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ISSN : 1225-1577(Print)
ISSN : 2384-0900(Online)
The Korean Journal of Oral and Maxillofacial Pathology Vol.45 No.4 pp.111-120
DOI : https://doi.org/10.17779/KAOMP.2021.45.4.001

Agarum clathratum Inhibits LPS-induced IL-1β Expression through the Regulation of the JNK/c-Jun Signaling Pathway

Jung-Min Han1), Sung-Dae Cho1), Gehoon Chung2), Su-Jung Choi1), Ji-Ae Shin1), Seong-Doo Hong1)*, Kyoung-Ok Hong1)**
1)Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea
2)Department of Oral Physiology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul 03080, Republic of Korea
#

These authors contributed equally to this work


* Correspondence: Seong-Doo Hong, Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea. Tel: +82-2-740-8682 Email: hongsd@snu.ac.kr
** Correspondence: Kyoung-Ok Hong, Department of Oral Pathology, School of Dentistry and Dental Research Institute, Seoul National University, Seoul, 03080, Republic of Korea. Tel: +82-2-740-8625 Email: hongko95@snu.ac.kr
June 9, 2021 June 18, 2021 August 13, 2021

Abstract


Agarum clathratum (A. clathratum) is a marine brown algal species that belongs to the Costariaceae family and has antioxidant and anti-microbial properties. However, the anti-inflammatory effects of A. clathratum and the molecular mechanisms involved have not been determined so far. This study aimed to investigate the anti-inflammatory effects of A. clathratum extracts in THP-1 macrophages stimulated by lipopolysaccharide (LPS) derived from Porphyromonas gingivalis. The THP-1 cells were differentiated with 12-O-tetradecanoylphorbol-13-acetate and treated with A. clathratum before LPS stimulation. Cell viability was assessed using the trypan blue exclusion assay. The expression of pro-inflammatory response-associated molecules was evaluated by quantitative real-time polymerase chain reaction and Western blot analysis. A. clathratum treatment inhibited the expression of interleukin-1β in LPS-stimulated THP-1 macrophages without causing any cytotoxicity. The anti-inflammatory effect of A. clathratum resulted in a significant repression of the JNK/c-Jun signaling axis, a key regulator in inflammation responses. This study highlights the possible role of A. clathratum in the inhibition of pro-inflammatory cytokines via suppression of the JNK/c-Jun signaling axis and suggests that A. clathratum could serve as a marine-derived anti-inflammatory agent in periodontitis.


Agarum clathratum , inflammation , periodontitis , interleukin-1β , c-Jun N-terminal kinases

Agarum clathratum의 JNK/c-Jun 신호기전 조절을 통한 LPS-유도 IL-1β 발현 억제에 관한 연구

한 정민1), 조 성대1), 정 지훈2), 최 수정1), 신 지애1), 홍 성두1)*, 홍 경옥1)**
1)서울대학교 치의학전문대학원 구강병리학교실, 치학연구소
2)서울대학교 치의학전문대학원 구강생리학교실, 치학연구소

초록

    Ⅰ. INTRODUCTION

    Periodontitis is an infectious and inflammatory disease that affects 10%–15% of the adult population resulting in loss of teeth and the tissues that support the teeth1-3). This inflammatory response is initiated by lipopolysaccharide (LPS) from Porphyromonas gingivalis, a gram-negative anaerobic bacteria and one of the most potent mediators of inflammation 4-6). Macrophages in gingival resident cells can be phenotypically polarized by various pathogens and activated by interferon (IFN)-γ and LPS. These activated macrophages induce the host immune response by releasing pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6, which is a key step in immune response and the inflammation process7,8). Therefore, regulation of the inflammation process is very important for the prevention and inhibition of periodontitis and the promotion of both oral health and the quality of life.

    Pro-inflammatory molecules are activated by diverse pathways, such as the PI3K/Akt, JAK/STAT, and MAPK pathways, which are driven by sub-gingival bacteria9). Emerging experimental evidence highlights that LPS-stimulated macrophages induce the activation of the MAPK- and NF-κB-dependent signaling pathways, leading to the upregulation of the pro-inflammatory cytokines10-12). Therefore, pharmacological inhibitors of the abovementioned pathway are considered important for the treatment of periodontitis. Although antibiotics and non-steroidal anti-inflammatory drugs are mainly used for the treatment of periodontal diseases, long-term use of these drugs may cause several side effects, such as the development of resistant bacteria, opportunistic infections, gastric disorders, and liver toxicity13,14). Thus, the development of novel therapeutic substances for the treatment of periodontitis is vital.

