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Review Article *Corresponding author Gian Luigi Mariottini, Department of Earth, Environment and Life Sciences, University of Genova, Viale Anti-Inflammatory Properties Benedetto XV 5, I-16132, Genova, Italy, Tel: +39-010- 3538070; Fax: +39-010-3538072; Email: of Diterpenoids from Submitted: 31 January 2017 Accepted: 25 May 2017 Cnidarians. A Possible Published: 27 May 2017 Copyright Perspective for Inflammation © 2017 Mariottini OPEN ACCESS and Fever Treatment? Keywords • Gian Luigi Mariottini* • Diterpenoids Department of Earth, Environment and Life Sciences, University of Genova, Italy • Inflammation • Anti-inflammatory compounds • Drug discovery Abstract Inflammation is involved in the pathogenesis of important diseases suchas arthritis, cancer, stroke, neurodegenerative and cardiovascular affections and it has often a strict relationship with fever. At present, several anti-inflammatory drugs are available and the research is exploring new ways useful to find new sources of anti- inflammatory compounds. In this connection, natural compounds are known to play an important role. It is known that oceans constitute the main part (more than 70%) of Earth, but they have been scarcely considered as a source of bioactive molecules or drugs. Taking into account that venomous organisms are viewed with particular interest for the development of bioactive compounds, this paper aims to review the existing data about anti-inflammatory diterpenoids isolated in Cnidaria, which are included among the most important venomous aquatic . The occurrence in Cnidaria of compounds able to interfere with some steps of the inflammation process, such as the superoxide anion generation, the elastase release, the production of prostaglandins, and the regulation of iNOS, are here considered.

ABBREVIATIONS LPS: Lipopolysaccharide; iNOS: Inducible Nitric Oxide byInflammation four main signscan be ( rubordistinguishedtumor incalor “acute”dolor and “chronic” on the Synthase; COX-2: Cyclooxygenase-2; 2D NMR: Two-Dimensional basismainly of duethe time to vasodilatation of persistence, ofand small it is classically blood vessels; characterized swelling Nuclear Magnetic Resonance; HRMS: High-Resolution Mass , , , ), namely redness, Spectrometry; FMLP/CB: Formylmethionylleucyl-Phenylalanine/ Dihydrocytochalasin B; Inh %: Percentage of Inhibition or edema, caused by the accumulation of fluids; heat, resulting INTRODUCTION from increased blood flow in the inflamed area; painfunctio caused laesa by) edema and by chemical mediators of inflammation (bradykinin, Several exogenous and endogenous stimuli can induce serotonin, prostaglandins) as well. A fifth sign ( indicates the loss of function of the inflamed area. inflammatory responses and cell damage in vascularized tissues. Inflammation has a strict relationship with fever and some According to Kumar et al. [1], the inflammation is “a complex arefactors produced contribute by mastocytes to the pathogenesis and are able of to feverstrengthen in inflammatory the activity reaction to harmful agents, such as microbes and damaged conditions. Prostaglandins are involved in these processes; they generally necrotic cells, which consists in a vascular response, a migration/activation of leucocytes and a systemic reaction”. of other mediators as well as to produce vasodilation, pain and Furthermore, the inflammation is strictly linked to the repair fever. Notably, Prostaglandin E2 (PGE2) is a main mediator of process, aiming at the recovery of damaged tissues after the inflammation in some diseases [3], it is hyperalgesic and it is also neutralization of the noxious stimulus. involved in the production of fever induced by cytokines during infections. In fact, inflammation is a defense mechanism which protects from infections and injuries, and it is known to be involved in Other mediators of inflammation, the cytokines IL-1, IL-6, the pathogenesis of important diseases such as arthritis, cancer, and TNF, are produced mainly by lymphocytes and by activated stroke, neurodegenerative and cardiovascular affections [2]. macrophages, but also by endothelial, epithelial and connective Cite this article: Mariottini GL (2017) Anti-Inflammatory Properties of Diterpenoids from Cnidarians. A Possible Perspective for Inflammation and Fever Treat- ment? J Fever 1(1): 1003. Mariottini (2017) Email:

