Oral Supplementation with Algal Sulphated Polysaccharide in Subjects with Inflammatory Skin Conditions: A Randomised Double-Blind Placebo-Controlled Trial and Baseline Dietary Differences.

We examined the effect of a dietary seaweed extract-sulfated xylorhamnoglucuronan (SXRG84)-on individuals with inflammatory skin conditions. A subgroup analysis of a larger trial was undertaken, where 44 participants with skin conditions were enrolled in a double-blind placebo-controlled crossover design. Subjects ingested either SXRG84 extract (2 g/day) for six weeks and placebo for six weeks, or vice versa. At baseline, six- and twelve-weeks inflammatory markers and the gut microbiota were assessed, as well as skin assessments using the dermatology quality of life index (DQLI), psoriasis area severity index (PASI) and visual analogue scales (VAS). There were significant differences at weeks six and twelve for pro-inflammatory cytokines IFN-γ (p = 0.041), IL-1ß (p = 0.030), TNF-α (p = 0.008) and the anti-inflammatory cytokine IL-10 (p = 0.026), determined by ANCOVA. These cytokines were all significantly higher at six weeks post placebo compared to twelve weeks post placebo followed by SXRG84 treatment. A total of 23% of participants reported skin improvements, as measured by VAS (mean difference 3.1, p = 0.0005) and the DQLI score (mean difference -2.0, p = 0.049), compared to the 'non-responders'. Thus, the ingestion of SXRG84 for 6 weeks reduced inflammatory cytokines, and a subset of participants saw improvements.

Improved Plasma Lipids, Anti-Inflammatory Activity, and Microbiome Shifts in Overweight Participants: Two Clinical Studies on Oral Supplementation with Algal Sulfated Polysaccharide.

Seaweed polysaccharides in the diet may influence both inflammation and the gut microbiome. Here we describe two clinical studies with an Ulva sp. 84-derived sulfated polysaccharide­"xylorhamnoglucuronan" (SXRG84)­on metabolic markers, inflammation, and gut flora composition. The first study was a double-blind, randomized placebo-controlled trial with placebo, and either 2 g/day or 4 g/day of SXRG84 daily for six weeks in 64 overweight or obese participants (median age 55 years, median body mass index (BMI) 29 kg/m2). The second study was a randomized double-blind placebo-controlled crossover trial with 64 participants (median BMI 29 kg/m2, average age 52) on placebo for six weeks and then 2 g/day of SXRG84 treatment for six weeks, or vice versa. In Study 1, the 2 g/day dose exhibited a significant reduction in non-HDL (high-density lipoprotein) cholesterol (−10% or −0.37 mmol/L, p = 0.02) and in the atherogenic index (−50%, p = 0.05), and two-hour insulin (−12% or −4.83 mU/L) showed trends for reduction in overweight participants. CRP (C-reactive protein) was significantly reduced (−27% or −0.78 mg/L, p = 0.03) with the 4 g/day dose in overweight participants. Significant gut flora shifts included increases in Bifidobacteria, Akkermansia, Pseudobutyrivibrio, and Clostridium and a decrease in Bilophila. In Study 2, no significant differences in lipid measures were observed, but inflammatory cytokines were improved. At twelve weeks after the SXRG84 treatment, plasma cytokine concentrations were significantly lower than at six weeks post placebo for IFN-γ (3.4 vs. 7.3 pg/mL), IL-1ß (16.2 vs. 23.2 pg/mL), TNF-α (9.3 vs. 12.6 pg/mL), and IL-10 (1.6 vs. 2.1 pg/mL) (p < 0.05). Gut microbiota abundance and composition did not significantly differ between groups (p > 0.05). Together, the studies illustrate improvements in plasma lipids and an anti-inflammatory effect of dietary SXRG84 that is participant specific.

Anti-Inflammatory Activity of Fucoidan Extracts In Vitro.

