Bioactive properties of fucoidan - the clinical evidence
More than 1400 independent, peer-reviewed research papers have been published on the bioactive properties of fucoidan. This extensive body of evidence includes comprehensive in vitro investigations, animal studies and human clinical trials. Research into the therapeutic properties of fucoidan has largely focussed on the six key health indications identified below.
- Mobilisation of stem cells
- Increased antibody production
- Increased phagocytosis
- Direct inhibition of viral entry
- Decreased allergic responses
Extensive research has been undertaken on the immune-modulatory properties of fucoidan. Published papers have reported that fucoidan may exert a range of beneficial effects on the human immune system, including the reduction of allergic responses and the activation of dendritic cells, natural killer cells and T cells. It has also been shown that fucoidan has the potential to boost important anti-viral and anti-tumour responses.
Boosting immune responses
Immune responses to vaccines or infections can be compromised, particularly during ill health and in older people. In a clinical setting, ingestion of fucoidan was shown to help boost the immune responses to seasonal influenza vaccinations (Negishi, 2013). The ingestion of fucoidan has also been shown to increase the anti-pathogenic activity of granulocytes and macrophages in healthy people (Myers, 2011). Increased immune activity after fucoidan ingestion can even eliminate the tropical protozoan parasite Leishmania, as seen in a mouse model (Kar, 2011). Fucoidans can also promote the maturation of dendritic cells, activate NK cells and promote cytotoxic activity (Zhang, 2015).
Damping allergic responses
Published research has reported that fucoidan can reduce allergic responses after ingestion (Maruyama, 2015) and even after topical application (Yang, 2012). Fucoidan can suppress the over-expression of the antibody IgE in immune cells in people with allergic dermatitis and can also decrease the actual number of cells producing IgE (Iwamoto, 2011). It has been proposed that the mechanism of action for this damping of allergic responses is via upregulation of galactin-9, a protein integral to the regulation of cell-to-cell interactions (Tanino, 2016).
Stem cell modulation
Immune function is fundamentally dependent upon the release and mobilisation of stem cells from bone marrow. As stem cells are released from bone marrow, they differentiate into all the different types of immune cells, including neutrophils, macrophages, cytotoxic natural killer (NK) cells, granulocytes and dendritic cells. Fucoidan has been reported to increase levels of the chemokine SDF1 in the blood and elicit the release of stem cells into the peripheral circulation when used intravenously in animal models (Sweeney, 2002). In humans, it has been shown that the oral ingestion of fucoidan over a period of days increases the number/release of CD34+ haemopoeitic stem cells (Irhimeh, 2007). The same study also showed fucoidan increased SDF1 and the number of CXCR4 receptors on stem cells, which may assist in the lodgement of those cells.
Fucoidans can block the entry of coated viruses to cells, thereby preventing or halting the progress of infections. Fucoidan has been shown to be a highly effective inhibitor of Herpes Simplex viruses (HSV1 and HSV2) (Thompson, 2004) and influenza viruses (Hayashi, 2008). Oral delivery of fucoidan also inhibits the lung damage and clinical signs of influenza A in vivo and protects against Herpes virus infection (Hayashi, 2008; Hayashi, 2008). In vitro, fucoidan has been shown to inhibit several different strains of influenza, including H1N1 (Hayashi, 2008), H5N1 (Makarenkova, 2010), H5N3 and H7N2 (Synytsa, 2014) and parainfluenza (Taoda, 2008). Clinically, fucoidan reduced pro-viral loads in patients with HTLV-1 (Araya, 2011) and showed benefits for patients with chronic hepatitis C (Mori, 2012). Fucoidan has also been shown to exhibit activity against Newcastle virus (Elizondo-Gonzalez, 2012), canine distemper (Trejo-Avila, 2014) and even the measles virus (Morán-Santibañez, 2016).
- Cell cycle arrest or apoptosis in cancer cells
- Increased immune clearance of cancer cells
- Decreased metastasis
- Inhibition of angiogenesis
Fucoidan is most widely known and used for its potential anti-cancer properties. A considerable amount of research has been undertaken in this area, with some researchers proposing that fucoidan not only increases patient wellbeing, but also assists in the treatment of disease. The potential for fucoidan as an anti-cancer agent is explored in several review publications, including those by Fitton (2015), Kwak (2014) and Lowenthal (2014).
