Research Progress in Anti-Inflammatory Bioactive Substances Derived from Marine Microorganisms, Sponges, Algae, and Corals

Inflammation is the body’s defense reaction in response to stimulations and is the basis of various physiological and pathological processes. However, chronic inflammation is undesirable and closely related to the occurrence and development of diseases. The ocean gives birth to unique and diverse bioactive substances, which have gained special attention and been a focus for anti-inflammatory drug development. So far, numerous promising bioactive substances have been obtained from various marine organisms such as marine bacteria and fungi, sponges, algae, and coral. This review covers 71 bioactive substances described during 2015–2020, including the structures (65 of which), species sources, evaluation models and anti-inflammatory activities of these substances. This review aims to provide some reference for the research progress of marine-organism-derived anti-inflammatory metabolites and give more research impetus for their conversion to novel anti-inflammatory drugs.


Introduction
Inflammation is a kind of defensive response when the body is affected by various inflammatory factors or local injuries, and it is an important protective mechanism of the biological body [1]. Inflammation usually helps maintain the body's normal function and promotes repair of damaged tissue to reduce the effect of external stimuli on the body [2,3]. However, an abnormal and excessive inflammatory response can also damage the body's health and even endanger life [4][5][6]. For instance, the recent SARS-CoV-2 can stimulate the innate immune system, and cause cytokine storms and acute inflammatory responses, which rapidly cause multiple organ failures [7,8]. Steroidal and nonsteroidal anti-inflammatory drugs are clinically applied to cure inflammatory disorders, but longterm use of them is often accompanied by significant side effects [9]. The exploration of safe and effective anti-inflammatory drugs has always been a hotspot of biomedical research.
The ocean is where life is born and nurtured. It covers about 70% of the earth's surface and 90% of the biosphere. The ocean has special physical and chemical conditions, including high salinity and weak alkalinity; the depths encompass an environment that is dark, cold, subject to high pressures, and presents many other complex characteristics [10]. To better to adapt to such an extreme environment, marine organisms have formed unique genetic systems and biosynthetic pathways and produced novel bioactive metabolites which constitute a huge natural active compound library [11]. For decades, researchers It is important to select an appropriate model to preliminarily evaluate the activity and the mechanism of anti-inflammatory drugs. The production of pro-inflammatory cytokines by immune cells is a key step in establishing and maintaining an inflammatory response, so it is regarded as the main target of anti-inflammatory intervention [28,29]. The inflammatory models established by macrophages and neutrophils (the main sites of inflammatory response) are the most commonly used and most effective means to assess the anti-inflammatory activity of drug molecules [30][31][32]. Specifically, in vitro anti-inflammatory activity can be evaluated by measuring NO release, mRNA expression and/or production of inflammatory modulators (IL-1/2/5/6/8/10/12/25, TNFα, PGE 2 , etc.), and expressions of key protein (iNOS, COX-2, etc.) in macrophage cells RAW264.7 or THP-1 and other cell types (splenocytes, BV2 microglia, dendritic cells (DCs), etc.) induced by LPS, ovalbumin, or IFN-γ [33,34]. Researchers also stimulated neutrophils with LPS and assessed the anti-inflammatory activity of the drug molecule by examining its influence on superoxide anion production or elastase secretion [12].
Mice or rats are commonly chosen as experimental animals to build the in vivo inflammation model. Xylene, arachidonic acid, or croton oil can induce acute exudative inflammatory edema in the ear of experimental animals [35,36]. Intra-plantar use of carrageenan in the hind paws of the experimental animals can also induce acute inflammation and the anti-inflammatory activity of drug molecule can be assessed by measuring improvements at the inflammatory site [37]. Furthermore, dextran sulphate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS) are frequently employed to induce colitis in mice. The typical characteristics of mouse colitis are shortened mucosal folds, swelling of the lamina propria and subepithelial mucosa, and severe infiltration of various inflammatory cells, increased mRNA expression of proinflammatory cytokines, increased intestinal mucosal permeability, etc. [38,39] The anti-inflammatory activity of drug molecules can be assessed by measuring the changes in such indicators. Additionally, the zebrafish is an attractive in vivo model due to its small size, high fecundity and full annotation of genome. Several chemical-based inflammation models of zebrafish induced by LPS, DSS, TNBS or CuSO 4 have been established and the anti-inflammatory activity of drug molecule can be evaluated through the suppression of various inflammatory symptoms [40,41].

