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6,6′-Bieckol, isolated from marine alga Ecklonia cava, suppressed LPS-induced nitric oxide and PGE 2 production and inflammatory cytokine expression in macrophages: The inhibition of NFκB
Abstract
Ecklonia cava is an edible brown alga that contains high levels of phlorotannins, which are unique marine polyphenolic compounds. In the present study, we investigated the anti-inflammatory effects and the underlying molecular mechanism of phlorotannin 6,6'-bieckol, which is an active component isolated from E. cava, on lipopolysaccharide (LPS)-stimulated primary macrophages and RAW 264.7 macrophage cells. 6,6'-Bieckol was found to inhibit nitric oxide (NO) and prostaglandin E₂ (PGE₂) production and to suppress the LPS-induced expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) at the mRNA and protein levels. In addition, 6,6'-bieckol downregulated the production and mRNA expression of the inflammatory cytokines TNF-α and IL-6. Moreover, pretreatment with 6,6'-bieckol decreased LPS-induced transactivation of nuclear factor-kappa B (NFκB) and nuclear translocation of p50 and p65 subunits of NFκB. Furthermore, chromatin immunoprecipitation assay revealed that 6,6'-bieckol inhibited LPS-induced NFκB binding to the TNF-α and IL-6 promoters. Taken together, these data suggest that the anti-inflammatory properties of 6,6'-bieckol are related to the down-regulation of iNOS, COX-2, and pro-inflammatory cytokines through the negative regulation of the NFκB pathway in LPS-stimulated macrophages.
... HaCaT cells Mouse (ICR) strain ear edema Cell-free enzymatic systems ↓ NO and HMGB-1 production ↓ MMP-2, MMP-9, TNF-α, COX-2, iNOS, TLR-4, VCAM-1, ICAM-1 and E-selectin expression ↓ Barrier disruption ↓ NF-κB activation ↓ p38 MAPK and Akt phosphorylation ↑ ZO-1 and occludin expression ↓ Leukocyte adhesion and migration ↓ AA-, TPA-and OXA-induced ear edema PLA 2 , COX and LOX inhibition Jung et al., 2013;Kim et al., 2012;Lee et al., 2012;Shibata et al., 2003;Sugiura et al., 2018Sugiura et al., , 2013Wei et al., 2016) Dioxinodehydroeckol ( ↓ iNOS and COX-2 expression and promoter activity ↓ NF-κB and AP-1 activation ↓ AA-, TPA-and OXA-induced ear edema PLA 2 , COX and LOX inhibition (Jung et al., 2013;Kim et al., 2009Kim et al., , 2011Lee et al., 2012;Shibata et al., 2003;Sugiura et al., 2018Sugiura et al., , 2013Wei et al., 2016) 1-(3′,5′-Dihydroxyphenoxy)-7-(2″,4″,6″-trihydroxyphenoxy)-2,4,9-trihydroxydibenzo-1,4dioxin ( ↓ iNOS and COX-2 expression ↓ NF-κB activation ↓ NF-κB binding to TNF-α and IL-6 promoters ↓ AA-, TPA-and OXA-induced ear edema (Sugiura et al., 2018(Sugiura et al., , 2017Wei et al., 2016;Yang et al., 2012) 8,8′-Bieckol ( (Shibata et al., 2003;Sugiura et al., 2018Sugiura et al., , 2013Yang et al., 2014) 7-Phloroeckol (9) ...
... Several studies have looked at the capacity of phlorotannins to act upon different critical steps of inflammatory response (Tables 1 and 2), generally using the in vitro model of RAW 264.7 macrophages following activation with the well-known bacterial endotoxin lipopolysaccharide (LPS), a potent elicitor of pro-inflammatory cytokines and inflammatory mediators' production (Barbosa et al., 2017;Jung, Jin, Ahn, Lee, & Choi, 2013;Kellogg, Esposito, Grace, Komarnytsky, & Lila, 2015;Kim et al., 2009Kim et al., , 2011Kim et al., , 2014Lee et al., 2012Lee et al., , 2016Lopes et al., 2012;Shin, Hwang, Kang, & Lee, 2006;Wei et al., 2016;Wijesinghe et al., 2013;Yang et al., 2012Yang et al., , 2016Yang, Jung, Lee, & Choi, 2014;Zaragozá et al., 2008). ...
... The works conducted by Yang et al. (2012Yang et al. ( , 2014 attempted at elucidating the molecular mechanisms of the anti-inflammatory effects of 6,6′-bieckol (7) and 8,8′-bieckol (8) isolated from E. cava, harvested at Jeju Island (Korea), on both LPS-stimulated primary macrophages and RAW 264.7 cells. Both phloroglucinol hexamers (7 and 8) inhibited the production of the key inflammatory mediator NO in a concentration-dependent manner, by suppressing LPS-induced expression of iNOS at the transcriptional level. ...
Background: Brown seaweeds are unanimously acknowledged as valuable producers of diverse and structurally complex compounds, with great potential in food and pharmaceutical industries. Among the brown algal high-value bioactive compounds, phlorotannins have been pointed out as potent modulators of several biochemical processes linked to the breakdown of homeostasis in major chronic diseases. The chronic nature of several emerging diseases, along with the lack of effective preventive and curative therapies, is directing research into new sources of bioactive compounds with multimodal actions. Inflammatory processes are at the root of several biological processes and, in the last decades, a complex interplay between inflammation and allergic reactions has been acknowledged. Scope and approach: This review comprehensively covers the available literature on chemistry, biosynthesis, as well as on the mechanisms underlying anti-inflammatory and anti-allergic potential of both isolated phlorotannins and phlorotannin-rich extracts/fractions. Key findings and conclusions: The many outcomes revisited herein support the potential of phlorotannins as key compounds from still underexplored natural matrices, with a large spectrum of activity and low toxicity. Moreover, this work prospects the development of innovative and more detailed in vitro and in vivo studies, highlighting some potential directions for future progress in the design of novel therapeutic strategies from seaweed-derived products, also considering the limitations of past and current approaches.
... As shown in Table 2 and Figure 2, there was a remarkable increase in marine anti-inflammatory pharmacology research during 2012-2013. The molecular mechanism of action of marine natural products (115)(116)(117)(118)(119)(120)(121)(122)(123)(124)(125)(126)(127)(128)(129)(130)(131)(132)(133)(134) was investigated in both in vitro and in vivo preclinical pharmacological studies which were completed using a variety of in vitro models including bone marrow-derived macrophages, human U937 monocytic cells, murine RAW 264.7 macrophages, human epidermoid carcinoma A431 cell line, human polymorphonuclear leukocytes, rat brain microglia, and mouse peritoneal macrophages. ...
... Song and colleagues determined that bis-N-norgliovictin (119) derived from a marine fungus S3-1-c inhibited TNF-α, IL-6, interferon-β, and MCP-1 production by LPS-stimulated RAW 264.7 macrophages and affecting Toll-like receptor 4 (TLR-4) signal transduction pathways, as well as LPS-induced septic shock in mice, thus suggesting bis-N-norgliovictin might result in a useful therapeutic candidate for "sepsis and other inflammatory diseases" [124]. Investigations by Yang and colleagues with phlorotannin 6,6'-bieckol (120), isolated from the marine brown alga Ecklonia cava, showed that the compound inhibited expression and release of nitric oxide, prostaglandin E 2 , TNF-α and IL-6 in LPS-stimulated macrophages, with concomitant inhibition of NFκB activation, suggesting that compound 120 is potentially useful for the treatment of inflammatory diseases [125]. Balunas and colleagues determined that the polyketide coibacin B (121), isolated from the Panamanian marine cyanobacterium, cf. ...
... Choi and colleagues demonstrated that the novel honaucin A (123) from the Hawaiian cyanobacterium Leptolyngbya crossbyana, which inhibited LPS-induced nitric oxide production, and TNF-α, IL-1β, IL-6 and iNOS gene transcription in RAW 264.7 macrophages, had functional groups "critical for anti-inflammatory... activity" [127]. Rat brain microglia, a macrophage type involved in neuroinflammation and neurodegeneration [180] was used by Mayer and colleagues to investigate several known diterpene isocyanide amphilectane metabolites (124,125) from the Caribbean marine sponge Hymeniacidon sp., which potently inhibited thromboxane B 2 generation from LPS activated rat neonatal microglia in vitro, with concomitant low lactate dehydrogenase release and minimal mitochondrial dehydrogenase inhibition. The authors concluded that the potency of these compounds warranted "further investigation . . . ...
The peer-reviewed marine pharmacology literature from 2012 to 2013 was systematically reviewed, consistent with the 1998–2011 reviews of this series. Marine pharmacology research from 2012 to 2013, conducted by scientists from 42 countries in addition to the United States, reported findings on the preclinical pharmacology of 257 marine compounds. The preclinical pharmacology of compounds isolated from marine organisms revealed antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral and anthelmitic pharmacological activities for 113 marine natural products. In addition, 75 marine compounds were reported to have antidiabetic and anti-inflammatory activities and affect the immune and nervous system. Finally, 69 marine compounds were shown to display miscellaneous mechanisms of action which could contribute to novel pharmacological classes. Thus, in 2012–2013, the preclinical marine natural product pharmacology pipeline provided novel pharmacology and lead compounds to the clinical marine pharmaceutical pipeline, and contributed significantly to potentially novel therapeutic approaches to several global disease categories.
... In the last decade, it was demonstrated that 6,6 -bieckol (6,6 -bis(3,5-dihydroxyphenoxy)- [1,1 -bidibenzo[b,e] [1,4]dioxin]-2, 2 ,4,4 ,7,7 ,9,9 -octaol (6)) ( Figure 1), isolated from E. cava, inhibited the expression and release of NO, PGE2, TNF-α, and IL-6 in LPS-stimulated macrophages, with concomitant inhibition of NF-κB activation [44]. More recently, Sugiura et al. [45] demonstrated using a rat mast cell line (RBL-2H3) that 6,6 -bieckol (6) and other phlorotannins such as eckol (3), 6,8 -bieckol (6,9 - (8)), PFF-A (4,9-bis(3,5-dihydroxyphenoxy)benzo[b]benzo [5,6] [1,4] dioxino [2,3-e]benzofuran-1,3,6,10,12-pentaol (4a)), and PFF-B (4b) isolated from Eisenia arborea, Areschoug, 1876, suppressed the release of chemical mediators (histamine, leukotriene B4, and PGE2) COX-2 mRNA expression and inhibited COX-2 activity at a 500 µM of concentration [45]. ...
... Moreover, their positive effect was better than the epigallocatechin gallate (EGCG), which was used as the positive control influence. The 6,8 -bieckol at 75 nmol exhibited the most potent suppression (77.8%) compared with the epigallocatechin gallate's weakest suppression (5.7%) [44]. ...
Inflammation is an organism’s response to chemical or physical injury. It is split into acute and chronic inflammation and is the last, most significant cause of death worldwide. Nowadays, according to the World Health Organization (WHO), the greatest threat to human health is chronic disease. Worldwide, three out of five people die from chronic inflammatory diseases such as stroke, chronic respiratory diseases, heart disorders, and cancer. Nowadays, anti-inflammatory drugs (steroidal and non-steroidal, enzyme inhibitors that are essential in the inflammatory process, and receptor antagonists, among others) have been considered as promising treatments to be explored. However, there remains a significant proportion of patients who show poor or incomplete responses to these treatments or experience associated severe side effects. Seaweeds represent a valuable resource of bioactive compounds associated with anti-inflammatory effects and offer great potential for the development of new anti-inflammatory drugs. This review presents an overview of specialized metabolites isolated from seaweeds with in situ and in vivo anti-inflammatory properties. Phlorotannins, carotenoids, sterols, alkaloids, and polyunsaturated fatty acids present significant anti-inflammatory effects given that some of them are involved directly or indirectly in several inflammatory pathways. The majority of the isolated compounds inhibit the pro-inflammatory mediators/cytokines. Studies have suggested an excellent selectivity of chromene nucleus towards inducible pro-inflammatory COX-2 than its constitutive isoform COX-1. Additional research is needed to understand the mechanisms of action of seaweed’s compounds in inflammation, given the production of sustainable and healthier anti-inflammatory agents.
... Furthermore, phlorofucofuroeckol-B suppressed the generation of NO and prostaglandins and downregulated the LPS-induced expression of inducible cyclooxygenase-2 and NO synthase in LPS-stimulated BV-2. The compound 6,6 -Bieckol decreased nitric oxide and prostaglandin production and suppressed LPS-induced expression of inducible cyclooxygenase-2 and NO synthase ( Figure 4) [71]. Importantly, 6,6 -bieckol inhibited the expression of IL-6 and TNF-α. ...
... Furthermore, phlorofucofuroeckol-B suppressed the generation of NO and prostaglandins and downregulated the LPS-induced expression of inducible cyclooxygenase-2 and NO synthase in LPS-stimulated BV-2. The compound 6,6′-Bieckol decreased nitric oxide and prostaglandin production and suppressed LPS-induced expression of inducible cyclooxygenase-2 and NO synthase ( Figure 4) [71]. Importantly, 6,6′-bieckol inhibited the expression of IL-6 and TNF-α. ...
Phlorotannins are a group of phenolic secondary metabolites isolated from a variety of brown algal species belonging to the Fucaceae, Sargassaceae, and Alariaceae families. The isolation of phlorotannins from various algal species has received a lot of interest owing to the fact that they have a range of biological features and are very biocompatible in their applications. Phlorotannins have a wide range of therapeutic biological actions, including antimicrobial, antidiabetic, antioxidant, anticancer, anti-inflammatory, anti-adipogenesis, and numerous other biomedical applications. The current review has extensively addressed the application of phlorotannins, which have been extensively investigated for the above-mentioned biological action and the underlying mechanism of action. Furthermore, the current review offers many ways to use phlorotannins to avoid certain downsides, such as low stability. This review article will assist the scientific community in investigating the greater biological significance of phlorotannins and developing innovative techniques for treating both infectious and non-infectious diseases in humans.
