• Logo
  • SBMUJournals

The Photomodulation Activity of Metformin Against Oral Microbiome

Shima Afrasiabi, Maryam Pourhajibagher, Abbas Bahador




Periodontitis is one of the most common inflammatory diseases of the periodontium, which results in the inflammatory destruction of supporting structures around teeth and is closely associated with the development of systemic disease. Due to a wide variety of antibiotic resistance periodontopathic bacteria, photodynamic therapy (PDT) is a non-invasive adjunctive therapeutic modality that is capable of destroying the whole range of microbes. Metformin (Metf) is an antidiabetic drug, and recent studies suggest that cancer patients who receive Metf and are exposed to radiotherapy and chemotherapy show better outcomes. Our surveys in this review introduce Metf as a potent stimulus in increasing the efficacy of PDT in the induction of destruction in microbial cells.


Periodontitis; Periodontopathic bacteria; Antibiotic resistance; Photodynamic Therapy; Metformin


Maisch T. Antimicrobial photodynamic treatment—A helpful approach in immunocompromised patients. Photodiagnosis Photodyn Ther. 2011;8(2):178.

Zandbergen D, Slot DE, Niederman R, Van der Weijden FA. The concomitant administration of systemic amoxicillin and metronidazole compared to scaling and root planing alone in treating periodontitis: =a systematic review=. BMC Oral Health. 2016;16:27. doi:10.1186/s12903-015-0123-6

Sukumar S, Roberts AP, Martin FE, Adler CJ. Metagenomic insights into transferable antibiotic resistance in oral bacteria. J Dent Res. 2016;95(9):969-976. doi:10.1177/0022034516648944

Soares GM, Figueiredo LC, Faveri M, Cortelli SC, Duarte PM, Feres M. Mechanisms of action of systemic antibiotics used in periodontal treatment and mechanisms of bacterial resistance to these drugs. J Appl Oral Sci. 2012;20(3):295-309.

Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation. Nat Rev Immunol. 2015;15(1):30-44. doi:10.1038/nri3785

Kim J, Amar S. Periodontal disease and systemic conditions: a bidirectional relationship. Odontology. 2006;94(1):10-21. doi:10.1007/s10266-006-0060-6

Pleszczynska M, Wiater A, Bachanek T, Szczodrak J. Enzymes in therapy of biofilm-related oral diseases. Biotechnol Appl Biochem. 2017;64(3):337-346. doi:10.1002/bab.1490

Diaz PI, Zilm PS, Rogers AH. Fusobacterium nucleatum supports the growth of Porphyromonas gingivalis in oxygenated and carbon-dioxide-depleted environments. Microbiology. 2002;148(Pt 2):467-472. doi:10.1099/00221287-148-2-467

Preshaw PM, Alba AL, Herrera D, et al. Periodontitis and diabetes: a two-way relationship. Diabetologia. 2012;55(1):21-31. doi:10.1007/s00125-011-2342-y

Payne JB, Golub LM, Thiele GM, Mikuls TR. The Link Between Periodontitis and Rheumatoid Arthritis: A Periodontist’s Perspective. Curr Oral Health Rep. 2015;2:20-29. doi:10.1007/s40496-014-0040-9

Bansal M, Khatri M, Taneja V. Potential role of periodontal infection in respiratory diseases - a review. J Med Life. 2013;6(3):244-248.

Dhadse P, Gattani D, Mishra R. The link between periodontal disease and cardiovascular disease: How far we have come in last two decades ? J Indian Soc Periodontol. 2010;14(3):148-154. doi:10.4103/0972-124x.75908

Srinivas SK, Parry S. Periodontal disease and pregnancy outcomes: time to move on? J Womens Health (Larchmt). 2012;21(2):121-125. doi:10.1089/jwh.2011.3023

Zuo C, Zhu Y, Wang X, Zeng X, Huang C. Tooth loss and risk of oral squamous cell carcinoma in Chinese Han population. Int J Clin Exp Med. 2015;8(11):21893-21897.

Whitmore SE, Lamont RJ. Oral bacteria and cancer. PLoS pathogens. 2014;10(3):e1003933.

