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 Table of Contents  
ORIGINAL HYPOTHESIS
Year : 2016  |  Volume : 7  |  Issue : 3  |  Page : 88-93

Bromelain: A potential strategy for the adjuvant treatment of periodontitis


1 Department of Biomedicine, Post Graduate Program in Biomedical Sciences, Parnaiba-PI, Brazil
2 Department of Scientific Methodology, Medicine School, Education Institute of Parnaiba Valley; Department of Biomedicine, Laboratory of Histological Analysis and Preparation, Parnaiba-PI, Brazil
3 Department of Biomedicine, Laboratory of Histological Analysis and Preparation, Parnaiba-PI, Brazil
4 Department of Biomedicine, Post Graduate Program in Biomedical Sciences; Department of Biomedicine, Laboratory of Histological Analysis and Preparation; Department of Dentistry, Post Graduation Program in Dentistry, Federal University of Piaui, Parnaiba-PI, Brazil

Date of Web Publication14-Sep-2016

Correspondence Address:
Daniel Fernando Pereira Vasconcelos
Universidade Federal do Piauí - UFPI; Campus Ministro Reis Veloso; Colegiado de Biomedicina; Av. São Sebastião, 2819, Reis Veloso; Parnaíba
Brazil
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2155-8213.190483

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  Abstract 

Introduction: Bromelain, a mixture of proteases derived from different parts of pineapple, has been described to have therapeutic benefits in a diversity of inflammatory diseases. Such effects are associated to its proteolytic activity. As one of the most common and multifactorial diseases, periodontitis is a bacterial infection that results from the damage to the integrity of the tissues around the tooth, which includes gingiva, periodontal ligament, and alveolar bone. In periodontitis, the recruitment of defense cells occurs, which releases several pro-inflammatory cytokines. At elevated levels, they can potentiate the alveolar bone loss. Studies have been conducted trying to alleviate the damage to the periodontium, however, the regeneration of the periodontal tissues is still limited. The Hypotheses: Based on previous studies showing that bromelain can act by decreasing the periodontal microorganism growth by proteolytically cleaving important cell surface molecules in leucocytes, by reducing neutrophils migration to periodontal sites, by downregulating the inflammation mediator levels, and by decreasing alveolar bone loss in the periodontitis. Evaluation of the Hypothesis: In a first moment, to evaluate this hypothesis, could be used two animal models: the ligature or bacteria inoculation induced periodontitis. If studies using animal models show encouraging results, appropriate clinical trials should be designed to evaluate the effect of bromelain as a complementary treatment for periodontal disease in humans, during the active phase or after the healing phase of mechanical therapy could be tested; to conduct a placebo-controlled study where health and periodontitis patients could be used.

Keywords: Bone, inflammation, periodontal disease, protease


How to cite this article:
da Silva FR, Vasconcelos AC, Alves EH, Junior PV, de Oliveira JS, Vasconcelos DF. Bromelain: A potential strategy for the adjuvant treatment of periodontitis. Dent Hypotheses 2016;7:88-93

How to cite this URL:
da Silva FR, Vasconcelos AC, Alves EH, Junior PV, de Oliveira JS, Vasconcelos DF. Bromelain: A potential strategy for the adjuvant treatment of periodontitis. Dent Hypotheses [serial online] 2016 [cited 2019 Jun 16];7:88-93. Available from: http://www.dentalhypotheses.com/text.asp?2016/7/3/88/190483


  Introduction Top


Periodontitis is a bacterial infection involving accumulative plaque beyond gingival sulcus and host-immune response with multifactorial processes. [1] It is well established that the inflammation resulting from periodontitis compromises the integrity of the tissues around the tooth, which includes gingiva, periodontal ligament, and alveolar bone. [2]