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cells. Further to their involvement in cell immune responses, they nematocysts– provided with are innerthe reservoirs double-walled of venom intracellular and are able capsules to respond – the are involved also in acute and chronic inflammation and are able fastnematocysts to physical – produced and chemical by the stimuli Golgi injecting apparatus the [13,14]. venomous The to modulate the functions of other cells. Therefore, fever is an evident manifestation of the acute phase life-threatening to humans due to their venomousness which is compounds. Some cnidarian species are dangerous and also of inflammation, mainly when the inflammation is associated to infection. In such conditions, and in response to the activity of the synthesis of prostaglandins in hypothalamic cells and the thought to be due mainly to proteins and phospholipases [15-18]. exogenous pyrogens, for example the lipopolysaccharide (LPS), For these reasons, cnidarians are thought to be an interesting neurotransmittersrelease of cytokines whose (endogenous action contributes pyrogens) to by the lymphocytes increase of potential source of new drugs or other useful compounds; in fact, is stimulated. All these factors stimulate the production of a lot ofth active molecules (over 2000), several of them having anti- inflammatory properties, were isolated during the first decade of body temperature. the 21 century [19]. process aimed at the restoration of healthy conditions through Therefore, notwithstanding the inflammation is a beneficial Taking into account the importance of the development characteristicsof new anti-inflammatory and the usefulness drugs andof diterpenoids of agents useful isolated for from the the eradication, by natural way, of the pathogenetic causes of a treatment of fever, following to a wider paper concerning the disease [4], the consequent manifestations such as pain, itching, fever, and the general discomfort produce always unpleasant cnidarians [20], this paper aims to review the published data sensations. Furthermore, intense inflammation can be also about anti-inflammatory diterpenoids isolated in these organisms harmful [5] or can induce chronic situations or inappropriate considering the possible utilization of these compounds in the immuneTHE USEFULNESS responses. OF NATURAL COMPOUNDS therapy of inflammatory conditions and of the consequent fever. The data have been acquired in the scientific databases PubMed, Scopus and ISI web of knowledge, using the keywords Natural compounds are known to be an important source aboveANTI-INFLAMMATORY reported (keywords list). A DITERPENOIDS time frame was not planned. FROM immunosuppressiveof pharmaceuticals having compounds effective derive therapeutic from natural employment. sources CNIDARIANS In fact, several antiinfective, anticancer, analgesics and or have been developed starting from natural compounds [6- 8]. Nevertheless, the bulk of useful natural compounds have Cnidarian stinging is known to induce inflammatory effects; been found in terrestrial organisms while other sources, such nevertheless, several cnidarian extracts have been studied as oceans, which anyhow constitute the main part of our planet also for their anti-inflammatory properties. Almost all anti- (covering more than 70% of the Earth’s surface and representing inflammatory diterpenoids coming from cnidarians have been found in octocorals () – soft and sea fans – organisms95% of the livingbiosphere therein [9], have so that been it waslittle stated explored that as “we sources live in of a planet of oceans” [7]) have been historically less considered and which are benthic cnidarians characterized by polyps immersed into a gelatinous mass from which arise the polyps’ summits. bioactive molecules or drugs [10,11]. This still scarce utilization mainlyThe colonies in littoral have tropical compact, waters lobated where or they branched are an shape important and is thought to be due to some factors, such as the difficulty calcareous spicules produced by the mesoglea. Alcyonacea occur amountof organisms of active sampling extracts in that the can marine be obtained environment, from organisms which is from the Caribbean gorgonian Pseudopterogorgia elisabethae obviously more difficult than in the terrestrial one, the scarce component of reef assemblages [21-23]. Pseudopterosins and the heterogeneity of extracted compounds [12]. Nevertheless, diterpenoidwere described pseudopterolide by Look et al. from [24, Pseudopterogorgia 25] as anti-inflammatory acerosa compounds being part of a complex mixture (Figure 1). The developedtaking into complexaccount that biological aquatic defensive organisms mechanisms live – and must which survive have – in a taxing and often dangerous environment, they must have increased their capability to resist to adverse environmental (Figure 2) was recognized to be a strong inhibitor of topical inflammation [26]. Pseudopterosins, with simple modifications, biodiversityconditions inducing of marine the organisms production which of metabolites, amounts approximately venoms and other useful compounds. Another important factor is the extreme is understandable that marine organisms could represent a vastto a halfsource of the for total the discovery biodiversity and [7]. development For all these of reasons bioactive it compounds to be used as drugs, therapeutics and for other purposes as well. Also natural venoms are viewed with particular interest from this point of view. Figure 1 Jellyfish, sea anemones and corals, organisms belonging to Structure of pseudopterosins A-D; redrawn after Look et al., 1986 the primitive Cnidaria, are among the most important [24]. Pseudopterosin A: R1, R2, R3, R4 = H; pseudopterosin B: R1, R3, R4 = H, venomous aquatic animals being provided with a complex R2 = Ac; pseudopterosin C: R1, R2, R4 = H, R3 = Ac; pseudopterosin D: R1, R2, R3 = H, R4 = Ac. stinging apparatus composed by stinging cells – the nematocytes J Fever 1(1): 1003 (2017) 2/12 Mariottini (2017) Email:

Central Bringing Excellence in Open Access have supposedly entered Phase I clinical trials for the evaluation as anti-inflammatory agents [27]. As to these modifications, Newman and Cragg [27] stated that unfortunately “the structure [... was ...] not listed in the reference to the trial [28], nor can any other record be found”. theyZanoni considered and Franzini the deep [29] waters described species bioactive Pseudopterogorgia secondary elisabethaemetabolites and diterpenoids from gorgonian corals. Notably,