Jeffcoat MK, Jeffcoat RL, Gladowski PA, Bramson JB, Blum JJ. Impact of periodontal therapy on general health: evidence from insurance data for five systemic conditions. Am J Prev Med. 2014;47(2):166-174. doi:10.1016/j. amepre.2014.04.001

Xu P, Gunsolley J. Application of metagenomics in understanding oral health and disease. Virulence. 2014;5(3):424-432. doi:10.4161/viru.28532

Høiby N, Bjarnsholt T, Givskov M, Molin S, Ciofu O. Antibiotic resistance of bacterial biofilms. International journal of antimicrobial agents. 2010;35(4):322-332.

Kim SM, Kim HC, Lee SW. Characterization of antibiotic resistance determinants in oral biofilms. J Microbiol. 2011;49(4):595-602. doi:10.1007/s12275-011-0519-1

Chen M, Yu Q, Sun H. Novel strategies for the prevention and treatment of biofilm related infections. International journal of molecular sciences. 2013;14(9):18488-18501.

Komerik N, MacRobert AJ. Photodynamic therapy as an alternative antimicrobial modality for oral infections. J Environ Pathol Toxicol Oncol. 2006;25(1-2).

Hamblin MR, Hasan T. Photodynamic therapy: a new antimicrobial approach to infectious disease? Photochem Photobiol Sci. 2004;3(5):436-450.

Chiniforush N, Pourhajibagher M, Parker S, Shahabi S, Bahador A. The in vitro effect of antimicrobial photodynamic therapy with indocyanine green on Enterococcus faecalis: Influence of a washing vs nonwashing procedure. Photodiagnosis Photodyn The. 2016;16:119-123.

Beytollahi L, Pourhajibagher M, Chiniforush N, et al. The efficacy of photodynamic and photothermal therapy on biofilm formation of Streptococcus mutans: an in vitro study. Photodiagnosis Photodyn The. 2017;17:56-60.

Nenu I, Popescu T, Aldea MD, et al. Metformin associated with photodynamic therapy--a novel oncological direction. J Photochem Photobiol B. 2014;138:80-91. doi:10.1016/j.jphotobiol.2014.04.027

Libby G, Donnelly LA, Donnan PT, Alessi DR, Morris AD, Evans JM. New users of metformin are at low risk of incident cancer: a cohort study among people with type 2 diabetes. Diabetes Care. 2009;32(9):1620-1625.doi:10.2337/dc08-2175

Giaccia AJ. Molecular radiobiology: the state of the art. J Clin Oncol. 2014;32(26):2871-2878. doi:10.1200/ jco.2014.57.2776

Robertson CA, Evans DH, Abrahamse H. Photodynamic therapy (PDT): a short review on cellular mechanisms and cancer research applications for PDT. J Photochem Photobiol B. 2009;96(1):1-8.

Huang Y-Y, Tanaka M, Vecchio D, et al. Photodynamic therapy induces an immune response against a bacterial pathogen. Expert Rev Clin Immunol. 2012;8(5):479-494.

Buytaert E, Dewaele M, Agostinis P. Molecular effectors of multiple cell death pathways initiated by photodynamic therapy. Biochim Biophys Acta. 2007;1776(1):86-107. doi:10.1016/j.bbcan.2007.07.001

Hamblin MR, O’Donnell DA, Murthy N, et al. Polycationic photosensitizer conjugates: effects of chain length and Gram classification on the photodynamic inactivation of bacteria. J Antimicrob Chemother. 2002;49(6):941-951.

Nitzan Y, Gutterman M, Malik Z, Ehrenberg B. Inactivation of gram-negative bacteria by photosensitized porphyrins. Photochem Photobiol. 1992;55(1):89-96.

