The common side effects of the current synthetic lipid-lowering drugs, i.e.
, hepatic and/or rhabdomyolysis [55
], have increased the tendency to move toward traditional and alternative treatments [56
]. In this field, the diet supplementation of seaweeds and/or extracts might have a potential protective role. This is supported by the fact that epidemiological observations show satisfactory results when associating the consumption of seaweeds, medicinal plants and fruits to the prevention of hyperlipidemia in many societies [57
]. Having this in mind, the potential effect of distinct macroalgae and/or its isolates in hyperlipidemia control has been largely tested in animal models. Due to the high number of reported studies in this topic, only the most recent ones have been selected for this review.
When supplementing the diets of hypercholesterolemic Wistar rats with 21% of Himanthalia elongata
or 23% of Gigartina pistillata
, Villanueva and coworkers [58
] showed that Himanthalia
-treated rats presented a reduction in the plasmatic levels of TG (28%) while increasing those of HDL-C (20%). In turn, the Gigartina
-supplemented diet produced a significant decrease of 31% in TG, 18% in total cholesterol (TC) and 16% in LDL-C [58
]. Identical effect was observed in studies using diets supplemented with tropical green seaweed (5% of dried Derbesia tenuissima
(DT)). DT did not change total body fat mass but it could decrease the plasmatic levels of TG by 38% and TC by 17% [59
In addition, the diet supplementation of high-cholesterol/high-fat (HF) Sprague-Dawley rats with 10% freeze dried red seaweed Gracilaria changii
) powder for eight weeks significantly lowered the plasmatic TC, LDL-C and TG contents by 40.34%, 35.95% and 30.91% respectively, as compared to the HF-induced rats group although no effect on HDL-C could be observed [60
]. Its hypolipidemic action was comparable to statin. As suggested by the authors, one of the potential mechanisms of action explaining the hypolipidemic effects of G. changii
might be due to its high dietary fiber (61.29%) [60
]. Supplementation of G. changii
to the normal rats showed less significant effect on the plasma TC, HDL-C, LDL-C and TG levels [60
]. These differences suggest that this seaweed is probably more effective for hyperlipidemia treatment purposes instead of preventive ones. In addition, brown algae Ecklonia cava
supplementation dose dependently suppressed TG, TC, and LDL-C concentrations in the serum in both normal and STZ-diabetic mice (supplementation of 5% of seaweed in diabetic mice causes a decrease in serum levels of 72%, 53%, and 78%, respectively) but failed to affect HDL-C concentrations in normal mice [61
For the last years, there are also distinct works reporting positive effects on lipid metabolism as a result of diet supplementation of extracts obtained from macroalgae. Ruqqia et al.
] showed that amongst the ethanol extracts of 13 seaweed species, those of Jolyna laminarioides
and Sargassum binderi
exhibited comparable hypolipidemic potential to common hypolipidemic drugs such as bezafibrate and fenofibrate (through decrement of TC, TG and LDL-C) in diet-induced hyperlipidemic rats and in triton-induced hyperlipidemic rats [62
]. The extract from Melanothamnus afaqhusainii
was also moderately active in lowering the levels of TC, TG and LDL-C in triton-induced hyperlipidemic rats [62
]. Liver and cardiac enzymes like lactate dehydrogenase, alkaline phosphatase, aspartate alanine aminotransferase were not adversely affected by administration of these three extracts [62
In addition, the ethanol extract of the brown seaweed Iyengaria stellate
(10 mg/200 g body weight to rabbits for 30 days) showed an overall decrease in total plasmatic lipid levels, although an increase in the contents of the liver enzymes alkaline phosphatase, glutamic-pyruvic transaminase (SGPT), glutamic oxaloacetic transaminase and γ-transaminase (with exception for SGPT) were also registered [63
]. Note that as SGPT is a more specific indicator of liver injury, the overall results gathered by the authors suggest that the intake of Iyengaria stellate
extract as a hypolipidemic agent should be followed by the monitoring of liver enzymes to ensure liver safety.
Furthermore, Dousip et al.