    A variety of naturally occurring products, such as plant extracts and polyphenols, have been used for the treatment of periodontal diseases; in addition, the use of plant sources has been extensively explored3,15). Some recent studies have focused on marine-derived medicinal substances that are useful as anti-inflammatory agents16,17). Marine organisms, such as macroalgae, have been reported to exhibit anticancer, antioxidant, and anti-inflammatory effects17,18).

    Agarum clathratum belongs to the Costariaceae family and is a typical representative of brown algae distributed in Hokkaido (Japan), the Kuril Islands (Russia), the Pacific Coast of the USA, and the northern region in the eastern coast of Korea19). A. clathratum is reported to prevent degenerative brain diseases through its antioxidant effects on CA1 pyramidal neurons20,21). However, to the best of our knowledge, the anti-inflammatory effects of this alga, particularly in periodontal diseases, have not been determined so far.

    Therefore, this study aims to determine the anti-inflammatory effect of a methanol extract from A. clathratum on THP-1 cells stimulated with P. gingivalis-derived LPS. In addition, the molecular mechanisms involved in the inhibition of pro-inflammatory cytokines in the THP-1 macrophages were evaluated.

    Ⅱ. MATERIALS AND METHODS

    1. Cell culture and chemical treatment

    The human monocytic leukemia cell line (THP-1) was obtained from the Korean Cell Line Bank and maintained in RPMI-1640 medium with 10% fetal bovine serum and 100 U/ml each penicillin in a CO2 incubator. M0 macrophages were generated by treating the THP-1 monocytes with 10 ng/ml of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 48 h. M1 macrophages were obtained by incubating the TPA-treated THP-1 cells (M0) with 0.5 μg/ml of P. gingivalis- derived LPS. Methanol extract from A. clathratum was kindly provided by the Marine Brown Algae Resources Bank at Chosun University. The extract was dissolved in dimethyl sulfoxide (DMSO), aliquoted, and stored at −20°C. A JNK inhibitor, SP600125, was purchased from Cell Signaling Technology, Inc. Stock solutions were diluted with culture medium to the indicated concentrations (final DMSO concentration, 0.1%).

    2. Trypan blue exclusion assay

    The effects of A. clathratum on cell viability were analyzed using the trypan blue exclusion assay. Cells were dyed with 0.4% trypan blue solution and counted using a hemocytometer.

    3. Western blot analysis

    Whole-cell lysates were extracted with RIPA lysis buffer containing phosphatase inhibitors and protease inhibitor cocktails. The protein concentrations of each sample were measured using a detergent-compatible protein assay kit. The same amount of protein was separated by SDS-PAGE and electrotransferred into an immunoblot polyvinylidene fluoride membrane. The membranes were blocked with 5% skim milk for 1 h at room temperature and incubated overnight with primary antibodies at 4°C. Subsequently, the membranes were incubated with horseradish peroxidase (HRP)-conjugated secondary antibodies for 2 h at room temperature. Rabbit anti-human monoclonal antibodies against IL-1β and c-Jun and rabbit anti-human polyclonal antibodies against SAPK/JNK and phospho-SAPK/JNK were obtained from Cell Signaling Technology. In addition, mouse anti-human monoclonal antibodies against β-actin were obtained from Santa Cruz Biotechnology. Proteins bound to an antibody were detected with an enhanced chemiluminescence (ECL) solution (Santa Cruz).

    4. Quantitative (real-time) polymerase chain reaction

    The resulting cDNA was subjected to qRT-PCR using AMPIGENE qPCR Green Mix HiRox. The qRT-PCR was performed using the Applied Biosystems StepOne Plus Real-Time PCR System; the resulting cDNA was amplified using the following primers: IL-1β sense, 5′-CCCAACTGGTACATCAGCAC-3′ and antisense, 5′-GGAAGACACAAATTGCATGG-3′ and GAPDH sense, 5′-GTGGTCTCCTCTGACTTCAAC-3′ and antisense, 5′-CCTGTTGCTGTAGCCAAATTC3′. The PCR test was carried out under the following conditions: 95°C for 2 min, followed by 40 cycles at 95°C for 10 s and 60°C for 30 s. Relative IL-1β mRNA expression levels were normalized to that of GAPDH and calculated using the 2−ΔΔCT method.