Al-Zahrani MS, Bamshmous SO, Alhassani AA, Al- Sherbini MM. Short-term effects of photodynamic therapy on periodontal status and glycemic control of patients with diabetes. J Periodontol. 2009;80(10):1568- 1573. doi:10.1902/jop.2009.090206

Bacellar IO, Tsubone TM, Pavani C, Baptista MS. Photodynamic Efficiency: From Molecular Photochemistry to Cell Death. Int J Mol Sci. 2015;16(9):20523-20559. doi:10.3390/ijms160920523

Pryor R, Cabreiro F. Repurposing metformin: an old drug with new tricks in its binding pockets. Biochem J. 2015;471(3):307-322. doi:10.1042/bj20150497

Song CW, Lee H, Dings RP, et al. Metformin kills and radiosensitizes cancer cells and preferentially kills cancer stem cells. Sci Rep. 2012;2:362. doi:10.1038/srep00362

Viollet B, Guigas B, Sanz Garcia N, Leclerc J, Foretz M, Andreelli F. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond). 2012;122(6):253- 270. doi:10.1042/cs20110386

Kim EH, Kim MS, Cho CK, Jung WG, Jeong YK, Jeong JH. Low and high linear energy transfer radiation sensitization of HCC cells by metformin. J Radiat Res. 2014;55(3):432-442. doi:10.1093/jrr/rrt131

Haugrud AB, Zhuang Y, Coppock JD, Miskimins WK. Dichloroacetate enhances apoptotic cell death via oxidative damage and attenuates lactate production in metformin-treated breast cancer cells. Breast Cancer Res Treat. 2014;147(3):539-550. doi:10.1007/s10549-014- 3128-y

Koritzinsky M. Metformin: A Novel Biological Modifier of Tumor Response to Radiation Therapy. Int J Radiat Oncol Biol Phys. 2015;93(2):454-464. doi:10.1016/j. ijrobp.2015.06.003

Scheide D, Huber R, Friedrich T. The proton-pumping NADH:ubiquinone oxidoreductase (complex I) of Aquifex aeolicus. FEBS

Lett. 2002;512(1-3):80-84.

Weiss H, Friedrich T, Hofhaus G, Preis D. The respiratorychain NADH dehydrogenase (complex I) of mitochondria. EJB Reviews

: Springer; 1991:55-68.

Friedrich T, Scheide D. The respiratory complex I of bacteria, archaea and eukarya and its module common with membrane bound multisubunit hydrogenases. FEBS Lett. 2000;479(1-2):1-5.

Salminen A, Kaarniranta K. AMP-activated protein kinase (AMPK) controls the aging process via an integrated signaling network. Ageing Res Rev. 2012;11(2):230-241. doi:10.1016/j.arr.2011.12.005

Hur KY, Lee MS. New mechanisms of metformin action: Focusing on mitochondria and the gut. J Diabetes Investig.

;6(6):600-609. doi:10.1111/jdi.12328

Bae HB, Zmijewski JW, Deshane JS, et al. AMP-activated protein kinase enhances the phagocytic ability of macrophages and neutrophils. Faseb J. 2011;25(12):4358- 4368. doi:10.1096/fj.11-190587

Carling D, Thornton C, Woods A, Sanders MJ. AMPactivated protein kinase: new regulation, new roles? Biochem J.


Binker MG, Zhao DY, Pang SJ, Harrison RE. Cytoplasmic linker protein-170 enhances spreading and phagocytosis in activated macrophages by stabilizing microtubules. J Immunol. 2007;179(6):3780-3791.

Nakano A, Kato H, Watanabe T, et al. AMPK controls the speed of microtubule polymerization and directional cell migration through CLIP-170 phosphorylation. Nat Cell Biol. 2010;12(6):583-590. doi:10.1038/ncb2060

Reginato E, Wolf P, Hamblin MR. Immune response after photodynamic therapy increases anti-cancer and anti-bacterial effects. World J Immunol. 2014;4(1):1-11. doi:10.5411/wji.v4.i1.1

Reginato E, Mroz P, Chung H, Kawakubo M, Wolf P, Hamblin MR. Photodynamic therapy plus regulatory T-cell depletion produces immunity against a mouse tumour that expresses a self-antigen. Br J Cancer. 2013;109(8):2167-2174. doi:10.1038/bjc.2013.580

Hsieh CM, Huang YH, Chen CP, Hsieh BC, Tsai T. 5-Aminolevulinic acid induced photodynamic inactivation on Staphylococcus aureus and Pseudomonas aeruginosa. J Food Drug Anal. 2014;22(3):350-355. doi:10.1016/j.jfda.2013.09.051

Ji HT, Chien LT, Lin YH, Chien HF, Chen CT. 5-ALA mediated photodynamic therapy induces autophagic cell death via AMP activated protein kinase. Mol Cancer. 2010;9:91. doi:10.1186/1476-4598-9-91

