Appl Microbiol Biotechnol (2016) 100:16451666
DOI 10.1007/s00253-015-7244-3
MINI-REVIEW
Marine natural products with anti-inflammatory activity
Randy Chi Fai Cheung 1 & Tzi Bun Ng 1 & Jack Ho Wong 1 & Yangchao Chen 1 &
Wai Yee Chan 1
Received: 29 September 2015 / Revised: 7 December 2015 / Accepted: 9 December 2015 / Published online: 28 December 2015
# Springer-Verlag Berlin Heidelberg 2015
Abstract Chronic inflammation is believed to play crucial
roles in the pathogenesis of various diseases. Several types
of drugs are used to treat inflammatory disorders, but they
cause adverse side effects. Natural products are alternatives
to these drugs which offer hope for discovery of bioactive lead
compounds that may be developed into drugs for treatment of
inflammatory disorders. The biological and chemical diversity
of marine habitats constitutes a sizeable reservoir of novel
compounds. Some of them, like sesquiterpenoids, diterpenes,
steroids, polysaccharides, alkaloids, fatty acids, proteins, and
other chemical compounds, isolated from marine organisms
are found to exhibit anti-inflammatory activity. This review
reports some recent (20112015) investigations and examples
of marine natural products and their synthetic derivatives with
anti-inflammatory activity. It also highlights those compounds
that are currently undergoing preclinical or clinical evaluation.
Keywords Anti-inflammatory activity . Clinical trials .
Marine natural products
Introduction
The process of inflammation is the result of activation of the
mammalian immune system which coordinates our bodys
normal defense mechanism in response to microbial infection
* Tzi Bun Ng
b021770@mailserv.cuhk.edu.hk
* Wai Yee Chan
chanwy@cuhk.edu.hk
1
School of Biomedical Sciences, Faculty of Medicine, The Chinese
University of Hong Kong, Hong Kong, China
or irritation or damage of tissues/organs. The word Banti-
inflammatory^ is defined as the ability of a substance or treat-
ment to minimize inflammation.
As part of our innate immunity system, inflammation is one
of the most generic responses. The purpose of inflammation is
to control damage to our body after tissue/organ injury or
infection by bacteria or viruses. Keeping the damage under
control is a beneficial consequence of inflammation, but in-
flammation becomes an annoyance when the body suffers
from severe or long-term inflammation (Ferrero-Miliani
et al. 2007). This type of uncontrolled inflammation (chronic
inflammation) is believed to play crucial roles in the patho-
genesis of various diseases, like cardiovascular diseases
(Libby et al. 2009), inflammatory bowel disease (Okamoto
and Watanabe 2015), cancer (Crusz and Balkwill 2015), dia-
betes (Pickup 2004), asthma (Kurakula et al. 2015), and
Alzheimers disease (Ghosh et al. 2015). Inflammation is
linked with aging, obesity, stroke, fatigue, depression, and
allergic reactions (Donath et al. 2013; Efthimiou and
Yadlapati 2015; Panickar and Jewell 2015; Ross 1999;
Skaper et al. 2014). It also inflicts damages to our body tissues
through multiple sclerosis, rheumatoid arthritis, systemic lu-
pus erythematosus, and other autoimmune diseases (Garcia-
Hernandez et al. 2014; Haider 2015; Mackern-Oberti et al.
2015). Our body must always maintain a balance between
inflammation and anti-inflammation. Excessive inflammation
brings about diseases that have just been mentioned above,
but a complete lack of inflammation attenuates our immune
system, which ensues in proneness to infection. It will be fatal
in both cases if we take them too lightly.
Several types of drugs are used to treat inflammatory dis-
orders. They are biological, steroidal, and nonsteroidal anti-
inflammatory drugs. However, they elicit adverse effects and
in case of biologics, the treatment is expensive. Natural prod-
ucts are alternatives to these drugs. They offer hope in
1646
discovery of bioactive lead compounds that may be developed
into therapeutic agents for combating inflammatory disorders
(Gautam and Jachak 2009).
The biological and chemical diversity of marine habitats fur-
nishes an enormous resource of novel therapeutic agents. Due to
the current advancement in structural elucidation, organic syn-
thesis, and biological assays, natural products from marine or-
ganisms or their derivatives with specific biological activities
can be easily identified, synthesized, and evaluated (Simmons
et al. 2005). A few available drugs and a number of drug can-
didates in preclinical or clinical trials have been developed from
marine-derived compounds (Molinski et al. 2009).
A plenty of unique natural products, like sesquiterpenoids,
diterpenes, steroids, polysaccharides, alkaloids, fatty acids,
proteins, and other chemical compounds have been isolated
from marine organisms and are found to manifest an anti-
inflammatory action. However, there is no marine-derived an-
ti-inflammatory agent currently on the market. This review
reports some recent investigations (20112015) of marine nat-
ural products and their derivatives with anti-inflammatory ac-
tivity. The products were sorted according to the chemical
classes they belong to. It also highlights those compounds that
are currently undergoing preclinical and clinical evaluation.
We hope that this review will provide a useful summary of
updated and comprehensive information pertaining to marine-
derived anti-inflammatory agents.
Evaluation of anti-inflammatory activity
The pro-inflammatory enzymes, inducible nitric oxide syn-
thase (iNOS) for nitric oxide (NO) production (Wong and
Billiar 1995) and cyclooxygenase-2 (COX-2) for prostaglan-
din production (Seibert et al. 1995), have been shown to play
key roles in inflammatory processes. Besides, neutrophils also
migrate toward the damaged tissue sites in the initial acute
inflammation phase (Kaplanski et al. 2003). The stimulated
neutrophils can produce superoxide anions and elastase that
are associated with the killing of invading pathogens (Hwang
et al. 2009). Therefore, evaluation of the inhibition of iNOS
and COX-2 expression, superoxide anion generation, and
elastase secretion in inflammatory cells/tissues by different
natural products has been used in preliminary in vitro screen-
ing of anti-inflammatory lead compounds for drug discovery
(Wei et al. 2013). An inflammatory animal model is also com-
monly used to evaluate in vivo anti-inflammatory activity of
lead compounds (Liu et al. 2015).
In general, in vitro anti-inflammatory activity is determined
by inhibition of iNOS and COX-2 expression in an inflamma-
tory cell line (macrophage cell line RAW264.7 or microglial
cell line BV2) induced by lipopolysaccharides (LPS) or
interferon- (IFN-) (Gresa-Arribas et al. 2012; Yang et al.
2015). The activity can also be evaluated from suppression of
superoxide anion generation and elastase secretion in formyl-
Appl Microbiol Biotechnol (2016) 100:16451666
Met-Leu-Phe/cytochalasin B (fMLP/CB)-activated human
neutrophils (Huang et al. 2015).
For establishing the in vivo inflammation model, usually
mice or rats are used. Inflammation is induced by
intraplantar injection of -carrageenan into the hind paws of
the experimental animals. The anti-inflammatory activity is
assessed by reversal of -carrageenan-induced edema in the
hind paws. The paw biopsies are taken for histopathological
examination, and the anti-inflammatory effect is assessed by
improvement of the edematous condition (reduction in inter-
cellular spaces of connective tissues) (Di Rosa et al. 1971).
Several pro-inflammatory markers in the paw tissues and
blood are analyzed. The -carrageenan-induced edema imme-
diately triggers the release of histamine, 5-hydroxytryptamine,
and bradykinin (Di Rosa et al. 1971). Later, the swelling is
associated with heightened production of tumor necrosis
factor- (TNF-), NO, and prostaglandin (Posadas et al.
2004). Pro-inflammatory cytokines like TNF-, IFN-,
interleukin-1 (IL-1), and interleukin-6 (IL-6) are expressed at
sites of inflammation and initiate the inflammatory mediator
cascade which targets the endothelium (Dinarello 2000).
Thus, biochemical parameters, such as expression of iNOS,
COX-2, and 5-lipoxygenase (Jean et al. 2008; Yan et al.
2015), and levels of TNF-, IFN-, IL-1, and IL-6 (Liu
et al. 2015; Qiu et al. 2014) are evaluated in an animal model
of inflammation . Furthermore, animal disease models are
deployed to further evaluate the potential therapeutic activities
of candidate compounds for particular diseases (Choi et al.
2014; Fang et al. 2015; Wang et al. 2014; Wen et al. 2010).
Marine natural products with anti-inflammatory activity
There has been a remarkable increase in pharmacological re-
search on anti-inflammatory marine biomolecules in recent
years. Natural products of nonmarine origins may also display
anti-inflammatory activity. Some herbs used in Traditional
Chinese Medicine (Cheung et al. 2015b; Sze et al. 2015),
other medicinal herbs (Ibrahim et al. 2012), human antimicro-
bial peptides like cathelicidin (Wong et al. 2012), lactoferrin-
derived antimicrobial peptides (Yin et al. 2014), Kunitz inhib-
itor from Erythrina velutina seeds (Machado et al. 2013),
curcumin (Anthwal et al. 2014), and resveratrol (She et al.
2003) exhibit anti-inflammatory activity and potential in
treating some diseases. The biomolecules are classified into
different chemical classes, encompassing sesquiterpenoids,
diterpenes, steroids, polysaccharides, alkaloids, fatty acids,
and proteins. The molecular mechanisms of action of several
marine natural products were reported in detail. They gener-
ally target neutrophils and macrophages both in vitro and
in vivo, which were shown in pharmacological studies.
Table 1 summarizes the selected marine natural products in
this review evaluated for anti-inflammatory activity. The
chemical structures are reported in Fig. 1.
Appl Microbiol Biotechnol (2016) 100:16451666 1647

Table 1 Anti-inflammatory activity of selected marine products

Types Compound Source Activities Reference

Sesquiterpenoid Lemnalol Lemnalia cervicorni 99.79 and 82.5 % inhibition of iNOS and COX-2 expression Lee et al. (2013)
in LPS-activated RAW264.7 macrophages at 10 M,
respectively; 65.5 and 40.6 % inhibition of iNOS and
COX-2 expression in carrageenan-activated rat paws
at a dose of 15 mg/kg, respectively
Clovane compound 1 Rumphella antipathies 29 and 24.9 % inhibition of superoxide anions generation Chung et al. (2013)
and elastase release in fMLP/CB-activated human
neutrophils, respectively
Clovane compound 2 28.5 % inhibition of elastase release in fMLP/CB-activated
human neutrophils
Rumphellaone C 24.7 and 21.1 % inhibition of superoxide anion generation Chung et al. (2014b)
and elastase release in fMLP/CB-activated human
neutrophils, respectively
Rumphellol A 31.95 and 51.64 % inhibition of superoxide anion Chung et al. (2014a)
generation and elastase release in fMLP/CB-activated
human neutrophils at 42.2 M, respectively
Rumphellol B 42.22 and 42.10 % inhibition of superoxide anion
generation and elastase release in fMLP/CB-activated
human neutrophils at 37.6 M, respectively
Strepsesquitriol Streptomyces sp. 35.4 % inhibition of TNF- production in LPS-activated Yang et al. (2013)
SCSIO 10355 RAW264.7 macrophages at 100 M
Lochmolins A Sinularia lochmodes 98.7 % inhibition of COX-2 expression in LPS-activated Tseng et al. (2012)
RAW264.7 macrophages at 100 M
Lochmolins B 82.4 % inhibition of COX-2 expression in LPS-activated
RAW264.7 macrophages at 100 M
Lochmolins C 67.2 % inhibition of COX-2 expression in LPS-activated
RAW264.7 macrophages at 100 M
Lochmolins D 28.7 % inhibition of COX-2 expression in LPS-activated
RAW264.7 macrophages at 100 M
Flavalin A Lemnalia flava ED50 of LPS-activated iNOS and COX-2 protein expression Lu et al. (2011)
were 4.8 g/ml (20.5 M) and 6.2 g/ml (26.5 M),
respectively
Diterpene Excavatolide B Briareum excavatum 36.1 and 69.2 % inhibition of iNOS expression in Lin et al. (2015)
carrageenan-activated rat paws at a dose of 15
and 60 mg/kg, respectively
Crassumol E Lobophytum crassum IC50 of NF-B activation was 9.23 M in TNF--activated Cuong et al. (2014)
HepG2 cells
(1R,4R,2E,7E,11E) IC50 of NF-B activation was 1.65 M in TNF--activated
-cembra-2,7,11-trien-4-ol HepG2 cells
Lobocrasol A IC50 of NF-B activation was 6.30 M in TNF--activated Thao et al. (2014)
HepG2 cells
Lobocrasol B IC50 of NF-B activation was 6.63 M in TNF--activated
HepG2 cells
Pseudopterane diterpene Pseudopterogorgia IC50 of NO, TNF-, IL-6, IL-1, and IFN--induced protein Gonzalez et al. (2013)
acerosa 10 production in LPS-activated macrophages were 7.54,
9.16, 12.25, 2.75, and 3.73 M, respectively
Briarane-type diterpenes Briareum excavatum 77 % inhibition of 12-O-tetradecanoylphorbol-13-acetate Wei et al. (2011)
(TPA)-induced vascular permeability at 1 mg/site; 89 %
inhibition of TPA-induced matrix metalloproteinases-9
expression in mouse skin at 1 mg/site/mouse; 97.6 %
inhibition of IL-6 expression of LPS-activated mouse
bone marrow-derived dendritic cells
Steroid/sterol Solomonsterol A Theonella swinhoei 30 % reduction in arthritic score in anti-type II collagen Mencarelli et al. (2013)
antibody-induced arthritis mice model
Ergosta-7,22-dien-3-ol Marthasterias glacialis 20 % inhibition of iNOS protein level in LPS-activated Pereira et al. (2014a)
RAW264.7 macrophages
Steroid compound 5 Astropecten polyacanthus IC50 of IL-12 p40, IL-6, and TNF- production in Thao et al. (2013)
LPS-activated mice bone marrow-derived dendritic
cells were 1.82, 5.76, and 4.94 M, respectively
Steroid compound 7 IC50 of IL-12 p40, IL-6 and TNF- production in
LPS-activated mice bone marrow-derived dendritic
cells were 3.90, 2.61, and 7.00 M, respectively
Sclerosteroid J Scleronephthya 27.2 and 71.6 % inhibition of iNOS and COX-2 expression Fang et al. (2013)
gracillimum in LPS-activated RAW264.7 macrophages at 10 M,
respectively
Sclerosteroid K 71.6 and 91.0 % inhibition of iNOS and COX-2 expression
in LPS-activated RAW264.7 macrophages at 10 M,
respectively
Sclerosteroid M
1648 Appl Microbiol Biotechnol (2016) 100:16451666

Table 1 (continued)

