*4.2. Fucoxantin and Cardiovascular Disease: Experimental Studies (Human and Animal)*

Experiments on stroke-prone spontaneously hypertensive rats (SHRSP) show the possible protective role of fucoxanthin in CVD. Thirty-three male SHRSP rats, 5 weeks of age, were purchased from the Disease Model Cooperative Research Association (Kyoto, Japan). Animals were divided into three groups: (1) kaolin group, which was given a normal diet [5% (w/w) kaolin, a non-nutrient material]; (2) Wakame (Undaria Pinnatifida) group [normal diet containing 5% (w/w) Wakame powder]; and (3) cellulose group [normal diet containing 5% (w/w) cellulose]. In this study, Wakame delayed the incidence of stroke signs and increased the life span of SHRSP. Wakame did not attenuate the development of hypertension in SHRSP [38]. 

Thrombosis is a major complication of coronary atherosclerosis that can lead to myocardial infarction. Docosahexaenoic acid (DHA) inhibits the synthesis of thromboxane A2 (TxA2) from arachidonic acid (AA) in platelets [39]. In addition, DHA enhances the production of prostacyclin, a prostaglandin that produces  vasodilation and less sticky platelets [40]. Also epidemiologic and clinical trials demonstrated that fish oil such as eicosapentaenoic acid (EPA) and DHA, decreased LDL-C, TG and increased HDL-C concentrations. DHA content in fish oil fed to experimental animals inhibits the development of atherosclerosis, so the fucoxanthin may have an potential role in the modulation and prevention of human diseases, particularly to reducing the incidence of CVD [41,42]. 

## *4.3. Fucoxantin and Metabolic Syndrome: Experimental Studies (Human and Animal)*

Among marine carotenoids, attention has been paid towards fucoxanthin in recent years, that is actually used for the treatment of methabolic syndrome and obesity [43], two important risk factors of CVD. Fucoxanthin has a unique structure including an allenic bond and 5,6-monoepoxide in 

the molecole, is a major carotenoid found in edible sceaweeds such as *Undaria pinnatifida*, *Hijikia fusiformis* and *Sargassum fulvelum* [44]. This molecule is under study for possible application in the fight against overweight and obesity since it promotes the reduction of abdominal fat. In this regard it is interesting to note an increased concentration of fat in the abdomen statistically correlated with an increased risk of CVD. A study conducted by Maeda *et al.* [43] in male Wister rats and female KK-Ay mice under different experimental diets (soybean oil, Undaria lipids, Undaria glycolipid fraction, crude fucoxanthin and purified fucoxanthin fed to different concentration according to their groups) for 4 weeks shows that Undaria lipids (containing 9.6% fucoxanthin) reduced significantly the weights of abdominal white adipose tissue (WAT) of both rats and mice. Body weights of mice fed Undaria lipid was significantly lower than that of controls [45]. Animal studies by one group of researchers suggest that fucoxanthin might prevent the growth of fat tissue and reduce abdominal fat, has a beneficial effects in stroke prevention, reduction of inflammation, and slowing the growth of various cancer cell type [38,45]. Woo *et al.* [37] in a recent study shows as, the fucoxanthin facilitates youthful energy metabolism by activating a special cellular mitochondrial protein called UCP-1, which induces the thermogenesis. This is important because obesity markedly increases the risk of CVD. Fucoxanthin has been found to reduce blood glucose in animals with diabetes and in normal mice that are fed high fat diets [46]. It appears that fucoxanthin is capable of upregulating glucose transporter, mRNA expression of L6 myotubes which are responsible for glucose transport in adult muscle tissue [47]. An interesting, extra, metabolic benefit of fucoxanthin administration in rodents is the promotion of the synthesis of DHA in the liver [43].

Because the metabolic syndrome is a collection of risk factors that substantially increase the chances of damage in the CVS, which can lead to a heart attack or stroke, the importance of the fucoxanthin in the regular metabolic syndrome would be very important to prevent CV damage. Clinical research also indicated that the metabolic boost from taking fucoxanthin did not stimulate the central nervous system,  meaning it did not cause the jitters or lost sleep like caffeine, nicotine, or thyroid hormones. Only one study has currently been conducted in humans which has evaluated the effectiveness of fucoxanthin supplementation for weight loss. This study reports that the supplement, Xanthigen, which contains 300 mg pomegranate seed oil and 300 mg brown marine algae fucoxanthin significantly increased weight loss and reduced body and liver fats content in obese women treated for 16 weeks [48]. 

Fucoxanthin proved safe with no side effects, and even provided other health benefits, including improved cardiovascular health, reduction of inflammation (a major cause of heart disease), healthy cholesterol and TG levels, improvements in blood pressure levels, and healthy liver function [49–51]. 

## **5. Conclusion**

Oxidative stress and inflammation play an important role in the pathophysiology of many chronic diseases including CVD [52]. The xanthophyll carotenoid dietary supplement, astaxanthin, has demonstrated to be a potential antioxidant and antiinflammatory therapeutic agent in models of CVD. There have been human clinical studies using astaxanthin to assess its safety, bioavailability and clinical aspects relevant to oxidative stress and inflammation in CVS. There were no adverse effects reported. These demonstrated reduced markers of oxidative stress and inflammation and improved blood rheology. Astaxanthin has great potential as a potent antioxidant to be tested in human clinical trials based on theoretical grounds related to its physicochemical properties and on the basis of exciting preliminary experimental studies in CV models. Although its use in human clinical studies has been limited, so far no safety concerns have arisen [53]. We predict that because of its greater antioxidant potency and membrane preservation, astaxanthin will reduce measures of oxidative stress and inflammation and provide vascular benefits [54]. 

The versatile effects of fucoxanthin on intermediate metabolism make this carotenoid of great potential value in the prevention or management of the metabolic syndrome and obesity. The animal experiments with fucoxanthin stimulated researchers to recommend human clinical trials with fucoxanthin. As a carotenoid, fucoxanthin is a powerful antioxidant that protects cells from FRs damage. Future clinical studies and trials will help determine the efficacy of these marine carotenoids (asthaxantin and fucoxanthin) on vascular structure, function, oxidative stress and inflammation in a variety of patients at risk of, or with established CVD. These may lead to large interventional trials assessing CV morbidity and mortality. 
