*4.1. Anti-Inflammatory Activity of Pigments from Sea Urchins*

Pigments isolated from the shells and spines of sea urchins are currently being widely studied for biological activity. EchA (Figure 5: (**11**)) is widely distributed in various species of sea urchins and has been screened for its biological activity [28]. The anti-inflammatory activity of EchA, isolated from different species, has been evaluated using various in vivo and in vitro models. EchA from *Scaphchinus mirabilis* attenuated macrophage activation and neutrophil infiltration in a bleomycin (BLM)-induced scleroderma mouse model. In the same study, EchA cotreatment markedly attenuated the BLM-induced increase in the TNFα and IFNγ levels [79]. The intravenous injection of EchA in DSS-induced colitis mice significantly reduced the disease activity index (DIA), improved the colon length, and reduced the accumulation of excessive immune cells (neutrophils and macrophages) within the epithelia and mesenchymal layers of damaged colons [80]. Furthermore, EchA treatment suppressed the in vitro activation of proinflammatory M1-type macrophages and increased the production of M2-type macrophages, which abate the inflammation and initiate tissue repair [80]. EchA also reduced the level of the inflammatory cells in the aqueous humor and reduced the levels of TNFα, NF-κB, and ROS in the aqueous humor in an endotoxininduced uveitis rat model [81]. EchA attenuated the phosphorylation of p38, ERK1/2, and JNK and thereby effectively modulated the MPAK pathway in cardiac myoblast H9c2(2-1) cells and isolated rat cardiomyocytes [82]. Histochrome®(containing 1% EchA) is a commercially available antioxidant product permitted for subconjunctival and intravenous use in Russia. Histochrome®reduced the expression of MMPs, collagen degradation, and dermal mast cell recruitment in an ultraviolet B-exposed hairless mouse model [83]. EchA treatment also reduced the inflammatory response-induced mast cell infiltration, as well

as the expression of proinflammatory cytokines such as IFNγ, IL-4, and IL-13, in an acute dermatitis mouse model [84]. Spinochromes A (Figure 5: (**12**)) and B (Figure 5: (**13**)) isolated from the shells and spine of *Evechinus chloroticus* have anti-inflammatory activity in the cotton pellet granuloma rat model of chronic inflammation [85,86]. Seven major spinochromes (including EchA and Spinochromes A–D) isolated from different sea urchin species reduced TNFα production in LPS-stimulated J774A.1 macrophages [87]. In addition, the pigment isolated from the spines and shells of sea urchin *Strongylocentrotus nudus* inhibited the production of NO, IL-6, TNFα, PGE2, and 6-keto-prostaglandin F (PGF)1α in LPS-stimulated RAW264.7 macrophages [88].

**Figure 5.** Structures of anti-inflammatory pigments derived from sea urchins (structures (**11**–**13**) re-used with permission from reference [85], Elsevier, 2020).