Types Compound Source Activities Reference

72.8 and 88.2 % inhibition of iNOS and COX-2 expression

in LPS-activated RAW264.7 macrophages at 10 M,
respectively
Sclerosteroid N 39.7 and 73.4 % inhibition of iNOS and COX-2 expression
in LPS-activated RAW264.7 macrophages at 10 M,
respectively
Polysaccharide Sulfated polysaccharides Porphyra haitanensis 34.2 % decrease in IgE level in tropomyosin-induced mouse Shi et al. (2015)
allergy model
Polysaccharides Digenea simplex 87.5 % reduction of edema volume in carrageenan-activated Pereira et al. (2014b)
mouse paws at 60 mg/kg
Sulfated polysaccharides Caulerpa mexicana 43 and 53 % reduction of edema volume and neutrophilic Carneiro et al. (2014)
infiltration in carrageenan-activated rat paws at
20 mg/kg, respectively; 44 and 37 % reduction of edema
volume in dextran and histamine-activated rat paws at
20 mg/kg, respectively
Sulfated polysaccharides Caulerpa racemosa 33.96 and 53.78 % reduction in neutrophil counts in Ribeiro et al. (2014)
peritoneal cavity and paws of carrageenan-activated rats
at 1 mg/kg, respectively; 79.3 and 47.36 % reduction of
edema volume in carrageenan and dextran-activated
mouse paws at 1 mg/kg, respectively
Alkaloid Neoechinulin B Eurotium sp. SF-5989 60 % inhibition of NO production in amyloid- Kim et al. (2013)
142-activated BV-2 cells at 100 M
Chaetoglobosin Fex Chaetomium globosum 56.7 and 50.1 % inhibition of TNF- and IL-6 production Dou et al. (2011)
QEN-14 in LPS-activated RAW264.7 macrophages at 2 g/ml,
respectively
Protein Lectin Caulerpa cupressoides 98.5 and 98 % reduction of leukocyte counts and da Conceicao Rivanor et al.
myeloperoxidase activity in rat temporomandibular (2014)
joint synovial lavage fluid in zymozan-activated rats
at 10 mg/kg, respectively
Lectin Holothuria grisea 68 % inhibition of neutrophil migration to peritoneal cavity Moura Rda et al. (2013)
in carrageenan-activated rats at 1 mg/kg; 81.6 %
reduction of myeloperoxidase activity in
carrageenan-activated rats at 10 mg/kg
Others Xanthone derivatives 3 Stachybotrys sp. HH1 IC50 of COX-2 activity was 10.6 M Qin et al. (2015)
Xanthone derivatives 4 ZSDS1F1-2 IC50 of COX-2 activity was 8.9 M
Xanthone derivatives 11 IC50 of COX-2 activity was 34.3 M

Sesquiterpenoids caryophyllane sesquiterpenoids with -lactone moieties,

The anti-inflammatory activity is usually associated with their
inhibitory action on iNOS and COX-2 expression in macro-
phages (Jean et al. 2008), superoxide anion generation, and
elastase release in neutrophils (Chung et al. 2014a).
The currently available treatment of acute gouty attack
characterized by pronounced joint inflammation has typically
led to undesirable side effects. Intense efforts have been di-
rected to ascertain efficacious and safe alternative therapeu-
tics. Lemnalol from Lemnalia cervicorni (a Taiwan soft coral),
with anti-inflammatory and analgesic actions, mitigated intra-
articular monosodium urate-induced gouty arthritis in rats.
Lemnalol alleviated mechanical allodynia, knee swelling and
paw edema, infiltration of inflammatory cells, and suppressed
expression of COX-2, iNOS, and c-Fos in synovial tissue.
Hence, lemnalol may be useful for treatment of gout and other
acute neutrophil-mediated inflammations (Lee et al. 2013).
Several sesquiterpenoids isolated from the Taiwan gorgo-
nian coral Rumphella antipathies were found to exhibit in
vitro anti-inflammatory activity. They are clovane-related
sesquiterpenoids, 2-beta-acetoxyclovan-9-alpha-ol and 9-al-
pha-acetoxyclovan-2-beta-ol (Chung et al. 2013); 4,5-seco-
rumphellaones B and C (Chung et al. 2014b), and
caryophyllene-type sesquiterpenoids, rumphellols A and B
(Chung et al. 2014a). They reduced superoxide anion produc-
tion and elastase release by human neutrophils.
Strepsesquitriol, a new caged sesquiterpene isolated from
Streptomyces sp. SCSIO 10355, manifested a mild suppression
of TNF- production in RAW264.7 macrophages stimulated by
LPS. Its molecular formula is (1R,2R,4S,5S,8S,10S)-4,9,9,10-
tetramethyl-2,5,10-trihydroxytricyclo[6.2.1.0(1,5)] undecane.
TNF- is one of the well-recognized inflammatory cytokines.
Suppression of TNF- production is regarded as beneficial in
many inflammation-related diseases (Yang et al. 2013).
Lochmolins AD were sesquiterpenoids obtained from a
Taiwan soft coral Sinularia lochmodes. They prevented ele-
vation of COX-2 in RAW264.7 macrophages stimulated by
LPS. Lochmolins A could reduce the levels of induced COX-
2 to 1.7 % at 100 M, and it might be considered to be a
promising COX-2 inhibiting agent and exhibited in vitro
anti-inflammatory activity (Tseng et al. 2012).
Flavalin A from the Taiwan soft coral Lemnalia flava
exerted in vitro anti-inflammatory effects by inhibiting lipo-
polysaccharide (LPS)-induced upregulation of pro-
Appl Microbiol Biotechnol (2016) 100:16451666 1649

O
CH3
H3C H CH3
CH2
H3C
H O
H3C O
OH H
H3C
H OH

lemnalol rumphellaone C
H H O

O OH

H H
OH

rumphellol A rumphellol B

H3C
HO
O
O

OH
CH3 H
HO H3C
H3C CH3

strepsesquitriol lochmolin A
OH OH
H
O
CH3

O HO
H H
CH3 CH3

lochmolin B lochmolin C
H
HO
O
O CH3O

HO
H
CH3 CH3 H
CH3

lochmolin D flavalin A
Fig. 1 Structures of different marine products with anti-inflammatory activity

inflammatory proteins iNOS and COX-2 in RAW264.7 mac- Diterpenes

rophage cells. It inhibited protein expression of iNOS and
COX-2 with ED50 values of 4.8 0.3 and 6.2 0.6 g/ml,
respectively. Flavalin A and another nardosinane-type
sesquiterpenoid flavalin B also exerted neuroprotective action
(Lu et al. 2011).
Diterpenes are often present in soft corals as secondary metab-
olites with anti-inflammatory activities. These coral diterpenes
are sometimes classified as nuclear factor-kappa B (NFB)
signaling pathway modulators for regulating immune response
1650 Appl Microbiol Biotechnol (2016) 100:16451666

H
O O
O O
O O
O
HO
H3C CH3
O OH CH2
HO

O O O O

H3C
H
O CH2

excavatolide B crassumol E
OH
H O OH
HO
HO
H O

(1R,4R,2E,7E,11E)-cembra-2,7,11-trien-4-ol lobocrasol A
O

CH3
H O OH H2C O

HO CH2
O
HO H3C O
O CH3 CH3
O
OH
O

lobocrasol B pseudopterane diterpene

O
O S OH
H3C
O
CH3
H3C
H3C CH3 CH3
OH CH3
O S O H CH3
CH3 H
O
H
H HO
O
H
O S O
OH

solomonsterol A ergosta-7,22-dien-3-ol
Fig. 1 (continued)

(Gonzalez et al. 2013; Wei et al. 2011). They exhibit their anti-
inflammatory activity by inhibiting the activation of the path-
way at different levels (de las Heras and Hortelano 2009).
Excavatolide B, a diterpene from cultured Taiwan gorgo-
nian Briareum excavatum, downregulated mRNA expression
of COX-2 and iNOS in mouse macrophages challenged with
LPS. It mitigated intraplantar carrageenan-elicited nociception
and inflammation, including thermal hyperalgesia, mechani-
cal allodynia, weight-bearing deficits and paw edema and in-
flammation, and expression of iNOS (Lin et al. 2015).
Lobocrasols A and B and other cembranoid diterpenes
(crassumol E and (1R,4R,2E,7E,11E)-cembra-2,7,11-trien-
Appl Microbiol Biotechnol (2016) 100:16451666 1651

H3C H3C
CH3 CH3
CH3
CH3
H3C
H3C
CH3
CH3
H
HO

OH HO
compound 5 compound 7
O CH2
CH3 O CH2
CH3
H3C O
H H3C O
H
H H
H3C H H
O
O H O
H3C
sclerosteroid J sclerosteroid K
O CH2 CH2
CH3 CH3
H3C O O
H H

H H H H

HO CH3 O HO CH3 O
H H
O H O
H H H
HO H HO H

H O O H O O

CH3 CH3
sclerosteroid M sclerosteroid N
O CH3 O CH3
Br HO HO
Br
O O
Br N N
H H
convolutamydine A ISA147
H
H2C N O
O CH3

HO O N
H
CH3
O
N N CH2
CH3
H H

ISA003 neoechinulin B
Fig. 1 (continued)

4-ol) were isolated from the methanolic extract of the activation in HepG2 cells. NFB is highly activated at
Vietnamese soft coral Lobophytum crassum. Their in vitro sites of inflammation in various diseases (Tak and
anti-inflammatory activity was evaluated by the inhibitory Firestein 2001), and potent inhibition of NFB activation
effect on TNF--induced nuclear NFB transcriptional was observed for the isolated compounds. They also
1652 Appl Microbiol Biotechnol (2016) 100:16451666

CH2
H3C OH
CH3
H

HN HO
N CH3 O
H OH
O O O CH3

Chaetoglobosin Fex docosahexaenoic acid

O CH3
CH3 O
HO CH3 O
CH3
O O
O
eicosapentaenoic acid
CH3
O O
CH3 OH O CH3

5-hydroxy-3,6,7,8,3,4- hexamethoxyflavone
OH O OH OH O OH

H3C H3C
O OH O O OH O
CH3 CH3
CH3 Cl CH3

compound 3 compound 4
CH3 O OH

HO O OH

compound 11
Fig. 1 (continued)

downregulated the mRNA expression of COX-2 and metalloproteinase-9 elicited by 12-O-tetradecanoylphorbol-