Tsai JC, Wu CL, Chien HF, Chen CT. Reorganization of cytoskeleton induced by 5-aminolevulinic acidmediated photodynamic therapy and its correlation with mitochondrial dysfunction. Lasers Surg Med. 2005;36(5):398-408. doi:10.1002/lsm.20179

Takahama U, Hirota S, Takayuki O. Detection of nitric oxide and its derivatives in human mixed saliva and acidified saliva. Methods Enzymol. 2008;440:381-396. doi:10.1016/s0076-6879(07)00824-5

Choudhari SK, Chaudhary M, Bagde S, Gadbail AR, Joshi V. Nitric oxide and cancer: a review. World Journal of Surgical Oncology. 2013;11(1):118.

Reher VG, Zenobio EG, Costa FO, Reher P, Soares RV. Nitric oxide levels in saliva increase with severity of chronic periodontitis. J Oral Sci. 2007;49(4):271-276.

Ambe K, Watanabe H, Takahashi S, Nakagawa T, Sasaki J. Production and physiological role of NO in the oral cavity. Japanese Dental Science Review. 2016;52(1):14-21.

Batista AC, Silva TA, Chun JH, Lara VS. Nitric oxide synthesis and severity of human periodontal disease. Oral Dis. 2002;8(5):254-260.

Leitao RF, Ribeiro RA, Chaves HV, Rocha FA, Lima V, Brito GA. Nitric oxide synthase inhibition prevents alveolar bone resorption in experimental periodontitis in rats. J Periodontol. 2005;76(6):956-963. doi:10.1902/ jop.2005.76.6.956

Brennan P, Thomas G, Langdon J. The role of nitric oxide in oral diseases. Arch of Oral Biol. 2003;48(2):93-100.

Girotti AW. Modulation of the anti-tumor efficacy of photodynamic therapy by nitric oxide. Cancers (Basel). 2016;8(10). doi:10.3390/cancers8100096

Reeves KJ, Reed MW, Brown NJ. Is nitric oxide important in photodynamic therapy? J Photochem Photobiol B.


Girotti AW. Tumor-generated nitric oxide as an antagonist of photodynamic therapy. Photochem Photobiol Sci.

;14(8):1425-1432. doi:10.1039/c4pp00470a

Zou M-H, Kirkpatrick SS, Davis BJ, et al. Activation of the AMP-activated protein kinase by the anti-diabetic drug metformin in vivo: role of mitochondrial reactive nitrogen species. J Biol Chem. 2004;279(42):43940-43951.

Korkmaz A, Reiter RJ, Topal T, Manchester LC, Oter S, Tan DX. Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med. 2009;15(1-2):43-50. doi:10.2119/molmed.2008.00117

Zou MH, Hou XY, Shi CM, et al. Activation of 5’-AMPactivated kinase is mediated through c-Src and phosphoinositide 3-kinase activity during hypoxiareoxygenation of bovine aortic endothelial cells. Role of peroxynitrite. J Biol Chem. 2003;278(36):34003-34010. doi:10.1074/jbc.M300215200

Pilon G, Dallaire P, Marette A. Inhibition of inducible nitric oxide synthase by activators of AMP-activated protein kinase: a new mechanism of action of insulinsensitizing drugs. J Biol Chem. 2004;279(20):20767-74.

Chavez MD, Lakshmanan N, Kavdia M. Impact of superoxide dismutase on nitric oxide and peroxynitrite levels in the microcirculation--a computational model. Conf Proc IEEE Eng Med Biol Soc. 2007;2007:1022-1026. doi:10.1109/iembs.2007.4352468

Saczko J, Skrzypek W, Chwilkowska A, et al. Photooxidative action in cervix carcinoma cells induced by HPD - mediated photodynamic therapy. Exp Oncol. 2009;31(4):195-199.

Korbelik M, Parkins CS, Shibuya H, Cecic I, Stratford MR, Chaplin DJ. Nitric oxide production by tumour tissue: impact on the response to photodynamic therapy. Br J Cancer. 2000;82(11):1835-1843. doi:10.1054/ bjoc.2000.1157

Bulut S, Uslu H, Ozdemir BH, Bulut OE. Expression of caspase-3, p53 and Bcl-2 in generalized aggressive periodontitis. Head Face Med. 2006;2:17. doi:10.1186/1746-160x-2-17

Bantel H, Beikler T, Flemmig TF, Schulze-Osthoff K. Caspase activation is involved in chronic periodontitis. FEBS Let. 2005;579(25):5559-5564.

