Next Article in Journal
Sinularin Induces Apoptosis through Mitochondria Dysfunction and Inactivation of the pI3K/Akt/mTOR Pathway in Gastric Carcinoma Cells
Next Article in Special Issue
Peptides, Peptidomimetics, and Polypeptides from Marine Sources: A Wealth of Natural Sources for Pharmaceutical Applications
Previous Article in Journal
Preparation of Chito-Oligomers by Hydrolysis of Chitosan in the Presence of Zeolite as Adsorbent
Previous Article in Special Issue
Synthesis and Anti-Influenza A Virus Activity of 6′-amino-6′-deoxy-glucoglycerolipids Analogs
 
 
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation

1
Graduate Institute of Natural Products, School of Traditional Medicine, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
2
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
3
Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
4
Department of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan
5
Division of Natural Products, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
6
Chinese Herbal Medicine Research Team, Healthy Aging Research Center, Chang Gung University, Taoyuan 333, Taiwan
7
Research Center for Industry of Human Ecology and Graduate Institute of Health Industry Technology, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan 333, Taiwan
*
Author to whom correspondence should be addressed.
Mar. Drugs 2016, 14(8), 141; https://doi.org/10.3390/md14080141
Submission received: 29 March 2016 / Revised: 31 May 2016 / Accepted: 7 July 2016 / Published: 26 July 2016
(This article belongs to the Special Issue Drug Design Based on Marine Natural Product Scaffolds)

Abstract

:
Neutrophils are widely recognized to play an important role in acute inflammatory responses, and recent evidence has expanded their role to modulating chronic inflammatory and autoimmune diseases. Reactive oxygen species (ROS) and microbicidal compounds released from neutrophils that are recruited to the site of inflammation contribute to the pathogenesis of multiple inflammation-associated diseases such as chronic obstructive pulmonary disease, atherosclerosis, and hepatitis. Marine organisms are a valuable source of bioactive compounds with potential for industrial and pharmaceutical application. Marine natural products that inhibit neutrophil activation could be used as drugs for the treatment of inflammatory diseases. Numerous studies investigating marine natural products have reported novel anti-inflammatory agents. Nevertheless, the detailed mechanisms underlying their actions, which could facilitate our understanding of the molecular events occurring in neutrophils, have not been reported in most of the associated research studies. Therefore, in this review, we will present marine products that inhibit neutrophil-associated inflammation. Furthermore, we will be limiting the detailed discussion to agents with well-investigated molecular targets.

Graphical Abstract

1. Introduction

Inflammation is a protective response initiated by activated immune cells and associated chemical mediators to counteract harmful stimuli such as pathogenic invasion, sterile injury, or irritants. Inflammation normally functions as a pivotal defense system for living organisms. Neutrophil granulocytes are the most numerous types of leukocytes (approximately 50%–70%) in mammals. They play a crucial role in the innate immune system and are the first effector cells to respond to chemotactic signals [1,2]. Activated neutrophils migrate to the site of infective or sterile inflammation where they perform various functions including phagocytosis, generation of reactive oxygen species (ROS), the release of proteolytic enzymes, and recruitment of other effector immune cells [2]. However, excessive neutrophil activation can cause prolonged self-induced damage and is involved in a variety of diseases such as cancer [3,4], respiratory disorders [5], liver diseases [6], inflammatory bone loss [7], and neurodegeneration [8]. Numerous studies have focused on exploring chemical or natural products that inhibit the activation of neutrophils to reduce excessive inflammation [9]. These research studies not only identified effective anti-inflammatory agents but also provided comprehensive analyses of the molecular targets of these compounds.
The origin and evolution of small organic molecules and creatures occur in the ocean, which covers approximately 70% of the earth’s surface. Since all organisms presently in existence have undergone intense evolutionary competition, it is reasonable to assume that marine organisms produce an enormous range of biologically active substances. Over the last decades, numerous marine natural products have been discovered with considerable pharmacological activities [10,11]. In particular, anti-inflammatory marine natural products have been the focus of intense interest due to their potential for use as therapeutic agents for inflammatory diseases.
This present report provides a systemic review of laboratory findings of investigated marine natural products and their derivatives with effects against neutrophil-associated inflammation. Although we are interested in all anti-inflammatory marine products, our particular focus will be on compounds with mechanisms of action that have been intensively investigated in neutrophils. We hope that this report will provide a useful foundation and source of data for further research into marine natural products with anti-neutrophil-induced inflammation potential. In addition, marine-based compounds may be tools for the elucidation of the mechanisms underlying neutrophil inflammatory responses.

2. Marine Natural Product Inhibitors of Formyl Peptide Receptor-1 (FPR-1) and Its Downstream Signaling Cascades

The formyl peptide receptor (FPR) family, which belongs to the G-protein-coupled receptor family, is one of the major mechanisms by which human neutrophils detect the presence of infective or sterile inflammatory signals. The FPR is a seven-transmembrane receptor with three loops exposed on the cell surface for ligand binding as well as intracellular loops for a series of signal transduction activities [12,13]. The human FPR family consists of the FPR1, FPR2/lipoxin A4 receptor (ALX), and FPR3, which all have pluripotent and diverse roles in the initiation, propagation, and resolution of inflammation [13,14]. FPR1 was the first identified and sequenced FPR in human neutrophils and is the predominant form in these cells. Various studies revealed that overwhelming activation of FPR1 on neutrophils induces severe inflammatory response syndrome and diseases [15,16]. The present review will refer to this FPR1 isoform only.
During infection, bacteria and affected host cells simultaneously release N-formylated peptides, the major FPR1 ligands [13,17]. The ligand interaction with FPR1 induces conformational changes in the receptor, causing G-proteins to dissociate into α and βγ subunits, which both activate a series of signal transduction pathways. There are numerous signaling pathways activated by Gα and Gβγ subunits, including the phosphatidylinositol-3-kinase (PI3K), Src-related tyrosine kinase, mitogen-activated protein kinase (MAPK), and phospholipase C (PLC). PLC cleaves the phospholipid phosphatidylinositol 4,5-bisphosphate (PIP2) into diacylglycerol and inositol 1,4,5-trisphosphate (IP3), which in turn releases Ca2+ from the endoplasmic reticulum and then activates protein kinase C (PKC). These molecular events induce a variety of functional responses including neutrophil chemotaxis, degranulation, and activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase to produce ROS and transcriptional activity.
The possibility that FPR1, downstream intracellular signaling events, or both could be therapeutic targets has gained interest over the decades. Numerous efforts have made to discover marine natural compounds that antagonize FPR1 and its downstream pathway. Several marine FPR1 pathway antagonists with the potential for use as therapeutic agents for inflammatory diseases have been reviewed [18].
Following the identification of N-formyl-methionyl-leucyl-phenylalanine (fMLF) as a potent FPR1 agonist with high potency and efficacy in human neutrophils [19], fMLF was commonly used in experiments, which were aimed at the neutrophil inflammatory pathway. Table 1 lists the marine natural products that were reported to inhibit formyl-methionyl-leucyl phenylalanine (fMLF)-induced functional responses in neutrophils. However, most of their mechanisms of action have not been elucidated. In the following section, we will restrict our focus to the marine natural products that have had their molecular targets investigated.

2.1. IA-LBI07-1

Initially, the extract of the marine Bacillus sp., IA-LBI07-1 reported to inhibit superoxide generation and elastase release in fMLF-activated neutrophils [56]. Further elucidation of the underlying mechanism revealed that IA-LBI07-1 inhibited the binding of N-formyl-Nle-Leu-Phe-Nle-Tyr-Lys-fluorescein, a fluorescent analog of fMLF, to FPR1 in human neutrophils and FPR1-transfected HEK293 cells. These data provided strong evidence that IA-LBI07-1 is the only marine natural product that directly interferes with the binding of ligands to FPR1.

2.2. Staurosporine Aglycone

Staurosporine, a natural product isolated from the bacterium Streptomyces staurosporeus [57], was discovered to have biological activities including antifungal and antihypertensive activities [58] and it non-selectively inhibited PKC. Substitution of one of the indole nitrogen atoms with non-glycosidic indolocarbazoles lacking an aminoalkyl side chain resulted in a staurosporine aglycone with increased selectivity for PKC. Horton et al. [59] isolated and identified the staurosporine aglycone (Figure 1) from a specimen of the marine ascidian, Eudistoma sp. They also found that the staurosporine aglycone inhibited the enzyme activity of seven of eight cloned PKC isoenzymes and inhibited oxygen release (detected by the presence of lucigenin) in neutrophils [59].