iNOS (Cuong et al. 2014; Thao et al. 2014).
A pseudopterane diterpene isolated from the octocoral
Pseudopterogorgia acerosa was tested for its in vitro anti-
inflammatory effects on TNF- and Toll-like receptor-induced
response in macrophages. It suppressed the expression and se-
cretion of COX-2, IFN--induced protein 10, IL-1, IL-6,
iNOS, monocyte chemoattractant protein-1, NO, and TNF-
induced by LPS in primary murine macrophages. The diterpene
suppressed inhibitor B- (IB) breakdown and NFB acti-
vation. It also undermined expression of the costimulatory mol-
ecules CD80 and CD86, a characteristic feature of macrophage
activation. The diterpene compound also downregulated the
response of macrophages to TNF- and ligands for Toll-like
receptors 2 and 3 (Gonzalez et al. 2013).
Briarane-type diterpenes from the marine coral Briareum
excavatum exerted a pronounced repressive action on cutane-
ous vascular permeability, edema, and expression of inflam-
mation indicators COX-2, iNOS, and matrix
13-acetate. This inhibition was brought about by perturbing
the Akt/NF-B-mediated signaling. Expression of IL-6 and
TNF- in LPS-stimulated bone marrow-derived dendritic
cells was downregulated. The 8,17-epoxide of briarane-type
diterpenes was paramount in reducing IL-6 expression, and
substitution of the C-12 hydroxyl group in the diterpenes by
longer esters diminished the potency (Wei et al. 2011).
Steroids/sterols
Marine organisms, especially sponges, are a rich source of
steroids with potent anti-inflammatory activity. They work
by attenuating the activity of the immune system and sup-
pressing inflammation. Recently, steroidal compounds isolat-
ed from sponges could modulate farnesoid X and pregnane X
receptors (Fiorucci et al. 2012). Some of them (pregnane X
receptor agaonist) are effective in reducing intestinal inflam-
mation and NFB activity, which is responsible for the
Appl Microbiol Biotechnol (2016) 100:16451666
production of pro-inflammatory cytokines (Sepe et al. 2011).
Therefore, their discovery holds promise in the treatment of
inflammation-driven intestinal disorders.
Solomonsterol A, a selective pregnane X receptor (PXR)
agonist from the marine sponge Theonella swinhoei, mitigated
systemic inflammation and derangement of the immune sys-
tem in a mouse rheumatoid arthritis model. Solomonsterol A
prevented arthritic development caused by injection of
anticollagen antibodies into transgenic mice harboring a hu-
manized pregnane X receptor 2 was affected. Solomonsterol
A protected experimental animals from systemic inflamma-
tion as evidenced by arthritis score, blood levels of C-
reactive protein and inflammatory markers (IFN-, IL-17,
TNF-, and chemokines MIP1 and RANTES) (Mencarelli
et al. 2013).
The in vitro anti-inflammatory activities of pregnane-type
steroids from soft coral Scleronephthya gracillimum against
the accumulation of pro-inflammatory iNOS and COX-2 pro-
teins were evaluated. Sclerosteroids K and M reduced the
accumulation of iNOS, and sclerosteroids J, K, L, and N
forestalled the accumulation of COX-2 in LPS-stimulated
RAW264.7 macrophages (Fang et al. 2013).
Cis 11-eicosenoic acid, cis 11,14 eicosadienoic acid, and
ergosta-7,22-dien-3-ol from the spiny sea-star Marthasterias
glacialis demonstrated in vitro anti-inflammatory activity in
the inflammatory model RAW 264.7 cells challenged with
LPS. The mechanism of action of the compounds was distinct
as they modulated different levels of the inflammation path-
way. The levels of the inflammatory markers NFB, iNOS,
IL-6, and COX-2 were downregulated. Ergosta-7,22-dien-3-
ol displayed the highest activity, and maximum activity was
obtained when all compounds were tested in combination,
thus suggesting a potentially synergistic activity of both clas-
ses of metabolites (Pereira et al. 2014a).
Several steroids were isolated from the starfish Astropecten
polyacanthus. They showed in vitro inhibitory effect on pro-
inflammatory cytokine secretion. Steroids 5 and 7 downregu-
lated the generation of IL-6, IL-12 p40, and TNF- in LPS-
stimulated bone marrow-derived dendritic cells. Steroid 1 sup-
pressed generation of IL-6 and IL-12 p40. Compounds 2, 3, 4,
and 6 curtailed the production of IL-12 p40. Compounds 3
and 4 undermined the formation of TNF- and IL-6, respec-
tively (Thao et al. 2013).
Polysaccharides
Marine polysaccharides such as alginate, porphyran, fucoidan,
chitin, and chitin derivatives have been proved as
downregulators of allergic responses (Vo et al. 2015).
Polysaccharides from algae, of which most are sulfated, have
long been demonstrated to express anti-inflammatory activity
both in vitro and in vivo (Cardoso et al. 2010; Matsui et al.
2003; Medeiros et al. 2008) which is attributed to their
1653
structure and physicochemical characteristics (de Jesus
Raposo et al. 2015). Leiro et al. showed that the sulfate content
was important in stimulation of macrophages due to partici-
pation of the sulfate moiety in the interaction between poly-
saccharide and cell surface receptors (Leiro et al. 2007). Some
studies disclosed that the polysaccharides inhibited migration
of leukocytes to the inflammation sites, and in some cases, this
is P- and/or L-selectin dependent (Cumashi et al. 2007). Some
polysaccharides inhibited NO and prostaglandin E2 produc-
tion by suppressing iNOS and COX-2 expression (Kang et al.
2011), enhanced Th1 cell and suppressed Th2 cell responses
(Maruyama et al. 2005), and lowered the serum level of im-
munoglobulin E and the production of IFN- (Ishihara et al.
2005).
Sulfated polysaccharide from Porphyra haitanensis atten-
uated the tropomyosin-elicited allergic reaction by regulating
the imbalance of the Th1/Th2 immune response. When
injected intraperitoneally into a murine model of allergy pro-
duced by using tropomyosin, the polysaccharide inhibited the
allergic response by modifying serum IgE, IgG1, and IgG2a
levels in mice. When the polysaccharide was administered
before the initial tropomyosin immunization, the IgE concen-
tration fell by 34.2 % relative to the control group. Histamine
release was reduced and jejunal pathology was repaired when
the polysaccharide was delivered orally to tropomyosin-
sensitized mice. The mRNA expression of the tropomyosin-
elicited Th2 cytokines (IL-4, IL-5, and IL-13) in splenic lym-
phocytes in vitro was suppressed, but the expression of Th1
and regulatory cytokines (IFN- and IL-10) was augmented in
response to the polysaccharide treatment. IFN- secretion me-
diated by the Jun N-terminal kinase and Janus kinase 2 sig-
naling pathways was upregulated (Shi et al. 2015).
Polysaccharides from the marine red alga Digenea simplex
mitigated carrageenan-triggered edema and minimized in-
flammation elicited by dextran, histamine, serotonin, and bra-
dykinin. Neutrophil migration into the murine peritoneal cav-
ity and paws was also impeded. This action was followed by a
decline in the concentrations of TNF- and IL-1 in the peri-
toneal fluid (Pereira et al. 2014b).
Sulfated polysaccharide from the green marine alga
Caulerpa mexicana (Cm-SPs) exerted its analgesic activity
in mice via a peripheral mechanism without exhibiting any
t o x i c i t y. C a r r a g e e n a n - i n d u c e d p a w e d e m a a n d
myeloperoxidase activity in the paw were mitigated. Paw ede-
ma elicited by histamine and dextran, but not serotonin, was
alleviated, indicating that histamine is the main target
(Carneiro et al. 2014).
The hemoxigenase-1 pathway was involved in the anti-
inflammatory action of a sulfated polysaccharide from the
green seaweed Caulerpa racemosa which was devoid of tox-
icity. The leukocyte number in the rat peritoneal cavity
dropped and the paw edema caused by dextran and carrageen-
an was alleviated. The concentration of myeloperoxidase in
1654
the paw tissue of carrageenan-treated groups declined follow-
ing treatment with the polysaccharide. However, the afore-
mentioned anti-inflammatory action was abolished following
treatment with a specific NO phenotype inhibitor named ZnPP
IX (Ribeiro et al. 2014).
Alkaloids
Alkaloids are a group of cyclic compounds with an array of
pharmacological activities. They are found mainly in higher
plants, but many marine organisms also contain alkaloids
(Dembitsky 2002; Guven et al. 2010). Due to their great struc-
tural diversity, there is no clear-cut boundary for regular clas-
sification for alkaloids. It is difficult to characterize them, and
their mechanisms of inflammatory action vary in different
classes.
Convolutamydine A, an oxindole alkaloid from a marine
bryozoans, and its two analogs (ISA003 and ISA147)
inhibited the intraplantarly injected formalin-induced licking
response, leukocyte migration, NO formation, and expression
of COX-2, iNOS, IL-6, prostaglandin E2, and TNF-
(Fernandes et al. 2014).
Two diketopiperazine type indole alkaloids, neoechinulins
A and B, from the marine fungus Eurotium sp. SF-5989
exerted in vitro anti-inflammatory action on RAW264.7 mac-
rophages stimulated by LPS. Neoechinulin A downregulated
prostaglandin E2 and NO generation, as well as iNOS and
COX-2 expression. Neoechinulin A, but not neoechinulin B,
was devoid of adverse effects on cell viability. Under the in-
fluence of neoechinulin A, the secretion of IL-1 and TNF-
was diminished. Phosphorylation of p38 mitogen-activated
protein kinase was hindered, and activation of NFB in
LPS-stimulated RAW264.7 macrophages was impaired by
suppressing the phosphorylation and breakdown of IB.
Neoechinulin B also curtailed NO production (Kim et al.
2013). Neoechinulin A, isolated from marine-derived
Microsporum sp., downregulated the formation or expression
of reactive nitrogen species, reactive oxygen species, COX-2,
iNOS, IL-1, IL-6, prostaglandin E2, and TNF- in BV-2
microglia cells activated by oligomeric amyloid- 142.
Apoptosis of pheochromocytoma PC-12 cells mediated by
activated microglia; phosphorylation of mitogen-activated
protein kinase molecule p38, apoptosis signal-regulating ki-
nase 1; and nuclear translocation of NFB p65 and p50 sub-
units were downregulated. Neoechinulin A may be useful for
inhibiting neuroinflammation in Alzheimers disease
(Dewapriya et al. 2013).
Chaetoglobosin Fex (Cha Fex), a cytochalasan-based alka-
loid was isolated from marine-derived endophytic fungus
Chaetomium globosum. The in vitro anti-inflammatory effect
was shown by suppression of LPS-stimulated generation of
IL-6, monocyte chemotactic protein-1, and TNF- in perito-
neal macrophages and mouse macrophage cells RAW264.7.
Appl Microbiol Biotechnol (2016) 100:16451666
The alkaloid lowered the cytokine mRNA expression, im-
paired the LPS-elicited breakdown of IB and entry of the
p65 subunit of NFB into the nucleus, and reduced the phos-
phorylation of extracellular-signal-related kinase (ERK1/2),
p38, and c-Jun N-terminal kinase. The alkaloid suppressed
the upregulation of membrane-associated CD14 expression
both on RAW cells and human monocytes induced by LPS.
The anti-inflammatory activity of the alkaloid may be ascribed
to NFB inhibition as well as the negative regulation of
ERK1/2, p38, and JNK1/2 phosphorylation. These inhibitory
effects may also be due to the blocking of mCD14 expression
(Dou et al. 2011).
Fatty acids
Fatty acids from fish oil, like eicosapentaenoic acid (EPA) and
docosahexaenoic acid (DHA), showed positive results in in
vivo inflammatory disorders models (Calder 2015). Clinical
evidence indicates that these fatty acids are beneficial as a
dietary supplement in several inflammatory diseases including
rheumatoid arthritis (Fortin et al. 1995; Goldberg and Katz
2007), inflammatory bowel disease (Belluzzi et al. 1996),
and child asthma (Nagakura et al. 2000). However, the data
for inflammatory bowel disease and asthma are inconsistent,
and more studies need to be done. Several mechanisms under-
lying the anti-inflammatory actions of these fatty acids have
been elucidated. They include suppression of leukocyte che-
motaxis (Kirsch et al. 1988), and inhibition of adhesion mol-
ecule expression and leukocyte-endothelial adhesive interac-
tions (Collie-Duguid and Wahle 1996; Yamada et al. 2008),
decreased production of eicosanoids like prostaglandins and
leukotrienes from arachidonic acid (Miller et al. 1989), re-
duced production of inflammatory cytokines (Oh et al.
2010), modified T cell reactivity (Petursdottir and
Hardardottir 2009), as well as increased production of anti-
inflammatory endocannabinoids (Balvers et al. 2010) and in-
flammation resolving mediators termed resolvins, protectins,
and maresins (Serhan et al. 2008).
Physical exercise can bring about a tilting of the balance
between cytokines producing an immunosuppressive state
and other cytokines eliciting an inflammatory state. Intake of
fish oil adjusts the imbalance resulting after vigorous exercise
and shifts the balance between T helper cells toward the Th2
phenotype. Fish oil curtailed the generation of interleukin and
tumor necrosis factor in elite paddlers, and augmented the
formation of IL-6, IFN-, and IL-10 while leaving IL-4 secre-
tion unaffected (Delfan et al. 2015).
EPA and DHA suppressed macrophage infiltration and an-
giotensin II infusion-induced abdominal aortic aneurysm in
apolipoprotein E-deficient mice, and downregulated the ex-
pression of matrix metalloproteinase-2, matrix metalloprotein-
ase-9, monocyte chemoattractant protein-1, transforming
growth factor-, TNF-, and vascular cell adhesion
Appl Microbiol Biotechnol (2016) 100:16451666
molecule-1 in the aortas. Arginase 2 (a marker of pro-
inflammatory macrophages) expression was downregulated
and Ym1 (a marker of anti-inflammatory macrophages) ex-
pression was upregulated. Similar findings were reported from
peritoneal macrophages. EPA and DHA inhibited formation
of abdominal aortic aneurysm through repression of aortic and
macrophage-mediated inflammation (Yoshihara et al. 2015).
EPA inhibited insulin resistance, obesity and inflammation,
and reversed adipocyte inflammation and hypertrophy in mice
brought about by a high-fat diet. It also regulated mitochon-
drial function by promoting fatty acid oxidation and oxygen
consumption (LeMieux et al. 2015).
Proteins
Usually, marine lectins were found to possess anti-
inflammatory activity. However, the detailed mechanism has
yet to be clarified. But it was suggested that the carbohydrate-
binding site of the lectin was involved in its action (Cheung
et al. 2015a).
Lectin from the green seaweed Caulerpa cupressoides, ad-
ministered intravenously half an hour before injection of zy-
mosan into the left temporomandibular joint, mitigated
zymosan-elicited arthritis and mechanical hypernociception
in rats, and suppressed leukocyte accumulation in the synovial
fluid as indicated by myeloperoxidase activity. On the other
hand, treatment with the opioid receptor antagonist naloxone
or ZnPP-IX (which inhibits the heme oxygenase-1 pathway)
failed to abolish the activity of the lectin, signifying that the
naloxone-sensitive opioid and heme oxygenase-1 pathways
are not implicated in the action of the lectin. The lectin
prevented leukocyte influx and TNF- and IL-1 expression
in the temporomandibular joint. Hence, the mechanism with
which the lectin attenuates temporomandibular joint hyper-
nociception and inflammation relies partly on suppression of
IL-1 and TNF-. The lectin may be useful for investigating
disorders affecting the temporomandibular joint (da
Conceicao Rivanor et al. 2014).
Holothuria grisea agglutinin is a thermostable dimeric
228-kDa lectin from the sea cucumber. When injected intra-
venously, the agglutinin prevented carrageenan-elicited neu-
trophil migration into the peritoneal cavity. The agglutinin
reduced myeloperoxidase activity and elevated the blood con-
centration of NO (Moura Rda et al. 2013).
The marine algal lectins Caulerpa cupressoides lectin,
Pterocladiella capillacea lectin, and Solieria filiformis lectin
were devoid of cytotoxicity. Their in vitro anti-inflammatory
effects were demonstrated by enhancing IL-10 formation but
did not affect IFN- and IL-2 production in murine
splenocytes. All three lectins increased IL-6 generation.
Caulerpa cupressoides lectin and Pterocladiella capillacea
lectin but not Solieria filiformis lectin augmented nitrite re-
lease (Monteiro Abreu et al. 2012).
1655
Host defense peptides, also known as antimicrobial pep-
tides, are part of the innate immune system, found among all
complex living organisms (Mansour et al. 2014). These pep-
tides may act as anti-inflammatory, immunosuppressive, or
immunostimulatory agents which are mediated through cyto-
kine and chemokine production. In case of anti-inflammatory
action, the peptides suppress the induced production of proin-
flammatory cytokines such as TNF-, IL-6, and IL-8, and
enhance the production of anti-inflammatory mediators in-
cluding IL-10 and chemokines such as monocyte chemotactic
protein 1 (Conlon 2015).
Epinecidin-1 was a host defense peptide isolated from a
marine grouper, Epinephelus coioides. In vivo study showed
that co-injection of synthetic epinecidin-1 and Pseudomonas
aeruginosa into mice resulted in increased circulating levels
of IgG1 and IL-10 (anti-inflammatory cytokine), indicating
that the peptide could enhance the Th2 cell adaptive immune
response to infection (Lee et al. 2012). Another host defense
peptide, chrysophsin-1 from the red sea bream Chrysophrys
major, inhibited the release of TNF- in macrophage cell line
RAW264.7 cells, indicating its in vitro anti-inflammatory ac-
tion (Hsu et al. 2011).
Others
Lyprinol is an oil extract from Perna canaliculus (also known
as New Zealand green-lipped mussel) containing a complex
mixture of triglycerides, sterol esters, sterols, polar lipids and
free fatty acids. It showed significant anti-inflammatory activ-
ity and relieved symptoms of arthritis in an animal model. The
mechanism of anti-inflammatory action of lyprinol remains to
be elucidated. It was proposed that lyprinol exerts the effect
through inhibition of both 5-LOX and COX arachidonate ox-
ygenation pathways (Whitehouse et al. 1997) and reduction of
pro-inflammatory leukotriene B4 production in monocytes
(Dugas 2000). Tenikoff et al. showed that lyprinol may be
useful in improving symptoms of inflammatory bowel disease
in mice (Tenikoff et al. 2005). There are several clinical stud-
ies on lyprinol which have shown significant anti-
inflammatory activity in osteoarthritis, rheumatoid arthritis,
and asthma patients (Cho et al. 2003; Emelyanov et al.
2002; Gruenwald et al. 2004).
A dietary supplement of either fish oil with an abundance
of -3 polyunsaturated fatty acid or lyprinol, which was a
mixture containing olive oil, vitamin E, and marine lipids,
was administered to mice prior to and during allergic airway
disease in a murine model of the disease caused by ovalbumin.
Lyprinol suppressed eosinophil accumulation in the broncho-
alveolar lavage fluid, the pulmonary tissue enveloping the
airways and the blood, and diminished mucus hypersecretion
in the lungs and airway hyperresponsiveness. Fish oil did not
have a similar action. The actions of lyprinol were not accom-
panied by changes in serum IgG1 or IgG2a, or the liberation of
1656
IL-4, IL-5, IL-13, and IFN-. Hence, dietary lyprinol may be
useful for preventing asthma (Wood et al. 2010).
A 3-week administration of the PCSO-524 (lyprinol/omega
XL) diet (the marine lipid fraction of the New Zealand green-
lipped mussel with an abundance of omega-3 fatty acids) mit-
igated the maximum fall in post-eucapnic voluntary hyper-
pnea forced expiratory volume in 1 s (FEV1) relative to the
group on a placebo diet. Declines in concentrations of
cysteinyl leukotrienes, and 8-isoprostane in exhaled breath
condensate, and urinary 9, 11- prostaglandin F2 and
Clara (CC16) protein, but better asthmatic symptom scores
and pH in exhaled breath condensate were observed. Thus,
the PCSO-524 (lyprinol/omega XL) diet may be useful for
hyperpnea-induced bronchoconstriction and asthma
(Mickleborough et al. 2013).
Flavones are a class of flavonoids widely present in our diet
such as fruits and vegetables. They exhibit a myriad of bene-
ficial health effects like anti-inflammatory activities.
A 5-hydroxy-3,6,7,8,3,4-hexamethoxyflavone from the
ethanolic extract of Hizikia fusiforme mitigated NO generation
triggered by LPS via attenuating the expression of iNOS in
BV2 microglia. It blocked LPS-induced phosphorylation of
IB, resulting in suppression of the nuclear translocation of
NFB subunits, namely p65 and p50, which are important
molecules involved in the regulation of iNOS expression.
Pyrrolidine dithiocarbamate, a specific NFB inhibitor, along
with 20S proteasome inhibitor, significantly inhibited LPS-
induced iNOS expression, which indirectly suggested that
5HHMF downregulated iNOS expression by suppressing
NFB activity. Thus, it was found that 5HHMF enhanced
heme oxygenase-1 (HO-1) expression via nuclear factor-
erythroid 2-related factor 2 activation. In addition, cobalt pro-
toporphyrin, a specific HO-1 inducer, predominantly sup-
pressed LPS-induced NO production. In contrast, zinc proto-
porphyrin, a specific HO-1 inhibitor, showed a partial sup-
pressive effect of 5HHMF on LPS-induced NO production.
Further, 5HHMF increased specific DNA-binding activity of
Nrf2, and transient knockdown with Nrf2 siRNA subsequent-
ly reversed 5HHMF-induced NO inhibition, which was
followed by suppression of HO-1 activity. It indicated that
5HHMF suppressed NO production through modulation of
iNOS, consequently suppressing NFB activity and induction
of Nrf2-dependent HO-1 activity (Kang et al. 2013). It has
been reported in several studies that HO-1 possessed benefi-
cial therapeutic effects against inflammatory diseases
(Husseini et al. 2015; Wei et al. 2015). It was also found that
5HHMF could mitigate prostaglandin E2 and NO formation
and undermined expression of iNOS and COX-2 in LPS-
stimulated RAW 264.7 mouse macrophage cells. The secre-
tion of TNF- and IL-1, and the LPS-elicited nuclear trans-
location of NFB implicated in the abrogation of inhibitory
IB breakdown and reduction in nuclear p65 concentrations,
were suppressed. The in vitro anti-inflammatory action of the
Appl Microbiol Biotechnol (2016) 100:16451666
polyhydroxyflavone probably involved suppression of iNOS,
COX-2, and cytokine expression by impairing NFB activa-
tion through IB breakdown in macrophages (Kim et al.
2014).
This polyhydroxyflavone, also occurring in citrus peel,
minimized skin inflammation in mice brought about by 12-
O-tetradecanoyl-phorbol-13-acetate through inhibiting the
mitogen-activated protein kinase and phosphatidylinositol 3
kinase/Akt signaling pathways (Sergeev et al. 2006). In addi-
tion, three xanthone derivatives found in cultures of a sponge-
derived fungus Stachybotrys sp. HH1 ZDDS1F1-2 exhibited
in vitro cycloooxygenase inhibitory activity (Qin et al. 2015).
Marine-derived anti-inflammatory agents in clinical trials
and on market
This section introduces the marine natural products that are
currently being or have been evaluated in preclinical studies or
clinical trials as anti-inflammatory agents. Many aforemen-
tioned natural products from marine organisms have been
proven in vitro and in vivo to have anti-inflammatory potency.
They could be used in the unmodified form or a derivative
form as potential drug candidates. As a matter of fact, a huge
number of bioactive molecules is known out of a probable
total of one million compounds isolated from marine species
(Bhatnagar and Kim 2012), but only a minute portion of these
molecules were approved for clinical trial and even less could
reach the market. Currently, only seven have been approved as
prescription drugs and one as an over-the-counter drug (Ng
et al. 2015). There are no marine-derived anti-inflammatory
drugs currently on the market. Figure 2 shows some of the
marine lead compounds that are currently being or have been
evaluated in preclinical studies or clinical trials as anti-
inflammatory agents. Table 2 summarizes compounds report-
ed to be in preclinical or clinical development and compounds
discontinued from development.
Anabaseine is a nemertine alkaloid toxin isolated from sev-
eral marine worms in Phylum Nemertea (Coates et al. 1971).
Its synthetic derivative 3-(2,4-dimethoxybenzylidene)-
anabaseine (also known as GTS-21 or DMXBA) has been
found to preferentially stimulate 7 nicotinic choline recep-
tors, which are expressed on neurons and astrocytes in the
central nervous system and on peripheral macrophages
(Kem et al. 2004). GTS-21 inhibits production of pro-
inflammatory cytokines through its effects on 7 nicotinic
acetylcholine receptors on macrophage (Cai et al. 2009;
Pavlov et al. 2007; Rosas-Ballina et al. 2009). Hence, these
findings disclose the anti-inflammatory effect of GTS-21 and
show its potential development as a new human anti-
inflammatory therapeutic. The pro-inflammatory cytokine
production in whole blood culture from rheumatoid arthritis
patients was found to be significantly attenuated by GTS-21.
The results suggest that it is possible to target the 7 nicotinic
Appl Microbiol Biotechnol (2016) 100:16451666 1657