Misra A, Rai S, Misra D. Functional role of apoptosis in oral diseases: An update. J Oral Maxillofac Pathol. 2016;20(3):491-496. doi:10.4103/0973-029x.190953

Berker E, Kantarci A, Hasturk H, Van Dyke TE. Effect of neutrophil apoptosis on monocytic cytokine response to Porphyromonas

gingivalis lipopolysaccharide. J Periodontol. 2005;76(6):964-971. doi:10.1902/ jop.2005.76.6.964

Atanasovska-Stojanovska A, Trajkov D, Nares S, Angelov N, Spiroski M. IL4 gene polymorphisms and their relation to periodontal disease in a Macedonian population. Hum Immunol. 2011;72(5):446-450. doi:10.1016/j. humimm.2011.02.005

Bastos MF, Lima JA, Vieira PM, Mestnik MJ, Faveri M, Duarte PM. TNF-alpha and IL-4 levels in generalized aggressive periodontitis subjects. Oral Dis. 2009;15(1):82-87. doi:10.1111/j.1601-0825.2008.01491.x

Yamamoto M, Fujihashi K, Hiroi T, McGhee JR, Van Dyke TE, Kiyono H. Molecular and cellular mechanisms for periodontal diseases: role of Th1 and Th2 type cytokines in induction of mucosal inflammation. J Periodontal Res. 1997;32(1 Pt 2):115-119.

Sawa T, Nishimura F, Ohyama H, Takahashi K, Takashiba S, Murayama Y. In vitro induction of activation-induced cell death in lymphocytes from chronic periodontal lesions by exogenous Fas ligand. Infect Immun. 1999;67(3):1450- 1454.

Elmore S. Apoptosis: a review of programmed cell death. Toxicol Pathol. 2007;35(4):495-516.

Zilfou JT, Lowe SW. Tumor suppressive functions of p53.Cold Spring Harbor perspectives in biology. 2009:a001883.

Hardwick JM, Soane L. Multiple functions of BCL-2 family proteins. Cold Spring Harbor perspectives in biology. 2013;5(2):a008722.

Jin S, Levine AJ. The p53 functional circuit. J Cell Sci. 2001;114(Pt 23):4139-40.

Zaika AI, Wei J, Noto JM, Peek RM. Microbial regulation of p53 tumor suppressor. PLoS pathogens. 2015;11(9):e1005099.

Kuboniwa M, Hasegawa Y, Mao S, Shizukuishi S, Amano A, Lamont RJ, et al. P. gingivalis accelerates gingival epithelial cell progression through the cell cycle. Microbes Infect. 2008;10(2):122-8.

Tang X, Asano M, O'Reilly A, Farquhar A, Yang Y, Amar S. p53 is an important regulator of CCL2 gene expression. Curr Mol Med. 2012;12(8):929-43.

Cekici A, Kantarci A, Hasturk H, Van Dyke TE. Inflammatory and immune pathways in the pathogenesis of periodontal disease. Periodontology 2000. 2014;64(1):57-80.

Munoz-Fontela C, Mandinova A, Aaronson SA, Lee SW. Emerging roles of p53 and other tumour-suppressor genes in immune regulation. Nat Rev Immunol. 2016;16(12):741-50.

Aoyama I, Yaegaki K, Calenic B, Ii H, Ishkitiev N, Imai T. The role of p53 in an apoptotic process caused by an oral malodorous compound in periodontal tissues: a review. J Breath Res. 2012;6(1):017104

Acedo P, Zawacka-Pankau J. p53 family members - important messengers in cell death signaling in photodynamic therapy of cancer? Photochem Photobiol Sci. 2015;14(8):1390-6.

Abo-Zeid MA, Liehr T, El-Daly SM, Gamal-Eldeen AM, Glei M, Shabaka A, et al. Molecular cytogenetic evaluation of the efficacy of photodynamic therapy by indocyanine green in breast adenocarcinoma MCF-7 cells. Photodiagnosis Photodyn Ther. 2013;10(2):194-202.

