Marinedrugs 17 00636 PDF

marine drugs
Review
A Review of Anti-Inflammatory Compounds from
Marine Fungi, 2000–2018
Jianzhou Xu, Mengqi Yi, Lijian Ding * and Shan He *
Li Dak Sum Yip Yio Chin Kenneth Li Marine Biopharmaceutical Research Center, College of Food and
Pharmaceutical Sciences, Ningbo University, Ningbo 315832, China; 176001796@nbu.edu.cn (J.X.);
ymqnbu@163.com (M.Y.)
* Correspondence: dinglijian@nbu.edu.cn (L.D.); heshan@nbu.edu.cn (S.H.); Tel.: +86-574-8760-4388 (L.D.)

Received: 16 October 2019; Accepted: 6 November 2019; Published: 9 November 2019
Abstract: 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.
Keywords: marine-derived fungi; marine natural products; anti-inflammatory
1. 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 PGE2 , 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 NH2 -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
Mar. Drugs 2019, 17, 636; doi:10.3390/md17110636 www.mdpi.com/journal/marinedrugs

Mar. Drugs 2019, 17, 636 2 of 24
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inflammatory mediators and factors are involved in cell damage and inflammatory such as redness, pain,
redness,
fever, andpain, fever,
swelling and swelling
[11,12]. Therefore, [11,12]. Therefore,
inhibition of the inhibition
overproduction of theof overproduction of thesetarget
these is an important is an
important
in the treatment targetofininflammatory
the treatmentdisease of inflammatory diseaseusually
[13]. Researchers [13]. Researchers
evaluated the usually evaluated the
anti-inflammatory
anti-inflammatory activity by the suppressed expression of pro-inflammatory
activity by the suppressed expression of pro-inflammatory cytokines, the pro-inflammatory enzyme cytokines, the pro- of
inflammatory
COX-2, iNOS and enzyme
their of COX-2,production,
derived iNOS and their derived
and the various production, and the various
inflammatory-related inflammatory-
protein in NF-κB
related
and MAPK protein
signalin pathways
NF-κB andinMAPK immune signal pathways
monocytes andinmacrophages
immune monocytes (BV2 cells,andRAW264.7
macrophages cells (BV2
and
cells, RAW264.7 cells and more) stimulated by LPS in vitro [14], or
more) stimulated by LPS in vitro [14], or by the inhibited swelling rate in mouse ear edema model by the inhibited swelling rate in
mouse ear
induced by edema
phorbolmodelmyristateinduced by phorbol
acetate (PMA) inmyristate
vivo [15].acetate (PMA) in vivo [15].
Toward the aim of discovering new natural productsproducts
Toward the aim of discovering new natural with anti-inflammatory
with anti-inflammatory activities,
activities, researchers
researchers spend a lot of time and energy to discover novel sources
spend a lot of time and energy to discover novel sources in different environment. The oceans in different environment. The
oceans
with with
their their unique
unique aquaticaquatic environment
environment and plentiful
and plentiful biodiversity
biodiversity has drawnhas drawn attention
attention for the forrich
the
rich source of diverse secondary metabolites with significantly anti-inflammatory,
source of diverse secondary metabolites with significantly anti-inflammatory, antitumor, antimicrobial, antitumor,
antimicrobial,
antiviral, antiviral,
antimalarial, andantimalarial,
anti-oxidant and anti-oxidant
activities [16,17].activities
According [16,17] . According
to the MarinLit to the MarinLit
database (http:
database (http://pubs.rsc.org/marinlit), annually more than 1200 novel
//pubs.rsc.org/marinlit), annually more than 1200 novel natural products are reported from a variety natural products are reported
from
of marinea variety
sources, of such
marine sources,
as algae, such as bryozoan,
ascidians, algae, ascidians, bryozoan, corals,sea
corals, microorganisms, microorganisms,
hares, sea squirts, sea
hares, sea
sponges, and squirts,
so on sponges,
[18,19]. Since and Alexander
so on [18,19]. Since discovered
Fleming Alexander penicillin
Fleming discovered
in 1928 frompenicillin
Penicilliumin [20],
1928
from Penicillium [20] , people have never stopped discovering new drugs
people have never stopped discovering new drugs from fungi. Fungi is a crucial source as lead structures from fungi. Fungi is a crucial
source
for novelaspharmaceuticals
lead structures for [21].novel
Fungi pharmaceuticals [21]. Fungi
also act as an important also actrole
ecological as aninimportant
the marineecological
environment, role
in theasmarine
such pathogensenvironment,
of marine such as pathogens
invertebrates, of marine
primary invertebrates,
decomposers, andprimary
obligate decomposers,
symbionts [22]. and
obligate symbionts [22] . Especially, marine-derived fungi play a vital
Especially, marine-derived fungi play a vital role in the discovery of new anti-inflammatory drugs. role in the discovery of new
anti-inflammatory
Many novel secondary drugs. Many novel
metabolites showing secondary metabolites showing
potent anti-inflammatory potent
activities haveanti-inflammatory
been discovered
activities have been discovered from fungi residing in or on algae,
from fungi residing in or on algae, sediments, water, and corals. Due to its unique mechanism sediments, water, and corals. Due
of action,
to its unique mechanism of action, marine fungal compounds have
marine fungal compounds have received more and more attention and become one of the hotspot area received more and more attention
andthe
for become one of the
development hotspot area for thedrugs.
of anti-inflammatory development of anti-inflammatory drugs.
This review provides a comprehensive
This review provides a comprehensive overview overviewof of133
133 marine
marine fungi-derived
fungi-derived anti-inflammatory
anti-inflammatory
compounds assorted into five structure types, including alkaloids
compounds assorted into five structure types, including alkaloids (Table 1), terpenoids (Table (Table 1), terpenoids (Table 2), 2),
polyketides(Table
polyketides (Table3), 3),peptides
peptides(Table
(Table4),4),and
andothers
others(Table
(Table5), 5),which
whichshow
showthe theproportion
proportionof ofstructure
structure
types, 16%, 35%, 40%, 5%, and 4%, respectively (Figure 1). A
types, 16%, 35%, 40%, 5%, and 4%, respectively (Figure 1). A large proportion of the secondary large proportion of the secondary
metabolitesproduced
metabolites producedby byAspergillus
Aspergillus(41.4%),
(41.4%),and andPenicillium
Penicillium(27.1%;(27.1%;Figure
Figure2). 2).Some
Someof ofthese
thesenatural
natural
products, such as preussin G (5) and preussin I (7), were shown
products, such as preussin G (5) and preussin I (7), were shown to have remarkable anti-inflammatory to have remarkable anti-
inflammatory activities even stronger than these of the positive control
activities even stronger than these of the positive control [23]. Therefore, these compounds will emerge [23]. Therefore, these
compounds
as will emerge
new lead structures foras new lead
potential structures for potential
anti-inflammatory drugs. anti-inflammatory drugs.
Figure 1. Anti-inflammatory compounds isolated from marine fungi according to structure types.
Figure 1. Anti-inflammatory compounds isolated from marine fungi according to structure types.
Mar. Drugs 2019, 17, 636 3 of 24
Figure 2. The sources of marine fungal compounds with anti-inflammatory activities.

Table 1. Anti-inflammatory alkaloids from marine fungi.
2. Alkaloids
Metabolites Species Activities Reference
The fungus Aspergillus flocculosus 16D-1 was associated with the inner tissue of the sponge
against IL–6 with IC values of
Preussins
Phakellia fuscaC–K (1–9)
colonizing in A.Yongxing 16D-1 China, and produced 50
flocculosus Island, new pyrrolidine [23]
alkaloids,
0.11–22 µM in LPS-activated THP-1
preussins C–I (1–7, Figure 3) and (11R)/(11S)–preussinsagainst J andiNOS
K (8 and
with 9,ICFigure 3) [23]. Compounds
50 values of
5 andAsperversiamides B, C, F,
7 showed remarkable anti-inflammatory activity toward interleukin (IL)–6 production in
A. versicolor 5.39–16.58 µM in LPS-activated [24]
G (10–13)
lipopolysaccharide (LPS)–activated THP-1 cells with IC50 values of 0.11 μM and 0.19 μM, which was
RAW264.7 cells
stronger than that of corylifol A, a positive control against with the NOIC 50 value
with of 0.67
IC50 value of μM, while other
Luteoridepossessed
compounds E (14) moderateA. terreus
inhibitory effects, with24.65
IC50µM in LPS-activated
values in the range of 2.3 to 22 [25]μM [23].
RAW264.7 cells
Chemical examination of the cultured mycelium of the fungus Aspergillus versicolor collected from the
mudChrysamide
of the South China SeaP. led
C (15)
chrysogenum againstnovel
to the isolation of some IL–6 with 40.06%
linearly inhibitory
fused prenylated
[26] indole
alkaloids: asperversiamides B, SCSIO41001
C, F, and G (10–13, Figureat 1.0 µM3). These compounds exerted potential
inducible nitric oxide synthase (iNOS) inhibitory effects against
andNO and PGE2 the
suppressed withrelease
IC50 of nitric oxide
(NO) in LPS-induced RAW264.7 cells. And of these compounds, asperversiamideinG showed a potent
values of 46.03 and 30.37 µM
Viridicaol (16) Penicillium sp. SF-5295 LPS-activated RAW264.7 and 43.03 [27]
inhibitory effect against iNOS with the IC50 value of 5.39 andμM,34.20while
µM inothers exhibited
LPS-activated BV2weak activities
with IC50 values ranging from 9.95 to 16.58 μM. Considering cells the significant inhibitory activity of
asperversiamide B, it can synthesize the potential derivatives against NO with in theIC50development
values of 27 of new anti-
Brevicompanines E, H
inflammatory drugs for the treatment of various related disorders
Penicillium sp. and 45 µg/mL in [24]. A prenylated tryptophan
LPS-activated [28]
(17, 18)
derivative, luteoride E (14, Figure 3) was purified fromRAW264.7 cells
the coral-associated fungus Aspergillus terreus
associated with the coral Sarcophyton subviride, which was gathered
against NO, PGE2,from the coast
iNOS, and of Xisha Island in
Methylpenicinoline
the South China Sea. This Penicillin sp.
(19) compound SF-5995 inhibitory
exhibited COX-2 with ICagainst
activity 50 valuesNO from 34 to
production [29]
with IC50
value of 24.65 μM in LPS-stimulated RAW264.7 cells [25]. 49 µM
significantly affection at
Neocechinulin A (20) Eurotium sp. SF-5989 [30]
concentrations exceeding 25 µM
Figure 3. Chemical structures of compounds 1–14.

Mar. Drugs 2019, 17, 636 4 of 24
Table 2. Anti-inflammatory terpenoids from marine fungi.

against NO with 47.7% and 37.3%
Brasilanones A and E (21, 22) A. terreus CFCC 81836 inhibition rates at 40 µM in [31]
LPS-activated RAW264.7 cells
Dihydrobipolaroxins B−D
against NO with moderate
(23−25) Aspergillus sp. SCSIOW2 [32]
anti-inflammatory effects
Dihydrobipolaroxin (26)
against NO with 22.5% inhibition
Thomimarine E (27) P. thomii KMM 4667 rate at 10.0 µM in LPS-activated [33]
RAW264.7 cells
against NO with IC50 value of
Graphostroma sp. MCCC
Graphostromane F (28) 14.2 µM in LPS-activated RAW264.7 [34]
3A00421
cells
against NO with IC50 values of
Graphostroma sp. MCCC
Khusinol B (29) 17 µM in LPS-activated RAW264.7 [35]
3A00421
cells
1R,6R,7R,10S-10- against NO with Emax values of
hydroxy-4(5)-cadinen- Hypocreales sp. HLS-104 10.22% at 1 µM in LPS-activated [36]
3-one (30) RAW264.7 cells
81% and 57% inhibition rate at 50 µg
Mangicols A and B (31, 32) F. heterosporum CNC-477 per ear in PMA-induced mouse ear [37]
edema assay
Chondroterpenes A, B, H
against NO with considerable
(33–35) Chondrostereum sp.
inhibitory effects at 20 µM in [38]
Hirsutanol A (36) NTOU4196
LPS-activated BV-2 cells
Chondrosterins A, B (37, 38)
against NO with IC50 value of
Lovastatin (39) A. terreus 17.45 µM in LPS-activated [25]
RAW264.7 cells
against IL-6 with 43% and 69%
Aspertetranones A−D (40−43) Aspergillus sp. ZL0-1b14 inhibition rates at 40 µM in [39]
against IL-6 with about 30.0%
Pleosporallins A−C (44−46) Phoma sp. NTOU4195 inhibition rate at 5–20 µg/mL in [40]
7-acetoxydehydroaustinol (47)
Austinolide (48) against NO with IC50 values of 61.0,
7-acetoxydehydroaustin (49) Penicillium sp. SF-5497 30.1, 58.3, 37.6, and 40.2 µM in [41]
11-hydroxyisoaustinone (50) LPS-activated BV-2 cells
11-acetoxyisoaustinone (51)
Citreohybridonol (52) P. atrovenetum anti-neuroinflammatory activity [42]
Tanzawaic acid Q (53) against NO with considerably
Tanzawaic acids A (54), C (55), P. steckii 108YD142 anti-inflammatory activity in [43]
D (56), and K (57) LPS-activated RAW264.7 cells
against NO with IC50 values of 37.8,
2E,4Z-tanzawaic acid D (58)
Penicillium sp. SF-6013 7.1, and 42.5 µM in LPS-activated [44]
Tanzawaicacids A (54), E (59)
RAW264.7 cells
Stachybotrysin C (60), against NO with IC50 values of 27.2,
Stachybonoid F (61), S. chartarum 952 52.5, and 17.9 µM in LPS-activated [45]
Stachybotylactone (62) RAW264.7 cells
Mar. Drugs 2019, 17, 636 5 of 24
Table 3. Anti-inflammatory polyketides from marine fungi.

