A Review of Anti-Inflammatory Compounds from Marine Fungi, 2000–2018

Inflammation is a generalized, nonspecific, and beneficial host response of foreign challenge or tissue injury. However, prolonged inflammation is undesirable. It will cause loss function of involve organs, such as heat, pain redness, and swelling. Marine natural products have gained more and more attention due to their unique mechanism of anti-inflammatory action, and have considered a hotspot for anti-inflammatory drug development. Marine-derived fungi are promising sources of structurally unprecedented bioactive natural products. So far, a plethora of new secondary metabolites with anti-inflammatory activities from marine-derived fungi had been widely reported. This review covers 133 fungal metabolites described in the period of 2000 to 2018, including the structures and origins of these secondary metabolites.


Introduction
Inflammation has been described as the general, complex, and beneficial immune system in response to external challenges or tissue damage [1]. It can ultimately restore tissue structure and function. Without inflammation, wounds would never be healed. However, if inflammation is not controlled for a long time, genetic mutations caused by immune cell-derived reactive oxygen species and numerous pathogenesis involved in the inflammatory response might contribute to many diseases, for example, cancer, multiple sclerosis, atherosclerosis, arthritis, heart disease, insulin resistance, and others [2,3]. At the same time, it will cause excessive expression of various inflammatory media to produce conditions conducive to many chronic diseases occurrence such as cancer, neurodegenerative disorders, diabetes, and cardiovascular diseases [4,5].
During the inflammatory process, the stimulated immune monocytes and macrophages trigger the transactivation of several important transcription factors. The well-known inflammatory signal pathway is NF-κB signal pathway called a canonical pathway [6]. NF-κB located in the cytoplasm is composed of two subunits (p50 and p65) as an inactive heterodimer bond to IκB-α, which is an inhibitory protein. In the stimulated condition, the phosphorylation and proteolytically degradation of IκB-α allows translocation of NF-κB into nuclear to regulate target gene transcription by binding to the κB site in the DNA's structure [7]. The NF-κB transactivation will increase activities of the downstream responses such as pro-inflammatory cytokines (such as IL-1β IL-6, and TNF-α) [8], the important pro-inflammatory enzymes (such as iNOS and COX-2) and their derived production NO and PGE 2 , respectively [9]. In addition to NF-κB activation, another important pathway, MAPK signal pathway such as extracellular signal-regulated kinases (ERK), p38 MAPK, and cJun NH 2 -terminal kinases (JNK) [7], also can be activated by inflammation and regulates the transcription of various inflammatory-related genes then overexpress the downstream inflammatory response [10]. Amounts of redness, pain, fever, and swelling [11,12]. Therefore, inhibition of the overproduction of these is an important target in the treatment of inflammatory disease [13]. Researchers usually evaluated the anti-inflammatory activity by the suppressed expression of pro-inflammatory cytokines, the proinflammatory enzyme of COX-2, iNOS and their derived production, and the various inflammatoryrelated protein in NF-κB and MAPK signal pathways in immune monocytes and macrophages (BV2 cells, RAW264.7 cells and more) stimulated by LPS in vitro [14], or by the inhibited swelling rate in mouse ear edema model induced by phorbol myristate acetate (PMA) in vivo [15].
Toward the aim of discovering new natural products with anti-inflammatory activities, researchers spend a lot of time and energy to discover novel sources in different environment. The oceans with their unique aquatic environment and plentiful biodiversity has drawn attention for the rich source of diverse secondary metabolites with significantly anti-inflammatory, antitumor, antimicrobial, antiviral, antimalarial, and anti-oxidant activities [16,17]. According to the MarinLit database (http://pubs.rsc.org/marinlit), annually more than 1200 novel natural products are reported from a variety of marine sources, such as algae, ascidians, bryozoan, corals, microorganisms, sea hares, sea squirts, sponges, and so on [18,19]. Since Alexander Fleming discovered penicillin in 1928 from Penicillium [20], people have never stopped discovering new drugs from fungi. Fungi is a crucial source as lead structures for novel pharmaceuticals [21]. Fungi also act as an important ecological role in the marine environment, such as pathogens of marine invertebrates, primary decomposers, and obligate symbionts [22]. Especially, marine-derived fungi play a vital role in the discovery of new anti-inflammatory drugs. Many novel secondary metabolites showing potent anti-inflammatory activities have been discovered from fungi residing in or on algae, sediments, water, and corals. Due to its unique mechanism of action, marine fungal compounds have received more and more attention and become one of the hotspot area for the development of anti-inflammatory drugs.

