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      Melatonin Receptor Agonists as the “Perioceutics” Agents for Periodontal Disease through Modulation of Porphyromonas gingivalis Virulence and Inflammatory Response

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          Abstract

          Aim

          “Perioceutics” including antimicrobial therapy and host modulatory therapy has emerged as a vital adjunctive treatment of periodontal disease. Melatonin level was significantly reduced in patients with periodontal diseases suggesting melatonin could be applied as a potential “perioceutics” treatment of periodontal diseases. This study aims to investigate the effects of melatonin receptor agonists (melatonin and ramelteon) on Porphyromonas gingivalis virulence and Porphyromonas gingivalis-derived lipopolysaccharide (Pg-LPS)-induced inflammation.

          Methods

          Effects of melatonin receptor agonists on Porphyromonas gingivalis planktonic cultures were determined by microplate dilution assays. Formation, reduction, and viability of Porphyromonas gingivalis biofilms were detected by crystal violet staining and MTT assays, respectively. Meanwhile, biofilms formation was also observed by confocal laser scanning microscopy (CLSM). The effects on gingipains and hemolytic activities of Porphyromonas gingivalis were evaluated using chromogenic peptides and sheep erythrocytes. The mRNA expression of virulence and iron/heme utilization was assessed using RT-PCR. In addition, cell viability of melatonin receptor agonists on human gingival fibroblasts (HGFs) was evaluated by MTT assays. After pretreatment of melatonin receptor agonists, HGFs were stimulated with Pg-LPS and then release of cytokines (IL-6 and lL-8) was measured by enzyme-linked immunosorbent assay (ELISA).

          Results

          Melatonin and ramelteon did exhibit antimicrobial effects against planktonic culture. Importantly, they inhibited biofilm formation, reduced the established biofilms, and decreased biofilm viability of Porphyromonas gingivalis. Furthermore, they at sub-minimum inhibitory concentration (sub-MIC) concentrations markedly inhibited the proteinase activities of gingipains and hemolysis in a dose-dependent manner. They at sub-MIC concentrations significantly inhibited the mRNA expression of virulence factors ( kgp, rgpA, rgpB, hagA, and ragA), while increasing the mRNA expression of ferritin ( ftn) or hemolysin ( hem). They did not show obvious cytotoxicity toward HGFs. They inhibited Pg-LPS-induced IL-6 and IL-8 secretion, which was reversed by luzindole, the melatonin receptor antagonist.

          Conclusion

          Melatonin receptor agonists can inhibit planktonic and biofilm growth of Porphyromonas gingivalis by affecting the virulent properties, as well as Pg-LPS-induced inflammatory response. Our study provides new evidence that melatonin receptor agonists might be useful as novel “perioceutics” agents to prevent and treat Porphyromonas gingivalis-associated periodontal diseases.

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          Most cited references60

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          Periodontitis: a polymicrobial disruption of host homeostasis.

          Periodontitis, or gum disease, affects millions of people each year. Although it is associated with a defined microbial composition found on the surface of the tooth and tooth root, the contribution of bacteria to disease progression is poorly understood. Commensal bacteria probably induce a protective response that prevents the host from developing disease. However, several bacterial species found in plaque (the 'red-complex' bacteria: Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola) use various mechanisms to interfere with host defence mechanisms. Furthermore, disease may result from 'community-based' attack on the host. Here, I describe the interaction of the host immune system with the oral bacteria in healthy states and in diseased states.
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            Melatonin as a natural ally against oxidative stress: a physicochemical examination.

            Oxidative stress has been proven to be related to the onset of a large number of health disorders. This chemical stress is triggered by an excess of free radicals, which are generated in cells because of a wide variety of exogenous and endogenous processes. Therefore, finding strategies for efficiently detoxifying free radicals has become a subject of a great interest, from both an academic and practical points of view. Melatonin is a ubiquitous and versatile molecule that exhibits most of the desirable characteristics of a good antioxidant. The amount of data gathered so far regarding the protective action of melatonin against oxidative stress is overwhelming. However, rather little is known concerning the chemical mechanisms involved in this activity. This review summarizes the current progress in understanding the physicochemical insights related to the free radical-scavenging activity of melatonin. Thus far, there is a general agreement that electron transfer and hydrogen transfer are the main mechanisms involved in the reactions of melatonin with free radicals. However, the relative importance of other mechanisms is also analyzed. The chemical nature of the reacting free radical also has an influence on the relative importance of the different mechanisms of these reactions. Therefore, this point has also been discussed in detail in the current review. Based on the available data, it is concluded that melatonin efficiently protects against oxidative stress by a variety of mechanisms. Moreover, it is proposed that even though it has been referred to as the chemical expression of darkness, perhaps it could also be referred to as the chemical light of health. © 2011 John Wiley & Sons A/S.
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              Multi-species biofilms: living with friendly neighbors.