Fucoidans are sulfated, complex, fucose-rich polymers found in brown seaweeds. Fucoidans have been shown to have multiple bioactivities, including anti-inflammatory effects, and are known to inhibit inflammatory processes via a number of pathways such as selectin blockade and enzyme inhibition, and have demonstrated inhibition of inflammatory pathologies in vivo. In this current investigation, fucoidan extracts from Undaria pinnatifida, Fucus vesiculosus, Macrocystis pyrifera, Ascophyllum nodosum, and Laminaria japonica were assessed for modulation of pro-inflammatory cytokine production (TNF-α, IL-1ß, and IL-6) by human peripheral blood mononuclear cells (PBMCs) and in a human macrophage line (THP-1). Fucoidan extracts exhibited no signs of cytotoxicity in THP-1 cells after incubation of 48 h. Additionally, all fucoidan extracts reduced cytokine production in LPS stimulated PBMCs and human THP-1 cells in a dose-dependent fashion. Notably, the 5-30 kDa subfraction from Macrocystis pyrifera was a highly effective inhibitor at lower concentrations. Fucoidan extracts from all species had significant anti-inflammatory effects, but the lowest molecular weight subfractions had maximal effects at low concentrations. These observations on various fucoidan extracts offer insight into strategies that improve their efficacy against inflammation-related pathology. Further studies should be conducted to elucidate the mechanism of action of these extracts.

Fucoidan Supplementation Restores Fecal Lysozyme Concentrations in High-Performance Athletes: A Pilot Study.

Nutritional strategies to help promote immune competence are of particular interest for a range of population groups. This study aimed to assess the potential impacts of fucoidan, a seaweed-derived bioactive polysaccharide, on gut markers of immunity and inflammation. A group of professional team-sport athletes were selected for inclusion in the study given the recognized potential for intense physical activity to induce alterations in immune function. A retrospective analysis was performed on stored fecal samples which had been collected from professional team-sport athletes (n = 22) and healthy adults (n = 11) before and after seven days of supplementation with fucoidan (Fucus vesiculosus/Undaria pinnatifida extract, 1 g/d). Fecal concentrations of calprotectin, secretory immunoglobulin A (sIgA) and lysozyme were determined using enzyme-linked immunosorbent assays. The supplement was well tolerated by participants with no adverse events reported. At baseline, fecal lysozyme concentrations were ~73% higher in the healthy adults compared to the professional athletes (p = 0.001). For the professional athletes, a significant (~45%) increase in fecal lysozyme was observed following the supplementation period (p = 0.001). These data suggest that fucoidan supplementation may have the potential to promote the secretion of antimicrobial peptides in specific population groups and contribute to the regulation of mucosal immune health.

Oral Fucoidan Attenuates Lung Pathology and Clinical Signs in a Severe Influenza a Mouse Model.

Fucoidans are known to be effective inhibitors of inflammation, and of virus binding and cellular entry. Undaria pinnatifida-derived fucoidan (UPF) was assessed in a severe influenza A (H1N1, PR8) infection model in mice. Initially, UPF was gavaged at 3.52 mg daily in a treatment model. Gross lung pathology (consolidation) was significantly reduced as compared to controls. UPF was then presented as a feed supplement at a rate of either nil, 3.52 mg/day or 7.04 mg/day in a prophylactic model, dosed three days before infection. A significant improvement was observed in the clinical signs of ill-health, as well as a reduction in gross lung pathology in animals treated with the higher dose, although there was no significant reduction in lung viral titres.

Effect of a Fucoidan Extract on Insulin Resistance and Cardiometabolic Markers in Obese, Nondiabetic Subjects: A Randomized, Controlled Trial.

OBJECTIVES: To determine whether a fucoidan extract reduced insulin resistance and/or altered other cardiometabolic markers in an obese, nondiabetic population. DESIGN: Single-site, double-blinded, placebo-controlled, randomized controlled trial. SETTING/LOCATION: Hobart, Tasmania, Australia. SUBJECTS: Eligible subjects were obese, with no history of diabetes, and ages between 18 and 65 years. INTERVENTIONS: Subjects were randomly assigned, in even blocks of 10, to either active fucoidan 500 mg or placebo capsules twice daily for 90 days, with identical measurements performed at baseline and follow-up. OUTCOME MEASURES: The primary outcome was insulin resistance, defined by the homeostasis model of assessment (HOMA) values. Secondary outcomes were lipid profile, glycosylated hemoglobin, urea electrolytes and creatinine, liver function tests, full/complete blood count, fasting insulin, fasting glucose, quantitative insulin sensitivity check index, glucose area under the curve, weight, body mass index, waist circumference, and systolic and diastolic blood pressure. The trial was registered with the Australian New Zealand Clinical Trial Registry (ACTRN12614000495628) and the Therapeutic Goods Administration (2014/0348), and was funded by Marinova Pty. Ltd. RESULTS: There were no differences in the 90-day outcome measures between placebo and active treatment in the intention-to-treat-analysis (n = 35 for active, n = 37 for placebo). The mean change in HOMA scores was 0 for the placebo and -0.1 for the active groups (p = 0.73). Self-reported adherence was high, consistent with capsule counting at the conclusion of the trial. CONCLUSIONS: Fucoidan taken twice daily for a period of 90 days did not markedly affect insulin resistance or other measured parameters of cardiometabolic health in an obese, nondiabetic cohort. This could be due to an intrinsic lack of efficacy, lower than measured adherence, or because longer therapy and/or higher baseline insulin resistance are required to exert a significant effect.