    5. Statistical analysis

    Statistical analysis was performed via one-way analysis of variance using SPSS 22. The Bonferroni correction was used as post-hoc analysis. All data are presented as the mean ± standard deviation. The statistical significance was defined as P < 0.05.

    Ⅲ. RESULTS

    1. Effect of A. clathratum on the viability of LPS-stimulated THP-1 cells

    To investigate the viability of A. clathratum-treated THP-1 cells, the cells were pretreated with 10 or 20 μg/ml of DMSO or A. clathratum for 1 h followed by LPS stimulation for 2 h. As shown in Fig. 1B, there was no significant difference between the DMSO and A. clathratum-treated cells, indicating that A. clathratum did not affect the viability of the THP-1 monocytes and macrophages.

    2. Effect of A. clathratum on LPS-induced expression of IL-1β in THP-1 cells

    Excessive inflammatory responses frequently lead to the development of oral diseases, such as gingivitis and periodontitis. IL-1β is vital for the mediation of LPS-induced pro-inflammatory responses in macrophages. The mRNA and protein levels of IL-1β were evaluated to determine the inhibitory effect of A. clathratum on LPS-induced pro-inflammatory responses in THP-1 cells. The mRNA and protein levels of IL-1β in the LPS-stimulated cells were markedly increased when compared to those in the unstimulated control cells. However, pretreatment with A. clathratum significantly reduced IL-1β expression in the THP-1 cells (Fig. 2A, B).

    3. Effects of A. clathratum on LPS-induced JNK/c-Jun signaling in THP-1 cells

    The expression levels of JNK and c-jun proteins were examined by Western blot analysis to investigate the role of A. clathratum in the regulation of the JNK/c-Jun signaling axis during LPS-stimulated macrophage activation. As shown in Fig. 3, the expression levels of p-JNK and c-Jun were relatively increased upon exposure to LPS alone when compared to those in the unstimulated control cells. However, the expression levels of both proteins were significantly decreased in the LPS-stimulated THP-1 cells that were pretreated with A. clathratum. The THP-1 cells were treated with the JNK inhibitor SP600125 for 2 h to determine whether JNK phosphorylation is essential for the expression of IL-1β. As shown in Figs. 4A, B, SP600125 markedly down-regulated the mRNA expression of IL-1β in a concentration- dependent manner with no significant effect on the cell viability. Furthermore, the use of 20 μM of SP600125 led to a noticeable attenuation in the protein levels of IL-1β, c-Jun, and p-JNK in the LPS-stimulated THP-1 cells (Figs. 4C). Therefore, these data suggest that LPS-induced pro-inflammatory responses can be alleviated by the downregulation of p-JNK in THP-1 macrophages. To further sup- port the anti-inflammatory effect of A. clathratum via the downregulation of the JNK/c-Jun signaling axis, LPS-stimulated THP-1 cells were pretreated with SP600125 (20 μM), following treatment of 20 μg/ml of A. clathratum. Notably, the expression levels of IL-1β (mRNA and protein) in the LPS-stimulated THP-1 cells were largely inhibited following treatment with both A. clathratum and SP600125 when compared to those observed after treatment with either one of them (Figs. 5A, B). In agreement with this finding, the expression levels of c-Jun and p-JNK were dramatically attenuated following treatment with A. clathratum and SP600125 in the THP-1 macrophages (Fig. 5C). Taken together, these results suggest that the anti-inflammatory effect of A. clathratum might involve the JNK/c-Jun signaling axis during LPS-stimulated macrophage activation.

    Ⅳ. DISCUSSION

    Advancements in periodontal disease research have been made over the past few decades owing to increased knowledge about the modulation of the host response to microbial challenges22). Despite the availability of several commercial agents for the alternative prevention and treatment of periodontal disease, these chemicals lead to undesirable side effects such as vomiting, diarrhea, and tooth staining23,24). Plant-derived compounds with immunomodulatory characteristics are beneficial for oral health15,25).