2.3. Secondary Metabolites of Marine Pseudomonas sp. (N11)

The secondary metabolites of a marine Pseudomonas sp. (N11) inhibited superoxide anion generation and elastase release in fMLF-activated human neutrophils, with half-maximal inhibitory concentration (IC50) values of 0.67 ± 0.38 and 0.84 ± 0.12 µg/mL, respectively [60]. Furthermore, a cell-free experimental system was used to verify that N11 had no ROS scavenging ability. It suppressed the phosphorylation of p38 MAPK, c-Jun N-terminal kinase (JNK), and calcium mobilization, but not extracellular signal-regulated kinase (ERK) and Akt in FMLP-induced human neutrophils. However, N11 failed to inhibit superoxide anion generation induced by phorbol myristate acetate (PMA), a specific PKC activator, suggesting that its inhibitory effect was not associated with the PKC pathway [60].

3. Marine Natural Product Inhibitors of Phospholipase A2 (PLA2) or Arachidonic Acid (AA) Metabolism

Phospholipase A2 (PLA2) is a lipolytic enzyme found in all types of mammalian cells as well as insect and snake venom [61,62]. PLA2 isoforms are subdivided into several protein families with common enzymatic activity. Secreted and cytosolic PLA2 (sPLA2 and cPLA2, respectively) are the two most notable PLA2 families expressed in neutrophils [62]. The sPLA2 family includes low-molecular-weight and Ca2+-dependent extracellular enzymes while the enzymes of the cPLA2 family are significantly larger. PLA2 hydrolyzes the glycerophospholipids at the sn-2 position [63], which releases AA and lysophospholipids. AA is oxygenated by 5-lipoxygenase (5-LO) and cyclooxygenase (COX) to produce 5′-hydroperoxyeicosatetraenoic acid (5-HPTETE) and prostaglandin H (PGH2), respectively. 5-HPTETE is the unstable precursor of 5-hydroxyicosatetraenoic acid (5-HETE), which is successively converted to leukotriene A4 (LTA4) and then leukotriene B4 (LTB4), a potent chemoattractant of leukocytes. PGH2 is converted to PGD2, PGE2, PGI2, and thromboxane A2 (TXA2) [62,64]. These PLA2-related chemical mediators are referred to as eicosanoids and play a critical role in virtually every step of the host defense and inflammatory response. Moreover, the molecular events following FPR1 activation are known to be involved in activating PLA2. Cytosolic PLA2 has been shown to be activated by the major molecular events downstream of FPR1 including activation of MAPK [65,66,67], intracellular Ca2+ [67,68], and PKC [69] signaling.
Since the discovery of manoalide, which is the first identified marine natural product with PLA2 inhibitory activity, various marine PLA2 inhibitors have been discovered and reviewed in detail in previous articles [70,71]. Here, we will further discuss the marine-based inhibitors of PLA2 or its downstream pathway in neutrophils that were not mentioned in previous reviews.

3.1. Avarol, Avarone, and Their Derivatives

Avarol and avarone (Figure 2a,b, respectively) are sesquiterpenoid hydroquinones isolated from the marine sponge Dysidea avara [72]. Avarol is a cytostatic agent with potent antileukemic activity [73], and it also displays antibacterial and antifungal activities against a limited range of microorganisms. Both avarol and avarone suppressed superoxide generation stimulated by fMLF or PMA in rat peritoneal leukocytes, which consist of approximately 80% neutrophils. They also reduced LTB4 and TLXB2 release induced by a calcium ionophore (A23187) in rat peritoneal leukocytes. In vivo studies revealed that both substances potently inhibited carrageenan- and PMA-induced murine paw and ear edema, respectively [72]. However, only avarol inhibited the activity of human recombinant synovial PLA2 directly [72]. In addition, the avarol derivative, avarol-3′-thiosalicylate (TA; Figure 2c) inhibited PMA-stimulated ROS generation in human neutrophils [74,75]. TA also inhibited LTB4 generation in human neutrophils stimulated with a calcium ionophore (A23187), as well as the activity of the human synovial recombinant sPLA2. These data suggest that avarol, avarone, and the derivative TA, are inhibitors of the PLA pathway in neutrophils.

3.2. 2-Octaprenyl-1,4-hydroquinone, 2-[24-Hydroxy]-octaprenyl-1,4-hydroquinone, 2-Prenyl-1,4-hydroquinone, 2-Diprenyl-1,4-hydroquinone, 2-Triprenyl-1,4-hydroquinone, and 2-Tetraprenyl-1,4-hydroquinone

Studies of two 2-polyprenyl-1,4-hydroquinone derivatives, 2-octaprenyl-1,4-hydroquinone and 2-[24-hydroxy]-octaprenyl-1,4-hydroquinone (IS2 and IS3, respectively; Figure 3a,b), and four prenyl-hydroquinone derivatives, 2-prenyl-1,4-hydroquinone, 2-diprenyl-1,4-hydroquinone, 2-triprenyl-1,4-hydroquinone, and 2-tetraprenyl-1,4-hydroquinone (H1, H2, H3, and H4, respectively; Figure 3c), isolated from the sponge Ircinia spinosula revealed their inhibitory effects on PLA2 activity in human neutrophils [76,77]. Both IS2 and IS3 reduced ROS generation and degranulation in human neutrophils stimulated with PMA. They decreased the synthesis and release of TXB2 and LTB4 in a mixed suspension of human neutrophils and platelets stimulated by the ionophore A23187. In animal studies, IS2 and IS3 showed topical anti-inflammatory activity against PMA-induced ear inflammation in mice. In another study, H1, H2, H3, and H4 scavenged ROS and inhibited 5-LO activity in human neutrophils induced by PMA [76]. The inhibition of 5-LO activity was also demonstrated in an air pouch animal model. These studies revealed that differences in the lateral chain of the prenyl-hydroquinones critically modified their anti-inflammatory activity. They also provide an example of how the modification of known natural products may offer a promising strategy for modulating the anti-inflammatory effect of drugs.

3.3. Lyprinol

Lyprinol is a freeze-dried, stabilized, green-lipped mussel (Perna canaliculus) powder, which is used as a nutritional supplement to ameliorate signs of inflammation. An in vitro study revealed that four of the lyprinol subfractions containing polyunsaturated acids with four, five, and six double bonds inhibited the transformation of added arachidonate to LTB4 and 5-HETE in neutrophils stimulated by A23187 [78].

3.4. Ircinin

A mixture of the C25 furanosesterterpene tetronic acid geometrical isomers ircinin-1 and ircinin-2, tentatively named ircinin (Figure 4) isolated from sponges of the Sarcotragus sp. directly inhibited Naja naja venom, human synovial recombinant, bee venom, and zymosan-injected rat air pouch sPLA2 activities. Furthermore, ircinin dose-dependently inhibited PMA-stimulated superoxide generation and elastase release stimulated by fMLF. Moreover, ircinin suppressed the release of LTB4 in A23187-induced human neutrophils [79].

3.5. Dihydroxyicosanoids

Three dihydroxyicosanoids, 12(R),13(R)-dihydroxyicosa-5(Z),8(Z),10(E),14(Z)-tetraenoic acid, 12(R),13(R)-dihydroxyicosa-5(Z),8(Z),10(E),14(Z),17(Z)-pentanoic acid, and 10(R*), 11(R*)-dihydroxyoctadeca-6(Z),8(E),12(Z)-trienoic acid, were isolated from the marine alga Farlowia mollis. These marine products inhibited ROS generation in fMLF-activated human neutrophils and modulated 5-LO activity in human neutrophils stimulated with A23187 [39].

4. Marine Natural Products that Regulate Phosphorylation of Intracellular Mediators

Okadaic acid (OKA, Figure 5), a toxin produced by several spp. of dinoflagellates, is a potent inhibitor of serine/threonine protein phosphatase (PP) type 1 (PP1) and type 2A (PP2A), which inhibit the dephosphorylation of proteins in numerous cells. OKA displayed contrasting effects on ROS generation in human neutrophils. OKA enhanced ROS generation in fMLF-stimulated neutrophils by inhibiting PP1 and PP2A [80,81,82]. Since OKA increases protein phosphorylation by inhibiting serine/threonine PPs, it is speculated that the enhanced fMLF-induced ROS generation by OKA was due to prolonged protein phosphorylation, which increased kinase activity and, thus, delayed the termination of the respiratory burst. On the other hand, pretreatment with OKA reduced PMA-stimulated superoxide generation [81,82,83]. In addition to its role as a serine/threonine phosphatase inhibitor, previous studies revealed that OKA increased tyrosine phosphatase activity and, thereby decreased tyrosine phosphorylation [83,84]. This might explain the mechanism by which OKA inhibited the PMA-induced respiratory burst. Moreover, OKA also increased the maximal rate and duration of superoxide release in response to arachidonate; however, OKA alone did not induce any release of superoxide [85]. Taken together, these studies using OKA, a thoroughly investigated marine natural product, revealed that phosphatases could positively or negatively affect the intensity of the respiratory responses induced by fMLF or PMA, respectively. These studies on OKA also provide examples of intensively investigated marine natural products that could be used as effective tools for the in-depth study of cellular inflammatory molecular mechanism.