... The attenuation was attributed to the suppression of activation and nuclear translocation of NF-κB, activation of signal transduction factors [protein kinase B (Akt), activator protein-1 (AP-1), JNK, and p38 MAPK], and phosphorylation of transcription factors (NF-κB and I-κBα) and signal transduction factors [Akt, ERK, IKK-α/β, JNK, p38 MAPK, and phosphatidylinositol-3 kinase (PI-3K)]. 32,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85] Regarding the other suppressive mechanism, 6,6 ′ -bieckol and PFF-A suppressed the signal transduction of the promoter region involved in COX-2, iNOS, IL-6, and TNF-α expression. 72,84 Dieckol caused superoxide dismutase (SOD) production and activation of heme oxygenase-1/nuclear factor erythroid 2-related factor 2 (HO-1/Nrf2) signaling because of the above-mentioned suppression of phosphorylation and nuclear translocation, and this regulation mechanism caused antiinflammation. ...
... 32,[68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84][85] Regarding the other suppressive mechanism, 6,6 ′ -bieckol and PFF-A suppressed the signal transduction of the promoter region involved in COX-2, iNOS, IL-6, and TNF-α expression. 72,84 Dieckol caused superoxide dismutase (SOD) production and activation of heme oxygenase-1/nuclear factor erythroid 2-related factor 2 (HO-1/Nrf2) signaling because of the above-mentioned suppression of phosphorylation and nuclear translocation, and this regulation mechanism caused antiinflammation. 79,80 Although these reports resulted from in vitro studies, there is a report on in vivo studies. ...
Because the number of people suffering from allergies has significantly increased, improved ways of treating these conditions by medical, pharmaceutical, and dietary means are required. Large numbers of studies on allergy have been conducted, and many anti-allergic compounds have been found. Phenolic compounds from terrestrial plants, including catechins and flavonoids, possess anti-allergic properties. Although polyphenols are present in some brown algae, their anti-allergic activities were not studied in detail before the 1990s. The focus was on the algal polyphenols, collectively called phlorotannins (eg., eckol, 6,6′-bieckol, 8,8′-bieckol, dieckol, and phlorofucofuroeckol-A), and research was conducted to clarify their anti-allergic activities. This review summarizes the anti-allergic effects of phlorotannins isolated from the brown alga, Eisenia nipponica, and related reports by other research groups.
... RAW 264.7 and HaCaT cells were pretreated with MAEO at 12.5-100 µg/mL for 1 h, followed by stimulation with LPS (0.1 µg/mL) for 24 h. Nitrite accumulation in the culture medium as an indicator of NO production was measured using Griess reagent [21]. The culture supernatant (100 µL) was mixed with 100 µL of Griess reagent (equal volumes of 1% (w/v) sulfanilamide in 0.1% (w/v) naphthyl ethylenediamine-HCl and 5% (v/v) phosphoric acid) for 10 min [20]. ...
... In LPS-stimulated macrophages, the MAPK/NF-κB pathway is closely related to LPSinduced transcriptional regulation of inflammation [21,31]. To identify whether MAEO influences NF-κB activity, we measured the phosphorylation level of P65, a subunit of NF-κB, after MAEO treatment under LPS-induced stimulatory conditions. ...
The mechanism of atopic dermatitis (AD) is modulated by the release of cytokines and chemokines through the mitogen-activated protein kinase (MAPK)/nuclear factor-kappa B (NF-κB) signaling pathway. Topical steroids are used to treat AD, but some people need safer anti-inflammatory drugs to avoid side effects. Mentha arvensis has been used as a herbal plant with medicinal properties, but its anti-inflammatory effects have not been elucidated in an AD model. In this study, we investigated the anti-inflammatory effects of M. arvensis essential oil (MAEO) and its underlying molecular mechanism in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages and HaCaT cells (human epidermal keratinocyte). Additionally, we examined the ameliorating effects of the MAEO in a dinitrochlorobenzene (DNCB)-induced murine model of AD. We found, in both RAW 264.7 cells and HaCaT cells, MAEO inhibited LPS-stimulated inflammatory mediators such as nitric oxide (NO) and prostaglandin E2 and proinflammatory cytokines, including IL-1β and IL-6, due to the suppression of COX-2 and iNOS expression. In LPS-stimulated macrophages, we also observed that MAEO inhibited the phosphorylation of ERK and P65. Furthermore, MAEO treatment attenuated AD symptoms, including the dermatitis score, ear thickness, epidermal thickness and infiltration of mast cells, in a DNCB-induced animal model of AD. Overall, our findings suggest that MAEO exerts anti-inflammatory and anti-atopic dermatitis effects via inhibition of the ERK/NF-κB signaling pathway.
... The majority of the phlorotannins obtained from these seaweeds were proven of being able to inhibit the expression of cellular adhesion molecules, like ICAM-1 and VCAM-1 and cytokines, namely TNF-α, IL-1β and IL-6, in several cells of the immune system [54,[79][80][81][82]. Likewise, the release of NO • and PG 2 , as well as the expression of enzymes responsible for their synthesis, i.e., iNOS and COX-2, respectively, were found reduced in cells treated with E. cava, E. stolonifera and E. arborea extracts [83][84][85][86][87], or phlorotannin compounds from them isolated including phloroglucinol, dieckol, fucofuroeckol A, 6,6 -bieckol and phlorofucofuroeckol A [38,[80][81][82]88,89]. Other seaweeds have proven their capability of inhibiting multiple pro-inflammatory markers as well. ...
... Similar observations were described for phlorofucofuroeckol A, which inhibited the phosphorylation of p38, ERK and JNK in LPS-stimulated Raw 264.7 cells [96], and for phloroglucinol, which blocked the phosphorylation of ERK in HT1080 cells [54], both resulting in the suppression of AP-1 activity, another transcription factor involved in the regulation of some pro-inflammatory mediators such as matrix metalloproteinases, a group of enzymes involved in the tissue remodeling during chronic inflammation and cell motility further in a tumor environment. The inhibitory effects of these and other isolated phlorotannins such as eckol, eckstolonol, 6,6 -bieckol, 8,8 -bieckol, fucofuroeckol-A over NF-κB and MAPKs have been reported in multiple cell lines elicited with different pro-inflammatory stimulus, including LPS-induced BV2 microglia cells, THP-1 or Raw 264.7 macrophages, Aβ 25-35 -stimulated PC12 pheochromocytoma cells, PMA-induced MG-63 human osteosarcoma cells, high glucose-induced HUVEC endothelial cells, hypoxia-induced primary mouse hepatocytes and gamma-irradiated primary rat hepatocytes [46,65,81,82,88,89,106,[109][110][111][112], suggesting that these compounds may act in a wide range of inflammatory conditions. ...
According to the WHO, cancer was responsible for an estimated 9.6 million deaths in 2018, making it the second global leading cause of death. The main risk factors that lead to the development of this disease include poor behavioral and dietary habits, such as tobacco use, alcohol use and lack of fruit and vegetable intake, or physical inactivity. In turn, it is well known that polyphenols are deeply implicated with the lower rates of cancer in populations that consume high levels of plant derived foods. In this field, phlorotannins have been under the spotlight in recent years since they have shown exceptional bioactive properties, with great interest for application in food and pharmaceutical industries. Among their multiple bioactive properties, phlorotannins have revealed the capacity to interfere with several biochemical mechanisms that regulate oxidative stress, inflammation and tumorigenesis, which are central aspects in the pathogenesis of cancer. This versatility and ability to act either directly or indirectly at different stages and mechanisms of cancer growth make these compounds highly appealing for the development of new therapeutical strategies to address this world scourge. The present manuscript revises relevant studies focusing the effects of phlorotannins to counteract the oxidative stress–inflammation network, emphasizing their potential for application in cancer prevention and/or treatment.
... The RBL cells were stimulated by antigen-antibody reaction or A23187. According to previously reported phlorotannin concentration ranging 1 to 200 µM in cultured model cell experiments [7,8,10,[26][27][28][29], we chose a concentration range from 10 to 200 µM in our experiments. ...
... The same two phlorotannins at 100 µM suppressed COX-2 mRNA expression in RBL cells, compared with the other four phlorotannins (Figure 2). It has been reported that the anti-inflammatory effect of 6,6 -bieckol is via the inhibition of COX-2 expression and activity through suppression of NF-κB and ERK 1/2 signaling [28,29]. The suppression effect of 6,6 -bieckol on ear swelling could be attributable to greater suppression of COX-2 mRNA expression than to inhibition of COX-2 activity. ...
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; 6,6-bieckol; 6,8-bieckol; 8,8-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 B 4 and prostaglandin E 2), 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 6,8-bieckol, 8,8-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.
... Moreover, 6,6′-bieckol suppressed COX-2 mRNA and protein expression in RAW 264.7 cells, a line of cultured mouse macrophages (Yang et al., 2012); accordingly, the suppressive effects of this agent on mouse ear swelling might be due to the suppression of COX-2 expression. Although the anti-oxidative effects of 6,8′-bieckol have been reported (Kwon et al., 2013), studies of its suppressive effects on COX-2 expression are required. ...
The anti-inflammatory effects of two phlorotannins identified in the brown alga Eisenia arborea, i.e., 6,6′-bieckol and 6,8′-bieckol, were previously determined in vitro. Here we investigated the in vivo effects of these phlorotannins in mice. In ICR mice, ear swelling was induced by three sensitizers: arachidonic acid, 12-O-tetradecanoylphorbol-13-acetate (TPA) and oxazolone (OXA). Swelling was suppressed after the two phlorotannins were applied to the mouse ears. In particular, compared with epigallocatechin gallate, a typical natural inhibitor, the phlorotannins had a significantly greater effect on OXA-induced ear swelling (6,6′-bieckol, p < 0.05; 6,8′-bieckol, p < 0.01). This is the first report to confirm the anti-inflammatory effects of 6,6′-bieckol and 6,8′-bieckol in vivo.
... Phlorotannins are polyphenols contained only in brown seaweeds as secondary metabolites, and are presumed to be biosynthesized via the acetate-malonate pathway. 1 Based on the means of linkage between phloroglucinol (1,3,5-trihydroxybenzene) units, phlorotannins can be classified into the following subclasses of compounds: those with an ether linkage (fuhalols and phlorethols), those with a phenyl linkage (fucols), those with ether and phenyl linkages (fucophlorethols), and those with a dibenzodioxin linkage (eckols and carmalols). 2,3 As a result of recent pharmacological research, it has been demonstrated that phlorotannins, especially eckols, have various physiological functions, e.g., antioxidant, [4][5][6][7][8] anti-glycation, [9][10][11][12][13] anti-diabetic, 14,15 antihypertension, 16 anti-inflammatory, 6,17,18 and suppression of melanogenesis. 8,19 Based on these scientific findings, phlorotannins are attracting attention as novel functional polyphenols derived from seaweed. ...
The brown seaweed Sargassum carpophyllum J. Agardh is an unused warm-temperate species in the family Sargassaceae that has been expanding its distribution along the coastal areas of Japan in recent years. In this study, 3 types of phlorotannins were identified from the EtOAc fraction of the 80% MeOH extract of S. carpophyllum. From the spectroscopic ( ¹ H NMR, ¹³ C NMR, and HMBC) and ESI/MS data and comparison with those of prior literature, it was demonstrated that the compounds are oligomers of phlorethol, which is one of the subclasses of phlorotannins, that is triphlorethol B (phloroglucinol trimer), tetraphlorethol C (phloroglucinol tetramer), and pentaphlorethol A (phloroglucinol pentamer). Among the phlorethols, tetraphlorethol C and pentaphlorethol A were isolated and identified for the first time from a brown seaweed collected from the East China Sea, including the coastal areas of Japan. The identified phlorethols were tested for their antioxidant properties. In the antioxidant assay using liposomes, the phlorethols showed comparable inhibitory effects to epigallocatechin gallate (tea polyphenol) and α-tocopherol (liposoluble vitamin) on lipid peroxidation by 4 mM 2,2′-azobis(2-methylpropionamidine) dihydrochloride. In addition, it was revealed that pentaphlorethol A has a superoxide anion scavenging activity (50% effective concentration: 21 μM) higher than that (50% effective concentration: 46 μM) of ascorbic acid (hydrosoluble vitamin).
... A study by Manandhar et al. (2019 ) highlighted the neuroprotective e ect of phlorotannins against oxidative stress and infl ammation. In lipopolysacchide-stimulated primary and RAW 264.7 macrophages, phlorotannin 6,6′-bieckol that are extracted from E. cava -inhibited NO and PGE2 production by suppressing the expression of iNOS and COX-2 ( Yang et al., 2012 ). Eckol, a phlorotannin, showed antiproliferation and pro-apoptotic e ects, thereby inhibiting tumor development in sarcoma 180 xenograft-bearing animals ( Zhang et al., 2019 ). ...
... However, in uncontrolled inflammatory reactions, ROS and several proteases may be produced, leading to chronic inflammation [37]. Previous studies have shown that polyphenols derived from algae have anti-inflammatory activity [38][39][40]. In this study, the potential anti-inflammatory properties of EEM isolated with 80% MeOH extraction were investigated. ...
Ecklonia maxima is a brown seaweed, which is abundantly distributed in South Africa. This study investigated an efficient approach using high-performance centrifugal partition chromatography (HPCPC), which has been successfully developed for the isolation and purification of phlorotannins, eckmaxol, and dieckol from the ethyl acetate fraction of E. maxima (EEM). We evaluated EEM for its inhibitory effect against lipopolysaccharide (LPS)-induced inflammatory responses in zebrafish embryos. The separation of eckmaxol and dieckol from samples of EEM using HPCPC was found to be of high purity and yield under an optimal solvent system composed of n-hexane:ethyl acetate:methanol:water (2:7:3:7, v/v/v/v). To evaluate the anti-inflammatory efficacy of EEM containing active compounds, zebrafish embryos exposed to LPS were compared with and without EEM treatment for nitric oxide (NO) production, reactive oxygen species (ROS) generation, and cell death two days after fertilization. These evaluations indicate that EEM alleviated inflammation by inhibiting cell death, ROS, and NO generation induced by LPS treatment. According to these results, eckmaxol and dieckol isolated from brown seaweed E. maxima could be considered effective anti-inflammatory agents as pharmaceutical and functional food ingredients.
