), are particularly difficult to treat. Fucoidan from Fucus vesiculosus inhibited head and neck squamous cell lines, causing cell cycle arrest ⁹². It also enhanced the response to the anticancer drug cisplatin in HPV-affected lines. Preclinical evaluations of fucoidans from Fucus vesiculosus and Undaria pinnatifida in a mouse model showed activity as sole agents and additive activity with anticancer agents in some breast cancer and ovarian cancer tumours ⁹³. It should be noted that fucoidans do not always act as inhibitors of cancer cell lines, and were ineffective against uveal melanoma cell lines ⁹⁴, instead providing protective and angiogenic effects.

The mechanisms of these anticancer activities are multifaceted. They include induction ⁹⁵ or even inhibition ⁹², of reactive oxygen species, destabilization of mitochondria, and the cleavage of caspases and PARP. Using a systematic screen of the entire set of 4733 haploid Saccharomyces cerevisiae gene deletion strains, an analysis of cell pathways revealed that multiple cellular pathways were affected by exposure to fucoidan extracts, and that cDNA damage and cell cycle arrest occurred in colon cancer cell lines. Normal fibroblasts were unaffected under the same conditions ⁹⁶. There were global effects of the fucoidan studied on a wide range of eukaryotic cellular processes, including RNA metabolism, protein synthesis, sorting, targeting and transport, carbohydrate metabolism, mitochondrial maintenance, cell cycle regulation and DNA damage repair-related pathways. Thus, the mechanisms by which fucoidans may act on cancer cells is becoming clearer. The lack of effect on normal fibroblasts means that fucoidan extracts have potential utility as anticancer agents.

In a Russian study ⁹⁷, fucoidan from Fucus evanescens was found to increase cancer susceptibility towards radiation. The growing amount of evidence described above suggests that fucoidans place stresses on multiple cellular pathways, thereby increasing cancer cell susceptibility to radiation or other agents. Conversely, fucoidans may confer radiation protection effects that help to prevent lung damage and subsequent fibrosis of healthy tissues ⁹⁸.

The immunosuppression experienced after chemotherapy can lead to infectious diseases and reduced quality of life. Previous research has shown some increase in circulating stem cells after ingestion of a fucoidan extract ⁹⁹. In a recent Russian study ¹⁰⁰, semisynthetic fucoidan fractions were assessed in a cyclophosphamide immune-suppressed mouse model. A subcutaneously delivered fucoidan-derived octasaccharide was more effective in neutrophil regeneration than the gold standard peptide treatment, rG-CSF. Recent research is summarized in Table 1.

Table 1. In vitro and in vivo fucoidan cancer studies

Source of Fucoidan	Aim of Study	Type of Study	Outcome	Reference
Undaria pinnatifida Fucus vesiculosus	Orthotopic cancers in mice	In vivo Mouse	Safety of fucoidan usage during breast cancer treatment and potential to improve tamoxifen activity.	101, 93
Semisynthetic fucoidan fraction	Cyclophosphamide-treated mice, haemopoiesis	In vivo mouse	Synthetic octasaccharide is identified as an effective stimulator of haematopoiesis.	100
Undaria pinnatifida	Cell cycle arrest in HCT116 and MOA yeast gene deletion study	In vitro	Global effects of fucoidan on a wide range of eukaryotic cellular processes and inhibitory effect on colon cancer cells.	96
Undaria pinnatifida	Uterine carcinoma and sarcoma cell lines	In vitro	Anticancer agent activity against endometrial stromal sarcoma and carcinosarcoma.	90
Fucus evanescens	Radio sensitisation human melanoma, breast adenocarcinoma, and colorectal carcinoma cell lines	In vitro	Increased the inhibitory effect of X-ray radiation on proliferation and colony formation-activating caspases, suppressed anti-apoptotic protein and enhanced fragmentation of DNA.	97
Fucus vesiculosus	Radiation-induced lung fibrosis	In vivo mouse	Fucoidan changed the expression patterns of inflammatory cytokines and attenuated radiation-induced lung fibrosis	98