5. Marine Natural Product Inhibitors of Neutrophils Migration and Adhesion

Following inflammation, circulating neutrophils are attracted by a precisely regulated sequential response induced by an increasing gradient of chemoattractants. The neutrophil extravasation is a complex process, and various molecules are involved. Briefly, as resident sentinel macrophages recognize invading pathogens, they release inflammatory mediators such as IL-1, TNF-α and C5a. These mediators upregulate the expression of P-selectin and E-selectin on the surface of endothelium. The binding of glycosylated ligands of neutrophil to the selectin of the endothelium tethers the rolling neutrophils. For tight adhesion, the rolling neutrophils are further activated, and the surface low-affinity integrin molecules were switched to a high-affinity state. To leave the vasculature, neutrophils have to transmigrate the endothelium. Transmigration requires multiple adhesion molecules, such as integrins, intercellular adhesion molecules, vascular cell adhesion protein 1, CD31, CD99, junctional adhesion molecules, and epithelial cell adhesion molecule [1]. Subsequently, the cytoskeletons of neutrophils are reorganized that neutrophils extend pseudopodia and pass through endothelial gaps. Finally, neutrophils have to move through the basement membrane, which was accomplished by digesting basement membrane with releasing proteases.
Stimuli targeting various intracellular signaling pathways such as Ca2+, MAPK, and PLA2 induced the activation and migration of neutrophils. Most marine natural products that were mentioned in the previous sections might also regulate neutrophil migration. In the following section, we will review studies involving experiments that described additional marine products that inhibited the migration of human neutrophils. Inflammatory cell migration is a complex process that involves a variety of immune and non-immune cells. The molecular mechanisms underlying the action of migration inhibitors not only target neutrophils but also target other inflammatory cells and chemical mediators.

5.1. Polysaccharides

Polysaccharides (PLS) extracted from substances of marine origin have shown several biological activities such as anti-inflammatory, antinociceptive, and anticoagulant [86,87,88,89]. A sulfated PLS fraction extracted from the alga Hypnea musciformis [86], reduced the inflammatory response and neutrophil migration, which appeared to be mediated by the nitric oxide (NO) signaling pathway. Regular and sulfated PLS extracted from Digenea simplex [88] and the algae Gracilaria caudate [87], respectively, reduced neutrophil migration by decreasing the production of pro-inflammatory cytokines. Moreover, a fucosylated chondroitin sulfate (fCS) extracted from the sea cucumber Holothuria forskali is composed of repeated trisaccharide units, and its poly- and oligosaccharides inhibited human neutrophil elastase activity and the migration of neutrophils through an endothelial cell layer by inhibiting selectin interactions [90].

5.2. Lectins

Lectins are ubiquitous proteins that bind specifically and reversibly to carbohydrate structures, particularly the sugar moiety of glycoconjugates and glycoproteins. One of the major functions of lectins in animals is to facilitate cell-cell contact. Marine algal lectins have lower molecular weights than those found in other organism and, therefore, have attractive biological applications. For example, small algal lectin molecules may be less antigenic than the larger plant lectins are [91]. Moreover, their structures contain several disulfide bonds that provide high thermostability [92]. Some lectins extracted from marine alga including Hypnea cervicornis agglutinin (HCA) isolated from the alga H. cervicornis [91], Pterocladiella capillacea lectin (PcL) from the red alga P. capillacea [93], Caulerpa cupressoides lectin (CcL) from the green alga C. cupressoides [94], and Holothuria grisea agglutinin (HGA) isolated from Holothuria grisea [95] were reported to have antinociceptive effects in murine inflammatory pain studies. The antinociceptive effect of these marine lectins was associated with reduced neutrophil recruitment to the inflammatory tissue. Furthermore, studies of HCA and HGA found that the mechanism underlying the antihypernociceptive activity of HCA and HGA is mediated by increased NO production. In contrast, some other marine-based lectins showed chemoattraction. Nattectin, a C-type lectin isolated from the venomous fish Thalassophryne nattereri, was investigated using a murine model of inflammation [96]. Neutrophils were recruited to the mouse footpad, which was injected with nattectin. Moreover, the levels of the chemoattractants including the lipid mediator LTB4, pro-inflammatory cytokine interleukin (IL)-1b, and chemokine KC were increased at the site of nattectin injection.

5.3. Miscellaneous

Numerous other compounds or derivatives that are distributed in marine organisms have shown inhibitory effects on neutrophil adhesion. Adociacetylenes A, C, and D (Figure 6a–c) isolated from sponges of the Adocia sp. were revealed to have inhibitory activity in the endothelial cell-neutrophil leukocyte adhesion assay in vitro [97]. Lemnalol (8-isopropyl-5-methyl-4-methylene-decahydro-1,5-cyclo-naphthalen-3-ol; Figure 6d), extracted from the soft corals Lemnalia tenuis or Lemnalia cervicorni, was investigated in a study on monosodium urate (MSU)-induced gouty arthritis in rats [98]. Lemnalol suppressed leukocytes infiltration (primary neutrophils) in synovium injected with MSU. It also reduced inducible NO synthase (iNOS) and COX-2 in synovial tissue. Moreover, some mucin-type glycoproteins purified from the mucous secretions of the starfish Marthasterias glacialis and Porania pulvillus, as well as the brittlestar Ophiocomina nigra were reported to inhibit the adhesion of human neutrophils to cultured human vascular endothelial cells [99].

6. Conclusions

Excessive levels of inflammation can lead to a variety of diseases and, therefore, the search for novel anti-inflammatory agents and their investigation has become the focus of biologists and chemists. Neutrophils play a pivotal role in inflammation, and therefore, are considered important targets for anti-inflammatory compounds. Significant progress has been achieved recently in identifying novel anti-neutrophil marine products. However, their mechanisms of action are largely unexplored. In this report, we reviewed numerous marine natural products with mechanisms of action that have been well investigated. In addition, the compounds listed in Table 1, whose molecular targets have not been fully elucidated, may offer excellent opportunities to researchers who are interested in investigating the intracellular molecular mechanisms of compounds in neutrophils.
During inflammation, activated neutrophils release neutrophil extracellular traps (NETs), which are extracellular networks primarily composed of DNA, granule proteins, and modified histone [100]. In addition to phagocytosis and secretion of antimicrobial materials, NETs are an important machinery of neutrophils used to attack invading microbes and are involved in inflammatory responses [100,101]. Nevertheless, exaggerated NETs formation also contributes to some inflammatory diseases, such as systemic lupus erythematosus [102], diabetes [103], disseminated intravascular coagulation [104], and cardiovascular diseases [105]. Although some drugs have been identified and developed to inhibit NETs, no marine natural product has been discovered to suppress NETs. Marine natural products are a valuable source of bioactive entities and potential drug scaffolds; therefore, we predict future comprehensive investigations can discover marine-based NETs inhibitors.
The chemical and biological diversities of marine products motivated some structure–activity relationship studies of some bioactive classes. Rational design and targeted modification of known bioactive marine natural products could offer biological activities improvement and enhance their therapeutic margin. Structure and ligand-based semisynthetic modifications of the thoroughly investigated anti-inflammatory marine-based entities have the potential to facilitate novel drug discoveries.
In conclusion, inflammation is a process that occurs in various cell types including immune and non-immune cells and has a role in fighting pathogenic or sterile injury. However, excessive inflammation can be deleterious to the body and leads to inflammatory diseases. This review provides an overview of previously conducted experiments that examined the anti-inflammatory effects of marine products in neutrophils, and it is our hope that additional studies investigating the detailed mechanisms of the anti-inflammatory effects of natural or synthetic products would be conducted not only on neutrophils but the entire complex immune system.

Acknowledgments

This review was financial supported by the grants from the Ministry of Science Technology (MOST 102-2628-B-255-003-MY3).

Author Contributions

Authors C.-Y.C. and T.-L.H. were responsible for the overall work of the manuscript. Author C.-Y.C. wrote the article. Author W.-Y.C, Y.-F.T., and S.-C.Y. managed the literature searches.