Marine Bacteria and Fungi
Marine bacteria and fungi are an important part of marine ecosystems; they can survive and reproduce continuously in low-pressure, low-temperature, or other extreme environments such as those under high pressure, high temperature, and high salinity. Compared with terrestrial microorganisms, marine bacteria and fungi are more likely to produce natural secondary metabolites with novel structures and high activities. Marine bacteria and fungi have been the frontier of drug discovery and numerous bioactive compounds have been obtained from them [42,43]. The anti-inflammatory bioactive substances derived from marine bacteria and fungi in this review were shown in Table 1. Among various microorganisms, marine actinomycetes have long been one of the favored strains in research related to drug development. Antimycin-type depsipeptides USF-19A (1), somalimycin (2), and urauchimycin D (3) (Figure 1) from a mutant strain of Streptomyces somaliensis SCSIO ZH66 can suppress the IL-5 production in splenocytes induced by ovalbumin in mouse [44]. Compound 1 demonstrated strong inhibitory activity with an IC 50 value of 0.57 µM, while compounds 2 and 3 displayed mild effects (>10 µM). Moreover, the three depsipeptides exhibited very weak cytotoxicity against human umbilical vein endothelial cells with LD 50 values of 62.6, 34.6, and 192.9 µM. The new cyclic peptide, violaceomide A (4) (Figure 1), from a marine sponge-derived fungus Aspergillus violaceofuscus showed inhibitory activity on the mRNA expression of IL-10 in the LPS-stimulated THP-1 cells (a human acute monocytic leukemia cell line) with inhibitory rate of 84.3% at 10 µM [45].
with an IC50 value of 0.57 μM, while compounds 2 and 3 displayed mild effects (> 10 μM). Moreover, the three depsipeptides exhibited very weak cytotoxicity against human umbilical vein endothelial cells with LD50 values of 62.6, 34.6, and 192.9 μM. The new cyclic peptide, violaceomide A (4) (Figure 1), from a marine sponge-derived fungus Aspergillus violaceofuscus showed inhibitory activity on the mRNA expression of IL-10 in the LPSstimulated THP-1 cells (a human acute monocytic leukemia cell line) with inhibitory rate of 84.3% at 10 μM [45].

Anti-Inflammatory Polyketides from Marine Bacteria and Fungi
A new polyketide-type metabolite, penicillospirone (5) (Figure 2) was isolated from the EtOAc extract of a marine-derived fungus Penicillium sp. SF-5292 and demonstrated inhibitory activity against the overproduction of NO and PGE 2 in LPS-induced RAW264.7 macrophages and BV2 microglia, which was correlated with the suppressive effect against over-expression of iNOS and COX-2. It could also inhibit the production of pro-inflammatory cytokines including TNFα, IL-1β, IL-6, and IL-12. Further study confirmed that the antiinflammatory effect of compound 5 was mediated through the negative regulation of the NF-κB pathway [46]. Six new polyketide derivatives, eurobenzophenones A-C, euroxanthones A-B, and (+)1-O-demethylvariecolorquinones A were isolated from the sponge associated fungus Aspergillus europaeus. Eurobenzophenones B (6) and euroxanthones A (7) (Figure 2) significantly down-regulated NF-κB in LPS-induced SW480 cells (human colon carcinoma cell line) with weak inhibition on NO production in LPS induced BV2 cells [47]. Curdepsidone C (8) (Figure 2) was obtained from fungus Curvularia sp. IFB-Z10 (isolated from the intestine of a white croaker) and showed remarkable anti-inflammatory activity against IL-1β release, with an IC 50 value of 7.47 ± 0.35 µM in Propionibacterium acnesinduced THP-1cells [48]. (+)-and (−)-actinoxocine (9a, 9b) ( Figure 2) were isolated from a marine-derived Streptomyces sp. and showed inhibition on TNFα protein release in LPSand Pam3CSK4-induced RAW 264.7 mouse macrophages, respectively [49].