] investigated the antihyperlipidemic effect of red seaweed Kappaphycus alvarezii
and brown seaweed Sargassum polycystum
aqueous extracts, as well as their synergistic effects, in high-cholesterol diet fed rats. The results showed that Sargassum polycystum
was more effective in decreasing plasma cholesterol (by 37.52%) when compared to Kappaphycus alvarezii
or with the mixture of the two extracts, though an increase in plasmatic TG levels by 16.66% was also observed. In turn, the Kappaphycus alvarezii
extract most effectively decreased the TG levels by 40.11% and the mixture of the two extracts further increased HDL-C (by 56.71%). All the three tested conditions (individual extracts or mixture) were able to reduce LDL-C levels when compared to the high-cholesterol group [64
]. Overall, hypercholesterolemic rats fed with the mixture of the extracts had the lowest atherogenic index among all groups [64
Besides the evidences of dietary supplementation of seaweeds and/or crude extracts on lipid metabolism, many authors have also been described positive effects for purified fractions and/or isolated compounds. Amongst them, the majority of the works have been focusing two major groups of compounds, namely seaweeds’ sulfated polysaccharides and lipids. Some recent examples are described below.
Borai et al.
] reported that the oral administration of sulfated polysaccharides (SP) from Ulva fasciata
to induced-hypercholesterolemic rats for four consecutive weeks did not exert any side effects and, simultaneously, it caused a significant decrement in serum lipid profile by reducing the plasmatic TC, TG, LDL-C and of very low density lipoproteins-cholesterol (VLDL-C). Notably, the scores for Ulva fasciata
ulvans effects were better than those observed for the reference drug fluvastatin [65
]. In addition, Hoang and coworkers [66
] reported that two types of SP isolated from the green alga Monostroma nitidum
showed the ability to reduce cellular lipid concentrations in lipid-loaded hepatocytes, when compared with controls, being this reduction accompanied by a reduced expression of cholesterol synthesis genes and an increment in the expression of genes dictating cholesterol degradation, LDL uptake and peroxisomal β-oxidation.
Another relevant work focusing the effects of ulvans in lipid metabolism has been performed by Hassan et al.
]. These authors described that the intragastric administration of Ulva lactuca
sulfated polysaccharides to dietary-induced hypercholesterolemic rats could cause a more evident effect in the increment of HDL-C level (by 180%) when compared to that induced by its oral administration [67
]. This paves the way for discussion of the effect of the administration mode and how to take advantage of this difference in results.
Along with ulvans, fucoidans have been largely evaluated as antihyperlipidemic agents. Recently, a fucoidan extracted from the brown seaweed Sargassum henslowianum
and whose structure was established as an α(1→3)-linked l
-fucopyranose backbone with sulfate groups mostly present at C-2, C-4 and occasionally at C-3, was tested in an obese mice model. The administration of this fucoidan at a dose of 100 mg/kg P/day to the animals caused a decrement in the plasmatic levels of cholesterol, TG and LDL-C [68
]. Unfortunately, definite conclusions on the effective effect of this polysaccharide still requires additional studies on dosage, administration time, in between other parameters.
In addition, Kim et al.
] have recently demonstrated that the dietary supplementation of a commercial fucoidan (Haewon Biotech, Inc., Seoul, Korea) induced a significant decrease on the plasmatic levels of TG, total cholesterol and of LDL-C. As reported by the authors, the beneficial effects of the fucoidan were probably partially associated to the down-regulation of adipogenic transcription factor [69
Carrageenans, another type of sulfated polysaccharide typically present in red algae, were recently used in a clinical trial study. Patients with ischemic heart disease (IHD) were reported to exhibit a significant effect on lipid profile by a short-term carrageenan supplement [70
]. In fact, the prophylactic administration of the carrageenan food supplement in the complex therapy of IHD patients could significantly decrease the plasmatic TC levels by 16.5% and LDL-C by 33.5% as compared with the baseline measurements (background therapy control and experimental groups) [70
Amongst the macroalgae lipids, fucoxanthin and fatty acids are widely mentioned when it comes to dyslipidemia regulation. Notably, the beneficial effects of fucoxanthin on cardiovascular diseases were recently reviewed by Gammone et al.