Versicolactone G (63) against NO with IC50 values of 15.72 and
A. terreus [25]
Territrem A (64) 29.34 µM in LPS-activated RAW264.7 cells
Eurobenzophenone B (65)
66 against NF-κB with significant inhibition
Canthone A (66)
in LPS-activated SW480 cells
3-de-O-methylsulochrin (67) A. europaeus
65, 67, 68, 69, 70 against NF-κB with [46]
Yicathin B (68) WZXY-SX-4-1
inhibition and against NO with weak
Dermolutein (69)
inhibition in LPS-activated SW480 cells
Methylemodin (70)
Violaceol II (71) against NO with weak inhibition in
A. sydowii J05B-7F-4 [47]
Cordyol E (72) LPS-activated RAW264.7 cells
against NO and PGE2 with considerable
TMC-256C1 (73) Aspergillus sp. SF-6354 anti-neuroinflammatory activity in [48]
LPS-activated BV2 cells
Aurasperone F (74)
against COX-2 with IC50 values of 11.1, 4.2,
Aurasperone C (75) A. niger SCSIO Jcsw6F30 [49]
and 6.4 µM in LPS-activated RAW264.7 cells
Asperpyrone A (76)
Diorcinol (77)
Cordyol C (78) Aspergillus sp. SCSIO against the COX-2 expression with IC50
[50]
3,7-dihydroxy-1,9- Ind09F01 values of 2.4−10.6 µM
Dimethyldibenzofuran (79)
Cladosporin 8-O-α-ribofuranoside (80)
Cladosporin (81) Asperentin
Aspergillus sp. SF-5974
6-O-methyl ether (82) Cladosporin against NO and PGE2 with IC50 values of
and Aspergillus sp. [51]
8-O-methyl ether (83) 20−65 µM in LPS-activated microglial cells
SF-5976
40 -hydroxyasperentin (84)
50 -hydroxyasperentin (85)
against NO and PGE2 in LPS-activated
Asperlin (86) Aspergillus sp. SF-5044 [52]
murine macrophages
against NO with 24.1% and 36.6%
Guaiadiol A (87)
P. thomii KMM 4667 inhibition at 10.0 µM in LPS-activated [33]
4,10,11-trihydroxyguaiane (88)
murine macrophages
against NO with IC50 values of 8.1 and
Citrinin H1 (89) Penicillium sp. SF-5629 [53]
8.0 µM in LPS-activated BV2 cells
against NO and PGE2 with IC50 values of
Penicillospirone (90) Penicillium sp. SF-5292 21.9–27.6 µM in LPS-activated RAW264.7 [27]
and BV2 cells
against NO, PGE2 , TNF-α, IL-1β and IL-6
with IC50 values of 20.47, 17.54, 8.63, 11.32,
Penicillinolide A (91) Penicillium sp. SF-5292 [54]
and 20.92 µM in LPS-activated RAW264.7
and BV2 cells
against NO, PGE2 , TNF-α, IL-1β with IC50
values of 12.32, 9.35, 13.54, and 18.32 µM in
Penstyrylpyrone (92) Penicillium sp. JF-55 [55]
LPS-activated murine peritoneal
macrophages
Curvularin (93),
(11R,15S)-11-hydroxycurvularin (94)
(11S,15S)-11-hydroxycurvularin (95)
(11R,15S)-11-methoxycurvularin (96) against NO and PGE2 with IC50 values of
(11S,15S)-11-methoxycurvularin (97) Penicillium sp. SF-5859 1.9–18.1, and 2.8–18.7 µM in LPS-activated [56]
(10E,15S)-10,11-dehydrocurvularin RAW264.7 cells
(98)
(10Z,15S)-10,11-dehydrocurvularin
(99)
against TNF-α and PGE2 in LPS-activated
Pyrenocine A (100) P. paxilli [57]
macrophages
against NO and PGE2 with 4.6% and 55.9%
Asperflavin (101) E. amstelodami inhibition rates to NO and PGE2 at 200 µM [58]
in LPS-activated RAW264.7 cells
against NO and PGE2 with 73.0% and 43.5%
Questinol (102) E. amstelodami inhibition rates at 200 µM against NO and [59]
PGE2
Mar. Drugs 2019, 17, 636 6 of 24
Table 3. Cont.

Flavoglaucin (103) against NO and PGE2 in LPS-activated
Eurotium sp. SF-5989 [60]
Isotecrahydro-auroglaucin (104) RAW264.7 cells
1-(2,5-dihydroxyphenyl)-3-
hydroxybutan-1-one (105) Paraconiothyrium sp.
3.9–12.5 µM in LPS-activated RAW264.7 [61]
1-(2,5-dihydroxyphenyl)-2- VK-13
cells
buten-1-one (106)
against NO with IC50 value of 44.5 µM in
(4R,10S,4’S)-leptothalenone B (107) L. chartarum 3608 [62]
against NO with E max and IC50 value of
Phomaketides A−C (108−110)
Phoma sp. NTOU4195 100% and 8.8 µM in LPS-activated [63]
FR-111142 (111)
RAW264.7 cells
against expression of COX-2 with IC50
values of 3.1, 5.6, 3.0, 5.1, 3.2, and 3.7 µM
Expansols A−F (112−117) Glimastix sp. ZSDS1-F11 [64]
against expression of COX-1 with 5.3, 16.2,
30.2, 41.0, and 56.8 µM
against NO with IC50 values of 30 and
Spicarins C (118) and D (119) S. elegans KLA03 [65]
75 µM in LPS-activated BV2 cells
(R)-5,6-dihydro-6-pentyl-2H- Hypocreales sp. strain against NO with Emax value of 26.46% at
[36]
pyran-2-one (120) HLS-104 1 µM in LPS-activated RAW264.7 cells
against NO and TNF-α, IL-6, and IL-1β in
Mycoepoxydiene (121) Diaporthe sp. HLY-1 [66]
LPS-activated macrophages
Table 4. Anti-inflammatory peptides from marine fungi.

Methyl 3,4,5-trimethoxy-2-
against NO with IC50 value of 5.48 µM
(2-(nicotinamido) A. terreus [25]
in LPS-activated RAW264.7 cells
benzamido)benzoate (122)
against IL-10 expression with inhibitory
Violaceotide A (123)
A. violaceofuscus rate of 84.3% and 78.1% at 10 µM in [67]
Diketopiperazine dimer (124)
LPS-activated THP-1 cells
against NO and PGE2 with IC50 values
Aurantiamide acetate (125) Aspergillus sp. of 49.70 and 51.3 µM in LPS-activated [68]
BV2 cells
(S)-2-(2-hydroxypropanamido) with the swelling rate of 191% at
P. citrinum SYP-F-2720 [69]
Benzoic Acid (126) 100 mg/kg
inhibition rate of 82% at 50 µg per ear in
Oxepinamide A (127) Acremonium sp. [70]
RTX-activated mouse ear edema assay
Alternaramide (128) Alternaria sp. SF-5016 ranging from 27.63 to 40.52 µM in [71]
LPS-activated RAW264.7 and BV2 cells
Table 5. Anti-inflammatory other compounds from marine fungi.