Anti-Inflammatory Polyketides from Marine Bacteria and Fungi
A new polyketide-type metabolite, penicillospirone (5) (Figure 2) was isolated from the EtOAc extract of a marine-derived fungus Penicillium sp. SF-5292 and demonstrated inhibitory activity against the overproduction of NO and PGE2 in LPS-induced RAW264.7 macrophages and BV2 microglia, which was correlated with the suppressive effect against over-expression of iNOS and COX-2. It could also inhibit the production of pro-inflammatory cytokines including TNFα, IL-1β, IL-6, and IL-12. Further study confirmed that the anti-inflammatory effect of compound 5 was mediated through the negative regulation of the NF-κB pathway [46]. Six new polyketide derivatives, eurobenzophenones A-C, euroxanthones A-B, and (+)1-O-demethylvariecolorquinones A were isolated from the sponge associated fungus Aspergillus europaeus. Eurobenzophenones B (6) and euroxanthones A (7) (Figure 2) significantly down-regulated NF-κB in LPS-induced SW480 cells (human colon carcinoma cell line) with weak inhibition on NO production in LPS induced BV2 cells [47]. Curdepsidone C (8) (Figure 2) was obtained from fungus Curvularia sp. IFB-Z10 (isolated from the intestine of a white croaker) and showed remarkable anti-inflammatory activity against IL-1β release, with an IC50 value of 7.47 ± 0.35 μM in Propionibacterium acnes-induced THP-1cells [48]. (+)-and (−)-actinoxocine (9a, 9b) ( Figure 2) were isolated from a marine-derived Streptomyces sp. and showed inhibition on TNFα protein release in LPS-and Pam3CSK4-induced RAW 264.7 mouse macrophages, respectively [49].

Marine Sponges
Sponges, as the most primitive multicellular animals, have been living in the ocean for around 600 million years. To date, more than 10,000 types of sponges have been discovered, accounting for about 1 /15 of all marine animal species. Sponge has become one of the most abundant marine organisms in the discovery of marine active substances and represents an excellent resource for marine drug exploitation. To date, approximately 84 anti-inflammatory compounds have been isolated from marine sponges [9]. The anti-inflammatory bioactive substances derived from sponges in this review were shown in Table 2.

Marine Sponges
Sponges, as the most primitive multicellular animals, have been living in the ocean for around 600 million years. To date, more than 10,000 types of sponges have been discovered, accounting for about 1 / 15 of all marine animal species. Sponge has become one of the most abundant marine organisms in the discovery of marine active substances and represents an excellent resource for marine drug exploitation. To date, approximately 84 anti-inflammatory compounds have been isolated from marine sponges [9]. The antiinflammatory bioactive substances derived from sponges in this review were shown in Table 2.  (Figure 6), a proline-rich cyclic heptapeptide isolated from the marine sponge Stylissa massa, could suppress NO production in LPS-induced murine RAW264.7 macrophage cells (EC 50 = 87 µM) [57]. Further study reported that the activities of a tertbutyl ether analogue of SA (tBuSA, 30b) ( Figure 6) were approximately six times stronger than natural SA (30a) (EC 50 = 12 µM) with little cytotoxicity at up to 200 µM [58]. A recent study also indicated that a SA derivative D-Tyr 1 -tBuSA (30c) ( Figure 6) could inhibit the production of IL-6 and TNFα (EC 50 = 1.4 and 5.9 µM, respectively) and the expression of iNOS (EC 50 = 20 µM) in LPS-stimulated RAW264.7 cells [59].  (Figure 6), a proline-rich cyclic heptapeptide isolated from the marine sponge Stylissa massa, could suppress NO production in LPS-induced murine RAW264.7 macrophage cells (EC50 = 87 μM) [57]. Further study reported that the activities of a tertbutyl ether analogue of SA (tBuSA, 30b) ( Figure 6) were approximately six times stronger than natural SA (30a) (EC50 = 12 μM) with little cytotoxicity at up to 200 μM [58]. A recent study also indicated that a SA derivative D-Tyr 1 -tBuSA (30c) ( Figure 6) could inhibit the production of IL-6 and TNFα (EC50 = 1.4 and 5.9 μM, respectively) and the expression of iNOS (EC50 = 20 μM) in LPS-stimulated RAW264.7 cells [59].

