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Algal Polysaccharides as Therapeutic Agents for Atherosclerosis

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Review

Algal Polysaccharides as Therapeutic Agents for Atherosclerosis

Nikita P Patil et al. Front Cardiovasc Med.

Abstract

Seaweed-derived polysaccharides including agar and alginate, have found widespread applications in biomedical research and medical therapeutic applications including wound healing, drug delivery, and tissue engineering. Given the recent increases in the incidence of diabetes, obesity and hyperlipidemia, there is a pressing need for low cost therapeutics that can economically and effectively slow the progression of atherosclerosis. Marine polysaccharides have been consumed by humans for millennia and are available in large quantities at low cost. Polysaccharides such as fucoidan, laminarin sulfate and ulvan have shown promise in reducing atherosclerosis and its accompanying risk factors in animal models. However, others have been tested in very limited context in scientific studies. In this review, we explore the current state of knowledge for these promising therapeutics and discuss the potential and challenges of using seaweed derived polysaccharides as therapies for atherosclerosis.

Keywords: alginate; atherosclerosis; fucoidan; hyperlipidemia; laminarin; microbiome; seaweed; ulvan.

Figures

Figure 1
Figure 1
Representative image of brown seaweeds (phaeophyceae) and chemical structures of derived polysaccharides. (A) Photograph of the brown seaweed laminaria digitata, which is a commons source for the polysaccharide laminarin. The inset image shows the cross section of the holdfast from the brown seaweed laminaria hyperborean. Photographs courtesy of David Fenwick, used with permission1. (B) Chemical structure of fucoidan derived from brown seaweeds. (C) Structure of laminarin sulfate, a chemically modified version of laminarin that is commonly derived from seaweeds of the family Laminariaceae. (D) Chemical structure of alginate, which is derived from the cell wall of brown seaweeds.
Figure 2
Figure 2
Representative image of red seaweeds (rhodophyta) and chemical structure of derived polysaccharides. (A) Photograph of the green seaweed ulva linza, a source of the polysaccharide ulvan. Inset image is a magnified view of the cellular structure of ulva linza. Photographs courtesy of David Fenwick, used with permission1. (B) Chemical structure of rhamnan sulfate, a branched polysaccharide derived from the green seaweeds monostrom nitidum and monostroma latissimum. (C,D) Two chemical structures for ulvan that have been isolated from green seaweeds.
Figure 3
Figure 3
Representative image of green seaweeds (chlorophyta/charophyta) and chemical structure of derived polysaccharides. (A) Photograph of the red seaweed gelidium pusillum, a source of agar. Inset image is a magnified view of the cellular structure of the gelidium pusillum frond. Photographs courtesy of David Fenwick, used with permission1. (B) Chemical structure of polysaccharide agar, derived from red algae. (C) Generalized chemical structure of carrageenan, a linear polysaccharide from edible red seaweeds.
Figure 4
Figure 4
Effects of fucoidan on atherosclerosis and hepatic lipid metabolism. ApoEshl mice were treated under control conditions (NFD), with a high fat diet (HFD), and a high fat diet with 1% and 5% fucoidan for 12 weeks (n = 6). (A) Oil-red O staining of intima of thoracic aorta to show atherosclerotic lesions. (B) Quantification of lesion area to total aorta calculated using ImageJ. The thickness of the intima was normalized to the thickness of the media to calculate the percentage of plaque. (C) Appearance of liver. (D–F) Total cholesterol, triacylglycerol and 4-hydroxynonenal concentrations in liver. Values are mean. *p < 0.05 vs. HFD. Modified and used with permission (11).
Figure 5
Figure 5
Effects of laminarin sulfate on atherosclerosis, heparanase and the intestinal microbiome. (A) Inhibition of heparanase by Inhibition of purified placental heparanase. Radiolabeled ECM was incubated with heparanase in the presence of LS (•) or heparin (○). Heparanase activity is expressed as Kav x cpm eluted in the second peak when the incubation media was analyzed by gel filtration chromatography. Modified and used with permission (47). (B) Severity of plaques in the small and large coronary arteries of rabbits that were treated under control conditions, with a high cholesterol diet (chol) or a high cholesterol diet with laminarin sulfate (LS). Male New Zealand rabbits were used with n = 26 for the control group, n = 24 for the chol group and n = 25 for the chol + LS group. Scores have been adjusted with maximum possible being 370 for large arteries and 544 for small arteries. Modified and used with permission (48). (C) Abundance of phylum (A) and genus levels (B) of bacteria in the gut in mice fed a high fat diet and laminarin sulfate for 42 days. Modified and used with permission (49).
Figure 6
Figure 6
Studies of the effects of agar derivatives on inflammation, oxidative stress, coagulation and bacteria of the gut flora. (A) Schematic of agarose hydrolysis yielding agaro-oligosaccharides (AOs) with varying degrees of polymerization (106). (B) Heme oxygenase−1 protein levels in the inflammation-induced colons of mice orally administered vehicle (Veh) or AOs (AGOs) (107). (C) Harvested mouse colons without colitis induction (sham) or with colitis induction by trinitrobenzene sulfonic acid (TNBS) and oral administration of vehicle (Veh) or AOs (AGOs; left panel). Damage scores for colons (right panel) (107). (D) Nitric oxide levels in LPS-stimulated RAW264.7 macrophages treated with the AOs agarobiose (AB), agarotetraose (AT) and agarohexaose (AH). p < 0.01 vs. LPS alone (106). (E) Nitric oxide production in stimulated peritoneal macrophages from mice orally administered water containing 3% of a mixture of AOs (AGOs), AB or AT at 10 ml/kg per day. **p < 0.01 vs. control with no stimulation (108). (F) Coagulation time (left) and plasma fibrinogen concentrations (right) of blood harvested from rats orally administered saline, agaropectin at various concentrations or propylene glycol alginate sulfate (PSS) (109). *p < 0.05 or **p < 0.01 vs. saline.
Figure 7
Figure 7
Lipid lowering activity of carrageenan. Rabbits were fed a high cholesterol diet and given daily 5 mg via intravenous injections of treatments including carrageenan for 18 weeks. (A) Lipid and (B) cholesterol serum levels were measured before and every two weeks after the start of the diet. A carrageenan-enriched diet demonstrated lower readings of both lipids and cholesterol at multiple time points. *p < 0.05 or p < 0.01 vs. control group. Used with permission (125). (C) Twenty human volunteers were given a carrageenan-enriched diet and monitored for 8 weeks. Groups included a healthy control group and an experimental group with ischemic heart disease. Both groups experienced reductions in total cholesterol (TC) and HDL. *Designates significantly different from all conditions (p < 0.05). Significantly different compared to control group (p < 0.05).Significant difference between “before” and “after” groups in either the control or experimental groups (p < 0.05). §Significantly different between control “after” group and experimental “after” group (p < 0.05). Used with permission (127).

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