(3E,7E)-4,8-di-methyl-undecane-3,7-
diene-1,11-diol (129)
A. terreus 17.45 and 29.34 µM in LPS-activated [25]
14α-hydroxyergosta-4,7,22-triene-3,6-
RAW264.7 cells
dione (130)
Methyl 8–hydroxy–3-methoxycarbonyl-2-
methylenenonanoate (131) (3S)-Methyl Penicillium sp. against IL-1β with weakly inhibition
[72]
9-hydroxy-3-methoxycarbonyl-2- (J05B-3-F-1) at 200 µM
methylenenonanoate (132)
strong inhibitory effect on nitrite
Trichodermanone C (133) T. citrinoviride levels in LPS-activated J774A.1 [73]
macrophages
Mar. Drugs 2019, 17, 636 7 of 24
2.
2. Alkaloids
Alkaloids
The fungusAspergillus
The fungus Aspergillusflocculosus
flocculosus 16D-1
16D-1 waswas associated
associated with with the tissue
the inner inner oftissue of the Phakellia
the sponge sponge
Phakellia fusca colonizing in Yongxing Island, China, and produced new
fusca colonizing in Yongxing Island, China, and produced new pyrrolidine alkaloids, preussins C–I pyrrolidine alkaloids,
preussins
(1–7, Figure C–I3) (1–7, Figure 3) and (11R)/(11S)–preussins
and (11R)/(11S)–preussins J and K (8 and 9,J andFigure K (8
3)and
[23].9,Compounds
Figure 3) [23]. Compounds
5 and 7 showed
5remarkable
and 7 showed remarkable anti-inflammatory activity toward interleukin
anti-inflammatory activity toward interleukin (IL)–6 production in lipopolysaccharide (IL)–6 production in
lipopolysaccharide
(LPS)–activated THP-1 (LPS)–activated
cells with ICTHP-1 cells with IC50 values of 0.11 μM and 0.19 μM, which was
50 values of 0.11 µM and 0.19 µM, which was stronger than that
stronger
of corylifol A, a positive control with the IC50control
than that of corylifol A, a positive value ofwith0.67 the
µM,IC 50 value
while of compounds
other 0.67 μM, while other
possessed
compounds possessed moderate inhibitory effects, with IC 50 values in the range
moderate inhibitory effects, with IC50 values in the range of 2.3 to 22 µM [23]. Chemical examination of 2.3 to 22 μM [23].
Chemical examination
of the cultured mycelium of the cultured
of the fungusmycelium
Aspergillusofversicolor
the fungus Aspergillus
collected from versicolor
the mud of collected
the South from the
China
mud of the South China Sea led to the isolation of some novel linearly fused
Sea led to the isolation of some novel linearly fused prenylated indole alkaloids: asperversiamides B, C, prenylated indole
alkaloids: asperversiamides
F, and G (10–13, Figure 3). TheseB, C,compounds
F, and G (10–13,
exerted Figure
potential 3).inducible
These compounds
nitric oxideexerted
synthase potential
(iNOS)
inducible
inhibitory effects and suppressed the release of nitric oxide (NO) in LPS-induced RAW264.7 cells.oxide
nitric oxide synthase (iNOS) inhibitory effects and suppressed the release of nitric And
(NO) in LPS-induced
of these RAW264.7 cells. G
compounds, asperversiamide And of these
showed compounds,
a potent inhibitoryasperversiamide G showed
effect against iNOS with athepotent
IC50
inhibitory
value of 5.39effect
µM,against iNOSexhibited
while others with the weak
IC50 value of 5.39
activities withμM,IC50while
valuesothers exhibited
ranging from 9.95weak activities
to 16.58 µM.
with IC 50 values ranging from 9.95 to 16.58 μM. Considering the significant inhibitory activity of
Considering the significant inhibitory activity of asperversiamide B, it can synthesize the potential
asperversiamide
derivatives in theB, it can synthesize
development of new the potential derivatives
anti-inflammatory drugs for in the
the treatment
development of new
of various anti-
related
inflammatory
disorders [24]. drugs for the treatment
A prenylated tryptophanofderivative,
various related disorders
luteoride [24]. A3)prenylated
E (14, Figure was purified tryptophan
from the
derivative, luteoride E (14, Figure 3) was purified from the coral-associated
coral-associated fungus Aspergillus terreus associated with the coral Sarcophyton subviride, which fungus Aspergillus terreus
was
associated with the coral Sarcophyton subviride, which was gathered from the
gathered from the coast of Xisha Island in the South China Sea. This compound exhibited inhibitory coast of Xisha Island in
the South
activity ChinaNO
against Sea.production
This compound
with ICexhibited inhibitory activity against NO production with IC50
50 value of 24.65 µM in LPS-stimulated RAW264.7 cells [25].
value of 24.65 μM in LPS-stimulated RAW264.7 cells [25].
Figure 3.
Figure Chemical structures
3. Chemical structures of
of compounds
compounds 1–14.
1–14.
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 IC50 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 E2
(PGE2 ) with an IC50 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
Mar. Drugs 2019, 17, 636 8 of 24
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 IC50 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 PGE2 production by attenuating iNOS and COX-2 expression,
respectively, in LPS-stimulated RAW264.7 macrophages and BV2 microglia with the IC50 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
PGE2 , 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
Mar. Drugs 2019, 17,RAW264.7
x FOR PEER macrophages
REVIEW and BV2 microglia [30]. 5 of 24
Figure
Figure 4. Chemical structures
of compounds
compounds 15–20.
15–20.
3. Terpenoids
Table 1. Anti-inflammatory alkaloids from marine fungi.
Two novel brasilane sesquiterpenoids, brasilanones A and E (21, 22, Figure 5), were separated
from the extract of the marine-derived
A. flocculosus fungus A. terreus
against IL–6 with IC50CFCC
values of81836,
0.11–22which
μM in displayed moderate
Preussins C–K (1–9) [23]
inhibitory activities against16D-1
NO production with inhibition
LPS-activated THP-1 rates of 47.7% and 37.3% at 40 µM in
RAW264.7Asperversiamides B,
mouse macrophages induced against
by iNOS[31].
LPS with ICLiyan
50 values of 5.39–16.58
Wang et al.μM
firstly reported three
A. versicolor [24]
C, F, G (10–13) in LPS-activated RAW264.7 cells
new eremophilane-type sesquiterpenoids of dihydrobipolaroxin B–D (23–25, Figure 5) and a known
against NO with IC50 value of 24.65 μM in LPS-
sesquiterpene
LuteorideofE dihydrobipolaroxin
(14) A. terreus (26,activated
FigureRAW264.7
5). These compounds were isolated
cells
[25] from a deep
sea-derived fungus, Aspergillus sp. SCSIOW2,
P. chrysogenum from a deep marine sediment sample gathered from the
Chrysamide C (15) against IL–6 with 40.06% inhibitory at 1.0 μM [26]
SCSIO41001
against NO and PGE2 with IC50 values of 46.03
Penicillium sp.
Viridicaol (16) and 30.37 μM in LPS-activated RAW264.7 and [27]
SF-5295
43.03 and 34.20 μM in LPS-activated BV2 cells
Brevicompanines E, against NO with IC50 values of 27 and 45 μg/mL
Penicillium sp. [28]
H (17, 18) in LPS-activated RAW264.7 cells
Mar. Drugs 2019, 17, 636 9 of 24
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
Mar. Drugs 2019, effects
17, x FOR PEER [32].
REVIEW 6 of 24
Figure
of compounds
compounds 21–26.
21–26.
Thomimarine E (27, Figure 6) was a new eudesmane-type sesquiterpene that was obtained from
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
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%
effect and inhibited the production of NO in LPS-stimulated RAW264.7 cells with inhibition rate of
± 5.1% at the concentration of 10.0 µM [33]. Graphostroma sp. MCCC 3A00421 isolated from Atlantic
22.5% ± 5.1% at the concentration of 10.0 μM [33]. Graphostroma sp. MCCC 3A00421 isolated from
Ocean hydrothermal sulfide deposit at a depth of 2721 m produced a new guaiane, graphostromane F
Atlantic Ocean hydrothermal sulfide deposit at a depth of 2721 m produced a new guaiane,
(28, Figure 6) [34]. Graphostromane F (28) exhibited considerable inhibitory activity by inhibiting the
graphostromane F (28, Figure 6) [34]. Graphostromane F (28) exhibited considerable inhibitory
release of NO in RAW264.7 macrophages induced by LPS with an IC50 value of 14.2 µM, which was even
activity by inhibiting the release of NO in RAW264.7 macrophages induced by LPS with an IC50 value
lower than the aminoguanidine as positive control with an IC50 value of 23.4 µM [34]. Another study
of 14.2 μM, which was even lower than the aminoguanidine as positive control with an IC50 value of
on the same Graphostroma sp. MCCC 3A00421 resulted in the discovery of a novel fungal sesquiterpene,
23.4 μM [34]. Another study on the same Graphostroma sp. MCCC 3A00421 resulted in the discovery
khusinol B (29, Figure 6) [35]. Khusinol B (29) was found considerable anti-inflammatory activity
of a novel fungal sesquiterpene, khusinol B (29, Figure 6) [35]. Khusinol B (29) was found considerable
in LPS-induced RAW264.7 cells against NO production with IC50 value of 17 µM, which was even
anti-inflammatory activity in LPS-induced RAW264.7 cells against NO production with IC50 value of
stronger than that of the positive control with the IC50 value was 23 µM [35]. Chemical study of the
17 μM, which was even stronger than that of the positive control with the IC50 value was 23 μM [35].
sea-derived fungus Hypocreales sp. strain HLS-104, which was isolated from a sponge Gelliodes carnosa
Chemical study of the sea-derived fungus Hypocreales sp. strain HLS-104, which was isolated from a
colonizing in the South China Sea afforded a derivative, 1R,6R,7R,10S-10-hydroxy-4(5)-cadinen-3-one
sponge Gelliodes carnosa colonizing in the South China Sea afforded a derivative, 1R,6R,7R,10S-10-
(30, Figure 6) with moderate anti-inflammatory activity [36]. The average maximum inhibition (Emax )
hydroxy-4(5)-cadinen-3-one (30, Figure 6) with moderate anti-inflammatory activity [36]. The
values of this molecule against the production of the NO in LPS-treated RAW264.7 cells was 10.22%
average maximum inhibition (Emax) values of this molecule against the production of the NO in LPS-
at the concentration of 1 µM [36]. William Fenical et al., isolated mangicols A and B (31 and 32,
treated RAW264.7 cells was 10.22% at the concentration of 1 μM [36]. William Fenical et al., isolated
Figure 6) from a marine fungus, Fusarium heterosporum CNC-477, which was separated from a driftwood
mangicols A and B (31 and 32, Figure 6) from a marine fungus, Fusarium heterosporum CNC-477,
sample collected from Sweetings Cay mangrove habitat, Bahamas [37]. Mangicols A and B were novel
which was separated from a driftwood sample collected from Sweetings Cay mangrove habitat,
sesterterpene polyols that exhibited considerable anti-inflammatory effects in the phorbol myristate
Bahamas [37]. Mangicols A and B were novel sesterterpene polyols that exhibited considerable anti-
acetate (PMA)-induced mouse ear edema assay with the reduction of 81% and 57%, respectively, at the
inflammatory effects in the phorbol myristate acetate (PMA)-induced mouse ear edema assay with
standard of 50of
the reduction per and
µg81% ear which were similar at
57%, respectively, to the
those of indomethacin,
standard theear
of 50 μg per positive
whichcontrol, with the
were similar to
reduction of 71% [37].
those of indomethacin, the positive control, with the reduction of 71% [37].
Mar. Drugs 2019, 17, 636 10 of 24
Mar. Drugs
Mar. Drugs 2019,
2019, 17,
17, xx FOR
FOR PEER
PEER REVIEW
REVIEW 77 of
of 24
24
Figure 6. Chemical structures of compounds 27–32.

Figure 6.
Figure 6. Chemical
Chemical structures
structures of
of compounds 27––32.
compounds 27 32.
George Hsiao et al. reported the isolation of eight novel hirsutane-type sesquiterpenoids along
George Hsiao
Hsiao et al.
al. reported
reported the
the isolation
isolation of
of eight
eight novel
novel hirsutane-type sesquiterpenoids
sesquiterpenoids along
along
with George
seven known et derivatives from the EtOAc extract of the hirsutane-type
fermented broth of Chondrostereum sp.
with seven known
with seven known derivatives from the EtOAc extract of the fermented broth of Chondrostereum sp.
NTOU4196, a fungalderivatives fromfrom
strain isolated the EtOAc extract
the marine red of thePterocladiella
alga fermented broth of Chondrostereum
capillacea, sp.
collected from the
NTOU4196, aa fungal
NTOU4196, fungal strain
strain isolated
isolated from
from the
the marine
marine red
red alga
alga Pterocladiella
Pterocladiella capillacea,
capillacea, collected
collected from
from
northeast and north intertidal zone of Taiwan [38]. Among them, chondroterpenes A, B, H (33–35,
the northeast
the northeast and north intertidal zone of Taiwan [38]. Among them, chondroterpenes A, B, H (33–
Figure 7) andand north intertidal
hirsutanol zone of
A (36, Figure 7),Taiwan [38]. Among
chondrosterins A andthem, chondroterpenes
B (37 and 38, FigureA,7)B,showed
H (33–
35, Figure
35, Figure 7) and hirsutanol
7) and hirsutanol A (36,
A (36, Figure 7), chondrosterins A and B (37 and 38, Figure 7) showed
strong anti-inflammatory effects andFigure 7), chondrosterins
possessed the expressionAofand NOBin(37 and 38,
murine Figure
BV-2 7) showed
microglial cells
strong anti-inflammatory
strong anti-inflammatory effects and
effects and ofpossessed
possessed the expression of NO in murine BV-2 microglial
the expression of NO in murine BV-2 microglial cells cells
stimulated by LPS at a concentration 20 µM [38].
stimulated by LPS at a concentration of 20
stimulated by LPS at a concentration of 20 μM [38].μM [38].
Figure 7.
Figure Chemical structures
of compounds 33––38.
compounds 33 38.
33–38.
Lovastatin (39,(39, Figure

Figure8)8)waswaspurified
purified from
from thethe coral-associated
coral-associated fungus
fungus A. terreus
A. terreus
terreus associated
associated with
Lovastatin (39, Figure 8) was purified from the coral-associated fungus A. associated with
with
the the coral
coral S. S. subviride,
subviride, collected
collected from from
the the coast
coast of of Xisha
Xisha Islandininthe
Island theSouth
South China
China SeaSea [25]. This
This
the coral S. subviride, collected from the coast of Xisha Island in the South China Sea [25]. This
compound
compound showedshowed inhibitory
showed inhibitory activity
inhibitory activity on
activity onthe NO
on the production
the NONO production with
production withIC value
with
50 IC50of 17.45 µM in RAW264.7
50 value of 17.45 μM in
compound IC value of 17.45 μM in
cells stimulated
RAW264.7 cells by LPS [25]. by
stimulated A sea
LPS green
[25].algal
A species
sea green Enteromorpha
algal species collected in Dongshi
Enteromorpha salt in
collected pan, Fujian
Dongshi
RAW264.7 cells stimulated by LPS [25]. A sea green algal species Enteromorpha collected in Dongshi
Province,
salt pan, China, Province,
Fujian resulted inChina,
the isolation
resultedof ainfungus
the Aspergillus
isolation of a sp. ZL0-1b14
fungus [39]. The
Aspergillus sp. fungus
ZL0-1b14extracts
[39].
salt pan, Fujian Province, China, resulted in the isolation of a fungus Aspergillus sp. ZL0-1b14 [39].
displaying
The fungus anti-inflammatory
fungus extracts
extracts displaying activities was
displaying anti-inflammatory chemically
anti-inflammatory activities analyzed,
activities was which
was chemicallyled to the
chemically analyzed,isolation
analyzed, which of a family
which ledled to
to
The
group
the of new of
isolation triketide-sesquiterpenoid
a family group of new meroterpenoids, aspertetranones
triketide-sesquiterpenoid A−D (40−43,
meroterpenoids, Figure 8) [39].
aspertetranones
the isolation of a family group of new triketide-sesquiterpenoid meroterpenoids, aspertetranones
Aspertetranones
A−D (40−43,
(40−43, Figure
FigureA−D 8) showed different anti-inflammatory
[39]. Aspertetranones
Aspertetranones showed activities.
A−D showed Notably, aspertetranones
different anti-inflammatory
anti-inflammatory A
activities.
A−D 8) [39]. A−D different activities.
and D exhibited
Notably, the suppress
aspertetranones A andpotency
and against
D exhibited
exhibited the
the production
suppress of IL-6
potency in LPS-stimulated
against productionRAW264.7
the production of IL-6
IL-6 in
in
Notably, aspertetranones A D the suppress potency against the of
macrophages
LPS-stimulated with 43% and 69%
RAW264.7 inhibition with
macrophages at 40 µM43% [39].
and Chemical
69% investigation
inhibition at 40 of
μM a marine-derived
[39]. Chemical
LPS-stimulated RAW264.7 macrophages with 43% and 69% inhibition at 40 μM [39]. Chemical
fungus, Pleosporales
investigation sp. strain derived
of aa marine-derived
marine-derived from a Pleosporales
fungus, marine alga sp. Enteromorpha
strain derived clathrate
derived fromcollected fromalga
the
investigation of fungus, Pleosporales sp. strain from aa marine
marine alga
South China Sea
Enteromorpha in Hainan
clathrate Province,
collected from the yielded
the SouththreeChina newSeacompounds,
in Hainan pleosporallins
Hainan Province,
Province, yieldedA−C (44−46,
three new
Enteromorpha clathrate collected from South China Sea in yielded three new
Figure 8) [40].pleosporallins
compounds, They possessed moderate
A−C (44−46, inhibitory
Figure 8) activities
[40]. They against
possessedthe production
moderate of proinflammatory
inhibitory activities
compounds, pleosporallins A−C (44−46, Figure 8) [40]. They possessed moderate inhibitory activities
cytokine
against the IL-6
the in LPS-stimulated
production RAW264.7cytokine
of proinflammatory
proinflammatory macrophages incells
IL-6 in with the inhibition
LPS-stimulated RAW264.7 ratemacrophages
about 30.0%
against production of cytokine IL-6 LPS-stimulated RAW264.7 macrophages
compared
cells with
cells to
thecontrol
with the at the
inhibition
inhibition concentration
rate
rate about 30.0%
about 30.0% ofcompared
5−20 µg/mL
compared to [40].
to control at
control at the
the concentration
concentration of of 5−20
5−20 μg/mL
μg/mL
[40].
[40].
Mar. Drugs 2019, 17, 636 11 of 24
Figure 8. Chemical structures of compounds 39−46.