acetylcholine receptors dependent control of cytokine release
pharmacologically in patients with reduced vagus nerve activ-
ity (Bruchfeld et al. 2010). As the receptor agonists improve
the clinical course of collagen-induced arthritis in an animal
model (Hu et al. 2014; van Maanen et al. 2009), it may be
possible in the future to explore whether GTS-21 can be used
as a potential treatment for rheumatoid arthritis patients. It also
showed nootropic (Kitagawa et al. 2003) and neuroprotective
effects (Meyer et al. 1998) and was investigated as a treatment
for schizophrenia and Alzheimers disease.
A phase 1 clinical trial yielded evidence for improvement
of cognitive and negative symptoms in schizophrenia treat-
ment by GTS-21 (Olincy et al. 2006). Nevertheless, the results
from the phase II trial did not show satisfactory enhancement
in the MATRICS cognitive measures over the three treatment
arms (Freedman et al. 2008). Thus, the development of GTS-

H
O H

N N O

H H O H
O O

O H3C O
H3C
H3C CH3

O CH3
CH3
CH3

3-(2,4-dimethoxybenzylidene)-anabaseine pseudopterosin A
OH H3C
CH3
O
H3C
CH3
CH3 H3C CH3
CH3
CH3

H
O OH
HO OH
H
OH OH O O OH

contignasterol manoalide
CH3
H

H3C CH3

CH3
O
CH3
O O
O
CH3

scalaradial
Fig. 2 Marine lead compounds that are currently being or have been evaluated in preclinical studies or clinical trials as anti-inflammatory agents
1658 Appl Microbiol Biotechnol (2016) 100:16451666

Table 2 Overview of marine natural products with anti-inflammatory activity under preclinical and clinical development or discontinued from
development

Compound Source Current stage

3-(2,4-Dimethoxybenzylidene)-anabaseine Synthetic alkaloid derivative of anabaseine Clinical trial for anti-inflammatory effectsa
(also known as GTS-21 or DMXBA) from marine nemertine Phase I/II for attention-deficit hyperactivity disorder
Phase II for schizophrenia
Phase II for Alzheimers disease
Pseudopterosin A Diterpene glycoside from Symbiodinium sp.Preclinical test for atopic dermatitisb
As an ingredient in a marketed cosmetic
skin care product called Resilience
Methopterosin Methyl ether derivative of pseudopterosin A Phase I/II for wound healingb
Contignasterol (also known as IZP 94,005) Steroid from Petrosia contignata Preclinical test for antiasthmatic effectsb
IPL576,092 Synthetic analog of contignasterol Phase II for antiasthmatic effectsb
Manoalide Nonsteroidal sesterterpenoid from Phase II for anti-inflammatory effectsb
Luffariella variabilis
4-(1-Acetoxytridecyl)-5-hydroxy-2(5H)furanone Analog of manoalide Preclinical test for anti-inflammatory effectsb
(also known as AGN 190383)
Scalaradial Terpenoid from Cacospongia mollior Preclinical test for anti-inflammatory effectsb
a
Study phase not provided
b
Preclinical or clinical tests discontinued