collected in West Indian sea which they defined “a goldmine for novel diterpenoids with rare carbon-skeleton architectures” – Elisabethanes – provided with interesting anti- Figure 4 inflammatory properties. Structure of briaexcavatin M, O, P [32]; redrawn after Bowden and coral Junceella fragilis Vasilescu [33]. R1 = ∆3 (briaexcavatin M); β-butanoate (briaexcavatin O); OAc In 2006 Sheu et al. [30], studying extracts from the gorgonian (briaexcavatin P). R2 = ∆3 (briaexcavatin M); α-OAc (briaexcavatin O); β-OAc , isolated and described junceellolides (briaexcavatin P). J-L (Figure 3), three 11,20-epoxybriarane diterpenoids having a cyclohexane ring. The chemical structure was analyzed by spectroscopic methods and, only for junceellolide J, by X-ray inhibiteddiffraction the analysis. elastase Junceellolide release by K human and a neutrophils known briarane at the named (-)-11R,20R-epoxy-4-deacetoxyjunceellolide [31] mildly concentration of 10 µg/mL. The percentage of inhibition (Inh %) of superoxide generation at the concentration of 10 µg/mL ranged between 5.55 ± 3.50 for junceellolide L to 22.62 ± 6.76 for briarane 4, and the percentage of inhibition (Inh %) of elastase release ranged between 5.17 ± 2.71 for junceellolide J to 15.36 ± 3.34 for briarane 4 [30]. Two years later Sung et al. [32] described, by means of spectral data analysis, the structure of briaexcavatins M-P, subsequently four new briarane-related diterpenoids from cultured octocorals Figure 5 Briareumfurther described excavatum by Bowden and Vasilescu [33] (Figures 4,5), Structure of briaexcavatin N [32]; redrawn after Bowden and ; 10 µg/ml of briaexcavatin P induced Vasilescu (2013) [33]. inhibition (14.99%) of superoxide anion generation by human neutrophils [32]. six new xenicane-type diterpenoids from Asterospicularia laurae In 2009, Lin et al. [34] isolated asterolaurinsin vitroA-F (Figure on human 6), neutrophils through the analysis of the inhibition of elastase and evaluated their anti-inflammatory activity 2%) inhibition release and of the generation of superoxide anion. The main elastase (68 ± 6%) and superoxide anion (56 ± was induced by asterolaurin D with IC50 values of 18.7 and 23.6 μM, respectively. The authors stated that the hemiacetal functionality observed in this compound “may play a significant Figure 2 role in the anti-inflammatory activity”. The other compounds Structure of pseudopterolide; redrawn after Fenical, 1987 [26]. induced elastase inhibition ranging from 40 ± 3b% (asterolaurin A) to 13 ± 6% (asterolaurin F), and superoxide anion inhibition ranging from 31 ± 7% (asterolaurin B) to -12 ± 4% (asterolaurin A) [34]. Klyxum simplex and described by In the same year simplexins A-I, nine eunicellin-based laboratoryditerpenoids, evaluation were isolated by immunoblot from analysis in LPS-stimulated Wu et al. [35]. The structure was analyzed by spectroscopy. The

inducibleRAW264.7 nitric macrophages, oxide synthase showed (iNOS) that 10 and μM cyclooxygenase-2 of simplexin E significantly inhibited the accumulation of the pro-inflammatory

Figure 3 (COX-2) proteins reducing the levels to 4.8 (1.8%) and 37.7 Structure of junceellolide J (a), K (b), L (c); redrawn after Sheu et al., (4.7%), respectively, in comparison to LPS only-stimulated 2006 [30]. control cells. Simplexins A and D at 10 μM significantly reduced J Fever 1(1): 1003 (2017) 3/12 Mariottini (2017) Email:

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that significantly inhibited iNOS expression (cespitularin S and compounds 7 and 8), resulting in a dose-dependent suppressive effects on iNOS protein expression emphasized by EC50 values of 7.8 ±Three 0.7, 18.8 sea whip± 3.7, chlorinated and 11.5 ± 1.9 briaranes mM, respectively were studied [36]. by Wang

Junceella fragilis Ellisella robusta (Figure et al. [37] who described fragilide J, a new compound from , and robustolide L from 9). Fragilide J at 10 µg/ml concentration induced inhibition of elastase release by human neutrophils (11.5%), and 10 µg/ml robustolide L caused inhibition (13.9%) of superoxide anion generation by the same cells. Junceella fragilis and described In 2011, frajunolides L–O (Figure 10), 8-hydroxybriarane Resonancediterpenoids, (2D were NMR) isolated spectroscopy from and High-Resolution Mass by Liaw et al. [38] by means of Two-Dimensional Nuclear Magnetic Figure 6 Structure of asterolaurin A (a), B (b), C (c), D (d), E and F (e, f); neutrophilsSpectrometry through (HRMS). superoxide The anti-inflammatory anion generation properties and elastase of redrawn after Lin et al, 2009 [34]. releasefrajunolide in response L and O resulted to the stimulant weak when formylmethionylleucyl- evaluated on human

compounds induced mild inhibitory effects both on superoxide phenylalanine/dihydrocytochalasin B (FMLP/CB). Notably, all

anion generation, ranging from 18.7 ± 2.6% (frajunolide L) to 0.6 ± 1.5% (frajunolide N), and on elastase release, ranging from 22.3 ± 7.7% (frajunolide N) and 13.3 ± 3.1 (frajunolide M) [38]. based diterpenoids from the Taiwanese soft coral Sinularia triangularIn the same year, Su and Wen [39] isolated five cembrane-