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

The following abbreviations are used in this manuscript:
ROSreactive oxygen species
FPRformyl peptide receptor
ALXlipoxin A4 receptor
PI3Kphosphatidylinositol-3-kinase
MAPKmitogen-activated kinase
PLCphospholipase C
PIP2phosphatidylinositol 4,5-bisphosphate
IP3inositol 1,4,5-trisphosphate
PKCprotein kinase C
NADPHnicotinamide adenine dinucleotide phosphate
fMLFformyl-methionyl-leucyl phenylalanine
JNKc-Jun N-terminal kinase
ERKextracellular signal-regulated kinase
PMAphorbol myristate acetate
OKAokadaic acid
PPprotein phosphatase
PLA2phospholipase A2
AAarachidonic acid
5-LO5-lipoxygenase
COXcyclooxygenase
5-HPTETE5′-hydroperoxyeicosatetraenoic acid
5-HETE5-hydroxyicosatetraenoic acid
PGH2prostaglandin H
LTlleukotriene
TXthromboxane
PLSpolysaccharide
Nitric oxideNO
fCSfucosylated chondroitin sulfate
MSUmonosodium urate
iNOSnitric oxide synthase
NETsneutrophil extracellular traps

References

  1. Kolaczkowska, E.; Kubes, P. Neutrophil recruitment and function in health and inflammation. Nat. Rev. Immunol. 2013, 13, 159–175. [Google Scholar] [CrossRef] [PubMed]
  2. Stapels, D.A.; Geisbrecht, B.V.; Rooijakkers, S.H. Neutrophil serine proteases in antibacterial defense. Curr. Opin. Microbiol. 2015, 23, 42–48. [Google Scholar] [CrossRef] [PubMed]
  3. Shen, M.; Hu, P.; Donskov, F.; Wang, G.; Liu, Q.; Du, J. Tumor-associated neutrophils as a new prognostic factor in cancer: A systematic review and meta-analysis. PLoS ONE 2014, 9, e98259. [Google Scholar] [CrossRef] [PubMed]
  4. Galdiero, M.R.; Bonavita, E.; Barajon, I.; Garlanda, C.; Mantovani, A.; Jaillon, S. Tumor associated macrophages and neutrophils in cancer. Immunobiology 2013, 218, 1402–1410. [Google Scholar] [CrossRef] [PubMed]
  5. Ciepiela, O.; Ostafin, M.; Demkow, U. Neutrophils in asthma—A review. Respir. Physiol. Neurobiol. 2015, 209, 13–16. [Google Scholar] [CrossRef] [PubMed]
  6. McDonald, B.; Kubes, P. Neutrophils and intravascular immunity in the liver during infection and sterile inflammation. Toxicol. Pathol. 2012, 40, 157–165. [Google Scholar] [CrossRef] [PubMed]
  7. Hajishengallis, G.; Moutsopoulos, N.M.; Hajishengallis, E.; Chavakis, T. Immune and regulatory functions of neutrophils in inflammatory bone loss. Semin. Immunol. 2016, 28, 146–158. [Google Scholar] [CrossRef] [PubMed]
  8. Ransohoff, R.M.; Brown, M.A. Innate immunity in the central nervous system. J. Clin. Investig. 2012, 122, 1164–1171. [Google Scholar] [CrossRef] [PubMed]
  9. Schepetkin, I.A.; Khlebnikov, A.I.; Kirpotina, L.N.; Quinn, M.T. Antagonism of human formyl peptide receptor 1 with natural compounds and their synthetic derivatives. Int. Immunopharmacol. 2015, 37, 43–58. [Google Scholar] [CrossRef] [PubMed]
  10. Kang, H.K.; Seo, C.H.; Park, Y. Marine peptides and their anti-infective activities. Mar. Drugs 2015, 13, 618–654. [Google Scholar] [CrossRef] [PubMed]
  11. Mayer, A.M.; Rodriguez, A.D.; Taglialatela-Scafati, O.; Fusetani, N. Marine pharmacology in 2009–2011: Marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis, and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action. Mar. Drugs 2013, 11, 2510–2573. [Google Scholar] [PubMed]
  12. Rabiet, M.J.; Huet, E.; Boulay, F. The N-formyl peptide receptors and the anaphylatoxin C5a receptors: An overview. Biochimie 2007, 89, 1089–1106. [Google Scholar] [CrossRef] [PubMed]
  13. Ye, R.D.; Boulay, F.; Wang, J.M.; Dahlgren, C.; Gerard, C.; Parmentier, M.; Serhan, C.N.; Murphy, P.M. International Union of Basic and Clinical Pharmacology. LXXIII. Nomenclature for the formyl peptide receptor (FPR) family. Pharmacol. Rev. 2009, 61, 119–161. [Google Scholar] [CrossRef] [PubMed]
  14. Dufton, N.; Perretti, M. Therapeutic anti-inflammatory potential of formyl-peptide receptor agonists. Pharmacol. Ther. 2010, 127, 175–188. [Google Scholar] [CrossRef] [PubMed]
  15. Lammers, K.M.; Chieppa, M.; Liu, L.; Liu, S.; Omatsu, T.; Janka-Junttila, M.; Casolaro, V.; Reinecker, H.C.; Parent, C.A.; Fasano, A. Gliadin Induces Neutrophil Migration via Engagement of the Formyl Peptide Receptor, FPR1. PLoS ONE 2015, 10, e0138338. [Google Scholar] [CrossRef] [PubMed]
  16. Zhang, Q.; Raoof, M.; Chen, Y.; Sumi, Y.; Sursal, T.; Junger, W.; Brohi, K.; Itagaki, K.; Hauser, C.J. Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature 2010, 464, 104–107. [Google Scholar] [CrossRef] [PubMed]
  17. Schiffmann, E.; Corcoran, B.A.; Wahl, S.M. N-formylmethionyl peptides as chemoattractants for leucocytes. Proc. Natl. Acad. Sci. USA 1975, 72, 1059–1062. [Google Scholar] [CrossRef] [PubMed]
  18. Wei, W.C.; Sung, P.J.; Duh, C.Y.; Chen, B.W.; Sheu, J.H.; Yang, N.S. Anti-inflammatory activities of natural products isolated from soft corals of Taiwan between 2008 and 2012. Mar. Drugs 2013, 11, 4083–4126. [Google Scholar] [CrossRef] [PubMed]
  19. Wilkinson, P.C. Synthetic peptide chemotactic factors for neutrophils: The range of active peptides, their efficacy and inhibitory activity, and susceptibility of the cellular response to enzymes and bacterial toxins. Immunology 1979, 36, 579–588. [Google Scholar] [PubMed]
  20. Sung, P.J.; Chen, B.Y.; Lin, M.R.; Hwang, T.L.; Wang, W.H.; Sheu, J.H.; Wu, Y.C. Excavatoids E and F: Discovery of two new briaranes from the cultured octocoral Briareum excavatum. Mar. Drugs 2009, 7, 472–482. [Google Scholar] [CrossRef] [PubMed]
  21. Su, J.H.; Chen, B.Y.; Hwang, T.L.; Chen, Y.H.; Huang, I.C.; Lin, M.R.; Chen, J.J.; Fang, L.S.; Wang, W.H.; Li, J.J.; et al. Excavatoids L–N, new 12-hydroxybriaranes from the cultured octocoral Briareum excavatum (Briareidae). Chem. Pharm. Bull. 2010, 58, 662–665. [Google Scholar] [CrossRef] [PubMed]
  22. Sung, P.J.; Li, G.Y.; Su, Y.D.; Lin, M.R.; Chang, Y.C.; Kung, T.H.; Lin, C.S.; Chen, Y.H.; Su, J.H.; Lu, M.C.; et al. Excavatoids O and P, new 12-hydroxybriaranes from the octocoral Briareum excavatum. Mar. Drugs 2010, 8, 2639–2646. [Google Scholar] [CrossRef] [PubMed]
  23. Liu, C.Y.; Hwang, T.L.; Lin, M.R.; Chen, Y.H.; Chang, Y.C.; Fang, L.S.; Wang, W.H.; Wu, Y.C.; Sung, P.J. Carijoside A, a bioactive sterol glycoside from an octocoral Carijoa sp. (Clavulariidae). Mar. Drugs 2010, 8, 2014–2020. [Google Scholar] [CrossRef] [PubMed]
  24. Chen, B.W.; Uvarani, C.; Huang, C.Y.; Hwang, T.L.; Dai, C.F.; Sheu, J.H. New anti-inflammatory tocopherol-derived metabolites from the Taiwanese soft coral Cladiella hirsuta. Bioorg. Med. Chem. Lett. 2015, 25, 92–95. [Google Scholar] [CrossRef] [PubMed]