Anti-skin aging

Fucoidans have been incorporated into skin care products due to their anti-inflammatory and antioxidant properties. In hairless mice, topically applied fucoidan was shown to be protective against ultraviolet B (UVB) induced skin photoaging by reducing neutrophil recruitment and associated inflammatory cytokine production (IL-1β) and oxidative stress induction ¹⁰². In a company sponsored clinical study (n=20) in Australia, topically applied 3% w/w fucoidan cream (Undaria pinnatifida extract with 8% fucoidan [27.4% sulfate] or Fucus vesiculosus extract with 60% fucoidan [10.1% sulfate], 30% polyphenol from Marinova) was effective at reducing erythema and transepithelial water loss after UV exposure compared to placebo ¹⁰³. Use of the Fucus vesiculosus extract for 60 days also led to trends for reduced skin spots (in 50% of participants), increased skin brightness (in 65%), and improved wrinkles (in 45%). In vitrostudies indicate that the extract can increase Sirt1 expression and has antioxidant properties, which may contribute to its protective effects. Another company sponsored placebo-controlled randomized controlled trial (n=94, average age 41) in Korea found that 400 mg of fucoidan containing capsules (MK-R7: Complex of 150 mg Cistanche tubulosa extract and 50 mg Laminaria japonica including echinacoside glycosides and fucoidan, Misuba RTech) increased hair density (23.29 n/cm2± 24.26 vs 10.35 n/cm2± 20.08) and hair diameter (0.018 mm ± 0.015 vs 0.003 mm ± 0.013) in people with mild to moderate patterned hair loss ¹⁰⁴. However, these effects appear to have marginally reached statistical significance, and it is unclear if the improvements are clinically meaningful.

Fucoidan in imaging and anti-coagulant function

French researchers have developed an extensive body of work regarding the use of radiolabelled fucoidan as an imaging agent to locate thrombi and image early-stage inflammatory processes in autoimmune endocarditis ¹⁰⁵. A clinical trial on the safety of the reagent was completed in 2019 ²⁰, clearing the way for commercialization and clinical use of this imaging tool.

This work has expanded to assist in the targeting of thrombi to deliver a clinically used thrombolytic agent, recombinant tissue plasminogen activator (rtPA). A fucoidan extract is incorporated into nanoparticles which are then loaded with the rtPA. This allows the specific targeting of thrombi at lower overall doses, and may avoid some of the haemorrhagic complications of using rtPA ¹⁰⁶. Interestingly, fucoidans themselves are good inhibitors of the tPA-PASI1 complex, and act as thrombolytics in their own right. Combined Korean- and Russian-based research has demonstrated the utility of these fractions, building on earlier work that demonstrated anti-thrombotic activity without anticoagulant activity in a fraction from Undaria pinnatifida ¹⁰⁷. The potential to use orally bioavailable thrombolytic approaches are attractive ¹⁰⁸.

Dextran-coated superparamagnetic iron oxide nanoparticles or ‘SPIONs’ are in use as MRI contrast agents. The wider clinical potential of SPIONs is limited by their rapid removal from circulation via the reticuloendothelial system. Fucoidan ingestion appears to increase the retention time of SPIONs by preventing their uptake into the reticuloendothelial system ¹⁰⁹. This useful activity expands on the applications for imaging of thrombi.

Gradually depolymerised fractions of Fucus vesiculosus fucoidans (without removing sulphates) were examined for bioactivity ¹¹⁰. Researchers concluded that the fractions gradually lost their anti-oxidative and anti-proliferative activities due to the removal of terpenoids and polyphenolics. It is likely that the terpenoid and polyphenolic components were co-extracted with the initial fucoidan and subsequently removed, rather than being incorporated within the structure of the fucoidan polymer itself. Interestingly, lower molecular weight fractions maintained an anti-inflammatory activity, whilst having a low anticoagulant activity. Studies are summarized in Table 2.

