*2.2. Phlorotannins*

Phlorotannins are phenolic compounds almost exclusive to *Phaeophytae* and also represent their main phenolic pool. In brown seaweeds, they are associated with a myriad of functions, ranging from structural cell wall components, to biosyinthetic percursors and defensive mediators against natural enemies, acting as herbivore deterrents, inhibitors of digestion and agents against bacteria [11]. Phlorotannins are known to accumulate mostly in physodes (i.e., specialized membrane-bound vesicles of the cell cytoplasm), with levels that might represent up to 25% of seaweed's DW, despite variations which occur depending on distinct factors [47]. For example, the higher levels of phlorotannins in *Fucus* spp. are associated with high salinity waters and solar exposure during summer [10].

Being part of the tannins group, phlorotannins present a polymeric structure derived from several phloroglucinol (1,3,5-trihydroxybenzene) units and possess a high number of hydroxy groups, thus conferring them solubility in water [48]. Depending on the linkage between phloroglucinol monomer units, a wide range of compounds with different molecular weights can be obtained [49], which overall, are divided in four categories for each type of linkage: Fuhalols and phlorethols based on ether linkage, fucols based on C-C linkage, fucophlorethols for a combination of the previous ones, and, finally, eckols and carmalols, based on dibenzodioxin linkage (Figure 2).

**Figure 2.** Some representative phlorotannins from brown seaweeds: (**A**) Fucol; (**B**) Fucophlorethol; (**C**) Phlorethol; (**D**) Fuhalol; (**E**) Carmalol; (**F**) Eckol.

Phenolic extracts from brown seaweeds have been demonstrated to exhibit various biological activities, including antioxidant, antidiabetic, anti-inflammatory and others [11,50,51]. In this regard, O'Sullivan et al. [52] observed the augment of glutathione levels in Caco-2 cell models when incubated with *A. nodosum*, *F. vesiculosus* and *F. serratus* phlorotannins extracts, while also highlighting the protective effects of the latter on the same model pretreated with H2O2. In vivo experiments have even demonstrated that the oral administration of 200 mg/kg/day of *F. vesiculosus* polyhenol-rich extracts over 4 weeks to Sprague-Dawley rats could increase the blood plasma reducing power, paraoxonase/arylesterase 1 (PON-1) activity and O2 •− scavenging activity by 29%, 33% and 25%, respectively [53]. Likewise, the antidiabetic properties of *A. nodosum* and *F. vesiculosus* phenolic-rich extract were observed in vivo as the postprandial blood glucose levels and insulin peak decreased 90% and 40%, respectively, on rats under hyperglycemic diets supplemented with 7.5 mg/kg compared to the unsupplemented group [54]. In fact, the ingestion of 500 mg of this mixture containing *A. nodosum* and *F. vesiculosus* 30 min prior to the consumption of carbohydrates was shown to reduce the insulin incremental area of the curve and an increase in insulin sensitivity in a human clinical trial [55]. Human trials have also been carried out to evaluate the potential antiobesity effect of polyphenolic-rich extracts of *A. nodosum* (100 mg/day for 8 weeks). Although the treatment did not exhibit any significant benefits (no significant changes in C-reactive protein, antioxidant status or inflammatory cytokines), with the exception of a modest decrease of the DNA damage in the obese group, several phlorotannin metabolites were detected in the subjects plasma and urine, indicating that these compounds are metabolised and absorbed into the systemic circulation [56]. These observations are in line with those reported by Corona et al. [57] who also described the appearance of phlorotannin metabolites in urine and plasma collected from humans after consuming a capsule of *A. nodosum* extract containing about 100 mg of polyphenols.