Alkaloids
The fungus Aspergillus flocculosus 16D-1 was associated with the inner tissue of the sponge Phakellia fusca colonizing in Yongxing Island, China, and produced new pyrrolidine alkaloids, preussins C-I (1-7, Figure 3) and (11R)/(11S)-preussins J and K (8 and 9, Figure 3) [23]. Compounds 5 and 7 showed remarkable anti-inflammatory activity toward interleukin (IL)-6 production in lipopolysaccharide (LPS)-activated THP-1 cells with IC50 values of 0.11 μM and 0.19 μM, which was stronger than that of corylifol A, a positive control with the IC50 value of 0.67 μM, while other compounds possessed moderate inhibitory effects, with IC50 values in the range of 2.3 to 22 μM [23]. Chemical examination of the cultured mycelium of the fungus Aspergillus versicolor collected from the mud of the South China Sea led to the isolation of some novel linearly fused prenylated indole alkaloids: asperversiamides B, C, F, and G (10-13, Figure 3). These compounds exerted potential inducible nitric oxide synthase (iNOS) inhibitory effects and suppressed the release of nitric oxide (NO) in LPS-induced RAW264.7 cells. And of these compounds, asperversiamide G showed a potent inhibitory effect against iNOS with the IC50 value of 5.39 μM, while others exhibited weak activities with IC50 values ranging from 9.95 to 16.58 μM. Considering the significant inhibitory activity of asperversiamide B, it can synthesize the potential derivatives in the development of new antiinflammatory drugs for the treatment of various related disorders [24]. A prenylated tryptophan derivative, luteoride E (14, Figure 3) was purified from the coral-associated fungus Aspergillus terreus associated with the coral Sarcophyton subviride, which was gathered from the coast of Xisha Island in the South China Sea. This compound exhibited inhibitory activity against NO production with IC50 value of 24.65 μM in LPS-stimulated RAW264.7 cells [25].

Alkaloids
The fungus Aspergillus flocculosus 16D-1 was associated with the inner tissue of the sponge Phakellia fusca colonizing in Yongxing Island, China, and produced new pyrrolidine alkaloids, preussins C-I (1-7, Figure 3) and (11R)/(11S)-preussins J and K (8 and 9, Figure 3) [23]. Compounds 5 and 7 showed remarkable anti-inflammatory activity toward interleukin (IL)-6 production in lipopolysaccharide (LPS)-activated THP-1 cells with IC 50 values of 0.11 µM and 0.19 µM, which was stronger than that of corylifol A, a positive control with the IC 50 value of 0.67 µM, while other compounds possessed moderate inhibitory effects, with IC 50 values in the range of 2.3 to 22 µM [23]. Chemical examination of the cultured mycelium of the fungus Aspergillus versicolor collected from the mud of the South China Sea led to the isolation of some novel linearly fused prenylated indole alkaloids: asperversiamides B, C, F, and G (10-13, Figure 3). These compounds exerted potential inducible nitric oxide synthase (iNOS) inhibitory effects and suppressed the release of nitric oxide (NO) in LPS-induced RAW264.7 cells. And of these compounds, asperversiamide G showed a potent inhibitory effect against iNOS with the IC 50 value of 5.39 µM, while others exhibited weak activities with IC 50 values ranging from 9.95 to 16.58 µM. Considering the significant inhibitory activity of asperversiamide B, it can synthesize the potential derivatives in the development of new anti-inflammatory drugs for the treatment of various related disorders [24]. A prenylated tryptophan derivative, luteoride E (14, Figure 3) was purified from the coral-associated fungus Aspergillus terreus associated with the coral Sarcophyton subviride, which was gathered from the coast of Xisha Island in the South China Sea. This compound exhibited inhibitory activity against NO production with IC 50 value of 24.65 µM in LPS-stimulated RAW264.7 cells [25].