... Therefore, the protection of E. cava is necessary for the conservation of the marine biodiversity in the coastal areas of the Northwest Pacific region. On the other hand, E. cava is also known to have various kinds of beneficial substances, and exhibit important biological activities, including antioxidant (Kim et al. 2014;Park et al. 2014), anti-viral effects (Ahn et al. 2004b), anaphylactic reaction (Ahn et al. 2015), improving blood circulation (Son et al. 2019b), anti-inflammatory properties (Yang et al. 2012), and modulating brown adipocyte function (Son et al. 2019a). As a result, E. cava is an important biological resource for human healthcare as well as a keystone species of marine biodiversity. ...
BackgroundsPolycyclic aromatic hydrocarbons (PAHs) are the most persistent environmental toxicants, which can be found in every part of the environment. The PAHs are known to induce cancer, malformation, and mutation in various kinds of biological organisms, including humans. However, only limited toxic effects of PAHs in seaweeds have been accumulated so far.Objectives
Differentially expressed genes (DEGs) against PAHs exposure were isolated using Ecava cDNA microarray and their biological functions were considered to anticipate the toxic effects of PAHs in Ecklonia cava.ResultsGene ontology (GO) analysis of DEGs showed that PAHs exposure affected several processes, namely cellular protein metabolic, macromolecule biosynthetic, nucleic acid metabolic, carbohydrate derivative biosynthetic, glycoprotein metabolic processes, photosynthesis, and finally oxidoreductase activity in kelp species. Functional analysis of the most frequently observed DEGs in each of the 24-h and 48-h experimental groups revealed that PAHs appeared to induce stress and defense responses, as well as interfere with Wnt signaling pathways and biological molecule metabolism in E. cava.Conclusion
This study demonstrated the discovery of DEGs in E. cava that may be impacted by environmental PAHs, as well as predicted how the transcript levels would affect physiology and metabolism. Such results will contribute to a better understanding of how seaweed reacts to pollution.
... To date, about 150 PTs have been isolated from these hydrobionts [15,37], many of which have anti-inflammatory and antioxidant properties. The most studied agents among them are florofucofuroeckol A (PFF-A) and florofucofuroeckol-B (PFF-B), as well as dieckol and 6,6 -bieckol [38][39][40]. However, other PTs, which exhibit high anti-inflammatory activity, are gradually being investigated and proposed as the basis for creating therapeutic agents. ...
Inflammatory reactions are part of a complex biological response that plays a vital role in the appearance of various stimuli resulting from tissue and cell damage, the invasion of pathogenic bacteria, and the formation of the subsequent adaptive immune response. The production of many triggers and mediators of inflammation, which are inducers of pro-inflammatory factors, is controlled by numerous differentiation programs, through which inflammation is resolved and tissue homeostasis is restored. However, prolonged inflammatory responses or dysregulation of pro-inflammatory mechanisms can lead to chronic inflammation. Modern advances in biotechnology have made it possible to characterize the anti-inflammatory activity of phlorotannins, polyphenolic compounds from brown seaweed, and the mechanisms by which they modulate the inflammatory response. The purpose of this review is to analyze and summarize the results of numerous experimental in vitro and in vivo studies, illustrating the regulatory mechanisms of these compounds, which have a wide range of biological effects on the body. The results of these studies and the need for further research are discussed.
... Thus, dieckol could contribute to the regulatory effect of EEB on MAPK/AP-1 activation. Several phlorotannins in EEB, such as dieckol, 6,6 -bieckol, and 8,8 -bieckol, are known to possess inhibitory effects on nuclear factor-κB (NF-κB), another transcription factor that upregulates MMP expression and inflammatory responses [26,[52][53][54]. ERK and p38 of MAPK are also responsible for NF-κB activation in addition to AP-1 via the phosphorylation of mitogen-and stress-activated kinase 1 (MSK1) [55]. ...
Chronic exposure to ultraviolet B (UVB) is a major cause of skin aging. The aim of the present study was to determine the photoprotective effect of a 30% ethanol extract of Eisenia bicyclis (Kjellman) Setchell (EEB) against UVB-induced skin aging. By treating human dermal fibroblasts (Hs68) with EEB after UVB irradiation, we found that EEB had a cytoprotective effect. EEB treatment significantly decreased UVB-induced matrix metalloproteinase-1 (MMP-1) production by suppressing the activation of mitogen-activated protein kinase (MAPK)/activator protein 1 (AP-1) signaling and enhancing the protein expression of tissue inhibitors of metalloproteinases (TIMPs). EEB was also found to recover the UVB-induced degradation of pro-collagen by upregulating Smad signaling. Moreover, EEB increased the mRNA expression of filaggrin, involucrin, and loricrin in UVB-irradiated human epidermal keratinocytes (HaCaT). EEB decreased UVB-induced reactive oxygen species (ROS) generation by upregulating glutathione peroxidase 1 (GPx1) and heme oxygenase-1 (HO-1) expression via nuclear factor erythroid-2-related factor 2 (Nrf2) activation in Hs68 cells. In a UVB-induced HR-1 hairless mouse model, the oral administration of EEB mitigated photoaging lesions including wrinkle formation, skin thickness, and skin dryness by downregulating MMP-1 production and upregulating the expression of pro-collagen type I alpha 1 chain (pro-COL1A1). Collectively, our findings revealed that EEB prevents UVB-induced skin damage by regulating MMP-1 and pro-collagen type I production through MAPK/AP-1 and Smad pathways.
... cytokines RAW 264.7 cells were seeded in a 12-well plate at a density of 1 × 10 6 cells per well and incubated for 12 h. [18] . ...
Diaporisoindole B (DPB), an isoprenylisoindole alkaloid isolated from the mangrove endophytic fungus Diaporthe sp. SYSU-HQ3, has been proved to inhibit the production of nitric oxide (NO) in lipopolysaccharide (LPS)-challenged RAW 264.7 mouse macrophages, showing potent anti-inflammatory effects. In this study, we further investigated the anti-inflammatory effects of DPB and explored the possible mechanisms in LPS-challenged RAW 264.7 mouse macrophages. The results showed that DPB (3.125, 6.2, 12.5 and 25 µM) could significantly reduce LPS-induced levels of PGE2, and inhibit the expressions of iNOS and COX-2 in a dose-dependent manner. In addition, DPB also inhibited LPS-induced production of inflammatory cytokines, including TNF-α, IL-1β, IL-6. Moreover, we further investigated signal transduction mechanisms by which DPB exerted anti-inflammatory effects. DPB could affect LPS-mediated nuclear factor kappa B (NF-kB) signaling pathway ac+;vat. 'n Vi a down-regulating the upstream myeloid differentiation protein 88 (MyD88) at the protein level. Additionally, DPB also strongly inhibited the phosphorylation of mitogen-activated protein kinases (MAPKs), including extracellular signal-regulated kinase (ERK) 1/2, c-Jun N-terminal kinase (JNK) and p38. Therefore, DPB might exert anti-inflammatory effects by suppressing NF-kB activation and MAPKs pathways via down-regulating MyD88 in RAW 264.7 cells. © 2021 Journal of Chinese Pharmaceutical Sciences, School of Pharmaceutical Sciences, Peking University. All Rights Reserved.
... HaCaT cells were pre-treated with methanol extract of liverwort and Racomitrium moss at 30 and 100 µg/mL for 1 h, followed by stimulation with LPS (1 µg/mL) for 24 h. Nitrite accumulation in the culture medium as an indicator of NO production was measured using Griess reagent [48]. The culture supernatant (100 µL) was mixed with 100 µL of Griess reagent (equal volumes of 1% (w/v) sulfanilamide in 0.1% (w/v) naphthyl ethylenediamine-HCl and 5% (v/v) phosphoric acid) for 10 min [47]. ...
Bryophytes contain a variety of bioactive metabolites, but studies about the anti-inflammatory effect of bryophytes are meager. Therefore, the present study aimed to compare the anti-inflammatory effect of methanol extract of Marchantia polymorpha L. (liverwort) and Racomitrium canescens (Racomitrium moss) in lipopolysaccharide (LPS)-induced HaCaT cells. To evaluate the anti-inflammatory effect of liverwort and Racomitrium moss, the levels of nitric oxide (NO) production and the mRNA expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and tumor necrosis factor-α (TNF-α), and interleukin (IL)-6 and IL-1β in LPS-induced HaCaT cells were measured. The methanol extract of liverwort and Racomitrium moss significantly decreased LPS-induced NO production in HaCaT cells. When compared with Racomitrium moss extract, pre-treatment with methanol extract of liverwort markedly inhibited the expression of iNOS, COX-2, IL-6, and IL-1β at the concentration of 100 µg/mL with the exception of TNF-α. Further, liverwort extract markedly attenuated the production of TNF-α, IL-6, and IL-1β in the culture medium. In addition, ethyl acetate and butanol fractions obtained from the methanol extract of liverwort showed remarkable inhibitory activity against the production of NO in LPS-stimulated HaCaT cells. The LC-MS data revealed the presence of bisbibenzyl types of bioactive components in the methanol extract of liverwort. These data demonstrate that liverwort extract exhibits effective inhibitory activity against the production of inflammatory mediators in LPS-induced HaCaT cells and may be useful for the treatment of inflammation-mediated diseases.
... cava) is widely distributed at the southern coasts of Korea and Japan, and utilized to produce food ingredients, animal feed, fertilizers and folk medicine in gynecopathy and so on [15]. E. cava contains two potential medicinal ingredients: polysaccharide and unique polyphenol, called "phlorotannins" [16]. In particular, E. cava is a rich phlorotannins, and includes eckol, DK, 6,6-BK, and PHB, which are formed by the polymerization of phloroglucinol monomer units [17]. ...
Skeletal muscle is an important tissue in energy metabolism and athletic performance. The use of effective synthetic supplements and drugs to promote muscle growth is limited by various side effects. Moreover, their use is prohibited by anti-doping agencies; hence, natural alternatives are needed. Therefore, we evaluated the muscle growth effect of substances that can act like synthetic supplements from edible marine algae. First, we isolated six marine algal polyphenols belonging to the phlorotannin class, namely dieckol (DK), 2,7′′-phloroglucinol-6,6′-bieckol (PHB), phlorofucofuroeckol A (PFFA), 6,6′-bieckol (6,6-BK), pyrogallol-phloroglucinol-6,6′-bieckol (PPB), and phloroglucinol (PG) from an edible brown alga, Ecklonia cava and evaluated their effects on C2C12 myoblasts proliferation and differentiation. Of the six phlorotannin isolates evaluated, DK and PHB induced the highest degree of C2C12 myoblast proliferation. In addition, DK and PHB regulates myogenesis by down-regulating the Smad signaling, a negative regulator, and up-regulating the insulin-like growth factor-1 (IGF-1) signaling, a positive regulator. Interestingly, DK and PHB bind strongly to myostatin, which is an inhibitor of myoblast proliferation, while also binding to IGF-1 receptors. Moreover, they bind to IGF-1 receptor. These results suggest that DK and PHB are potential natural muscle building supplements and could be a safer alternative to synthetic drugs.
... Various reports on the anti-inflammatory and protective effects of phlorotannins are documented using RAW 264.7 macrophages induced by lipopolysaccharide (bacterial endotoxin). Phlorotannins were reported to inhibit the LPS-induced production of NO and PGE 2 via downregulation of NO synthase and COX-2 expression in LPS-induced RAW 264.7 murine macrophages (Barbosa et al., 2019;Jung et al., 2013;Yang et al., 2012Yang et al., , 2014. Furthermore, they reduced pro-inflammatory cytokine levels (IL-1β, IL-6, TNF-α), inhibited inflammatory mediators (iNOS and COX-2), transcriptional factors (NF-κB, nuclear translocation of p50 and p65 subunits and AP-1) and activated Akt and p38 MAPK signaling pathways (Lee, Kwon, et al., 2012). ...
Phlorotannins are polyphenolic compounds mostly found in brown seaweed and are comprised of polymeric chains of phloroglucinol residues (1,3,5-trihydroxybenzene) connected via C–C and/or C–O–C couplings. Due to the presence of highly complex polymeric mixtures of structural and conformational isomers of phlorotannins and the absence of available commercial phlorotannin standards, accurate chemical identification from extracts using MS/MS is difficult. Therefore, the optimal approach for identification of specific phlorotannins includes both NMR (1D and 2D) analysis coupled with HRMS. Herein, a library (1H and 13C) of the reported phlorotannins has been generated to assist with further identification. Additionally, a range of phlorotannins have been ascribed bioactivity and potential use as nutraceuticals and supplements, including trials of phlorotannin-rich extracts used as nutritional supplements in livestock feed to improve overall growth and condition. Bioactivity studies have identified neuroprotective, antidiabetic, anticancer, antioxidant, anti-inflammatory, antimicrobial and microbiome-beneficial properties, highlighting a multi-faceted potential of phlorotannins. Overall, the majority of such findings have been generated via biochemical and cell-based assays, with only a limited number of in vivo animal experiments conducted. Further preclinical and clinical studies will be required to comprehensively investigate bioavailability, efficacy and safety of phlorotannins, to further define the potential of these unique brown algal polyphenols in animal and human health.
... In particular, brown algae (Ecklonia cava, Eisenia arborea, Ecklonia stolinifera and Eisenia bicyclis) have been studied for this reason, as they are interesting sources of bioactive phenolic compounds [39]. Phlorotannins from brown algae exhibited anti-inflammatory effects on mouse ear edema and are considered particularly potent inhibitors of proinflammatory cytokines such as nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) and 6 (IL-6) [40]. ...