Skinner HD, Sandulache VC, Ow TJ, Meyn RE, Yordy JS, Beadle BM, et al. TP53 disruptive mutations lead to head and neck cancer treatment failure through inhibition of radiation-induced senescence. Clin Cancer Res. 2012;18(1):290-300.

Sun Y, Tao C, Huang X, He H, Shi H, Zhang Q, et al. Metformin induces apoptosis of human hepatocellular carcinoma HepG2 cells by activating an AMPK/p53/miR-23a/FOXA1 pathway. Onco Targets Ther. 2016;9:2845-53.

Jones RG, Plas DR, Kubek S, Buzzai M, Mu J, Xu Y, et al. AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005;18(3):283-93.

Tibbetts RS, Brumbaugh KM, Williams JM, Sarkaria JN, Cliby WA, Shieh SY, et al. A role for ATR in the DNA damage-induced phosphorylation of p53. Genes Dev. 1999;13(2):152-7.

Srivastava M, Ahmad N, Gupta S, Mukhtar H. Involvement of Bcl-2 and Bax in photodynamic therapy-mediated apoptosis. Antisense Bcl-2 oligonucleotide sensitizes RIF 1 cells to photodynamic therapy apoptosis. J Biol Chem. 2001;276(18):15481-8.

Kasprzak A, Hausmann M, Małkowska-Lanzafame A, Surdyk-Zasada J, Przybyszewska W, Siodła E, et al. Immunocytochemical indicators of apoptosis in gingival tissues of patients with chronic periodontitis. Journal of Medical Science. 2016;83(1):37-46.

Nakhjiri SF, Park Y, Yilmaz O, Chung WO, Watanabe K, El-Sabaeny A, et al. Inhibition of epithelial cell apoptosis by Porphyromonas gingivalis. FEMS Microbiol Lett. 2001;200(2):145-9.

Stathopoulou PG, Galicia JC, Benakanakere MR, Garcia CA, Potempa J, Kinane DF. Porphyromonas gingivalis induce apoptosis in human gingival epithelial cells through a gingipain-dependent mechanism. BMC Microbiol. 2009;9:107.

Koukourakis MI, Corti L, Skarlatos J, Giatromanolaki A, Krammer B, Blandamura S, et al. Clinical and experimental evidence of Bcl-2 involvement in the response to photodynamic therapy. Anticancer Res. 2001;21(1b):663-8.

Chiaviello A, Postiglione I, Palumbo G. Targets and mechanisms of photodynamic therapy in lung cancer cells: a brief overview. Cancers (Basel). 2011;3(1):1014-41.

Kim H-RC, Luo Y, Li G, Kessel D. Enhanced apoptotic response to photodynamic therapy after bcl-2 transfection. Cancer research. 1999;59(14):3429-32.

Kessel D. Promotion of PDT efficacy by a Bcl-2 antagonist. Photochem Photobiol. 2008;84(3):809-14.

Feng Y, Ke C, Tang Q, Dong H, Zheng X, Lin W, et al. Metformin promotes autophagy and apoptosis in esophageal squamous cell carcinoma by downregulating Stat3 signaling. Cell Death Dis. 2014;5:e1088.

Jiang X, Wang X. Cytochrome c promotes caspase-9 activation by inducing nucleotide binding to Apaf-1. Journal of Biological Chemistry. 2000;275(40):31199-203.

Wall DM, McCormick BA. Bacterial secreted effectors and caspase-3 interactions. Cell Microbiol. 2014;16(12):1746-56.

Renatus M, Stennicke HR, Scott FL, Liddington RC, Salvesen GS. Dimer formation drives the activation of the cell death protease caspase 9. Proc Natl Acad Sci U S A. 2001;98(25):14250-5.

Brentnall M, Rodriguez-Menocal L, De Guevara RL, Cepero E, Boise LH. Caspase-9, caspase-3 and caspase-7 have distinct roles during intrinsic apoptosis. BMC Cell Biol. 2013;14:32.

Chiu SM, Oleinick NL. Dissociation of mitochondrial depolarization from cytochrome c release during apoptosis induced by photodynamic therapy. Br J Cancer. 2001;84(8):1099-106.

