Berberine as a promising natural compound for the treatment of periodontal disease: A focus on anti‐inflammatory properties

Abstract Accumulating evidence during the last two decades has addressed the potential anti‐inflammatory properties of berberine (BBR), a bioactive alkaloid compound isolated from Coptidis rhizoma, in controlling or treating several inflammatory diseases. Periodontitis is one of the most common chronic and serious inflammatory diseases, in which uncontrolled and unabated host immune responses against periodontopathic pathogens play critical and crucial roles in the disease pathogenesis. Hence, regulating inflammatory responses in periodontitis has a valuable approach and holds promise in treating periodontitis. For the first time, this paper reviews the evidence from in vitro and in vivo experimental models to explore the anti‐inflammatory effects of BBR in periodontitis and exhibits that BBR has the high potency to exert anti‐inflammatory effects by reducing expression and secretion of pro‐inflammatory mediators including TNF‐α, IL‐1β, IL‐17, RANKL, MMP‐2, MMP‐9 and MCP‐1. The BBR‐mediated anti‐inflammatory actions could translate into the inhibition of the periodontal tissues and alveolar bone destruction and the control of the disease in vivo. As the second aim of this paper, we also paid attention to the therapeutic potential of BBR in treating human diseases regarding its anti‐inflammatory properties.


| INTRODUC TI ON
Periodontitis is the most common chronic inflammatory disorder of oral characterized by the uncontrolled inflammation in the periodontium and the tooth-supporting tissues, which subsequently contributes to the destruction of periodontal tissues and alveolar bone. 1 Meanwhile, in the severe form of the disease (aggressive periodontitis), periodontitis can affect systemic health by increasing the patients' risk for several diseases such as rheumatoid arthritis (RA), atherosclerosis, cancer, adverse pregnancy outcomes and pneumonia. 1,2 In light of recent evidence in the pathogenesis of the periodontal disease, it is well-documented that subgingival bacterial pathogens, Porphyromonas gingivalis, and other periodontitis-associated species, by colonizing in the dental plaque elicit host pro-inflammatory responses. 2,3 These pro-inflammatory responses are complex and contain both protective and destructive responses. 4 Although periodontal pro-inflammatory responses are protective against periodontopathic bacteria, failure in the mechanisms that tightly regulate inflammation in the oral cavity results in the generation of destructive and unabated inflammatory reactions that mediate tissue damages. 4 It is now well established that both innate and adaptive immune responses play crucial roles in the immunopathogenesis of periodontitis. 5 Local inflammation is the main feature of periodontitis that is characterized by the infiltration of several inflammatory immune cells such as neutrophils, macrophages, dendritic cells (DCs), as well as B and T cells in the periodontium. 5,6 In innate immune responses, neutrophils and macrophages by producing different types of inflammatory cytokines such as tumour necrosis factorα (TNFα), interleukin 1β (IL-1β), IL-8 and monocyte chemoattractant protein 1 (MCP-1) as well as by secreting several tissue-degrading enzymes such as collagenases and matrix metalloproteinases (MMPs) play fundamental roles in the initiation of the periodontitis. 7 In adaptive immune responses, inflammatory CD4 + T cells, especially IL-17-producing CD4 + T cells, are the main players in the development of the periodontium. 8,9 IL-17 is one of the most important pro-inflammatory cytokines that contribute to the destructive periodontal inflammation by recruiting neutrophils as well as by inducing the production of pro-inflammatory mediators such as TNFα, IL-1, IL-6 and receptor activator of nuclear factor kappa-Β (NF-κB) ligand (RANKL), which eventually leads to the periodontal tissues destruction and alveolar bone resorption through osteoclast formation and activation. 10 Understanding the mechanisms that contribute to the pathogenesis of periodontitis has led to the development of therapeutics aiming at treating or managing the disease. Therapeutic agents such as adjuvant administration of systemic antibiotics, corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs) are the fundamental property of periodontitis treatment; however, the main obstacle facing with long-term use of these therapies is limitations and adverse effects such as microbial resistance, the influence on the entire microbiome of the human organism, infections, liver injury, gastrointestinal damage and heart failure. 11,12 Hence, there exists an urgent need to address alternative therapeutic agents, which may consist of synthetic or natural origin, for the treatment of periodontitis.
The past two decades have seen increasingly rapid advances in the field of pharmacology using naturally occurring medicine. [13][14][15][16] In this regard, mounting evidence has addressed the potential antiinflammatory properties of berberine (BBR), a bioactive alkaloid compound isolated from Coptidis rhizoma, in controlling or treating several inflammatory diseases. For the first, this paper provides an overview of BBR's anti-inflammatory effects and its therapeutic potential for the treatment of periodontitis. 17

| B B R : A P OTENTIAL NATUR AL OCCURRING COMP OUND
Berberine (benzyltetrahydroxyquinoline) (BBR) is an isoquinoline alkaloid originally isolated from the Chinese herb huanglian (Coptidis rhizoma). 18 Studies over the past two decades have provided important evidence on the polytrophic pharmacological effects of BBR including anti-microbial, anti-oxidant, anti-tumour, and antiinflammatory, and anti-diabetic activities. 14,19-21 Interestingly, a considerable amount of research studies have been published on the immunomodulatory effects of BBR in the immune system. 19,22 These studies have confirmed that BBR's anti-inflammatory effect arises from its interaction with different types of immune cells including keratinocytes, epithelial cells, DCs, macrophages, mast cells, and T and B cells. 14,19 Interestingly, recent findings have been indicated that BBR as a pleiotropic molecule by interacting on several signaling molecules and transcription factors such as NF-κB, activated protein 1 (AP1), janus kinases/signal transducer and activator of transcriptions (JAKs/STATs), mitogen-activated protein kinases (MAPKs), and AMP-activated protein kinase (AMPK) can effectively mediate its anti-inflammatory roles in the immune system. 23 32 In this regard, the molecular mechanisms by which BBR exerts its anti-inflammatory effects in periodontitis have been described in detail. 32 BBR by increasing the protein expression of G proteincoupled estrogen receptor (GPR30) effectively inhibited the activation of two important inflammatory signaling pathways involved in the pathogenesis of periodontitis including NF-κB and MAPKs cascades. 32 Further investigation also confirmed the anti-inflammatory effects of BBR in periodontitis, as it has been shown that following treatment with BBR, the expression levels of pro-inflammatory cytokines including TNFα, IL-1β, and RANKL markedly downregulated in rat with periodontitis. 33 In this study, proprotein convertase subtilisin/kexin type 9 (PCSK9), a key enzyme for the promotion of inflammatory responses, has been identified as a new target for BBR's anti-inflammatory action. In this regard, BBR treatment by reducing the production of PCSK9, which is subsequently followed by inhibition of inflammatory responses, remarkably alleviated P.g.induced periodontitis. 33 As an important pathologic cytokine in periodontitis, RANKL, which is produced by activated T cells, mediates differentiation and activation of osteoclasts, leading to the alveolar bone resorption. 34 Hence, BBR is capable of inhibiting bone destruction in periodontitis through hampering production of RANKL. 33 Likewise, Yu et al hold the view that BBR exerts anti-inflammatory effects in periodontitis, as they clearly indicated that BBR is efficacious to downregulate the expression of TNFα and ILβ in periodontal tissues of rat with periodontitis. 35 Table 1 provides an overview of the anti-inflammatory effects of BBR in several preclinical (in vitro and in vivo) studies. Figure 1 also presents the BBR's anti-inflammatory effects in periodontitis.
Considering aforementioned findings, it can be suggested that BBR by acting on inflammatory signaling pathways, which play key roles in initiating and promoting inflammatory responses in periodontitis, is capable of inhibiting inflammation that is represented TA B L E 1 A brief overview of the anti-inflammatory effects of berberine in vitro and in vivo Type of study Cell/animal model Biological effects Ref.

In vitro In vivo
Gingival fibroblast cells U937 macrophages Rat model of periodontitis Inhibit the activities of pro-MMP-2, MMP-2 and MMP-9 [29] In vitro PDLCs Reduce the secretion of MCP-1 [30] In vivo Rat model of periodontitis Attenuate the production of TNFα and IL-17, as well as the number of IL-17A + cells [31] In vivo Rat model of periodontitis Reduce the levels of pro-inflammatory cytokines TNFα and IL-1β [32] In vivo Rat model of periodontitis Reduce the production of TNFα, IL-1β and RANKL [33] In vivo Rat model of periodontitis Reduce the production of TNFα and IL-1β [35] F I G U R E 1 A schematic view of berberine's (BBR) anti-inflammatory effects in periodontitis. BBR is capable of inhibiting the production of proinflammatory mediators including TNFα, IL-1β, IL-17, MCP-1 IL-8, and RANKL as well as the expression and activities of MMP-2 and MMP-9 by inflammatory immune cells in the context of the periodontium by reduced production of pro-inflammatory mediators and several tissue degrading enzymes.

| ANTI -INFL AMMATORY EFFEC TS OF B B R IN CLINI C AL TRIAL
What we know about the anti-inflammatory effects of BBR is largely based upon the findings that emerged from in vitro and in vivo experimental studies. Besides, some clinical studies have also investigated the therapeutic potential of BBR regarding its anti-inflammatory properties. In a randomized double-blind phase I trial on patients with ulcer colitis, it has been shown that treatment with BBR (900 mg/day) for would be interesting to assess the anti-inflammatory effects and therapeutic potential of BBR in patients with periodontitis.

CO N FLI C T O F I NTE R E S T
We wish to confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analysed in this study.