As a multifactorial disease, locally, lipopolysaccharides derived from bacteria such as Porphyromonas gingivalis, Prevotella intermedia, Treponema denticola, Tannerella forsythia and Aggregatibacter actinomycetemcomitans[3],[4] induce inflammatory infiltrate with the recruitment of polymorphonuclear neutrophils (PMN), leukocytes, and macrophages. Neutrophils degranulate large quantities of tissue-destroying enzymes, e.g., matrix metalloproteinases and generate reactive oxygen species. [5],[6],[7]]

In addition, these cells release several pro-inflammatory cytokines such as factor-alpha tumor necrosis (TNF-α), IFN-γ, [8] granulocyte-macrophage-colony-stimulating factor (GMCSF), [9] which are involved with the inflammation response and bone resorption, [10] acting via RANK/RANKL/OPG (RANK, receptor activator of NF-κB; RANKL, receptor activator of NF-κB ligand, and OPG, osteoprotegerin) pathway. [11],[12]

Scaling and root planning, mechanical therapy, and oral hygiene instructions have been used as the most frequently therapy for periodontitis. Although scaling and root planning plus oral hygiene instruction promotes an enhancement in the clinical periodontal parameters in the majority of patients, it is usually insufficient to a profile compatible with periodontal health. This way, studies have been conducted trying to alleviate the damage to the periodontium, [13],[14],[15] and still in this trend several hypotheses have been presented. [16],[17],[18] However, the repair of the periodontal tissues still is limited.

In this direction, bromelain, an extract derived from Ananas comosus (popularly known as pineapple), contains proteinases that exhibits anti-inflammatory properties. [19],[20] Studies have shown efficacy similar to standard anti-inflammatory drugs [21],[22],[23] for the bromelain treatment. Furthermore, bromelain presents a large variety of activities such as anti-inflammatory properties in endometriosis, [19] reduction of the neutrophil migration to sites of inflammation, [24] antibacterial effect against periodontopathogens, [25] and what may influence the periodontal disease. This article hypothesizes the possible mechanisms of bromelain to ameliorate the development and progression of periodontitis.

Bromelain: Its biological and anti-inflammatory activities

Bromelain is a term used to describe proteolytic enzymes found in tissues, such as the stem, fruit, and leaves of pineapple. It mainly comprises multiple glycosylated enzymes from the papain superfamily, with different proteolytic enzymatic activities, molar masses from 20 to 31 kDa, and isoelectric points between 4.6 and 10. [26],[27] However, bromelain also contains peroxidase, acid phosphatase, and several protease inhibitors. Although a complex mixture constitutes bromelain, some of its pharmacological properties such as anti-inflammatory and antibacterial effects require that the bromelain be proteolytically active. [19],[20],[25]

The anti-inflammatory properties of bromelain treatment are evidenced by decreased secretion of several pro-inflammatory cytokines, such as interferon gamma (IFNγ), tumor necrosis factor (TNF-α) and GMCSF in patients with Crohn's disease. [20] These cytokines are involved in the development and progression of periodontitis. [28],[29]

There are two important inflammation mediators, ciclooxigenase (Cox) type 1 (Cox-1) and 2 (Cox-2). Cox-1 is constitutively expressed in several tissues and supports the prostaglandin biosynthesis necessary for maintaining tissue homeostasis. Cox-2 is induced during the stimulation with pro-inflammatory molecules as IFNγ, TNF-α, and GMCSF. It is upregulated during inflammation. [30] Cox-2 is involved in the synthesis of prostaglandin E2 (PGE-2), which has been demonstrated to appear in significantly higher levels in gingival crevicular fluid of patients exhibiting periodontal diseases than it does in periodontally healthy individuals. [31],[32] Interestingly, bromelain treatment has been shown to downregulate Cox-2 expression in several experiments. [33],[34],[35]

Furthermore, a study [36] revealed that bromelain treatment also removed several cell surface molecules involved in leucocytes adhesion and activation by its proteolytic activity. Cells are present in higher amounts in inflamed periodontal sites. [5]