Cancer cell inhibition
Research confirms that fucoidan has direct in vitro effects on cancer cells. Studies have shown that cancer cells apoptose in the presence of fucoidan and may also enter a cell cycle arrest, making them unable to multiply. Immune cells also clear cancer cells and fucoidan enhances this effect (Jin, 2014). Whilst apoptosis pathways are not always identified, there is evidence to support the induction of both intrinsic and extrinsic apoptosis pathways. Studies have demonstrated the induction of these apoptosis pathways is via the activation of ERK1/2 MAPK, the down-regulation of Wnt/beta-catenin signalling (Boo, 2013), the induction of caspase 8 in breast cancer cells (Yamasaki, 2012) and the induction of endoplasmic reticulum stress cascades (Chen, 2014). Fucoidan has also been shown to enhance the activity of chemotherapeutic agents against breast cancer cells (Zhang, 2013).
Reduction of tumour growth
A variety of animal models have demonstrated reductions in tumour growth when fucoidan is administered orally, intravenously or intraperitoneally. The models include blood, ovarian, breast, prostate, liver and head and neck cancers, as explored by Kwak (2014) and Fitton (2015). These studies have shown marked differences in the rate of growth of tumours when fucoidan is administered either intraperitoneally or orally. In one colon cancer model (Azuma, 2012), tumour weights were up to 6 times lower in fucoidan groups than the control group, and life span increased by up to 100%. Aside from direct inhibition and immune clearance of cancer cells, studies have also indicated that fucoidan inhibits angiogenesis (Yang, 2016) and metastasis (Gassmann, 2010).
Amelioration of side effects & improved quality of life
There is increasing interest in the potential for fucoidan to improve quality of life and ameliorate the side effects of conventional cancer treatments. Research in this area has included clinical studies involving the co-administration of fucoidan with common chemotherapies. A recent interaction study has shown that orally delivered fucoidan does not alter serum levels of the commonly used drugs tamoxifen and letrozole in breast cancer patients (Tocaciu, 2016, in press). In some patients, reduced side effects were also noted. In another study, colon cancer patients undergoing chemotherapy experienced reduced fatigue when taking fucoidan and were able to tolerate more rounds of therapy (Ikeguchi, 2011). Ingesting fucoidan has also been shown to reduce cachexia, the debilitating muscle wasting and fat loss that can often occur during cancer (Chen, 2016).
- Prevention of pathogenic bacteria and viruses
- Improvement in gut microbial balance
- Decreased inflammatory processes
- Modulation of liver enzymes
There is rapidly growing interest in the potential for fucoidan to address a range of human gastric health indications. Published research has already reported a range of beneficial effects of fucoidan on models of digestive function, including the amelioration of debilitating conditions such as colitis and gastric ulcers. Fucoidan also has anti-pathogenic properties that may be beneficial for gastric function, as well as a strong research record in liver and kidney health.
The stomach: Helicobacter pylori
Helicobacter pylori (H. pylori) is a pathogen than can cause stomach ulcers. With increasing resistance to existing therapies, new approaches are required to address H. pylori infections. Fucoidans from both Undaria pinnatifida and Fucus vesiculosus have been shown to be highly effective inhibitors of H. pylori adhesion to human gastric epithelia (Chua, 2015). This is consistent with clinical work that confirmed increased rates of healing for stomach ulcers after fucoidan ingestion (Juffrie, 2015). The anti-inflammatory effect observed in a colitis model has also been observed in the stomach, where fucoidan successfully alleviated aspirin-induced damage (Lean, 2015; Choi, 2010).
The upper and lower intestine: Colitis
Fucoidan delivered in feed has been shown to be a highly effective inhibitor of colitis. In one animal model, clinical signs of inflammation, bowel histology and cytokine analysis all indicated a strong, significant inhibitory effect of fucoidan on the development of colitis (Lean, 2015). Fucoidan may also elicit favourable changes in the microbial environment of the gut. Recent research has shown that dietary fucoidan can increase the proportions of beneficial bacteria, Lactobacillus and Ruminococcaceae, in the gut, in addition to reducing inflammation (Shang, 2016). A combination of direct anti-inflammatory action and favourable changes to the microbiome indicate a beneficial role for dietary fucoidan in inflammatory conditions of the gut.