Marine resources exist in vast numbers and show enormous diversity. As a result, there are likely many possible applications for marine molecules of interest in the cosmetic industry, whether as excipients or additives, but especially as active substances. It is possible to obtain extracts from active substances; for example, quite a few algae species can be used in moisturizing or anti-ageing products. In the field of topical photoprotection, mycosporine-like amino acids and gadusol are important lines of enquiry that should not be overlooked. In the field of additives, the demonstration that certain seaweed (algae) extracts have antimicrobial properties suggests that they could provide alternatives to currently authorized preservatives. These promising leads must be explored, but it should be kept in mind that it is a long process to bring ingredients to market that are both effective and safe to use.
... In-vitro Through negative regulation of the NF-κB pathway, 6,6′ Bieckol down-regulated COX-2, iNOS, and pro inflammatory cytokines in LPS-stimulated macrophages. Yang et al. (2012) E. stolonifera ...
Seaweeds are among the significant currently exploited marine plant resources which are gaining full applications in culinary, cosmetic, pharmaceutical, and biotechnological processes. Much attention has been devoted to seaweeds based on their proven health benefits and is considered as a rich source of structurally different bioactive metabolites for the discovery of novel functional food-based pharmacophores/drugs. Nonetheless, there is still a dearth of updated compilation and analysis of the in-depth pharmacological activities of these compounds. This review, therefore, aims to provide a piece of up-to-date detailed information on the major compounds isolated from various seaweed species together with their in-vitro and in-vivo biological properties. These compounds were found to possess broad pharmacological properties and inhibitory enzyme activities against critical enzymes involved in the aetiology of noncommunicable diseases. However, their toxicity, clinical efficacy, mechanisms of action, and interaction with conventional foods, are still less explored and require more attention in future studies.
... The phlorotannins from Ecklonia cava (E. cava), is an edible brown seaweed and is found on coastal shore near Jeju, Korea have multiple biological activities, including anti-inflammatory [41,42], antioxidant [43], and anti-adipogenic [44]. In addition, E. cava-sourced phlorotannins have been reported to prevent EC death [45,46]. ...
It is well known that perivascular fat tissue (PVAT) dysfunction can induce endothelial cell (EC) dysfunction, an event which is related with various cardiovascular diseases. In this study, we evaluated whether Ecklonia cava extract (ECE) and pyrogallol-phloroglucinol-6,6-bieckol (PPB), one component of ECE, could attenuate EC dysfunction by modulating diet-induced PVAT dysfunction mediated by inflammation and ER stress. A high fat diet (HFD) led to an increase in the number and size of white adipocytes in PVAT; PPB and ECE attenuated those increases. Additionally, ECE and PPB attenuated: (i) an increase in the number of M1 macrophages and the expression level of monocyte chemoattractant protein-1 (MCP-1), both of which are related to increases in macrophage infiltration and induction of inflammation in PVAT, and (ii) the expression of pro-inflammatory cytokines (e.g., tumor necrosis factor-α (TNF-α) and interleukin (IL)-6, chemerin) in PVAT which led to vasoconstriction. Furthermore, ECE and PPB: (i) enhanced the expression of adiponectin and IL-10 which had anti-inflammatory and vasodilator effects, (ii) decreased HFD-induced endoplasmic reticulum (ER) stress and (iii) attenuated the ER stress mediated reduction in sirtuin type 1 (Sirt1) and peroxisome proliferator-activated receptor γ (PPARγ) expression. Protective effects against decreased Sirt1 and PPARγ expression led to the restoration of uncoupling protein -1 (UCP-1) expression and the browning process in PVAT. PPB or ECE attenuated endothelial dysfunction by enhancing the pAMPK-PI3K-peNOS pathway and reducing the expression of endothelin-1 (ET-1). In conclusion, PPB and ECE attenuated PVAT dysfunction and subsequent endothelial dysfunction by: (i) decreasing inflammation and ER stress, and (ii) modulating brown adipocyte function.
... Ecklonia cava is a brown alga that contains phlorotannins, polyphenolic compounds that have multiple biological activities including anti-inflammatory [12,13] and antioxidant activities [14]. One study has shown that polyphenol extract from E. cava attenuated renal inflammation induced by a high-fat diet by decreasing pro-inflammatory signaling via TNF-α and NF-κB [15]. ...
The hypoxia/reoxygenation (H/R) injury causes serious complications after the blood supply to the kidney is stopped during surgery. The main mechanism of I/R injury is the release of high-mobility group protein B1 (HMGB1) from injured tubular epithelial cells (TEC, TCMK-1 cell), which triggers TLR4 or RAGE signaling, leading to cell death. We evaluated whether the extracts of Ecklonia cava (E. cava) would attenuate TEC death induced by H/R injury. We also evaluated which phlorotannin—dieckol (DK), phlorofucofuroeckol A (PFFA), pyrogallol phloroglucinol-6,6-bieckol (PPB), or 2,7-phloroglucinol-6,6-bieckol (PHB)—would have the most potent effect in the context of H/R injury. We used for pre-hypoxia treatment, in which the phlorotannins from E. cava extracts were added before the onset of hypoxia, and a post- hypoxia treatment, in which the phlorotannins were added before the start of reperfusion. PPB most effectively reduced HMGB1 release and the expression of TLR4 and RAGE induced by H/R injury in both pre- and post-hypoxia treatment. PPB also most effectively inhibited the expression of NF-kB and release of the inflammatory cytokines TNF-α and IL-6 in both models. PPB most effectively inhibited cell death and expression of cell death signaling molecules such as Erk/pErk, JNK/pJNK, and p38/pp38. These results suggest that PPB blocks the HGMB1–TLR4/RAGE signaling pathway and decreases TEC death induced by H/R and that PPB can be a novel target for renal H/R injury therapy.
... Unique polyphenolic phlorotannins are a large class of well-characterized marine secondary metabolites. The phlorotannins from the E. cava have multiple biological activities such as anti-inflammatory [14,15], antioxidant [16], and antiadipogenic activities [17][18][19][20]. Phlorotannins (e.g., eckol, dieckol, and phlorofucofuroeckol A) have anti-obesity effects in zebrafish [17], mice [18][19][20], and cell cultures [21]. ...
Leptin resistance in the hypothalamus has an essential role in obesity. Saturated fatty acids such as palmitate bind to Toll-like receptor 4 (TLR4) and lead to endoplasmic reticulum (ER) stress and leptin resistance. In this study, we evaluated whether extracts of Ecklonia cava would attenuate the ER stress induced by palmitate and reduce leptin resistance in hypothalamic neurons and microglia. We added palmitate to these cells to mimic the environment induced by high-fat diet in the hypothalamus and evaluated which of the E. cava phlorotannins—dieckol (DK), 2,7-phloroglucinol-6,6-bieckol (PHB), pyrogallol-phloroglucinol-6,6-bieckol (PPB), or phlorofucofuroeckol-A (PFFA)—had the most potent effect on attenuating leptin resistance. TLR4 and NF-κB expression induced by palmitate was attenuated most effectively by PPB in both hypothalamic neurons and microglia. ER stress markers were increased by palmitate and were attenuated by PPB in both hypothalamic neurons and microglia. Leptin resistance, which was evaluated as an increase in SOCS3 and a decrease in STAT3 with leptin receptor expression, was increased by palmitate and was decreased by PPB in hypothalamic neurons. The culture medium from palmitate-treated microglia increased leptin resistance in hypothalamic neurons and this resistance was attenuated by PPB. In conclusion, PPB attenuated leptin resistance by decreasing ER stress in both hypothalamic neurons and microglia.
... . Moreover, 6,6 0 -bieckol and dieckol isolated from E. cava phlorotannins have been shown antiinflammatory activitiesYang et al., 2012). Regarding ...
Prolonged endotracheal intubation is the most common cause of tracheal stenosis, which may lead to serious airway obstruction. Development of an endotracheal tube coated with biomaterials that exhibit anti‐inflammatory or anti‐fibrogenic effects may prevent tracheal stenosis. This study demonstrates that an endotracheal tube coated with phlorotannin, which is present in extracts of the brown alga Ecklonia cava, can prevent tracheal stenosis in a rabbit model. An in vitro study shows that phlorotannin inhibits proliferation of human tracheal fibroblasts treated with transforming growth factor β1. Phlorotannin‐coated endotracheal tubes show steady release of phlorotannin for up to 7 days, and removal of the tube 1 week after insertion reveals a reduction in both fibrogenesis and thickening of tracheal submucosa. Western blot analysis of tracheal tissues after removal of the phlorotannin‐coated tube shows decreased protein expression levels of phenotypic markers of fibrosis such as collagen type I and α‐smooth muscle actin. The ability of phlorotannin‐coated endotracheal tube to prevent tracheal stenosis caused by endotracheal intubation indicates that phlorotannin may be considered as a candidate biomaterial for coating the cuff of endotracheal tubes to prevent tracheal stenosis.
... 6 Besides, 6,6′-bieckol exerts anti-inflammatory activity by downregulating iNOS, COX-2, and pro-inflammatory cytokines in LPS-stimulated macrophages through the NF-κB pathway. 7 Thus, phlorotannins have attracted much attention as anti-inflammatory agents. Phlorotannins are structurally diverse and more than 150 are known. ...
Trifuhalol A, a phlorotannin, was extracted from Agarum cribrosum with ethyl acetate and fractionated using Sephadex LH-20 column chromatography (SF1-SF6). The ethyl acetate fraction (EAF) and SF5-containing trifuhalol A exhibited strong inhibitory activity against hyaluronidase. The anti-inflammatory activity of the phlorotannin, EAF, and SF5 was determined through the inhibition of nitric oxide (NO) production in lipopolysaccharide-stimulated RAW264.7 cells. Furthermore, the inhibition of NO production was validated by confirming the appreciable downregulation of inducible nitric oxide synthase expression. Agarum cribrosum phlorotannin also markedly suppressed the expression of cyclooxygenase-2, interleukin (IL)-1β, IL-6, and tumor necrosis factor-α. In addition, the anti-inflammatory action was verified by examining its effects on proinflammatory signaling pathways. The activation of nuclear factor (NF)-κB and mitogen-activated protein kinases (MAPKs) was attenuated via the inhibition of NF-κB p-65, c-Jun N-terminal kinase, extracellular signal-regulated kinase 1/2, and p38 MAPK phosphorylation. Therefore, trifuhalol A is a potential source for either the prevention or the treatment of inflammation.
... Moreover, the phlorotannin-rich the fermented E. cava processing by-product extract was reported to inhibit NO and PGE 2 production, suppress the inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions, and attenuate interleukin-1β and interleukin-6 production in lipopolysaccharide stimulated RAW 264.7 cells 119 . Recently, phlorotannin 6,6'-bieckol from E. cava was found to inhibit NO and PGE 2 production by suppressing the expression of iNOS and COX-2 at the mRNA and protein levels in LPS-stimulated primary macrophages and RAW 264.7 macrophage cells 120 . Moreover, 6,6'-bieckol down-regulated the production and mRNA expression of the inflammatory cytokines TNF-α and IL-6. ...
... The open-chain trimeric phlorotannin, eckol, reduces H 2 O 2 -induced oxidative stress by increasing catalase expression in Chinese hamster lung fibroblast cells (V79-4) [9]. The hexameric phlorotannin, 6, 6'-bieckol strongly inhibits production of pro-inflammatory mediators such as iNOS and COX-2 and shows anti-inflammatory effect [10]. In addition, E. cava ethanol extract (ECE) has neuroprotective effects in BV2 microglia cells [11]. ...
Ecklonia cava, an edible marine brown alga (Laminariaceae), is a rich source of bioactive compounds such as fucoidan and phlorotannins. Ecklonia cava extract (ECE) was prepared using 70% ethanol extraction and ECE contained 67% and 10.6% of total phlorotannins and dieckol, respectively. ECE treatment significantly inhibited receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation of RAW 264.7 cells and pit formation in bone resorption assay (p ＜0.05). Moreover, it suppressed RANKL-induced NF-κB and mitogen-activated protein kinase signaling in a dose dependent manner. Downregulated osteoclast-specific gene (tartrate-resistant acid phosphatase, cathepsin K, and matrix metalloproteinase-9) expression and osteoclast proliferative transcriptional factors (nuclear factor of activated T cells-1 and c-fos) confirmed ECE-mediated suppression of osteoclastogenesis. ECE treatment (100 μg/ml) increased heme oxygenase-1 expression by 2.5-fold and decreased intercellular reactive oxygen species production during osteoclastogenesis. The effective inhibition of RANKL-stimulated osteoclast differentiation and oxidative stress by ECE suggest that ECE has therapeutic potential in alleviating osteoclast-associated disorders.
... This activation may be due to the fact that both species contain chemical compounds with pro-and anti-inflammatory properties, attributed to their great diversity of metabolites of different natures [61]. Other studies have shown that seaweed extracts increase the phagocity and secretion activity of macrophages [62,63]. Extracts of the red algae Porphyra yezoensis have been shown to induce the production of TNF-α both in vitro and in vivo for murine macrophages [64]. ...
This study was designed to evaluate the potential use of algal extracts in cosmeceuticals, including factors related to biosecurity. The aqueous crude extracts of Hydropuntia cornea and Gracilariopsis longissima showed a good photoprotective capacity (Sun Protection Factor, SPF) due to, among other reasons, the presence of five types of mycosporine-like amino acids (MAAs) detected by high pressure liquid chromatography-photodiode array detector (HPLC-PDA) and electrospray ionization mass spectrometry (ESI-MS) (Palythine, Asterina-330, Shinorine, Porphyra-334, and Palythinol). The toxicity of the extracts was evaluated by the MTT assay, which is based on the metabolic reduction of MTT [3-(4,5-dimethylthiazol-2yl)-diphenyl tetrazolium bromide] by the action of the mitochondrial enzyme succinate dehydrogenase. This assay was carried out in vitro in three cell lines: one related to the immune system (murine macrophages of the immune system: RAW264.7) and two human cell lines related to the skin (gingival fibroblasts: HGF, and immortalized human keratinocytes: HaCaT). Both extracts showed no cytotoxic activity in both types of human cells, whereas they showed cytotoxicity in murine tumor cells of the immune system (macrophages: RAW264.7). On the other hand, the immunological activity in the murine macrophage RAW264.7 was studied at a concentration lower than 100 μg mL−1 and lower than the EC50, and evaluated by the production of pro-inflammatory compounds through an immunosorbent assay linked to enzymes such as tumor necrosis factor-α (TNF-α) or anti-inflammatory/proinflammatory enzymes such as interleukin-6 (IL-6). Both algae extracts induced the biosynthesis of TNF-α and IL-6. The production of TNF-α was much higher than that observed in the control (at a concentration of the aqueous extract higher than 5 μg mL−1). These results support the theory that the extracts of H. cornea and G. longissima actively induce the production of cytokines. In summary, the extracts of these species did not show cytotoxicity in human cells, and they present with immunomodulatory and photoprotection capacity.