Ricci JE, Gottlieb RA, Green DR. Caspase-mediated loss of mitochondrial function and generation of reactive oxygen species during apoptosis. J Cell Biol. 2003;160(1):65-75.

Paiva CN, Bozza MT. Are reactive oxygen species always detrimental to pathogens? Antioxidants & redox signaling. 2014;20(6):1000-37.

Mroz P, Yaroslavsky A, Kharkwal GB, Hamblin MR. Cell death pathways in photodynamic therapy of cancer. Cancers. 2011;3(2):2516-39.

Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 2014;3:e02242.

Gao ZY, Liu Z, Bi MH, Zhang JJ, Han ZQ, Han X, et al. Metformin induces apoptosis via a mitochondria-mediated pathway in human breast cancer cells in vitro. Exp Ther Med. 2016;11(5):1700-6.

Wang X. The expanding role of mitochondria in apoptosis. Genes Dev. 2001;15(22):2922-33.

Li P, Nijhawan D, Budihardjo I, Srinivasula SM, Ahmad M, Alnemri ES, et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell. 1997;91(4):479-89.

Ferrario A, Chantrain CF, von Tiehl K, Buckley S, Rucker N, Shalinsky DR, et al. The matrix metalloproteinase inhibitor prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model. Cancer Res. 2004;64(7):2328-32.

Lu P, Takai K, Weaver VM, Werb Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harbor perspectives in biology. 2011:a005058.

Bali P, Kalaivanan D, Divater V. Matrix metalloproteinases: A double edge sword. Dentistry and Medical Research. 2016;4(1):3-.

Pittayapruek P, Meephansan J, Prapapan O, Komine M, Ohtsuki M. Role of Matrix Metalloproteinases in Photoaging and Photocarcinogenesis. Int J Mol Sci. 2016;17(6).

Honibald EN, Mathew S, Padmanaban J, Sundaram E, Ramamoorthy RD. Perioceutics: Matrix metalloproteinase inhibitors as an adjunctive therapy for inflammatory periodontal disease. J Pharm Bioallied Sci. 2012;4(Suppl 2):S417-21.

De Souza AP, Da Silva R, Da Silva M, Catanzaro-Guimarães S, Line SRP. Matrix metalloproteinases: the most important pathway involved with periodontal destruction. 2005.

Franco C, Patricia HR, Timo S, Claudia B, Marcela H. Matrix Metalloproteinases as Regulators of Periodontal Inflammation. Int J Mol Sci. 2017;18(2).

How KY, Song KP, Chan KG. Porphyromonas gingivalis: An Overview of Periodontopathic Pathogen below the Gum Line. Front Microbiol. 2016;7:53.

Murakami Y, Machino M, Fujisawa S. Porphyromonas gingivalis Fimbria-Induced Expression of Inflammatory Cytokines and Cyclooxygenase-2 in Mouse Macrophages and Its Inhibition by the Bioactive Compounds Fibronectin and Melatonin. ISRN Dent. 2012;2012:350859.

Murakami Y, Yuhara K, Takada N, Arai T, Tsuda S, Takamatsu S, et al. Effect of melatonin on cyclooxygenase-2 expression and nuclear factor-kappa B activation in RAW264. 7 macrophage-like cells stimulated with fimbriae of Porphyromonas gingivalis. In Vivo. 2011;25(4):641-7.

Kirkby NS, Chan MV, Zaiss AK, Garcia-Vaz E, Jiao J, Berglund LM, et al. Systematic study of constitutive cyclooxygenase-2 expression: role of NF-κB and NFAT transcriptional pathways. Proceedings of the National Academy of Sciences. 2016;113(2):434-9.

Mesa F, Aguilar M, Galindo‐Moreno P, Bravo M, O'valle F. Cyclooxygenase‐2 expression in gingival biopsies from periodontal patients is correlated with connective tissue loss. Journal of periodontology. 2012;83(12):1538-45.

Ferrario A, Chantrain CF, von Tiehl K, Buckley S, Rucker N, Shalinsky DR, et al. The matrix metalloproteinase inhibitor prinomastat enhances photodynamic therapy responsiveness in a mouse tumor model. Cancer research. 2004;64(7):2328-32.

Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. International journal of cell biology. 2010;2010.

Castano AP, Demidova TN, Hamblin MR. Mechanisms in photodynamic therapy: part two-cellular signaling, cell metabolism and modes of cell death. Photodiagnosis Photodyn Ther. 2005;2(1):1-23.

Saber MM, Galal MA, Ain-Shoka AA, Shouman SA. Combination of metformin and 5-aminosalicylic acid cooperates to decrease proliferation and induce apoptosis in colorectal cancer cell lines. BMC Cancer. 2016;16:126.

Mohammad G, Kowluru RA. Novel role of mitochondrial matrix metalloproteinase-2 in the development of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2011;52(6):3832-41.

Song J, Wei Y, Chen Q, Xing D. Cyclooxygenase 2-mediated apoptotic and inflammatory responses in photodynamic therapy treated breast adenocarcinoma cells and xenografts. J Photochem Photobiol B. 2014;134:27-36.

Hayden MS, Ghosh S. Shared principles in NF-kappaB signaling. Cell. 2008;132(3):344-62.

Rahman MM, McFadden G. Modulation of NF-kappaB signalling by microbial pathogens. Nat Rev Microbiol. 2011;9(4):291-306.

Harada K, Ohira S, Isse K, Ozaki S, Zen Y, Sato Y, et al. Lipopolysaccharide activates nuclear factor-kappaB through toll-like receptors and related molecules in cultured biliary epithelial cells. Lab Invest. 2003;83(11):1657-67.

D'Ignazio L, Rocha S. Hypoxia Induced NF-kappaB. Cells. 2016;5(1).

Groeger S, Jarzina F, Domann E, Meyle J. Porphyromonas gingivalis activates NFkappaB and MAPK pathways in human oral epithelial cells. BMC Immunol. 2017;18(1):1.

Wan J, Shan Y, Fan Y, Fan C, Chen S, Sun J, et al. NF-kappaB inhibition attenuates LPS-induced TLR4 activation in monocyte cells. Mol Med Rep. 2016;14(5):4505-10.

Hans M, Hans VM. Toll-like receptors and their dual role in periodontitis: a review. J Oral Sci. 2011;53(3):263-71.

Sahu K, Sharma M, Gupta PK. Modulation of inflammatory response of wounds by antimicrobial photodynamic therapy. Laser Ther. 2015;24(3):201-8.

Sharma M, Bansal H, Gupta PK. Virulence of Pseudomonas aeruginosa cells surviving photodynamic treatment with toluidine blue. Curr Microbiol. 2005;50(5):277-80.

Choi BH, Lee DH, Kim J, Kang JH, Park CS. Controls of Nuclear Factor-Kappa B Signaling Activity by 5'-AMP-Activated Protein Kinase Activation With Examples in Human Bladder Cancer Cells. Int Neurourol J. 2016;20(3):182-7.

Isoda K, Young JL, Zirlik A, MacFarlane LA, Tsuboi N, Gerdes N, et al. Metformin inhibits proinflammatory responses and nuclear factor-kappaB in human vascular wall cells. Arterioscler Thromb Vasc Biol. 2006;26(3):611-7.

Martelli AM, Nyakern M, Tabellini G, Bortul R, Tazzari PL, Evangelisti C, et al. Phosphoinositide 3-kinase/Akt signaling pathway and its therapeutical implications for human acute myeloid leukemia. Leukemia. 2006;20(6):911-28.

Saponaro C, Cianciulli A, Calvello R, Dragone T, Iacobazzi F, Panaro MA. The PI3K/Akt pathway is required for LPS activation of microglial cells. Immunopharmacol Immunotoxicol. 2012;34(5):858-65.

Bai D, Ueno L, Vogt PK. Akt-mediated regulation of NFkappaB and the essentialness of NFkappaB for the oncogenicity of PI3K and Akt. Int J Cancer. 2009;125(12):2863-70.

Milward MR, Chapple IL, Wright HJ, Millard JL, Matthews JB, Cooper PR. Differential activation of NF-kappaB and gene expression in oral epithelial cells by periodontal pathogens. Clin Exp Immunol. 2007;148(2):307-24.

DOI: https://doi.org/10.22037/jlms.v10i3.24127