Table 2. Fucoidan imaging and anti-coagulation studies

Fucoidan Source	Aim of Study	Type of Study	Outcome	Reference
Radiolabelled fucoidan source unspecified	Safety	Human clinical	Safe to use. Maximum activity in liver. Activity reduced to <5% after 24 h.	20
Undaria pinnatifida Fucus evanescens Saccharina cichorioides Costaria costata Fucus vesiculosus Eisenia bicyclis	Thrombolytic activity of fucoidan	In vivo mouse thrombosis model, iv	Fucoidans inhibit the tPA-PAI1 complex, indicating activation of plasma tissue-type plasminogen activator is a mechanism of fucoidan-mediated thrombolysis in a mouse thrombosis model	107
Unspecified	Thrombolytic therapy based on fucoidan nanoparticles with recombinant tissue plasminogen activator (rtPA)	In vivo mouse model with induced clotting, iv	Successful thrombolysis	106
Laminaria japonica	Anti-thrombotic	In vivo mouse model. Oral delivery	Lower molecular weight fucoidan was most effective	108
Fucus vesiculosus and 18 gradually depolymerised fractions	Degraded fucoidan fractions	In vitro	Anti-inflammatory activity, however only negligible anticoagulant activity and FXII-activating potency	110
Fucus vesiculosus Macrocystis pyrifera Undaria pinnatifida	Intravenous fucoidan administration prior to SPIONs	In vivo mouse model In vitro	Increased residence time of circulating superparamagnetic iron oxide nanoparticles (SPIONs) for imaging by blocking their uptake by reticuloendothelial uptake	111

Neuroprotective benefit

Fucoidan can protect against onset of inflammatory and oxidative damage by mitigating immune cell activation in animal models. However, fucoidan is unlikely to significantly benefit after onset of neurological damage. Types of evidence: 2 clinical trials for seaweed extract for cognitive function (n=60, n=59) and numerous laboratory studies (various fucoidan formulations). Due to its high molecular weight and low bioavailability, orally supplemented fucoidan is not expected to be brain penetrant ¹¹². However, the neuroprotective effects described in preclinical studies are largely indirect and primarily involve the ability of fucoidan to promote a neuroprotective environment through the reduction of inflammatory and oxidative stressors. Fucoidan appears to be most effective when used as a preventative, to mitigate tissue damaging immune cell infiltration and activation.

No studies have directly tested the specific effects of fucoidan supplementation, however, there have been a couple of placebo-controlled clinical trials examining the effects of brown seaweed extract supplementation on cognitive function. One study testing fermented extract from Laminaria japonicain healthy elderly Japanese adults (Treatment: n=28, age 72.35 ± 5.54; Placebo: n=32, age 74.57 ± 5.69) found that 6 weeks of supplementation (1.5 g/day) led to improvements on tests for cognitive function and memory [K-MMSE, numerical memory test (working memory), Raven’s test (visual and spatial reasoning), iconic memory test (visual spatial memory)] relative to placebo ¹¹³. Another study tested post-prandial cognitive function following consumption of a hot water extract derived from Ascophyllum nodosumand Fucus vesiculosus (InSea2® 500 mg, equivalent to 10 g dried seaweed) in healthy adults (Treatment n=30, age 33.1±14.6; Placebo n=29, age 37.9 ±16.9) and found improvements in accuracy on digit vigilance and choice reaction time tests ¹¹⁴. The fermented extract was characterized for GABA content (mean 54.5± 0.071 mg/g), while the hot water extract was characterized for polyphenol content (>20%). These studies suggest that brown seaweed contains compounds that can at least temporarily improve some aspects of cognitive function, however, the fucoidan content of these preparations was not characterized, thus it is not clear if any of these effects can be attributed to fucoidan.