; two of them (triangulene A and triangulene B –

Figure 7

Structure of simplexins A (a), B (b), C, D, E, F, G (c, d, e, f, g), H R2 2CH2CH 2CH2CH ; R2 and I (h, i); redrawn, after Wu et al., 2009 [35]. In simplexin C (c): R1, 2CH2CH 2; R2 = Ac; R3 = COCH 3. In simplexin D (d): R1 = COCH 3 R 2CH2CH 2 = Ac; R3 = COCH 3. In simplexin E (e): R1 = COCH=CH = Ac; 2 3 = COCH 3. In simplexin F (f): R1, R = Ac; R3 = H. In simplexin G (g): R1 = H; R , R3 = Ac. iNOS expression to 15.9 (14.5%) and 37.7 (7.2%), respectively, Figure 8 Structure of cespitularins R (a) and S (b); redrawn after but did not induce inhibition of COX-2 expression [35]. new verticillane diterpenoids from the soft coral Cespitularia The structure of cespitularins R and S (Figure 8), two hypotentaculata Cheng et al., 2010 [36].

was published by Cheng et al. [36] after spectroscopic studies, and the anti-inflammatoryin vitro on LPS-stimulated activity of the two new compounds and of other seven known diterpenoids iNOS(named and compounds COX-2 proteins 3-9) was was evaluated observed after stimulation of RAW 264.7 macrophages. Up-regulation of proinflammatory macrophages with LPS; notably, 10m M of cespitularin S induced decrease of iNOS (52.7 ± 3.2%) and COX-2 (78.3 ± 0.6%) when compared with LPS alone-stimulated cells (controls). Two of known compounds (7 and 8) failed in inhibit COX-2 expression, but were active in inhibiting iNOS expression resulting in 86.7 ± 8.4% and 72.0 ± 15.1% inhibition, respectively. On the whole, cespitularin R and the compounds 3, 4, 5, 6, and 9 indid vitro not ofresult the Figure 9 Structure of fragilide J (a) and robustolide L (b); redrawn dose-dependentactive. The inhibition relationship of iNOS was expression carried out was for observed compounds to follow a dose-dependent pattern. The evaluation after Wang et al., 2010 [37]. J Fever 1(1): 1003 (2017) 4/12 Mariottini (2017) Email:

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epi-sinulariolide 11-dehydrosinulariolide (21.1 ± 6.0), 14-deoxycrassin (0.5 ± 0.2), 11-epi-sinulariolide acetate (23.8 ± 7.9), and 11- (46.6 ± 13.0). On the basis of these results, the authors stated that flexibilisolide C, 11-dehydrosinulariolide, 11-epi-sinulariolide acetate, and 11-epi-sinulariolide might have an application as anti-inflammatory agents [40].

cellsThe induced inhibition by twelve of diterpenoids the production isolated of from pro-inflammatory the methanol extractcytokines of Sinularia in LPS-stimulated maxima bone marrow-derived dendritic

was studied by Thao et al. [41], who found three active compounds: sinumaximol B, sinumaximol C, and isomandapamate (Figure 13). Sinumaximol B and C inhibited remarkably interleukin(IL)-12 production, with IC50 values of

Figure 10

Structure of frajunolide L (a), M (b), N, (c), and O (d); redrawn after Liaw et al., 2011 [38]. Figure 11 Structure of triangulenes A (a) and B (b); redrawn after Su and 2D NMR spectroscopy were employed to elucidate the Figure 11) resulted to be new metabolites. Mass spectroscopy and Wen, 2011 [39]. structures of the new compounds.in vitro The known metabolites sinularin, dihydrosinularin, and (−)14-deoxycrassin exhibited anti-inflammatory activity emphasized by inhibition of iNOS expression, as assessed in LPS-stimulated RAW264.7 macrophages. Notably, 10 μm of sinularin, dihydrosinularin, and (−)14-deoxycrassin reduced the levels of the iNOS protein to 1.2 ± 0.3%, 5.1 ± 1.6%, and 0.9 ± 0.7%, respectively. The expression of COX-2 in macrophages was reduced by dihydrosinularin, and (−)14-deoxycrassin (24.9 ± 7.4% and 5.9 ± 1.0%, respectively) when used at a concentration of 10 μm. Therefore, both pro- inflammatory proteins resulted upregulated [39]. of iNOSDuring and 2012 COX-2 LPS-stimulated accumulation RAW264.7 induced by macrophages seven new were used again by Shih et al. [40] to evaluate the inhibition metabolite diterpenoids, flexibilisolides C-G, flexibilisin C, andepi- 11,12-secoflexibillin (Figure 12), and by seven known cembranoids, 11-dehydrosinulariolide, flexilarin D, 14-deoxycrassin,epi 11- isolatedsinulariolide from South acetate, China Sea 3,4:8,11-bisepoxy-7-acetoxycembra- soft corals Sinularia flexibilis 15(17)-en-1,12-olide, sinulariolide, and 11- -sinulariolide, . The reduction of accumulation of iNOS, expressed as percent of LPS- induced iNOS protein, was observed using 10 mM flexibilisolides C (0.9 ± 0.2) and D (4.6 ± 0.3), 11-dehydrosinulariolide (1.1 ± 0.4), flexilarin D (17.9 ± 7.7), 14-deoxycrassin (0.1 ± 0.03), Figure 12 11-epi-sinulariolide epi acetate (3.5 ± 1.2), 3,4:8,11-bisepoxy-7- acetoxycembra-15(17)-en-1,12-olide (15.6 ± 6.7), sinulariolide Structure of flexibisolide C (a), D (b), E (c), F (d), and G (e), 2 In (18.1 ± 8.5), and 11- -sinulariolide (7.1 ± 2.4), while reduction flexibilisin C (f), and 11,12-secoflexibillin (g), redrawn after Shih et 2 of COX-2 levels, expressed as percent of LPS-induced COX-2 al., 2012 [40]. In flexibisolide D (b): R1, R = O; R3 = OH; R4 = CH3. protein, was observed with 10 mM flexibilisolide C (72.5 ± 2.1), flexibisolide G (e): R1 = H; R = OAc; R3 = OOH; R4 = CH3. J Fever 1(1): 1003 (2017) 5/12 Mariottini (2017) Email:

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15.20 and 4.35 μM, respectively. Also isomandapamate exhibited strong effect with IC50 value of 18.04 μM. IL-6 production was affected mainly by sinumaximol C (IC50 = 17.72 μM) and, to a lesser extent, by isomandapamate (IC50 = 54.32 μM) and sinumaximol B (IC50 = 59.77 μM). Sinumaximol C also moderately inhibited the production of TNF-α (IC 50 = 62.33 μM) [41]. of compounds isolated from the gorgonian Echinomuricea In 2012 three papers described anti-inflammatory properties Echinomuricea sp.: 10 μg/mL of the halimane-type diterpenoid echinohalimane A (Figure 14a) from sp. affected the elastase release by human neutrophils in response to FMLP/CB with IC50 of 0.38 ± 0.14 μg/mL and showed an inhibitory effect to superoxide anion generation with 20.55 ± 5.18 Inh% (percentage of inhibition) diterpenoidand IC50 >10 from μg/mL Echinomuricea [42]. The same research group reported Figure 14 data about echinolabdane A (Figure 14b), a new labdane-type Structure of echinohalimane A (a), redrawn after Chung et sp., which at concentration al., 2012 [42], and echinolabdane A (b), redrawn after Chung et al., 10 μg/mL was found to inhibit the release of elastase by 2012 [43]. human neutrophils (1.83 ± 3.46 Inh%; IC50 >10 μg/mL), and the generation of superoxide anions (2.52 ± 3.02 Inh%; IC50 from>10 μg/mL)Echinomuricea [43]. Another new diterpenoid (clerodane-type), echinoclerodane A (Figure 15), was isolated by Cheng et al. [44], sp.; at 10 μg/mL this compound displayed effect both on the generation of superoxide anion (significant Inh = 68.6%), and on the release of elastase (moderate Inh = 35.4%) by human neutrophils. Junceella juncea TheChang structure et al. of[45], these isolated compounds three new was briaranes elucidated (juncenolides through M-O;spectroscopic Figure 16) analysis from and the 2D-NMR gorgonian showing coral that juncenolide.

TheM is evaluationa chlorinated of briarane, elastase release juncenolide in human N has a neutrophils free hydroxy in at C-2, and juncenolide O possesses a rare methyl ester at C-5. response to FMLP/CB showed that 10 μg/mL of juncenolides N Figure 15 and O induce moderate effect (Inh = 29.0±5.6% and 35.9±7.4%, Structure of echinoclerodane A; redrawn after Cheng et al., respectively), while the effect of juncenolide M was mild (Inh = 2012 [44]. 15.9 ± 5.5%). As to the inhibition of superoxide anion generation, The same research group reported data about three new juncenolide O exhibited moderate activity with Inh = 27.6 ± 7.0%, Cespitularia while juncenolides M and N showed mild activity (Inh = 7.6 ± taeniata 2.8%, and 6.7 ± 2.9%, respectively at 10 μg/mL [45]. elastaseverticillanes, release cespitulins by human (E-G; neutrophils Figure in17), response from to FMLP/ . The activity on superoxide-anion generation and

CB was evaluated for cespitulins E and G. Cespitulin G inhibited elastase release (IC50 = 2.7 ± 0.2 µg/mL) and superoxide anion generation (IC50 = 6.2 ± 0.8 µg/mL) at 10 µg/mL, while Cespitulin E showed less activity (Inh = 30.6 ± 6.0%, and 33.8 ± 4.1%, respectively) [46]. Cladiella Chen et al. [47], isolated cladieunicellin H, a new hemiketal andeunicellin-based observed moderate diterpenoid, inhibition from of elastase sp. release sampled and inof Indonesian waters, determined the structure by spectroscopy,

superoxide anion generation by human neutrophils. Briarenolides F and G (Figure 18), two new briarane anionditerpenoids, generation were by isolated human from neutrophils in sp. response by Hong et to al. FMLP/ [48]. Briarenolide F induced a significant inhibition of superoxide Figure 13 CB (Inh = 76.65±4.21%; IC50 = 3.82±0.45 μg/mL) and less Structure of sinumaximol B (a) and C (b), and of effect on elastase release (Inh = 27.48±6.60%; IC50 >10 μg/mL). isomandapamate (c); redrawn after Thao et al., 2012 [41]. Briarenolide G resulted less effective with Inh values of 22.04 J Fever 1(1): 1003 (2017) 6/12 Mariottini (2017) Email:

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Klyxum molleKlymollins I−S (Figure 21), eleven new eunicellin-based suppressionditerpenoids, of were FMLP/CB-induced isolated from the superoxide ethanol extractanion generation of and elastase, a soft release coral sampled induced in by Taiwanese the eleven waters compounds [51]. was The evaluated in human neutrophils to verify the effects on

neutrophil pro-inflammatory responses. Only klymollin M Figure 16 showed significant activity on both superoxide anion generation (Inh = 81.56 ± 3.23%; IC50 = 3.13±0.39 µM) and elastase Structure of juncenolides M (a), N (b), and O (c); redrawn release (Inh = 89.16 ± 5.77%; IC50 = 2.92 ± 0.27 µM). Moderate after Chang et al., 2012 [45]. activity on elastase release was shown also by klymollin O (Inh = 16.75±2.08%) and klymollin R (Inh = 11.55 ± 4.14%), and on

Figure 17

Structure of cespitulin E (a), F (b), and G (c); redrawn after Chang et al., 2012 [46].

Figure 19

Structure of flexibilin A (a), B (b), and C (c); redrawn after Hu et al., 2013 [49].

Figure 18

Structure of briarenolides F (a) and G (b); redrawn after Hong et al., 2012 [48].

± 3.43%, and 12.98 ± 4.68% for superoxide anion and elastase release,The softrespectively coral Sinularia (IC50 flexibilis>10 μg/mL in both cases) [48]. yielded flexibilins A-C (Figure inhibitory19), three neweffect cembrane-type on elastase release diterpenoids, by human which neutrophils were studied (Inh by Hu et al. [49]. Flexibilin B, at 10 μg/mL induced moderate

= 45.76 ± 2.92%; IC50 >10 μg/mL). Flexibilins A and C resulted in Inh values of 22.67 ± 5.32% and 10.56 ± 2.75%, respectively, both with IC50 >10 μg/mL. As to the generation of superoxide anions, the most effective compound was again Flexibilin B (Inh = 22.03 ± 3.88%), followed by flexibilin C (Inh = 18.80 ± 3.81%), and flexibilin A (Inh = 12.31 ± 3.04%); all IC50 values were >10 μg/mL [49]. diterpenoids) from the acetone extract of the Taiwanese gorgonianLiaw et Junceella al. [50] isolated fragilis frajunolides P–S (8-hydroxybriarane

(Figure 20). Frajunolide P and Q at 10 μg/mL inhibited moderately the release of elastase (Inh = Figure 20 35.6 ± 3.2% and 34.1±2.9%, respectively) and the generation of superoxide anions (Inh = 32.5 ± 1.5% and 28.7 ± 3.4%, Structure of frajunolide P (a), Q (b), R (c), and S (d); redrawn respectively) by human neutrophils in response to FMLP/CB. after Liaw et al., 2013 [50]. J Fever 1(1): 1003 (2017) 7/12 Mariottini (2017) Email:

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superoxide anion generation by klymollin Q (Inh = 14.74±4.32%). diterpenoidsAll other compounds isolated showed from soft weak corals or null sampled activity in with Taiwanese all IC50 values >10 µM [51]. Several other data about anti-inflammatory waters were reported in a comprehensive review by Wei et al. [52].

PennatulaIn 2014 aculeata Bahl et al. [53], isolated 2-acetoxyverecynarmin C, a moderatelynew briarane-type inhibitory diterpenoid, to cyclooxygenase from the as methanolic assessed in extract in vitro of (Octocorallia, Pennatulacea), which resulted