]. In agreement with distinct reported studies, these authors highlighted that fucoxanthin metabolites (amarouciaxanthin A and fucoxanthinol) are the active in vivo
forms of fucoxanthin and that their ability in regulating lipids plasmatic levels are mainly due to their antioxidant activity [71
]. In addition, fucoxanthin and its metabolite fucoxanthinol are accepted to exhibit extra-metabolic benefic effects, including the regulation of polyunsaturated fatty acids (PUFA) biosynthesis by the promotion of the upregulation of enzymatic activities related to the bioconversion of omega-3 PUFA and omega-6 PUFA to docosahexaenoic acid (DHA) and arachidonic acid (AA), respectively [72
]. Furthermore, it has been demonstrated that both these compounds could induce a decrease in the content of eicosapentaenoic acid (EPA) on cultured rat hepatoma BRL-3A, thus suggesting a down-regulation of metabolic enzymes such as fatty acid desaturase and elongase [75
]. In rodents, fed fucoxanthin promotes the synthesis of DHA in the liver [72
], resulting in the improvement of the lipid profile since this acid inhibits the synthesis of thromboxane A2 and enhances the production of prostacyclin, a prostaglandin that produces vasodilation and less sticky platelets [76
As previously mentioned, fatty acids from seaweeds may have itself beneficial properties relevant to cardiovascular disease since they are good sources of the long-chain omega-3 PUFAs EPA and DHA acids [74
], which in turn promote beneficial effects in serum EPA, TC and TG levels and in LDL-C/HDL-C ratio [77
]. As demonstrated in KK-Ay mouse, DHA and AA levels are significantly increased by the feeding of lipids from Sargassum horneri
and Cystoseira hakodatensis
, but not by those obtained from Undaria pinnatifida
]. As suggested by the authors, this difference can be due to the higher fucoxanthin content in the first two seaweeds. The authors have additionally reported that the plasmatic levels of TC, HDL-C and phospholipid of mouse fed with seaweeds lipids were significantly increased while those of hepatic cholesterol and triacylglycerol were decreased as compared with the control group [83
]. The increase of serum cholesterol levels by fucoxanthin, in KK-Ay mice, was studied by Beppu et al.
]. The results suggest that fucoxanthin exerts its effects on cholesterol metabolism and in the transport system by down-regulation of the LDL receptor and the class B type 1 scavenger receptor, along with inducing sterol regulatory element binding protein expression [84
]. Further studies however are required for clarifying whether the responses to cholesterol metabolism are specific for rodents or extended to Human.
The preventive hypertensive effects of seaweeds have since ever been associated with their richness in dietary fibers and mineral contents and, although reported literature regarding this issue is clearly scarce when compared to that dealing with dyslipidemia, in vitro and in vivo studies support this association. In addition, recent literature data suggests that bioactive components like fucoxanthin, phlorotannins and peptides can also play a role in seaweeds’ antihypertensive effects.
As mentioned before, inhibition of ACE-I is a well-established approach in the treatment of hypertension and, because of that, many authors have screened the potential of seaweeds in inhibiting this enzyme, either using crude extracts, purified fractions and/or isolated components (see selected examples in Table 1
Cha et al.
] screened the in vitro
ACE-I inhibitory activity of methanol and aqueous extracts from twenty-six red Korean algae, obtained at 20 °C or at 70 °C. The authors have found several potential extracts, with IC50
values for ACE-I in the range of 12.21–124.69 μg·mL−1
, being the lowest value found for the aqueous extract of Lomentaria catenata
at 20 °C. In addition, Jung et al.
] found that among the ethanol extracts of ten Korean seaweeds, including four Rhodophyta
, Gigartina tenella
, Porphyra tenera
and Chondria crassicaulis
), five Phaeophyta
, Ecklonia cava
, Hizikia fusiforme
, Pelvetia siliquosa
and Undaria pinnatifida
) and one Chlorophyta
), those of E. cava
, E. stolonifera
, P. siliquosa
, G. tenella
and U. pinnatifida
were the most promising in targeting ACE-I, all causing inhibition above 50% at 163.9 μg·mL−1
. Since several purified fractions and isolated phlorotannins from the extract of E. stolonifera
also exhibited marked ACE-I inhibitory activity, the authors concluded that phlorotannins, in particular eckol, phlorofucofuroeckol A and dieckol could be partially responsible for the protective activity of the crude extract [86
In another study, Wisesingh and coworkers [87
] also suggested that phlorotannins could be key constituents of extracts when concerning ACE-I targeting. The authors demonstrated that the ethanol extract of E. cava
was the most active against ACE-I activity when compared to other organic extracts obtained with ethyl acetate, chloroform, hexane or diethyl ether. Besides, they reported that the isolated phlorotannins from this seaweed were active against ACE-I.