Alkaloids
The fungus Aspergillus flocculosus 16D-1 was associated with the inner tissue of the sponge Phakellia fusca colonizing in Yongxing Island, China, and produced new pyrrolidine alkaloids, preussins C-I (1-7, Figure 3) and (11R)/(11S)-preussins J and K (8 and 9, Figure 3) [23]. Compounds 5 and 7 showed remarkable anti-inflammatory activity toward interleukin (IL)-6 production in lipopolysaccharide (LPS)-activated THP-1 cells with IC50 values of 0.11 μM and 0.19 μM, which was stronger than that of corylifol A, a positive control with the IC50 value of 0.67 μM, while other compounds possessed moderate inhibitory effects, with IC50 values in the range of 2.3 to 22 μM [23]. Chemical examination of the cultured mycelium of the fungus Aspergillus versicolor collected from the mud of the South China Sea led to the isolation of some novel linearly fused prenylated indole alkaloids: asperversiamides B, C, F, and G (10-13, Figure 3). These compounds exerted potential inducible nitric oxide synthase (iNOS) inhibitory effects and suppressed the release of nitric oxide (NO) in LPS-induced RAW264.7 cells. And of these compounds, asperversiamide G showed a potent inhibitory effect against iNOS with the IC50 value of 5.39 μM, while others exhibited weak activities with IC50 values ranging from 9.95 to 16.58 μM. Considering the significant inhibitory activity of asperversiamide B, it can synthesize the potential derivatives in the development of new antiinflammatory drugs for the treatment of various related disorders [24]. A prenylated tryptophan derivative, luteoride E (14, Figure 3) was purified from the coral-associated fungus Aspergillus terreus associated with the coral Sarcophyton subviride, which was gathered from the coast of Xisha Island in the South China Sea. This compound exhibited inhibitory activity against NO production with IC50 value of 24.65 μM in LPS-stimulated RAW264.7 cells [25].  Chrysamide C (15, Figure 4), a new dimeric nitrophenyl trans-epoxyamides, was obtained from the marine-derived fungus Penicillium chrysogenum SCSIO41001, collected from deep sea sediment in the Indian Ocean [26]. Chrysamide C was observed to be most active on inhibitory activity toward the proinflammatory cytokine IL-17 production, while inhibitory rate of chrysamide C was found to 40.06% at 1.0 µM [26]. A new quinolone alkaloid, viridicatol (16, Figure 4), was discovered in the marine-derived fungus Penicillium sp. SF-5295 [27]. Compound 16 displayed anti-inflammatory potency in LPS-stimulated RAW264.7 cells and BV2 cells. Viridicatol inhibited the production of iNOS-derived NO in RAW264.7 cells with IC 50 values of 46.03 µM in RAW264.7 cells and 43.03 µM in BV2 cells and suppressed the production of cyclooxygenase-2 (COX-2)-derived prostaglandin E 2 (PGE 2 ) with an IC 50 value of 30.37 µM in RAW264.7 cells and 34.20 µM in BV2 cells. Compound 16 also inhibited the mRNA expression of IL-1β, IL-6, and tumor necrosis factor-α (TNF-α), which were pro-inflammatory cytokines [27]. In the further evaluation, compound 16 exerted anti-inflammatory activity through suppressing the NF-κB pathway by blocking the phosphorylation of inhibitor kappa B (IκB)-α, and suppressing the translocation of NF-κB dimers, namely p50 and p65 in RAW264.7 macrophages and BV2 microglia induced by LPS [27]. Another study on the Penicillium sp. derived from a deep ocean sediment resulted in the discovery of two novel diketopiperazine alkaloids, brevicompanines E and H (17 and 18, Figure 4) [28]. These compounds were shown to have the moderate anti-inflammatory activity to inhibit NO production in LPS-induced BV2 microglial cells, with IC 50 values of 27 and 45 µg/mL, respectively [28]. In addition, these compounds displayed no cytotoxic effect at these concentrations. Some evidence indicate that substituents at the N-6 position were significant for inhibitory activity of NO production [28]. These compounds may be a potential for finding a chemotherapeutic candidate that has anti-inflammatory with no cytotoxic effects [28]. A soft coral samples collected at Terra Nova bay, Antaratica, resulted in the isolation of Penicillium sp. SF-5995, which led to the isolation of a pyrrolyl 4-quinoline alkaloid, methylpenicinoline (19, Figure 4) [29]. Compound 19 suppressed the NO and PGE 2 production by attenuating iNOS and COX-2 expression, respectively, in LPS-stimulated RAW264.7 macrophages and BV2 microglia with the IC 50 values of ranging from 34-49 µM [29]. Furthermore, compound 19 inhibited the pro-inflammatory cytokine IL-1β production [29]. In the further study, compound 19 suppressed the expression of pro-inflammatory cytokines through the NF-κB and mitogen-activated protein kinase (MAPK) pathway in LPS-induced RAW264.7 macrophages and BV2 cells [29]. Another marine fungus Eurotium sp. SF-5989 was also isolated from a soft coral collected at Terra Nova bay, Antarctica. Chemical investigation of the fungus Eurotium sp. SF-5989 afforded a diketopiperazine-type indole alkaloid, neoechinulin A (20, Figure 4) [30]. Compound 20 suppressed the production of pro-inflammatory mediators, NO and PGE 2 , and these inhibitory activities were mediated by inhibiting the expression of COX-2 and iNOS in RAW264.7 macrophages stimulated by LPS. The anti-inflammatory mechanism of compound 20 was due to attenuation of two major signaling pathways, NF-κB pathway and MAPK signaling pathway in LPS-stimulated RAW264.7 macrophages and BV2 microglia [30].