Anti-Inflammatory Terpenoids from Marine Sponge
Dactylospongins A (31) and B (32) (Figure 7) are new sesquiterpenoids isolated from the marine sponge Dactylospongia sp. collected from the South China Sea. They can inhibit the production of various cytokines (IL-6, IL-1β, IL-8, and PGE 2 ) in LPS-stimulated THP-1 cells; however, neither showed significant effects on the production of monocyte chemotactic protein 1 and TNFα [60]. Three meroterpenoids (septosones A-C) were isolated from the marine sponge Dysidea septosa. Septosone A (33) (Figure 7) indicated in vivo anti-inflammatory activity that it could alleviate migration and reduce the number of macrophages surrounding the neuromast in CuSO 4 -induced transgenic zebrafish in a dose-dependent manner and could inhibit TNFα-induced NF-κB activation in human HEK-293T cells with an IC 50 value of 6.8 µM

Other Anti-Inflammatory Substances from Marine Sponge
Geobarrettin B (36) and C (37) (Figure 8) are new bromoindole alkaloids isolated from the sub-Arctic sponge Geodia barretti. Compounds 36 and 37 reduced IL-12p40 secretion of DCs, but compound 37 concomitantly increased IL-10 production. Maturing DCs treated with compound 36 or 37 before co-culturing with allogeneic CD4⁺ T cells were found to reduce the IFN-γ secretion, indicating potential for the treatment of TH1-type inflammation [64]. A new phylloketal derivative, deacetylphylloketal (38) (Figure 8), was obtained from the sponge genus Phyllospongia and could suppress the production and/or gene expression of NO, PGE2, IL-6, IL-1β, and TNFα. Compound 38 could also suppress the expression of iNOS and COX-2 in a co-culture system that consisted of human epithelial Caco-2 cells and PMA-differentiated THP-1 macrophage cells [65].

Other Anti-Inflammatory Substances from Marine Sponge
Geobarrettin B (36) and C (37) (Figure 8) are new bromoindole alkaloids isolated from the sub-Arctic sponge Geodia barretti. Compounds 36 and 37 reduced IL-12p40 secretion of DCs, but compound 37 concomitantly increased IL-10 production. Maturing DCs treated with compound 36 or 37 before co-culturing with allogeneic CD4 + T cells were found to reduce the IFN-γ secretion, indicating potential for the treatment of TH1-type inflammation [64]. A new phylloketal derivative, deacetylphylloketal (38) (Figure 8), was obtained from the sponge genus Phyllospongia and could suppress the production and/or gene expression of NO, PGE 2 , IL-6, IL-1β, and TNFα. Compound 38 could also suppress the expression of iNOS and COX-2 in a co-culture system that consisted of human epithelial Caco-2 cells and PMA-differentiated THP-1 macrophage cells [65]. treated with compound 36 or 37 before co-culturing with allogeneic CD4⁺ T cells were found to reduce the IFN-γ secretion, indicating potential for the treatment of TH1-type inflammation [64]. A new phylloketal derivative, deacetylphylloketal (38) (Figure 8), was obtained from the sponge genus Phyllospongia and could suppress the production and/or gene expression of NO, PGE2, IL-6, IL-1β, and TNFα. Compound 38 could also suppress the expression of iNOS and COX-2 in a co-culture system that consisted of human epithelial Caco-2 cells and PMA-differentiated THP-1 macrophage cells [65].