Antioxidants, including phlorotannins and fucoxanthin, were also recently shown to be components of Saccharina japonica and Sargassum horneri oils, either obtained by environmental friendly supercritical-CO2 with ethanol as a co-solvent or by conventional extraction using ethanol, hexane or a (1:1, v/v) mixture of acetone:methanol. All the extracts exhibited moderate-to-high activity against ACE-I, and authors have suggested that this activity could be attributed in part to fucoxanthin, although no direct correlations between its concentration in the extracts and the inhibitory activity were observed.
Recently, distinct studies applying proteolytic enzymatic digestion to seaweeds has led to detection of a number of renin- or ACE-I-inhibitory bioactive peptide. Examples of potential peptides have been described for red macroalgae (e.g., from Porphyra columbina
, Porphyra yezoensis
, and Palmaria palmata
), as well as for green algae (Caulerpa microphysa
) and brown algae (Undaria pinnafita
) (Table 1
). As seaweed hydrolysates consist of a complex mixture of constituents and the amino acid sequence of bioactive peptides in ACE-active hydrolysates has not been commonly determined, more experimental data should be gathered in order to allow solid conclusions on structural-active relations. However, according to Suetsuna and coworkers [88
], the presence of Tyr residues in dipeptides seems to improve their ability of targeting ACE-I.
Selected studies reporting inhibitory abilities of seaweeds extracts and isolates on the renin-angiotensin-system.
Selected studies reporting inhibitory abilities of seaweeds extracts and isolates on the renin-angiotensin-system.
|ACE-I inhibition of extracts|
|Twenty-six red algae||MeOH and Aq Ext 20 °C and 70 °C||Aq Ext 20 °C IC50 (µg/mL): Lomentaria catenata = 13.78; Lithophyllum okamurae = 12.21; MeOH Ext 20 °C IC50 (µg/mL): Ahnfeltiopsis flabelliformis = 13.84; Laurencia okamurae = 106.15; MeOH Ext70 °C: Bonnemaisonia hamifera, Grateloupia filicina, Sinkoraena lancifolia, Grateloupia lanceolata, Gracilaria vermiculophylla and L. okamurae ranging from 25.82 to 124.69|||
|Ten Korean seaweeds ||EtOH Ext||Ecklonia stolonifera, E. cava, Pelvetia siliquosa, Undaria Pinnatifida and Gigartina tenella: above 50% inhibition of ACE at 163.93 µg/mL|||
|Ecklonia cava||EtOH, EtAc, CHCl3, Hex, DE||Best inhibition for EtOH Ext, IC50 = 0.96 mg/mL|||
|ACE-I inhibition associated with antioxidants|
|Ecklonia stolonifera||Purified Phlorotannins||Best inhibition recorded for eckol, dieckol and phlorofucofuroeckol. IC50 (μM): eckol = 70.82; phlorofucofuroeckol A = 12.74; dieckol = 34.25|||
|Ecklonia cava||Purified Phlorotannins||IC50 (mM): phloroglucinol = 2.57 ± 0.09; eckol = 2.27 ± 0.08; triphlorethol-A = 2.01 ± 0.36; dieckol = 1.47 ± 0.04; eckstolonol = 2.95 ± 0.28|||
|Saccharina japonica (SJ) Sargassum horneri (SH)||Supercritic CO2 vs. Acet: MeOH||IC50 (µg/mL): SJ CO2 Ext = 0.89 ± 0.07; SJ Acet:MeOH Ext = 1.05 ± 0.14; SH CO2 Ext = 0.97 ± 0.11; SH Acet:MeOH Ext = 1.28 ± 0.50;|||
|ACE-I or Renin inhibition associated with peptides|
|Porphyra columbina||Enzymatic in thermostatic reactor (A/AF)||ACE-I IC50 (g/L): A = 1.2 ± 0.1; AF = 1.7 ± 0.0|||