Figure 22 Structure of sinularbols A (a) and B (b); redrawn after Chen COX-1 and COX-2 assays [53]. Sinularia arborea Other two new diterpenoids, sinularbols A and B (Figure et al., 2014 [54]. superoxide22), isolated anion from and the the soft elastase coral release by human neutrophils, displayed a moderate/weak activity in inhibiting the generation of in response to FMLP/CB. Notably, at 10 μg/mL sinularbol A showed moderate activity on elastase release (Inh = 11.71 ± 1.35%), and sinularbol B inhibited moderately superoxide anion formation (Inh = 23.94 ± 6.35%) [54]. An interesting research was carried out by Deghrigue et al. the[55], gorgonian who studied Eunicella the anti-inflammatory singularis and gastroprotective effect of the organic extract (and semi-purified fractions) from . From the ethanolic fraction the diterpenoid palmonine D (Figure 23) was isolated, together Figure 23 compoundwith five sterols. and the The gastroprotective carrageenan-induced activity rat waspaw assessededema test in was utilized to evaluate the anti-inflammatory activity of this Structure of palmonine D; redrawn after Deghrigue et al., administration of the organic extract induced inhibition of edema 2014 [55]. gastric ulcers experimentally induced in rats. The intra-peritoneal ranged from 10.53% of edema inhibition after 5 hours at 25 mg/ ranging from 18.26% (after 1 hour, at 50 mg/Kg) to 64.31% Kg for the acetone semi-purified fraction, to 66.12% inhibition (after 3 hours, at 200 mg/Kg). The activity of purified fractions after 3 hours at 50 mg/Kg ethanol semi-purified fraction.Eunicella On the whole,singularis the most effective fraction resulted the ethanolic one. As to the gastroprotective activity, the organic extract from produced a significant decrease of gastric lesions with 59.84% inhibition at 50 mg/Kg, 68.84% at 100 mg/Kg, and 75.16 Theat 200 results mg/Kg. were The compared purified fractions to those induced obtained inhibition with ranitidine ranging from 15.17% to 70.27% at doses ranging from 5 to 25 mg/Kg.

(65% inhibition at 60 mg/Kg) and omeprazol (87.53% inhibition at 30 mg/Kg) [55]. Briareum violacea Liaw et al. [56], studying the Taiwanese soft coral , isolated ten briarane diterpenoids (briaviolides A-J) together with other six known compounds. At 10 μg/mL two compounds (braviolides E and I; Figure 24) induced moderate inhibition of superoxide-anion generation (Inh = 34.17±0.79% and 28.66 ± 1.99%, respectively) and elastase release (Inh = 26.03 ± 9.51 and 28.81 ± 6.37%, respectively) by human neutrophils in response to FMLP/CB. The Inh% for superoxide anion of other Figure 21 compounds ranged between 4.48 ± 1.47 (braviolide D) to 17.35 Structure of klymollins I, J, K, L (a, b, c, d), M (e), N, O, P, Q, R ± 6.91 (braviolide F). The Inh% for elastase release of other R 2 2 (f, g, h, i, j), S (k); redrawn after Lin et al., 2013 [51]. In klymollin I (a): 2 2 compounds ranged between 6.40 ± 4.29 (braviolide C) to 18.78 1, R = OAc. In klymollin J (b): R1 = OH, R = OAc. In klymollin K (c): R1 n 2 1 n 1 ± 2.29 (braviolide H). The derivative benzyl briaviolide A showed R= OAc, R = H. In klymollin L (d): R = OH, R = H. In klymollin N (f): R = 2 3 4 n 1 2 selective activity for the inhibition of elastase release (Inh = -PrCOO, R = OAc, R = OH, R = OAc. In klymollin O (g): R = -PrCOO, R 2 = OAc, R3 = OAc, R4 = OH. In klymollin P (h): R1 = -PrCOO, R = OH, 28.60 ± 7.54%) [56]. 3 4 2 1 3 4 Briareum = OH, R = OAc. In klymollin Q (i): R = OAc, R = OAc, R = OH, R = Recently [57], the briarane-type diterpenoids briarenolides H. In klymollin R (j): R1 = OAc, R = OH, R3 = OH, R4 = H. K and L (Figure 25) were isolated from sp. and J Fever 1(1): 1003 (2017) 8/12 Mariottini (2017) Email:

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were studied for the upregulation of pro-inflammatory iNOS and COX-2 protein expression in LPS-stimulated RAW264.7 macrophages. The results of immunoblot analysis showed that 10 μM of both compounds significantly inhibit the accumulation of pro-inflammatory iNOS, reducing them to 23.67 ± 1.86% and 31.71 ± 8.75%, respectively. Taking into account the lacking of cytotoxic effects to RAW264.7 cells, the authors stated that these compounds “might be promising as anti-inflammatoryBriareum agents”. Finally, Su et al. [58], found in sp. six new 9-hydroxybriarane diterpenoids, which they named briarenolides ZI–ZVI (Figure 26), whose structures were elucidated by spectroscopy. Using Western blot analysis, the expression of iNOS in LPS-stimulated RAW264.7 macrophages was seen to be inhibited by briarenolides ZII and ZVI (reduction to 47.2 and 55.7%, respectively at 10 µM). COX-2 expression was reduced mainlyDISCUSSION by briarenolide & CONCLUSION ZIV (65.0 ± 6.4%).