Marine Algae
Marine algae are the oldest existing lower cryptogamous plants, with a wide variety of species (about 30,000 known to date). At present, four groups of seaweeds have been extensively exploited, including blue algae, red algae, brown algae, and green algae. Marine algae are known to be a rich source of bioactive metabolites and interesting pharmacological substances. The search for bioactive metabolites from seaweed has been very active [66]. The anti-inflammatory bioactive substances derived from marine algae in this review were shown in Table 3.

Marine Algae
Marine algae are the oldest existing lower cryptogamous plants, with a wide variety of species (about 30,000 known to date). At present, four groups of seaweeds have been extensively exploited, including blue algae, red algae, brown algae, and green algae. Marine algae are known to be a rich source of bioactive metabolites and interesting pharmacological substances. The search for bioactive metabolites from seaweed has been very active [66]. The anti-inflammatory bioactive substances derived from marine algae in this review were shown in Table 3.

Anti-Inflammatory Peptides and Proteins from Marine Algae
Marine lectins are glycoproteins or peptides that bind to specific mono or oligosaccharides, which can promote cell recognition and adhesion, and some of them also showed strong anti-inflammatory activity. A lectin from the red marine alga Solieria filiformis reduced neutrophil migration in a peritonitis model and decreased paw edema induced by carrageenan, dextran, and serotonin with no signs of systemic damage in mice [67]. The anti-inflammatory mechanism of a lectin from the green seaweed Caulerpa cupressoides var. lycopodium was investigated and showed that it decreased the carrageenan-induced rat paw edema and neutrophilic infiltration at 0.1, 1 or 10 mg/kg, and inhibited the expression of IL-1β, IL-6, TNFα and COX-2 at 1 mg/kg [68].

Anti-Inflammatory Polysaccharides from Marine Algae
Polysaccharides are the main components of marine algae, which have attracted much attention because of their various health benefits [79]. Certain marine algal polysaccharides showed significant anti-inflammatory activities, which have been confirmed by several inflammatory models. A fucoidan from brown algae inhibited Poly(I:C) (a TLR3 agonist that mimics viral RNA)-induced expression of some cytokines (IL-1α, IL-1β, TNFα, and IL-6) and PGE 2 but did not change the IL-12/25 production, indicating that locally applied fucoidan might suppress airway inflammation in viral infections [69]. The high molecular weight fucoidan from Fucus vesiculosus L. (Mw 735 kDa, sulfate content 27%, fucose 73.5 mol%, glucose 11.8 mol%, galactose 3.7 mol%, xylose 6.6 mol%, mannose 0.2 mol%, and arabinose 0.2 mol%) showed remarkable anti-inflammatory activity through the inhibition of COX-1/2, hyaluronidase and MAPK p38 [70]. The purified fucoidan fraction from Turbinaria ornate (sulfate content 27%) displayed anti-inflammatory potential that could suppress NO production (IC 50 = 30.83 ± 1.02 µg·mL −1 ) and dose-dependently reduce iNOS, COX-2, and pro-inflammatory cytokines including PGE 2 levels in LPS-induced RAW264.7 macrophages and inhibit the production of NO and ROS in LPS-induced ze-brafish embryo [71]. Turbinaria ornata, a brown alga of the Sargassaceae family, is rich in bioactive molecules with various biological activities. The sulfated polysaccharide isolated from T. ornate could significantly reduce the paw volume and arthritic score in complete Freund's adjuvant induced arthritis in rats. Interestingly, the sulfated polysaccharide could alleviate inflammation and bone damage at a low dose (5 mg/kg), indicating its potential in the management of chronic inflammatory diseases [72].
through the inhibition of COX-1/2, hyaluronidase and MAPK p38 [70]. The purified fucoidan fraction from Turbinaria ornate (sulfate content 27%) displayed anti-inflammatory potential that could suppress NO production (IC50 = 30.83 ± 1.02 μg·mL −1 ) and dose-dependently reduce iNOS, COX-2, and pro-inflammatory cytokines including PGE2 levels in LPS-induced RAW264.7 macrophages and inhibit the production of NO and ROS in LPS-induced zebrafish embryo [71]. Turbinaria ornata, a brown alga of the Sargassaceae family, is rich in bioactive molecules with various biological activities. The sulfated polysaccharide isolated from T. ornate could significantly reduce the paw volume and arthritic score in complete Freund's adjuvant induced arthritis in rats. Interestingly, the sulfated polysaccharide could alleviate inflammation and bone damage at a low dose (5 mg/kg), indicating its potential in the management of chronic inflammatory diseases [72].