In addition, bromelain showed inhibition of the growth of Saccharomyces cerevisiae, Escherichia coli, and Staphylococcus aureus.[37] A similar effect was demonstrated for Streptococcus mutans, Enterococcus fecalis, Aggregatibacter actinomycetemcomitans (Aa), and Porphyromonas gingivalis (Pg), microorganisms found in the periodontal disease. [25] Numerous clinical trials of bromelain have shown effectiveness for treating inflammation conditions. These include osteoarthritis of the hip, [38] osteoarthritis of the knee, [39] and rhinosinusitis. [40]


  The Hypothesis Top


Periodontitis is a disease with a multifactorial etiology; [1] the regeneration of periodontal tissues is still limited. Periodontal disease starts with the accumulation of microorganisms that stimulate the immunologic system response. This response can occur with the migration of leucocytes, especially neutrophils, and the release of several cytokines from different cells. One of the results of this process is alveolar bone loss. [2] Our research team believes that bromelain treatment could be useful for the adjuvant periodontal treatment because of the properties discussed above.

Our hypotheses is based on the following points: (1) Bromelain can decrease the periodontal microorganism growth; (2) Bromelain may proteolytically remove important cell surface molecules (CD25) in leucocytes; (3) Bromelain may reduce neutrophils migration to periodontal sites; (4) Bromelain can downregulate the inflammation mediators such as IFNγ, TNF, GMCSF, and Cox-2; and (5) Bromelain can decrease the osteoclastogenesis process with a decrease in alveolar bone loss in periodontitis [Figure 1].
Figure 1: The figures represent the possible mechanisms of action of bromelain ameliorating the progression and development of periodontitis, indicated by five points: (a) Bromelain can decrease the periodontal microorganism growth; (b) Bromelain proteolytically can remove important cell surface molecules in leucocytes; (c) Bromelain can reduce neutrophils migration to periodontal sites; (d) Bromelain downregulates the inflammation mediators; (e) Bromelain can decrease the osteoclastogenesis process with reduction of alveolar bone loss in periodontitis

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First, bromelain was able to inhibit the growth of a wide array of microorganisms including A. actinomycetemcomitans (Aa), P. gingivalis (Pg), and S. mutans, which are mainly associated with periodontitis [25] [Figure 1]a. Bromelain has an anti-adhesion property that prevents the bacteria from adhering to specific glycoprotein receptors located on the surface, similar to the hypothesis of Praveen et al. [25]

Second, this hypothesis is supported by the in vivo capacity of bromelain to proteolytically remove cell surface molecules, reducing activated CD4+ T leukocytes, especially CD4+ CD25+ T cells, when administered in a murine model of allergic airway disease, [41] along with a reduction of CD25 molecules in a dose-dependent manner, keeping the biological function of the CD4+ T cells in vitro.[42] Immunohistological analyses demonstrated an elevated infiltrate of CD4+ CD25+ T cells in periodontitis lesions. [43] Therefore, we hypothesized that bromelain treatment can ameliorate the condition of the periodontal tissues, reducing the effects caused by the CD4+ CD25+ T cells that suppress immune responses to self. [44] [Figure 1]b.

Third, it is well-known that the hyperactivity of neutrophils results in damage to the periodontium. [6] A study demonstrated that the severity of gingival inflammation is consistent with elevated neutrophil count in patients with periodontitis. [7] In addition, the neutrophils release several pro-inflammatory cytokines. [10] Bromelain was able to reduce the migration of neutrophils in 50-85% and affect the firm adhesion of leukocytes to blood vessels, removing CD128 from the surface of the neutrophils [24] [Figure 1]c.