    On the other hand, the marine environment is a treasure trove of new bioactive compounds, with characteristics that are usually not present in terrestrial natural products16). Marine organisms, such as algae, have been reported to produce secondary metabolites that are extremely important sources of anti-inflammatory and anti-infective drugs26,27). Ecklonia cava, an edible marine brown alga (Laminariaceae), demonstrated anti-inflammatory effects in P. gingivalis LPS-induced RAW 264.7 cells28). Ascophyllum nodosum (brown algae) reduced the secretion of inflammatory cytokines in LPS-stimulated U937 cells29). Consistent with these reports, this study demonstrated that A. clathratum, a typical representative of brown algae, has considerable potential to exert an inhibitory effect in LPS-induced THP-1 cells (Fig. 2). Despite a dearth of studies on the anti-inflammatory effects of marine brown algae in periodontal disease, this is the first study to show that A. clathratum exhibits an anti-inflammatory effect on P. gingivalis LPS-stimulated macrophages.

    c-Jun N-terminal kinases, members of the MAPK signaling pathway, are linked to a diversity of diseases, such as neurodegeneration, diabetes, and cancer; they are particularly involved in regulating the synthesis of inflammatory mediators 30-32). Several studies have reported that the JNK/c-Jun pathway plays an important role in the expression of inflammatory cytokines in regulatory immune cells and c-Jun is known as a factor that induces the expression of IL-1β following LPS exposure33). IL-1β secretion in LPS-stimulated THP-1 cells was blocked following treatment with SP60012534). In this study, IL-1β expression was significantly reduced in THP-1 cells induced by P. gingivalis LPS following treatment with SP600125, resulting in the inhibition of the JNK/c-Jun signaling axis (Figs. 3 and 4). These findings emphasized that the inhibition of JNK might have a therapeutic effect in inflammatory diseases, such as periodontitis.

    About 25% of the druggable genome belong to kinases, and the number of protein kinase inhibitors derived from natural products approved by the Food and Drug Administration has increased every year35,36). This encourages the discovery and development of new protein kinase inhibitors from marine organisms. In this study, A. clathratum was found to exert an anti-inflammatory effect via the inhibition of the JNK/c-Jun pathway in LPS-stimulated THP-1 cells (Fig. 5). Only one other study demonstrated the anti-inflammatory effects of eckols from Eisenia bicyclis (brown algae) via the inhibition of p-JNK in human dental pulp cells37). These findings suggest that A. clathratum might have the potential to prevent and treat periodontitis; in addition, the JNK signaling pathway might be the potential molecular targets of A. clathratum during an LPS-induced inflammatory response.

    In conclusion, to the best of our knowledge, this is the first study to demonstrate that pretreatment with A. clathratum ameliorated the LPS-stimulated inflammatory response in THP-1 macrophages through the regulation of the JNK/c-Jun signaling pathway. Thus, JNK might be a valuable target in periodontitis, and A. clathratum could be used to serve as a template for marine‑derived new protein kinase inhibitors.

    ACKNOWLEDGMENTS

    This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT, and Future Planning [2019R1A2C1085896, 2020R1F1A1050880, and 2021R1A2C1006470].

    Figure

    KAOMP-45-4-111_F1.gif

    Effect of A. clathratum on cell viability in LPS-stimulated THP-1 cells

    (A) The black square of the map indicates the location of the sampling site of A. clathratum. (B) After pretreatment with DMSO or A. clathratum (10, 20 μg/ml) for 1 h, the THP-1 cells were stimulated with LPS (0.5 μg/ml) for 2 h. Cell viability was measured using the trypan blue exclusion assay. The graph shows the means ± standard deviation of three independent experiments.

    KAOMP-45-4-111_F2.gif

    Effect of A. clathratum on IL-1β expression in LPS-stimulated THP-1 cells

    (A–B) After pretreatment with DMSO or A. clathratum (10, 20 μg/ml) for 1 h, THP-1 cells were stimulated with LPS (0.5 μg/ml) for 2 h. Then, IL-1β expression was measured using qRT-PCR and Western blot. The graph shows the means ± SD of three independent experiments. Significance (p < 0.05) compared with unstimulated control group (#) or LPS-stimulated group (*).

    KAOMP-45-4-111_F3.gif

    Effect of A. clathratum on the JNK/c-Jun signaling axis in LPS-stimulated THP-1 cells

    (A–B) The effects of A. clathratum on the expression of p-JNK, JNK, and c-Jun proteins were measured by Western blot. The graphs show the means ± SD of three independent experiments. Significance (p < 0.05) compared with unstimulated control group (#) or LPS-stimulated group (*).