|Porphyra yezoensis||pH and enzymatic ||ACE-I IC50 (g/L): 1.6|||
|Palmaria palmata||Papain ||Ile-Arg-Leu-Ile-Ile-Val-Leu-Met-Pro-Ile-Leu-Met-Ala Renin inhibitory bioassay: ↓ renin activities by 58.97% (±1.26) at 1 mg/mL.|||
|Solieria chordalis (SC) Palmaria palmata (PP)||Chymotrypsin (ChTr) or trysin (Tr)||<10 kDa fractions of SC: hydrolyzed with ChTr (IC50 ACE 3.50 mg/mL) or Tr (IC50 ACE 20.34 mg/mL); <10 kDa fractions of PP: hydrolyzed with ChTr (ACE IC50 460.05 mg/mL)|||
|Caulerpa microphysa||Pepsin, alcalase, flavourzyme||ACE-I IC50 (mg/L): pepsin = 0.20; flavourzyme = 29.74; alcalase = 31.71|||
|Undaria pinnafida||Pepsin ||ACE-I IC50 (µM): Ala-Ile-Tyr-Lys = 213; Tyr-Lys-Tyr-Tyr = 64.2; Lys-Phe-Tyr-Gly = 90.5; Tyr-Asn-Lys-Leu = 21|||
|Undaria pinnatifida||Aq hot Ext dyalisis, chromatography||ACE-I IC50 (µM): Tyr-His = 5.1; Lys-Trp = 10.8; Lys-Tyr = 7.7; Lys-Phe = 28.3; Phe-Tyr = 3.7; Val-Trp = 10.8; Val-Phe = 43.7; Ile-Tyr = 2.7; Ile-Trp = 12.4; Val-Tyr = 11.3|||
Because non-invasive measure of blood pressure in lab animals is a difficult task, this parameter has also not been widely screened when evaluating the beneficial effects of the dietary supplementation of seaweeds or isolates in CVDs-related animal models. Still, some authors described the diet-supplementation of seaweeds and/or seaweed isolates in blood pressure (see resume of selected studies in Table 2
Selection of studies that include the assessment of blood pressure or antioxidant, anti-inflammatory or endothelium restoring as a consequence of diet supplementation of seaweeds or isolates, as evaluated in vivo models.
Selection of studies that include the assessment of blood pressure or antioxidant, anti-inflammatory or endothelium restoring as a consequence of diet supplementation of seaweeds or isolates, as evaluated in vivo models.
|Seaweed Species (Extract)||Model Dose||Effects||Ref.|
|Ulva ohnoi (UO) Derbesia tenuissima (DT)||High-carbohydrate, HF diet-fed rats 5% for 8 weeks||UO: ↓ total final body fat mass by 24% and sBP by 29 mmHg; ↑ Glc utilization and insulin sensitivity; DT: ↓ TG by 38% and TC by 17%|||
|Ulva linza (UL) Lessonia trabeculata (LT)||High-sucrose, HF diet-fed rats|400 mg·kg−1 for 8 weeks||UL, LT: ↓ levels of intra-abdominal fat, arterial BP, insulin resistance, TC, TG, SOD; ↓ liver expression levels SOD and GPx and ↑ CAT in control groups and ↓ in algae-fed rats; LT: ↓ GPx activity|||
|Gracilaria changii||HF, HC diet-induced rats|5% and 10% for 8 weeks||5%: ↓ TC (−39.19%), LDL-C (−36.36%), and TG (−25.45%); 10%: ↓ TC, LDL-C and TG content by 40.34%, 35.95% and 30.91%, respectively; lowest AI; 5% and 10%: in plasma = ↓ LipPerox; ↓ AST and ALT levels; in erythrocyte = ↑ SOD, CAT and GSH-Px|||
|Not detailed||Healthy children from 3 to 6 years diet including seaweed intake using 3-day dietary records||Cross-section study in healthy preschoolers: Girls with higher seaweed intake had significantly lower systolic BP (102.4, 99.2 and 96.9 mmHg for girls with the lowest, middle and highest tertiles of seaweed intake, respectively); seaweed intake was negatively related to dBP in boys and to sBP in girls.|||
