Orally Administered Phlorotannins from Eisenia Arborea Suppress Chemical Mediator Release and Cyclooxygenase-2 Signaling to Alleviate Mouse Ear Swelling
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marine drugs Article Orally Administered Phlorotannins from Eisenia arborea Suppress Chemical Mediator Release and Cyclooxygenase-2 Signaling to Alleviate Mouse Ear Swelling Yoshimasa Sugiura 1,*, Masakatsu Usui 1, Hirotaka Katsuzaki 2, Kunio Imai 2, Makoto Kakinuma 3, Hideomi Amano 3 and Masaaki Miyata 1 1 Laboratory of Food Function and Biochemistry, Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, Shimonoseki 759-6595, Japan; usuim@fish-u.ac.jp (M.U.); mmiyata@fish-u.ac.jp (M.M.) 2 Laboratory of Bioorganic Chemistry, Graduate School of Bioresources, Mie University, Tsu 514-8507, Japan; [email protected] (H.K.); [email protected] (K.I.) 3 Laboratory of Marine Biochemistry, Graduate School of Bioresources, Mie University, Tsu 514-8507, Japan; [email protected] (M.K.); [email protected] (H.A.) * Correspondence: ysugiura@fish-u.ac.jp; Tel.: +81-83-286-5111; Fax: +81-83-286-7434 Received: 3 July 2018; Accepted: 28 July 2018; Published: 2 August 2018 Abstract: Phlorotannin is the collective term for polyphenols derived from brown algae belonging to the genera Ascopyllum, Ecklonia, Eisenia, Fucus and Sargassum etc. Since the incidence of allergies is currently increasing in the world, there is a focus on phlorotannins having anti-allergic and anti-inflammatory effects. In this study, six purified phlorotannins (eckol; 6,60-bieckol; 6,80-bieckol; 8,80-bieckol; phlorofucofuroeckol (PFF)-A and PFF-B) from Eisenia arborea, orally administered to mice, were examined for their suppression effects on ear swelling. In considering the suppression, we also examined whether the phlorotannins suppressed release of chemical mediators (histamine, leukotriene B4 and prostaglandin E2), and mRNA expression and/or the activity of cyclooxygenase-2 (COX-2), using RBL-2H3 cells, a cultured mast cell model. Results showed that the phlorotnannins exhibited suppression effects in all experiments, with 6,80-bieckol, 8,80-bieckol and PFF-A showing the strongest of these effects. In conclusion, orally administered phlorotannins suppress mouse ear swelling, and this mechanism apparently involves suppression of chemical mediator release and COX-2 mRNA expression or activity. This is the first report of the anti-allergic effects of the orally administered purified phlorotannins in vivo. Phlorotannins show potential for use in functional foods or drugs. Keywords: brown algae; phlorotannins; anti-allergy; mouse ear swelling; arachidonic acid cascade; chemical mediators 1. Introduction In developed countries, an increase in the incidence of allergies such as food allergy, asthma, atopic dermatitis and hay fever, has become an acute problem [1]. In particular, according to the Health, Labour and Welfare Ministry of Japan, half of the Japanese population may suffer allergies of some kind [2]. In Japan, where allergies are a societal problem, natural remedies and foods possessing anti-allergic and anti-inflammatory effects are needed, and much research into compounds and products with anti-allergic effects is underway. Phenolic compounds (polyphenols) are a well-known class of natural anti-allergic natural compounds that are derived from food materials. Polyphenols Mar. Drugs 2018, 16, 267; doi:10.3390/md16080267 www.mdpi.com/journal/marinedrugs Mar. Drugs 2018, 16, 267 2 of 14 Mar. Drugs 2018, 16, x 2 of 14 in terrestrial plants include tea catechins, flavonoids and tannins. In particular, the anti-allergenic materials. Polyphenols in terrestrial plants include tea catechins, flavonoids and tannins. In particular, mechanisms of tea catechins are well reported [3]. the anti-allergenic mechanisms of tea catechins are well reported [3]. Polyphenols are also present in seaweed and the collective term for seaweed polyphenol is Polyphenols are also present in seaweed and the 0 collective term0 for seaweed polyphenol is phlorotannins.phlorotannins. Phlorotannins, Phlorotannins, such assuch eckol, as dieckol, eckol, 6,6 -bieckol,dieckol, 8,86,6-bieckol′-bieckol, and 8,8 phlorofucofuroeckol′-bieckol and (PFF)-A,phlorofucofuroeckol are well-known (PFF)-A, components are well-known of brown components algae [ 4of]. brown They algae are secondary[4]. They are metabolites secondary of photosynthesismetabolites of andphotosynthesis protect algae and from protect ultraviolet algae from (UV) ultraviolet radiation (UV) and fromradiation consumption and from by herbivores.consumption In humans,by herbivores. phlorotannins In humans, incorporated phlorotannins into incorporated health foods into or health used asfoods drugs or used are useful as physiologically-activedrugs are useful physiologically-active