The Effect of Undaria pinnatifida Fucoidan on the Pharmacokinetics of Letrozole and Tamoxifen in Patients With Breast Cancer.

BACKGROUND: Although the use of complementary and alternative medicines is widespread in cancer patients, clinical evidence of their benefits is sparse. Furthermore, while they are often assumed to be safe with regard to concurrent use of anticancer therapies, few studies have been carried out to investigate possible interactions. Fucoidans are a group of sulfated carbohydrates, derived from marine brown algae, which have long been used as dietary supplements due to their reported medicinal properties, including anticancer activity. The aim of this study was to investigate the effect of co-administration of fucoidan, derived from Undaria pinnatifida, on the pharmacokinetics of 2 commonly used hormonal therapies, letrozole and tamoxifen, in patients with breast cancer. METHODS: This was an open label non-crossover study in patients with active malignancy taking letrozole or tamoxifen (n = 10 for each group). Patients took oral fucoidan, given in the form of Maritech extract, for a 3-week period (500 mg twice daily). Trough plasma concentrations of letrozole, tamoxifen, 4-hydroxytamoxifen, and endoxifen were measured using HPLC-CAD (high-performance liquid chromatography charged aerosol detector), at baseline and after concomitant administration with fucoidan. RESULTS: No significant changes in steady-state plasma concentrations of letrozole, tamoxifen, or tamoxifen metabolites were detected after co-administration with fucoidan. In addition, no adverse effects of fucoidan were reported, and toxicity monitoring showed no significant differences in all parameters measured over the study period. CONCLUSIONS: Administration of Undaria pinnatifida fucoidan had no significant effect on the steady-state trough concentrations of letrozole or tamoxifen and was well tolerated. These results suggest that fucoidan in the studied form and dosage could be taken concomitantly with letrozole and tamoxifen without the risk of clinically significant interactions.

Fucoidan Extracts Ameliorate Acute Colitis.

Inflammatory bowel diseases (IBD), such as ulcerative colitis and Crohn's disease, are an important cause of morbidity and impact significantly on quality of life. Overall, current treatments do not sustain a long-term clinical remission and are associated with adverse effects, which highlight the need for new treatment options. Fucoidans are complex sulphated, fucose-rich polysaccharides, found in edible brown algae and are described as having multiple bioactivities including potent anti-inflammatory effects. Therefore, the therapeutic potential of two different fucoidan preparations, fucoidan-polyphenol complex (Maritech Synergy) and depyrogenated fucoidan (DPF) was evaluated in the dextran sulphate sodium (DSS) mouse model of acute colitis. Mice were treated once daily over 7 days with fucoidans via oral (Synergy or DPF) or intraperitoneal administration (DPF). Signs and severity of colitis were monitored daily before colons and spleens were collected for macroscopic evaluation, cytokine measurements and histology. Orally administered Synergy and DPF, but not intraperitoneal DPF treatment, significantly ameliorated symptoms of colitis based on retention of body weight, as well as reduced diarrhoea and faecal blood loss, compared to the untreated colitis group. Colon and spleen weight in mice treated with oral fucoidan was also significantly lower, indicating reduced inflammation and oedema. Histological examination of untreated colitis mice confirmed a massive loss of crypt architecture and goblet cells, infiltration of immune cells and oedema, while all aspects of this pathology were alleviated by oral fucoidan. Importantly, in this model, the macroscopic changes induced by oral fucoidan correlated significantly with substantially decreased production of at least 15 pro-inflammatory cytokines by the colon tissue. Overall, oral fucoidan preparations significantly reduce the inflammatory pathology associated with DSS-induced colitis and could therefore represent a novel nutraceutical option for the management of IBD.