Jin-Soo Park et al. separated two novel meroterpenoid-type metabolites along with eight known
Jin-Soo Park et al. separated two novel meroterpenoid-type metabolites along with eight known
analogs fromPark
Jin-Soo the ethyl
et al. acetate
separatedextract
two of a marine-derived
novel meroterpenoid-type strain Penicillium
fungal metabolites alongsp. SF-5497,
with which
eight known
analogs from the ethyl acetate extract of a marine-derived fungal strain Penicillium sp. SF-5497, which
was isolated
analogs from from a sample
the ethyl acetateof sea sand
extract collected from Gijiang-gun,
of a marine-derived Busan [41].sp.All
fungal strain Penicillium the isolated
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
was isolated from a sample of sea sand collected from Gijiang-gun, Busan [41]. All the isolated in microglial BV-2
metabolites were evaluated for anti-inflammatory activities against NO production in microglial BV-
cells challenged
metabolites werebyevaluated
LPS, onlyfor 7-acetoxydehydroaustinol
anti-inflammatory activities (47, against
Figure 9),
NOand four otherinknown
production analogs
microglial BV-
2 cells challenged by LPS, only 7-acetoxydehydroaustinol (47, Figure 9), and four other known
austinolide (48, Figure
2 cells challenged by 9), 7-acetoxydehydroaustin
LPS, (49, Figure 9),
only 7-acetoxydehydroaustinol 11-hydroxyisoaustinone
(47, Figure 9), and four other(50, Figure
known9),
analogs austinolide (48, Figure 9), 7-acetoxydehydroaustin (49, Figure 9), 11-hydroxyisoaustinone
and 11-acetoxyisoaustinone (51, Figure 9), were shown to have weak inhibitory effects
analogs austinolide (48, Figure 9), 7-acetoxydehydroaustin (49, Figure 9), 11-hydroxyisoaustinone with IC 50 values
(50, Figure 9), and 11-acetoxyisoaustinone (51, Figure 9), were shown to have weak inhibitory effects
of 61.0,
(50, 30.1,9),
Figure 58.3,
and37.6, and 40.2 µM, respectively
11-acetoxyisoaustinone [41]. The
(51, Figure marine
9), were fungus
shown Penicillium
to have atrovenetum
weak inhibitory was
effects
with IC50 values of 61.0, 30.1, 58.3, 37.6, and 40.2 μM, respectively [41]. The marine fungus Penicillium
shown
with ICto produce
50 values ofan undescribed
61.0, 30.1, 58.3, meroterpenoid,
37.6, and 40.2 μM,citreohybridonol (52, The
respectively [41]. Figure 9) [42].
marine This compound
fungus Penicillium
atrovenetum was shown to produce an undescribed meroterpenoid, citreohybridonol (52, Figure 9)
was found towas
atrovenetum have anti-neuroinflammatory
shown activity [42].
to produce an undescribed meroterpenoid, citreohybridonol (52, Figure 9)
[42]. This compound was found to have anti-neuroinflammatory activity [42].

Figure 9. structures of
of compounds
compounds 47−52.
47−52.
A new tanzawaic acid derivative, tanzawaic acid Q (53, Figure 10), together with four known
AA new
new tanzawaic
tanzawaic acid
acid derivative,
derivative, tanzawaic
tanzawaic acidacid QQ (53,
(53, Figure
Figure 10),
10), together
together with
with four
four known
known
analogues, tanzawaic acids A (54, Figure 10), C (55, Figure 10), D (56, Figure 10), and K (57, Figure
analogues, tanzawaic acids A (54, Figure 10), C (55, Figure 10), D (56, Figure 10), and
analogues, tanzawaic acids A (54, Figure 10), C (55, Figure 10), D (56, Figure 10), and K (57, Figure K (57, Figure 10),
10), have been isolated from a marine-derived fungus, Penicillium steckii 108YD142, residing in a
have been isolated from a marine-derived fungus, Penicillium steckii 108YD142,
10), have been isolated from a marine-derived fungus, Penicillium steckii 108YD142, residing in a residing in a marine
marine sponge sample collected at Wangdolcho, in the Republic of Korea’s Eastern reef [43]. These
sponge
marine sample
spongecollected at Wangdolcho,
sample collected in the Republic
at Wangdolcho, in theofRepublic
Korea’s Eastern
of Korea’sreefEastern
[43]. These
reefcompounds
[43]. These
compounds considerably inhibited LPS-stimulated NO production in RAW264.7 macrophages cells.
considerably inhibited LPS-stimulated NO production in RAW264.7
compounds considerably inhibited LPS-stimulated NO production in RAW264.7 macrophages macrophages cells. Moreover,
cells.
Moreover, tanzawaic acid Q reduced the expression of pro-inflammatory mediators such as COX-2
tanzawaic
Moreover, tanzawaic acid Q reduced the expression of pro-inflammatory mediators such iNOS
acid Q reduced the expression of pro-inflammatory mediators such as COX-2 and and
as COX-2
and iNOS and also possessed the production of PGE2, TNF-α, and IL-1β mRNA protein [43]. Marine-
also
and possessed
iNOS and the alsoproduction
possessed theof PGE 2 , TNF-α,ofand
production PGE IL-1β mRNA
2, TNF-α, and protein [43]. Marine-derived
IL-1β mRNA fungus
protein [43]. Marine-
derived fungus Penicillium sp. SF-6013 derived from the sea urchin Brisaster latifrons collected from
Penicillium sp. SF-6013 derived from the sea urchin Brisaster latifrons collected from
derived fungus Penicillium sp. SF-6013 derived from the sea urchin Brisaster latifrons collected from the Sea of Okhotsk,
the Sea of Okhotsk, was shown to produce a new tanzawaic acid derivative, 2E,4Z-tanzawaic acid D
was shown
the Sea to produce
of Okhotsk, wasa new
shown tanzawaic
to produce acidaderivative, 2E,4Z-tanzawaic
new tanzawaic acid derivative,acid2E,4Z-tanzawaic
D (58, Figure 10),acidalongD
(58, Figure 10), along with two known analogues, tanzawaic acids A (54) and E (59, Figure 10). These
(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
three tanzawaic acids inhibited the overproduction of NO in BV-2 microglial cells activated by LPS
Mar. Drugs 2019, 17, 636 12 of 24
Mar. Drugs
with
with two 2019,
IC50known 17, xanalogues,
values FOR
of PEER7.1,
37.8, REVIEW
and 42.5acids
tanzawaic μM, Arespectively [44].Figure
(54) and E (59, Furthermore,
10). Thesetanzawaic 9 also
of 24
acid Aacids
three tanzawaic
inhibited the
inhibited the overproduction
NO production of and
NOreduced
in BV-2the expression
microglial ofactivated
cells iNOS andbyCOX-2 in RAW264.7
LPS with IC50 valuesand BV2
of 37.8,
with IC
cellsand 50 values of 37.8, 7.1, and 42.5 μM, respectively [44]. Furthermore, tanzawaic acid A also
stimulated
7.1, 42.5 µM,by LPS [44]. [44]. Furthermore, tanzawaic acid A also inhibited the NO production
respectively
inhibited the NO production and reduced the expression of iNOS and COX-2 in RAW264.7 and BV2
and reduced the expression of iNOS and COX-2 in RAW264.7 and BV2 cells stimulated by LPS [44].
cells stimulated by LPS [44].