Terpenoids
Two novel brasilane sesquiterpenoids, brasilanones A and E (21, 22, Figure 5), were separated from the extract of the marine-derived fungus A. terreus CFCC 81836, which displayed moderate inhibitory activities against NO production with inhibition rates of 47.7% and 37.3% at 40 µM in RAW264.7 mouse macrophages induced by LPS [31]. Liyan Wang et al. firstly reported three new eremophilane-type sesquiterpenoids of dihydrobipolaroxin B-D (23-25, Figure 5) and a known sesquiterpene of dihydrobipolaroxin (26, Figure 5). These compounds were isolated from a deep sea-derived fungus, Aspergillus sp. SCSIOW2, from a deep marine sediment sample gathered from the South China Sea at a depth of 2439 m [32]. All of these compounds were shown to have moderate anti-inflammatory effects to inhibit NO induced by LPS/INF-γ. Meanwhile, all four compounds exhibited no cytotoxic effects [32]. Thomimarine E (27, Figure 6) was a new eudesmane-type sesquiterpene that was obtained from marine fungus Penicillium thomii KMM 4667 [33]. Thomimarine E (27) exhibited anti-inflammatory effect and inhibited the production of NO in LPS-stimulated RAW264.7 cells with inhibition rate of 22.5% ± 5.1% at the concentration of 10.0 μM [33]. Graphostroma sp. MCCC 3A00421 isolated from Atlantic Ocean hydrothermal sulfide deposit at a depth of 2721 m produced a new guaiane, graphostromane F (28, Figure 6) [34]. Graphostromane F (28) exhibited considerable inhibitory activity by inhibiting the release of NO in RAW264.7 macrophages induced by LPS with an IC50 value of 14.2 μM, which was even lower than the aminoguanidine as positive control with an IC50 value of 23.4 μM [34]. Another study on the same Graphostroma sp. MCCC 3A00421 resulted in the discovery of a novel fungal sesquiterpene, khusinol B (29, Figure 6) [35]. Khusinol B (29) was found considerable anti-inflammatory activity in LPS-induced RAW264.7 cells against NO production with IC50 value of 17 μM, which was even stronger than that of the positive control with the IC50 value was 23 μM [35]. Chemical study of the sea-derived fungus Hypocreales sp. strain HLS-104, which was isolated from a sponge Gelliodes carnosa colonizing in the South China Sea afforded a derivative, 1R,6R,7R,10S-10hydroxy-4(5)-cadinen-3-one (30, Figure 6) with moderate anti-inflammatory activity [36]. The average maximum inhibition (Emax) values of this molecule against the production of the NO in LPStreated RAW264.7 cells was 10.22% at the concentration of 1 μM [36]. William Fenical et al., isolated mangicols A and B (31 and 32, Figure 6) from a marine fungus, Fusarium heterosporum CNC-477, which was separated from a driftwood sample collected from Sweetings Cay mangrove habitat, Bahamas [37]. Mangicols A and B were novel sesterterpene polyols that exhibited considerable antiinflammatory effects in the phorbol myristate acetate (PMA)-induced mouse ear edema assay with the reduction of 81% and 57%, respectively, at the standard of 50 μg per ear which were similar to those of indomethacin, the positive control, with the reduction of 71% [37]. Thomimarine E (27, Figure 6) was a new eudesmane-type sesquiterpene that was obtained from marine fungus Penicillium thomii KMM 4667 [33]. Thomimarine E (27) exhibited anti-inflammatory effect and inhibited the production of NO in LPS-stimulated RAW264.7 cells with inhibition rate of 22.5% ± 5.1% at the concentration of 10.0 µM [33]. Graphostroma sp. MCCC 3A00421 isolated from Atlantic Ocean hydrothermal sulfide deposit at a depth of 2721 m produced a new guaiane, graphostromane F (28, Figure 6) [34]. Graphostromane F (28) exhibited considerable inhibitory activity by inhibiting the release of NO in RAW264.7 macrophages induced by LPS with an IC 50 value of 14.2 µM, which was even lower than the aminoguanidine as positive control with an IC 50 value of 23.4 µM [34]. Another study on the same Graphostroma sp. MCCC 3A00421 resulted in the discovery of a novel fungal sesquiterpene, khusinol B (29, Figure 6) [35]. Khusinol B (29) was found considerable anti-inflammatory activity in LPS-induced RAW264.7 cells against NO production with IC 50 value of 17 µM, which was even stronger than that of the positive control with the IC 50 value was 23 µM [35]. Chemical study of the sea-derived fungus Hypocreales sp. strain HLS-104, which was isolated from a sponge Gelliodes carnosa colonizing in the South China Sea afforded a