Quantitative determination of fucoidan using polyion-sensitive membrane electrodes.

The use of polyanion and polycation-sensitive membrane electrodes to detect five different preparations of fucoidan is described. Unlike linear polyanionic molecules previously measured with polymer membrane-based electrochemical sensors, fucoidans from marine brown algae are all highly branched, sulfated polysaccharides with varying charge densities and structures, depending on the species of seaweed, method of extraction used and extent of purification. When tridodecylmethylammonium (TDMA) was used as the ion-exchanger, a large, non-equilibrium EMF response was observed over a concentration range of 0.5-50 µg mL(-1) fucoidan. Fucoidan was also measured by titration with polycationic protamine, using a dinonylnaphthalene sulfonate (DNNS)-doped membrane electrode as the potentiometric endpoint detector. Potentiometric titration was used to determine the binding ratio between protamine and fucoidan at the neutralization endpoint for each fucoidan preparation. This binding ratio was then used to successfully determine the fucoidan content of commercially available nutritional supplements. Fucoidan was also measured in undiluted blood serum, demonstrating that this method may be applicable for measuring fucoidan for clinical applications.

A combined Phase I and II open-label study on the immunomodulatory effects of seaweed extract nutrient complex.

BACKGROUND: Isolated fucoidans from brown marine algae have been shown to have a range of immune-modulating effects. This exploratory study aimed to determine whether a seaweed nutrient complex containing a blend of extracts from three different species of brown algae plus nutrients is safe to administer and has biological potential as an immune modulator. The study was undertaken as an open-label combined Phase I and II study. METHODS: Participants (n = 10) were randomized to receive the study medication at either a 100 mg (n = 5) or 1000 mg (n = 5) dose over 4 weeks. The primary outcome measurement was in vivo changes in lymphocyte subsets. The secondary outcome measures were ex vivo changes in T-lymphocyte (CD4 and CD8) activation, phagocytosis of granulocytes and monocytes, T helper 1/T helper 2 cytokines, and serum oxygen radical absorbance capacity. RESULTS: The preparation was found to be safe over the 4 weeks at both doses tested. There were no clinically relevant changes to blood measurements of hemopoietic, hepatic, or renal function. Immunomodulatory measurements showed no dose response between the two doses. The combined results from the two doses demonstrated a significant increase in cytotoxic T cell numbers and phagocytic capacity in monocytes, and a significant decrease in levels of the inflammatory cytokine interleukin 6. A separate analysis of the 100 mg dose (n = 5) alone showed a significant linear component over time (P < 0.05) for phagocytosis by both granulocytes and monocytes. CONCLUSION: The seaweed nutrient complex was safe to use when taken orally over 4 weeks. The preparation was demonstrated to have potential as an immune modulator, and this bioactivity deserves further exploration.

A combined phase I and II open label study on the effects of a seaweed extract nutrient complex on osteoarthritis.

BACKGROUND: Isolated fucoidans from brown marine algae have been shown to have a range of anti-inflammatory effects. PURPOSE: This present study tested a Maritech((R)) extract formulation, containing a blend of extracts from three different species of brown algae, plus nutrients in an open label combined phase I and II pilot scale study to determine both acute safety and efficacy in osteoarthritis of the knee. PATIENTS AND METHODS: Participants (n = 12, five females [mean age, 62 +/- 11.06 years] and seven males [mean age, 57.14 +/- 9.20 years]) with a confirmed diagnosis of osteoarthritis of the knee were randomized to either 100 mg (n = 5) or 1000 mg (n = 7) of a Maritech((R)) extract formulation per day. The formulation contained Maritech((R)) seaweed extract containing Fucus vesiculosis (85% w/w), Macrocystis pyrifera (10% w/w) and Laminaria japonica (5% w/w) plus vitamin B6, zinc and manganese. Primary outcome was the average comprehensive arthritis test (COAT) score which is comprised of four sub-scales: pain, stiffness, difficulty with physical activity and overall symptom severity measured weekly. Safety measures included full blood count, serum lipids, liver function tests, urea, creatinine and electrolytes determined at baseline and week 12. All adverse events were recorded. RESULTS: Eleven participants completed 12 weeks and one completed 10 weeks of the study. Using a multilevel linear model, the average COAT score was reduced by 18% for the 100 mg treatment and 52% for the 1000 mg dose at the end of the study. There was a clear dose response effect seen between the two treatments (P