Three meroterpenoids, Figure 10. Chemical
named structures of
as stachybotrysin C compounds
(60, Figure 53−59.
11), stachybonoid F (61, Figure
11), and stachybotylactone
Three (62, Figure
meroterpenoids, named 11) were obtained
as stachybotrysin from Stachybotrys
C (60, Figure chartarum
11), stachybonoid 952
F (61, isolated
Figure 11),
Three meroterpenoids,
fromstachybotylactone
a marine crinoid(62, named as stachybotrysin
(Himerometra magnipinna) C (60, Figure 11),60,stachybonoid F moderately
(61, Figure
and Figure 11) were obtained[45].
fromCompounds 61, and
Stachybotrys chartarum 95262isolated from
11), and stachybotylactone (62, Figure 11) were obtained from Stachybotrys chartarum 95252.5,
isolated
asuppressed the production
marine crinoid (Himerometraof NO (the pro-inflammatory
magnipinna) [45]. Compounds mediator)
60, 61,with
andIC values of 27.2,
6250moderately suppressed and
from a marine crinoid (Himerometra magnipinna) [45]. Compounds 60, 61, and 62 moderately
the μM in RAW264.7
17.9production of NO (the pro-inflammatory
macrophages mediator)
stimulated by LPS with
[45]. IC50 values of 27.2, 52.5, and 17.9 µM in
suppressed the production of NO (the pro-inflammatory mediator) with IC50 values of 27.2, 52.5, and
RAW264.7 macrophages stimulated by LPS [45].
17.9 μM in RAW264.7 macrophages stimulated by LPS [45].
Figure 11.
structures of
of compounds
compounds 60−62.
60−62.
4. Polyketides Figure
Table 11. Chemical structures
2. Anti-inflammatory of compounds
terpenoids 60−62.
from marine fungi.
A detailed chemical investigation
Metabolites Activities fungus A. terreus, cultured
of a coral-associated from the coral S.
Table 2.Species
Anti-inflammatory terpenoids from marine fungi. Reference
subviride collected from the coast of Xisha Island in the NO
against SouthwithChina
47.7% andSea, resulted in the isolation of
37.3%
Brasilanones A and E A. terreus CFCC
Metabolites
one unusual Species
metabolite, versicolactone G (63, Figure inhibition
Activities rates atwith
12), along 40 μM a in LPS- analog,
known [31]
Reference
territrem A (64,
(21, 22) 81836
activated
against NO RAW264.7
with 47.7% cells
and 37.3%
Figure 12)Brasilanones
[25]. TheyAwere and E shown to potent
A. terreus CFCC anti-inflammatory activity with IC50 values of 15.72 and
Dihydrobipolaroxins inhibition rates at 40 μM in LPS- [31]
(21, 22) 81836 Aspergillus
29.34 µM,B−D
respectively,
(23−25) against LPS-induced
Aspergillus sp. NO production
against
activatedNO [25].
with
RAW264.7 cells anti- europaeus WZXY-SX-4-1
moderate
[32]
was foundDihydrobipolaroxin
in the marine spongeSCSIOW2
Dihydrobipolaroxins Xestospongia testudinaria, and produced
inflammatory effects two new polyketide derivatives,
(26)
B−D (23−25) B (65, Figure
eurobenzophenone Aspergillus sp.
12), xanthone against
A (66, NO with
Figure 12),moderate
along withanti- four known compounds,
[32]
Dihydrobipolaroxin SCSIOW2 against NO with
inflammatory 22.5% inhibition
effects
3-de-O-methylsulochrin (67, Figure 12), yicathin B (68, Figure 12), dermolutein (69, Figure 12), and
Thomimarine
(26) E (27) P. thomii KMM 4667 rate at 10.0 μM in LPS-activated [33]
methylemodin (70, Figure 12) [46]. 3-de-O-methylsulochrin RAW264.7 showed the significant inhibition against
against NOcells
with 22.5% inhibition
NF-κB pathway
Thomimarinein LPS-stimulated
Graphostromane F
E (27) P. thomiiSW480
Graphostroma
KMM cells [46].
sp.4667 against Eurobenzophenone
NOμM
rate at 10.0 withinIC 50 value of 14.2
LPS-activated B, xanthone
[33] A, yicathin
[34]
(28)
B, dermolutein, and methylemodin MCCC 3A00421
showed to inhibitμM in LPS-activated
RAW264.7NF-κB RAW264.7
cells pathway andcells
weakly suppressed the
expressionGraphostromane
of NOBin F Graphostroma
LPS-stimulated SW480 sp. cells [46].
against NO with IC50 values
value ofof14.2
17
Khusinol (29) [35]
[34]
(28) MCCC 3A00421 μM in LPS-activated RAW264.7 cells
1R,6R,7R,10S-10- Graphostroma sp. against NO with E ICmax
50 values of 17
Khusinol B (29) Hypocreales sp. HLS- [35]
hydroxy-4(5)-cadinen- MCCC 3A00421 10.22% at 1 μM in LPS-activated
μM in LPS-activated RAW264.7 cells [36]
104
3-one (30)
1R,6R,7R,10S-10- RAW264.7
against NOcells
with Emax values of
Hypocreales sp. HLS-
hydroxy-4(5)-cadinen- 81% andat57%
10.22% 1 μMinhibition rate at 50 μg
in LPS-activated [36]
Mangicols A and B F.
104heterosporum
3-one (30) per ear in PMA-induced
RAW264.7 cells mouse ear [37]
(31, 32) CNC-477
edema
81% andassay
57% inhibition rate at 50 μg
Mangicols A and B F. heterosporum
per ear in PMA-induced mouse ear [37]
(31, 32) CNC-477
edema assay
Mar. Drugs 2019, 17, 636 13 of 24
Figure
of compounds
compounds 63−70.
63−70.
In order to search for bioactive secondary metabolites from marine fungi, Sen Liu et al. isolated
In order to search for bioactive secondary metabolites from marine fungi, Sen Liu et al. isolated
two new metabolites
In order together
to search with sixsecondary
for bioactive diphenylethers, a diketopiperazine,
metabolites from marine fungi,a chromone,
Sen Liu and
et aal.xanthone
isolated
two new metabolites together with six diphenylethers, a diketopiperazine, a chromone, and a
from
two newan EtOAc extract of
metabolites together withAspergillus
the fungus sydowii J05B-7F-4
six diphenylethers, associated witha the
a diketopiperazine, marine sponge
chromone, and a
xanthone from an EtOAc extract of the fungus Aspergillus sydowii J05B-7F-4 associated with the
Stelletta
xanthone sp.from
[47]. an
Among
EtOAc them, only of
extract violaceol II (71,Aspergillus
the fungus Figure 13) and cordyol
sydowii E (72, Figure
J05B-7F-4 13) displayed
associated with the
marine sponge Stelletta sp. [47]. Among them, only violaceol II (71, Figure 13) and cordyol E (72,
weak
marine inhibitory effect against
sponge Stelletta LPS-induced
sp. [47]. Among them, NO production in RAW264.7
only violaceol cells 13)
II (71, Figure [47].and
A marine
cordyolfungus,
E (72,
Figure 13) displayed weak inhibitory effect against LPS-induced NO production in RAW264.7 cells
identified Aspergillusweak
Figure 13)asdisplayed sp. SF-6354,
inhibitorywaseffect
found to produce
against TMC-256C1
LPS-induced NO(73, Figure 10)in[48].
production TMC-256C1
RAW264.7 cells
[47]. A marine fungus, identified as Aspergillus sp. SF-6354, was found to produce TMC-256C1 (73,
showed considerable
[47]. A marine anti-neuroinflammatory
fungus, identified as Aspergillus activity toward the
sp. SF-6354, wasmRNA
foundexpression
to produce ofTMC-256C1
TNF-α, IL-6 and (73,
Figure 10) [48]. TMC-256C1 showed considerable anti-neuroinflammatory activity toward the mRNA
IL-12
Figure production in LPS-activated
10) [48]. TMC-256C1 showed BV2 cells. This compound
considerable also suppressedactivity
anti-neuroinflammatory NO andtoward
PGE2 production
the mRNA
expression of TNF-α, IL-6 and IL-12 production in LPS-activated BV2 cells. This compound also
in LPS-activated
expression BV2 cells
of TNF-α, IL-6byandthe IL-12
suppression of iNOS
production in and COX-2 protein
LPS-activated BV2 expression
cells. This [48]. The surface
compound also
suppressed NO and PGE2 production in LPS-activated BV2 cells by the suppression of iNOS and
of a marine algae
suppressed NO and Sargassum sp. from theinYongxing
PGE2 production Island,BV2
LPS-activated South China
cells by Sea, provided Aspergillus
the suppression of iNOSniger and
COX-2 protein expression [48]. The surface of a marine algae Sargassum sp. from the Yongxing Island,
COX-2Jcsw6F30,
SCSIO protein expression [48]. The
which produced surface
three of a marine algae
asperpyrone-type Sargassum sp. from the
bis-naphtho-γ-pyrones Yongxing
(BNPs): Island,
aurasperone
South China Sea, provided Aspergillus niger SCSIO Jcsw6F30, which produced three asperpyrone-
FSouth China Sea,
(74, Figure 13), provided
aurasperone Aspergillus niger SCSIO
C (75, Figure Jcsw6F30,
13), and whichAproduced
asperpyrone (76, Figure three
13)asperpyrone-
[49]. These
type bis-naphtho-γ-pyrones (BNPs): aurasperone F (74, Figure 13), aurasperone C (75, Figure 13), and
type bis-naphtho-γ-pyrones
compounds possessed significant(BNPs): aurasperone F (74,
anti-inflammatory Figure
potency 13), aurasperone
through down-regulate C (75, Figure
the 13), and
expression of
asperpyrone A (76, Figure 13) [49]. These compounds possessed significant anti-inflammatory
asperpyrone
the COX-2 protein A (76, Figure 13) [49].
in LPS-activated These compounds
RAW264.7 macrophagespossessed significant
with IC50 values anti-inflammatory
of 11.1, 4.2, and 6.4 µM,
potency through down-regulate the expression of the COX-2 protein in LPS-activated RAW264.7
potency through
respectively [49]. down-regulate the expression of the COX-2 protein in LPS-activated RAW264.7
macrophages with IC50 values of 11.1, 4.2, and 6.4 μM, respectively [49].

Figure 13. Chemical
structures of
of compounds
compounds 71−76.
71−76.
Two new compounds together with 10 known compounds were detected in the EtOAc extract
of the fungal strain Aspergillus sp. SCSIO Ind09F01, which was isolated from the deep-sea sediment
of the fungal strain Aspergillus sp. SCSIO Ind09F01, which was isolated from the deep-sea sediment
sample of Indian Ocean [50]. Among them, only three known compounds, diorcinol (77, Figure 14),
Mar. Drugs 2019, 17, 636 14 of 24
Mar. Drugs
of the 2019, strain
fungal 17, x FOR PEER REVIEW
Aspergillus sp. SCSIO Ind09F01, which was isolated from the deep-sea sediment12 of 24
cordyol
cordyol CC (78,
(78, Figure
Figure 14),
14), and
and 3,7-dihydroxy-1,9-dimethyldibenzofuran
3,7-dihydroxy-1,9-dimethyldibenzofuran (79, (79, Figure
Figure 14)
14) possessed
possessed the
the
inhibitory effects on the expression of COX-2 with the IC50 values from 2.4 to 10.6 μM [50]. Dong-
inhibitory effects on the expression of COX-2 with the IC50 values from 2.4 to 10.6 µM [50]. Dong-Cheol
Cheol
Kim etKimal. et al. isolated
isolated a newa dihydroisocoumarin
new dihydroisocoumarin derivative,
derivative, cladosporin
cladosporin 8-O-α-ribofuranoside
8-O-α-ribofuranoside (80,
(80, Figure 14), along with five known metabolites, cladosporin (81, Figure 14), asperentin 6-O-methyl
Figure 14), along with five known metabolites, cladosporin (81, Figure 14), asperentin 6-O-methyl ether
ether (82, Figure 14), cladosporin 8-O-methyl ether (83, Figure 14), 4′-hydroxyasperentin (84, Figure
(82, Figure 14), cladosporin 8-O-methyl ether (83, Figure 14), 40 -hydroxyasperentin (84, Figure 14), and
14), and 5′-hydroxyasperentin (85, Figure 14) from the EtOAc extracts of marine-derived fungus
50 -hydroxyasperentin (85, Figure 14) from the EtOAc extracts of marine-derived fungus Aspergillus sp.
Aspergillus sp. SF-5974 and Aspergillus sp. SF-5976, obtained from an unidentified red macroalgae
SF-5974 and Aspergillus sp. SF-5976, obtained from an unidentified red macroalgae collected using a
collected using a dredge at a depth of 300 m at the Ross Sea [51]. These compounds showed to inhibit
dredge at a depth of 300 m at the Ross Sea [51]. These compounds showed to inhibit the production
the production of NO and PGE2 in LPS-stimulated microglial cells with IC50 values ranging from 20
of NO and PGE2 in LPS-stimulated microglial cells with IC50 values ranging from 20 to 65 µM due
to 65 μM due to suppressing the expression of iNOS and COX-2, respectively [51]. Furthermore,
to suppressing the expression of iNOS and COX-2, respectively [51]. Furthermore, cladosporin
cladosporin 8-O-α-ribofuranoside exhibited the suppression of the phosphorylation and degradation
8-O-α-ribofuranoside exhibited the suppression of the phosphorylation and degradation of IκB-α and
of IκB-α and NF-κB, and also reduced the activation of p38 mitogen-activated protein kinase (MAPK)
NF-κB, and also reduced the activation of p38 mitogen-activated protein kinase (MAPK) [51]. The
[51]. The marine-derived Aspergillus sp. SF-5044 produced a crystalline metabolite, asperlin (86,
marine-derived Aspergillus sp. SF-5044 produced a crystalline metabolite, asperlin (86, Figure 14) [52].
Figure 14) [52]. The isolated compound 86 was evaluated for its anti-inflammatory potency. It
The isolated compound 86 was evaluated for its anti-inflammatory potency. It suppressed the
suppressed the expression of the iNOS protein and reduced iNOS-derived NO, inhibited the
expression of the iNOS protein and reduced iNOS-derived NO, inhibited the expression of the COX-2
expression of the COX-2 protein and reduced the COX-derived PGE2 in murine peritoneal
protein and reduced the COX-derived PGE2 in murine peritoneal macrophages and RAW264.7 caused
macrophages and RAW264.7 caused by activated of LPS [52]. Compound 86 also can reduce the
by activated of LPS [52]. Compound 86 also can reduce the production of pro-inflammatory cytokines
production of pro-inflammatory cytokines including TNF-α and IL-1β. In addition, it suppressed the
including TNF-α and IL-1β. In addition, it suppressed the phosphorylation of IκB-α and the p65 nuclear
phosphorylation of IκB-α and the p65 nuclear translocation [52]. Further, compound 86 reduced the
translocation [52]. Further, compound 86 reduced the expression of pro-inflammatory cytokines and
expression of pro-inflammatory cytokines and mediators in LPS-activated RAW264.7 cells by
mediators in LPS-activated RAW264.7 cells by increasing HO activity [52].
increasing HO activity [52].