Marine Corals
Coral is a large group of invertebrates belonging to the phylum Cnidaria, which is a low primitive organism with a wide distribution and with a wide variety of species (about 7000 known at time of writing). Coral is a marine biological resource that can be used extensively, in particular, soft corals and Gorgonians have been ranked highly with regard to the discovery of bioactive metabolites with potential pharmaceutical applications [80]. In recent decades, researchers have isolated a variety of bioactive compounds from soft corals and Gorgonians, including terpenoids, sterols, alkaloids, and long-chain fatty acids, some of which have novel structures and significant physiological activities such as antivirus, anti-inflammatory, antibacterial, anti-tumor, and immunosuppressive activities [81]. The anti-inflammatory bioactive substances derived from corals in this review were shown in Table 4.  Figure 10. Structures of apo-9 -fucoxanthinone, disulfide and monoolein from marine algae.

Marine Corals
Coral is a large group of invertebrates belonging to the phylum Cnidaria, which is a low primitive organism with a wide distribution and with a wide variety of species (about 7000 known at time of writing). Coral is a marine biological resource that can be used extensively, in particular, soft corals and Gorgonians have been ranked highly with regard to the discovery of bioactive metabolites with potential pharmaceutical applications [80]. In recent decades, researchers have isolated a variety of bioactive compounds from soft corals and Gorgonians, including terpenoids, sterols, alkaloids, and long-chain fatty acids, some of which have novel structures and significant physiological activities such as antivirus, anti-inflammatory, antibacterial, anti-tumor, and immunosuppressive activities [81]. The anti-inflammatory bioactive substances derived from corals in this review were shown in Table 4.

Other Anti-Inflammatory Substances from Marine Corals
Two new cembranes (columnariols A (59) and B (60)) ( Figure 13), were isolated from the soft coral Nephthea columnaris and play a significant inhibitory role in the accumulation of the pro-inflammatory iNOS and COX-2 protein in LPS-stimulated RAW264.7 macrophage cells. Compound 58 showed moderate cytotoxicity against human prostatic carcinoma tumor cells with an IC50 value of 9.80 μg/mL [89]. A sterol (5,6-epoxylitosterol, 61) ( Figure 13) obtained from the octocoral Nephthea columnaris showed anti-inflammatory activity via suppressing superoxide anion production and elastase secretion in fMet-Leu-Phe/Cytochalastin B-induced human neutrophils [90]. A new polyoxygenated steroid (michosterols A, 62) ( Figure 13) isolated from the ethyl acetate extract of the soft coral Lobophytum michaelae also showed superior anti-inflammatory activity via suppressing superoxide anion generation and elastase release in fMLP/CB-stimulated human neutrophils [91].