Fourth, bromelain downregulates the inflammation mediators such as IFNγ, TNF, and GMCSF in patients with Crohn's disease, [20] as well as Cox-2 expression in mouse skin papillomas stimulated by 7,12-dimethylbenz(a) anthracene. [33] All mentioned inflammation mediators appeared in the periodontitis at elevated concentrations when compared to healthy periodontum. [31],[32] We believe that bromelain treatment may also downregulate the same mediators in periodontitis [Figure 1]d, promoting the reduction of clinical inflammatory parameters. Inchiongolo et al. [45] tested the anti-inflammatory effect of bromelain treatment after third molar surgery and found a reduction of postoperative pain and edema in patients that was comparable to diclofenac sodium treatment. De la Barrera-Núñez et al. [22] demonstrated less inflammation and improved oral aperture, even though the bromelain treatment was done with 150 mg per day, whereas in the study by Inchiongolo et al., [45] a dose of 250 mg per day was used.

Fifth, bromelain may reduce the rate of bone resorption in periodontal inflammation due to the capacity of inhibition of MAP kinase signaling pathway [46] because the pro-inflammatory cytokines contribute with bone resorption through osteoclast differentiation by MAP kinase-JAK-STAT signaling, [47] as well as by interfering in the mechanism of osteoclastogenesis. Bromelain inhibited the phosphorylation of Ser-32 residue of phosphor-inhibitor kappa B (IkB), an important molecule for the translocation and function of nuclear factor-kappa B (NF-kB), [48] consequently blocking NF-kB action. [33],[48] NF-kB, its receptor activator (also known as RANK) and ligand (RANKL) are involved in bone resorption during periodontitis due to the enhancement of osteoclast differentiation and stimulation of osteoclastogenesis. [12] We have hypothesized that this process can be decreased by bromelain treatment [Figure 1]e.


  Evaluation of the Hypothesis Top


First, studies using animals should be designed to evaluate this hypothesis. A potential approach to confirm this hypothesis is to evaluate the effect of bromelain (commercially available by Sigma-Aldrich;) on periodontitis models in mice or rats. Two models could be used to investigate the periodontitis, i.e., using the ligature [49],[50] or bacteria inoculation, [3],[9] both of which have been widely used in initial studies. We believe that both methods could be tested; we suggest a minimal regime of the 20 days for bromelain treatment in the periodontitis-induced animals. We suggest administrating bromelain at a dosage of 15 mg/kg body weight daily because our research team has already obtained encouraging results with this treatment design in other animal models (unpublished data). In addition, the ligature model to induce periodontitis can possible confirm the hypothesis regarding the effect of bromelain on bacterial growth inhibition. Using this study design, it is possible evaluate the benefits on periodontium as well the potential systemic effects.

To confirm the hypothesis, the data must show that animals treated with bromelain demonstrate significant reduction of osteoclastogenesis, neutrophils migration to periodontal site, inflammation mediators' levels such as IFNγ, TNF, GMCSF and Cox-2 than the ones treated with placebo. Therefore, this finding would characterize amelioration in the progression and development of periodontitis.

If studies using animal models show encouraging results, such as significant reduction in alveolar bone loss, inflammation histological and clinical score, myeloperoxidase, stress oxidative, lipid peroxidation, and pro-inflammatory cytokines, appropriate clinical trials should be designed to evaluate this hypothesis. A possible way to evaluate the effect of bromelain as a complementary treatment for periodontal disease in humans is to conduct a placebo-controlled, double blind, randomized study where patients with periodontitis are divided in groups such as "bromelain and periodontal therapy" and "periodontal therapy," or "bromelain gel (topic application) and periodontal therapy" and "periodontal therapy." This idea is based on the most frequent therapy for periodontitis, scaling and root planning, as well as oral hygiene instructions in non-surgical therapy. Bromelain as a complementary treatment for periodontal disease in humans can also be tested for complementing the surgical therapies.