There is a considerable body of scientific evidence supporting the protective effects of orally delivered fucoidan on liver function. Studies have shown that fucoidan not only protects against damage in toxicity models of liver disease (CCL4, Con A) (Hayashi, 2008; Li, 2016), but also in alcohol-induced (Lim, 2015) and non-alcohol-induced fibrosis (Kawano, 2007; Kim, 2014). Fucoidan has also been found to be useful in the treatment of patients with chronic hepatitis C, HCV-related cirrhosis and hepatocellular carcinoma (Mori, 2012). In this study, it was shown that fucoidan inhibited the expression of HCV on a dose-dependent basis. It was also shown that HCV RNA levels were significantly lower relative to the baseline after 8 months of treatment. This marked protective effect on liver function may provide further insight into the beneficial effects of fucoidan on other disease processes, including vascular health and cancer.
In addition to inhibiting H. pylori adhesion, fucoidan has been shown to clear Leishmania parasites (Kar, 2011) and potentiate the activity of oral antibiotics (Lee, 2013). Orally delivered fucoidan has also been shown to protect against damaging endotoxins, which are produced by some infectious disease bacteria. Excess endotoxin production often results in life threatening disease. The protective activity induced by fucoidan included reductions in inflammatory markers, excess coagulation and organ damage (Kuznetsova, 2014).
- Direct inhibition of receptor binding
- Prevention of inflammatory cell accumulation
- Inhibition of inflammatory enzymes COX-1, COX-2 and LOX-15
- Reduction of allergic and UV induced inflammation
Fucoidan shows potential therapeutic anti-inflammatory activity, particularly as a selectin blocker. Fucoidan has potential to be very effective in addressing systemic inflammation, as well as local inflammation in the digestive tract when orally ingested and on the skin when applied topically. The mechanisms of action may include inhibition of inflammatory enzymes and increased integrity of cellular junctions.
Fucoidan is a successful inhibitor of inflammatory disease. Using dietary fucoidan, research shows a decrease in inflammation in diverse settings, including a UV irradiated mouse model (Maruyama, 2015) and in a colitis model (Lean, 2015). Fucoidan can also lessen liver damage caused by inflammation (Lim, 2015). In another animal model, fucoidan inhibited the development of osteoarthritis (Lee, 2015), a disease that involves the painful degradation of joint function. Rheumatoid arthritis is an inflammatory disease and osteoarthritis also has an inflammatory component. Clinical studies showed that 1 gram per day of fucoidan could reduce the symptoms of osteoarthritis by 52% (Myers, 2010). Normal healthy people also showed a reduction in the chronic inflammation marker, IL6 (Myers, 2011).
The selectin blockade activity of fucoidan has been widely reported and reviewed (Fitton, 2011). L-Selectins are cell surface receptors on white blood cells, which perform a braking function for the cells. This braking function allows them to roll on endothelial surfaces and ultimately enter tissue spaces, reducing inflammation. Fucoidan inhibits selectins and thus leukocyte adhesion, thereby increasing the potential to reduce systemic inflammation. P-selectins are expressed on platelets, which are essential for the process of clotting. Cancer cells use both L-selectins and P-selectins as a way to metastasize to other tissue sites, sticking to the endothelial lining of blood vessels. Fucoidan has been shown to inhibit this process (Gassman, 2010). Fucoidan has also been developed as a radiolabeled P-selectin marker for imaging of platelet-rich thrombi (Rouzet, 2011).
Inflammatory enzyme inhibition
Fucoidan exhibits inhibition against the cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, which are key targets for anti-inflammatory drug development (Dewi, 2016). COX has two well-known isoforms: COX-1 and COX-2. COX-2 predominates at sites of inflammation, while COX-1 is expressed primarily in the gastrointestinal tract, where at normal levels, it is essential for normal gut function. LOX inhibition is desirable, as it is associated with the progression of cancer, psoriasis and atherosclerosis. Research conducted by Marinova has indicated that fucoidan can inhibit LOX-15, COX-1 and COX-2 enzymes very effectively at low concentrations (IC50 <100 mcg/ml).
Inflammation of the gut
Inflammation of the gut is successfully inhibited with fucoidan. In a colitis model using dietary fucoidan, clinical signs of inflammation, bowel histology and cytokine analysis all indicated a strong inhibitory effect of oral fucoidan towards colitis (Lean, 2015). Fucoidan has also been shown to inhibit aspirin-induced inflammation of the stomach (Choi, 2010), as well as increase the integrity of tight junctions (Shang, 2016). Increasing the integrity of tight junctions within the gastrointestinal tract may elicit favourable changes in bowel microbiome, which, in turn, has been associated with decreased inflammation.