21 as a therapeutic for neurocognitive dysfunction in schizo-
phrenia requires continued phase II clinical trial testing.
Currently, clinical studies on safety and efficacy in adults with
attention-deficit hyperactivity disorder (ClinicalTrials.gov
Identifier NCT00419445), cognition improvement in schizo-
phrenia (ClinicalTrials.gov Identifier NCT01400477), and
anti-inflammatory effects of GTS-21 in human endotoxemia
model (ClinicalTrials.gov Identifier NCT00783068) have just
been completed. Moreover, several clinical trials are ongoing
at present, including phase I trial for autistic treatment, phase I
trial for body mass index effects and neuronal response, phase
II trial for schizophrenia treatment, and phase II trial for
smoking behavior and neurocognitive functions with
ClinicalTrials.gov Identifier NCT02111551, NCT02458313,
NCT00100165, and NCT02432066, respectively.
A study in 2002 on 18 healthy male subjects showed an
apparent relationship between GTS-21 exposure and magni-
tude of cognitive response (Kitagawa et al. 2003). Another
study (ClinicalTrials.gov Identifier NCT00414622) was con-
ducted in 2007 to investigate the safety and tolerability of
GTS-21 in patients with probable Alzheimers disease. Since
then, there have been no further reports or clinical studies on
GTS-21 as possible treatment for Alzheimers disease.
Pseudopterosins are described as a class of diterpene gly-
cosides which show potent anti-inflammatory and analgesic
activities. Pseudopterosins AD were first members of this
class that were isolated in 1986 from the Caribbean octocoral
Pseudopterogorgia elisabethae (Look et al. 1986). But, later
investigations revealed that the pseudopterosin biosynthesis
originated from symbiotic dinoflagellate Symbiodinium sp.
inhabiting inside the coral (Mydlarz et al. 2003). They have
been shown to exhibit anti-inflammatory, analgesic (Look
et al. 1986), wound healing (Mayer et al. 2010) and
irritation-preventing (Rouhi 1995) activities.
Pseudopterosin mediates the anti-inflammatory action by
suppressing eicosanoid release from the inflammatory cells
through the inhibition of phospholipase and 5-lipoxygenase
(Potts et al. 1992). Pseudopterosin A was found to inhibit
prostaglandin E2 and leukotriene C4 production in
zymosan-stimulated murine peritoneal macrophages release.
The crucial roles played by prostaglandin and leukotriene in
asthma, arthritis, and inflammatory bowel disease suggest that
pseudopterosins can be used as novel therapeutics for these
diseases (Mayer et al. 1998). A preclinical test of
pseudopterosin as an anti-inflammatory agent for topical use
in atopic dermatitis has been completed but the study was
discontinued (Rouhi 1995). The pseudopterosin extract was
included in a marketed cosmetic skin care product called
Resilience. It can prevent skin irritation caused by exposure
to the sun or chemicals (Rouhi 1995).
Pseudopterosins aid in wound healing, probably through
stimulation of angiogenesis. Thus, the results offer extra mo-
tivation to investigate the potentials of pseudopterosins.
Extensive preclinical studies on a methyl ether derivative of
pseudopterosin A, methopterosin, showed that wound healing
was speeded up and re-epithelialization activity in partial and
full thickness wounds was observed in several animal models
(Mayer et al. 2010). Phase I and II clinical trials of
methopterosin as a wound healing agent were completed,
and the results revealed an increase in reepithelialization and
qualitative improvement during early wound repair. However,
the low aqueous solubility of methopterosin limits its efficacy
Appl Microbiol Biotechnol (2016) 100:16451666
in biological model systems. Because of this major obstacle,
the study was also discontinued (Martins et al. 2014).
Contignasterol was isolated from extracts of the marine
sponge Petrosia contignata found in Papua New Guinea
(Burgoyne et al. 1992). This highly oxygenated steroid is a
strong antihistamine agent which inhibited histamine release
in anti-immunoglobulin E activated rat peritoneal mass cells
(Takei et al. 1994). It also demonstrated antiasthmatic proper-
ties in both in vivo and in vitro models. Contignasterol inhibited
ovalbumin-induced contractions of tracheal tissue in vitro and
protected against the bronchoconstriction produced during
acute ovalbumin challenge in sensitized guinea pigs (Bramley
et al. 1995). Later reports revealed that contignasterol was top-
ically active and showed anti-inflammatory effects in the tra-
cheobronchial airways on allergen-induced plasma protein ex-
udation inhibition in the sensitized guinea pig model (Coulson
and ODonnell 2000). IPL576,092, a synthetic analog of
contignasterol, was tested in in vivo models of ovalbumin-
induced bronchoconstriction and airway inflammation.
Protective effect was found in four different animal models
without any synthetic glucocorticoid therapy-associated side
effects. IPL576,092 significantly soothed the asthmatic symp-
toms, indicating its therapeutic potential as a leukocyte sup-
pressing anti-inflammatory drug (Kasserra et al. 2004).
Though statistical significance was not attained, positive results
were obtained from a phase II clinical trial evaluating IPL576,
092 as an oral treatment for asthma. An improvement in late-
phase bronchoconstriction, airway hyper-reactivity to hista-
mine provocation and prevention of eosinophil increase in in-
duced sputum was found. However, it is now withdrawn from
development in further clinical phases (Martins et al. 2014).
Manoalide a nonsteroidal sesterterpenoid antibiotic from the
marine sponge Luffariella variabilis (de Silva and Scheuer
1980) manifests analgesic and anti-inflammatory activities.
Manoalide is a phospholipase A2 (PLA2) inhibitor and thus
suppresses the in vitro synthesis of inflammatory lipids like
prostaglandins, leukotrienes, and platelet activating factor (de
Freitas et al. 1984; Mayer et al. 1988). It was also tested in a
number of in vivo models (Mayer and Spitzer 1993; Sanchez
and Moreno 1999; Schrier et al. 1996), and the results showed
that it is active in acute and subacute animal models of inflam-
mation. It has been clinically evaluated in man and reached
phase II clinical studies as a topical anti-inflammatory drug.
Due to disappointing results in treatment of psoriatic patients
arising from insufficient bioavailability, the clinical develop-
ment of manoalide was discontinued (Tibes and Friebe 1997).
Manoalide, however, still served as a template for the design of
new analogs for anti-inflammatory agents. One example is
AGN 190383, a manoalide analogue which inhibits phorbol
ester-induced mouse ear edema when applied topically (De
Vries et al. 1991). Another analog, WO9528394, was disclosed
as an anti-inflammatory lead compound, but no experimental
data on in vitro and in vivo activity or human pharmacology are
1659
available. WY-19735 and WAY-125,353 are two other
manoalide analogs which have once been announced for clin-
ical development, but unfortunately no further progress has
been made (Tibes and Friebe 1997).
Another marine natural product isolated from the sponge
(Cacospongia mollior) known as scalaradial (de Carvalho and
Jacobs 1991) possesses anti-inflammatory properties in vitro
and in vivo. This terpenoid inhibited phospholipase A2 and
blocked arachidonic acid release in stimulated neutrophils
(Jacobson and Schrier 1993). It also reduced edema formation
in phorbol ester treated-mouse ears when applied topically
(Marshall et al. 1994). It has been suggested for development
of anti-inflammatory agents. Unfortunately, no data have been
reported and its development is likely no longer pursued
(Tibes and Friebe 1997).
The first marine-derived natural product, cytarabine, be-
came available in the market for cancer treatment in 1969. It
took over 30 years for another natural product, ziconotide, to
secure approval and become part of the pharmacopeia in 2004.
Since then, several other marine natural products or deriva-
tives have been marketed or investigated in current preclinical
and clinical studies. Continued pharmacological research will
contribute to enhance the marine pharmaceutical clinical pipe-
line. There is a strong likelihood for these products to be
included in the future pharmacopeia.
Conclusion
The process of drug research and development is lengthy,
tough, and costly. It may necessitate decades of hard work,
screening of millions of compounds, and investment of bil-
lions of dollars in order to bring one drug to the market. The
process begins from target identification, validation, and lead
discovery (Hughes et al. 2011). A target, in a broad sense, can
be applied to biological entities including proteins, genes, and
RNA or biological phenomena, including molecular func-
tions, pathways, and phenotypes, involved in the disorder of
interest, on which the Bpotential drug^ is meant to act (Rask-
Andersen et al. 2011).
Data mining employs a bioinformatics approach to help
identify and select potential disease targets. It leads to a signif-
icant increase in target identification (Andrews and Sanger
2014; Lotsch et al. 2015; Yang et al. 2012). Another approach
is to use phenotypic screening to identify disease relevant tar-
gets (Chang and Kwon 2015). When the target is identified, it
needs to be validated. The process is conducted in animal or
human primary cells, cell lines, tissues, explants from patients
with the relevant disease, or humanized animal models of the
relevant diseases (Knowles 2013). Transgenic (genes knock-in
and knockout) animals are an attractive validation tool as they
involve whole animals, and these animals closely simulate what
happens during treatment (Jones et al. 2013; Rakhade et al.
1660
2012). However, the use of transgenic animals is expensive and
time-consuming. Hence, the use of small interfering RNA
(siRNA) has become increasingly popular for target validation.
These siRNAs base-pair to their target mRNA to be silenced
and induce cleavage of the mRNA, thereby preventing it from
being used as a translation template (Jimenez-Sanchez et al.
2015). Another useful tool for validation known as chemical
genomics, which is defined as the study of genomic responses
to chemical compounds, has come forward recently. It deter-
mines the broad, conditional effects of chemical libraries on
whole biological systems (Bredel and Jacoby 2004; Khare
et al. 2015; Zanders et al. 2002).
The final major component of early drug discovery project
is lead discovery process. A lead compound may come from
different sources like natural products (Sharma and Gupta
2015), combinatorial chemistry (Guido et al. 2011), or rational
drug design (Kellici et al. 2015). The lead compounds are
often tested by high-throughput screenings which screen the
entire compound library directly against the drug target (Fox
et al. 2006; van der Westhuyzen et al. 2015). It allows millions
of essays to be conducted rapidly using robotics, data process-
ing, control software, liquid handling devices, and sensitive
detectors. The lead is usually suboptimal and requires struc-
tural modification, in order to improve its potency, selectivity,
pharmacokinetic parameters, to acquire more Bdruglikeness.^
This process is known as lead optimization which is achieved
by employing knowledge of the structure-activity relationship
(Wang et al. 2015) or structure-based design (Staker et al.
2015). It is subjected to various assays designed to provide
important information with regard to in silico and in vitro
absorption, distribution, metabolism, excretion, and toxicity
(ADMET) properties, as well as drug efficacy in animal
models (Gleeson and Montanari 2012; Xiao et al. 2015).
Most of the drugs we used today are derived from natural
products (Newman and Cragg 2007). The investigations
aiming at searching novel active compounds were once limit-
ed to terrestrial organisms but have now been extended to
marine organisms. A range of marine natural products with
exploitable activities has been reported which includes anti-
cancer, anti-inflammatory, antidiabetic, antibacterial, antiviral,
antifungal, antituberculosis, antiprotozoal, immunological,
and neurological disorders (Blunt et al. 2015; Mayer et al.
2013; Villa and Gerwick 2010). Many investigators and phar-
maceutical companies are dedicated to research on marine
natural products with the intent to develop them into potential
therapeutic drugs. But, there is a general tendency that more
attention was paid to anticancer drugs. More resources and
efforts have been invested in the pharmacological research,
discovery, and development on anticancer drugs than other
drugs like anti-inflammatory drugs. However, research on
anti-inflammatory drug development is gaining in importance
as researchers have found more evidence relating chronic in-
flammation to several chronic diseases. Many inflammatory
Appl Microbiol Biotechnol (2016) 100:16451666
markers in our body are directly or indirectly linked to cardio-
vascular diseases, cancer, diabetes, asthma, and Alzheimers
disease. Besides, the healthy cells sometimes abnormally in-
duce an immune response attack on joints, connective tissues,
and nerves. This is another example of inflammation associ-
ated with autoimmune diseases like multiple sclerosis, rheu-
matoid arthritis, and lupus (He et al. 2015).
At present, several promising marine-derived drugs that
reached preclinical assessment and clinical trials were for
anticancer, antiviral, and analgesic applications. In terms of
evaluating marine natural products for future pharmaceuti-
cal application, despite the abundance of unique marine
natural products identified, the extremely low quantity of a
given compound of interest that can be isolated from marine
organisms may be a big hurdle which impedes evaluation of
in vivo bioactivities and development for pharmaceutical
applications. Fortunately, due to the recent advancement
in aquaculture technologies, aquacultural cultivation of var-
ious types of specific soft corals is becoming possible (Chen
et al. 2011). As a result, more abundant and routine prepa-
rations of experimental materials will become available for
global distribution and collaborative research purposes.
Nonetheless, the vast volume of marine organisms and the
small base of knowledge so far assembled on soft coral-
derived marine chemicals calls for increased international
cooperation in this field.
New technologies and close collaborations between insti-
tutional and industrial investigators will be crucial to ensure
the future success of marine peptides as novel therapeutics that
