# Therapeutic Potential of Seaweed-Derived Bioactive Compounds for Cardiovascular Disease Treatment
## 2 Seaweed-Derived Phlorotannins with Therapeutic Potential against CVD
The inhibition of starch-digesting enzymes using synthetic drugs exhibiting antidiabetic effects with \(\alpha\)-glucosidase inhibitory properties, such as acarbose, voglibose, migilot, and emiglitate, is an important clinical strategy for controlling postprandial hyperglycemia. However, these synthetic drugs have been reported to effectively lower postprandial blood glucose levels but cause serious side effects, such as liver disorders [45; 47]. The use of enzyme inhibitors derived from natural products (terrestrial plants or seaweeds) with a lower risk of the potential side effects caused by synthetic enzyme inhibitors is recommended. Therefore, to avoid or reduce the side effects caused by currently used synthetase inhibitors, the use of enzyme inhibitors (\(\alpha\)-amylase and \(\alpha\)-glucosidase) from natural products is considered the best alternative. It has been reported that minor phlorotannin derivatives such as eckol, 2-phloroeckol, 8,8'-bieckol, 6,8'-bieckol, and 2-O-(2,4,6-trihydroxyphenyl)-6,6'-bieckol isolated from _E. cava_ showed \(\alpha\)-glucosidase inhibitory activity, with an IC\({}_{50}\) value ranging from 2.3 to 59.8 \(\upmu\)M (Table 1). Among the minor phlorotannin derivatives, 8,8'-bieckol and 6,8'-bieckol exhibited the strongest \(\alpha\)-glucosidase inhibitory activity. In addition, molecular docking studies revealed that both phlorotannins act as \(\alpha\)-glucosidase inhibitors by competitive inhibition [48]. In addition, several researchers have found that phlorotannins such as fucodiphloroethol G, dieckol, 6,6'-bieckol, 7-phloroeckol, phloroofucofuroeckol A, and 2,7'-phloroglucinol-6,6'-bieckol isolated from _Ecklonia cava_ have inhibitory activity against \(\alpha\)-glucosidase and \(\alpha\)-amylase [49; 50; 51]. [PERSON] et al. revealed that phlorotannins, such as phloroglucinol, dioxinodehydroeckol, eckol, phloroofucofuroeckol-A, dieckol, and 7-phloroeckol isolated from Ecklonia stolinifera (E. stolinifera) have anti-diabetic effects by inhibiting \(\alpha\)-glucosidase. In addition, it was confirmed that these phlorotannins effectively inhibit protein tyrosine phosphatase 1 B, an enzyme that plays an important role in the development of insulin resistance, thereby preventing a rapid increase in postprandial blood glucose levels [52]. In addition, diphlorotohydrocarmalol (DPHC), shophlorogluc A (IPA), and octaphloroth A (OPA) were isolated from _I. okamurae_ and _Ishige foliacea_ (L foliacea) from the Ishigeaceae family and showed \(\alpha\)-glucosidase and \(\alpha\)-amylase inhibitory activity [53; 54]. In particular, oral administration of 100 mg/kg DPHC significantly suppressed the postprandial blood glucose levels in streptozotocin-induced diabetic mice [55]. According to [PERSON] et al., molecular docking analysis revealed that OPA interacts with amino acid residues in the region close to the active site of \(\alpha\)-glucosidase. Hence, OPA has the potential to be used as a non-competitive inhibitor with a high-affinity binding site for \(\alpha\)-glucosidase [54]. Insulin resistance and impaired glucose metabolism are the most common factors promoting the development of type 2 diabetes mellitus. Type 2 diabetes mellitus is typically caused by two factors: impaired insulin production by pancreatic \(\beta\) cells and a failure of insulin-sensitive tissues to respond appropriately to insulin [56]. Signaling pathways involved in insulin secretion in \(\beta\)-cells under physiological conditions can be divided into a few stages. First, insulin release is primarily triggered by high glucose concentrations, mainly via glucose transporter 2 (GLUT2). When glucose catabolism is stimulated, intracellular ATP levels increase and close the cell membrane potassium channels, increasing intracellular Ca\({}^{2+}\) concentrations and amplifying insulin secretion [57; 58]. Furthermore, the AMP-activated protein kinase (AMPK) system simulates the effect of insulin on glucose transport in the muscle and glucose production in the liver.