Figure 26

The relationship between inflammation and fever is well Structure of briarenolide ZI (a), ZII (b), ZIII (c), ZIV, ZV and R 2 -OC(O)(CH2)2CH naturalknown andselection has been has widelyselected studied this response [59, 60]. to In allow general, the bodyfever tois ZVI (d, e, f); redrawn after Su et al., 2016 [58]. In briarenolide ZIV (d): 2 2 “a hallmark of infection and inflammatory disease” [61] and the 1 = OH, R = α-H, R3 = α 3. In briarenolide ZV (e): R1 = H, R = β-OH, R3 = α-OH. In briarenolide ZVI (f): R1 = OAc, R = α-H, R3 fightMultiple injuries and pathway to restore. mechanisms have been suggested for = β-OH. the induction of fever [62] and also attempts to relate the important in the physiologic response to acute brain injury [64], inflammation of unknown origin with fever of unknown origin and inflammatory fever has been also associated with acute have been suggested [63]. Inflammation is thought to be aortic dissection [65-67]. Therefore, although inflammation is considered an advantageous process, often it is to be fought and their unpleasant effects are to be reduced. This aspect is regarded as a priority for the development of new useful compounds.

of humanIn fact, (but the also discovery veterinary and or development plant) diseases of newand to drugs face isold a continuous challenge to meet new requirements in the therapy of new sources of bioactive and useful compounds is a priority in and new therapeutic problems. For this reason, the exploitation

sourcethe research. of interesting In this connection, molecules it and should metabolites be considered produced that the by oceans, covering most of the Earth’s surface, could be a primary

Figure 24 organisms living therein, and an enormous potential resource for 2CH(CH )2 Structure of braviolide E (a) and I (b); redrawn after Liaw the production of drugs and bioactive compounds to be utilized 3 et al., 2014 [56]. R = β-OCOCH in different fields and situations. Venomous organisms, such as cnidarians, are thought to be particularly interesting from this point of view; therefore, they are studied to find a practical utilization of their extracts [4]. Nevertheless, unfortunately none of them has reached an effective utilization and only pseudopterosin, eleutherobin, and sarcodictynsA number have of researchbeen evaluated have beenin preclinical carried trials out to[68,69]. discover

new anti-inflammatory compounds from cnidarians and, among interestingthem, several activity have in studied inhibiting anti-inflammatory superoxide anion diterpenoids. generation As reported in this review, some diterpenoids have exhibited Figure 25 Structure of briarenolide K (a) and L (b); redrawn after Su and elastase release by human neutrophils. This could be et al., 2015 [57]. interesting because of the known pathogenetic role of toxic reactive oxygen species and of enzymes produced by neutrophils J Fever 1(1): 1003 (2017) 9/12 Mariottini (2017) Email:

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in the genesis of inflammation and in the damage of tissues [51]. 11. Cragg GM, Newman DJ. Natural products: a continuing source of novel Other compounds have evidenced activity in inhibiting COX (1 drug leads. Biochim Biophys Acta. 2013; 1830: 3670-3695. Cotylorhiza tuberculata modulates gap junction intercellular and 2) and upregulating iNOS. COX-1 and COX-2 are known to 12. Leone A, Lecci RM, Durante M, Piraino S. Extract from the zooxanthellate be involved in prostaglandin production and in the inflammation jellyfish and, consequently, in the genesis of fever [2]. Notably, COX-2 is communication in human cell cultures. Mar Drugs. 2013; 11: 1728- Ö known to be a key-enzyme in the conversion of arachidonic acid 1762. to prostaglandins, the principal mediators of inflammation [3]. 13. Beckmann A, zbek S. The nematocyst: a molecular map of the Therefore, the occurrence of COX-2 inhibitors in cnidarian extracts cnidarian stinging organelle. Int J Dev Biol. 2012; 56: 577-582. could reduce PGE2 production, decrease the inflammation 14. Marino A, Morabito R, La Spada G. Physiology of Nematocytes. haveand alsobeen to reported be useful to inbe neurodegenerativean indirect proof of conditions,the role of asCOX-2 the Proceedings of the 83th National Congress of the SIBS, 2013 October beneficial effects of COX-2 inhibitors in experimental models 24-25. Palermo, Italy. Abstract No. 36. cytotoxin from the northern Scyphozoa Cyanea capillata 15. Lassen S, Helmholz H, Ruhnau C, Prange A. A novel proteinaceous in neurodegeneration [70]. Furthermore, inducible nitric oxide (L.) with synthase (iNOS) are known to be regulated by mediators of structural homology to cubozoan haemolysins. Toxicon. 2011; 57: inflammation, such as cytokines and LPS, and to be implicated in 721-729. the inflammatory response [71]; iNOS expression has been found Pelagia 16. Morabito R, Condello S, Currò M, Marino A, Ientile R, La Spada G. in several chronic inflammatory conditions (see Kröncke et al. noctiluca Oxidative stress induced by crude venom from the jellyfish [72], and the references therein). in neuronal-like differentiated SH-SY5Y cells. Toxicol In Vitro. 2012; 26: 694-699. thereforeIn conclusion, the development several diterpenoids of the research from and cnidarian the study extracts of this have undoubtedly interesting anti-inflammatory properties, 17. Mariottini GL. Hemolytic venoms from marine cnidarian jellyfish - an overview. J Venom Res. 2014; 5: 22-32. neurodegenerativeaspect are desirable. and Considering cardiovascular that the diseases incidence are of expected several 18. Mariottini GL, Pane L. Cytotoxic and cytolytic cnidarian venoms. 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Cite this article Mariottini GL (2017) Anti-Inflammatory Properties of Diterpenoids from Cnidarians. A Possible Perspective for Inflammation and Fever Treatment? J Fever 1(1): 1003.

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