derivative, 1R,6R,7R,10S-10-hydroxy-4(5)-cadinen-3-one (30, Figure 6) with moderate anti-inflammatory activity [36]. The average maximum inhibition (E max ) values of this molecule against the production of the NO in LPS-treated RAW264.7 cells was 10.22% at the concentration of 1 µM [36]. William Fenical et al., isolated mangicols A and B (31 and 32, Figure 6) from a marine fungus, Fusarium heterosporum CNC-477, which was separated from a driftwood sample collected from Sweetings Cay mangrove habitat, Bahamas [37]. Mangicols A and B were novel sesterterpene polyols that exhibited considerable anti-inflammatory effects in the phorbol myristate acetate (PMA)-induced mouse ear edema assay with the reduction of 81% and 57%, respectively, at the standard of 50 µg per ear which were similar to those of indomethacin, the positive control, with the reduction of 71% [37]. Mar. Drugs 2019, 17, x FOR PEER REVIEW 7 of 24  Lovastatin (39, Figure 8) was purified from the coral-associated fungus A. terreus associated with the coral S. subviride, collected from the coast of Xisha Island in the South China Sea [25]. This compound showed inhibitory activity on the NO production with IC50 value of 17.45 μM in RAW264.7 cells stimulated by LPS [25]. A sea green algal species Enteromorpha collected in Dongshi salt pan, Fujian Province, China, resulted in the isolation of a fungus Aspergillus sp. ZL0-1b14 [39]. The fungus extracts displaying anti-inflammatory activities was chemically analyzed, which led to the isolation of a family group of new triketide-sesquiterpenoid meroterpenoids, aspertetranones A−D (40−43, Figure 8) [39]. Aspertetranones A−D showed different anti-inflammatory activities. Notably, aspertetranones A and D exhibited the suppress potency against the production of IL-6 in LPS-stimulated RAW264.7 macrophages with 43% and 69% inhibition at 40 μM [39]. Chemical investigation of a marine-derived fungus, Pleosporales sp. strain derived from a marine alga Enteromorpha clathrate collected from the South China Sea in Hainan Province, yielded three new compounds, pleosporallins A−C (44−46, Figure 8) [40]. They possessed moderate inhibitory activities against the production of proinflammatory cytokine IL-6 in LPS-stimulated RAW264.7 macrophages cells with the inhibition rate about 30.0% compared to control at the concentration of 5−20 μg/mL [40].  Lovastatin (39, Figure 8) was purified from the coral-associated fungus A. terreus associated with the coral S. subviride, collected from the coast of Xisha Island in the South China Sea [25]. This compound showed inhibitory activity on the NO production with IC50 value of 17.45 μM in RAW264.7 cells stimulated by LPS [25]. A sea green algal species Enteromorpha collected in Dongshi salt pan, Fujian Province, China, resulted in the isolation of a fungus Aspergillus sp. ZL0-1b14 [39]. The fungus extracts displaying anti-inflammatory activities was chemically analyzed, which led to the isolation of a family group of new triketide-sesquiterpenoid meroterpenoids, aspertetranones A−D (40−43, Figure 8) [39]. Aspertetranones A−D showed different anti-inflammatory activities. Notably, aspertetranones A and D exhibited the suppress potency against the production of IL-6 in LPS-stimulated RAW264.7 macrophages with 43% and 69% inhibition at 40 μM [39]. Chemical investigation of a marine-derived fungus, Pleosporales sp. strain derived from a marine alga Enteromorpha clathrate collected from the South China Sea in Hainan Province, yielded three new compounds, pleosporallins A−C (44−46, Figure 8) [40]. They possessed moderate inhibitory activities against the production of proinflammatory cytokine IL-6 in LPS-stimulated RAW264.7 macrophages cells with the inhibition rate about 30.0% compared to control at the concentration of 5−20 μg/mL [40]. Lovastatin (39, Figure 8) was purified from the coral-associated fungus A. terreus associated with the coral S. subviride, collected from the coast of Xisha Island in the South China Sea [25]. This compound showed inhibitory activity on the NO production with IC 50 value of 17.45 µM in RAW264.7 cells stimulated by LPS [25]. A sea green algal species Enteromorpha collected in Dongshi salt pan, Fujian Province, China, resulted in the isolation of a fungus Aspergillus sp. ZL0-1b14 [39]. The fungus extracts displaying anti-inflammatory activities was chemically analyzed, which led to the isolation