... Our previous study shown the 4 compounds identified using 1 H NMR and 13 C NMR and HPLC-DAD-ESI/MS (negative ion mode) analyses [16] and each chemical structure shown in Figure 1. Previous studies on various biological properties of phlorotannins including anti-oxidant [17], anti-inflammation [18], anti-neurodegeneration [19], anti-cancer [20,21], and anti-cardiovascular diseases [22] of E. cava extract have shown. Among numerous properties, anti-oxidant activities of E. cava phlorotannins extract on reactive oxygen species (ROS) have shown it exhibits radical scavenging activity against oxidized low-density lipoprotein (ox-LDL), 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, and peroxynitrite [14,16,17] and these anti-oxidant activities closely related with other beneficial effects of E. cava. ...
Ecklonia cava (E. cava) can alleviate vascular dysfunction in diseases associated with poor circulation. E. cava contains various polyphenols with different functions, but few studies have compared the effects of these polyphenols. Here, we comparatively investigated four major compounds present in an ethanoic extract of E. cava. These four major compounds were isolated and their effects were examined on monocyte-associated vascular inflammation and dysfunctions. Pyrogallol-phloroglucinol-6,6-bieckol (PPB) significantly inhibited monocyte migration in vitro by reducing levels of inflammatory macrophage differentiation and of its related molecular factors. In addition, PPB protected against monocyte-associated endothelial cell death by increasing the phosphorylations of PI3K-AKT and AMPK, decreasing caspase levels, and reducing monocyte-associated vascular smooth muscle cell proliferation and migration by decreasing the phosphorylations of ERK and AKT. The results of this study show that four compounds were effective for reduction of monocyte-associated vascular inflammation and dysfunctions, but PPB might be more useful for the treatment of vascular dysfunction in diseases associated with poor circulation.
... 6,14,38,39 This is an adequate model for screening new substances with anti-inflammatory potential and for evaluating inhibitors of pathways that lead to the induction of pro-inflammatory enzymes and cytokines. 40 ...
The aim of this study was to evaluate in vitro the antifungal, antibiofilm and antiproliferative activities of the extract from the leaves of Guapira graciliflora Mart. The phytochemical characterization of the extract was performed using electrospray ionization mass spectrometry (ESI-MS). The antimicrobial activity of the extract and its fractions was evaluated using the broth microdilution method against species of Candida. The inhibition of C. albicans biofilm was evaluated based on the number of colony-forming units (CFU) and metabolic activity (MTT). The antiproliferative activity of the extract and its fraction was evaluated in the presence of human tumor and non-tumor cells, and the cytotoxicity of the extract was determined on the RAW 264.7 macrophage line – both using the sulforhodamine B method. The phytochemical characterization indicated the presence of the flavonoids rutin and kaempferol. The extract and the methanol fraction exhibited moderate antifungal activity against C. albicans, C. krusei, and C. glabrata, and strong activity against C. dubliniensis. In the biofilms at 24 and 48 hours, the concentration of 12500 µg/mL of the extract was the most effective at reducing the number of CFU s/mL (44.4% and 42.9%, respectively) and the metabolic activity of C. albicans cells (34.6% and 52%, respectively). The extract and its fractions had no antiproliferative effect on the tumor lines tested, with mean activity (log GI50) equal to or greater than 1.71 µg/mL. Macrophage cell viability remained higher than 80% for concentrations of the extract of up to 62.5 µg/mL. G. graciliflora has flavonoids in its chemical composition and demonstrates potential antifungal and antibiofilm activity, with no evidence of a significant change in the viability of human tumor and non-tumor cell lines.
... This is related with the immune defense capacity of the body and, consequently, many diseases. In this regard, positive results for some bioactive compounds of algae are found as important [30,[56][57][58] . ...
Researches on novel marine compounds has increased over the past decades in various areas such as medical, veterinary, pharmaceutical, cosmetics or bioenergy. Some compounds isolated from marine algae were revealed to have anti-aging, anti-cancer, anti-coagulant, anti-inflammatory, anti-microbial, anti-oxidant, anti-diabetic, anti-Alzheimer and anti-tuberculose activities. Algal secondary metabolites such as fatty acids, lipopeptides, alkaloids, steroids, terpenoids and most carotenoids, flavonoids with different potent activity have the potential to be produced commercially using bio-engineering techniques. This review provides an overview of novel publications related to the developments in these topics.
... Phlorotannins, which are polyphenol components of E. cava, have been isolated and demonstrated to include fucodiphlorethol G, eckol, 8-8'-bieckol, dieckol, eckstolonol, phlorofucofuroeckol A, phloroglucinol and dioxinodehydroeckol (31)(32)(33). Studies on E. cava have demonstrated its anti-inflammatory (24,34,35), anti-oxidative (22)(23)(24)(25)32,(36)(37)(38)(39), anti-bacterial (40,41), anti-cancer (42)(43)(44) and hair growth (45,46) effects as well as its actions against Alzheimer's disease (47,48). ...
The present study investigated the anti‑obesity effects of enzyme‑treated Ecklonia cava extract (EEc) in C57BL/6N mice with high‑fat diet (HFD)‑induced obesity. The EEc was separated and purified with the digestive enzymes pectinase (Rapidase X‑Press L) and cellulase (Rohament CL) and its effects on the progression of HFD‑induced obesity were examined over 10 weeks. The mice were divided into 6 groups (n=10/group) as follows: Normal diet group, HFD group, mice fed a HFD with 25 mg/kg/day Garcinia cambogia extract and mice fed a HFD with 5, 25 or 150 mg/kg/day EEc (EHD groups). Changes in body weight, fat, serum lipid levels and lipogenic enzyme levels were determined. The body weight and liver weight were increased in the HFD group compared with those in the ND group, which was significantly reduced by EEc supplementation. In addition, significant reductions in epididymal, perirenal and mesenteric white adipose tissues were present in the EHD groups and all three EHD groups exhibited decreases in insulin, leptin and glutamate pyruvate transaminase levels compared with those in the HFD group. In addition, EEc treatment significantly decreased the serum and hepatic triglyceride levels compared with those in the HFD group. However, the levels of high‑density lipoprotein cholesterol/total cholesterol ration increased significantly in EHD‑25 and ‑150 groups compared with those in the HFD group. Changes in adipogenic and lipogenic protein expression in the liver was assessed by western blot analysis. The EHD‑25 and -150 groups exhibited reduced levels of CCAAT/enhancer‑binding protein α and peroxisome proliferator activated receptor γ. However, the phosphorylation ratios of AMP‑activated protein kinase and acetyl‑CoA carboxylase were significantly increased in the liver tissue obtained from the EHD (5, ‑25 and ‑150 mg/kg/day) groups compared with those in the HFD group. EEc supplementation reduced levels of sterol regulatory element‑binding protein‑1c, adipose fatty acid‑binding protein, fatty acid synthase and leptin, while it significantly increased glucose transporter type 4 and adiponectin protein levels in the liver tissues of all three EHD groups compared with those in the HFD group. Taken together, these results suggest that EEc exerts anti‑obesity effects by reducing body weight and the serum and hepatic levels of obesity‑associated factors. Thus, EEc supplementation reduces HFD‑induced obesity in C57BL/6N mice and has the potential to prevent obesity and subsequent metabolic disorders.
... RAW 264.7 is a murine macrophage cell line chosen for in vitro studies of mechanism of action as it has been proven to be an excellent model for screening anti-inflammatory drugs and consequent evaluation of inhibitors of the signaling pathways that lead to induction of pro-inflammatory mediators [26][27][28][29]. ...
In the last decades, a growing need to discover new compounds for the prevention and treatment of inflammatory diseases has led researchers to consider drugs derived from natural products as a valid option in the treatment of inflammation-associated disorders. The purpose of the present study was to investigate the anti-inflammatory effects of a new formulation of Moringa oleifera-derived 4-(α-L-rhamnopyranosyloxy)benzyl isothiocyanate as a complex with alpha-cyclodextrin (moringin + α-CD) on lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophage cells, a common model used for inflammation studies. In buffered/aqueous solution, the moringin + α-CD complex has enhanced the water solubility and stability of this isothiocyanate by forming a stable inclusion system. Our results showed that moringin + α-CD inhibits the production of inflammatory mediators in LPS-stimulated macrophages by down-regulation of pro-inflammatory cytokines (TNF-α and IL-1β), by preventing IκB-α phosphorylation, translocation of the nuclear factor-κB (NF-κB), and also via the suppression of Akt and p38 phosphorylation. In addition, as a consequence of upstream inhibition of the inflammatory pathway following treatment with moringin + α-CD, the modulation of the oxidative stress (results focused on the expression of iNOS and nitrotyrosine) and apoptotic pathway (Bax and Bcl-2) was demonstrated. Therefore, moringin + α-CD appears to be a new relevant helpful tool to use in clinical practice for inflammation-associated disorders.
... DHE was found to increase phosphorylated Smad (p-Smad) in differentiating MC3T3-E1 cells, suggesting that the effect of DHE on osteoblastogenesis may be in relation to the activation of the BMP signaling pathway. On the other hand, non-Smad pathways have also been shown to be activated in BMP-induced osteoblastogenesis [26,27]. Moreover, ERK and JNK pathways are also activated during osteoblastogenesis by BMP signaling in a Smad-independent way, along with the elevated levels of phosphorylated ERK, JNK, and Rux-2 proteins [28]. ...
Lack of bone formation-related health problems are a major problem for the aging population in the modern world. As a part of the ongoing trend of developing natural substances that attenuate osteoporotic bone loss conditions, dioxinodehydroeckol (DHE) from edible brown alga Ecklonia cava was tested for its effects on osteoblastogenic differentiation in MC3T3-E1 pre-osteoblasts. DHE was observed to successfully enhance osteoblast differentiation, as indicated by elevated cell proliferation, alkaline phosphatase activity, intracellular cell mineralization, along with raised levels of osteoblastogenesis indicators at the concentration of 20 ?M. Results suggested a possible intervening of DHE on the bone morphogenetic protein (BMP) signaling pathway, according to elevated protein levels of BMP-2, collagen-I, and Smads. In addition, the presence of DHE was also able to raise the phosphorylated extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK) levels which are also activated by the BMP signaling pathway. In conclusion, DHE is suggested to be a potential bioactive compound against bone loss that could enhance osteoblastogenesis with a suggested BMP pathway interaction.
... Many of the diverse marine organisms are rich natural sources for structurally unique and biologically active chemicals [1]. Recent in vitro studies have identified various biological functions for compounds derived from brown algae, including antioxidant [2], anti-inflammatory [3,4], antibacterial [5], anti-HIV [6], and anti-allergic [7] properties. Such findings suggest that brown algae species may be a novel source of pharmacophores that have the potential to serve as therapy for an array of human diseases. ...
Long-term cigarette smoking increases the risk for chronic obstructive pulmonary disease (COPD), characterized by irreversible expiratory airflow limitation. The pathogenesis of COPD involves oxidative stress and chronic inflammation. Various natural marine compounds possess both anti-oxidant and anti-inflammatory properties, but few have been tested for their efficacy in COPD models. In this study, we conducted an in vitro screening test to identify natural compounds isolated from various brown algae species that might provide protection against cigarette smoke extract (CSE)-induced cytotoxicity. Among nine selected natural compounds, apo-9′-fucoxanthinone (Apo9F) exhibited the highest protection against CSE-induced cytotoxicity in immortalized human bronchial epithelial cells (HBEC2). Furthermore, the protective effects of Apo9F were observed to be associated with a significant reduction in apoptotic cell death, DNA damage, and the levels of mitochondrial reactive oxygen species (ROS) released from CSE-exposed HBEC2 cells. These results suggest that Apo9F protects against CSE-induced DNA damage and apoptosis by regulating mitochondrial ROS production.
Allelochemicals are secondary metabolites which function as a natural protection against grazing activities by algae and higher plants. They are one of the major metabolites engaged in the interactions of organisms. The chemically mediated interactions between organisms significantly influence the functioning of the ecosystems. Most of these compounds are secondary metabolites comprising sterols, terpenes, and polyphenols. These compounds not only play a defensive role, but also exhibit biological activities such as antioxidants, anti-cancer, anti-diabetes, anti-inflammation, and anti-microbial properties. This review article discusses the current understanding of the allelochemicals of seaweeds and their bioprospecting potential that can bring benefit to humanity. Specifically, the bioactive substances having specific health benefits associated with the consumption or application of seaweed-derived compounds. The properties of such allelochemicals can have implications for bioprospecting pharmaceutical, nutraceutical and cosmetic applications.
