Effects of melatonin on insulin signaling and inflammatory pathways of rats with apical periodontitis

Tavares, Bruna S.; Tsosura, Thaís Verônica Saori; Mattera, Maria Sara de Lima Coutinho; Santelli, Julia Ogata; Belardi, Bianca Elvira; Chiba, Fernando Yamamoto; Cintra, Luciano Tavares Ângelo; Silva, C C; Matsushita, Dóris Hissako

doi:10.1111/iej.13474

Cited by 19 publications

(14 citation statements)

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“…Enterococcus faecalis and P. gingivalis are commonly detected pathogens in infected root canals and apical root surfaces of periapical periodontitis, respectively ( 183 , 262 ). IL-1β may play vital roles in bone loss in periapical periodontitis: IL1B gene polymorphisms are involved in the risk of periapical periodontitis development ( 263 ); IL-1β production is increased in periapical periodontitis in vivo ( 264 ); and IL-1β levels and osteoclast differentiation are upregulated in an in vitro coculture system of osteoblasts and osteoclasts ( 186 ). However, the roles of IL-18 in the pathogenesis and development of periapical periodontitis remain unclear.…”

Section: Inflammasomes In Inflammatory Osteolysis Of the Alveolar Bone And Jawsmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

2021

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Bone remodeling is tightly controlled by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. Fine tuning of the osteoclast–osteoblast balance results in strict synchronization of bone resorption and formation, which maintains structural integrity and bone tissue homeostasis; in contrast, dysregulated bone remodeling may cause pathological osteolysis, in which inflammation plays a vital role in promoting bone destruction. The alveolar bone presents high turnover rate, complex associations with the tooth and periodontium, and susceptibility to oral pathogenic insults and mechanical stress, which enhance its complexity in host defense and bone remodeling. Alveolar bone loss is also involved in systemic bone destruction and is affected by medication or systemic pathological factors. Therefore, it is essential to investigate the osteoimmunological mechanisms involved in the dysregulation of alveolar bone remodeling. The inflammasome is a supramolecular protein complex assembled in response to pattern recognition receptors and damage-associated molecular patterns, leading to the maturation and secretion of pro-inflammatory cytokines and activation of inflammatory responses. Pyroptosis downstream of inflammasome activation also facilitates the clearance of intracellular pathogens and irritants. However, inadequate or excessive activity of the inflammasome may allow for persistent infection and infection spreading or uncontrolled destruction of the alveolar bone, as commonly observed in periodontitis, periapical periodontitis, peri-implantitis, orthodontic tooth movement, medication-related osteonecrosis of the jaw, nonsterile or sterile osteomyelitis of the jaw, and osteoporosis. In this review, we present a framework for understanding the role and mechanism of canonical and noncanonical inflammasomes in the pathogenesis and development of etiologically diverse diseases associated with alveolar bone loss. Inappropriate inflammasome activation may drive alveolar osteolysis by regulating cellular players, including osteoclasts, osteoblasts, osteocytes, periodontal ligament cells, macrophages, monocytes, neutrophils, and adaptive immune cells, such as T helper 17 cells, causing increased osteoclast activity, decreased osteoblast activity, and enhanced periodontium inflammation by creating a pro-inflammatory milieu in a context- and cell type-dependent manner. We also discuss promising therapeutic strategies targeting inappropriate inflammasome activity in the treatment of alveolar bone loss. Novel strategies for inhibiting inflammasome signaling may facilitate the development of versatile drugs that carefully balance the beneficial contributions of inflammasomes to host defense.

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Section: Inflammasomes In Inflammatory Osteolysis Of the Alveolar Bone And Jawsmentioning

confidence: 99%

Inflammasomes in Alveolar Bone Loss

2021

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“…Melatonin reduces the LPS-induced COX-2 and IL-1β expression of HDPCs [ 18 ]. Interestingly, melatonin has been shown to exert an anti-inflammatory effect on experimental apical periodontitis, reduce TNF-α and IL-1β levels, and inhibit periapical bony resorption [ 16 , 17 ]. It also reduces the extent of acute pulpitis and IL-1β and TNF-α production in the pulp of acute pulpitis in animal experiments [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

“…Melatonin can reduce inflammation, regulate cell proliferation, and increase odontoblast activity, but cannot initiate the differentiation of undifferentiated pulp cells [ 14 , 15 ]. Administering melatonin also reduces inflammation and bone resorption in experimentally induced apical lesions in rats [ 16 , 17 ]. These events can be mediated in a receptor-dependent and -independent manner.…”

Section: Introductionmentioning

confidence: 99%

Melatonin exerts anti-fibrinolytic effects by regulating IL-1β-induced changes in uPA, uPAR, and PAI-1 expression/production in human dental pulp cells

Chang¹,

Zhong²,

Lee³

et al. 2022

Journal of Food and Drug Analysis

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Interleukin-1β (IL-1β) is a pro-inflammatory cytokine and its expression is increased in inflamed dental pulp. IL-1β affects plasminogen activation system molecules, which are crucial for tissue inflammation, fibrinolysis, matrix turnover, and cell adhesion and migration. Melatonin, which provides circadian and seasonal signals, is a physiological endocrine generated by the pineal gland. It has anti-oxidant and anti-inflammatory properties. Studies are warranted to determine whether melatonin prevents IL-1β-induced expression/production of plasminogen system molecules. Human dental pulp cells (HDPCs) were exposed to IL-1β or melatonin alone or to IL-1β with/without pretreatment with melatonin or other inhibitors. The mRNA expression of uPA, uPAR, and PAI-1 was quantified using real-time polymerase chain reaction analysis. The cellular uPA, PAI-1, and soluble uPAR (suPAR) production was determined using an enzyme-linked immunosorbent assay. Signaling molecules’ protein expression was analyzed by immunofluorescent staining. We found that IL-1β (0.1–10 ng/mL) stimulated uPA and uPAR expression/production but inhibited PAI-1 expression/ production of HDPCs. Melatonin inhibited uPA but stimulated uPAR/suPAR and PAI-1 expression/production. Intriguingly, melatonin prevented IL-1β-induced uPA mRNA expression/production. Conversely, melatonin enhanced the IL-1β-induced uPAR and PAI-1 mRNA expression/protein production of HDPCs. IL-1β-induced suPAR production was attenuated by U0126 (a MEK/ERK inhibitor), SB203580 (a p38 inhibitor), and 5Z-7oxozeaenol (a TAK1 inhibitor), whereas SB203580 prevented an IL-1β-induced decline of PAI-1 production. Moreover, melatonin attenuated the IL-1β-induced p-ERK, p-p38, p-Akt and p-TAK1. These results revealed the crucial role of IL-1β in the pathogenesis of pulpal inflammation/repair via stimulation of uPA and uPAR and inhibition of PAI-1, which can be differentially regulated by p38, Akt, MEK/ERK, and TAK1. Melatonin exerts an anti-fibrinolytic effect on IL-1β-induced changes in uPA, uPAR, and PAI-1 in HDPCs. Clinically, the melatonin levels of patients may affect pulpal inflammatory response. Melatonin and signal transduction inhibitors may be administered concomitantly for the prevention and treatment of pulpal inflammatory diseases.

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“…It was already shown that E. faecalis is able to promote CASP1 activation and pro-IL-1β expression, which subsequently increases IL-1β levels [ 185 ]. Moreover, increasing IL-1β production during periapical PD [ 186 ] might be associated with an interplay between this inflammatory disease and the NLRP3 inflammasome.…”

Section: Periapical Periodontitismentioning

confidence: 99%

Nrf2 in the Field of Dentistry with Special Attention to NLRP3

et al. 2022

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The aim of this review article was to summarize the functional implications of the nuclear factor E2-related factor or nuclear factor (erythroid-derived 2)-like 2 (Nrf2), with special attention to the NACHT (nucleotide-binding oligomerization), LRR (leucine-rich repeat), and PYD (pyrin domain) domains-containing protein 3 (NLRP3) inflammasome in the field of dentistry. NLRP3 plays a crucial role in the progression of inflammatory and adaptive immune responses throughout the body. It is already known that this inflammasome is a key regulator of several systemic diseases. The initiation and activation of NLRP3 starts with the oral microbiome and its association with the pathogenesis and progression of several oral diseases, including periodontitis, periapical periodontitis, and oral squamous cell carcinoma (OSCC). The possible role of the inflammasome in oral disease conditions may involve the aberrant regulation of various response mechanisms, not only in the mouth but in the whole body. Understanding the cellular and molecular biology of the NLRP3 inflammasome and its relationship to Nrf2 is necessary for the rationale when suggesting it as a potential therapeutic target for treatment and prevention of oral inflammatory and immunological disorders. In this review, we highlighted the current knowledge about NLRP3, its likely role in the pathogenesis of various inflammatory oral processes, and its crosstalk with Nrf2, which might offer future possibilities for disease prevention and targeted therapy in the field of dentistry and oral health.

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Effects of melatonin on insulin signaling and inflammatory pathways of rats with apical periodontitis

Cited by 19 publications

References 74 publications

Inflammasomes in Alveolar Bone Loss

Inflammasomes in Alveolar Bone Loss

Melatonin exerts anti-fibrinolytic effects by regulating IL-1β-induced changes in uPA, uPAR, and PAI-1 expression/production in human dental pulp cells

Nrf2 in the Field of Dentistry with Special Attention to NLRP3

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