|Undaria pinnatifida (UP)||Men/Women with MS|Gr1:1 month (m) 4 g/day UP; Gr2: 1 m 4 g plus 1 m g/day UP (pills)||Randomized double-blinded placebo-controlled trial. Gr2: ↓ systolic BP 10.5 mmHg after a month of 6 g/day seaweed (primarily in subjects with high-normal baseline BP); ↓ waist circumference for women participants (↓ 2.1 cm after 4 g/day and further 1.8 cm after 1 m 6 g/day seaweed). No changes in lipid profile.|||
|Undaria pinnatifida (UP)||19 patients MS|3.3 g in capsules ||sBP: ↓ 13 mmHg below the baseline after 4 weeks and 8 mmHg after 8 weeks. dBP: ↓ 9 mmHg after 4 weeks and 8 mmHg after 8 weeks; hypercholesterolemia ↓ 8% by week 4|||
|Extracts|| || || |
|Sargassum subrepandum (MeOH Ext)||Rats with atherogenic diet|100 mg/kg b.wt||↓ TC, TG, LDL-C and ↑ HDL-C; ↓ MDA, NO, leptin, TNF-alpha levels; ↑ adiponectin level;|||
|Ulva fasciata (Ulvans/Aq Ext at 4 °C or 100 °C plus EtOH pp)||HC rats|175 mg/kg for 4 weeks||Both Ext: No side effects; ↓ TC, TG, TG, LDL-C and VLDL-C; ↓ liver NO•; ↓ ICAM-1 and VCAM-1; ↑ IL-10; ↓ atherogenic plaques in the aorta more than fluvastatin; |||
|Ulva lactuca (Ulvans/Aq Ext at 100 °C plus EtOH pp)||HC rats|175 mg/kg for 4 weeks||↓TL, TG, TC, LDL-C and VLDL-C; ↑ HDL-C; ↓ AI, creatine kinase and LDH; ↓ liver ALT, AST and ALP activities and serum urea, creatinine and urea/creatinine ratio; ↑ hepatic CAT, GSH-Px; ↑ GSH, Total thiol levels|||
|Not detailed (Low-MW Commercial alginates)||DOCA salt-induced hypertensive rats|250 or 500 mg/kg for 30 days||↓ sBP; dose-dependent normalization of changes induced by DOCA salt, with the exception of further increasing sodium excretion|||
|Gloiopeltis complanata (Funoran/Aq hot Ext plus various purification steps)||HC, high-sal fed rats|1000 mg/kg for 20 days||↓ sBP; ↓ TC, TG, LDL-C, AI; ↑ urine excretion of sodium, chloride; ↑ urine Na/K ratio|||
|Not detailed (Seaweed fiber (SF))||Hypertensive Patients|Pills with 0.33 g; 25 min before meals for 4 weeks||↓ mean and sBP; ↑ plasma renin activity; ↓ urinary secretion of Na, K and Na/K ratio|||
|Palmaria palmata (protein hydrolysate and tridecapeptide IRLIIVLMPILMA)||Spontaneously Hypertensive rats|50 mg/kg b.wt||After 24 h ingestion: ↓ 34 mm Hg in sBP; IRLIIVLMPLIMA: ↓ 33 mm Hg|||
When evaluating the response of dietary supplementation of Ulva ohnoi
and Derbesia tenuissima
in a rat model of human metabolic syndrome, Kumar et al.
] reported that Ulva ohnoi
could induce a marked decrease in systolic blood pressure (by 29 mmHg), along with a decrease in the final body fat mass (by 24%) and the improvement of glucose utilization and insulin sensitivity. On the basis of chemical composition of the two algae, the authors have suggested that the better scores of Ulva ohnoi
with respect to those induced by Derbesia tenuissima
could be due to its richness in soluble fibers and magnesium. A similar trend on blood pressure were also registered by Ramirez-Huigera et al.
], when testing the effects of diet-suplementation of Ulva linza
and Lessonia trabeculata
in rats fed with a hypercaloric diet.
Despite scarce and sometimes inconsistent, the effect of diet supplementation of macroalgae in human blood pressure, either in healthy or in hypertensive scenarios has also been evaluated. The cross-section studies reported by Wada et al.