can make a vital contribution to the treatment or prevention of
various diseases.
Acknowledgments We gratefully acknowledge the award of Health
and Medical Research Fund research grants (number 12110282 and
12131221) from Food and Health Bureau, Hong Kong Special Adminis-
tration Region Government, and research grants from National Natural
Science Foundation of China (no. 81201270 and 81273275).
Compliance with ethical standards
Conflict of interest The authors declare no conflict of interest.
Ethical statement This article does not contain any studies with human
participants or animals performed by any of the authors.
References
Andrews PL, Sanger GJ (2014) Nausea and the quest for the perfect anti-
emetic. Eur J Pharmacol 722:10821. doi:10.1016/j.ejphar.2013.09.
072
Anthwal A, Thakur BK, Rawat MS, Rawat DS, Tyagi AK, Aggarwal BB
(2014) Synthesis, characterization and in vitro anticancer activity of
C-5 curcumin analogues with potential to inhibit TNF-alpha-
Appl Microbiol Biotechnol (2016) 100:16451666
induced NF-kappaB activation. Biomed Res Int 2014:524161. doi:
10.1155/2014/524161
Balvers MG, Verhoeckx KC, Plastina P, Wortelboer HM, Meijerink J,
Witkamp RF (2010) Docosahexaenoic acid and eicosapentaenoic
acid are converted by 3T3-L1 adipocytes to N-acyl ethanolamines
with anti-inflammatory properties. Biochim Biophys Acta
1801(10):110714. doi:10.1016/j.bbalip.2010.06.006
Belluzzi A, Brignola C, Campieri M, Pera A, Boschi S, Miglioli M (1996)
Effect of an enteric-coated fish-oil preparation on relapses in
Crohns disease. N Engl J Med 334(24):155760. doi:10.1056/
NEJM199606133342401
Bhatnagar I, Kim SK (2012) Pharmacologically prospective antibiotic
agents and their sources: a marine microbial perspective. Environ
Toxicol Pharmacol 34(3):631643. doi:10.1016/j.etap.2012.08.016
Blunt JW, Copp BR, Keyzers RA, Munro MH, Prinsep MR (2015)
Marine natural products. Nat Prod Rep 32(2):116211. doi:10.
1039/c4np00144c
Bramley AM, Langlands JM, Jones AK, Burgoyne DL, Li Y, Andersen
RJ, Salari H (1995) Effects of IZP-94005 (contignasterol) on
antigen-induced bronchial responsiveness in ovalbumin-sensitized
guinea-pigs. Br J Pharmacol 115(8):14338
Bredel M, Jacoby E (2004) Chemogenomics: an emerging strategy for
rapid target and drug discovery. Nat Rev Genet 5(4):26275. doi:10.
1038/nrg1317nrg1317
Bruchfeld A, Goldstein RS, Chavan S, Patel NB, Rosas-Ballina M, Kohn
N, Qureshi AR, Tracey KJ (2010) Whole blood cytokine attenuation
by cholinergic agonists ex vivo and relationship to vagus nerve
activity in rheumatoid arthritis. J Intern Med 268(1):94101. doi:
10.1111/j.1365-2796.2010.02226.x
Burgoyne DL, Andersen RJ, Allen TM (1992) Contignasterol, a highly
oxygenated steroid with the unnatural 14.beta configuration from
the marine sponge Petrosia contignata Thiele, 1899. J Org Chem
57(2):525528. doi:10.1021/jo00028a024
Cai B, Chen F, Ji Y, Kiss L, de Jonge WJ, Conejero-Goldberg C, Szabo C,
Deitch EA, Ulloa L (2009) Alpha7 cholinergic-agonist prevents
systemic inflammation and improves survival during resuscitation.
J Cell Mol Med 13(9B):377485. doi:10.1111/j.1582-4934.2008.
00550.x
Calder PC (2015) Marine omega-3 fatty acids and inflammatory process-
es: effects, mechanisms and clinical relevance. Biochim Biophys
Acta 1851(4):469484. doi:10.1016/j.bbalip.2014.08.010
Cardoso ML, Xavier CAC, Bezerra MBE, Paiva AOA, Carvalho MFG,
Benevides NMB, Rocha FAC, Leite EL (2010) Assessment of
zymosan-induced leukocyte influx in a rat model using sulfated
polysaccharides. Planta Med 76(02):113119. doi:10.1055/s-0029-
1186003
Carneiro JG, Rodrigues JA, de Sousa Oliveira Vanderlei E, Souza RB,
Quindere AL, Coura CO, de Araujo IW, Chaves HV, Bezerra MM,
Benevides NM (2014) Peripheral antinociception and anti-
inflammatory effects of sulphated polysaccharides from the alga
Caulerpa mexicana. Basic Clin Pharmacol Toxicol 115(4):33542.
doi:10.1111/bcpt.12234
Chang J, Kwon H (2015) Discovery of novel drug targets and their func-
tions using phenotypic screening of natural products. J Ind
Microbiol Biotechnol. doi:10.1007/s10295-015-1681-y
Chen BW, Chao CH, Su JH, Tsai CW, Wang WH, Wen ZH, Huang CY,
Sung PJ, Wu YC, Sheu JH (2011) Klysimplexins I-T, eunicellin-
based diterpenoids from the cultured soft coral Klyxum simplex. Org
Biomol Chem 9(3):83444. doi:10.1039/c0ob00351d
Cheung RCF, Wong JH, Pan W, Chan YS, Yin C, Dan X, Ng TB (2015a)
Marine lectins and their medicinal applications. Appl Microbiol
Biotechnol 99(9):37553773. doi:10.1007/s00253-015-6518-0
Cheung TS, Song TH, Ng TB, Wu FH, Lao LX, Tang SC, Ho JC, Zhang
KY, Sze SC (2015b) Therapeutic effects of herbal chemicals in
Traditional Chinese Medicine on Alzheimers Disease. Curr Med
Chem 22(19):2392403
1661
Cho SH, Jung YB, Seong SC, Park HB, Byun KY, Lee DC, Song EK,
Son JH (2003) Clinical efficacy and safety of Lyprinol, a patented
extract from New Zealand green-lipped mussel (Perna Canaliculus)
in patients with osteoarthritis of the hip and knee: a multicenter 2-
month clinical trial. Eur Ann Allergy Clin Immunol 35(6):2126
Choi YJ, Kim N, Lee JY, Nam RH, Chang H, Seo JH, Kang KK, Kim HJ,
Lee HS, Lee DH (2014) Protective effects of garlic extract, PMK-
S005, against nonsteroidal anti-inflammatory drugs-induced acute
gastric damage in rats. Dig Dis Sci 59(12):292734. doi:10.1007/
s10620-014-3370-5
Chung HM, Wang WH, Hwang TL, Wu YC, Sung PJ (2013) Natural
clovanes from the gorgonian coral Rumphella antipathies. Nat Prod
Commun 8(8):103740
Chung HM, Wang WH, Hwang TL, Chen JJ, Fang LS, Wen ZH, Wang
YB, Wu YC, Sung PJ (2014a) Rumphellols A and B, new
caryophyllene sesquiterpenoids from a Formosan gorgonian coral,
Rumphella antipathies. Int J Mol Sci 15(9):1567988. doi:10.3390/
ijms150915679
Chung HM, Wang WH, Hwang TL, Li JJ, Fang LS, Wu YC, Sung PJ
(2014b) Rumphellaones B and C, new 4,5-seco-caryophyllane
sesquiterpenoids from Rumphellan antipathies. Molecules 19(8):
123207. doi:10.3390/molecules190812320
Coates RM, Kem WR, Abbott BC (1971) Isolation and structure of a
hoplonemertine toxin. Toxicon 9(1):1522
Collie-Duguid ES, Wahle KW (1996) Inhibitory effect of fish oil N-3
polyunsaturated fatty acids on the expression of endothelial cell
adhesion molecules. Biochem Biophys Res Commun 220(3):969
74. doi:10.1006/bbrc.1996.0516
Conlon JM (2015) Host-defense peptides of the skin with therapeutic
potential: from hagfish to human. Peptides 67:2938. doi:10.1016/
j.peptides.2015.03.005
Coulson FR, O'Donnell SR (2000) The effects of contignasterol (IZP-94,
005) on allergen-induced plasma protein exudation in the tracheo-
bronchial airways of sensitized guinea-pigs in vivo. Inflamm Res
49(3):1237
Crusz SM, Balkwill FR (2015) Inflammation and cancer: advances and
new agents. Nat Rev Clin Oncol doi:nrclinonc.2015.105 doi: 10.
1038/nrclinonc.2015.105
Cumashi A, Ushakova NA, Preobrazhenskaya ME, D'Incecco A, Piccoli
A, Totani L, Tinari N, Morozevich GE, Berman AE, Bilan MI, Usov
AI, Ustyuzhanina NE, Grachev AA, Sanderson CJ, Kelly M,
Rabinovich GA, Iacobelli S, Nifantiev NE (2007) A comparative
study of the anti-inflammatory, anticoagulant, antiangiogenic, and
antiadhesive activities of nine different fucoidans from brown sea-
weeds. Glycobiology 17(5):54152. doi:10.1093/glycob/cwm014
Cuong NX, Thao NP, Luyen BTT, Ngan NTT, Thuy DTT, Song SB, Nam
NH, Kiem PV, Kim YH, Minh CV (2014) Cembranoid diterpenes
from the soft coral Lobophytum crassum and their anti-
inflammatory activities. Chem Pharm Bull (Tokyo) 62(2):203
208. doi:10.1248/cpb.c13-00805
da Conceicao Rivanor RL, Chaves HV, do Val DR, de Freitas AR, Lemos
JC, Rodrigues JA, Pereira KM, de Araujo IW, Bezerra MM,
Benevides NM (2014) A lectin from the green seaweed Caulerpa
cupressoides reduces mechanical hyper-nociception and inflamma-
tion in the rat temporomandibular joint during zymosan-induced
arthritis. Int Immunopharmacol 21(1):3443. doi:10.1016/j.intimp.
2014.04.009
de Carvalho MS, Jacobs RS (1991) Two-step inactivation of bee venom
phospholipase A2 by scalaradial. Biochem Pharmacol 42(8):16216
de Freitas JC, Blankemeier LA, Jacobs RS (1984) In vitro inactivation of
the neurotoxic action of beta-bungarotoxin by the marine natural
product, manoalide. Experientia 40(8):8645
de Jesus Raposo MF, de Morais AM, de Morais RM (2015) Marine
polysaccharides from algae with potential biomedical applications.
Mar Drugs 13(5):29673028. doi:10.3390/md13052967
1662
de las Heras B, Hortelano S (2009) Molecular basis of the anti-
inflammatory effects of terpenoids. Inflamm Allergy Drug Targets
8(1):2839
de Silva ED, Scheuer PJ (1980) Manoalide, an antibiotic sesterterpenoid
from the marine sponge Luffariella variabilis (Polejaeff).
Tetrahedron Lett 21(17):16111614. doi:10.1016/S0040-4039(00)
77766-5
De Vries GW, Lee G, Amdahl L, Wenzel M, Garst M, Wheeler LA (1991)
AGN 190383, a novel phospholipase inhibitor with topical anti-
inflammatory activity. Agents Actions 34(12):702
Delfan M, Ebrahim K, Baesi F, Mirakhori Z, Ghalamfarsa G, Bakhshaei
P, Saboor-Yaraghi AA, Razavi A, Setayesh M, Yousefi M, Jadidi-
Niaragh F (2015) The immunomodulatory effects of fish-oil supple-
mentation in elite paddlers: a pilot randomized double blind
placebo-controlled trial. Prostaglandins Leukot Essent Fatty
Acidsss 99:3540. doi:10.1016/j.plefa.2015.04.011
Dembitsky VM (2002) Bromo- and iodo-containing alkaloids from ma-
rine microorganisms and sponges. Bioorg Khim 28(3):196208
Dewapriya P, Li YX, Himaya SW, Pangestuti R, Kim SK (2013)
Neoechinulin A suppresses amyloid-beta oligomer-induced microg-
lia activation and thereby protects PC-12 cells from inflammation-
mediated toxicity. Neurotoxicology 35:3040. doi:10.1016/j.neuro.
2012.12.004
Di Rosa M, Giroud JP, Willoughby DA (1971) Studies on the mediators
of the acute inflammatory response induced in rats in different sites
by carrageenan and turpentine. J Pathol 104(1):1529. doi:10.1002/
path.1711040103
Dinarello CA (2000) Proinflammatory cytokines. Chest 118(2):5038
Donath MY, Dalmas E, Sauter NS, Boni-Schnetzler M (2013)
Inflammation in obesity and diabetes: islet dysfunction and thera-
peutic opportunity. Cell Metab 17(6):86072. doi:10.1016/j.cmet.
2013.05.001
Dou H, Song Y, Liu X, Gong W, Li E, Tan R, Hou Y (2011)
Chaetoglobosin Fex from the marine-derived endophytic fungus
inhibits induction of inflammatory mediators via Toll-like receptor
4 signaling in macrophages. Biol Pharm Bull 34(12):186473
Dugas B (2000) Lyprinol inhibits LTB4 production by human mono-
cytes. Allerg Immunol (Paris) 32(7):2849
Efthimiou P, Yadlapati S (2015) Impact of IL-1 inhibition on fatigue
associated with autoinflammatory syndromes. Mod Rheumatol:1
22 doi: 10.3109/14397595.2015.1069459
Emelyanov A, Fedoseev G, Krasnoschekova O, Abulimity A, Trendeleva
T, Barnes PJ (2002) Treatment of asthma with lipid extract of New
Zealand green-lipped mussel: a randomised clinical trial. Eur Respir
J 20(3):596600
Fang HY, Hsu CH, Chao CH, Wen ZH, Wu YC, Dai CF, Sheu JH (2013)
Cytotoxic and anti-inflammatory metabolites from the soft coral
Scleronephthya gracillimum. Mar Drugs 11(6):185365. doi:10.
3390/md11061853
Fang Q, Zhao L, Wang Y, Zhang Y, Li Z, Pan Y, Kanchana K, Wang J,
Tong C, Li D, Liang G (2015) A novel chalcone derivative attenu-
ates the diabetes-induced renal injury via inhibition of high glucose-
mediated inflammatory response and macrophage infiltration.
Toxicol Appl Pharmacol 282(2):12938. doi:10.1016/j.taap.2014.
10.021
Fernandes PD, Zardo RS, Figueiredo GS, Silva BV, Pinto AC (2014)
Anti-inflammatory properties of convolutamydine A and two struc-
tural analogues. Life Sci 116(1):1624. doi:10.1016/j.lfs.2014.08.
019
Ferrero-Miliani L, Nielsen OH, Andersen PS, Girardin SE (2007)
Chronic inflammation: importance of NOD2 and NALP3 in
interleukin-1beta generation. Clin Exp Immunol 147(2):22735.
doi:10.1111/j.1365-2249.2006.03261.x
Fiorucci S, Distrutti E, Bifulco G, D'Auria MV, Zampella A (2012)
Marine sponge steroids as nuclear receptor ligands. Trends
Pharmacol Sci 33(11):591601. doi:10.1016/j.tips.2012.08.004
Appl Microbiol Biotechnol (2016) 100:16451666
Fortin PR, Lew RA, Liang MH, Wright EA, Beckett LA, Chalmers TC,
Sperling RI (1995) Validation of a meta-analysis: the effects of fish
oil in rheumatoid arthritis. J Clin Epidemiol 48(11):137990
Fox S, Farr-Jones S, Sopchak L, Boggs A, Nicely HW, Khoury R, Biros
M (2006) High-throughput screening: update on practices and suc-
cess . J Biomol S creen 11 (7):864 9 . do i :1 0. 11 77 /
1087057106292473
Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L,
Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J,
Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F,
Kem WR (2008) Initial phase 2 trial of a nicotinic agonist in schizo-
phrenia. Am J Psychiatry 165(8):10407. doi:10.1176/appi.ajp.
2008.07071135
Garcia-Hernandez MH, Gonzalez-Amaro R, Portales-Perez DP (2014)
Specific therapy to regulate inflammation in rheumatoid arthritis:
molecular aspects. Immunotherapy 6(5):62336. doi:10.2217/imt.
14.26
Gautam R, Jachak SM (2009) Recent developments in anti-inflammatory
natural products. Med Res Rev 29(5):767820. doi:10.1002/med.
20156
Ghosh S, Banerjee S, Sil PC (2015) The beneficial role of curcumin on
inflammation, diabetes and neurodegenerative disease: a recent up-
date. Food Chem Toxicol 83:111124. doi:10.1016/j.fct.2015.05.
022
Gleeson MP, Montanari D (2012) Strategies for the generation, validation
and application of in silico ADMET models in lead generation and
optimization. Expert Opin Drug Metab Toxicol 8(11):143546. doi:
10.1517/17425255.2012.711317
Goldberg RJ, Katz J (2007) A meta-analysis of the analgesic effects of
omega-3 polyunsaturated fatty acid supplementation for inflamma-
tory joint pain. Pain 129(12):21023. doi:10.1016/j.pain.2007.01.
020
Gonzalez Y, Doens D, Santamaria R, Ramos M, Restrepo CM, Barros de
Arruda L, Lleonart R, Gutierrez M, Fernandez PL (2013) A
pse udo pteran e diterp ene is olated fro m t he octo coral
Pseudopterogorgia acerosa inhibits the inflammatory response me-
diated by TLR-ligands and TNF-alpha in macrophages. PLoS One
8(12):e84107. doi:10.1371/journal.pone.0084107PONE-D-13-
23643
Gresa-Arribas N, Vieitez C, Dentesano G, Serratosa J, Saura J, Sola C
(2012) Modelling neuroinflammation in vitro: a tool to test the po-
tential neuroprotective effect of anti-inflammatory agents. PLoS
One 7(9):e45227. doi:10.1371/journal.pone.0045227PONE-D-12-
09499
Gruenwald J, Graubaum HJ, Hansen K, Grube B (2004) Efficacy and
tolerability of a combination of Lyprinol and high concentrations of
EPA and DHA in inflammatory rheumatoid disorders. Adv Ther
21(3):197201
Guido RV, Oliva G, Andricopulo AD (2011) Modern drug discovery