The dosages of bromelain selected for previous studies could be based in previous clinical trials [22],[38],[39],[40],[45] that administrated 150-250 mg per day. Patients treated with bromelain should exhibit improvement in clinical parameters when compared to patients that did not receive bromelain treatment, providing support for the utility of bromelain as a complementary treatment of periodontitis. According to a recent meta-analysis that demonstrated the clinical efficacy of probiotics as an adjunctive therapy to nonsurgical periodontal treatment of chronic periodontitis, [51] bromelain as an adjuvant treatment of periodontitis presents a potential future.


  Conclusion Top


This article indicates the possible mechanisms through which bromelain may ameliorate the progression and development of periodontitis. Bromelain can act by decreasing periodontal microorganism growth, by proteolytically cleaving important cell surface molecules in leucocytes, by reducing neutrophil migration to periodontal sites, by downregulating the inflammation mediator levels, and by decreasing alveolar bone loss in periodontitis.

Financial support and sponsorship

Study supported by the Federal University of Piaui (UFPI - BIAMA 03/2014 and Edital PIBIC 2014/2015), CNPq (455104/2014-0).

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Genco RJ, Borgnakke WS. Risk factors for periodontal disease. Periodontol 2000 2013;62:59-94.  Back to cited text no. 1
    
2.
Hajishengallis G. Periodontitis: From microbial immune subversion to systemic inflammation. Nat Rev Immunol 2015;15:30-44.  Back to cited text no. 2
    
3.
Blasco-Baque V, Garidou L, Pomié C, Escoula Q, Loubieres P, Le Gall-David S, et al. Periodontitis induced by Porphyromonas gingivalis drives periodontal microbiota dysbiosis and insulin resistance via an impaired adaptive immune response. Gut 2016;2. pii: gutjnl-2015-309897.  Back to cited text no. 3
    
4.
Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, Jacobs DR Jr, Sacco RL, et al. Periodontal microbiota and carotid intima-media thickness: The Oral Infections and Vascular Disease Epidemiology Study (INVEST). Circulation 2005;111:576-82.  Back to cited text no. 4
    
5.
Hajishengallis G, Chavakis T, Hajishengallis E, Lambris JD. Neutrophil homeostasis and inflammation: Novel paradigms from studying periodontitis. J Leukoc Biol 2015;98:539-48.  Back to cited text no. 5
    
6.
Bhansali RS, Yeltiwar RK, Bhat KG. Assessment of peripheral neutrophil functions in patients with localized aggressive periodontitis in the Indian population. J Indian Soc Periodontol 2013;17:731-6.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
7.
Moosani A, Sigal MJ, Glogauer M, Lawrence HP, Goldberg M, Tenenbaum HC. Evaluation of periodontal disease and oral inflammatory load in adults with special needs using oral neutrophil quantification. Spec Care Dentist 2014;34:303-12.  Back to cited text no. 7
    
8.
Garlet GP, Cardoso CR, Campanelli AP, Garlet TP, Avila-Campos MJ, Cunha FQ, et al. The essential role of IFN-gamma in the control of lethal Aggregatibacter actinomycetemcomitans infection in mice. Microbes Infect 2008;10:489-96.  Back to cited text no. 8
    
9.
Lam RS, O′Brien-Simpson NM, Hamilton JA, Lenzo JC, Holden JA, Brammar GC, et al. GM-CSF and uPA are required for Porphyromonas gingivalis-induced alveolar bone loss in a mouse periodontitis model. Immunol Cell Biol 2015;93:705-15.  Back to cited text no. 9
    
10.
Cavalla F, Araujo-Pires AC, Biguetti CC, Garlet GP. Cytokine networks regulating inflammation and immune defense in the oral cavity. Curr Oral Health Rep 2014;1:104-13.  Back to cited text no. 10
    
11.
Barbato L, Francioni E, Bianchi M, Mascitelli E, Marco LB, Tonelli DP. Periodontitis and bone metabolism. Clin Cases Miner Bone Metab 2015;12:174-7.  Back to cited text no. 11
    
12.
Mori G, D′Amelio P, Faccio R, Brunetti G. The Interplay between the bone and the immune system. Clin Dev Immunol 2013;2013:720504.  Back to cited text no. 12
    