Guaiadiol A (87, Figure 15) and 4,10,11-trihydroxyguaiane (88, Figure 15) were obtained from
Guaiadiol
marine fungus P.Athomii
(87, Figure
KMM 15)
4667and 4,10,11-trihydroxyguaiane
[33]. These compounds exhibited (88,anti-inflammatory
Figure 15) were obtained from
effects against
marine fungus inP.LPS-stimulated
NO production thomii KMM murine4667 [33]. These compounds
macrophages by 24.1% ±exhibited
2.7%, andanti-inflammatory effects
36.6% ± 6.4%, respectively,
against NO production in LPS-stimulated murine macrophages by 24.1% ± 2.7%, and
at the concentration of 10.0 µM [33]. Nguyen Thi Thanh Ngan et al., isolated citrinin H1 (89, Figure 36.6% ± 6.4%,
15)
respectively, at the concentration of 10.0 μM [33]. Nguyen Thi Thanh Ngan et al., isolated
from the marine-derived fungal strain Penicillium sp. SF-5629 [53]. Citrinin H1 was found to be active on citrinin H1
(89, Figureeffects
inhibitory 15) from
on thetheproduction
marine-derived fungal
of NO and PGEstrain Penicillium sp. SF-5629 [53]. Citrinin H1 was
2 in LPS-activated BV2 microglia, with IC50 values of
found to be active on inhibitory effects on the production
8.1 ± 1.9 and 8.0 ± 2.8 µM [53]. Penicillospirone (90, Figure 15), ofaNO
newand PGE2 in LPS-activated
polyketide-type metabolite, BV2
was
microglia, with IC 50 values of 8.1 ± 1.9 and 8.0 ± 2.8 μM [53]. Penicillospirone (90, Figure 15), a new
isolated from an EtOAc extract of the sea-derived fungal Penicillium sp. SF-5292 [27]. Penicillospirone
polyketide-type metabolite, was
exerted the anti-inflammatory isolated
effect fromderived
on iNOS an EtOAc NOextract of thederived
and COX-2 sea-derived
PGE2fungal Penicillium
production with
sp.
IC50 values from 21.9 to 27.6 µM in RAW264.7 macrophages and BV2 microglia stimulated byand
SF-5292 [27]. Penicillospirone exerted the anti-inflammatory effect on iNOS derived NO LPS COX-
[27].
2Furthermore,
derived PGEpenicillospirone
2 production with IC50 values from 21.9 to 27.6 μM in RAW264.7 macrophages and BV2
also suppressed the mRNA expression of proinflammatory cytokines,
microglia stimulated by LPS [27]. Furthermore, penicillospirone also suppressed the mRNA
expression of proinflammatory cytokines, including TNF-α, IL-1β, IL-6, and IL-12. In the further
evaluation, penicillospirone was shown to inhibit NF-κB pathway in RAW264.7 and BV2 cells
stimulated by LPS [27]. Chemical study was applied to the EtOAc extract of marine Penicillium sp.
SF-5292, resulting in the discovery of a new 10-membered lactone, penicillinolide A (91, Figure 15)
Mar. Drugs 2019, 17, 636 15 of 24
including TNF-α, IL-1β, IL-6, and IL-12. In the further evaluation, penicillospirone was shown to
Mar. Drugs
inhibit 2019, 17,
NF-κB x FOR PEER
pathway in REVIEW
RAW264.7 and BV2 cells stimulated by LPS [27]. Chemical study 13 was
of 24
applied to the EtOAc extract of marine Penicillium sp. SF-5292, resulting in the discovery of a new
[54]. Penicillinolide
10-membered lactone,A inhibited the NOAand
penicillinolide (91,PGE 2 production by suppressing the expression of iNOS
Figure 15) [54]. Penicillinolide A inhibited the NO and
and COX-2
PGE in LPS-stimulated
production by suppressing macrophages,
the expression of with
iNOS IC 50 values of 20.47 and 17.54 μM [54].
and COX-2 in LPS-stimulated macrophages,
2
with IC50 values of 20.47 and 17.54 µM [54]. Penicillinolide A also IL-1β,
Penicillinolide A also inhibited the mRNA expression of TNF-α, andthe
inhibited IL-6 with IC
mRNA 50 values of
expression of
8.63, 11.32, and 20.92 μM due to the degradation of IκB-α, NF-κB nuclear
TNF-α, IL-1β, and IL-6 with IC50 values of 8.63, 11.32, and 20.92 µM due to the degradation translocation, and ofNF-κB
IκB-α,
DNA binding
NF-κB nuclear activity [54]. Dong-Sung
translocation, and NF-κB DNA Lee etbinding
al., successfully purified
activity [54]. penstyrylpyrone
Dong-Sung (92, Figure
Lee et al., successfully
15), a styrylpyrone-type metabolite from the methylethylketone extract of
purified penstyrylpyrone (92, Figure 15), a styrylpyrone-type metabolite from the methylethylketone sea-derived fungus
Penicillium sp. JF-55 colonizing in an unidentified sponge gathered from the shores
extract of sea-derived fungus Penicillium sp. JF-55 colonizing in an unidentified sponge gathered from of Jeju Island [55].
Penstyrylpyrone
the inhibited
shores of Jeju Island [55].the overproductioninhibited
Penstyrylpyrone of NO and thePGE 2 with IC50 values of 12.32 and 9.35 μM
overproduction of NO and PGE2 with IC50
in LPS-stimulated murine peritoneal macrophages
values of 12.32 and 9.35 µM in LPS-stimulated murine peritoneal and these inhibitory
macrophagesactivities
and were
these correlated
inhibitory
with the were
activities overexpressions
correlated with of the
iNOS and COX-2, of
overexpressions respectively.
iNOS and COX-2,Penstyrylpyrone
respectively.also inhibited the
Penstyrylpyrone
mRNA
also expression
inhibited of pro-inflammatory
the mRNA cytokines such ascytokines
expression of pro-inflammatory TNF-α, IL-1β with
such as IC50 IL-1β
TNF-α, valueswith
of 13.54
IC50
and18.32 μM [55]. In addition, penstyrylpyrone was shown to inhibit IκB-α pathway
values of 13.54 and18.32 µM [55]. In addition, penstyrylpyrone was shown to inhibit IκB-α pathway and the NF-κB
DNA-binding
and the NF-κBactivity
DNA-bindingin LPS-stimulated murine peritoneal
activity in LPS-stimulated macrophages
murine peritoneal[55].
macrophages [55].
Figure 15. Chemical structures of

Figure 15. of compounds
compounds 87−92.
87−92.
Chemical
Chemical study
study on on aa marine-derived
marine-derived fungal strain Penicillium
fungal strain Penicillium sp. SF-5859 resulted
sp. SF-5859 resulted inin the
the
discovery
discovery ofof seven
seven compounds,
compounds, namely
namely curvularin
curvularin (93,
(93, Figure
Figure 16),
16), (11R,15S)-11-hydroxycurvularin
(11R,15S)-11-hydroxycurvularin
(94,
(94, Figure
Figure 16),
16), (11S,15S)-11-hydroxycurvularin
(11S,15S)-11-hydroxycurvularin (95, (95, Figure
Figure 16),
16), (11R,15S)-11-methoxycurvularin
(11R,15S)-11-methoxycurvularin (96, (96,
Figure 16), (11S,15S)-11-methoxycurvularin (97, Figure 16), (10E,15S)-10,11-dehydrocurvularin
Figure 16), (11S,15S)-11-methoxycurvularin (97, Figure 16), (10E,15S)-10,11-dehydrocurvularin (98, (98,
Figure
Figure 16),
16),and
and(10Z,15S)-10,11-dehydrocurvularin
(10Z,15S)-10,11-dehydrocurvularin (99,(99,
Figure 16) [56].
Figure TheseThese
16) [56]. analogs exhibited
analogs strong
exhibited
inhibitory effects on NO and PGE with
strong inhibitory effects on NO and2 PGE2 with IC values ranging from 1.9 to 18.1 µM, and
50 IC50 values ranging from 1.9 to 18.1 μM, and from from 2.82.8
to
18.7 µM,
to 18.7 μM,respectively, in in
respectively, RAW264.7
RAW264.7 cells induced
cells induced byby LPS
LPS[56].
[56].Compound
Compound99 99also
also suppressed
suppressed the the
production of iNOS and COX-2. Furthermore, (10E,15S)-10,11-dehydrocurvularin exhibited
production of iNOS and COX-2. Furthermore, (10E,15S)-10,11-dehydrocurvularin exhibited to inhibit to inhibit
the
the NF-κB
NF-κB pathway
pathway [56]. The fungus
[56]. The Penicillium paxilli
fungus Penicillium paxilli Ma(G)K
Ma(G)K isolated
isolated from
from aa sponge sample Mycale
sponge sample Mycale
angulosa,
angulosa, produced
produced aa novel
novel compound
compound pyrenocine
pyrenocine A A (100,
(100, Figure
Figure 16),
16), which
which possessed
possessed considerable
considerable
anti-inflammatory
anti-inflammatory effect
effect against
against TNF-α
TNF-α and
and PGE
PGE22 in
in LPS-stimulated
LPS-stimulated macrophages
macrophages [57].
[57].
Mar.
Mar. Drugs 2019, 17,
Drugs 2019, 17, 636
x FOR PEER REVIEW 16
14 of
of 24
24
Figure 16. Chemical

Chemical structures
structures of
of compounds 93−100.
93−100.
Figure
Figure 16.
16. Chemical structures of compounds
compounds 93−100.
Asperflavin (101,
Asperflavin (101, Figure
Figure 17)
17) was isolated from the sea-derived fungus Eurotium amstelodami [58].
Asperflavin (101, Figure 17) was isolated from the sea-derived fungus Eurotium amstelodami [58].
Asperflavin displayed
Asperflavin displayed the the overproduction
overproductionofofproinflammatory
proinflammatory mediators
mediators NONO and and PGE2PGE in LPS-
2 in
Asperflavin displayed the overproduction of proinflammatory mediators NO and PGE2 in LPS-
stimulated RAW264.7
LPS-stimulated RAW264.7 cellscells
by by4.6%4.6%andand55.9%
55.9% at atthe
theconcentration
concentrationofof200 200 μM.
µM. Additionally,
stimulated RAW264.7 cells by 4.6% and 55.9% at the concentration of 200 μM. Additionally,
asperflavin possessed
asperflavin possessed the expression of mRNA mRNA proinflammatory cytokines, including TNF-α, IL-1β,
asperflavin possessed the expression of mRNA proinflammatory cytokines, including TNF-α, IL-1β,
IL-6, and IL-12 [58].
IL-6, [58]. Chemical
Chemicalstudy studyofofthethemarine-derived
marine-derived fungus
fungus E. E.
amstelodami
amstelodami separated
separated fromfroman
IL-6, and IL-12 [58]. Chemical study of the marine-derived fungus E. amstelodami separated from an
unidentified
an unidentified marine animal
marine collected
animal fromfrom
collected the Sungsan
the Sungsan coastcoast
in Jeju
inIsland, Korea,Korea,
Jeju Island, have beenhavefound
been
unidentified marine animal collected from the Sungsan coast in Jeju Island, Korea, have been found
an anthraquinone
found an anthraquinone analog,analog,
questinol (102, Figure
questinol (102,17) [59]. 17)
Figure Questinol showed considerable
[59]. Questinol inhibitory
showed considerable
an anthraquinone analog, questinol (102, Figure 17) [59]. Questinol showed considerable inhibitory
effect on NO
inhibitory effectandonPGE
NO 2andproduction in LPS-stimulated
PGE2 production RAW264.7
in LPS-stimulated cells withcells
RAW264.7 thewith
inhibition rates of
the inhibition
effect on NO and PGE2 production in LPS-stimulated RAW264.7 cells with the inhibition rates of
73.0%ofand
rates 73.0%43.5%andat43.5%
the concentrations of 200 μM
at the concentrations andµM
of 200 alsoand
displayed to inhibit
also displayed to the production
inhibit of pro-
the production
73.0% and 43.5% at the concentrations of 200 μM and also displayed to inhibit the production of pro-
inflammatory
of pro-inflammatory cytokines such as such
cytokines TNF-α, as IL-1β,
TNF-α, and IL-6 [59].
IL-1β, Furthermore,
and IL-6 questinol also
[59]. Furthermore, suppressed
questinol also
inflammatory cytokines such as TNF-α, IL-1β, and IL-6 [59]. Furthermore, questinol also suppressed
the proteinthe
suppressed expression of iNOS ofbut
protein expression iNOS weak inhibited
but weak the protein
inhibited the proteinexpression
expression of ofCOX-2
COX-2at the
at the
the protein expression of iNOS but weak inhibited the protein expression of COX-2 at the
concentration of 200
concentration 200 µM
μM [59].
[59]. Two
Two benzaldehyde-type
benzaldehyde-type fungal analogs, flavoglaucin (103, Figure 17)
concentration of 200 μM [59]. Two benzaldehyde-type fungal analogs, flavoglaucin (103, Figure 17)
and isotecrahydro-auroglaucin
and isotecrahydro-auroglaucin (104, (104,Figure
Figure17)17)were
wereextracted
extracted in in
culture extracts
culture of Eurotium
extracts of Eurotium sp. SF-
sp.
and isotecrahydro-auroglaucin (104, Figure 17) were extracted in culture extracts of Eurotium sp. SF-
5989 [60].
SF-5989 Compounds
[60]. Compounds 103103andand
104 104
can can
suppress
suppressthe production
the production of pro-inflammatory
of pro-inflammatory mediators, NO
mediators,
5989 [60]. Compounds 103 and 104 can suppress the production of pro-inflammatory mediators, NO
andand
NO PGEPGE2, and these
2 , and inhibitory
these inhibitoryactivities were
activities weremediated
mediatedbybyinhibiting
inhibitingthetheexpression
expression of of COX-2 and and
and PGE2, and these inhibitory activities were mediated by inhibiting the expression of COX-2 and
iNOS in
iNOS in RAW264.7
RAW264.7 macrophages
macrophages stimulated
stimulated by by LPS.
LPS. The
The anti-inflammatory
anti-inflammatory activities
activities ofof compounds
compounds
iNOS in RAW264.7 macrophages stimulated by LPS. The anti-inflammatory activities of compounds
103 and
103 and 104
104 were
were due due to
to attenuation
attenuation of of major
major signaling
signaling pathways,
pathways, NF-κB
NF-κB pathway
pathway in in LPS-stimulated
LPS-stimulated
103 and 104 were due to attenuation of major signaling pathways, NF-κB pathway in LPS-stimulated
RAW264.7macrophages.
RAW264.7 macrophages. Furthermore,
Furthermore, the the anti-inflammatory
anti-inflammatory effects effects of
of these
these were
were observed
observed through
through
RAW264.7 macrophages. Furthermore, the anti-inflammatory effects of these were observed through
reduction of
reduction of HO-1
HO-1 expression
expression regulated
regulated by by nuclear
nuclear transcription
transcription factorE2-related
factorE2-related factor
factor 22 (Nrf2)
(Nrf2) [60].
[60].
reduction of HO-1 expression regulated by nuclear transcription factorE2-related factor 2 (Nrf2) [60].
Figure 17. Chemical