    KAOMP-45-4-111_F4.gif

    Effects of JNK inhibition on IL-1β/JNK/c-Jun expression in LPS-stimulated THP-1 cells

    (A) THP-1 cells were exposed to various concentrations of SP600125 for 4 h. Cell viability was measured using the trypan blue exclusion assay. (B) LPS-stimulated THP-1 cells were treated with various concentrations of SP600125 for 2 h. The mRNA level of IL-1β was measured by qRT-PCR. (C) The effects on the expression levels of IL-1β, p-JNK, JNK, and c-Jun were measured using Western blot. All graphs show the means ± SD of three independent experiments. Significance (p < 0.05) compared with LPS-stimulated group (*).

    KAOMP-45-4-111_F5.gif

    Effects of A. clathratum on IL-1β/JNK/c-Jun expression in LPS-stimulated THP-1 cells

    (A-B) After pretreatment with A. clathratum (20 μg/ml) for 1 h, the LPS-stimulated THP-1 cells were treated with SP600125 (20 μM) for 2 h. The mRNA and protein levels of IL-1β were measured by qRT-PCR and Western blot, respectively. (C) The effects of A. clathratum on the JNK/c-Jun signaling axis were confirmed by Western blot. All graphs show the means ± SD of three independent experiments. Significance (p < 0.05) compared with unstimulated control group (#) or LPS-stimulated group (*).