13.
Nagayasu-Tanaka T, Anzai J, Takaki S, Shiraishi N, Terashima A, Asano T, et al. Action Mechanism of Fibroblast Growth Factor-2 (FGF-2) in the Promotion of Periodontal Regeneration in Beagle Dogs. PLoS One 2015;10:e0131870.  Back to cited text no. 13
    
14.
Vasconcelos DF, Marques MR, Benatti BB, Barros SP, Nociti FH Jr, Novaes PD. Intermittent parathyroid hormone administration improves periodontal healing in rats. J Periodontol 2014;85:721-8.  Back to cited text no. 14
    
15.
Cochran DL, Oh TJ, Mills MP, Clem DS, McClain PK, Schallhorn RA, et al. A Randomized Clinical Trial Evaluating rh-FGF-2/β-TCP in Periodontal Defects. J Dent Res 2016;23 [Epub ahead of print].  Back to cited text no. 15
    
16.
Badran Z, Struillou X, Verner C, Clee T, Rakic M, Martinez MC, et al. Periodontitis as a risk factor for systemic disease: Are microparticles the missing link? Med Hypotheses 2015;84:555-6.  Back to cited text no. 16
    
17.
Morimoto-Yamashita Y, Kawakami Y, Tatsuyama S, Miyashita K, Emoto M, Kikuchi K, et al. A natural therapeutic approach for the treatment of periodontitis by MK615. Med Hypotheses 2015;85:618-21.  Back to cited text no. 17
    
18.
Huang RY, Lu SH, Su KW, Chen JK, Fang WH, Liao WN, et al. Diacerein: A potential therapeutic drug for periodontal disease. Med Hypotheses 2012;79:165-7.  Back to cited text no. 18
    
19.
Agostinis C, Zorzet S, De Leo R, Zauli G, De Seta F, Bulla R. The combination of N-acetyl cysteine, alpha-lipoic acid, and bromelain shows high anti-inflammatory properties in novel in vivo and in vitro models of endometriosis. Mediators Inflamm 2015;2015:918089.  Back to cited text no. 19
    
20.
Onken JE, Greer PK, Calingaert B, Hale LP. Bromelain treatment decreases secretion of pro-inflammatory cytokines and chemokines by colon biopsies in vitro. Clin Immunol 2008;126:345-52.  Back to cited text no. 20
    
21.
Inchingolo F, Tatullo M, Marrelli M, Inchingolo AM, Picciariello V, Inchingolo AD, et al. Clinical trial with bromelain in third molar exodontia. Eur Rev Med Pharmacol Sci 2010;14:771-4.  Back to cited text no. 21
    
22.
de la Barrera-Núñez MC, Yáñez-Vico RM, Batista-Cruzado A, Heurtebise-Saavedra JM, Castillo-de Oyagüe R, Torres-Lagares D. Prospective double-blind clinical trial evaluating the effectiveness of Bromelain in the third molar extraction postoperative period. Med Oral Patol Oral Cir Bucal 2014;19:e157-62.  Back to cited text no. 22
    
23.
Wittenborg A, Bock PR, Hanisch J, Saller R, Schneider B. Comparative epidemiological study in patients with rheumatic diseases illustrated in an example of a treatment with non-steroidal anti-inflammatory drugs versus an oral enzyme combination preparation. Arzneimittelforschung 2000;50:728-38.  Back to cited text no. 23
    
24.
Fitzhugh DJ, Shan S, Dewhirst MW, Hale LP. Bromelain treatment decreases neutrophil migration to sites of inflammation. Clin Immunol 2008;128:66-74.  Back to cited text no. 24
    
25.
Praveen NC, Rajesh A, Madan M, Chaurasia VR, Hiremath NV, Sharma AM. In vitro Evaluation of Antibacterial Efficacy of Pineapple Extract (Bromelain) on Periodontal Pathogens. J Int Oral Health 2014;6:96-8.  Back to cited text no. 25
    