Figure17. Chemical structures
structures of
of compounds
compounds 101−104.
101−104.
One new phenolic metabolite, 1-(2,5-dihydroxyphenyl)-3-hydroxybutan-1-one (105, Figure 18),
One new phenolic metabolite, 1-(2,5-dihydroxyphenyl)-3-hydroxybutan-1-one (105, Figure 18),
alongOne new
with phenolic metabolite, 1-(2,5-dihydroxyphenyl)-3-hydroxybutan-1-one
1-(2,5-dihydroxyphenyl)-2-buten-1-one (105,
(106, Figure 18), were found in the Figure
EtOAc 18),
extract
along with 1-(2,5-dihydroxyphenyl)-2-buten-1-one (106, Figure 18), were found in the EtOAc extract
along with 1-(2,5-dihydroxyphenyl)-2-buten-1-one (106, Figure 18), were found in the EtOAc extract
of the marine endophytic fungus Paraconiothyrium sp. VK-13 [61]. 1-(2,5-dihydroxyphenyl)-3-
Mar. Drugs 2019, 17, 636 17 of 24

hydroxybutan-1-one and
hydroxybutan-1-one 1-(2,5-dihydroxyphenyl)-2-buten-1-one displayed
and 1-(2,5-dihydroxyphenyl)-2-buten-1-one displayed inhibitory
inhibitory effect against
effect against
iNOS derived NO and COX-2 derived PGE in LPS-stimulated RAW264.7
iNOS derived NO and COX-2 derived PGE2 in LPS-stimulated RAW264.7 cells, with IC50 values from
2 cells, with IC 50 values from3.9
3.9 and 12.5 μM [61]. The anti-inflammatory effects of these compounds were
and 12.5 µM [61]. The anti-inflammatory effects of these compounds were attributed to the significant attributed to the
significantof
inhibition inhibition of the of
the expression expression
iNOS andofCOX-2iNOS proteins
and COX-2 and proteins and the
the inhibition inhibition
of mRNA of mRNA
expression of
expression of anti-pressure cytokines including TNF-α, IL-1β, IL-6, and IL-12
anti-pressure cytokines including TNF-α, IL-1β, IL-6, and IL-12 [61]. From a marine crinoid collected [61]. From a marine
crinoid
in Xuwen,collected
Zhanjing in City,Xuwen,
Guangdong Zhanjing
Province,City, Guangdong
China, fungal strain Province, China, chartarum
Leptosphaerulina fungal strain
3608,
Leptosphaerulina chartarum 3608, was selected for chemical study [62]. One new
was selected for chemical study [62]. One new secondary metabolite, (4R,10S,4’S)-leptothalenone B secondary metabolite,
(4R,10S,4’S)-leptothalenone
(107, Figure 18), was discovered B (107,
in Figure 18), was
the fungus [62].discovered in the fungus
It was observed [62]. It
to suppress NO was observed in
production to
suppress NORAW264.7
LPS-induced production in LPS-induced
cells, RAW264.7
with an IC50 value of 44.5cells, withAan
µM [62]. IC50 value
detailed of 44.5
chemical μM [62]. of
investigation A
detailed chemical investigation of an in-house marine-derived fungi Phoma sp. NTOU4195
an in-house marine-derived fungi Phoma sp. NTOU4195 associated with the marine red alga P. capillacea associated
with thein
resulted marine red alga
the isolation P. capillacea
of three resulted in with
novel polyketides the isolation of three novel
anti-inflammatory polyketides
activity, phomaketideswith A−C
anti-
inflammatory
(108−110, Figureactivity, phomaketides
18), along with a known A−C (108−110,
analog, Figure(111,
FR-111142 18),Figure
along 18)
with a known
[63]. analog,A−C
Phomaketides FR-
111142 (111, Figure 18) [63]. Phomaketides A−C and FR-111142 exhibited
and FR-111142 exhibited strong inhibitory effect on NO production murine macrophage RAW264.7 strong inhibitory effect on
NO production
cells induced bymurine
LPS [63].macrophage
Phomaketides RAW264.7
C exerted cells
theinduced by LPS [63].
most significant Phomaketides
inhibition C exerted
activity with Emax
the most significant inhibition activity with
and IC50 value of 100% and 8.8 µM, respectively [63]. E max and IC 50 value of 100% and 8.8 μM, respectively [63].
O OH OH O
O
OH
HO O
HO
O
O O
OH
OH OH OH
105 106 107

O O
O H O H
OH O O
O O
OH Cl O OH Cl
OH
108 109
O O
O H O H
O OH O
O O
O O O
OH
110 111
Figure
of compounds
105−111.
Expansols A−F (112−117, Figure 19) were polyphenols that were isolated from the marine-derived
Expansols A−F (112−117, Figure 19) were polyphenols that were isolated from the marine-
fungus Glimastix sp. ZSDS1-F11 associated with marine sponge samples, P. fusca gathered from the
derived fungus Glimastix sp. ZSDS1-F11 associated with marine sponge samples, P. fusca gathered
Yongxing island of Xisha [64]. All these compounds strongly suppressed the protein expression of
from the Yongxing island of Xisha [64]. All these compounds strongly suppressed the protein
COX-2 with IC50 values of 3.1, 5.6, 3.0, 5.1, 3.2, and 3.7 µM, respectively [64]. Furthermore, expansols
expression of COX-2 with IC50 values of 3.1, 5.6, 3.0, 5.1, 3.2, and 3.7 μM, respectively [64].
A−F also exhibited strong COX-1 inhibitory activity with IC50 values of 5.3, 16.2, 30.2, 41.0 and 56.8 µM,
Furthermore, expansols A−F also exhibited strong COX-1 inhibitory activity with IC50 values of 5.3,
respectively [64]. Two isobenzofuran dimers, spicarins C (118, Figure 19) and D (119, Figure 19),
16.2, 30.2, 41.0 and 56.8 μM, respectively [64]. Two isobenzofuran dimers, spicarins C (118, Figure 19)
were purified from the marine-derived fungus Spicaria elegans KLA03 collected from the marine
and D (119, Figure 19), were purified from the marine-derived fungus Spicaria elegans KLA03
sediments in Jiaozhou Bay, China [65]. These compounds inhibited the overproduction of NO in
collected from the marine sediments in Jiaozhou Bay, China [65]. These compounds inhibited the
BV2 microglial cells induced with LPS with IC50 values of 30 and 75 µM, respectively [65]. Chemical
overproduction of NO in BV2 microglial cells induced with LPS with IC50 values of 30 and 75 μM,
study of the sea-derived fungus Hypocreales sp. strain HLS-104 isolated from a sponge G. carnosa
respectively [65]. Chemical study of the sea-derived fungus Hypocreales sp. strain HLS-104 isolated
colonizing in the South China Sea afforded two derivatives, (R)-5,6-dihydro-6-pentyl-2H-pyran-2-one
from a sponge G. carnosa colonizing in the South China Sea afforded two derivatives, (R)-5,6-dihydro-
(120, Figure 19) [36]. They showed moderate anti-inflammatory activity against the production of
6-pentyl-2H-pyran-2-one (120, Figure 19) [36]. They showed moderate anti-inflammatory activity
the NO in LPS-treated RAW264.7 cells with average maximum inhibition (Emax ) values of 26.46% at
against the production of the NO in LPS-treated RAW264.7 cells with average maximum inhibition
1 µM [36]. The polyketide mycoepoxydiene (121, Figure 19) was discovered from Diaporthe sp. HLY-1,
(Emax) values of 26.46% at 1 μM [36]. The polyketide mycoepoxydiene (121, Figure 19) was discovered
which was isolated from submerged rotten leaves of Kandelia candel collected in a mangrove forest in
from Diaporthe sp. HLY-1, which was isolated from submerged rotten leaves of Kandelia candel
Fujian Province, China [66]. Compound 121 markedly suppressed the LPS-stimulated production of
collected in a mangrove forest in Fujian Province, China [66]. Compound 121 markedly suppressed
pro-inflammatory mediators and cytokines such as NO, TNF-α, IL-6, and IL-1β in macrophages [66].
the LPS-stimulated production of pro-inflammatory mediators and cytokines such as NO, TNF-α, IL-
Furthermore, the effect of compound 121 on LPS-stimulated activation were due to block the NF-κB
6, and IL-1β in macrophages [66]. Furthermore, the effect of compound 121 on LPS-stimulated
pathway and MAPK signaling pathway [66].
activation were due to block the NF-κB pathway and MAPK signaling pathway [66].
Mar. Drugs 2019, 17, 636 18 of 24
Figure 19. Chemical

