*3.1. Anti-Inflammatory Activity of Polysaccharides from Sea Cucumbers*

Several studies have emphasized the valuable anti-inflammatory effects of polysaccharides obtained from sea cucumbers. Sulphated fucan, fucoidan, and fucosylated chondroitin

sulfate (FCS) are major polysaccharides isolated from several species of sea cucumbers, such as *Thelenota ananas*, *Stichopus variegatus*, *Holothuria nobilis*, *Ypsilothuria bitentaculata*, *Cucumaria frondosa*, *Stichopus (Apostichopus) japonicus*, *Stichopus choloronotus*, and *Isostichopus badionotus*. These polysaccharides have shown potent anti-inflammatory activity in various cellular, as well as animal, models of chronic inflammation. The chronic administration of fucoidan (Figure 1: (**1**)) derived from *Isostichopus badionotus* reduced the hepatic expression and serum concentrations of inflammatory cytokines and other inflammatory markers (TNFα, IL-1β, IL-6, IL-10, macrophage inflammatory protein 1 (MIP-1), and CRP) in dietinduced obese mice. The anti-inflammatory response of fucoidan was achieved by the inactivation of JNK and IκB/NF-κB pathways in hepatocytes [36]. Moreover, fucoidan isolated from *Apostichopus japonicus* reduced the expression of TNFα, IL-1β, and IL-6 by inactivating the MAPK/ NF-κB pathway in the lipopolysaccharide (LPS)-challenged liver injury mouse model [37]. Fucoidan, isolated from *Acaudina molpadioides*, alleviated renal fibrosis and inflammation by decreasing the expression of transforming growth factor β1 (TGFβ1), plasminogen activator inhibitor 1, and phosphorylated Smad3 in diabetic mice [38]. Fucoidans derived from *Thelenota ananas* prevented ethanol-induced gastric ulceration by downregulating the expression of proinflammatory cytokines and related transcription factors (TNFα, IL-6, and NF-κB) [39]. Fucoidan oligosaccharides isolated from *Pearsonothuria graeffei* and *Isostichopus Badionotus* alleviated high-fat diet (HFD)-induced low-grade inflammation by lowering the serum TNFα and LPS levels in mice [40]. The primary glycosaminoglycan FCS was purified from *Isostichopus badionotus* and screened in vivo and in vitro for anti-inflammatory activity. FCS downregulated the NF-kB gene expression and thereby suppressed the expression of downstream genes such as COX-2, iNOS, and TNFα and attenuated the inflammation and tissue damage caused by TPA in a mouse ear inflammation model [15]. Furthermore, FCS (Figure 1: (**2**)) isolated from edible sea cucumbers *Apostichopus japonicus*, *Stichopus chloronotus*, *Cucumaria djakonovi*, and *Acaudina molpadioidea* reduced carrageenan-induced paw edema in a mouse model [14,41]. More recently, Zhu et al. [42] demonstrated that the sulfated fucan/FCS-dominated polysaccharide fraction from low-edible-value sea cucumber species reduced the levels of proinflammatory cytokines (such as TNFα and IL-6) of HFD and streptozotocin (STZ)-induced type 2 diabetic rats, indicating a decreased inflammatory response. FCS, isolated from *Lymantria grisea*, inhibited neutrophil recruitment and TNFα production in thioglycollate-induced peritonitis and LPS-induced lung inflammation mouse models [43]. Interestingly, the heteroglycan (sulphated polysaccharide) fractions derived from the cartilage of *Curcumaria frondosa* (at concentrations of 0.1–100 μg/mL) increased the oxidative stress and decreased cell viability, as evidenced by the induced levels of TNFα, IL-6, and IL-10 in THP-1 macrophages [44].

**Figure 1.** Structures of anti-inflammatory polysaccharides derived from sea cucumbers (structure (**1**) re-used with permission from reference [36], Elsevier, 2016; structure (**2**) re-used with permission from reference [14], Elsevier, 2018).

#### *3.2. Anti-Inflammatory Activity of Triterpenoid Glycosides from Sea Cucumbers*

Triterpenoid glycosides are broadly distributed in plants, animals, and marine organisms such as holothurians and sponges. Triterpenoid glycosides play a crucial role in chemical defenses and possess a variety of pharmacological activities. Approximately 300 triterpenoid glycosides have been identified and categorized from sea cucumbers. Relatively few anti-inflammatory triterpenoid glycosides from sea cucumbers are documented in the literature. Triterpenoid glycosides isolated from the Egyptian sea cucumber *Holothuria thomasi* significantly decreased the serum levels of TNFα and IL-6, as well as glucose, adiponectin, liver malondialdehyde, and α-amylase activity, in STZ-induced diabetic rats [45]. Similarly, a liposomal preparation of triterpenoid glycoside (Holothurin A (Figure 2: (**3**)) and Echinoside A (Figure 2: (**4**)) isolated from *Pearsonothuria graeffei* reduced the inflammation by inhibiting the release of proinflammatory cytokines and infiltration of macrophages in the adipose tissue of HFD-fed obese mice. Moreover, this liposomal triterpenoid glycoside preparation significantly reduced the PGE2 levels in adipose tissue by modulating the p-ERK/cPLA2/COX-1 pathway [46]. Moreover, holothurin A and echinoside A also attenuated inflammation by downregulating the expression of proinflammatory cytokines in vascular and peritoneal macrophages of ApoE−/<sup>−</sup> mice [47].

**Figure 2.** Structures of anti-inflammatory triterpenoid glycosides derived from sea cucumbers (structures (**3**) and (**4**) re-used from reference [47]).