of a family group of new triketide-sesquiterpenoid meroterpenoids, aspertetranones A−D (40−43, Figure 8) [39]. Aspertetranones A−D showed different anti-inflammatory activities. Notably, aspertetranones A and D exhibited the suppress potency against the production of IL-6 in LPS-stimulated RAW264.7 macrophages with 43% and 69% inhibition at 40 µM [39]. Chemical investigation of a marine-derived fungus, Pleosporales sp. strain derived from a marine alga Enteromorpha clathrate collected from the South China Sea in Hainan Province, yielded three new compounds, pleosporallins A−C (44−46, Figure 8) [40]. They possessed moderate inhibitory activities against the production of proinflammatory cytokine IL-6 in LPS-stimulated RAW264.7 macrophages cells with the inhibition rate about 30.0% compared to control at the concentration of 5−20 µg/mL [40]. Jin-Soo Park et al. separated two novel meroterpenoid-type metabolites along with eight known analogs from the ethyl acetate extract of a marine-derived fungal strain Penicillium sp. SF-5497, which was isolated from a sample of sea sand collected from Gijiang-gun, Busan [41]. All the isolated metabolites were evaluated for anti-inflammatory activities against NO production in microglial BV-2 cells challenged by LPS, only 7-acetoxydehydroaustinol (47, Figure 9), and four other known analogs austinolide (48, Figure 9), 7-acetoxydehydroaustin (49, Figure 9), 11-hydroxyisoaustinone (50, Figure 9), and 11-acetoxyisoaustinone (51, Figure 9), were shown to have weak inhibitory effects with IC50 values of 61.0, 30.1, 58.3, 37.6, and 40.2 μM, respectively [41]. The marine fungus Penicillium atrovenetum was shown to produce an undescribed meroterpenoid, citreohybridonol (52, Figure 9) [42]. This compound was found to have anti-neuroinflammatory activity [42]. A new tanzawaic acid derivative, tanzawaic acid Q (53, Figure 10), together with four known analogues, tanzawaic acids A (54, Figure 10), C (55, Figure 10), D (56, Figure 10), and K (57, Figure  10), have been isolated from a marine-derived fungus, Penicillium steckii 108YD142, residing in a marine sponge sample collected at Wangdolcho, in the Republic of Korea's Eastern reef [43]. These compounds considerably inhibited LPS-stimulated NO production in RAW264.7 macrophages cells. Moreover, tanzawaic acid Q reduced the expression of pro-inflammatory mediators such as COX-2 and iNOS and also possessed the production of PGE2, TNF-α, and IL-1β mRNA protein [43]. Marinederived fungus Penicillium sp. SF-6013 derived from the sea urchin Brisaster latifrons collected from the Sea of Okhotsk, was shown to produce a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (58, Figure 10), along with two known analogues, tanzawaic acids A (54) and E (59, Figure 10). These three tanzawaic acids inhibited the overproduction of NO in BV-2 microglial cells activated by LPS Jin-Soo Park et al. separated two novel meroterpenoid-type metabolites along with eight known analogs from the ethyl acetate extract of a marine-derived fungal strain Penicillium sp. SF-5497, which was isolated from a sample of sea sand collected from Gijiang-gun, Busan [41]. All the isolated metabolites were evaluated for anti-inflammatory activities against NO production in microglial BV-2 cells challenged by LPS, only 7-acetoxydehydroaustinol (47, Figure 9), and four other known analogs austinolide (48, Figure 9), 7-acetoxydehydroaustin (49, Figure 9), 11-hydroxyisoaustinone (50, Figure 9), and 11-acetoxyisoaustinone (51, Figure 9), were shown to have weak inhibitory effects with IC 50 values of 61.0, 30.1, 58.3, 37.6, and 40.2 µM, respectively [41]. The marine fungus Penicillium atrovenetum was shown to produce an undescribed meroterpenoid, citreohybridonol (52, Figure 9) [42]. This compound was found to have anti-neuroinflammatory activity [42]. Jin-Soo Park et al. separated two novel meroterpenoid-type metabolites along with eight known analogs from the ethyl acetate extract of a marine-derived fungal strain Penicillium sp. SF-5497, which was isolated from a sample of sea sand collected from Gijiang-gun, Busan [41]. All the isolated metabolites were evaluated for anti-inflammatory activities against NO production in microglial BV-2 cells challenged by LPS, only 7-acetoxydehydroaustinol (47, Figure 9), and four other known analogs austinolide (48, Figure 9), 7-acetoxydehydroaustin (49, Figure 9), 11-hydroxyisoaustinone (50, Figure 9), and 11-acetoxyisoaustinone (51, Figure 9), were shown to have weak inhibitory effects with IC50 values of 61.0, 30.1, 58.3, 37.6, and 40.2 μM, respectively [41]. The marine fungus Penicillium atrovenetum was shown to produce an undescribed meroterpenoid, citreohybridonol (52, Figure 9) A new tanzawaic acid derivative, tanzawaic acid Q (53, Figure 10), together with four known analogues, tanzawaic acids A (54, Figure 10), C (55, Figure 10), D (56, Figure 10), and K (57, Figure  10), have been isolated from a marine-derived fungus, Penicillium steckii 108YD142, residing in a marine sponge sample collected at Wangdolcho, in the Republic of Korea's Eastern reef [43]. These compounds considerably inhibited LPS-stimulated NO production in RAW264.7 macrophages cells. Moreover, tanzawaic acid Q reduced the expression of pro-inflammatory mediators such as COX-2 and iNOS and also possessed the production of PGE2, TNF-α, and IL-1β mRNA protein [43]. Marinederived fungus Penicillium sp. SF-6013 derived from the sea urchin Brisaster latifrons collected from the Sea of Okhotsk, was shown to produce a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (58, Figure 10), along with two known analogues, tanzawaic acids A (54) and E (59, Figure 10). These three tanzawaic acids inhibited the overproduction of NO in BV-2 microglial cells activated by LPS A new tanzawaic acid derivative, tanzawaic acid Q (53, Figure 10), together with four known analogues, tanzawaic acids A (54, Figure 10), C (55, Figure 10), D (56, Figure 10), and K (57, Figure 10), have been isolated from a marine-derived fungus, Penicillium steckii 108YD142, residing in a marine sponge sample collected at Wangdolcho, in the Republic of Korea's Eastern reef [43]. These compounds considerably inhibited LPS-stimulated NO production in RAW264.7 macrophages cells. Moreover, tanzawaic acid Q reduced the expression of pro-inflammatory mediators such as COX-2 and iNOS and also possessed the production of PGE 2 , TNF-α, and IL-1β mRNA protein [43]. Marine-derived fungus Penicillium sp. SF-6013 derived from the sea urchin Brisaster latifrons collected from the Sea of Okhotsk, was shown to produce a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D (58, Figure 10), along with two known analogues, tanzawaic acids A (54) and E (59, Figure 10). These three tanzawaic acids inhibited the overproduction of NO in BV-2 microglial cells activated by LPS with IC 50 values of 37.8, 7.1, and 42.5 µM, respectively [44]. Furthermore, tanzawaic acid A also inhibited the NO production and reduced the expression of iNOS and COX-2 in RAW264.7 and BV2 cells stimulated by LPS [44]. with IC50 values of 37.8, 7.1, and 42.5 μM, respectively [44]. Furthermore, tanzawaic acid A also inhibited the NO production and reduced the expression of iNOS and COX-2 in RAW264.7 and BV2 cells stimulated by LPS [44]. Three meroterpenoids, named as stachybotrysin C (60, Figure 11), stachybonoid F (61, Figure  11), and stachybotylactone (62, Figure 11) were obtained from Stachybotrys chartarum 952 isolated from a marine crinoid (Himerometra magnipinna) [45]. Compounds 60, 61, and 62 moderately suppressed the production of NO (the pro-inflammatory mediator) with IC50 values of 27.2, 52.5, and 17.9 μM in RAW264.7 macrophages stimulated by LPS [45].   Three meroterpenoids, named as stachybotrysin C (60, Figure 11), stachybonoid F (61, Figure 11), and stachybotylactone (62, Figure 11) were obtained from Stachybotrys chartarum 952 isolated from a marine crinoid (Himerometra magnipinna) [45]. Compounds 60, 61, and 62 moderately suppressed the production of NO (the pro-inflammatory mediator) with IC 50 values of 27.2, 52.5, and 17.9 µM in RAW264.7 macrophages stimulated by LPS [45]. with IC50 values of 37.8, 7.1, and 42.5 μM, respectively [44]. Furthermore, tanzawaic acid A also inhibited the NO production and reduced the expression of iNOS and COX-2 in RAW264.7 and BV2 cells stimulated by LPS [44]. Three meroterpenoids, named as stachybotrysin C (60, Figure 11), stachybonoid F (61, Figure  11), and stachybotylactone (62, Figure 11) were obtained from Stachybotrys chartarum 952 isolated from a marine crinoid (Himerometra magnipinna) [45]. Compounds 60, 61, and 62 moderately suppressed the production of NO (the pro-inflammatory mediator) with IC50 values of 27.2, 52.5, and 17.9 μM in RAW264.7 macrophages stimulated by LPS [45].