Potential prevention of Alzheimer’s disease

Different preparations of fucoidan have been found to protect against beta amyloid (Aβ) induced cytotoxicity in cell culture and Caenorhabditis elegans (roundworm), and mitigate scopolamine, ethanol, sodium nitrate, D-galactose, or A40 induced cognitive impairment in rodents ¹¹⁵. The neuroprotective effects were generally seen when fucoidan was administered prior to or shortly after exposure to the cell stressor, and were associated with reduced production of reactive oxygen species (ROS). Fucoidan treatment was also associated with less caspase activation and apoptosis. Fucoidans are similar in structure to glycosaminoglycans, which are known to regulate oxidative stress induced apoptosis. The properties most important for neuroprotective activity have not been fully characterized, but likely include the degree of sulfation, molecular weight, and sugar composition. One study comparing fucoidans with different chemical compositions derived from Fucus vesiculosusor Undaria pinnatifidafound that the sample with the highest polyphenol content, lowest carbohydrates, lowest sulfate content, and highest molecular weight showed the lowest neuroprotection against beta amyloid (Aβ) in PC12 cells ¹¹⁵. Some of the fucoidans (molecular weight 33-56 kDa, sulfates 23-31%) enhanced neurite outgrowth, which has also been seen with bioactive polysaccharides from other species. In rat cognitive impairment models, a fucoidan isolated from Sargassum fusiforme, SFPS65A, with a sulfate content of 17.5% was protective, while a related isolate, SFPS65B, with a lower sulfate content of 2.7% was not neuroprotective ¹¹⁶.

Potential prevention of Parkinson’s disease

Fucoidan pretreatment has been found to be protective in models of MPTP, 6-OHDA, or rotenone mediated dopaminergic neurotoxicity ¹¹⁷. Fucoidan can reduce toxin induced behavioral deficits, mitochondrial dysfunction, and dopamine neuron cell death. The protective effects primarily involve the inhibition of microglial activation, and a reduction in levels of oxidative stress (ROS, protein carbonylation, lipid peroxidation). In these studies ¹¹⁸, ¹¹⁹, ¹²⁰ benefits were seen with fucoidan derived from Laminaria japonicafrom Qingdao, China (48% total sugar, 28% fucose, 29% sulfate, fucose: galactose 1:0.24, MW 7kDa), a 198 kDa L-fucose-4-sulfate fucoidan from the China National Institute for Control of Pharm and Biological products (16121901), and a fucoidan from Turbinaria decurrenscollected in Yervadi, India (carbohydrate 59.62%, sulfate 26.52%, and uronic acid 6.3%, MW 234 kDa). Since the protective effects appear to stem largely from preventing the induction of pathological processes associated with the onset of neuronal damage, it is not clear whether fucoidan would benefit as a treatment for patients with established disease.

Potential benefit in stroke and traumatic brain injury

Fucoidan pretreatment has been found to be protective in rodent models of cerebral ischemia (stroke) ¹²¹, ¹²², LPS-induced neuroinflammation ¹²³, ¹²⁴, intracerebral hemorrhage ¹²⁵ and traumatic brain injury ¹²⁶. The vast majority of these studies used a fucoidan preparation supplied by Sigma which is derived from Fucus vesiculosusand contains 44% fucose and 26% sulfate ¹²⁷. Fucoidan treated animals had reduced neurological deficit scores, reduced infarct/lesion volumes, decreased cell death near the lesion, reduced pro-inflammatory cytokines (IL-1β, IL-6, TNFα, MPO), and reduced oxidative stress markers (8-OHdG, 4-HNE, MDA). Effects were typically dose dependent, with lower doses (typically under 50 mg/kg) failing to show benefits. The neuroprotective effects may also be contingent on time of administration, as fucoidan was protective in a model of traumatic brain injury when given from 0-4 hours after injury, but failed to protect against neurological deficits when given 6 hours after injury ¹²⁷. In this study, the protective effects were attributed to the induction of Sirt3. The time window effect may relate to its mechanism of action in inhibiting the entry of activated immune cells into the brain by blocking P-selectin mediated interactions, which can mitigate the damage. Therefore, fucoidan would not be expected to have a significant effect once immune cells have entered, and damage has occurred.

Immunosenescence

Immunosenescence refers to the gradual deterioration of your immune system as you get older. The ability to mount an effective immune response to a pathogen declines with age due to the rise of senescent immune cells. It involves your capacity to respond to infections and maintain your long-term immune memory that was acquired (usually in your early life) either by infection or vaccination. Consequently, elderly people tend to produce weaker responses to viral antigens in vaccines, and thus have reduced immunity. Adjuvants are often added to vaccines to boost immune responses in the elderly. In a placebo-controlled randomized controlled trial in elderly adults in Japan (n=70, average age 87, 91% female), treatment with 300 mg of Mekabu fucoidan (derived from Undaria pinnatifida, Riken) for 4 weeks prior to receiving the flu vaccine increased antibody titers for all 3 flu strains in the vaccine ¹²⁸. The antibody titers were maintained for over 20 weeks after vaccination. Fucoidan treated patients also experienced a transient increase in natural killer (NK) cell activity, suggesting that fucoidan can help reverse some of the signs of aging-associated immunosenescence.