              Our knowledge regarding the nature and development of microbial biofilms has grown significantly since the first report of these communities by Antonie van Leeuwenhoek in the late 1600s. Nevertheless, most biofilm studies examine mono-species cultures, whereas nearly all biofilm communities in nature comprise a variety of microorganisms. The species that constitute a mixed biofilm and the interactions between these microorganisms critically influence the development and shape of the community. In this review, we focus on interactions occurring within a multi-species biofilm and their effects on the nature of the mixed community. In general, interspecies interactions involve communication, typically via quorum sensing, and metabolic cooperation or competition. Interactions among species within a biofilm can be antagonistic, such as competition over nutrients and growth inhibition, or synergistic. The latter can result in the development of several beneficial phenotypes. These include the promotion of biofilm formation by co-aggregation, metabolic cooperation where one species utilizes a metabolite produced by a neighboring species, and increased resistance to antibiotics or host immune responses compared to the mono-species biofilms. These beneficial interactions in mixed biofilms have important environmental, industrial, and clinical implications. The latter, for example, impacts the course and treatment of biofilm-related infections, such as those manifested in the lungs of cystic fibrosis patients. © 2012 Federation of European Microbiological Societies. Published by Blackwell Publishing Ltd. All rights reserved.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                10 November 2016
                2016
                : 11
                : 11
                : e0166442
                Affiliations
                [1 ]Department of Periodontology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, 639 Zhi Zao Ju Road, Shanghai 200011, China
                [2 ]Shanghai Research Institute of Stomatology, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai Key Laboratory of Stomatology, 639 Zhi Zao Ju Road, Shanghai 200011, China
                [3 ]Department of Pharmacy, Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 639 Zhi Zao Ju Road, Shanghai 200011, China
                Taipei Medical University, TAIWAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: WZ JPL ZCS.

                • Formal analysis: WZ XZ.

                • Funding acquisition: WZ ZCS.

                • Investigation: WZ XZ JPL ZCS.

                • Methodology: WZ XZ CLZ ZYH.

                • Project administration: JPL ZCS.

                • Resources: JPL ZCS CLZ ZYH.

                • Supervision: JPL ZCS.

                • Validation: WZ XZ.

                • Writing – original draft: WZ XZ JPL ZCS.

                • Writing – review & editing: WZ XZ JPL ZCS.

                Article
                PONE-D-16-09979
                10.1371/journal.pone.0166442
                5104381
                27832188
                66469e6c-6d20-4e6a-8f46-61e2e9b37a07
                © 2016 Zhou et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 9 March 2016
                : 29 October 2016
                Page count
                Figures: 8, Tables: 2, Pages: 20
                Funding
                Funded by: the National Natural Science Foundation of China
                Award ID: 81271156
                Award Recipient :
                Funded by: the National Natural Science Foundation of China
                Award ID: 81670992
                Award Recipient :
                Funded by: Shanghai Municipal Education Commission-Summit and Plateau Disciplines
                Award ID: No.20152523
                Award Recipient :
                Funded by: Shanghai Jiao Tong University Cooperation Grant of Medicine, Science, Engineering
                Award ID: YG2015MS07
                Award Recipient :
                Funded by: Shanghai Jiao Tong University Cooperation Grant of Medicine, Science, Engineering
                Award ID: YG2015MS04
                Award Recipient :
                Funded by: Chinese Stomatological Association Grant
                Award ID: CSA-Y2015-01
                Award Recipient :
                Funded by: Shanghai Cooperation of Industry, University and Research Institute by Shanghai Education Commission
                Award Recipient :
                This work was supported by the National Natural Science Foundation of China (No.81271156, No.81670992), Shanghai Municipal Education Commission - Summit & Plateau Disciplines (No.20152523), Shanghai Jiao Tong University Cooperation Grant of Medicine, Science, Engineering (YG2015MS07, YG2015MS04), Chinese Stomatological Association Grant (CSA-Y2015-01), Shanghai Cooperation of Industry, University and Research Institute by Shanghai Education Commission. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Hormones
                Melatonin
                Biology and Life Sciences
                Microbiology
                Bacteriology
                Bacterial Biofilms
                Biology and Life Sciences
                Microbiology
                Biofilms
                Bacterial Biofilms
                Biology and Life Sciences
                Microbiology
                Biofilms
                Medicine and Health Sciences
                Oral Medicine
                Oral Diseases
                Periodontal Diseases
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Virulence Factors
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Antimicrobials
                Biology and Life Sciences
                Microbiology
                Microbial Control
                Antimicrobials
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                Red Blood Cells
                Biology and Life Sciences
                Organisms
                Bacteria
                Anaerobic Bacteria
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                All relevant data are within the paper.

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