This study aimed to elucidate the anti-inflammatory activity of C. tinctorius leaves by measuring inflammatory parameters such as nitric oxide (NO) production and mRNA expression of iNOS, interleukin-6 (IL-6), and IL-1β in lipopolysaccharide (LPS)-induced HaCaT cells. Further, the effect of C. tinctorius ethanol extract on the MAPKs/NF-κB signaling pathway was examined in HaCaT cells. The phytochemical profile of the ethanol extract of C. tinctorius leaves was determined using UPLC-QTOF-MS/MS. The results indicated that the ethanol extract of C. tinctorius effectively attenuated LPS-induced secretion of NO, IL-6, and IL-1β in HaCaT cells. Further, LPS-stimulated mRNA and protein expressions of iNOS were decreased by pre-treatment with C. tinctorius ethanol extract at the transcriptional level in HaCaT cells. Moreover, the ethanol extract of C. tinctorius suppressed NF-κB signaling in LPS-induced HaCaT cells. This suppression was mediated by MAPKs/NF-κB signaling, inhibiting the phosphorylation of p38 and p65 in HaCaT cells. However, there is no significant effect on the phosphorylation of JNK by the ethanol extract. The QTOF-MS/MS analysis revealed the identification of 27 components in the ethanol extract of C. tinctorius leaves. The data demonstrate that the ethanol extract of C. tinctorius leaves protects the LPS-induced HaCaT cells by inhibiting the expression of iNOS, IL-6, and IL-1β and suppressing the phosphorylation of the p38, p65, p-JNK via inactivation of MAPKs/NF-κB signaling pathway. These results demonstrate that C. tinctorius leaves may serve as a potential candidate to prevent inflammation-related diseases.
PRIMER SIMPOSIO INTERNACIONAL DE CIENCIAS FARMACÉUTICAS Y ALIMENTARIAS: “Identificando propuestas para la solución de problemas prioritarios de los sectores farmacéutico y alimentario”. PRESENTACIÓN En la ciudad de Medellín - Colombia, en el marco de la celebración de la XV Reunión de la Comisión Permanente Conferencia Ibero-americana de Facultades de Farmacia (COIFFA), a realizarse el 26 de septiembre de 2012 y a la cual asistirán un número importante de Decanos de las Facultades de Farmacia de Ibero-América, la Facultad de Química Farmacéutica de la Universidad de Antioquia y el Colegio Nacional de Químicos Farmacéuticos de Colombia, regional Antioquia (AQUIFAR) nos hemos comprometido con la realización del Primer Simposio Internacional de Ciencias Farmacéuticas y Alimentarias: “Identificando propuestas para la solución de problemas prioritarios de los sectores farmacéutico y alimentario”, evento que se realizará del 27 al 29 de septiembre de 2012. El Comité Académico ha estructurado un programa que pretende presentar los avances y novedades nacionales e internacionales relacionados con las ciencias farmacéuticas y alimentarias. Para tal fin, como ponentes participarán líderes académicos e investigadores nacionales e internacionales, reconocidos por sus aportes al avance en el estado del arte de las temáticas definidas para cada uno de los sectores. En este sentido, se desarrollarán 4 conferencias plenarias de interés común para los sectores farmacéutico y alimentario, 4 mesas de debate específicas en los ejes temáticos definidos en cada uno de los dos sectores, 1 mesa orientada a la formación farmacéutica y alimentaria, y 11 presentaciones de trabajos de investigación y/o avances. Con ello, el Comité Académico busca favorecer la definición de propuestas para la solución de problemas prioritarios de los sectores farmacéutico y alimentario en Ibero-América, en especial en el contexto latinoamericano. Sector Farmacéutico • Producción, regulación y comercialización de Productos biológicos y biotecnológicos. • Investigación y obtención de sustancias de interés farmacéutico. • Diseño y desarrollo de medicamentos. • Utilización adecuada de medicamentos. Sector Alimentario • Nanotecnología y su aplicación en alimentos. • Compuestos bioactivos de interés alimentario. • Nuevas Tecnologías en transformación y procesamiento de alimentos. • Globalización Alimentaria: Un reto para todos Sector Farmacéutico - Alimentario: Educación Farmacéutica y Alimentaria. Pedro Amariles Doctor en Farmacia (homologado a Doctor en Farmacología en Colombia) Profesor Universidad de Antioquia. Responsable del Grupo de Investigación Promoción y Prevención Farmacéutica. Universidad de Antioquia, Medellín.
Acute lung injury (ALI), a clinical syndrome of acute respiratory failure due to acute lung inflammation, remains a substantial public health problem in the worldwide. Ligusticum Chuanxiong Rhizoma and Angelicae Sinensis Radix was herb-pair of the traditional Chinese medicine. Modern pharmacological studies have shown that volatile oil extracted from Chuanxiong Rhizome and Angelicae Sinensis Radix is identified as an important active ingredient, which has good antipyretic, analgesic and anti-inflammatory effects. However, whether their volatile oil combination (CA-VO), has effects on the prevention and treatment of ALI has not been reported yet. Due to poor water solubility and low oral bioavailability of CA-VO, CA -VO-loaded microemulsion (CA-VO-ME) was formulated to enhance its oral bioavailability. The physical properties of CA-VO-ME were characterized. The pharmacokinetic parameters and the effect on ALI were evaluated. The particle size, polydispersity index, zeta potential, and encapsulation efficiency of CA-VO-ME were 20.19 ± 0.08 nm, 0.091 ± 0.01, 36.33 ± 4.29%, and 93.75%, respectively. CA-VO-ME had a greater bioavailability (214%) than CA-VO. CA-VO-ME reduced the lipopolysaccharide (LPS)-induced increase in levels of nitric oxide (NO), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1β (IL-1β), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) in vitro and/or in vivo. Moreover, CA-VO-ME treatment notably decreased the lung index, ameliorated histopathological changes and prolonged the survival of ALI mice. By comparison, CA-VO-ME exerted a better effect on ALI than CA-VO, suggesting that CA-VO-ME is a promising drug for the treatment of ALI.
Phlorotannins are known to possess several therapeutic properties such as anti‐inflammatory and anti‐oxidant effects, both of which are related to prevent tissue adhesion. Therefore, this study sought to fabricate phlorotannin‐coated PCL films for the prevention of post‐surgical adhesion. Phlorotannin‐coated PCL films were fabricated via the solvent casting and coating methods. After which the fabricated film was characterized using water contact angle analysis, Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA), and drug release ability analysis. Furthermore, the anti‐inflammatory and cell proliferation‐inhibiting properties of the fabricated film were assessed in LPS‐stimulated RAW264.7 macrophage cells and NHDF‐neo cells using the nitric oxide production assay, the WST‐1 assay kit, and Hoechst 33342 dye. The results indicated that the phlorotannin‐coated PCL film significantly inhibited nitric oxide production and reduced NHDF‐neo cell proliferation. These results suggest that phlorotannin‐coated PCL films constitute a promising anti‐adhesive bioactive compound with applicability in the field of DDSs.
Nonalcoholic fatty liver disease (NAFLD), which promotes serious health problems, is related to the increase in the nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome and pyroptosis by a high-fat diet (HFD). Whether dieckol (DK), a component of Ecklonia cava extracts (ECE), attenuated NAFLD in an HFD-induced NAFLD animal model was evaluated. The expression of high mobility group box 1/Toll-like receptor 4/nuclear factor-κB, which initiated the NLRP3 inflammasome, was increased in the liver of HFD-fed animals and significantly decreased with ECE or DK administration. The expression of NLRP3/ASC/caspase-1, which are components of the NLRP3 inflammasome, and the number of pyroptotic cells were increased by HFD and decreased with ECE or DK administration. The accumulation of triglycerides and free fatty acids in the liver was increased by HFD and decreased with ECE or DK administration. The histological NAFLD score was increased by HFD and decreased with ECE or DK administration. The expression of lipogenic genes (FASN, SREBP-2, PPARγ, and FABP4) increased and that of lipolytic genes (PPARα, CPT1A, ATGL, and HSL) was decreased by HFD and attenuated with ECE or DK administration. In conclusion, ECE or DK attenuated NAFLD by decreasing the NLRP3 inflammasome and pyroptosis.
Inflammation and Natural Products brings together research in the area of the natural products and their anti-inflammatory action in medical, nutraceutical and food products, addressing specific chronic inflammatory diseases like cancer and the mechanistic aspects of the mode of action of some key natural products. Inflammation is a complicated process, driven by infection or injury or genetic changes, which results in triggering signalling cascades, activation of transcription factors, gene expression, increased levels of inflammatory enzymes, and release of various oxidants and pro-inflammatory molecules in inflammatory cells. Excessive oxidants and inflammatory mediators have a harmful effect on normal tissue, including toxicity, loss of barrier function, abnormal cell proliferation, inhibiting normal function of tissues and organs and finally leading to systemic disorders. The emerging development of natural product formulations utilizing the unique anti-inflammatory compounds such as polyphenols, polysaccharides, terpenes, fatty acids, proteins and several other bioactive components has shown notable successes. Inflammation and Natural Products: Recent Development and Current Status provides a comprehensive resource, ranging from detailed explanation on inflammation to molecular docking strategies for naturally occurring compounds with anti-inflammatory activity. It is useful for graduate students, academic and professionals in the fields of pharmaceutical and medical sciences and specialists from natural product-related industries.
Inflammation is considered as an adaptive response to stimuli like injury or infection. But prolonged or chronic inflammation is capable of causing damage and is proved to be the trigger behind many diseases. So the mechanisms are extensively studied to get a grip on the control over them. There unveiled the multiverse of mechanisms, which raised the requirement of multitarget drugs, than “one target-one drug” concept. Synthetic drugs are invented to meet the purpose but mostly associated with considerable side effects. So the natural compounds with the multitarget approach have become the needs of the time. The current chapter discusses multiple targets involved in the inflammation events and some significant natural compounds that exhibit multitarget perspective on antiinflammatory activities.
Aging is a major risk factor for many chronic diseases, such as cancer, cardiovascular disease, and diabetes. The exact mechanisms underlying the aging process are not fully elucidated. However, a growing body of evidence suggests that several pathways, such as sirtuin, AMP-activated protein kinase, insulin-like growth factor, autophagy, and nuclear factor erythroid 2-related factor 2 play critical roles in regulating aging. Furthermore, genetic or dietary interventions of these pathways can extend lifespan by delaying the aging process. Seaweeds are a food source rich in many nutrients, including fibers, polyunsaturated fatty acids, vitamins, minerals, and other bioactive compounds. The health benefits of seaweeds include, but are not limited to, antioxidant, anti-inflammatory, and anti-obese activities. Interestingly, a body of studies shows that some seaweed-derived extracts or isolated compounds, can modulate these aging-regulating pathways or even extend lifespans of various animal models. However, few such studies have been conducted on higher animals or even humans. In this review, we focused on potential anti-aging bioactive substances in seaweeds that have been studied in cells and animals mainly based on their anti-aging cellular and molecular mechanisms.
The world’s oceans represent an enormous resource for the discovery of potential therapeutic agents. During the last decades, numerous novel compounds have been isolated from marine organisms and many of them have been applied for phamacological industry. Notably, marine algae are known to be one of the most important producers of variety of chemically active metabolites. Among them, phlorotannins, a polyphenol from brown algae, have been revealed to possess numerous biological activities such as UV-protective, anti-oxidant, anti-viral anti-allergic, anti-cancer, anti-inflammatory, anti-diabetes, and anti-obesity activities. Therefore, phlorotannins are considered as promising agents for the development of pharmaceuticals. This contribution focuses on phlorotannins from brown algae and presents an overview of their biological activities and health benefit effects.
α-Glucosidase is an enzyme that plays a key role in raising blood sugar level and is considered a good target for developing drugs to treat type 2 diabetes. This study was performed to evaluate the inhibition of the catalytic reaction of α-glucosidase by minor phlorotannin derivatives (1–5) from Ecklonia cava. These derivatives demonstrated inhibitory activity, with IC50 values ranging from 2.3 ± 0.1 to 59.8 ± 0.8 μM. Among the phlorotannins identified, compounds 2 and 3–5 were revealed to be non-competitive and competitive inhibitors, respectively. Furthermore, a fluorescence-quenching study of receptor–ligand binding was performed to calculate the kinetic parameters (Ksv, Kq, and K). These signal data indicated a 1:1 ratio of ligand–receptor binding. The binding conformations of the phlorotannin ligands were visually solved through molecular simulation. In conclusion, these minor phlorotannins may serve as α-glucosidase inhibitors targeted for the treatment of type 2 diabetes.
Introduction: the red alga Galaxaura rugosa (J. Ellis & Solander) J.V. Lamouroux (Galaxauraceae) is one of the most abundant species on the rocky platform of the Cuban coral reef. However, little is known about its pharmacological properties. Objectives: evaluate the anti-inflammatory and analgesic activity of a dichloromethane extract from the red alga G. rugosa and determine the phytochemical composition of the species. Methods: the algae were collected from the northern coast of Havana. Phytochemical characterization of the alga was performed using Chabra's method. The extract was obtained with a Soxhlet device with dichloromethane at 40 ºC. Topical anti-inflammatory activity was studied with the croton oil ear edema test model in male OF-1 mice at doses of 10*10-3, 0.125, 0.25, 0.5, 1 and 2 mg/ear. The analgesic activity of the extract was evaluated on a model of writhing induced by 0.8 % acetic acid administered intraperitoneally (i.p.) at doses of 3, 6, 12.5, 25 and 100 mg/kg. Results: phytochemical analysis of G. rugosa revealed the presence of fatty, lactonic, triterpenic and/or steroidal compounds, as well as carbohydrates. The dichloromethane extract of G. rugosa at the dose of 0.125 mg/ear displayed a potent anti-inflammatory activity (above 40 %). The extract reduced writhing by more than 75 % with a dose of 6 mg/kg. Conclusions: results show that dichloromethane extract of the red alga G. rugosa is composed of a mixture of compounds capable of inhibiting the acute inflammatory response and the pain induced by chemical agents with a high pharmacological efficacy.
In the present study, the effects of 6,6′-bieckol isolated from Ecklonia cava on angiotensin I-converting enzyme (ACE) inhibition and nitric oxide (NO) production, and the inhibitor’s binding modes using the crystal structure of ACE were examined. The effects of 6,6′-bieckol on systolic blood pressure (SBP) after meals were also investigated. We predicted the 3D structure of ACE and used a docking algorithm to understand the binding between ACE and 6,6′-bieckol. The molecular docking study revealed that ACE inhibitory activity of 6,6′-bieckol was mainly attributed to the hydrogen bond interactions (Lys454, His353, Glu162, Glu376, Glu384 and Glu411) and Pi interactions (Lys511 and His513) between ACE and 6,6′-bieckol. 6,6′-bieckol significantly increased the production of nitric oxide (NO) and by phosphorylating endothelial nitric oxide synthase (eNOS) in human endothelial cells. Furthermore, antihypertensive effect in spontaneously hypertensive rats (SHRs) also revealed that oral administration of the compound can down-regulate (28.6 mmHg in 6 h) systolic blood pressure (SBP).