  25. Huang, T.Z.; Chen, B.W.; Huang, C.Y.; Hwang, T.L.; Dai, C.F.; Sheu, J.H. Eunicellin-based diterpenoids, hirsutalins N-R, from the formosan soft coral Cladiella hirsuta. Mar. Drugs 2014, 12, 2446–2457. [Google Scholar] [CrossRef] [PubMed]
  26. Huang, T.Z.; Chen, B.W.; Huang, C.Y.; Hwang, T.L.; Uvarani, C.; Dai, C.F.; Sung, P.J.; Su, J.H.; Sheu, J.H. Eunicellin-Based Diterpenoids, Hirsutalins S–V, from the Formosan Soft Coral Cladiella hirsuta. Mar. Drugs 2015, 13, 2757–2769. [Google Scholar] [CrossRef] [PubMed]
  27. Lee, Y.N.; Tai, C.J.; Hwang, T.L.; Sheu, J.H. Krempfielins J–M, new eunicellin-based diterpenoids from the soft coral Cladiella krempfi. Mar. Drugs 2013, 11, 2741–2750. [Google Scholar] [CrossRef] [PubMed]
  28. Lee, Y.N.; Tai, C.J.; Hwang, T.L.; Sheu, J.H. Krempfielins N–P, New anti-inflammatory eunicellins from a Taiwanese soft coral Cladiella krempfi. Mar. Drugs 2014, 12, 1148–1156. [Google Scholar] [CrossRef] [PubMed]
  29. Tai, C.J.; Chokkalingam, U.; Cheng, Y.; Shih, S.P.; Lu, M.C.; Su, J.H.; Hwang, T.L.; Sheu, J.H. Krempfielins Q and R, two new eunicellin-based diterpenoids from the soft coral Cladiella krempfi. Int. J. Mol. Sci. 2014, 15, 21865–21874. [Google Scholar] [CrossRef] [PubMed]
  30. Chen, Y.H.; Hwang, T.L.; Su, Y.D.; Chang, Y.C.; Chen, Y.H.; Hong, P.H.; Hu, L.C.; Yen, W.H.; Hsu, H.Y.; Huang, S.J.; et al. New 6-hydroxyeunicellins from a soft coral Cladiella sp. Chem. Pharm. Bull. 2012, 60, 160–163. [Google Scholar] [CrossRef] [PubMed]
  31. Chen, Y.H.; Tai, C.Y.; Hwang, T.L.; Weng, C.F.; Li, J.J.; Fang, L.S.; Wang, W.H.; Wu, Y.C.; Sung, P.J. Cladielloides A and B: New eunicellin-type diterpenoids from an Indonesian octocoral Cladiella sp. Mar. Drugs 2010, 8, 2936–2945. [Google Scholar] [CrossRef] [PubMed]
  32. Chen, Y.H.; Tai, C.Y.; Kuo, Y.H.; Kao, C.Y.; Li, J.J.; Hwang, T.L.; Fang, L.S.; Wang, W.H.; Sheu, J.H.; Sung, P.J. Cladieunicellins A–E, new eunicellins from an Indonesian soft coral Cladiella sp. Chem. Pharm. Bull. 2011, 59, 353–358. [Google Scholar] [CrossRef] [PubMed]
  33. Chen, Y.H.; Tai, C.Y.; Hwang, T.L.; Sung, P.J. Cladieunicellin H, a new hemiketal eunicellin-based diterpenoid from the octocoral Cladiella sp. Nat. Prod. Commun. 2012, 7, 481–484. [Google Scholar] [PubMed]
  34. Chen, Y.H.; Tai, C.Y.; Su, Y.D.; Chang, Y.C.; Lu, M.C.; Weng, C.F.; Su, J.H.; Hwang, T.L.; Wu, Y.C.; Sung, P.J. Discovery of new eunicellins from an Indonesian octocoral Cladiella sp. Mar. Drugs 2011, 9, 934–943. [Google Scholar] [CrossRef] [PubMed]
  35. Chung, H.M.; Hong, P.H.; Su, J.H.; Hwang, T.L.; Lu, M.C.; Fang, L.S.; Wu, Y.C.; Li, J.J.; Chen, J.J.; Wang, W.H.; et al. Bioactive compounds from a gorgonian coral Echinomuricea sp. (Plexauridae). Mar. Drugs 2012, 10, 1169–1179. [Google Scholar] [CrossRef] [PubMed]
  36. Cheng, C.H.; Chung, H.M.; Hwang, T.L.; Lu, M.C.; Wen, Z.H.; Kuo, Y.H.; Wang, W.H.; Sung, P.J. Echinoclerodane A: A new bioactive clerodane-type diterpenoid from a gorgonian coral Echinomuricea sp. Molecules 2012, 17, 9443–9450. [Google Scholar] [CrossRef] [PubMed]
  37. Chung, H.M.; Hu, L.C.; Yen, W.H.; Su, J.H.; Lu, M.C.; Hwang, T.L.; Wang, W.H.; Sung, P.J. Echinohalimane A, a bioactive halimane-type diterpenoid from a Formosan gorgonian Echinomuricea sp. (Plexauridae). Mar. Drugs 2012, 10, 2246–2253. [Google Scholar] [CrossRef] [PubMed]
  38. Sung, P.J.; Lin, M.R.; Chen, J.J.; Lin, S.F.; Wu, Y.C.; Hwang, T.L.; Fang, L.S. Hydroperoxysterols from the tunicate Eudistoma sp. Chem. Pharm. Bull. 2007, 55, 666–668. [Google Scholar] [CrossRef] [PubMed]
  39. Solem, M.L.; Jiang, Z.D.; Gerwick, W.H. Three new and bioactive icosanoids from the temperate red marine alga Farlowia mollis. Lipids 1989, 24, 256–260. [Google Scholar] [CrossRef] [PubMed]
  40. Fang, H.Y.; Chokkalingam, U.; Chiou, S.F.; Hwang, T.L.; Chen, S.L.; Wang, W.L.; Sheu, J.H. Bioactive chemical constituents from the brown alga Homoeostrichus formosana. Int. J. Mol. Sci. 2015, 16, 736–746. [Google Scholar] [CrossRef] [PubMed]
  41. Liaw, C.C.; Shen, Y.C.; Lin, Y.S.; Hwang, T.L.; Kuo, Y.H.; Khalil, A.T. Frajunolides E-K, briarane diterpenes from Junceella fragilis. J. Nat. Prod. 2008, 71, 1551–1556. [Google Scholar] [CrossRef] [PubMed]
  42. Sheu, J.H.; Chen, Y.P.; Hwang, T.L.; Chiang, M.Y.; Fang, L.S.; Sung, P.J. Junceellolides J-L, 11,20-epoxybriaranes from the gorgonian coral Junceella fragilis. J. Nat. Prod. 2006, 69, 269–273. [Google Scholar] [CrossRef] [PubMed]
  43. Sung, P.J.; Pai, C.H.; Hwang, T.L.; Fan, T.Y.; Su, J.H.; Chen, J.J.; Fang, L.S.; Wang, W.H.; Sheu, J.H. Junceols D-H, new polyoxygenated briaranes from sea whip gorgonian coral Junceella juncea (Ellisellidae). Chem. Pharm. Bull. 2008, 56, 1276–1281. [Google Scholar] [CrossRef] [PubMed]
  44. Lin, M.C.; Chen, B.W.; Huang, C.Y.; Dai, C.F.; Hwang, T.L.; Sheu, J.H. Eunicellin-based diterpenoids from the Formosan soft coral Klyxum molle with inhibitory activity on superoxide generation and elastase release by neutrophils. J. Nat. Prod. 2013, 76, 1661–1667. [Google Scholar] [CrossRef] [PubMed]
  45. Kao, C.Y.; Su, J.H.; Lu, M.C.; Hwang, T.L.; Wang, W.H.; Chen, J.J.; Sheu, J.H.; Kuo, Y.H.; Weng, C.F.; Fang, L.S.; et al. Lobocrassins A-E: New cembrane-type diterpenoids from the soft coral Lobophytum crassum. Mar. Drugs 2011, 9, 1319–1331. [Google Scholar] [CrossRef] [PubMed]
  46. Kao, S.Y.; Su, J.H.; Hwang, T.L.; Sheu, J.H.; Wen, Z.H.; Wu, Y.C.; Sung, P.J. Menelloides C and D, new sesquiterpenoids from the Gorgonian coral Menella sp. Mar. Drugs 2011, 9, 1534–1542. [Google Scholar] [CrossRef] [PubMed]
  47. Kao, S.Y.; Chang, Y.C.; Su, J.H.; Lu, M.C.; Chen, Y.H.; Sheu, J.H.; Wen, Z.H.; Wang, W.H.; Kuo, Y.H.; Hwang, T.L.; et al. (−)-Hydroxylindestrenolide, a new sesquiterpenoid from a gorgonian coral Menella sp. (Plexauridae). Chem. Pharm. Bull. 2011, 59, 1048–1050. [Google Scholar] [CrossRef] [PubMed]
  48. Chen, Y.H.; Kuo, J.; Su, J.H.; Hwang, T.L.; Chen, Y.H.; Lee, C.H.; Weng, C.F.; Sung, P.J. Pseudoalteromone B: A novel 15C compound from a marine bacterium Pseudoalteromonas sp. CGH2XX. Mar. Drugs 2012, 10, 1566–1571. [Google Scholar] [CrossRef] [PubMed]
  49. Chung, H.M.; Wang, W.H.; Hwang, T.L.; Wu, Y.C.; Sung, P.J. Natural clovanes from the gorgonian coral Rumphella antipathies. Nat. Prod. Commun. 2013, 8, 1037–1040. [Google Scholar] [PubMed]
  50. Chung, H.M.; Wang, W.H.; Hwang, T.L.; Fang, L.S.; Wen, Z.H.; Chen, J.J.; Wu, Y.C.; Sung, P.J. Rumphellaoic acid A, a novel sesquiterpenoid from the formosan gorgonian coral Rumphella antipathies. Mar. Drugs 2014, 12, 5856–5863. [Google Scholar] [CrossRef] [PubMed]