Conclusions and Research Prospects
Inflammation, especially chronic inflammation, is a crucial contributor to the development of various human diseases. Regulation of inflammation to maintain its normal level is a key step in the treatment of related diseases. Although existing steroidal and non-steroidal anti-inflammatory drugs contribute a great deal, long-term use often causes adverse effects, including gastrointestinal discomfort, liver and kidney dysfunction, damage to the cardiovascular system, endocrine system, and so on. Marine organisms offer hope for the development of safe and effective new anti-inflammatory drugs. This review was conducted to provide reference for the research progress and give more impetus for the conversion of marine-organism-derived natural products to anti-inflammatory drugs. The Web of Science (WOS), PubMed, ScienceDirect, SpringerLink, and ACS databases were used for the preparation of the review, and some keywords such as "anti-inflammatory activity, natural product, marine bacteria and fungi, sponges, algae, and coral, etc." were used for the search of relevant information. Finally, 71 bioactive substances described during 2015-2020 were presented, including the structures (65 of which), species sources, evaluation models and anti-inflammatory activities. Furthermore, some limitations could be obtained in this review: although a wide coverage was expected to be achieved, it's extremely difficult to cover all the relevant literatures in view of the huge richness and diversity of marine organisms and their natural products; furthermore, a certain degree of randomness indeed exists for the presentation of the relevant literatures

Conclusions and Research Prospects
Inflammation, especially chronic inflammation, is a crucial contributor to the development of various human diseases. Regulation of inflammation to maintain its normal level is a key step in the treatment of related diseases. Although existing steroidal and non-steroidal anti-inflammatory drugs contribute a great deal, long-term use often causes adverse effects, including gastrointestinal discomfort, liver and kidney dysfunction, damage to the cardiovascular system, endocrine system, and so on. Marine organisms offer hope for the development of safe and effective new anti-inflammatory drugs. This review was conducted to provide reference for the research progress and give more impetus for the conversion of marine-organism-derived natural products to anti-inflammatory drugs. The Web of Science (WOS), PubMed, ScienceDirect, SpringerLink, and ACS databases were used for the preparation of the review, and some keywords such as "anti-inflammatory activity, natural product, marine bacteria and fungi, sponges, algae, and coral, etc." were used for the search of relevant information. Finally, 71 bioactive substances described during 2015-2020 were presented, including the structures (65 of which), species sources, evaluation models and anti-inflammatory activities. Furthermore, some limitations could be obtained in this review: although a wide coverage was expected to be achieved, it's extremely difficult to cover all the relevant literatures in view of the huge richness and diversity of marine organisms and their natural products; furthermore, a certain degree of randomness indeed exists for the presentation of the relevant literatures in the research field.
Research into anti-inflammatory drugs derived from marine organisms started relatively late, but it has developed rapidly. As reviewed here, many anti-inflammatory substances have been obtained from a wide variety of marine organisms, including marine bacteria and fungi, sponges, algae, and corals. Preliminary studies have been conducted on their anti-inflammatory activities and mechanisms. Of course, we also need to be aware that the development and application of marine drugs still face many challenges. First, the extreme environment in which marine organisms live is difficult to simulate in the laboratory, which makes it extremely difficult to cultivate marine organisms and obtain large quantities of their active ingredients. Furthermore, the clinical effect and market application of some marine active substances remain uncertain due to their own limitations. For instance, although bioactive peptides have many well-known advantages, their clinical effects are often unable to match experimental results from the laboratory due to their complex structure, low concentration of active components, and closed N-terminal. Finally, a thorough safety assessment is crucial, as small differences in the amount used may lead to a shift in the role of the active products between poison and therapeutic.
In future, we should try to investigate two aspects of this research: (1) take the isolated anti-inflammatory active substances from marine organisms as lead compounds, conduct functional modifications thereof, and study their structure-function relationship, so as to screen anti-inflammatory drugs with better efficacy; (2) strengthen resource integration, establish a comprehensive and efficient technological platform integrating detection, fermentation culture, separation and purification, functional modification, and effect evaluation, thus improving the efficiency of the development and application of new anti-inflammatory drugs. The ocean is a vast treasure trove, and there are still many bioactive compounds that have not been exploited. More extensive and in-depth studies should be conducted to find other, potentially valuable, marine drugs.