The abundance and activation of macrophages in the inflamed synovial membrane/pannus significantly correlates with the severity of rheumatoid arthritis (RA). Although unlikely to be the 'initiators' of RA (if not as antigen-presenting cells in early disease), macrophages possess widespread pro-inflammatory, destructive, and remodeling capabilities that can critically contribute to acute and chronic disease. Also, activation of the monocytic lineage is not locally restricted, but extends to systemic parts of the mononuclear phagocyte system. Thus, selective counteraction of macrophage activation remains as efficacious approach to diminish local and systemic inflammation, as well as to prevent irreversible joint damage. AP = activator protein; BST = bone marrow stromal antigen; DMARD = disease-modifying antirheumatic drug; EBER(s) = Epstein-Barr virus-encoded small nuclear RNA(s); GM-CSF = granulocyte–macrophage colony-stimulating factor; GRO = growth-related oncogene protein; HLA = human leucocyte antigen; MCP = monocyte chemoattractant protein; MIP = macrophage inflammatory protein; NF-κB = nuclear factor-κB; NO = nitric oxide; RA = rheumatoid arthritis; TGF = transforming growth factor; Th = T-helper (cell); TIMP = tissue inhibitor of metalloproteinase; TNF = tumour necrosis factor.
Psoralea corylifolia (PC) is an herb widely used in medicine for the treatment of a variety of ailment. PC is also known to have immunomodulatory activity. However, its mechanism of action is not known. In the present study we investigated effect of PC on nitric oxide (NO) and tumour necrosis factor-alpha (TNF-alpha) production in mouse peritoneal macrophages and also examined the mechanism by which PC regulates NO production.
MTT assay performed for cell viability test and nitrite concentration was measured by using Griess reagent. The amount of TNF-alpha secreted by the cells was measured by a modified enzyme-linked immunosorbent assay (ELISA). Expression of iNOS was investigated by western blot analysis.
PC in combination with recombinant interferon-gamma (rIFN-gamma) showed a marked co-operative induction of NO production, with no effect on NO production by itself. The increased production of NO from rIFN-gamma plus PC-stimulated cells was almost completely inhibited by pre-treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor kappa B (NF-kappaB). Furthermore, treatment of peritoneal macrophages with rIFN-gamma plus PC caused a significant increase in tumour necrosis factor-alpha (TNF-alpha) production. PDTC also decreased the effect of PC on TNF-alpha production significantly.
As NO and TNF-alpha play an important role in immune function and host defense, PC treatment could modulate several aspects of host defense mechanisms due to stimulation of the inducible nitric oxide synthase.
Seven phlorotannins were isolated and characterized from an edible marine brown alga Ecklonia cava (EC), along with three common sterol derivatives (fucosterol, ergosterol, and cholesterol) according to the comprehensive spectral analysis of MS and NMR data. Compounds 5 (7-phloro eckol) and 7 (6,6'-bieckoll) of phlorotannin derivatives were obtained for the first time with the high yields. No reports of compound 3 (Fucodiphloroethol G) was published up to date. The antioxidant properties of all phlorotannins were assessed by total antioxidant activity in a linoleic acid model, free radicals scavenging assay using electron spin resonance spectrometry (ESR) technique, cellular reactive oxygen species (ROS) assay by DCFH-DA, membrane protein oxidation assay; measurement of cellular glutathione (GSH) level in RAW264.7 cell line, and myeloperoxidase (MPO) assay in HL-60 cell line. The results revealed that all phlorotannins had antioxidant properties in vitro, especially, compounds 7 (6,6'-bieckol), 6, and 3 showed the significant activities compared to the other phlorotannins. Furthermore, the structure-activity relationship (SAR) was discussed based on the structural differences of the tested phlorotannins which have polymeriged phloroglucinal units with diverse skeletons and linkages. It could be suggested that phlorotaninns from this genus would be more potential candidates for the development of unique natural antioxidants for further industrial applications as functional foods, cosmetics and pharmaceuticals. As well as our results makes it clear to understand the reason behind the use of EC as traditional folk herb for a long history.
Nitric oxide (NO) is a colorless gas at room temperature and one of the simplest molecules known, yet it has been implicated in a wide variety of regulatory mechanisms ranging from
Nitric oxide (NO) from Ca(2+)-dependent neuronal nitric oxide synthase (nNOS) in skeletal muscle fibers may modulate vascular tone by a cGMP-dependent pathway similar to NO derived from NOS in endothelial cells (eNOS). In isolated fast-twitch extensor digitorum longus (EDL) muscles from control mice, cGMP formation increased approximately 166% with electrical stimulation (30 Hz, 15 s). cGMP levels were not altered in slow-twitch soleus muscles. The NOS inhibitor N(omega)-nitro-l-arginine abolished the contraction-induced increase in cGMP content in EDL muscles, and the NO donor sodium nitroprusside (SNP) increased cGMP content approximately 167% in noncontracting EDL muscles. SNP treatment but not electrical stimulation increased cGMP formation in muscles from nNOS(-/-) mice. cGMP formation in control and stimulated EDL muscles from eNOS(-/-) mice was less than that obtained with similarly treated muscles from control mice. Arteriolar relaxation in contracting fast-twitch mouse cremaster muscle was attenuated in muscles from mice lacking either nNOS or eNOS. These findings suggest that increases in cGMP and NO-dependent vascular relaxation in contracting fast-twitch skeletal muscle may require both nNOS and eNOS.
The pro-inflammatory signalling pathways and cellular mechanisms that initiate the inflammatory response have become increasingly well characterized. However, little is known about the mediators and mechanisms that switch off inflammation. Recent data indicate that the resolution of inflammation is an active process controlled by endogenous mediators that suppress pro-inflammatory gene expression and cell trafficking, as well as induce inflammatory-cell apoptosis and phagocytosis, which are crucial determinants of successful resolution. This review focuses on this emerging area of inflammation research and describes the mediators and mechanisms that are currently stealing the headlines.
The bactericidal activity of phlorotannins from brown algae against food-borne pathogenic bacteria (25 strains), methicillin-resistant Staphylococcus aureus (MRSA) (nine strains) and Streptococcus pyogenes (one strain) was examined and compared with that of catechins. In addition, the effect of the oral administration of phlorotannins on mice was investigated. Phlorotannins, which are oligomers of phloroglucinol, were extracted from thalli of the brown alga Ecklonia kurome and prepared by silicic acid chromatography. The bactericidal activity of polyphenols was determined using a broth microdilution method. Of the bacteria tested, Campylobacter spp. were the most susceptible to the phlorotannins. The MBCs of the crude phlorotannins, dieckol and 8,8'-bieckol (hexamers), and that of epigallocatechin gallate (EGCG) against Campylobacter jejuni were 50 mg/L, 0.03 micromol/mL and 0.03 micromol/mL, respectively. On the whole, the bactericidal effects of the phlorotannins were more pronounced than those of the catechins. The phlorotannins were as effective against MRSA as against the other bacteria tested. At twice the MBCs, all Vibrio parahaemolyticus were killed within 0.5-2 h. However, at the same concentration, catechins showed little bactericidal activity within 4 h. No effect on mice was observed with oral administration of the phlorotannins under the conditions tested.
The bioassay-directed isolation of a marine brown alga, Ecklonia cava, afforded four phlorotannin derivatives, eckol (1), 8,8'-bieckol (2), 8,4"'-dieckol (3), and phlorofucofuroeckol A (4). Among these compounds, 2 and 3 exhibited an inhibitory effect on human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) and protease. Specifically, they inhibited the RT more potently than the protease. The inhibitory activity of compound 2 (IC(50), 0.51 microM) against HIV-1 RT was comparable to that of nevirapine (IC(50), 0.28 microM), a reference compound. An enzyme kinetic assay showed that this compound inhibited the RNA-dependent DNA synthesis activity of HIV-1 RT noncompetitively against dUTP/dTTP with a K(i) value of 0.78 microM. With respect to the homopolymeric template/primer, (rA)n(dT)15, 8,8'-bieckol (2) displayed an uncompetitive type of inhibition (K(i), 0.23 microM).
Osteoarthritis is thought to be induced by the ageing-related loss of homeostatic balance between degeneration and repair mechanism around cartilage tissue in which inflammatory mediators such as reactive oxygen species, cytokines and prostaglandins are prone to over-production under undesirable physiological conditions. Phlorotannins are unique polyphenolic compounds bearing dibenzo-1,4-dioxin skeleton which are not found in terrestrial plants but found only in some brown algal species such as Ecklonia and Eisenia families. Phlorotannin-rich extracts of Ecklonia cava including LAD103 showed significant antioxidant activities such as DPPH radical scavenging, ferric ion reduction, peroxynitrite scavenging, and inhibition of LDL oxidation, indicating their possible antioxidative interference both in onset and downstream consequences of osteoarthritis. LAD103 also showed significant down regulation of PGE2 generation in LPS-treated RAW 246.7 cells, and significant inhibition of human recombinant interleukin-1alpha-induced proteoglycan degradation, indicating its beneficial involvement in pathophysiological consequences of osteoarthritis, the mechanism of which needs further investigation. Since LAD103 showed strong therapeutic potentials in arthritic treatment through several in vitro experiments, it is highly encouraged to perform further mechanistic and efficacy studies.
1. Background The ancient inhabitants of the Japanese archipelago seem to have eaten seaweeds. In fact, remains of marine algae such as Eisenia and Sargassum are often found mixed with shells and fish bones in relics of aborigines of the Jomon-pattern (BC 300-6000) and Yayoi-pattern eras (BC 300-AD 400) in Japanese prehistory. In the Law of Taiho (AD 701) which was established by the Emperor at that time, marine algae such as Laminaria, Undaria and its sporophyll, Porphyra and Gelidium are included among marine products which were paid to the Court as tax. According to the Wamyosho, the oldest ChineseJapanese dictionary in Japan, which had been edited by the order of the Emperor Daigo (897-930), twenty-one species of marine algae including green, brown and red algae were already used as food among people in an earlier stage of the Heiam era (794-1185); and even the cooking formulations were described (Miyashita, 1974). Toward the end of the Muromachi era (1336-1573), various struggles arose between each Daimyo (feudal lord) in Japan to cause the socalled Age of Civil Wars (1467-1507), and common foodstuffs were often liable to be lacking in every feudal domain. According to the literature, some of the lords would lay up edible seaweeds such as Hizikia, Laminaria, Eisenia, Undaria, Nemacystus and Porphyra as army provisions in addition to various shellfish and fishes. Japanese history then passed into the Edo era (1603-1912) and peaceful times visited. During this era, however, people in Edo (present-day Tokyo) were sometimes subject to great famines, and the feudal government at that time employed a policy of storing cereals and other foodstuffs including the brown seaweeds Laminaria, Undaria, Ecklonia and Hizikia. In addition, several seaweed products were commercialized locally during this period in many regions of Japan. Some of these algal products have continued to be manufactured in the same style up to the present; as examples, the following products may be cited: a product from Undaria made in Nagoya area and called mikawa-wakame, one from Laminaria made in Aomori area and called matumae-konbu, and one from Porphyra made in the Shinagawa area of Tokyo. The latter has expanded throughout Japan as the present hoshi-nori products. On the other hand, some seaweeds including Laminaria were used for confectionaries in the beginning of the Edo era and agar, a seaweed product made earlier in Japan than anywhere else, was also manufactured in this period. As early as about the second half of the Edo era, the cultivation of Porphyra began, being driven by necessity, because the amounts of natural Porphyra decreased due to water pollution caused by the increasing population of Edo. Then in 1717, the first trial of Porphyra cultivation was conducted, and this has been developed to the scale of being the largest in the world at present (Arasaki & Arasaki, 1978).
Bioactivity-guided fractionation of Ecklonia stolonifera was used to determine the chemical identity of bioactive constituents, with potent antioxidant activities. The structures of the phlorotannins were determined on the basis of spectroscopic analysis, including NMR and mass spectrometry analysis. The antioxidant activities of the isolated compounds were evaluated by free radical scavenging activities in both in vitro and cellular systems. The anti-inflammatory effects of the isolated compounds were evaluated by determining their inhibitory effects on the production of nitric oxide (NO) and prostaglandin E(2) (PGE(2)) in lipopolysaccharide (LPS)-induced RAW 264.7 murine macrophage cells. The results indicated that phlorofucofuroeckol A, dieckol, and dioxinodehydroeckol showed potential radical scavenging activities against 2,2-diphenyl-1-picrylhydrazyl. Among them, phlorofucofuroeckol A and dieckol significantly suppressed the intracellular reactive oxygen species level assayed by 2',7'-dichlorofluorescein diacetate assay in LPS-induced RAW 264.7 cells. Phlorofucofuroeckol A significantly inhibited the LPS-induced production of NO and PGE(2) through the down-regulation of inducible nitric oxide synthase and cyclooxygenase 2 protein expressions. In conclusion, these results suggest that phlorofucofuroeckol A has a potential for functional foods with antioxidant and anti-inflammatory activities.