technologies: opportunities and challenges in lead discovery.
Comb Chem High Throughput Screen 14(10):8309
Guven KC, Percot A, Sezik E (2010) Alkaloids in marine algae. Mar
Drugs 8(2):26984. doi:10.3390/md8020269
Haider L (2015) Inflammation, iron, energy failure, and oxidative stress
in the pathogenesis of multiple sclerosis. Oxid Med Cell Longev
2015:725370. doi:10.1155/2015/725370
He Y, Yue Y, Zheng X, Zhang K, Chen S, Du Z (2015) Curcumin,
inflammation, and chronic diseases: how are they linked?
Molecules 20(5):9183
Hsu JC, Lin LC, Tzen JT, Chen JY (2011) Characteristics of the antitumor
activities in tumor cells and modulation of the inflammatory re-
sponse in RAW264.7 cells of a novel antimicrobial peptide,
chrysophsin-1, from the red sea bream (Chrysophrys major).
Peptides 32(5):90010. doi:10.1016/j.peptides.2011.02.013
Hu Y, Liu R, Li J, Yue Y, Cheng W, Zhang P (2014) Attenuation of
collagen-induced arthritis in rat by nicotinic alpha7 receptor partial
Appl Microbiol Biotechnol (2016) 100:16451666
agonist GTS-21. Biomed Res Int 2014:325875. doi:10.1155/2014/
325875
Huang TZ, Chen BW, Huang CY, Hwang TL, Uvarani C, Dai CF, Sung
PJ, Su JH, Sheu JH (2015) Eunicellin-based diterpenoids, hirsutalins
S-V, from the Formosan soft coral Cladiella hirsuta. Mar Drugs
13(5):275769. doi:10.3390/md13052757
Hughes JP, Rees S, Kalindjian SB, Philpott KL (2011) Principles of early
drug discovery. Br J Pharmacol 162(6):123949. doi:10.1111/j.
1476-5381.2010.01127.x
Husseini M, Wang GS, Patrick C, Crookshank JA, MacFarlane AJ, Noel
JA, Strom A, Scott FW (2015) Heme oxygenase-1 induction pre-
vents autoimmune diabetes in association with pancreatic recruit-
ment of M2-like macrophages, mesenchymal cells, and fibrocytes.
Endocrinology 156(11):393749. doi:10.1210/en.2015-1304
Hwang TL, Su YC, Chang HL, Leu YL, Chung PJ, Kuo LM, Chang YJ
(2009) Suppression of superoxide anion and elastase release by C18
unsaturated fatty acids in human neutrophils. J Lipid Res 50(7):
1395408. doi:10.1194/jlr.M800574-JLR200
Ibrahim B, Sowemimo A, van Rooyen A, Van de Venter M (2012)
Antiinflammatory, analgesic and antioxidant activities of Cyathula
prostrata (Linn.) Blume (Amaranthaceae). J Ethnopharmacol
141(1):2829. doi:10.1016/j.jep.2012.02.032
Ishihara K, Oyamada C, Matsushima R, Murata M, Muraoka T (2005)
Inhibitory effect of porphyran, prepared from dried BNori^, on con-
tact hypersensitivity in mice. Biosci Biotechnol Biochem 69(10):
182430
Jacobson PB, Schrier DJ (1993) Regulation of CD11b/CD18 expression
in human neutrophils by phospholipase A2. J Immunol 151(10):
563952
Jean YH, Chen WF, Duh CY, Huang SY, Hsu CH, Lin CS, Sung CS,
Chen IM, Wen ZH (2008) Inducible nitric oxide synthase and
cyclooxygenase-2 participate in anti-inflammatory and analgesic ef-
fects of the natural marine compound lemnalol from Formosan soft
coral Lemnalia cervicorni. Eur J Pharmacol 578(23):32331. doi:
10.1016/j.ejphar.2007.08.048
Jimenez-Sanchez M, Lam W, Hannus M, Snnichsen B, Imarisio S,
Fleming A, Tarditi A, Menzies F, Ed Dami T, Xu C, Gonzalez-
Couto E, Lazzeroni G, Heitz F, Diamanti D, Massai L, Satagopam
VP, Marconi G, Caramelli C, Nencini A, Andreini M, Sardone GL,
Caradonna NP, Porcari V, Scali C, Schneider R, Pollio G, O'Kane
CJ, Caricasole A, Rubinsztein DC (2015) siRNA screen identifies
QPCT as a druggable target for Huntingtons disease. Nat Chem
Biol 11(5):347354
Jones A, Teschendorff AE, Li Q, Hayward JD, Kannan A, Mould T, West
J, Zikan M, Cibula D, Fiegl H, Lee SH, Wik E, Hadwin R, Arora R,
Lemech C, Turunen H, Pakarinen P, Jacobs IJ, Salvesen HB, Bagchi
MK, Bagchi IC, Widschwendter M (2013) Role of DNA methyla-
tion and epigenetic silencing of HAND2 in endometrial cancer de-
velopment. PLoS Med 10(11):e1001551. doi:10.1371/journal.
pmed.1001551PMEDICINE-D-13-01308
Kang SM, Kim KN, Lee SH, Ahn G, Cha SH, Kim AD, Yang XD, Kang
MC, Jeon YJ (2011) Anti-inflammatory activity of polysaccharide
purified from AMG-assistant extract of Ecklonia cava in LPS-
stimulated RAW 264.7 macrophages. Carbohydr Polym 85(1):80
85. doi:10.1016/j.carbpol.2011.01.052
Kang CH, Kim MJ, Seo MJ, Choi YH, Jo WS, Lee KT, Jeong YK, Kim
GY (2013) 5-Hydroxy-3,6,7,8,34-hexamethoxyflavone inhibits
nitric oxide production in lipopolysaccharide-stimulated BV2 mi-
croglia via NF-kappaB suppression and Nrf-2-dependent heme
oxygenase-1 induction. Food Chem Toxicol 57:11925. doi:10.
1016/j.fct.2013.03.019
Kaplanski G, Marin V, Montero-Julian F, Mantovani A, Farnarier C
(2003) IL-6: a regulator of the transition from neutrophil to
monocyte recruitment during inflammation. Trends Immunol
24(1):259
1663
Kasserra CE, Harris P, Stenton GR, Abraham W, Langlands JM (2004)
IPL576,092, a novel anti-inflammatory compound, inhibits leuko-
cyte infiltration and changes in lung function in response to allergen
challenge. Pulm Pharmacol Ther 17(5):30918. doi:10.1016/j.pupt.
2004.07.003
Kellici T, Ntountaniotis D, Vrontaki E, Liapakis G, Moutevelis-
Minakakis P, Kokotos G, Hadjikakou S, Tzakos AG, Afantitis
A, M el a gr ak i G , B ry a n t S, La ng e r T, D i M ar zo V,
Mavromoustakos T (2015) Rational drug design paradigms:
the odyssey for designing better drugs. Comb Chem High
Throughput Screen 18(3):23856
Kem WR, Mahnir VM, Prokai L, Papke RL, Cao X, LeFrancois S,
Wildeboer K, Prokai-Tatrai K, Porter-Papke J, Soti F (2004)
Hydroxy metabolites of the Alzheimer's drug candidate 3-[(2,4-
dimethoxy)benzylidene]-anabaseine dihydrochloride (GTS-21):
Their molecular properties, interactions with brain nicotinic recep-
tors, and brain penetration. Mol Pharmacol 65(1):5667. doi:10.
1124/mol.65.1.56
Khare S, Roach SL, Barnes SW, Hoepfner D, Walker JR, Chatterjee AK,
Neitz RJ, Arkin MR, McNamara CW, Ballard J, Lai Y, Fu Y,
Molteni V, Yeh V, McKerrow JH, Glynne RJ, Supek F (2015)
Utilizing chemical genomics to identify cytochrome b as a novel
drug target for Chagas Disease. PLoS Pathog 11(7):e1005058. doi:
10.1371/journal.ppat.1005058
Kim KS, Cui X, Lee DS, Sohn J, Yim J, Kim YC, Oh H (2013) Anti-
inflammatory effect of neoechinulin A from the marine fungus
Eurotium sp. SF-5989 through the suppression of NF-B and p38
MAPK pathways in lipopolysaccharide-stimulated RAW264.7 mac-
rophages. Molecules 18(11):13245
Kim MJ, Lee HH, Jeong JW, Seo MJ, Kang BW, Park JU, Kim KS, Cho
YS, Seo KI, Kim GY, Kim JI, Choi YH, Jeong YK (2014) Anti-
inflammatory effects of 5-hydroxy-3,6,7,8,3,4-
hexamethoxyflavone via NF-kappaB inactivation in
lipopolysaccharide-stimulated RAW 264.7 macrophage. Mol Med
Rep 9(4):1197203. doi:10.3892/mmr.2014.1922
Kirsch CM, Payan DG, Wong MY, Dohlman JG, Blake VA, Petri MA,
Offenberger J, Goetzl EJ, Gold WM (1988) Effect of
eicosapentaenoic acid in asthma. Clin Allergy 18(2):17787
Kitagawa H, Takenouchi T, Azuma R, Wesnes KA, Kramer WG, Clody
DE, Burnett AL (2003) Safety, pharmacokinetics, and effects on
cognitive function of multiple doses of GTS-21 in healthy, male
volunteers. Neuropsychopharmacology 28(3):54251. doi:10.
1038/sj.npp.13000281300028
Knowles RG (2013) Development of anti-inflammatory drugsthe re-
search and development process. Basic Clin Pharmacol Toxicol
114(1):712. doi:10.1111/bcpt.12130
Kurakula K, Vos M, Logiantara A, Roelofs JJ, Nieuwenhuis MA,
Koppelman GH, Postma DS, van Rijt LS, de Vries CJ (2015)
Nuclear receptor Nur77 attenuates airway inflammation in mice by
suppressing NF-kappaB activity in lung epithelial cells. J Immunol.
doi:10.4049/jimmunol.1401714
Lee SC, Pan CY, Chen JY (2012) The antimicrobial peptide, epinecidin-
1, mediates secretion of cytokines in the immune response to bacte-
rial infection in mice. Peptides 36(1):1008. doi:10.1016/j.peptides.
2012.04.002
Lee HP, Huang SY, Lin YY, Wang HM, Jean YH, Wu SF, Duh CY, Wen
ZH (2013) Soft coral-derived lemnalol alleviates monosodium
urate-induced gouty arthritis in rats by inhibiting leukocyte infiltra-
tion and iNOS, COX-2 and c-Fos protein expression. Mar Drugs
11(1):99113. doi:10.3390/md11010099
Leiro JM, Castro R, Arranz JA, Lamas J (2007) Immunomodulating
activities of acidic sulphated polysaccharides obtained from the sea-
weed Ulva rigida C. Agardh Int Immunopharmacol 7(7):879888.
doi:10.1016/j.intimp.2007.02.007
LeMieux MJ, Kalupahana NS, Scoggin S, Moustaid-Moussa N (2015)
Eicosapentaenoic acid reduces adipocyte hypertrophy and
1664
inflammation in diet-induced obese mice in an adiposity-
independent manner. J Nutr 145(3):4117. doi:10.3945/jn.114.
202952
Libby P, Ridker PM, Hansson GK (2009) Inflammation in atherosclero-
sis: from pathophysiology to practice. J Am Coll Cardiol 54(23):
212938. doi:10.1016/j.jacc.2009.09.009
Lin YY, Lin SC, Feng CW, Chen PC, Su YD, Li CM, Yang SN, Jean YH,
Sung PJ, Duh CY, Wen ZH (2015) Anti-Inflammatory and analgesic
effects of the marine-derived compound excavatolide B isolated
from the culture-type Formosan gorgonian Briareum excavatum.
Mar Drugs 13(5):255979. doi:10.3390/md13052559
Liu CY, Chiu YJ, Kuo CL, Chien TM, Wu LY, Peng WH (2015)
Analgesic and anti-inflammatory activities of the ethanol extract of
Taxillus tsaii Chiu in mice. Drug Dev Res 76(4):17684. doi:10.
1002/ddr.21252
Look SA, Fenical W, Matsumoto GK, Clardy J (1986) The
pseudopterosins: a new class of antiinflammatory and analgesic di-
terpene pentosides from the marine sea whip Pseudopterogorgia
elisabethae (Octocorallia). J Org Chem 51(26):51405145. doi:10.
1021/jo00376a016
Lotsch J, Daiker H, Hahner A, Ultsch A, Hummel T (2015) Drug-target
based cross-sectional analysis of olfactory drug effects. Eur J Clin
Pharmacol 71(4):46171. doi:10.1007/s00228-015-1814-2
Lu Y, Li PJ, Hung WY, Su JH, Wen ZH, Hsu CH, Dai CF, Chiang MY,
Sheu JH (2011) Nardosinane sesquiterpenoids from the Formosan
soft coral Lemnalia flava. J Nat Prod 74(2):16974. doi:10.1021/
np100541a
Machado RJ, Monteiro NK, Migliolo L, Silva ON, Pinto MF, Oliveira
AS, Franco OL, Kiyota S, Bemquerer MP, Uchoa AF, Morais AH,
Santos EA (2013) Characterization and pharmacological properties
of a novel multifunctional Kunitz inhibitor from Erythrina velutina
seeds. PLoS One 8(5):e63571. doi:10.1371/journal.pone.
0063571PONE-D-13-05749
Mackern-Oberti JP, Llanos C, Riedel CA, Bueno SM, Kalergis AM (2015)
Contribution of dendritic cells to the autoimmune pathology of sys-
temic lupus erythematosus. Immunology. doi:10.1111/imm.12504
Mansour SC, Pena OM, Hancock RE (2014) Host defense peptides:
front-line immunomodulators. Trends Immunol 35(9):44350. doi:
10.1016/j.it.2014.07.004
Marshall LA, Winkler JD, Griswold DE, Bolognese B, Roshak A, Sung
CM, Webb EF, Jacobs R (1994) Effects of scalaradial, a type II
phospholipase A2 inhibitor, on human neutrophil arachidonic acid
mobilization and lipid mediator formation. J Pharmacol Exp Ther
268(2):70917
Martins A, Vieira H, Gaspar H, Santos S (2014) Marketed marine natural
products in the pharmaceutical and cosmeceutical industries: tips for
success. Mar Drugs 12(2):1066101. doi:10.3390/md12021066
Maruyama H, Tamauchi H, Hashimoto M, Nakano T (2005) Suppression
of Th2 immune responses by mekabu fucoidan from Undaria
pinnatifida sporophylls. Int Arch Allergy Immunol 137(4):28994.
doi:10.1159/000086422
Matsui M, Muizzuddin N, Arad S, Marenus K (2003) Sulfated polysac-
charides from red microalgae have antiinflammatory properties in
vitro and in vivo. Appl Biochem Biotechnol 104(1):1322. doi:10.
1385/abab:104:1:13
Mayer AM, Spitzer JA (1993) Modulation of superoxide anion genera-
tion by manoalide, arachidonic acid and staurosporine in liver infil-
trated neutrophils in a rat model of endotoxemia. J Pharmacol Exp
Ther 267(1):4009
Mayer AM, Glaser KB, Jacobs RS (1988) Regulation of eicosanoid bio-
synthesis in vitro and in vivo by the marine natural product
manoalide: a potent inactivator of venom phospholipases. J
Pharmacol Exp Ther 244(3):8718
Mayer AM, Jacobson PB, Fenical W, Jacobs RS, Glaser KB (1998)
Pharmacological characterization of the pseudopterosins: novel
Appl Microbiol Biotechnol (2016) 100:16451666
anti-inflammatory natural products isolated from the Caribbean soft
coral, Pseudopterogorgia elisabethae. Life Sci 62(26):PL4017
Mayer AM, Glaser KB, Cuevas C, Jacobs RS, Kem W, Little RD,
McIntosh JM, Newman DJ, Potts BC, Shuster DE (2010) The odys-
sey of marine pharmaceuticals: a current pipeline perspective. Trends
Pharmacol Sci 31(6):25565. doi:10.1016/j.tips.2010.02.005
Mayer AM, Rodriguez AD, Taglialatela-Scafati O, Fusetani N (2013)
Marine pharmacology in 20092011: marine compounds with anti-
bacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal,
antituberculosis, and antiviral activities; affecting the immune and
nervous systems, and other miscellaneous mechanisms of action.
Mar Drugs 11(7):251073. doi:10.3390/md11072510
Medeiros VP, Queiroz KC, Cardoso ML, Monteiro GR, Oliveira FW,
Chavante SF, Guimaraes LA, Rocha HA, Leite EL (2008) Sulfated
galactofucan from Lobophora variegata: anticoagulant and anti-
inflammatory properties. Biochemistry (Mosc) 73(9):101824
Mencarelli A, D'Amore C, Renga B, Cipriani S, Carino A, Sepe V,
Perissutti E, D'Auria MV, Zampella A, Distrutti E, Fiorucci S
(2013) Solomonsterol A, a marine pregnane-X-receptor agonist, at-
tenuates inflammation and immune dysfunction in a mouse model
of arthritis. Mar Drugs 12(1):3653. doi:10.3390/md12010036
Meyer EM, King MA, Meyers C (1998) Neuroprotective effects of 2,4-
dimethoxybenzylidene anabaseine (DMXB) and
tetrahydroaminoacridine (THA) in neocortices of nucleus basalis
lesioned rats. Brain Res 786(12):2524
Mickleborough TD, Vaughn CL, Shei RJ, Davis EM, Wilhite DP (2013)
Marine lipid fraction PCSO-524 (lyprinol/omega XL) of the New
Zealand green lipped mussel attenuates hyperpnea-induced
bronchoconstriction in asthma. Respir Med 107(8):115263. doi:
10.1016/j.rmed.2013.04.010
Miller C, Yamaguchi RY, Ziboh VA (1989) Guinea pig epidermis gener-
ates putative anti-inflammatory metabolites from fish oil polyunsat-
urated fatty acids. Lipids 24(12):9981003
Molinski TF, Dalisay DS, Lievens SL, Saludes JP (2009) Drug develop-
ment from marine natural products. Nat Rev Drug Discov 8(1):69
85. doi:10.1038/nrd2487
Monteiro Abreu T, Castelo Melo Silva LM, Vanderlei ES, de Melo CM,
Pereira VR, Barros Benevides NM (2012) Cytokine production in-
duced by marine algae lectins in BALB/c mice splenocytes. Protein
Pept Lett 19(9):97581
Moura Rda M, Aragao KS, de Melo AA, Carneiro RF, Osorio CB, Luz
PB, de Queiroz AF, Dos Santos EA, de Alencar NM, Cavada BS
(2013) Holothuria grisea agglutinin (HGA): the first invertebrate
lectin with anti-inflammatory effects. Fundam Clin Pharmacol
27(6):65668. doi:10.1111/j.1472-8206.2012.01073.x