    Table

    Reference

    1. Hajishengallis G: Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol 2015;15:30-44.
    2. Dixon DR, Bainbridge BW, Darveau RP: Modulation of the innate immune response within the periodontium. Periodontol 2000 2004;35:53-74.
    3. Sczepanik FSC, Grossi ML, Casati M: Periodontitis is an inflammatory disease of oxidative stress: We should treat it that way. Periodontol 2000 2020;84:45-68.
    4. Pathirana RD, O'Brien-Simpson NM, Reynolds EC: Host immune responses to Porphyromonas gingivalis antigens. Periodontol 2000 2010;52:218-237.
    5. Elburki MS, Rossa C, Jr., Guimaraes-Stabili MR: A Chemically Modified Curcumin (CMC 2.24) Inhibits Nuclear Factor kappaB Activation and Inflammatory Bone Loss in Murine Models of LPS-Induced Experimental Periodontitis and Diabetes-Associated Natural Periodontitis. Inflammation 2017;40:1436- 1449.
    6. Chanput W, Mes JJ, Wichers HJ: THP-1 cell line: an in vitro cell model for immune modulation approach. Int Immunopharmacol 2014;23:37-45.
    7. Daigneault M, Preston JA, Marriott HM, Whyte MK: Dockrell DH. The identification of markers of macrophage differentiation in PMA-stimulated THP-1 cells and monocyte- derived macrophages. PLoS One 2010;5:e8668.
    8. Martinez FO, Helming L, Gordon S: Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 2009;27:451-483.
    9. Ahmad SF, Ansari MA, Zoheir KM: Regulation of TNF-alpha and NF-kappaB activation through the JAK/STAT signaling pathway downstream of histamine 4 receptor in a rat model of LPS-induced joint inflammation. Immunobiology 2015;220:889-898.
    10. Reddy DB, Reddanna P: Chebulagic acid(CA) attenuates LPS-induced inflammation by suppressing NF-kappaB and MAPK activation in RAW 264.7 macrophages. Biochem Biophys Res Commun 2009;381:112-117.
    11. Woo JS, Choo GS, Yoo ES: Apigenin induces apoptosis by regulating Akt and MAPK pathways in human melanoma cell A375SM. Mol Med Rep 2020;22: 4877-4889.
    12. Hoare A, Soto C, Rojas-Celis V, Bravo D: Chronic Inflammation as a Link between Periodontitis and Carcinogenesis. Mediators Inflamm 2019;2019: 1029857.
    13. Oliveira J, Reygaert WC: Gram Negative Bacteria. In: StatPearls. Treasure Island(FL)2021.
    14. Xie H, Yang L, Hu Q: Effects of inducing apoptosis and inhibiting proliferation of siRNA on polyadenylate-binding protein-interacting protein 1 in tongue cell carcinoma. Head Neck 2020.
    15. Ohtani M, Nishimura T: The preventive and therapeutic application of garlic and other plant ingredients in the treatment of periodontal diseases. Exp Ther Med 2020;19:1507-1510.
    16. Lu WY, Li HJ, Li QY, Wu YC: Application of marine natural products in drug research. Bioorg Med Chem 2021;35:116058.
    17. Kapoor S, Nailwal N, Kumar M, Barve K: Recent Patents and Discovery of Anti-inflammatory Agents from Marine Source. Recent Pat Inflamm Allergy Drug Discov 2019;13:105-114.
    18. Meresse S, Fodil M, Fleury F, Chenais B: Fucoxanthin, a Marine-Derived Carotenoid from Brown Seaweeds and Microalgae: A Promising Bioactive Compound for Cancer Therapy. Int J Mol Sci 2020;21:23.
    19. Lee S, Park MS, Lee H, Kim JJ, Eimes JA, Lim YW: Fungal Diversity and Enzyme Activity Associated with the Macroalgae, Agarum clathratum. Mycobiology 2019;47:50-58.
    20. Kim IH, Yoo KY, Park JH: Comparison of neuroprotective effects of extract and fractions from Agarum clathratum against experimentally induced transient cerebral ischemic damage. Pharm Biol 2014;52:335-343.
    21. Pereira L, Valado A: The Seaweed Diet in Prevention and Treatment of the Neurodegenerative Diseases. Mar Drugs 2021;19(3).
    22. Figueiredo RDA, Ortega AC, Gonzalez Maldonado LA: Perillyl alcohol has antibacterial effects and reduces ROS production in macrophages. J Appl Oral Sci 2020;28:e20190519.
    23. Park KM, You JS, Lee HY, Baek NI, Hwang JK. Kuwanon G: an antibacterial agent from the root bark of Morus alba against oral pathogens. J Ethnopharmacol 2003;84:181-185.
    24. Chung JY, Choo JH, Lee MH, Hwang JK: Anticariogenic activity of macelignan isolated from Myristica fragrans (nutmeg) against Streptococcus mutans. Phytomedicine 2006;13:261-266.
    25. Bunte K, Hensel A, Beikler T: Polyphenols in the prevention and treatment of periodontal disease: A systematic review of in vivo, ex vivo and in vitro studies. Fitoterapia 2019;132:30-39.
    26. Kim JA, Kim SK: Bioactive peptides from marine sources as potential anti-inflammatory therapeutics. Curr Protein Pept Sci 2013;14:177-182.
    27. Cragg GM, Newman DJ: Chemical diversity: a function of biodiversity. Trends Pharmacol Sci 2002;23:404-405; author reply 405.
    28. Kim S, Choi SI, Kim GH, Imm JY: Anti-Inflammatory Effect of Ecklonia cava Extract on Porphyromonas gingivalis Lipopolysaccharide-Stimulated Macrophages and a Periodontitis Rat Model. Nutrients 2019;11(5).
    29. Tamanai-Shacoori Z, Chandad F, Rebillard A, Cillard J, Bonnaure-Mallet M: Silver-zeolite combined to polyphenol- rich extracts of Ascophyllum nodosum: potential active role in prevention of periodontal diseases. PLoS One 2014;9:e105475.
    30. Albanito L, Reddy CE, Musti AM: c-Jun is essential for the induction of Il-1beta gene expression in in vitro activated Bergmann glial cells. Glia 2011;59:1879-1890.
    31. Lee HN, Shin SA, Choo GS: Antiinflammatory effect of quercetin and galangin in LPSstimulated RAW264.7 macrophages and DNCBinduced atopic dermatitis animal models. Int J Mol Med 2018;41:888-898.
    32. Li G, Qi W, Li X, Zhao J, Luo M, Chen J: Recent Advances in c-Jun N-Terminal Kinase (JNK) Inhibitors. Curr Med Chem 2021;28:607-627.
    33. Sahingur SE, Yeudall WA: Chemokine function in periodontal disease and oral cavity cancer. Front Immunol 2015;6:214.
    34. Diya Z, Lili C, Shenglai L, Zhiyuan G, Jie Y: Lipopolysaccharide (LPS) of Porphyromonas gingivalis induces IL-1beta, TNF-alpha and IL-6 production by THP-1 cells in a way different from that of Escherichia coli LPS. Innate Immun 2008;14:99-107.
    35. Li T, Wang N, Zhang T: A Systematic Review of Recently Reported Marine Derived Natural Product Kinase Inhibitors. Mar Drugs 2019;17:9.
    36. Ning C, Wang HD, Gao R: Marine-derived protein kinase inhibitors for neuroinflammatory diseases. Biomed Eng Online 2018;17:46.
    37. Paudel U, Lee YH, Kwon TH: Eckols reduce dental pulp inflammation through the ERK1/2 pathway independent of COX-2 inhibition. Oral Dis 2014;20: 827-832.
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