] in healthy Japanese preschoolers allowed to observe that girls with higher seaweed intake had lower systolic blood pressure while diastolic bold pressure in boys also decreased. Additionally, systolic and diastolic blood pressure in hypertensive elderly Japanese patients have been shown to be significantly decreased after daily doses of 5 g of dried Undaria pinnatifida
powder for eight weeks [99
]. The same trend was registered in a randomized double-blinded placebo-controlled trial with metabolic syndrome patients (also including hypertension) taking daily pill dosages of 6 g of U. pinnafita
The benefit of seaweeds’ dietary fiber supplementation in hypertensive rats has also been previously demonstrated by distinct authors. Some authors suggested that their positive effects could be due to retention of dietary Na [102
] or to an enhanced intestinal K absorption [101
] or to these two effects in simultaneous [103
]. It should however be remarked that as the cationic exchange ability of fibers is dependent on factors like the type of fiber and the mineral content of the diet, further information regarding this topic is still required.
Antihypertensive abilities of macroalgaes’ peptides have also been investigated in vivo
models. Fitzgerald et al.
] showed that the diet supplementation of a tridecapeptide derived from a papain digest of Palmaria palmata
(IRLIIVLMPILMA, previously shown to be active against renin [92
]) could cause a decrease in systolic blood pressure of about 33 mmHg in spontaneously-hypertensive rats. Further simulation of gastric digestion allowed the authors to conclude that the active forms of IRLIIVLMPILMA are probably dipeptides originated along the passage through the gastrointestinal tract. In addition, Suetsuna and coworkers have characterized several di- and tetrapeptides from digests of Undaria pinnafita
Amongst them, the dipetides Tyr-His, Lys-Tyr, Phe-Tyr and Ile-Tyr, as well as the tetrapeptides Ala-Ile-Tyr-Lys, Tyr-Lys-Tyr-Tyr, Lys-Phe-Tyr-Gly and Tyr-Asn-Lys-Leu, were shown to efficiently decrease the blood pressure of spontaneous hypertensive rats through diet supplementation [88
3.3. Biological Pathways Underlying Atherosclerotic-Related Events
As previously referred, the formation and progression of atherosclerotic plaques involves a multitude of factors, including oxidative and inflammatory events. In this context, antioxidants and anti-inflammatory sources are of interest in the quest for antiatherogenic activity. Still, it is noteworthy that only a scarce number of research studies have previously monitored these biological pathways when evaluating the potential diet supplementation of macroalgae in atherosclerosis-related models, being those studies major tested with extracts or isolated compounds (included in Table 2
). Besides, structure-bioactive studies are almost non-existent. Because of that, this topic demands urgent research.
Phlorotannins are one the seaweeds’ bioactive compounds that could hold a potential in this particular field. In fact, Costa-Mugica and coworkers [105
] demonstrated an effective protection of LDL oxidation by phlorotannin-enriched fractions isolated from Halimeda incrassata
, as measured in two heparin-precipitated LDL models. Moreover, the phlorotannins phloroglucinol, eckol, and dieckol (Figure 1
) have been shown to protect against proinflammatory responses in human umbilical vein endothelial cells (HUVEC) and in an animal model of acute inflammation, in response to the endotoxin high-mobility group protein B1 (HMGB1) [106
]. Phlorotannins inhibited lipopolysaccharide (LPS)-induced HMGB1 release, HMGB1-mediated barrier disruption, the expressions of CAMs and the adhesion/transendothelial migration of leukocytes to human endothelial cells. The three phlorotannins could also suppress acetic acid-induced hyperpermeability and carboxymethylcellulose-induced leukocytes migration in the animal model [106
]. Notably, this study also highlighted the importance of phlorotannins’ hydroxyl groups regarding the vascular barrier protective effects, since the magnitude of protection on HMGB1-mediated hyperpermeability and monocytes adhesion noticed in HUVEC cells followed the pattern dieckol > eckol > phloroglucinol and were even lowered when the hydroxyl groups of dieckol were replaced by methyl groups. Based on the overall results, the authors hypothesized that the presence of hydrogen bond donors and hydrophilic moieties in phlorotannins may play a central role in its affinity for membrane receptors on human endothelial cells [106
Besides phlorotannins, fucoxanthin has also been associated to the positive effects of a methanol extract of Sargassum subrepandum
]. In their study, the authors showed that in addition to the improvement of lipid profile, the oral administration of the extract in a dose of 100 mg/kg.wt for four months caused a marked decrease in serum malonaldialdehyde (MDA, i.e.
, a oxidative stress biomarker) and in the proinflammatory markers leptin and TNF-α levels, with a simultaneous increase in the level of adiponectin, i.e.