compounds that can compounds be used to preventthat can lifestyle-related be used to prevent diseases, lifestyle-related such as cancer anddiseases, diabetes such [5]. as There cancer are, and therefore, diabetes [5]. several There reports are, therefore, of their several anti-allergenic reports of and their anti-inflammatory anti-allergenic effects.and anti-inflammatory In recent reports, phlorotannineffects. In recent extracts reports, from Fucalesphlorotannin inhibited extracts lipoxygenase from Fucales activity inhibited and nitrite oxidelipoxygenase production activity from RAWand nitrite 264.7 oxide cells, andproduction some phlorotannins from RAW 264.7 from cells,Ecklonia and cavasome, Ecklonia phlorotannins stolonifera andfromEisenia Ecklonia bicyclis cavasuppressed, Ecklonia inflammationstolonifera and throughEisenia thebicyclis MAPK suppressed cascade orinflammation through chemical through mediator the productionMAPK cascade in BV-2, or through HaCaT chemical and RAW mediator 264.7 cellsproduction [6–10]. in InBV-2, our HaCaT previous and study,RAW 264.7 we isolated cells [6– six phlorotannins10]. In our previous (eckol; 6,6study,0-bieckol; we isolated 6,80-bieckol; six phlorotannins 8,80-bieckol; (eckol; PFF-A 6,6 and′-bieckol; PFF-B, 6,8 Figure′-bieckol;1) from 8,8′-bieckol; the brown algaPFF-AEisenia and arborea PFF-B, [11Figure,12], and1) from reported the brown the anti-allergenic alga Eisenia arborea and anti-inflammatory [11,12], and reported effects the ofanti- their phlorotanninsallergenic and [13 anti-inflammatory,14]. Validation studies effects of their effective phlorotannins extraction [13,14]. or purification Validation methods studies ofof themeffective using supercriticalextraction or fluid purification extraction, methods pressurized of them liquid using extraction, supercritical liquid–liquid fluid extraction, or solid–liquid pressurized separation, liquid extraction, liquid–liquid or solid–liquid separation, chromatographic methods and liquid chromatographic methods and liquid chromatography high-resolution mass spectrometry have also chromatography high-resolution mass spectrometry have also been reported since publication of the been reported since publication of the usefulness of phlorotannins [15–18]. usefulness of phlorotannins [15–18]. FigureFigure 1.1. The chemical structures structures of of six six phlorotannins. phlorotannins. While the anti-allergenic effects of terrestrial plant polyphenols are well documented, there are fewerWhile published the anti-allergenic studies on phlorotannins effects of terrestrial on the plant anti-allergenic polyphenols and are anti-inflammatory well documented, effects there ofare fewerphlorotannins published and studies most onreports phlorotannins concern in vitro on the studie anti-allergenics. In this context, and we anti-inflammatory aimed to the efficacy effects of of phlorotanninsphlorotannins and as anti-allergenic most reports concernand anti-inflammatoin vitro studies.ry compounds In this context, in vivo. we In aimeda previous to the study, efficacy we of phlorotanninshad investigated as anti-allergenic the inhibitory effects and anti-inflammatory of six pirified phlorotannins compounds onin allergic vivo. Ininflammation-related a previous study, we hadenzymatic investigated activities the inhibitory [13,14] and effects their ofefficacy six pirified in suppressing phlorotannins mouse on allergicear swelling inflammation-related [19,20]. When enzymaticpercutaneously activities administered, [13,14] and the their phlorotannins efficacy in su suppressingppressed the mousemouse ear swelling swelling by [19 sensitizers,20]. When percutaneouslyincluding arachidonic administered, acid (AA), the 12- phlorotanninsO-tetradecanoylphorbol-13-acetat suppressed the mousee (TPA) ear and swelling oxazolone by sensitizers (OXA) including[19,20]. However, arachidonic the therapeutic acid (AA), effects 12- Oof-tetradecanoylphorbol-13-acetate phlorotannins remains to be investigated. (TPA) In and addition, oxazolone the (OXA)efficacy [19 of,20 phlorotanins]. However, when the given therapeutic in food (intestinal effects ofabsorption) phlorotannins or when remains taken as toan anti-allergenic be investigated. Indrug addition, needs the to be efficacy investigated. of phlorotanins In fact, fucoxanthi when givenn, a marine in food carotenoid, (intestinal and absorption) isoflavonoids or when possess taken asbioactive an anti-allergenic properties drugto convert needs to fucoxanthinol be investigated. and In equol, fact, fucoxanthin,respectively, ainmarine the intestine carotenoid, [21,22]. and Mar. Drugs 2018, 16, 267 3 of 14 isoflavonoids possess bioactive properties to convert to fucoxanthinol and equol, respectively, in the intestine [21,22]. Therefore, in this study, we also examined whether