Ecklonia cava (EC) is a brown alga that has demonstrated radical scavenging, bactericidal, tyrosinase inhibitory, and protease inhibitory activities. However, the molecular mechanisms underlying its anti-inflammatory action remain unclear. In the current study, we attempted to determine whether pretreatment with EC induces a significant inhibition of anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated murine BV2 microglia. Our results indicate that EC inhibits LPS-induced nitric oxide (NO) and prostaglandin E(2) (PGE(2)) production in a concentration-dependent manner and inhibits inducible nitric oxide (iNOS) and cyclooxygenase (COX)-2 in BV2 microglia without significant cytotoxicity. EC treatment significantly reduced nuclear factor-kappaB (NF-kappaB) translocation and DNA-binding in LPS-stimulated BV2 microglia. This effect was mediated through the inhibition of the degradation of the inhibitor kappaB and by inhibition of the mitogen-activated protein kinase (MAPK) phosphorylation, at least in part by inhibiting the generation of reactive oxygen species. Our data also indicate that EC extracts exert anti-inflammatory effects by suppressing proinflammatory cytokines. Collectively, these results suggest that EC suppresses the induction of cytokines by LPS, as well as iNOS and COX-2 expression, by blocking NF-kappaB and MAPK activation. These findings provide mechanistic insights into the anti-inflammatory and neuroprotective actions of EC in BV2 microglia.
Ecklonia cava (EC), which is an edible marine brown alga with a broad range of bioactivities, belongs to the family of Laminariaceae. The bioactive 6,6'-bieckol, one of the main phloroglucinol derivatives naturally occurred from this genus, was isolated and characterized by NMR techniques. For the first time, human immunodeficiency virus type-1 (HIV-1) inhibitory activity of 6,6'-bieckol showed wild inhibition against HIV-1 induced syncytia formation (EC(50) 1.72 microM), lytic effects (EC(50) 1.23 microM), and viral p24 antigen production (EC(50) 1.26 microM), respectively. This result was strongly and clearly supported by the further investigation also, which 6,6'-bieckol selectively inhibited the activity of HIV-1 reverse transcriptase (RT) enzyme with EC(50) of 1.07 microM, as well as HIV-1 entry. Moreover, unlike most of other tannins, 6,6'-bieckol exhibited no cytotoxicity at concentrations which inhibited HIV-1 replication almost completely. Thus, it can be suggested that the potentially effective 6,6'-bieckol might be employed as a drug candidate for development of new generation therapeutic agents against HIV.
Eckol (1), a novel phlorotannin with a dibenzo-1,4-dioxin skeleton, has been isolated from the brown alga Ecklonia kurome Okamura as a potent and specific anti-plasmin inhibitor. Its structure has been elucidated based on the spectral data, in particular, by means of negative nuclear Overhauser effect (NOE), and finally established as 1-(3,5-dihydroxyphenoxy)-2,4,7,9-tetrahydroxydibenzo-1,4-dio xin by X-ray analysis. Some partially methoxylated derivatives of eckol were prepared by methylation with diazomethane and also by selective dimethylation of eckol permethylate (1b) to establish the structural requirements for inhibitory activities on alpha 2-macroglobulin and alpha 2-plasmin inhibitor, the main plasmin inhibitors in plasma.
Numerous investigations have shown that COX-2 is a participant in the pathway of colon carcinogenesis, especially when mutation of the APC tumor suppressor is the initiating event. Moreover, it seems that the amount of COX-2 is important, since there is a correlation between its level of expression and the size of the tumors and their propensity to invade underlying tissue [40]. Inhibiting COX-2 at an early stage blocks the development of malignant tumors, causes pre-malignant tumors to regress and may improve the outcome once the cancer is completely established. This set of findings seems to link very strongly with the traditional observation that chronic inflammation is a precursor to a variety of types of cancer. By this formulation, inflammatory stimuli increase COX-2 and the downstream events that it induces promote tumor formation. All of these finding suggest that existing NSAIDs will be useful for the prophylaxis of colon cancer and polyps and we eagerly await clinical investigations that will generate guidelines that suggest those individuals that are the most appropriate recipients for such therapy. Although this field has progressed rapidly in the last few years, many important questions remain.
Cytokines are produced by various types of cells and have profound effects on the regulation of immune reactions, hematopoiesis, and inflammation. Herein, we will discuss the pathophysiological relevance of cytokine receptor expression, particularly focusing on chemokine receptor expression. Chemokines are cytokines with 4 cysteines at the well-conserved positions and exhibit potent chemotactic activities for various types of leukocytes. To date, accumulating evidence has indicated the potential involvement of these chemokines in inflammatory reactions through regulating inflammatory cell infiltration. Moreover, several lines of evidence demonstrate that different sets of chemokine receptors are expressed by T helper type 1 (Th1) and Th2 cells and that Th1 and Th2 cells respond to distinct sets of chemokines. These observations establish the essential roles of chemokines in helper T lymphocyte migration in vivo. Furthermore, several chemokine receptors are utilized as co-factors for human immunodeficiency virus entry and mutation in one chemokine receptor confers marked resistance to HIV infection. Therefore, the determination of chemokine receptors may provide invaluable information on the immune status and susceptibility to HIV infection.
A wide array of phenolic substances, particularly those present in edible and medicinal plants, have been reported to possess substantial anticarcinogenic and antimutagenic activities. The majority of naturally occurring phenolics retain antioxidative and anti-inflammatory properties which appear to contribute to their chemopreventive or chemoprotective activity. Cyclooxygenase-2 (COX-2) inducible and nitric oxide synthase (iNOS) are important enzymes that mediate inflammatory processes. Improper up-regulation of COX-2 and/or iNOS has been associated with pathophysiology of certain types of human cancers as well as inflammatory disorders. Since inflammation is closely linked to tumor promotion, substances with potent anti-inflammatory activities are anticipated to exert chemopreventive effects on carcinogenesis, particularly in the promotion stage. Examples are curcumin, a yellow pigment of turmeric (Curcuma longa L., Zingiberaceae), the green tea polyphenol epigallocatechin gallate (EGCG), and resveratrol from grapes (Vitis vinifera, Vitaceae) that strongly suppress tumor promotion. Recent studies have demonstrated that eukaryotic transcription factor nuclear factor-kappa B (NF-kappa B) is involved in regulation of COX-2 and iNOS expression. Several chemopreventive phytochemicals have been shown to inhibit COX-2 and iNOS expression by blocking improper NF-kappa B activation. Multiple lines of compelling evidence indicate that extracellular-regulated protein kinase and p38 mitogen-activated protein kinase are key elements of the intracellular signaling cascades responsible for NF-kappa B activation in response to a wide array of external stimuli. Curcumin, EGCG and resveratrol have been shown to suppress activation of NF-kappa B. One of the plausible mechanisms underlying inhibition of NF-kappa B activation by aforementioned phytochemicals involves repression of degradation of the inhibitory unit I kappa B alpha, which hampers subsequent nuclear translocation of the functionally active subunit of NF-kappa B.
The enzyme cyclooxygenase (COX) catalyzes the first step of the synthesis of prostanoids. In the early 1990s, COX was demonstrated to exist as two distinct isoforms. COX-1 is constitutively expressed as a "housekeeping" enzyme in most tissues. By contrast, COX-2 can be up-regulated by various pro-inflammatory agents, including lipopolysaccharide, cytokines, and growth factors. Whereas many of the side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., gastrointestinal ulceration and bleeding, platelet dysfunctions) are caused by a suppression of COX-1 activity, inhibition of COX-2-derived prostanoids facilitates the anti-inflammatory, analgesic, and antipyretic effects of NSAIDs. During the past few years specific inhibitors of the COX-2 enzyme have emerged as important pharmacological tools for treatment of pain and arthritis. However, although COX-2 was initially regarded as a source of pathological prostanoids only, recent studies have indicated that this isoenzyme mediates a variety of physiological responses within the organism. The present review assesses recent advances in COX-2 research, with particular emphasis on new insights into pathophysiological and physiological functions of this isoenzyme.
Interleukin-10 (IL-10) is a pleiotropic cytokine that modulates the function of several adaptive immunity-related cells. Although generally considered an immunosuppressive molecule, IL-10 possesses immunostimulatory properties in several in vitro and in vivo models. These very different outcomes are believed to depend upon experimental conditions, the dominant immune effector mediating a given immune response, the timing of IL-10 production/administration, and IL-10 dose and/or location of expression. In the present work, we review the current knowledge regarding IL-10 activity on adaptive immunity related cells, emphasize new insights on IL-10 molecular/cellular targets, and summarize the available data on the relationship between IL-10 and some pathological conditions (e.g. infectious diseases, autoimmunity, allergy, cancer and transplantation) involving adaptive immunity.
In order to develop new anti-photoaging agents, we examined the inhibitory effects of 29 seaweed extracts on transcriptional activities of NF-kappaB and AP-1, and MMP-1 expression. The extracts from 3 species of Alariaceae, Eisenia bicyclis, Ecklonia cava and Ecklonia stolonifera, have showed strong inhibition of both NF-kappaB and AP-1 reporter activity, which were well correlated with their abilities to inhibit MMP-1 expression. In addition, MMP-1 expression was dramatically attenuated by treatment with eckol or dieckol which were purely isolated from E. stolonifera, indicating that these compounds are active principles to inhibit MMP-1 expression in human dermal fibroblasts. Taken together, our data demonstrate the inhibitory effect of eckol and dieckol from Ecklonia species on MMP-1 expression in human dermal fibroblasts and provide a possibility to develop as an agent for the prevention and treatment of skin aging.
Chronic exposure of the skin to ultraviolet B (UVB) radiation induces oxidative stress, which plays a crucial role in the induction of skin cancer. In this study, the effect of dietary feeding and topical application of brown algae polyphenols on UVB radiation-induced skin carcinogenesis in SKH-1 mice was investigated. SKH-1 hairless mice were randomly divided into 9 groups, including control, UVB control and treatment groups. They were treated orally (0.1% and 0.5% with AIN-76 diet, w/w) and topically (3 and 6 mg/0.2 ml of vehicle) with brown algae polyphenols and irradiated with UVB for 26 weeks. Dietary feeding (0.1% and 0.5%) of brown algae polyphenols significantly reduced tumor multiplicity (45% and 56%) and tumor volume (54% and 65%), and topical administration (3 and 6 mg) significantly decreased tumor multiplicity (60% and 46%) and tumor volume (66% and 57%), respectively, per tumor-bearing mouse. Dietary feeding and topical administration of the polyphenols also inhibited tumor incidence by 6% and 21%, respectively, but the results were not significant. Dietary and topical administration of the polyphenols markedly inhibited cyclooxygenase-2 activity and cell proliferation. These observations show that brown algae polyphenols have an antiphotocarcinogenic effect which may be associated with the prevention of UVB-induced oxidative stress, inflammation, and cell proliferation in the skin.
Cyclooxygenases-1 and -2 (COX-1 and -2) catalyze the committed step in prostaglandin formation. Each isozyme subserves different biological functions. This is, at least in part, a consequence of differences in patterns of COX-1 and COX-2 expression. COX-1 is induced during development, and COX-1 mRNA and COX-1 protein are very stable. These latter properties can explain why COX-1 protein levels usually remain constant in those cells that express this isozyme. COX-2 is usually expressed inducibly in association with cell replication or differentiation. Both COX-2 mRNA and COX-2 protein have short half-lives relative to those of COX-1. Therefore, COX-2 protein is typically present for only a few hours after its synthesis. Here we review and develop the concepts that (a) COX-2 gene transcription can involve at least six different cis-acting promoter elements interacting with trans-acting factors generated by multiple, different signaling pathways, (b) the relative contribution of each cis-acting COX-2 promoter element depends on the cell type, the stimulus and the time following the stimulus and (c) a unique 27 amino acid instability element located just upstream of the C-terminus of COX-2 targets this isoform to the ER-associated degradation system and proteolysis by the cytosolic 26S proteasome.
Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis.
Reactive oxygen species (ROS) play an important role in the pathogenesis of many human degenerative diseases such as cancer, aging, arteriosclerosis, and rheumatism. Much attention has been focused on the development of safe and effective antioxidants. To discover sources of antioxidative activity in marine algae, extracts from 17 kinds of seaweed were screened for their inhibitory effect on total ROS generation in kidney homogenate using 2',7'-dichlorofluorescein diacetate (DCFH-DA). ROS inhibition was seen in three species: Ulva pertusa, Symphyocladia latiuscula, and Ecklonia stolonifera. At a final concentration of 25 microg/mL, U. pertusa inhibited 85.65+/-20.28% of total ROS generation, S. latiscula caused 50.63+/-0.09% inhibitory, and the Ecklonia species was 44.30+/-7.33% inhibition. E. stolonifera Okamura (Laminariaceae), which belongs to the brown algae, has been further investigated because it is commonly used as a foodstuff in Korea. Five compounds, phloroglucinol (1), eckstolonol (2), eckol (3), phlorofucofuroeckol A (4), and dieckol (5), isolated from the ethyl acetate soluble fraction of the methanolic extract of E. stolonifera inhibited total ROS generation.
Three phlorotannins, including phloroglucinol, diphlorethohydroxycarmalol, and 6,6'-bieckol, were isolated from Ishige okamurae by column chromatography. The structures of the phlorotannins were determined on the basis of spectroscopic analysis, including NMR and mass spectrometry (MS) techniques. Antioxidant effects of phlorotannins were measured by direct free radical scavenging activities using the electron spin resonance spectrometry (ESR) technique and cellular systems in vitro. The results indicated that diphlorethohydroxycarmalol and 6,6'-bieckol showed potential radical scavenging activities against the 2,2-diphenyl-1-picrylhydrazyl (DPPH), hydroxyl, alkyl, and superoxide radicals. Moreover, no cytotoxicities of the phlorotannins on human fetal lung fibroblasts cell line (MRC-5), mouse macrophages cell line (RAW264.7), and human leukemic cell line (HL-60) were observed. In addition, diphlorethohydroxycarmalol and 6,6'-bieckol significantly reduced the intracellular reactive oxygen species level assessed by 2',7'-dichlorofluorescein diacetate (DCFH-DA) assay in RAW264.7 cells, and myeloperoxide (MPO) activity in HL-60 cells and radical-mediated oxidation of cell membrane proteins in RAW264.7 cells were dose-dependently inhibited in the presence of diphlorethohydroxycarmalol and 6,6'-bieckol. In conclusion, these results suggested that phlorotannins could be used as novel functional foodstuffs or antioxidants in the cosmetic and drug industries.
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