*4.4. Anti-Inflammatory Activity of Miscellaneous Compounds from Sea Urchins*

Several bioactive compounds such as lactones, polyketides, terpenes, and sulphonic acid derivates have been isolated from various species of sea urchins and tested for antiinflammatory activity. Salmachroman (Figure 6: (**14**)), a polyketide isolated from *Salmacis bicolor*, possesses dual-inhibition potential against proinflammatory enzymes COX-2 and 5-LOX [94]. The polyoxygenated furanocembranoids salmacembranes A (Figure 6: (**15**)) and B (Figure 6: (**16**)) from this species also exhibited significant COX-1, COX-2, and 5-LOX inhibitory activity [95]. Several compounds have been isolated from the long-spined sea urchin *Stomopneustes variolaris* and tested for their potential to inhibit the proinflammatory eicosanoid pathway enzymes COX-2 and 5-LOX [96].

A cembrane diterpenoid, characterized as 4-hydroxy-1-(16-methoxyprop-16-en-15 yl)-8-methyl-21,22 dioxatricyclo [11.3.1.15,8], and octadecane-3,19-dione (Figure 6: (**17**)) exhibited greater inhibitory potential against inflammatory agent 5-LOX than ibuprofen. The selectivity ratio of COX-1 to COX-2 inhibition was also higher for this compound in comparison to ibuprofen [96]. The macrocyclic lactone stomopneulactone D (Figure 7: (**18**)) inhibited the generation of iNOS and inhibited COX-2 and 5-LOX in LPS-stimulated macrophages [97]. Fourteen-membered macrocyclic pyrone derivatives named stomopnolides A (Figure 7: (**19**)) and B (Figure 7: (**20**)) also showed marked 5-LOX inhibitory activity [98]. A crude lipid extract from the body wall of the sea urchin *Strongylocentrotus droebachiensis* exhibited MAPK p38, COX-1, and COX-2 inhibitory activity in LPS-stimulated human mononuclear U-937 monocytes [99]. A sulfonic acid derivative, (Z)-4-methylundeca-1,9-diene-6-sulfonic acid (Figure 8: (**21**)), isolated from the cold-water sea urchin *Brisaster latifrons* suppressed the production of proinflammatory cytokines and inflammatory responses by inactivation of the JNK/p38 MAPK and NF-κB pathways in LPS-stimulated RAW264.7 macrophages [100]. Hp-S1 ganglioside (Figure 8: (**22**)), isolated from the sperm of sea urchin *Hemicentrotus pulcherrimus* or the ovary of *Diadema setosum*, decreased the expression of iNOS and COX-2, as well as the proinflammatory cytokines TNFα, IL-1β, and IL-6. These effects of Hp-S1 were mediated through downregulating the MyD88-mediated NF-κB and JNK/p38 MAPK signaling pathways in LPS-stimulated microglial cells [101]. Ovithiol A, isolated from sea urchin *Paracentrotus lividus* eggs, decreased the expression of adhesion molecules ICAM-1 and VCAM-1 and decreased the monocyte–human umbilical vein endothelial cells interaction [102]. Phenolics, flavonoids, and proteins extracted from viscera, spines, shells, and gonads from the sea urchin *Stomopneustes variolaris* exhibit antioxidant and anti-inflammatory activities in vitro [103].

**Figure 6.** Structures of anti-inflammatory polyketides, furanocembranoids, and cembrane diterpenoids derived from sea urchins (structure (**14**) re-used with permission from [94], Taylor & Francis, 2021; structures (**15**) and (**16**) re-used with permission from reference [95], Springer Nature, 2020; structure (**17**) re-used with permission from reference [96], Springer Nature, 2020).

**Figure 7.** Structures of anti-inflammatory macrocyclic compounds derived from sea urchins (structure (**18**) re-used with permission from reference [97], Elsevier, 2020; structures (**19**) and (**20**) re-used with permission from reference [98], Taylor & Francis, 2021).

**Figure 8.** Structures of anti-inflammatory miscellaneous compounds from sea urchins (structure (**21**) re-used with permission from reference [100], Springer Nature, 2013; structure (**22**) re-used from reference [101]).


**Table 2.** *Cont.*


#### **5. Anti-Inflammatory Compounds from Starfish**

Starfish (sea stars) are invertebrates that belong to the class Asteroidea, phylum Echinodermata. There are over 1500 species around the world, mostly inhabiting oceans, while a few occur in brackish water [105,106]. Several starfish species have been used in traditional Chinese medicine to treat various ailments such as goiters, body aches, and rheumatism [105]. In this section, we summarized the findings on the anti-inflammatory potential of various bioactive components isolated from starfish, such as glycosides, triterpenoid glycosides, steroids, and fatty acid derivatives. Several glycosides have been isolated from different species of starfish that exhibited promising preliminary anti-inflammatory activity, such as the inhibition of ROS and NO production in macrophages. Table 3 summarizes the anti-inflammatory effects displayed on LPS-stimulated RAW264.7 macrophages and bone marrow-derived dendritic cells (BMDCs) by bioactive compounds isolated from different species of starfish. Astrosterioside A (Figure 9: (**23**)) and D (Figure 9: (**24**)) and sulphated steroidal hexasaccharides isolated from starfish *Astropecten monacanthus* showed potent anti-inflammatory activity, inhibiting the secretion of proinflammatory cytokines (TNFα, IL-6, and IL-1) in LPS-stimulated BMDCs [107]. The fatty acid-rich fraction of the skin and gonads of starfish *Asterias amurensis* significantly downregulated the expression of the inflammatory mediators IL-1 β, IL-6, TNFα, iNOS, and COX-2 in LPS-stimulated RAW264.7 macrophages. This anti-inflammatory effect of fatty acids is driven through activation of the NF-κB and MAPK pathways [108]. The lipidomic profiling of spiny starfish *Marthasterias glacialis* led to the discovery of cis-11-eicosenoic and cis-11,14 eicosadienoic acids (fatty acids), as well as the unsaturated sterol ergosta-7,22-dien-3-ol. These lipids were thought to have potent anti-inflammatory activity through the reduction of ROS, NO, and proinflammatory cytokines in LPS-stimulated macrophages. Furthermore, these compounds downregulate the expression of various inflammatory genes, including iNOS, COX-2, IkBα, C/EBP homologous protein (CHOP), and NF-κB, in stimulated macrophages [109]. Oxygenated steroid derivatives (Figure 10: (**25**–**28**)) isolated from a methanol extract of the