Mydlarz LD, Jacobs RS, Boehnlein J, Kerr RG (2003) Pseudopterosin
biosynthesis in Symbiodinium sp., the dinoflagellate symbiont of
Pseudopterogorgia elisabethae. Chem Biol 10(11):10516
Nagakura T, Matsuda S, Shichijyo K, Sugimoto H, Hata K (2000) Dietary
supplementation with fish oil rich in omega-3 polyunsaturated fatty
acids in children with bronchial asthma. Eur Respir J 16(5):8615
Newman DJ, Cragg GM (2007) Natural products as sources of new drugs
over the last 25 years. J Nat Prod 70(3):461477. doi:10.1021/
np068054v
Ng TB, Cheung RC, Wong JH, Bekhit AA, Bekhit Ael D (2015)
Antibacterial products of marine organisms. Appl Microbiol
Biotechnol 99(10):414573. doi:10.1007/s00253-015-6553-x
Oh DY, Talukdar S, Bae EJ, Imamura T, Morinaga H, Fan W, Li P, Lu WJ,
Watkins SM, Olefsky JM (2010) GPR120 is an omega-3 fatty acid
receptor mediating potent anti-inflammatory and insulin sensitizing
effects. Cell 142(5):687698. doi:10.1016/j.cell.2010.07.041
Okamoto R, Watanabe M (2015) Role of epithelial cells in the pathogen-
esis and treatment of inflammatory bowel disease. J Gastroenterol.
doi:10.1007/s00535-015-1098-410.1007/s00535-015-1098-4
Olincy A, Harris JG, Johnson LL, Pender V, Kongs S, Allensworth D,
Ellis J, Zerbe GO, Leonard S, Stevens KE, Stevens JO, Martin L,
Appl Microbiol Biotechnol (2016) 100:16451666
Adler LE, Soti F, Kem WR, Freedman R (2006) Proof-of-concept
trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen
Psychiatry 63(6):6308. doi:10.1001/archpsyc.63.6.630
Panickar KS, Jewell DE (2015) The beneficial role of anti-inflammatory
dietary ingredients in attenuating markers of chronic low-grade in-
flammation in aging. Horm Mol Biol Clin Invest. doi:10.1515/
hmbci-2015-0017/j/hmbci.ahead-of-print/hmbci-2015-0017/hmbci-
2015-0017.xml
Pavlov VA, Ochani M, Yang LH, Gallowitsch-Puerta M, Ochani K, Lin
X, Levi J, Parrish WR, Rosas-Ballina M, Czura CJ, Larosa GJ,
Miller EJ, Tracey KJ, Al-Abed Y (2007) Selective alpha7-
nicotinic acetylcholine receptor agonist GTS-21 improves survival
in murine endotoxemia and severe sepsis. Crit Care Med 35(4):
113944. doi:10.1097/01.CCM.0000259381.56526.96
Pereira DM, Correia-da-Silva G, Valentao P, Teixeira N, Andrade PB
(2014a) Anti-inflammatory effect of unsaturated fatty acids and
ergosta-7,22-dien-3-ol from Marthasterias glacialis: prevention of
CHOP-mediated ER-stress and NF-kappaB activation. PLoS One
9(2):e88341. doi:10.1371/journal.pone.0088341PONE-D-13-
39336
Pereira JG, Mesquita JX, Aragao KS, Franco AX, Souza MH, Brito TV,
Dias JM, Silva RO, Medeiros JV, Oliveira JS, Abreu CM, de Paula
RC, Barbosa AL, Freitas AL (2014b) Polysaccharides isolated from
Digenea simplex inhibit inflammatory and nociceptive responses.
Carbohydr Polym 108:1725. doi:10.1016/j.carbpol.2014.01.105
Petursdottir DH, Hardardottir I (2009) Dietary fish oil decreases secretion
of T helper (Th) 1-type cytokines by a direct effect on murine splenic
T cells but enhances secretion of a Th2-type cytokine by an effect on
accessory cells. Br J Nutr 101(7):10406. doi:10.1017/
S0007114508048290
Pickup JC (2004) Inflammation and activated innate immunity in the
pathogenesis of type 2 diabetes. Diabetes Care 27(3):81323
Posadas I, Bucci M, Roviezzo F, Rossi A, Parente L, Sautebin L, Cirino G
(2004) Carrageenan-induced mouse paw oedema is biphasic, age-
weight dependent and displays differential nitric oxide
cyclooxygenase-2 expression. Br J Pharmacol 142(2):331338.
doi:10.1038/sj.bjp.0705650
Potts BC, Faulkner DJ, Jacobs RS (1992) Phospholipase A2 inhibitors
from marine organisms. J Nat Prod 55(12):170117
Qin C, Lin X, Lu X, Wan J, Zhou X, Liao S, Tu Z, Xu S, Liu Y (2015)
Sesquiterpenoids and xanthones derivatives produced by sponge-
derived fungus Stachybotry sp. HH1 ZSDS1F1-2. J Antibiot
(Tokyo) 68(2):1215. doi:10.1038/ja.2014.97
Qiu YY, Zhu JX, Bian T, Gao F, Qian XF, Du Q, Yuan MY, Sun H, Shi
LZ, Yu MH (2014) Protective effects of astragaloside IV against
ovalbumin-induced lung inflammation are regulated/mediated by
T-bet/GATA-3. Pharmacology 94(12):519. doi:10.1159/
000362843
Rakhade SN, Fitzgerald EF, Klein PM, Zhou C, Sun H, Huganir RL,
Jensen FE (2012) Glutamate receptor 1 phosphorylation at Serine
831 and 845 modulates seizure susceptibility and hippocampal hy-
perexcitability following early life seizures. J Neurosci 32(49):
1780017812. doi:10.1523/jneurosci.6121-11.2012
Rask-Andersen M, Almen MS, Schioth HB (2011) Trends in the exploi-
tation of novel drug targets. Nat Rev Drug Discov 10(8):57990.
doi:10.1038/nrd3478
Ribeiro NA, Abreu TM, Chaves HV, Bezerra MM, Monteiro HS, Jorge
RJ, Benevides NM (2014) Sulfated polysaccharides isolated from
the green seaweed Caulerpa racemosa plays antinociceptive and
anti-inflammatory activities in a way dependent on HO-1 pathway
activation. Inflamm Res 63(7):56980. doi:10.1007/s00011-014-
0728-2
Rosas-Ballina M, Goldstein RS, Gallowitsch-Puerta M, Yang L, Valdes-
Ferrer SI, Patel NB, Chavan S, Al-Abed Y, Yang H, Tracey KJ
(2009) The selective alpha7 agonist GTS-21 attenuates cytokine
production in human whole blood and human monocytes activated
1665
by ligands for TLR2, TLR3, TLR4, TLR9, and RAGE. Mol Med
15(78):195202. doi:10.2119/molmed.2009.00039
Ross R (1999) Atherosclerosisan inflammatory disease. N Engl J Med
340(2):11526. doi:10.1056/NEJM199901143400207
Rouhi AM (1995) Supply issues complicate trek of chemicals from sea to
market. Chem Eng News 73(47):4244. doi:10.1021/cen-
v073n047.p042
Sanchez T, Moreno JJ (1999) Role of prostaglandin H synthase isoforms
in murine ear edema induced by phorbol ester application on skin.
Prostaglandins Other Lipid Mediat 57(23):11931
Schrier DJ, Flory CM, Finkel M, Kuchera SL, Lesch ME, Jacobson PB
(1996) The effects of the phospholipase A2 inhibitor, manoalide, on
cartilage degradation, stromelysin expression, and synovial fluid cell
count induced by intraarticular injection of human recombinant
interleukin-1 alpha in the rabbit. Arthritis Rheum 39(8):12929
Seibert K, Masferrer J, Zhang Y, Gregory S, Olson G, Hauser S, Leahy K,
Perkins W, Isakson P (1995) Mediation of inflammation by cyclo-
oxygenase-2. Agents Actions Suppl 46:4150
Sepe V, Ummarino R, D'Auria MV, Mencarelli A, D'Amore C, Renga B,
Zampella A, Fiorucci S (2011) Total synthesis and pharmacological
characterization of solomonsterol A, a potent marine pregnane-X-
receptor agonist endowed with anti-inflammatory activity. J Med
Chem 54(13):45909. doi:10.1021/jm200241s
Sergeev IN, Li S, Colby J, Ho CT, Dushenkov S (2006)
Polymethoxylated flavones induce Ca(2+)-mediated apoptosis in
breast cancer cells. Life Sci 80(3):24553. doi:10.1016/j.lfs.2006.
09.006
Serhan CN, Chiang N, Van Dyke TE (2008) Resolving inflammation:
dual anti-inflammatory and pro-resolution lipid mediators. Nat Rev
Immunol 8(5):34961. doi:10.1038/nri2294
Sharma SB, Gupta R (2015) Drug development from natural resource: a
systematic approach. Mini Rev Med Chem 15(1):527
She QB, Ma WY, Wang M, Kaji A, Ho CT, Dong Z (2003) Inhibition of
cell transformation by resveratrol and its derivatives: differential
effects and mechanisms involved. Oncogene 22(14):214350. doi:
10.1038/sj.onc.12063701206370
Shi C, Pan T, Cao M, Liu Q, Zhang L, Liu G (2015) Suppression of Th2
immune responses by the sulfated polysaccharide from Porphyra
haitanensis in tropomyosin-sensitized mice. Int Immunopharmacol
24(2):2118. doi:10.1016/j.intimp.2014.11.019
Simmons TL, Andrianasolo E, McPhail K, Flatt P, Gerwick WH (2005)
Marine natural products as anticancer drugs. Mol Cancer Ther 4(2):
333342
Skaper SD, Facci L, Giusti P (2014) Neuroinflammation, microglia and
mast cells in the pathophysiology of neurocognitive disorders: a
review. CNS Neurol Disord Drug Targets 13(10):165466
Staker BL, Buchko GW, Myler PJ (2015) Recent contributions of structure-
based drug design to the development of antibacterial compounds.
Curr Opin Microbiol 27:1338. doi:10.1016/j.mib.2015.09.003
Sze SC, Tong Y, Ng TB, Cheng CL, Cheung HP (2015) Herba Epimedii:
anti-oxidative properties and its medical implications. Molecules
15(11):786170. doi:10.3390/molecules15117861
Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory
diseases. J Clin Invest 107(1):711. doi:10.1172/JCI11830
Takei M, Burgoyne DL, Andersen RJ (1994) Effect of contignasterol on
histamine release induced by anti-immunoglobulin E from rat peri-
toneal mast cells. J Pharm Sci 83(9):12345
Tenikoff D, Murphy KJ, Le M, Howe PR, Howarth GS (2005) Lyprinol
(stabilised lipid extract of New Zealand green-lipped mussel): a po-
tential preventative treatment modality for inflammatory bowel dis-
ease. J Gastroenterol 40(4):3615. doi:10.1007/s00535-005-1551-x
Thao NP, Cuong NX, Luyen BT, Quang TH, Hanh TT, Kim S, Koh YS,
Nam NH, Van Kiem P, Van Minh C, Kim YH (2013) Anti-
inflammatory components of the starfish Astropecten polyacanthus.
Mar Drugs 11(8):291726. doi:10.3390/md11082917
1666
Thao NP, Luyen BT, Ngan NT, Song SB, Cuong NX, Nam NH, Kiem PV,
Kim YH, Minh CV (2014) New anti-inflammatory cembranoid
diterpenoids from the Vietnamese soft coral Lobophytum crassum.
Bioorg Med Chem Lett 24(1):22832. doi:10.1016/j.bmcl.2013.11.033
Tibes U, Friebe WG (1997) Phospholipase A2 inhibitors in development.
Expert Opin Invest Drugs 6(3):27998. doi:10.1517/13543784.6.3.279
Tseng YJ, Shen KP, Lin HL, Huang CY, Dai CF, Sheu JH (2012)
Lochmolins A-G, new sesquiterpenoids from the soft coral
Sinularia lochmodes. Mar Drugs 10(7):157281. doi:10.3390/
md10071572marinedrugs-10-01572
van der Westhuyzen R, Winks S, Wilson CR, Boyle GA, Gessner RK,
Soares de Melo C, Taylor D, de Kock C, Njoroge M, Brunschwig C,
Lawrence N, Rao SP, Sirgel F, van Helden P, Seldon R, Moosa A,
Warner DF, Arista L, Manjunatha UH, Smith PW, Street LJ, Chibale
K (2015) Pyrrolo [3,4-c]pyridine-1,3(2H)-diones: a novel
antimycobacterial class targeting mycobacterial respiration. J Med
Chem. doi:10.1021/acs.jmedchem.5b01542
van Maanen MA, Lebre MC, van der Poll T, LaRosa GJ, Elbaum D,
Vervoordeldonk MJ, Tak PP (2009) Stimulation of nicotinic acetyl-
choline receptors attenuates collagen-induced arthritis in mice.
Arthritis Rheum 60(1):11422. doi:10.1002/art.24177
Villa FA, Gerwick L (2010) Marine natural product drug discovery: leads
for treatment of inflammation, cancer, infections, and neurological
disorders. Immunopharmacol Immunotoxicol 32(2):22837. doi:10.
3109/08923970903296136
Vo TS, Ngo DH, Kang KH, Jung WK, Kim SK (2015) The beneficial
properties of marine polysaccharides in alleviation of allergic re-
sponses. Mol Nutr Food Res 59(1):12938. doi:10.1002/mnfr.
201400412
Wang Y, Sun J, Liu C, Fang C (2014) Protective effects of crocetin pre-
treatment on myocardial injury in an ischemia/reperfusion rat model.
Eur J Pharmacol 741:2906. doi:10.1016/j.ejphar.2014.07.052
Wang T, Wu MB, Lin JP, Yang LR (2015) Quantitative structure-activity
relationship: promising advances in drug discovery platforms.
Expert Opin Drug Discov 10(12):1283300. doi:10.1517/
17460441.2015.1083006
Wei WC, Lin SY, Chen YJ, Wen CC, Huang CY, Palanisamy A, Yang
NS, Sheu JH (2011) Topical application of marine briarane-type
diterpenes effectively inhibits 12-O-tetradecanoylphorbol-13-ace-
tate-induced inflammation and dermatitis in murine skin. J Biomed
Sci 18:94. doi:10.1186/1423-0127-18-94
Wei WC, Sung PJ, Duh CY, Chen BW, Sheu JH, Yang NS (2013) Anti-
inflammatory activities of natural products isolated from soft corals
of Taiwan between 2008 and 2012. Mar Drugs 11(10):4083126.
doi:10.3390/md11104083
Wei J, Fan G, Zhao H, Li J (2015) Heme oxygenase-1 attenuates inflam-
mation and oxidative damage in a rat model of smoke-induced em-
physema. Int J Mol Med 36(5):138492. doi:10.3892/ijmm.2015.
2353
Wen ZH, Chao CH, Wu MH, Sheu JH (2010) A neuroprotective sulfone
of marine origin and the in vivo anti-inflammatory activity of an
Appl Microbiol Biotechnol (2016) 100:16451666
analogue. Eur J Med Chem 45(12):59986004. doi:10.1016/j.
ejmech.2010.09.067
Whitehouse MW, Macrides TA, Kalafatis N, Betts WH, Haynes DR,
Broadbent J (1997) Anti-inflammatory activity of a lipid fraction
(lyprinol) from the NZ green-lipped mussel.
Inflammopharmacology 5(3):23746. doi:10.1007/s10787-997-
0002-0
Wong JM, Billiar TR (1995) Regulation and function of inducible nitric
oxide synthase during sepsis and acute inflammation. Adv
Pharmacol 34:15570
Wong CC, Zhang L, Li ZJ, Wu WK, Ren SX, Chen YC, Ng TB, Cho CH
(2012) Protective effects of cathelicidin-encoding Lactococcus
lactis in murine ulcerative colitis. J Gastroenterol Hepatol 27(7):
120512. doi:10.1111/j.1440-1746.2012.07158.x
Wood LG, Hazlewood LC, Foster PS, Hansbro PM (2010) Lyprinol
reduces inflammation and improves lung function in a mouse model
of allergic airways disease. Clin Exp Allergy 40(12):178593. doi:
10.1111/j.1365-2222.2010.03503.x
Xiao Z, Morris-Natschke SL, Lee KH (2015) Strategies for the optimiza-
tion of natural leads to anticancer drugs or drug candidates. Med Res
Rev. doi:10.1002/med.21377
Yamada H, Yoshida M, Nakano Y, Suganami T, Satoh N, Mita T, Azuma
K, Itoh M, Yamamoto Y, Kamei Y, Horie M, Watada H, Ogawa Y
(2008) In vivo and in vitro inhibition of monocyte adhesion to en-
dothelial cells and endothelial adhesion molecules by
eicosapentaenoic acid. Arterioscler Thromb Vasc Biol 28(12):
21739. doi:10.1161/ATVBAHA.108.171736
Yan WX, Zhang JH, Zhang Y, Meng DL, Yan D (2015) Anti-
inflammatory activity studies on the stems and roots of Jasminum
lanceolarium Roxb. J Ethnopharmacol 171:33541. doi:10.1016/j.
jep.2015.05.044
Yang Y, Adelstein SJ, Kassis AI (2012) Target discovery from data min-
ing approaches. Drug Discov Today 17(Suppl):S1623. doi:10.
1016/j.drudis.2011.12.006
Yang XW, Peng K, Liu Z, Zhang GY, Li J, Wang N, Steinmetz A, Liu Y
(2013) Strepsesquitriol, a rearranged zizaane-type sesquiterpenoid
from the deep-sea-derived actinomycete Streptomyces sp. SCSIO
10355. J Nat Prod 76(12):23603. doi:10.1021/np400923c
Yang WQ, Song YL, Zhu ZX, Su C, Zhang X, Wang J, Shi SP, Tu PF
(2015) Anti-inflammatory dimeric furanocoumarins from the roots
of Angelica dahurica. Fitoterapia 105:187193. doi:10.1016/j.fitote.
2015.07.006
Yin C, Wong JH, Ng TB (2014) Recent studies on the antimicrobial
peptides lactoferricin and lactoferrampin. Curr Mol Med 14(9):
113954
Yoshihara T, Shimada K, Fukao K, Sai E, Sato-Okabayashi Y, Matsumori R,
Shiozawa T, Alshahi H, Miyazaki T, Tada N, Daida H (2015) Omega 3
polyunsaturated fatty acids suppress the development of aortic aneu-
rysms through the inhibition of macrophage-mediated inflammation.
Circ J 79(7):14701478. doi:10.1253/circj.CJ-14-0471
Zanders ED, Bailey DS, Dean PM (2002) Probes for chemical genomics
by design. Drug Discov Today 7(13):7118