26.
de Lencastre Novaes LC, Jozala AF, Lopes AM, de Carvalho Santos-Ebinuma V, Mazzola PG, Pessoa Junior A. Stability, purification, and applications of bromelain: A review. Biotechnol Prog 2016;32:5-13.  Back to cited text no. 26
    
27.
Maurer HR. Bromelain: Biochemistry, pharmacology and medical use. Cell Mol Life Sci 2001;58:1234-45.  Back to cited text no. 27
    
28.
Papathanasiou E, Teles F, Griffin T, Arguello E, Finkelman M, Hanley J, et al. Gingival crevicular fluid levels of IFNγ, but not interleukin-4 or -33 or thymic stromal lymphopoietin, are increased in inflamed sites in patients with periodontal disease. J Periodontal Res 2014;49:55-61.  Back to cited text no. 28
    
29.
Varghese SS, Thomas H, Jayakumar ND, Sankari M, Lakshmanan R. Estimation of salivary tumor necrosis factor-alpha in chronic and aggressive periodontitispatients. Contemp Clin Dent 2015;6(Suppl 1):S152-6.  Back to cited text no. 29
    
30.
Kraemer SA, Meade EA, DeWitt DL. Prostaglandin endoperoxide synthase gene structure: Identification of the transcriptional start site and 5-flanking regulatory sequences. Arch Biochem Biophys 1992;293:391-400  Back to cited text no. 30
    
31.
Offenbacher S, Odle BM, Van Dyke TE. The use of crevicular fluid prostaglandin E2 levels as a predictor of periodontal attachment loss. J Periodontal Res 1986;21:101-12.  Back to cited text no. 31
    
32.
Noguchi K, Ishikawa I. The roles of cyclooxygenase-2 and prostaglandin E2 in periodontal disease. Periodontol 2000 2007;43:85-101.  Back to cited text no. 32
    
33.
Kalra N, Bhui K, Roy P, Srivastava S, George J, Prasad S, et al. Regulation of p53, nuclear factor kappaB and cyclooxygenase-2 expression by bromelainthrough targeting mitogen-activated protein kinase pathway in mouse skin. Toxicol Appl Pharmacol 2008;226:30-7.  Back to cited text no. 33
    
34.
Huang JR, Wu CC, Hou RC, Jeng KC Bromelain inhibits lipopolysaccharide-induced cytokine production in human THP-1 monocytes via the removal of CD14. Immunol Invest 2008;37:263-77.  Back to cited text no. 34
    
35.
Hou RC, Chen YS, Huang JR, Jeng KC. Cross-linked bromelain inhibits lipopolysaccharide-induced cytokine production involving cellular signaling suppression in rats. J Agric Food Chem 2006;54:2193-8.  Back to cited text no. 35
    
36.
Hale LP, Greer PK, Sempowski GD. Bromelain treatment alters leukocyte expression of cell surface molecules involved in cellular adhesion and activation. Clin Immunol 2002;104:183-90.  Back to cited text no. 36
    
37.
Dutta S, Bhattacharyya D. Enzymatic, antimicrobial and toxicity studies of the aqueous extract of Ananas comosus (pineapple) crown leaf. J Ethnopharmacol 2013;150:451-7.  Back to cited text no. 37
    
38.
Klein G, Kullich W, Schnitker J, Schwann H. Efficacy and tolerance of an oral enzyme combination in painful osteoarthritis of the hip. A double-blind, randomised study comparing oral enzymes with non-steroidal anti-inflammatory drugs. Clin Exp Rheumatol 2006;24:25-30.  Back to cited text no. 38
    
39.
Brien S, Lewith G, Walker AF, Middleton R, Prescott P, Bundy R. Bromelain as an adjunctive treatment for moderate to severe osteoarthritis of the knee: A randomized placebo-controlled pilot study. QJM 2006;99:841-50.  Back to cited text no. 39
    