  51. Chung, H.M.; Wang, W.H.; Hwang, T.L.; Li, J.J.; Fang, L.S.; Wu, Y.C.; Sung, P.J. Rumphellaones B and C, new 4,5-seco-caryophyllane sesquiterpenoids from Rumphellan antipathies. Molecules 2014, 19, 12320–12327. [Google Scholar] [CrossRef] [PubMed]
  52. Chung, H.M.; Wang, W.H.; Hwang, T.L.; Chen, J.J.; Fang, L.S.; Wen, Z.H.; Wang, Y.B.; Wu, Y.C.; Sung, P.J. Rumphellols A and B, new caryophyllene sesquiterpenoids from a Formosan gorgonian coral, Rumphella antipathies. Int. J. Mol. Sci. 2014, 15, 15679–15688. [Google Scholar] [CrossRef] [PubMed]
  53. Lin, K.H.; Tseng, Y.J.; Chen, B.W.; Hwang, T.L.; Chen, H.Y.; Dai, C.F.; Sheu, J.H. Tortuosenes A and B, new diterpenoid metabolites from the Formosan soft coral Sarcophyton tortuosum. Org. Lett. 2014, 16, 1314–1317. [Google Scholar] [CrossRef] [PubMed]
  54. Chen, K.H.; Dai, C.F.; Hwang, T.L.; Chen, C.Y.; Li, J.J.; Chen, J.J.; Wu, Y.C.; Sheu, J.H.; Wang, W.H.; Sung, P.J. Discovery of novel diterpenoids from Sinularia arborea. Mar. Drugs 2014, 12, 385–393. [Google Scholar] [CrossRef] [PubMed]
  55. Hu, L.C.; Su, J.H.; Chiang, M.Y.; Lu, M.C.; Hwang, T.L.; Chen, Y.H.; Hu, W.P.; Lin, N.C.; Wang, W.H.; Fang, L.S.; et al. Flexibilins A–C, new cembrane-type diterpenoids from the Formosan soft coral, Sinularia flexibilis. Mar. Drugs 2013, 11, 1999–2012. [Google Scholar] [CrossRef] [PubMed]
  56. Yang, S.C.; Lin, C.F.; Chang, W.Y.; Kuo, J.; Huang, Y.T.; Chung, P.J.; Hwang, T.L. Bioactive secondary metabolites of a marine Bacillus sp. inhibit superoxide generation and elastase release in human neutrophils by blocking formyl peptide receptor 1. Molecules 2013, 18, 6455–6468. [Google Scholar] [CrossRef] [PubMed]
  57. Omura, S.; Iwai, Y.; Hirano, A.; Nakagawa, A.; Awaya, J.; Tsuchya, H.; Takahashi, Y.; Masuma, R. A new alkaloid AM-2282 OF Streptomyces origin. Taxonomy, fermentation, isolation and preliminary characterization. J. Antibiot. 1977, 30, 275–2782. [Google Scholar] [CrossRef] [PubMed]
  58. Ruegg, U.T.; Burgess, G.M. Staurosporine, K-252 and UCN-01: Potent but nonspecific inhibitors of protein kinases. Trends Pharmacol. Sci. 1989, 10, 218–220. [Google Scholar] [CrossRef]
  59. Horton, P.A.; Longley, R.E.; McConnell, O.J.; Ballas, L.M. Staurosporine aglycone (K252-c) and arcyriaflavin A from the marine ascidian, Eudistoma sp. Experientia 1994, 50, 843–845. [Google Scholar] [CrossRef] [PubMed]
  60. Yang, S.C.; Sung, P.J.; Lin, C.F.; Kuo, J.; Chen, C.Y.; Hwang, T.L. Anti-inflammatory effects of secondary metabolites of marine Pseudomonas sp. in human neutrophils are through inhibiting P38 MAPK, JNK, and calcium pathways. PLoS ONE 2014, 9, e114761. [Google Scholar] [CrossRef] [PubMed]
  61. Nicolas, J.P.; Lin, Y.; Lambeau, G.; Ghomashchi, F.; Lazdunski, M.; Gelb, M.H. Localization of structural elements of bee venom phospholipase A2 involved in N-type receptor binding and neurotoxicity. J. Biol. Chem. 1997, 272, 7173–7181. [Google Scholar] [CrossRef] [PubMed]
  62. Murakami, M.; Taketomi, Y.; Miki, Y.; Sato, H.; Hirabayashi, T.; Yamamoto, K. Recent progress in phospholipase A(2) research: From cells to animals to humans. Prog. Lipid Res. 2011, 50, 152–192. [Google Scholar] [CrossRef] [PubMed]
  63. Kramer, R.M.; Roberts, E.F.; Manetta, J.; Putnam, J.E. The Ca2(+)-sensitive cytosolic phospholipase A2 is a 100-kDa protein in human monoblast U937 cells. J. Biol. Chem. 1991, 266, 5268–5272. [Google Scholar] [PubMed]
  64. Quach, N.D.; Arnold, R.D.; Cummings, B.S. Secretory phospholipase A2 enzymes as pharmacological targets for treatment of disease. Biochem. Pharmacol. 2014, 90, 338–348. [Google Scholar] [CrossRef] [PubMed]
  65. Lin, L.L.; Wartmann, M.; Lin, A.Y.; Knopf, J.L.; Seth, A.; Davis, R.J. cPLA2 is phosphorylated and activated by MAP kinase. Cell 1993, 72, 269–278. [Google Scholar] [CrossRef]
  66. Wijkander, J.; Sundler, R. Macrophage arachidonate-mobilizing phospholipase A2: Role of Ca2+ for membrane binding but not for catalytic activity. Biochem. Biophys. Res. Commun. 1992, 184, 118–124. [Google Scholar] [CrossRef]
  67. Levy, R. The role of cytosolic phospholipase A2-alfa in regulation of phagocytic functions. Biochim. Biophys. Acta 2006, 1761, 1323–1334. [Google Scholar] [CrossRef] [PubMed]
  68. Nalefski, E.A.; Sultzman, L.A.; Martin, D.M.; Kriz, R.W.; Towler, P.S.; Knopf, J.L.; Clark, J.D. Delineation of two functionally distinct domains of cytosolic phospholipase A2, a regulatory Ca(2+)-dependent lipid-binding domain and a Ca(2+)-independent catalytic domain. J. Biol. Chem. 1994, 269, 18239–18249. [Google Scholar] [PubMed]
  69. van Rossum, D.B.; Patterson, R.L. PKC and PLA2: Probing the complexities of the calcium network. Cell Calcium 2009, 45, 535–545. [Google Scholar] [CrossRef] [PubMed]
  70. Folmer, F.; Jaspars, M.; Schumacher, M.; Dicato, M.; Diederich, M. Marine natural products targeting phospholipases A2. Biochem. Pharmacol. 2010, 80, 1793–1800. [Google Scholar] [CrossRef] [PubMed]
  71. Potts, B.C.; Faulkner, D.J.; Jacobs, R.S. Phospholipase A2 inhibitors from marine organisms. J. Nat. Prod. 1992, 55, 1701–1717. [Google Scholar] [CrossRef] [PubMed]
  72. Ferrandiz, M.L.; Sanz, M.J.; Bustos, G.; Paya, M.; Alcaraz, M.J.; De Rosa, S. Avarol and avarone, two new anti-inflammatory agents of marine origin. Eur. J. Pharmacol. 1994, 253, 75–82. [Google Scholar] [CrossRef]
  73. Muller, W.E.; Maidhof, A.; Zahn, R.K.; Schroder, H.C.; Gasic, M.J.; Heidemann, D.; Bernd, A.; Kurelec, B.; Eich, E.; Seibert, G. Potent antileukemic activity of the novel cytostatic agent avarone and its analogues in vitro and in vivo. Cancer Res. 1985, 45, 4822–4826. [Google Scholar] [PubMed]
  74. Amigo, M.; Paya, M.; De Rosa, S.; Terencio, M.C. Antipsoriatic effects of avarol-3′-thiosalicylate are mediated by inhibition of TNF-alpha generation and NF-kappaB activation in mouse skin. Br. J. Pharmacol. 2007, 152, 353–365. [Google Scholar] [CrossRef] [PubMed]
  75. Amigo, M.; Terencio, M.C.; Mitova, M.; Iodice, C.; Paya, M.; De Rosa, S. Potential antipsoriatic avarol derivatives as antioxidants and inhibitors of PGE(2) generation and proliferation in the HaCaT cell line. J. Nat. Prod. 2004, 67, 1459–1463. [Google Scholar] [CrossRef] [PubMed]