In topical formulations fucoidan has been shown to impart a range of anti-inflammatory properties. In a clinical setting, it has been shown to significantly inhibit erythema and water loss from skin when applied before or after exposure to UVA and UVB. Using in vitro skin models, fucoidan has also been shown to induce immune response genes. In other in vitro models, fucoidan inhibits the activity of matrix degrading enzymes such as elastase, collagenase and hyaluronidase, and induces the expression of the ‘anti- aging’ protein sirtuin (SIRT1) (Fitton, 2015). It has also been demonstrated that fucoidan limits the inflammation caused by allergy and topically applied fucoidan has been shown to be as effective as cortisone in combatting allergic dermatitis (Yang, 2012).
- Improved serum lipids
- Decreased inflammatory processes
- Improved tissue vascularisation
- Modulation of irregular coagulation
Fucoidan has the potential to support cardiovascular health in a number of ways. The ingestion of fucoidan has been shown to regulate serum lipids and cholesterols, which are important factors in the development of vascular diseases. This propensity to reduce cardiovascular damage is further enhanced by the ability of fucoidan to block scavenger receptors on macrophages, which may reduce LDL cholesterol uptake into artery walls (Park, 2016). Research has also demonstrated that fucoidan has beneficial effects on blood pressure, coagulation and tissue vascularisation.
Fucoidan has been shown to assist in the reactivation of tissue vascularisation after injury, as well as help prevent post-inflammatory tissue damage after ischemic events (Sarlon, 2012; Fitton, 2011). The type of stem cells that can make new vessels are prone to senescence (or ageing) when cultured. It has also been demonstrated that fucoidan can reverse the ageing of endothelial colony forming cells during culture, rendering them particularly useful for revascularisation (Lee, 2015).
Fucoidan has a heparin-like effect in normal blood and reduces clotting, acting via a blood clotting protein called anti-thrombin III (Irhimeh, 2009). However, when ingested at high levels, fucoidan does not move blood clotting parameters out of the normal range. In haemophiliac blood, where factors in the clotting cascade are missing, fucoidan can act as a bridge in the cascade, allowing a normal coagulation response. Research has demonstrated the minimum requirement for the structure and size of fucoidan to be able to act in as a useful coagulation aid for people with clotting disorders (Zhang, 2014).
High blood pressure is a common feature of inflammatory disease. It poses potentially serious health consequences, particularly in ageing populations. It has been shown that when a population of overweight people took fucoidan daily over three months, a decrease in blood pressure was observed (Hernandez-Corona, 2014). In addition to a significant decrease in diastolic blood pressure, this study also showed a significant reduction in low-density cholesterol (LDL-C).
- Prevention of neuronal damage
- Increased SIRT1 expression
- Decreased inflammatory processes
- Improved serum lipids
- Inhibition of matrix degrading enzymes
Research on fucoidan has shown a marked effect on ageing related processes. Fucoidan can potentially reverse ageing in endothelial stem cells (Lee, 2015) and is known to increase sirtuin levels in cell models (Fitton, 2015). In addition to inhibiting key enzymes associated with human ageing processes, research has demonstrated that fucoidan may promote vascular health and stimulate immune responses. It has also been shown to exhibit neuroprotective properties in animal models.
Fucoidan may be useful in the prevention of disease processes in the brain. In vitro and animal studies demonstrate the protective effects of fucoidan in models of Alzheimer’s disease and Parkinson’s disease (Jhamandas, Luo, Fitton). Fucoidan also appears to prevent amyloid accumulation and neuronal cell death, and inhibit the uptake of fragmented DNA, which is often seen in these diseases (Li, 2004). Interestingly, orally delivered fucoidan has also been shown to prevent depression in otherwise healthy animals in a behaviour model (Lee, 2013).
It has been shown that skin sensitisation or atopic dermatitis may be addressed by topical application of fucoidan (Yang, 2012). The classic signs of ageing (wrinkling, age spots and roughness) can also be addressed by topical application of a low concentration of fucoidan (Fitton, 2015). These effects are reflected by in vitro data that demonstrates both matrix degrading enzyme inhibition (collagenase and elastase) and the upregulation of sirtuin (SIRT1) in a cellular system. Increasing the levels of SIRT1 can mimic the benefits of caloric restriction, enhancing sugar and lipid metabolism and maintaining a renewed physiology.