40.
Guo R, Canter PH, Ernst E. Herbal medicines for the treatment of rhinosinusitis: A systematic review. Otolaryngol Head and Neck Surg 2006;135:496-506.  Back to cited text no. 40
    
41.
Secor ER Jr, Carson WF 4 th , Cloutier MM, Guernsey LA, Schramm CM, Wu CA, et al. Bromelain exerts anti-inflammatory effects in an ovalbumin-induced murine model of allergic airway disease. Cell Immunol 2005;237:68-75.  Back to cited text no. 41
    
42.
Secor ER Jr, Singh A, Guernsey LA, McNamara JT, Zhan L, Maulik N, et al. Bromelain treatment reduces CD25 expression on activated CD4+T cells in vitro. Int Immunopharmacol 2009;9:340-6.  Back to cited text no. 42
    
43.
Okui T, Aoki Y, Ito H, Honda T, Yamazaki K. The presence of IL-17+/FOXP3+double-positive cells in periodontitis. J Dent Res 2012;91:574-9.  Back to cited text no. 43
    
44.
Cardoso CR, Garlet GP, Moreira AP, Júnior WM, Rossi MA, Silva JS. Characterization of CD4+CD25+natural regulatory T cells in the inflammatory infiltrate of human chronic periodontitis. J Leukoc Biol 2008;84:311-8.  Back to cited text no. 44
    
45.
Inchingolo F, Tatullo M, Marrelli M, Inchingolo AM, Scacco S, Inchingolo AD, et al. Trial with Platelet-Rich Fibrin and Bio-Oss used as grafting materials in the treatment of the severemaxillar bone atrophy: Clinical and radiological evaluations. Eur Rev Med Pharmacol Sci 2010;14:1075-84.  Back to cited text no. 45
    
46.
Mynott TL, Crossett B, Prathalingam SR. Proteolytic inhibition of Salmonella enterica serovar typhimurium-induced activation of the mitogen-activated protein kinases ERK and JNK in cultured human intestinal cells. Infect Immun 2002;70:86-95.  Back to cited text no. 46
    
47.
Menezes R, Garlet TP, Trombone AP, Repeke CE, Letra A, Granjeiro JM, et al. The potential role of suppressors of cytokine signaling in the attenuation of inflammatory reaction and alveolar bone loss associated with apical periodontitis. J Endod 2008;34:1480-4.  Back to cited text no. 47
    
48.
Bhui K, Tyagi S, Srivastava AK, Singh M, Roy P, Singh R, et al. Bromelain inhibits nuclear factor kappa-B translocation, driving human epidermoid carcinoma A431 and melanoma A375 cells through G (2)/M arrest to apoptosis. Mol Carcinog 2012;51:231-43.  Back to cited text no. 48
    
49.
Pereira Vasconcelos DF, Dias da Silva MA, Rocha Marques M, Gibilini C, Cardoso Guimarães Vasconcelos AC, Pereira Barros S. Effects of simultaneous nicotine and alcohol use in periodontitis progression in rats: A histomorphometric study. J Clin Exp Dent 2013;1;5:e95-9.  Back to cited text no. 49
    
50.
Campi P, Herrera BS, de Jesus FN, Napolitano M, Teixeira SA, Maia-Dantas A, et al. Endothelial dysfunction in rats with ligature-induced periodontitis: Participation of nitric oxide and cycloxygenase-2-derived products. Arch Oral Biol 2016;63:66-74.  Back to cited text no. 50
    
51.
Martin-Cabezas R, Davideau JL, Tenenbaum H, Huck O. Clinical efficacy of probiotics as an adjunctive therapy to non-surgical periodontal treatment of chronic periodontitis: A systematic review and meta-analysis. J Clin Periodontol 2016;43:520-30.  Back to cited text no. 51
    


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