Fucoidan dosage

Fucoidan clinically beneficial dose has been not established. Fucoidan is derived from brown algae and sold OTC as a supplement. The biological activity of the fucoidan can vary greatly depending on a variety of factors including: the species of brown seaweed from which it was obtained, the location the seaweed was grown, the time of year the seaweed was harvested, the method of extraction, the sugar content of the fucan backbone, and the level of branching of the backbone ⁸³. The fucoidan content in brown seaweed is maximal in late autumn and early winter, which is also the time when it has the highest degree of sulfation ¹²⁹. The most important aspects for bioactivity appear to be the molecular weight and the degree of sulfation. High molecular weight fucoidans with high levels of sulfates tend to have the most bioactivity in vitro, however, low molecular weight fucoidans have much greater bioavailability in vivo ⁸³. In many of the commonly used extraction methods, particularly acidic hydrolysis, branching and sulfates are eliminated, which reduces the bioactivity. Extraction via gamma irradiation or enzymatic degradation is better at preserving the bioactive sulfate groups. The optimal form of fucoidan for therapeutic use has not been established, and is likely to vary for different disease indications based on the properties necessary for therapeutic benefit ¹⁸. It is anticipated that in order to be a viable therapy, a low molecular weight formulation will need to be developed which contains a high proportion of the bioactive sulfate groups.

Due to the low oral bioavailability noted in various fucoidan preparations in clinical trials, there is no clear evidence that currently available preparations of fucoidan supplements can elicit the types of benefits seen in preclinical studies. Therefore, incorporating fucoidan rich brown seaweed, such as Kombu (Saccharina japonica), Wakame (Undaria pinnatifida), Hijiki (Sargassum fusiforme), Nori (Pyropia tenera), and Mozuku (Nemacystus decipiens), into your diet is likely the best currently available source of fucoidan. Brown seaweed is also rich in various minerals and other compounds with purported antioxidant and anti-inflammatory properties, which may act to increase the bioavailability of fucoidan and/or act synergistically. However, seaweed is rich in iodine, so very high consumption may increase the risk for thyroid cancer.

Fucoidan side effects

Fucoidan is well-tolerated with no adverse events in clinical trials, even at high doses. Possible risk for increased bleeding when used in combination with blood thinners.

Fucoidan intake, even at high doses, has been shown to be safe in clinical studies. Up to 4.05 g per day of fucoidan (in 150 ml from Cladosiphon okamuranus [Okinawamozuku], Marine Products Kimuraya Co., Ltd) has been tested inhealthy volunteers for 2 weeks ¹³⁰ and in cancer patients for 6 months ⁸⁴ with no evidence of adverse effects. In all clinical trials, fucoidan use was well-tolerated, not associated with an increase in adverse events, did not induce significant changes on blood tests or vital signs, and exhibited no evidence of cytotoxicity. As a rich source of water-soluble fiber, fucoidan can promote bowel movements, and in one study a subset of patients (4/13) developed diarrhea that resolved upon discontinuation of fucoidan ¹³¹. Due to fucoidan’s anti-clotting activity, although generally weak in vivo, it has drug interactions with blood thinners, such as warfarin and heparin ¹³². It is possible that the low incidence of adverse events is related to the low oral bioavailability, determined to be less than 0.6% in humans in a pharmacokinetic study ¹³³ and that preparations with higher oral bioavailability may be associated with more side effects. Although fucoidan has not been tested as a supplement in clinical trials longer than 1-year, long-term intake of fucoidan rich brown algae is associated with health benefits (i.e. Okinawa diet). In Japan, the daily intake of fucoidan from brown algae and other dietary sources is estimated to be about 400 mg/capita ¹³⁴.

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