Review Article © 2018 - ISSN 1807-2577 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 work is properly cited. Rev Odontol UNESP. 2023;52:e20230031. DOI: https://doi.org/10.1590/1807-2577.03123 1/11 Endocannabinoid system and periodontitis: mechanisms and therapeutic implications Sistema endocanabinoide e periodontite: mecanismos e implicações terapêuticas Lélio Fernando Ferreira SOARESa , Luan Viana FARIAa , Joni Augusto CIRELLIa*  aUNESP – Universidade Estadual Paulista Júlio de Mesquita Filho, Faculdade de Odontologia de Araraquara, Departamento de Diagnóstico e Cirurgia, Araraquara, SP, Brasil How to cite: Soares LFF, Faria LV, Cirelli JA. Endocannabinoid system and periodontitis: mechanisms and therapeutic implications. Rev Odontol UNESP. 2023;52:e20230031. https://doi.org/10.1590/1807-2577.03123 Resumo Introdução: A periodontite é um importante problema de saúde pública. Embora o princípio da terapia da periodontite esteja focado principalmente na remoção do biofilme dental e dos fatores associados, sua fisiopatologia registra diferentes eventos moleculares e inflamatórios relacionados ao sistema imunológico do hospedeiro, como a participação do sistema endocanabinoide. Objetivo: Esta revisão teve como objetivo explorar e elucidar os mecanismos e papéis do sistema endocanabinoide na fisiopatologia da periodontite e suas possibilidades para futuras terapias relacionadas. Material e método: Realizou-se uma busca eletrônica na plataforma PubMed por estudos envolvendo a ação do sistema endocanabinoide sobre a periodontite. Resultado: Dezenove estudos clínicos e pré-clínicos foram incluídos nesta revisão narrativa. Conclusão: Os receptores canabinoides tipo 1 e 2 são componentes integrais do sistema endocanabinoide e manifestam-se de várias formas nos tecidos periodontais. As ações e mecanismos através dos quais os receptores canabinoides são ativados em locais saudáveis ou inflamados continuam a ser o foco de investigações em curso. Além disso, os fitocanabinoides e canabinoides sintéticos apresentam potencial como tratamentos, com estudos pré-clínicos indicando benefícios na redução da inflamação e na facilitação da reparação dos tecidos. Descritores: Canabinoides; receptor CB1 de canabinoide; receptor CB2 de canabinoide; inflamação; periodontite. Abstract Introduction: Periodontitis is a major public health problem. Although the principle of periodontitis therapy is mainly focused on removing dental biofilm and associated factors, its physiopathology enrolls different molecular and inflammatory events related to the host immune system, as the participation of the endocannabinoid system. Objective: This review aimed to explore and elucidate the mechanisms and roles of the endocannabinoid system on periodontitis physiopathology and its possibilities for future related therapies. Material and method: An electronic search was carried out on the PubMed platform for studies involving the action of the endocannabinoid system on periodontitis. Result: Nineteen clinical and preclinical studies were included in this narrative review. Conclusion: Cannabinoid receptors type 1 and 2 are integral components of the endocannabinoid system, manifesting in various forms in the periodontal tissues. The actions and mechanisms through which cannabinoid receptors are activated in healthy or inflamed sites remain the focus of ongoing investigations. Moreover, phytocannabinoids and synthetic cannabinoids show therapeutic potential, with pre-clinical studies indicating benefits in reducing inflammation and facilitating tissue repair. Descriptors: Cannabinoids; CB1 receptor; CB2 receptor; inflammation; periodontitis. https://creativecommons.org/licenses/by/4.0/ https://orcid.org/0000-0003-4174-2943 https://orcid.org/0000-0003-2336-9946 https://orcid.org/0000-0002-7082-9290 Endocannabinoid System and Periodontitis Rev Odontol UNESP. 2023;52:e20230031. DOI: https://doi.org/10.1590/1807-2577.03123 2/11 INTRODUCTION Periodontitis (PD) is a chronic inflammatory multifactorial disease associated with the presence of a dysbiotic biofilm1,2. Characterized by progressive destruction of the tooth- supporting apparatus, if untreated, PD may lead to tooth loss, although it is treatable and preventable in most cases3-5. Furthermore, its importance is highlighted as a major public health problem, being the most common chronic inflammatory non-communicable disease of humans3,6. Although the principle of PD therapy mainly focuses on removing dental biofilm and associated factors, its physiopathology enrolls different molecular and inflammatory events related to the host immune system7,8. The activation of innate immune mechanisms by different receptors, such as Toll-like receptors (TLRs), are not only capable of recognizing pathogen-associated molecular patterns (PAMPs) but also modulating downstream signaling cascades, resulting in the activation of different transcription factors, such as nuclear factor-kappa B (NF-κB)7,9,10. Finally, these events are signaled by cytokine networks and different molecular mediators that dictate disease progression. These characteristics and events of PD highlight the importance of mechanisms related to the inflammatory response and its modulation for new insights and therapies11,12. Recently, much has been discussed about the role of the endocannabinoid system (ECS) and the action of the phytocannabinoids in human health and inflammatory processes13-15. The ECS comprises endocannabinoids, cannabinoid receptors (CBs) type 1 (CB1) and type 2 (CB2), and enzymes governing endocannabinoid metabolism, offering a finely tuned regulatory apparatus13,16. Endocannabinoids are lipidic mediators deriving from arachidonic acid, synthesized in a stimulus- dependent manner, engaging cannabinoid receptors, expressed on immune cells and pertinent cell populations17,18. This interaction can elicit the regulation of proinflammatory cytokines production and immune cell activation, with potential interest in new investigations on PD inflammatory processes and new therapies focused on host immune modulation19-21. This review aims to explore and elucidate the mechanisms and roles of the ECS on PD physiopathology and its possibilities for future related therapies. LITERATURE REVIEW Cannabinoid Receptors and Periodontitis Cannabinoid receptors, CB1 and CB2, are integral components of the ECS and are present in the periodontal tissues19. Belonging to the family of G protein-coupled receptors (GPCR) on the surface of cell membranes, they are found in inactive and active functional states. Once activated, these receptors modulate the release of pro-inflammatory cytokines22,23. CB1 receptors, although also present in periodontal tissues, are primarily concentrated in the central nervous system22. When activated by endocannabinoids or exogenous ligands like tetrahydrocannabinol (THC), CB1 receptors interact with Gαi/o proteins, leading to the inhibition of adenylyl cyclase and subsequent reduction in cyclic AMP (cAMP) levels24. This action results in the dampening of intracellular signaling pathways, influencing neurotransmitter release and synaptic transmission25. The Gαi/o protein coupling also activates mitogen-activated protein kinases (MAPK) and protein kinase B (Akt) pathways, contributing to the regulation of not only synaptic plasticity and neuronal function but also participating of immune response and inflammation processes by the triggered pathways26. CB2 receptors, however, are primarily found on immune cells and in peripheral tissues that interact with Gαi proteins to modulate various immune responses and inflammatory processes27,28. It is reported that the activation of CB2 receptors is also capable of inhibiting adenylyl cyclase activity, reducing cAMP levels, but leading to a decrease in protein kinase A (PKA) activation, contributing to the dampening of immune cell activation and cytokine release29. Endocannabinoid System and Periodontitis Rev Odontol UNESP. 2023;52:e20230031. DOI: https://doi.org/10.1590/1807-2577.03123 3/11 Confirming previous findings in the literature, Liu et al.30, reports that CB1 receptors are located sparsely in the periodontal tissues of healthy mice, with more concentration in perivascular cells and some infiltrated cells in the gingival epithelium. CB2 distribution, in turn, is widely expressed in the periodontal tissues at more abundant levels, from the junctional epithelium, gingival connective tissue, and PDL until the alveolar bone surface. These characteristics and distributions of CBs are aligned with the information that CB1 is more present in the central nervous system, and CB2 in peripheral tissues22,27,28. Moreover, it is demonstrated that CB2 activation on human periodontal ligament fibroblasts (hPDLF) is also related to other downstream transcriptional and signaling effectors, such as NF- κB, jun N-terminal kinase (JNK), c-Jun (activator protein-1, AP-1), extracellular signal-regulated kinase (ERK), p38, and cAMP response element-binding protein (CREB)31-33. The interaction of CB2 receptors with G-proteins plays a crucial role in regulating the immune system, positioning it as a potential therapeutic target for inflammatory conditions such as PD21,34. Two recent clinical cross-sectional studies have described the presence and activation of CB1 and CB2 receptors in gingival biopsies of periodontitis patients21,34. According to, Ataei et al.34, gene expression analyses by real-time quantitative polymerase chain reaction (RT-qPCR) resulted in significantly lower expression of CB2 receptors in periodontitis patients' biopsies compared with healthy patients. Besides, the expression of CB1 was not significantly different in both groups of patients in this study. Conversely, Pellegrini et al.21 reported by immunohistochemistry analyses that the number of CB1 and CB2 receptors in inflamed sites of recurrent periodontitis patients were significantly higher than in those with non-recurrent disease and in healthy subjects. Results from the autoradiography for G- protein detection of activated CBs, however, reported that inflamed sites of recurrent periodontitis patients had significantly lower CBs receptor activation than those of healthy subjects. Combined, these results indicate that the activation of CB receptors might provide a protective effect on periodontal tissues since they were more expressed in healthy individuals, mostly CB2, and dysregulated in periodontitis patients21,34. Furthermore, according to the authors, the increased CB expression in recurrent PD patients might indicate a higher susceptibility of the tissues to activate the protective cellular/molecular mechanisms against inflammatory stimuli, but ineffectively21. Conversely, Konermann et al.35 describe more immunohistochemical staining of CB1 than CB2 receptors in PDL cells of healthy individuals. In periodontitis patients, while there is no variation in CB1 levels, CB2 receptors are more expressed than in healthy individuals. Furthermore, Alves et al.36 reported that external stimuli, like electroacupuncture, could reduce bone loss in the furcation of experimental periodontitis animals by enhancing CB2 activity. These pre-clinical and clinical findings and inconsistencies highlight the importance of new investigations on the presence and activation of CBs in inflammatory sites of periodontitis. While remains ambiguous about the number, type, and activation of CBs in healthy or periodontitis sites, their better understanding might help in the future detection of inflammatory processes initiation and susceptibility to PD recurrence, such as in the treatment of the disease itself by administration of local or systemically cannabinoids21,34. Furthermore, little is still known about the action of the ECS in the osseointegration process of dental implants or peri-implantitis. Cannabinoids and Periodontitis Cannabinoids are considered a broader category of compounds that include those found in the cannabis plant (phytocannabinoids) and those produced synthetically13. Endocannabinoids, in turn, are a specific type of cannabinoids produced endogenously within the body and represent a class of lipid signaling molecules that serve as central components of the ECS16,18. These endogenous compounds play a crucial role modulating a diverse array of physiological processes, Endocannabinoid System and Periodontitis Rev Odontol UNESP. 2023;52:e20230031. DOI: https://doi.org/10.1590/1807-2577.03123 4/11 with a complex signaling network that relies on the interactions between endocannabinoids and specific cannabinoid receptors (CB1 and CB2)13. Two primary endocannabinoids, AEA and 2-AG, also present in periodontal tissues, have been extensively characterized (Table 1)19,20,39. Table 1. Included studies on ECS and PD Reference (Year) Study design CB receptor Cell line Animal model CB agonist / test drug Main findings Nakajima et al.19 (2006) In vitro CB1 and CB2 HGF - AEA AEA significantly reduced the production of IL-6, IL-8, and MCP-1 induced by P. gingivalis LPS in HGFs, attenuated by AM251 and SR144528. AEA blocked LPS- triggered NF-kB activation. Kozono et al.20 (2010) In vitro, In vivo and Clinical cross- sectional CB1 and CB2 HGF Oral wounds / rats AEA; CP55940; 2-AG Upregulation of the expression of CB1/CB2 receptors in wound-healing model. Proliferation of HGFs by AEA were attenuated by AM251 and AM630. CP55940 induced phosphorylation of ERK 1/2, p38MAPK, and Akt in HGFs. Wound closure by CP55940 in an in-vitro scratch assay was significantly suppressed by inhibitors of MEK, p38MAPK, and PI3-K. Increase in AEA levels in the gingival crevicular fluid after periodontal surgery in human patients with periodontitis. Qian et al.27 (2010) In vitro CB2 hPDL - HU-308 HU-308 enhanced the mRNA levels of osteogenic genes. Expression of the OPG was up-regulated, whereas RANKL expression was downregulated. Accelerated mineralization was observed in hPDL cells with HU-308. Ossola et al.37 (2012) In vivo CB1 - LPS-induced periodontitis / rats Meth-AEA Topical Meth-AEA significantly diminished alveolar bone loss. Reduction of biological mediators of periodontal disease augmented by LPS. Rettori et al.38 (2012) In vivo CB1 and CB2 - Ligature- induced periodontitis + immobilization stress / rats AEA Local injection of AEA decreased corticosterone plasma levels and the content of the cytokines TNF-α and IL-1β in gingival tissue in periodontitis-stress groups. AEA-induced inhibitions were mediated by CB1 and CB2. Özdemir et al.39 (2014) In vitro CB1 and CB2 hPDL - AEA; 2-AG hPDL viability was significantly increased by AEA in the presence of P. gingivalis LPS. In P.gingivalis LPS stimulated hPDL, AEA down-regulated gene- expression and protein production of IL-6, IL-8, and MCP-1. Ossola et al.40 (2016) In vivo CB2 - LPS-induced periodontitis / rats HU-308 HU-308 attenuated alveolar bone loss resulted by LPS- induced periodontitis, and reduction of inflammatory mediators augmented in LPS-injected rats (iNOS, TNF-α, and PGE2). Endocannabinoid System and Periodontitis Rev Odontol UNESP. 2023;52:e20230031. DOI: https://doi.org/10.1590/1807-2577.03123 5/11 Reference (Year) Study design CB receptor Cell line Animal model CB agonist / test drug Main findings Konermann et al.35 (2017) In vitro, In vivo and Clinical cross- sectional CB1 and CB2 hPDL Mechanically- induced root resorptions - CB1 expression was significantly higher in healthy PDL structures compared to CB2. Bacterial inflammation affected a decrease in CB1, but an increase in CB2. Abidi et al.31 (2018) In vitro CB2 hPDLF - AEA, HU-308 LPS, TNF-α, and IL-1β increased IL-6 and MCP-1 production, which were inhibited by AEA, SMM-189, and HU-308. AEA alone significantly increased IL-6, but not MCP-1 levels. Alves et al.36 (2019) In vivo CB1 and CB2 - Ligature- induced periodontitis / rats Electroacupuncture Increased bone loss in the furcation of experimental periodontitis (EP) and experimental periodontitis- electroacupuncture (EA) - sham groups. Enhanced CB2 immunolabeling was observed in the periodontal tissues in the EP-EA group when compared to the EP and EP-EA-sham groups. Gu et al.24 (2019) In vitro and In vivo CB2 TIGK; CD14+ human monocytes Gavage Infection Model / knockout CB2−/− mice CBD; CBN; THC CBD, CBN, and THC each suppressed P. gingivalis- induced IL-12 p40, IL-6, IL-8, and TNF release while enhancing the anti- inflammatory cytokine, IL- 10, from human innate cells. Similar phenomena were observed in F. alocis- and T. denticola-exposed human monocytes and human gingival keratinocytes. Liu et al.30 (2019) In vitro and in vivo CB1 and CB2 hPDLF Periodontal tissue biopsies / mice THC Both CB1 and CB2 were expressed in periodontal tissues but with different expression patterns. THC promoted periodontal cell wound healing by inducing hPDLF cell adhesion and migration. The effect of cannabinoids on periodontal fibroblast cell adhesion and migration was mainly dependent on the CB2. Yan et al.41 (2019) In vitro CB1 PDLSC - R-1 Meth CB1 overexpression or R-1 Meth promoted the osteo/dentinogenic differentiation of PDLSCs. Deletion of CB1 or the application of AM251 repressed the osteo/dentinogenic differentiation of PDLSCs. The activation of CB1 enhanced the TNF‐α‐ and INF‐γ‐impaired osteo/dentinogenic differentiation potential in PDLSCs. CB1 activated p38 MAPK and JNK signaling and repressed PPAR‐γ and Erk1/2 signaling. Abidi et al.32 (2020) In vitro CB2 hPDLF - AEA, HU-308 AEA exhibited pro- inflammatory and anti- inflammatory effects. CB2R ligands attenuated p-p38 and p-NFĸB, but a late rise in p-38 was seen with HU-308. Table 1. Continued... Endocannabinoid System and Periodontitis Rev Odontol UNESP. 2023;52:e20230031. DOI: https://doi.org/10.1590/1807-2577.03123 6/11 Reference (Year) Study design CB receptor Cell line Animal model CB agonist / test drug Main findings As p-ERK levels declined, a significant increase in p-ERK was observed later in the time course by synthetic CB2R ligands. P-JNK was significantly affected by SMM-189 only, while p-CREB was elevated significantly by CB2R ligands. HU-308 affected both cAMP and β- arrestin pathway. SMM-189 only stimulated cAMP. Ossola et al.42 (2020) In vivo CB2 - LPS-induced periodontitis / rats HU-308 Rats subjected to experimental periodontitis showed higher bone resorption areas, number of osteoclasts and gingival content of prostaglandin E2 than controls, while HU 308 prevented, the deleterious effects. Zhang et al.43 (2020) In vitro CB1 and CB2 hPDL - Meth-AEA Meth-AEA significantly inhibited P. gingivalis LPS- induced production of IL-6, IL-8, and MCP-1. Abidi et al.33 (2022) In vitro CB1 and CB2 HGF - CBVN; CBG; CBD In IL-1β-stimulated HGFs, PGE2 production was significantly suppressed by CBG and CBVN. CBD and CBG elevated PGE2. IL-β- stimulated HGF with pCBs significantly reduced INF-ɣ, TNF-α, and IL-2. Suppression of IL-4 was seen with CBD and CBVN, while only CBVN exerted suppression of IL-13. pCBs significantly increased IL-6, IL-10, and IL-12 levels, while none of the pCBs reduced the expression of IL- 8 in IL-1β-stimulated HGF. Ataei et al.34 (2022) Clinical cross- sectional CB1 and CB2 - - - Expression of CB2 in periodontitis patients was significantly lower than in healthy patients. Expression of CB1 was not significantly different in periodontitis or healthy patients. Pellegrini et al.21 (2023) Clinical cross- sectional CB1 and CB2 - - - The number of CBs in inflamed sites of recurrent periodontitis was significantly higher than in those with non-recurrent disease and in healthy subjects, but less activated. Levels of AEA in inflamed sites of non-recurrent patients were higher than in inflamed recurrent sites and in healthy sites. After periodontal therapy, levels of AEA were significantly lower in both periodontal groups. In recurrent sites, AEA was lower than in non-recurrent and healthy subjects. 2-arachidonylglycerol (2-AG); Anandamide (AEA); Cannabidiol (CBD); Cannabidivarin (CBVN); Cannabigerol (CBG); Cannabinol (CBN); Cannabinoid receptor type 1 (CB1); Cannabinoid receptor type 2 (CB2); Embryonic stem cell-derived microglia cells (ESdM); Human gingival fibroblasts (HGF); Human PDL cells (hPDL); Human periodontal ligament fibroblasts (hPDLF); Human telomerase-immortalized gingival keratinocytes (TIGK); Methanandamide (Meth-AEA); Palmitoylethanolamide (PEA); Periodontal ligament stem cells (PDLSC); Phytocannabinoids (pCBs); R-1 methanandamide (R-1 Meth); Selective agonist of CB2 (HU-308); Selective antagonist of CB1 (AM251); Selective antagonist of CB2 (SR144528); Selective CB2 cannabinoid antagonist/inverse agonist (AM630); Selective CB2 inverse agonist (SMM-189); Synthetic cannabinoid agonist (CP55940); Tetrahydrocannabinol (THC). Table 1. Continued... Endocannabinoid System and Periodontitis Rev Odontol UNESP. 2023;52:e20230031. DOI: https://doi.org/10.1590/1807-2577.03123 7/11 AEA is an endocannabinoid derived from arachidonic acid. Acting as a partial agonist for CB1 receptors, it is expressed mainly in the central nervous system44. On periodontal tissues, although AEA is mainly linked to CB1 activation, studies have shown that it might also regulate periodontal inflammation via receptors CB1 and CB2 in inflamed gingival tissue biopsies and human gingival fibroblast (HGF)19,20. By reducing proinflammatory cytokines, such as TNF-α, IL-1β, IL-6, IL-8, and MCP-1, AEA inhibits NF-κB transcription, reducing corticosterone plasma levels19,20,38,39. Moreover, it was also reported the AEA capability of promoting HGF proliferation and epithelial formation at wound healing sites via ERK1/2 with CB1 and CB2 activation in animal models20. Lastly, it is also reported that the presence and quantification of endogenous AEA in periodontal tissues might indicate inflammatory disease activity20,21. Thus, according to Pellegrini et al.21, from a clinical perspective, low levels of AEA may indicate a predisposition for the reactivation of the disease in periodontitis patients under a periodontal maintenance program. In contrast to AEA, 2-AG interacts with both CB1 and CB2 in different tissues as a full agonist45. Its interaction with CB2 receptors is essential in various events of cytokines release, cell migration, and tissue homeostasis17. Moreover, 2-AG appears to promote detrimentally inflammatory processes and has been reported in higher concentrations in the gingival crevicular fluid (GCF) of periodontitis patients compared to healthy subjects39. Conversely, 2-AG appears not to interfere or vary pre-surgically and post-surgically at periodontal wounds20. The selective activation of these cannabinoid receptors by endocannabinoids is a critical aspect of the ECS, as it allows for context-specific regulation of various physiological functions15,34. The presence of both AEA and 2-AG, as other endocannabinoids, with their distinct affinities and receptor interactions, enables the ECS to finely tune cellular responses to maintain homeostasis and adapt to external challenges13. The use of phytocannabinoids or synthetic cannabinoids is also a therapeutic possibility in PD treatment under investigation24,27,30,32,33,37,40-43. Pre-clinical studies have demonstrated that systemic or local application of different cannabinoids (Table 1) might mimic endocannabinoids action and interact with both CB1 and CB2 in periodontitis models in vitro and in vivo24,33. The main findings related to their use in periodontitis models are upregulation expression of osteogenic genes during repair of diseased sites27, attenuation of alveolar bone loss37,40,42, suppression of proinflammatory cytokines24,27,33,37,43, and inhibition of periodontal pathogens growth24 (Table 1). In summary, this body of evidence under construction underscores the potential therapeutic value of cannabinoids in the treatment of PD. Future investigations in the area may provide a better understanding of the role of CBs and their modulation by endocannabinoids, or drugs that mimic their action, in treating PD as other diseases. CONCLUSION a. CB1 and CB2 are integral components of the ECS and manifest in various forms within periodontal tissues. b. The actions and mechanisms through which CBs are activated in healthy or inflamed sites remain the focus of ongoing investigations. c. Phytocannabinoids and synthetic cannabinoids show therapeutic potential, with pre-clinical studies indicating benefits in reducing inflammation and facilitating tissue repair. d. Additional research is necessary to comprehend their mechanisms and clinical applications in periodontitis management. AUTHOR CONTRIBUTIONS Lélio Fernando Ferreira Soares: Conceptualization, research, methodology, writing of the original manuscript. Luan Viana Faria: Conceptualization, methodology, writing of the original manuscript. Joni Augusto Cirelli: Endocannabinoid System and Periodontitis Rev Odontol UNESP. 2023;52:e20230031. DOI: https://doi.org/10.1590/1807-2577.03123 8/11 Conceptualization, methodology, project management, supervision, validation of data and experiments, proofreading and editing. FUNDING São Paulo Research Foundation (FAPESP), grant number 2023/06881-0. REFERENCES 1. Papapanou PN, Sanz M, Buduneli N, Dietrich T, Feres M, Fine DH, et al. 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CONFLICTS OF INTERESTS The authors declare no conflicts of interest. *CORRESPONDING AUTHOR Joni Augusto Cirelli, UNESP – Universidade Estadual Paulista, Faculdade de Odontologia de Araraquara, Departamento de Diagnóstico e Cirurgia, Rua Humaita, 1680, 14801-903 Araraquara - SP, Brasil, e-mail: joni.cirelli@unesp.br Received: October 31, 2023 Accepted: October 31, 2023 https://doi.org/10.1111/cpr.12691 https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=31599069&dopt=Abstract https://doi.org/10.54589/aol.33/2/143 https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=32920617&dopt=Abstract https://doi.org/10.1186/s12903-020-01087-6 https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=32295577&dopt=Abstract https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=32295577&dopt=Abstract https://doi.org/10.1016/S0014-5793(00)01313-2 https://doi.org/10.1016/S0014-5793(00)01313-2 https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10734225&dopt=Abstract https://doi.org/10.1016/j.pharmthera.2009.01.005 https://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=19248809&dopt=Abstract