Peptides
Methyl 3,4,5-trimethoxy-2-(2-(nicotinamido) benzamido) benzoate (122, Figure 20), was isolated from a coral-associated fungus A. terreus associated with the coral S subviride, which was gathered from Xisha Island in the South China Sea [25]. This compound showed a considerable anti-inflammatory activity with an IC 50 value of 5.48 µM [25]. Bioassay-guided investigation of the EtOAc extract of marine sponge-derived fungus Aspergillus violaceofuscus afforded new anti-inflammatory activity metabolites named violaceotide A (123, Figure 20) and diketopiperazine dimer (124, Figure 20) [67]. The fungus A. violaceofuscus was isolated from the inner part of the marine sponge Reniochalina sp. collected from the Xisha Islands in the South China Sea. Violaceotide A and diketopiperazine dimer reduced IL-10 expression in THP-1 cells stimulated by LPS with inhibitory rate of 84.3% and 78.1% at concentration of 10 µM, respectively [67]. Investigation of biologically active peptides from the marine fungus Aspergillus sp. SF-5921 (from an unidentified sponge, Sea of Ross) resulted in isolation of aurantiamide acetate (125, Figure 20) [68]. Compound 125 showed inhibitory potency against the LPS-stimulated production of NO and PGE 2 with IC 50 values of 49.70 and 51.3 µM in BV2 microglia cells [68]. In addition, it has anti-neuron-flammatory effects through its inhibition of the NF-κB, c-Jun N-terminal kinases (JNK), and p38 pathways [68]. (S)-2-(2-hydroxypropanamido) benzoic acid (126, Figure 20), a novel benzoic acid, was isolated as natural product from a sponge-derived marine fungus P. chrysogenum SYP-F-2720 [69]. Compound 126 exhibited stronger anti-inflammatory activity than aspirin (swelling rate of 193%) with the swelling rate of 191% in the mouse ear edema model induced by xylene when administered at 100 mg/kg [69]. Chemical investigation of a marine-derived fungus Acremonium sp. from the surface of the Caribbean tunicate Ecteinascidia turbinata. yielded a new peptide derivative, oxepinamide A (127, Figure 20) [70]. Oxepinamide A showed potent anti-inflammatory effect in a topical resiniferatoxin (RTX)-induced mouse ear edema assay, with the inhibition rate of 82% at the standard testing dose of 50 µg per ear [70]. Alternaramide (128, Figure 20), a marine Alternaria sp. SF-5016 metabolite, was interesting in that it contained unusual hydrophobic D-amino acid residues [71]. Compound 128 suppressed the production of PGE 2 and NO, and these inhibitory effects were correlated with down-regulation of iNOS and COX-2 expression in LPS-induced RAW264.7 and BV2 macroglia cells with IC 50 values ranging from 27.63 to 40.52 µM [71]. It also inhibited pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-12 in LPS-induced RAW264.7 and BV2 macroglia cells. In addition, the compound 128 suppressed the NF-κB and MAPK signaling pathway. Furthermore, compound 128 significantly reduced the Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) in LPS-induced RAW264.7 and BV2 macroglia cells at the mRNA and protein levels [71].
that it contained unusual hydrophobic D-amino acid residues [71]. Compound 128 suppressed the production of PGE2 and NO, and these inhibitory effects were correlated with down-regulation of iNOS and COX-2 expression in LPS-induced RAW264.7 and BV2 macroglia cells with IC50 values ranging from 27.63 to 40.52 μM [71]. It also inhibited pro-inflammatory cytokines, such as TNF-α, IL-1β, IL-6, and IL-12 in LPS-induced RAW264.7 and BV2 macroglia cells. In addition, the compound 128 suppressed the NF-κB and MAPK signaling pathway. Furthermore, compound 128 significantly reduced the Toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) in LPS-induced RAW264.7 and BV2 macroglia cells at the mRNA and protein levels [71].

Conclusions
The inflammatory disease is one of the most common diseases around the world [74]. Recent literatures showed that the prevalence, severity, and complexity of the disease were rising rapidly and adding to the healthcare costs considerably [75]. What is more, the inflammatory disease operates