  76. Terencio, M.C.; Ferrandiz, M.L.; Posadas, I.; Roig, E.; de Rosa, S.; De Giulio, A.; Paya, M.; Alcaraz, M.J. Suppression of leukotriene B4 and tumour necrosis factor alpha release in acute inflammatory responses by novel prenylated hydroquinone derivatives. Naunyn-Schmiedeberg′s Arch. Pharmacol. 1998, 357, 565–572. [Google Scholar] [CrossRef]
  77. Gil, B.; Sanz, M.J.; Terencio, M.C.; De Giulio, A.; De Rosa, S.; Alcaraz, M.J.; Paya, M. Effects of marine 2-polyprenyl-1,4-hydroquinones on phospholipase A2 activity and some inflammatory responses. Eur. J. Pharmacol. 1995, 285, 281–288. [Google Scholar] [CrossRef]
  78. Halpern, G.M. Anti-inflammatory effects of a stabilized lipid extract of Perna canaliculus (Lyprinol). Allerg. Immunol. 2000, 32, 272–278. [Google Scholar]
  79. Cholbi, R.; Ferrandiz, M.L.; Terencio, M.C.; De Rosa, S.; Alcaraz, M.J.; Paya, M. Inhibition of phospholipase A2 activities and some inflammatory responses by the marine product ircinin. Naunyn-Schmiedeberg's Arch. Pharmacol. 1996, 354, 677–683. [Google Scholar] [CrossRef]
  80. Berkow, R.L.; Dodson, R.W. Regulation of neutrophil respiratory burst by protein phosphatases. Life Sci. 1993, 52, 1727–1732. [Google Scholar] [CrossRef]
  81. Garcia, R.C.; Whitaker, M.; Heyworth, P.G.; Segal, A.W. Okadaic acid produces changes in phosphorylation and translocation of proteins and in intracellular calcium in human neutrophils. Relationship with the activation of the NADPH oxidase by different stimuli. Biochem. J. 1992, 286 Pt 3, 687–692. [Google Scholar] [CrossRef] [PubMed]
  82. Lu, D.J.; Takai, A.; Leto, T.L.; Grinstein, S. Modulation of neutrophil activation by okadaic acid, a protein phosphatase inhibitor. Am. J. Physiol. 1992, 262 Pt 1, C39–C49. [Google Scholar] [PubMed]
  83. Mayer, A.M.; Choudhry, M.A.; Sayeed, M.M.; Spitzer, J.A. The marine toxin okadaic acid reduces O2-generation and tyrosine phosphorylation in LPS-primed rat neutrophils. Life Sci. 1997, 61, PL199–PL204. [Google Scholar] [CrossRef]
  84. Shinozaki, T.; Watanabe, H.; Arita, S.; Chigira, M. Amino acid phosphatase activity of alkaline phosphatase. A possible role of protein phosphatase. Eur. J. Biochem. FEBS 1995, 227, 367–371. [Google Scholar] [CrossRef]
  85. Steinbeck, M.J.; Hegg, G.G.; Karnovsky, M.J. Arachidonate activation of the neutrophil NADPH-oxidase. Synergistic effects of protein phosphatase inhibitors compared with protein kinase activators. J. Biol. Chem. 1991, 266, 16336–16342. [Google Scholar] [PubMed]
  86. De Brito, T.V.; Prudencio Rda, S.; Sales, A.B.; Vieira, F., Jr.; Candeira, S.J.; Franco, A.X.; Aragao, K.S.; Ribeiro Rde, A.; Ponte de Souza, M.H.; Chaves Lde, S.; et al. Anti-inflammatory effect of a sulphated polysaccharide fraction extracted from the red algae Hypnea musciformis via the suppression of neutrophil migration by the nitric oxide signalling pathway. J. Pharm. Pharmacol. 2013, 65, 724–733. [Google Scholar] [CrossRef] [PubMed]
  87. Chaves Lde, S.; Nicolau, L.A.; Silva, R.O.; Barros, F.C.; Freitas, A.L.; Aragao, K.S.; Ribeiro Rde, A.; Souza, M.H.; Barbosa, A.L.; Medeiros, J.V. Antiinflammatory and antinociceptive effects in mice of a sulfated polysaccharide fraction extracted from the marine red algae Gracilaria caudata. Immunopharmacol. Immunotoxicol. 2013, 35, 93–100. [Google Scholar] [CrossRef] [PubMed]
  88. Pereira, J.G.; Mesquita, J.X.; Aragao, K.S.; Franco, A.X.; Souza, M.H.; Brito, T.V.; Dias, J.M.; Silva, R.O.; Medeiros, J.V.; Oliveira, J.S.; et al. Polysaccharides isolated from Digenea simplex inhibit inflammatory and nociceptive responses. Carbohydr. Polym. 2014, 108, 17–25. [Google Scholar] [CrossRef] [PubMed]
  89. Cumashi, A.; Ushakova, N.A.; Preobrazhenskaya, M.E.; D’Incecco, A.; Piccoli, A.; Totani, L.; Tinari, N.; Morozevich, G.E.; Berman, A.E.; Bilan, M.I.; et al. Consorzio Interuniversitario Nazionale per la Bio-Oncologia, I. A comparative study of the anti-inflammatory, anticoagulant, antiangiogenic, and antiadhesive activities of nine different fucoidans from brown seaweeds. Glycobiology 2007, 17, 541–552. [Google Scholar] [CrossRef] [PubMed]
  90. Panagos, C.G.; Thomson, D.S.; Moss, C.; Hughes, A.D.; Kelly, M.S.; Liu, Y.; Chai, W.; Venkatasamy, R.; Spina, D.; Page, C.P.; et al. Fucosylated chondroitin sulfates from the body wall of the sea cucumber Holothuria forskali: Conformation, selectin binding, and biological activity. J. Biol. Chem. 2014, 289, 28284–28298. [Google Scholar] [CrossRef] [PubMed]
  91. Figueiredo, J.G.; Bitencourt, F.S.; Cunha, T.M.; Luz, P.B.; Nascimento, K.S.; Mota, M.R.; Sampaio, A.H.; Cavada, B.S.; Cunha, F.Q.; Alencar, N.M. Agglutinin isolated from the red marine alga Hypnea cervicornis J. Agardh reduces inflammatory hypernociception: Involvement of nitric oxide. Pharmacol. Biochem. Behav. 2010, 96, 371–377. [Google Scholar] [CrossRef] [PubMed]
  92. Nagano, C.S.; Debray, H.; Nascimento, K.S.; Pinto, V.P.; Cavada, B.S.; Saker-Sampaio, S.; Farias, W.R.; Sampaio, A.H.; Calvete, J.J. HCA and HML isolated from the red marine algae Hypnea cervicornis and Hypnea musciformis define a novel lectin family. Protein Sci. 2005, 14, 2167–2176. [Google Scholar] [CrossRef] [PubMed]
  93. Silva, L.M.; Lima, V.; Holanda, M.L.; Pinheiro, P.G.; Rodrigues, J.A.; Lima, M.E.; Benevides, N.M. Antinociceptive and anti-inflammatory activities of lectin from marine red alga Pterocladiella capillacea. Biol. Pharm. Bull. 2010, 33, 830–835. [Google Scholar] [CrossRef] [PubMed]
  94. Vanderlei, E.S.; Patoilo, K.K.; Lima, N.A.; Lima, A.P.; Rodrigues, J.A.; Silva, L.M.; Lima, M.E.; Lima, V.; Benevides, N.M. Antinociceptive and anti-inflammatory activities of lectin from the marine green alga Caulerpa cupressoides. Int. Immunopharmacol. 2010, 10, 1113–1118. [Google Scholar] [CrossRef] [PubMed]
  95. Moura Rda, M.; Aragao, K.S.; de Melo, A.A.; Carneiro, R.F.; Osorio, C.B.; Luz, P.B.; de Queiroz, A.F.; Dos Santos, E.A.; de Alencar, N.M.; Cavada, B.S. Holothuria grisea agglutinin (HGA): The first invertebrate lectin with anti-inflammatory effects. Fundam. Clin. Pharmacol. 2013, 27, 656–668. [Google Scholar] [CrossRef] [PubMed]
  96. Lopes-Ferreira, M.; Magalhaes, G.S.; Fernandez, J.H.; Junqueira-de-Azevedo Ide, L.; Le Ho, P.; Lima, C.; Valente, R.H.; Moura-da-Silva, A.M. Structural and biological characterization of Nattectin, a new C-type lectin from the venomous fish Thalassophryne nattereri. Biochimie 2011, 93, 971–980. [Google Scholar] [CrossRef] [PubMed]