structures of
of compounds
112−121.
5. Peptides
Table 3. Anti-inflammatory polyketides from marine fungi.
Methyl 3,4,5-trimethoxy-2-(2-(nicotinamido) benzamido) benzoate (122, Figure 20), was isolated
from a coral-associated fungus A. terreus associated with
against NO the
with IC50 S
coral subviride,
values of which was gathered from
Versicolactone G (63)
Xisha Island in the South China Sea A. [25].
terreusThis compound
15.72 and 29.34 showed
μM in LPS- a considerable [25] anti-inflammatory
Territrem A (64)
activated RAW264.7 cells
activity with an IC50 value of 5.48 µM [25]. Bioassay-guided investigation of the EtOAc extract
Eurobenzophenone B
of marine sponge-derived fungus Aspergillus violaceofuscus
66 against NF-κB afforded new anti-inflammatory activity
with significant
(65)
metabolites named violaceotide inhibition in LPS-activated
A (123, Figure 20) and diketopiperazine SW480 dimer (124, Figure 20) [67].
Canthone A (66)
A. europaeus cells
The fungus A. violaceofuscus was isolated from the inner part of the marine sponge Reniochalina sp.
3-de-O-
WZXY-SX- 65, 67, 68, 69, 70 against NF-κB with [46]
collected from methylsulochrin
the Xisha Islands(67) in4-1
the South China Sea.andViolaceotide A and diketopiperazine dimer
inhibition against NO with
Yicathin B (68)
reduced IL-10 expression in THP-1 cells stimulated by LPS in
weak inhibition with inhibitory rate of 84.3% and 78.1%
LPS-activated
Dermolutein (69)
at concentration of 10 µM, respectively [67]. SW480 cells
Investigation of biologically active peptides from the
Methylemodin (70)
marine fungus Aspergillus
Violaceol II (71) sp. SF-5921 (from
A. sydowii an unidentified sponge, Sea
against NO with weak inhibition in of Ross) resulted in isolation
[47]
Cordyol E (72) J05B-7F-4 LPS-activated RAW264.7 cells
of aurantiamide acetate (125, Figure 20) [68]. Compound 125 showed inhibitory potency against the
LPS-stimulated production of NO and PGE2 with against
IC50NO and PGE
values with and 51.3 µM in BV2 microglia
of2 49.70
Aspergillus considerable anti-
cells [68]. In addition,
TMC-256C1it(73)has anti-neuron-flammatory
sp. SF-6354
effects through its inhibition
neuroinflammatory activity in LPS-
[48]of the NF-κB, c-Jun
N-terminal kinases (JNK), and p38 pathways [68]. (S)-2-(2-hydroxypropanamido)
activated BV2 cells benzoic acid (126,
Figure 20), a novel benzoic
Aurasperone acid, was
F (74) A.isolated
niger as natural product
against COX-2 with from a sponge-derived
IC50 values of marine fungus
Aurasperone C (75) SCSIO 11.1, 4.2, and 6.4 μM in LPS-
P. chrysogenum SYP-F-2720 [69]. Compound 126 exhibited stronger anti-inflammatory activity than [49]
Asperpyrone A (76) Jcsw6F30 activated RAW264.7 cells
aspirin (swelling rate of 193%) with the swelling rate of 191% in the mouse ear edema model induced
Diorcinol (77)
by xylene when administered
Cordyol C (78) at 100 mg/kg [69]. Chemical investigation of a marine-derived fungus
Aspergillus
against the COX-2 expression with
Acremonium sp. from the surface of the
3,7-dihydroxy-1,9- Caribbean tunicate Ecteinascidia turbinata. [50]
sp. SCSIO yielded a new peptide
IC50 values of 2.4−10.6 μM
Dimethyldibenzofuran
derivative, oxepinamide A (127, FigureInd09F0120) [70]. Oxepinamide A showed potent anti-inflammatory
(79)
effect in a topical resiniferatoxin (RTX)-induced mouse ear edema assay, with the inhibition rate of
Cladosporin 8-O-α-
82% at the standard testing
ribofuranoside (80) dose of 50 µg per ear [70]. Alternaramide (128, Figure 20), a marine
Alternaria sp.Cladosporin
SF-5016 metabolite,
(81) was interesting in that it contained unusual hydrophobic D-amino
Aspergillus
Asperentin 6-O-methyl
acid residues [71]. Compound 128 sp. suppressed the production of2 with
PGEIC and NO, and these inhibitory
SF-5974 against NO and PGE 2 50
ether (82) Cladosporin
effects were correlated with down-regulation and of iNOS
valuesand COX-2
of 20−65 μM inexpression
LPS- in LPS-induced
[51] RAW264.7
8-O-methyl ether (83)
and BV2 macroglia Aspergillus activated microglial cells
cells with IC50 values ranging from 27.63 to 40.52 µM [71]. It also inhibited
4′-hydroxyasperentin
sp. SF-5976
pro-inflammatory
(84) cytokines, such as TNF-α, IL-1β, IL-6, and IL-12 in LPS-induced RAW264.7 and
BV2 macroglia 5′-hydroxyasperentin
cells. In addition, the compound 128 suppressed the NF-κB and MAPK signaling
(85)
pathway. Furthermore, compound 128 significantly reduced the Toll-like receptor 4 (TLR4) and myeloid
Aspergillus against NO and PGE2 in LPS-
Asperlin (86) [52]
sp. SF-5044 activated murine macrophages
Guaiadiol A (87) against NO with 24.1% and 36.6%
P. thomii
4,10,11- inhibition at 10.0 μM in LPS- [33]
KMM 4667
trihydroxyguaiane (88) activated murine macrophages
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,
Mar.
Mar. Drugs and 17, 636
2019, IL-12 in PEER
x FOR LPS-induced
REVIEW 19 of 24
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
differentiation primary receptor 4 (TLR4)
response gene and myeloid
88 (MyD88) differentiation
in LPS-induced primary
RAW264.7 response
and BV2 genecells
macroglia 88
(MyD88) in LPS-induced RAW264.7
at the mRNA and protein levels [71]. and BV2 macroglia cells at the mRNA and protein levels [71].
Table 4. Anti-inflammatory peptides from marine fungi.

Methyl 3,4,5-trimethoxy-2-(2-
against NO with IC50 value of 5.48 μM in
(nicotinamido)benzamido)benzoate A. terreus [25]
(122)
against IL-10 expression with inhibitory
Violaceotide A (123) A.
rate of 84.3% and 78.1% at 10 μM in LPS- [67]
Diketopiperazine dimer (124) violaceofuscus
activated THP-1 cells
Aurantiamide acetate (125) Aspergillus sp. 49.70 and 51.3 μM in LPS-activated BV2 [68]
cells
(S)-2-(2-hydroxypropanamido) P. citrinum with the swelling rate of 191% at 100
[69]
Benzoic Acid (126) SYP-F-2720 mg/kg
Acremonium inhibition rate of 82% at 50 μg per ear in
Oxepinamide A (127) [70]
sp. RTX-activated mouse ear edema assay
Alternaria sp.
Alternaramide (128) ranging from 27.63 to 40.52 μM in LPS- [71]
SF-5016
activated RAW264.7 and BV2 cells
6. Others
6. Others
A novel
A novellinear aliphatic
linear alcohol,
aliphatic (3E,7E)-4,8-di-methyl-undecane-3,7-diene-1,11-diol
alcohol, (3E,7E)-4,8-di-methyl-undecane-3,7-diene-1,11-diol (129, Figure
(129,
21), together
Figure with three
21), together known
with compounds,
three 14α-hydroxyergosta-4,7,22-triene-3,6-dione
known compounds, (130, Figure
14α-hydroxyergosta-4,7,22-triene-3,6-dione
21) were
(130, purified
Figure 21) from
were the coral-associated
purified from the fungus A. terreus associated
coral-associated fungus A.with the coral
terreus S. subviride,
associated with
which
the was S.
coral collected fromwhich
subviride, the coastwasof collected
Xisha Island in the
from theSouth
coastChina Sea [25].
of Xisha These
Island in compounds
the South
exhibited
China Seaconsiderable
[25]. inhibitory
These activity exhibited
compounds against NOconsiderable
production with IC50 values
inhibitory ranging
activity from 17.45
against NO
to 29.34 μM [25]. Two hexylitaconic acid derivatives, methyl8-hydroxy-
production with IC50 values ranging from 17.45 to 29.34 µM [25]. Two hexylitaconic acid 3-methoxycarbonyl-2-
methylenenonanoate
derivatives, (131, Figure
methyl8-hydroxy- 21) and (3S)-methyl9-hydroxy-3- (131,
3-methoxycarbonyl-2-methylenenonanoate methoxycarbonyl-2-
Figure 21) and
methylenenonanoate (132, Figure 21), were separated from the EtOAc
(3S)-methyl9-hydroxy-3- methoxycarbonyl-2-methylenenonanoate (132, Figure 21), were extract of the fungal strain
separated
Penicillium
from sp. (J05B-3-F-1)
the EtOAc colonizing
extract of the in a sponge
fungal strain Stelletta
Penicillium sp. collected
sp. (J05B-3-F-1) from the in
colonizing coast of JejuStelletta
a sponge island,
Korea [72]. The two isolates weakly inhibited the production of IL-1β at the concentration
sp. collected from the coast of Jeju island, Korea [72]. The two isolates weakly inhibited the production of 200 μM
[72]. Trichodermanone C (133, Figure 21) was isolated from the marine
of IL-1β at the concentration of 200 µM [72]. Trichodermanone C (133, Figure 21) was isolated fromfungal strain A12 of
Trichoderma
the marine fungalcitrinoviride associated
strain A12 with the
of Trichoderma green alga
citrinoviride Cladophora
associated sp. green
with the collected in Italy [73].
alga Cladophora sp.
Trichodermanone C was evaluated to show strong inhibitory effect on nitrite levels
collected in Italy [73]. Trichodermanone C was evaluated to show strong inhibitory effect on nitrite in LPS-stimulated
J774A.1
levels inmacrophages
LPS-stimulated [73].
J774A.1 macrophages [73].
Figure 21. Chemical

structures of
of compounds
129−133.
7. Conclusions
Table 5. Anti-inflammatory other compounds from marine fungi.
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(3E,7E)-4,8-di-methyl-
the healthcare costs considerably [75]. What is more, the inflammatory disease operates
A. terreus 17.45 and 29.34 μM in LPS- [25]
undecane-3,7-diene-1,11-diol
activated RAW264.7 cells
Mar. Drugs 2019, 17, 636 20 of 24
by an advanced system and has a broad influence on physiological aspects and human pathology.
Currently, with the development of the synthetic drug formulation, some classes of anti-inflammatory
drugs such as aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and corticosteroids are used
in the clinic [76]. However, all the therapeutics can cause quite harmful side effects to human beings
after long-term and high-dose medication. Marine fungi have the potential ability to produce diverse
chemical structures with anti-inflammatory activities. During 2000–2018, about 133 anti-inflammatory
compounds in 52 references belonging to five diverse chemical classes were reported, including
alkaloids, terpenoids, polyketides, peptides, and others. Over 50 compounds were found to display
significantly anti-inflammatory activities. For example, preussions G (5) and I (7), graphostromanes F
(28), khusinol B (29), and mangicol A (31), which IC50 values or reduction were even stronger than
that positive control. From distribution point of view, 75% of all anti-inflammatory structures were
polyketides and terpenoids indicating that polyketides and terpenoids have great potential in the
development of anti-inflammatory drugs. This review provided a lot of potential lead compounds
for finding novel anti-inflammatory agents from marine-derived fungi, especially, Aspergillus (41.4%),
and Penicillium (27.1%). Lots of potential agents derived from marine fungi were found to have
significant effects against inflammation. Therefore, it could be suggested that marine fungi-derived
natural products will play a vital role in developing novel drugs against inflammation with satisfactory
tolerability for long-term use [77,78].
Author Contributions: J.X., M.Y. and L.D. collected the references; J.X. and S.H. analyzed the data; J.X. and L.D.
wrote the paper.
Funding: This research was funded by Natural Science Foundation of China (41776168, 41706167), the National
College Students’ Innovation and Entrepreneurship Training Program, the Program of “Xinmiao” Talents in
Zhejiang Province, Ningbo Public Service Platform for High-Value Utilization of Marine Biological Resources
(NBHY-2017-P2), the National 111 Project of China (D16013), the Li Dak Sum Yip Yio Chin Kenneth Li Marine
Biopharmaceutical Development Fund, and the K.C. Wong Magna Fund in Ningbo University.
Conflicts of Interest: The authors declare no conflict of interest.
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marine drugs

Keywords: marine-derived fungi; marine natural products; anti-inflammatory

Mar. Drugs 2019, 17, 636; doi:10.3390/md17110636 www.mdpi.com/journal/marinedrugs

Mar. Drugs 2019, 17, x FOR PEER REVIEW 2 of 24

Figure 2. The sources of marine fungal compounds with anti-inflammatory activities.

Figure 3. Chemical structures of compounds 1–14.

Table 2. Anti-inflammatory terpenoids from marine fungi.

Metabolites Species Activities Reference

Table 3. Anti-inflammatory polyketides from marine fungi.

Metabolites Species Activities Reference

Metabolites Species Activities Reference

Table 4. Anti-inflammatory peptides from marine fungi.

Metabolites Species Activities Reference

Table 5. Anti-inflammatory other compounds from marine fungi.

Metabolites Species Activities Reference

Figure 6. Chemical structures of compounds 27–32.

Lovastatin (39,(39, Figure

Figure 8. Chemical structures of compounds 39−46.

Figure 9. Chemical structures of compounds 47−52.

Figure 10. Chemical structures of compounds 53−59.

Figure 13. Chemical structures of compounds 71−76.

Figure 14. Chemical structures of compounds 77−86.

Figure 15. Chemical structures of

Figure 16. Chemical

Figure 17. Chemical

Mar. Drugs 2019, 17, x FOR PEER REVIEW 15 of 24

105 106 107

Figure 19. Chemical

Metabolites Species Activities Reference

Figure 21. Chemical

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