Vietnamese starfish *Protoreaster nodosus* exhibit potent anti-inflammatory activity in LPSstimulated BMDCs, inhibiting the secretion of proinflammatory cytokines, including IL-12 p40, IL-6, and TNFα [110]. Steroids (Figure 11: (**29**–**35**)) from another Vietnamese starfish *Astropecten polyacanthus*, used as a tonic in Vietnamese ancient medicine, also exhibited potent anti-inflammatory activity when tested against LPS-stimulated BMDCs [111].

**Figure 9.** Structures of anti-inflammatory steroidal hexasaccharides derived from starfish *Astropecten monacanthus* (structures (**23**) and (**24**) re-used with permission from reference [107], ACS Publications, 2013).

**Figure 10.** Structures of anti-inflammatory steroid derivatives derived from starfish *Protoreaster nodosus* (structures (**25**–**28**) re-used with permission from reference [110], Springer Nature, 2015).

**Figure 11.** Structures of anti-inflammatory steroids derived from starfish *Astropecten polyacanthus* (structures (**29**–**35**) re-used from reference [111]).



**Figure 12.** Structures of anti-inflammatory triterpenoid glycosides derived from starfish (structures (**36**–**39**) re-used with permission from reference [112], John Wiley and Sons, 2016; structure (**40**) re-used with permission from reference [113], ACS Publications, 2016).

**Figure 13.** Structures of anti-inflammatory pentaregulosides (glycosides) derived from starfish *Pentaceraster regulus* (structures (**41**–**43**) re-used with permission from reference [114], ACS Publications, 2016).

**Figure 14.** Structures of anti-inflammatory plancipyrrosides (glycosides) derived from starfish *Pentaceraster regulus* (structures (**44**–**45**) re-used from reference [115]).

**Figure 15.** Structures of anti-inflammatory astebatheriosides (glycosides) derived from starfish *Asterina batheri* (structures (**46**–**48**) re-used with permission from reference [116], Elsevier, 2016).

#### **6. Application to the Pharmaceutical Industry**

The drug discovery process is a very lengthy, time-consuming, and costly process for the pharmaceutical industry, and it includes target identification, lead compound discovery, the structure–activity relationship (SAR) study, in vitro and in vivo screening, and, finally, clinical trials on large human populations. More recently, the bioinformatics approach has been employed for target identification and the discovery of lead compounds, which has significantly reduced the length of the drug discovery process [117]. Lead compounds may come from combinational chemistry, computer-aided drug design, or from natural

products [118,119]. However, lead compounds often produce suboptimal biological responses and require chemical modifications to improve their efficacy and potency. The majority of drugs available clinically are derived from natural sources. Indeed, many of the anticancer small molecules available on the market are either natural products or derived from natural products [120]. The search for novel or lead compounds was previously limited to plant-based natural products but has now been expanded to marine-derived natural products as well. There have been reports of a variety of marine natural products with exploitable properties, including those that treat cancer and inflammation and neurological, immunological, and metabolic disorders [121–123]. The global preclinical marine pharmacology pipeline, which is still producing significant preclinical data on numerous pharmacological classes, is what provides new leads [124]. In fact, some pharmaceutical companies are focusing on marine natural product research. However, there is a general trend that anticancer drugs have received more attention, resources, and efforts in terms of pharmacological research, discovery, and development than other drugs classes, such as anti-inflammatory drugs. For example, several marine organism-derived anticancer drugs (such as vidarabine (Ara-A) for Hodgkin's lymphoma and chronic large cell anaplastic lymphoma, cytarabine, Ara-C for acute non-lymphoblastic leukemia, and trabectedin vedotin for ovarian cancer and soft tissue sarcoma) have been approved by the FDA. Moreover, several anticancer molecules are in Phase I, II, or III clinical trials [125,126]. However, the discovery of several marine-derived anti-inflammatory molecules also has ignited the pharmaceutical industry's interest in developing them into lead compounds for the drug discovery process [127,128]. Unfortunately, to date, no marine-derived anti-inflammatory drug has been approved by the FDA, but a few promising anti-inflammatory compounds are under various phases of clinical trials: for example, pseudopterosin A (a diterpene glycoside obtained from soft coral) and IPL-576092 (a polyhydroxylated steroid obtained from a sponge) [129]. This suggests the notable involvement of marine-derived natural products in the potential pharmaceutical industry and encourages the pursuit of new antiinflammatory lead compound discoveries. Productive teamwork among researchers from various universities and/or institutes and the leadership of the pharmaceutical industry is required to ensure the development of future therapeutic entities that will significantly contribute to the treatment of various inflammatory disorders.