, an adipocyte-specific protein that is thought to act as anti-inflammatory, anti-atherogenic and insulin enhancer [107
Sulfate polysaccharides, including ulvans, carragenans and fucoidans, are the most exploited compounds when regarding the protective effects on atheroclerotic-plaque formation and progression-related problems. e.g., Hassan and coworkers [67
] proved that the oral supplementation of hypercholesterolemic rats with an ulvan purified extract from Ulva lactuca
could ameliorate the activity of the antioxidant enzymes catalase (CAT), glutathione peroxidase (GSH-Px) and superoxide dismutase (SOD) by 110%, 77% and 23%, respectively, when compared with the hypercholesterolemic control rats. Apart from that, the authors also described beneficial effects on non-enzymatic antioxidants parameters (hepatic reduced glutathione, total thiol and lipid peroxidation), suggesting that the defensive effect of ulvan was in part mediated by protection of liver against free radicals.
The atheropreventive activity of ulvans from Ulva fasciata
was also recently reported by Borai and coworkers [65
]. After the oral administration of crude cold and hot extracts to hypercholesterolemic rats extracts at a dose 175 mg/kg body weight for four weeks, the authors registered an improvement of serum lipid profile and of the endothelial dysfunction. In particular, in comparison to hypercholesterolemic rats, the ulvans-supplemented animals showed a decrease of the NO•
liver levels of 38.95% and 69.46% (for cold and hot extracts, respectively), while this effect was of 58.19% for the reference drug (fluvastatin). Both extracts also caused a significant decrease in the levels of the soluble adhesion molecules ICAM-1 and VCAM-1, along with an increase in the amounts of the anti-inflammatory marker IL-10 (about 30%, 18% and 34% compared to control, for cold, hot ulvan-enriched extracts and fluvastatin, respectively). In addition, morphometric measurements of atherosclerotic lesion in untreated/treated rats showed that the oral supplementation of U. fasciata
extracts induced a reduction in the medial cross-section area of the aorta (19.50% and 26.46%, respectively). This result was also consistent with histological data, which demonstrated that in contrast with the untreated rats, those subjected to algae-enriched diet exhibited no oblivious lesions in the aorta, showing thin intimae and no visible swelling, endothelial cells basically intact and without desquamation, no migration of smooth muscle cells to the under-intimae, no proliferation of smooth muscle cells and smooth muscle cells arranged in a regular pattern.
Amongst SP, fucoidans have very promising biomedical/medical applications with regard to atherosclerosis and associated progressive complications. The anti-inflammatory potential of these polysaccharides in hypercholesterolemic rats has been reported by Preetha et al.
], using a hot water-extracted fucoidan from Sargassum wightii
and a comercial fucoidan from Fucus vesiculosos
, which overall resulted in almost equally effects. The subcutaneous treatment with the algae fucoidans at a dose of 5 mg/kg bwt/day during seven days reduced the increased serum levels of the inflammatory biomarkers TNF-α and C-reactive protein, the NO•
concentrations in plasma and cardiac tissues, as well as the levels of cardiac mRNA iNOS and of COX-2 (two potent proinflammatory enzymes). In addition, the authors also demonstrated the anticoagulant effect of these polysaccharides, as estimated by the levels of plasmatic fibrinogen, a central protein in the formation of blood clots.
At this point, one should remark that fucoidans and in general SP have been proved to exert potent antithrombotic effects. Indeed, these polysaccharides share common structural features with heparin, i.e.
, a highly sulfated glycosaminoglycan that is widely used in clinical practice as an injectable anticoagulant. The anticoagulant activities of SP, along with their inhibition of platelet aggregation and thrombolytic activities has been the focus of many investigations and have been recently revised by distinct authors [22
], which also highlight the high molecular weight and the high sulfation level (particularly with substitution at C-2 or C-2 and C-3 positions of fucose) as positive structural factors affecting these properties [22
]. Still, reported data focusing these benefits do not take into account bioacessibility and bioavailability issues, as SP in vivo
models have been administered subcutaneously (as for the above mentioned work of Preetha et al.
]) or, in the majority of cases, as an intravenous injection. In this context, although there are a growing body of evidences that fucoidans and other SP can be partly absorbed [112
] or suffer favorable changes by intestinal microbiota [113
], these topics are not elucidated, hampering the understanding if SP exert effective antithrombotic activities when orally ingested.