  97. Kobayashi, M.; Mahmud, T.; Tajima, H.; Wang, W.; Aoki, S.; Nakagawa, S.; Mayumi, T.; Kitagawa, I. Marine natural products. XXXVI. Biologically active polyacetylenes, adociacetylenes A, B, C, and D, from an Okinawan Marine sponge of Adocia sp. Chem. Pharm. Bull. 1996, 44, 720–724. [Google Scholar] [CrossRef] [PubMed]
  98. Lee, H.P.; Huang, S.Y.; Lin, Y.Y.; Wang, H.M.; Jean, Y.H.; Wu, S.F.; Duh, C.Y.; Wen, Z.H. Soft coral-derived lemnalol alleviates monosodium urate-induced gouty arthritis in rats by inhibiting leukocyte infiltration and iNOS, COX-2 and c-Fos protein expression. Mar. Drugs 2013, 11, 99–113. [Google Scholar] [CrossRef] [PubMed]
  99. Bavington, C.D.; Lever, R.; Mulloy, B.; Grundy, M.M.; Page, C.P.; Richardson, N.V.; McKenzie, J.D. Anti-adhesive glycoproteins in echinoderm mucus secretions. Comp. Biochem. Physiol. Part B Biochem. Mol. Biol. 2004, 139, 607–617. [Google Scholar] [CrossRef] [PubMed]
  100. Vorobjeva, N.V.; Pinegin, B.V. Neutrophil extracellular traps: Mechanisms of formation and role in health and disease. Biochemistry 2014, 79, 1286–1296. [Google Scholar] [CrossRef] [PubMed]
  101. Pinegin, B.; Vorobjeva, N.; Pinegin, V. Neutrophil extracellular traps and their role in the development of chronic inflammation and autoimmunity. Autoimmun. Rev. 2015, 14, 633–640. [Google Scholar] [CrossRef] [PubMed]
  102. Barnado, A.; Crofford, L.J.; Oates, J.C. At the Bedside: Neutrophil extracellular traps (NETs) as targets for biomarkers and therapies in autoimmune diseases. J. Leukoc. Biol. 2016, 99, 265–278. [Google Scholar] [CrossRef] [PubMed]
  103. Fadini, G.P.; Menegazzo, L.; Scattolini, V.; Gintoli, M.; Albiero, M.; Avogaro, A. A perspective on NETosis in diabetes and cardiometabolic disorders. Nutr. Metab. Cardiovasc. Dis. 2016, 26, 1–8. [Google Scholar] [CrossRef] [PubMed]
  104. Liaw, P.C.; Ito, T.; Iba, T.; Thachil, J.; Zeerleder, S. DAMP and DIC: The role of extracellular DNA and DNA-binding proteins in the pathogenesis of DIC. Blood Rev. 2015. [Google Scholar] [CrossRef] [PubMed]
  105. Warnatsch, A.; Ioannou, M.; Wang, Q.; Papayannopoulos, V. Inflammation. Neutrophil extracellular traps license macrophages for cytokine production in atherosclerosis. Science 2015, 349, 316–320. [Google Scholar] [CrossRef] [PubMed]
Figure 1. The structures of staurosporine aglycone.
Figure 1. The structures of staurosporine aglycone.
Marinedrugs 14 00141 g001
Figure 2. The structures of: avarol (a); avarone (b); and avarol-3′-thiosalicylate (c).
Figure 2. The structures of: avarol (a); avarone (b); and avarol-3′-thiosalicylate (c).
Marinedrugs 14 00141 g002aMarinedrugs 14 00141 g002b
Figure 3. The structures of: IS2 (a); IS3 (b); and prenyl-hydroquinones (H1: n = 1; H2: n = 2; H3: n = 3, H4: n = 4) (c).
Figure 3. The structures of: IS2 (a); IS3 (b); and prenyl-hydroquinones (H1: n = 1; H2: n = 2; H3: n = 3, H4: n = 4) (c).
Marinedrugs 14 00141 g003aMarinedrugs 14 00141 g003b
Figure 4. The structure of ircinin.
Figure 4. The structure of ircinin.
Marinedrugs 14 00141 g004
Figure 5. The structures of okadaic acid.
Figure 5. The structures of okadaic acid.
Marinedrugs 14 00141 g005
Figure 6. (ac) The structures of Adociacetylenes A, C, and D; (d) The structure of Lemnalol (8-isopropyl-5-methyl-4-methylene-decahydro-1,5-cyclo-naphthalen-3-ol).
Figure 6. (ac) The structures of Adociacetylenes A, C, and D; (d) The structure of Lemnalol (8-isopropyl-5-methyl-4-methylene-decahydro-1,5-cyclo-naphthalen-3-ol).
Marinedrugs 14 00141 g006
Table 1. Marine nature products that inhibit reactive oxygen species (ROS) or elastase release (E) in N-formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils.
Table 1. Marine nature products that inhibit reactive oxygen species (ROS) or elastase release (E) in N-formyl-methionyl-leucyl-phenylalanine-stimulated neutrophils.
CompoundSourcesActivities *Ref.
Excavatoid EBriareum excavatumE[20]
Excavatoid FBriareum excavatumE[20]
Excavatoid LBriareum excavatumROS, E[21]
Excavatoid OBriareum excavatumROS, E[22]
Excavatoid PBriareum excavatumROS, E[22]
Carijoside ACarijoa sp.ROS, E[23]
Hirsutocospiro ACladiella hirsutaROS, E[24]
Hirsutalin NCladiella hirsutaE[25]
Hirsutalin SCladiella hirsutaROS, E[26]
Krempfielin KCladiella krempfiE[27]
Krempfielin MCladiella krempfiE[27]
Krempfielin NCladiella krempfiE[28]
Krempfielin PCladiella krempfiROS, E[28]
Krempfielin QCladiella krempfiROS, E[29]
Krempfielin RCladiella krempfiROS, E[29]
6-epi-cladieunicellin FCladiella sp.ROS, E[30]
Cladielloide BCladiella sp.ROS, E[31]
Cladieunicellin CCladiella sp.ROS[32]
Cladieunicellin HCladiella sp.ROS, E[33]
(–)-solenopodin CCladiella sp.ROS, E[34]
6-epi-Yonarasterol BEchinomuricea sp.ROS, E[35]
Echinoclerodane AEchinomuricea sp.ROS, E[36]
Echinohalimane AEchinomuricea sp.E[37]
7β-HydroperoxycholesterolEudistoma sp.E[38]
DihydroxyicosanoidsFarlowia mollisROS, E[39]
MethylfarnesylquinoneHomoeostrichus formosanaROS, E[40]
Frajunolide EJunceella fragilisROS, E[41]
Frajunolide JJunceella fragilisROS, E[41]
Junceellolide KJunceella fragilisE[42]
(−)-11β,20β-Epoxy-4-deacetoxyjunceellolide DJunceella fragilisE[42]
Junceol EJunceella junceaROS[43]
Junceol FJunceella junceaROS[43]
Junceol GJunceella junceaROS[43]
Junceol HJunceella junceaROS[43]
Klymollin MKlyxum molleROS, E[44]
Lobocrassin BLobophytum crassumROS, E[45]
Menelloide DMenella sp.E[46]
(−)-HydroxylindestrenolideMenella sp.ROS[47]
Pseudoalteromone BPseudoalteromonas sp.E[48]
2β-Acetoxyclovan-9α-olRumphella antipathiesROS, E[49]
9α-Acetoxyclovan-2β-olRumphella antipathiesROS, E[49]
Rumphellaoic acid ARumphella antipathiesE[50]
Rumphellaone CRumphella antipathiesROS, E[51]
Rumphellol ARumphella antipathiesROS, E[52]
Rumphellol BRumphella antipathiesROS, E[52]
Tortuosene ASarcophyton tortuosum.ROS[53]
Sinularbol BSinularia arboreaROS[54]
Flexibilin BSinularia flexibilisE[55]
* Inhibition of reactive oxygen species (ROS) and elastase (E).

Share and Cite

MDPI and ACS Style

Chen, C.-Y.; Tsai, Y.-F.; Chang, W.-Y.; Yang, S.-C.; Hwang, T.-L. Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation. Mar. Drugs 2016, 14, 141. https://doi.org/10.3390/md14080141

AMA Style

Chen C-Y, Tsai Y-F, Chang W-Y, Yang S-C, Hwang T-L. Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation. Marine Drugs. 2016; 14(8):141. https://doi.org/10.3390/md14080141

Chicago/Turabian Style

Chen, Chun-Yu, Yung-Fong Tsai, Wen-Yi Chang, Shun-Chin Yang, and Tsong-Long Hwang. 2016. "Marine Natural Product Inhibitors of Neutrophil-Associated Inflammation" Marine Drugs 14, no. 8: 141. https://doi.org/10.3390/md14080141

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop