Dental Pulp Defence and Repair Mechanisms in Dental Caries

Dental caries is a chronic infectious disease resulting from the penetration of oral bacteria into the enamel and dentin. Microorganisms subsequently trigger inflammatory responses in the dental pulp. These events can lead to pulp healing if the infection is not too severe following the removal of diseased enamel and dentin tissues and clinical restoration of the tooth. However, chronic inflammation often persists in the pulp despite treatment, inducing permanent loss of normal tissue and reducing innate repair capacities. For complete tooth healing the formation of a reactionary/reparative dentin barrier to distance and protect the pulp from infectious agents and restorative materials is required. Clinical andin vitroexperimental data clearly indicate that dentin barrier formation only occurs when pulp inflammation and infection are minimised, thus enabling reestablishment of tissue homeostasis and health. Therefore, promoting the resolution of pulp inflammation may provide a valuable therapeutic opportunity to ensure the sustainability of dental treatments. This paper focusses on key cellular and molecular mechanisms involved in pulp responses to bacteria and in the pulpal transition between caries-induced inflammation and dentinogenic-based repair. We report, using selected examples, different strategies potentially used by odontoblasts and specialized immune cells to combat dentin-invading bacteriain vivo.

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Enhancing the Nrf2 Antioxidant Signaling Provides Protection Against Trichloroethene-mediated Inflammation and Autoimmune Response

Toxicological Sciences ◽

10.1093/toxsci/kfaa022 ◽

2020 ◽

Vol 175 (1) ◽

pp. 64-74 ◽

Cited By ~ 3

Author(s):

Nivedita Banerjee ◽

Hui Wang ◽

Gangduo Wang ◽

M Firoze Khan

Keyword(s):

Oxidative Stress ◽

T Cells ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Autoimmune Response ◽

Mediated Effects ◽

Antioxidant Gene Expression ◽

Responsive Element

Abstract Trichloroethene (trichloroethylene, TCE) and one of its reactive metabolites dichloroacetyl chloride (DCAC) are associated with the induction of autoimmunity in MRL+/+ mice. Although oxidative stress plays a major role in TCE-/DCAC-mediated autoimmunity, the underlying molecular mechanisms still need to be delineated. Nuclear factor (erythroid-derived 2)-like2 (Nrf2) is an oxidative stress-responsive transcription factor that binds to antioxidant responsive element (ARE) and provides protection by regulating cytoprotective and antioxidant gene expression. However, the potential of Nrf2 in the regulation of TCE-/DCAC-mediated autoimmunity is not known. This study thus focused on establishing the role of Nrf2 and consequent inflammatory responses in TCE-/DCAC-mediated autoimmunity. To achieve this, we pretreated Kupffer cells (KCs) or T cells with/without tert-butylhydroquinone (tBHQ) followed by treatment with DCAC. In both KCs and T cells, DCAC treatment significantly downregulated Nrf2 and HO-1 expression along with induction of Keap-1 and caspase-3, NF-κB (p65), TNF-α, and iNOS, whereas pretreatment of these cells with tBHQ attenuated these responses. The in vitro findings were further verified in vivo by treating female MRL+/+ mice with TCE along with/without sulforaphane. TCE exposure in mice also led to reduction in Nrf2 and HO-1 but increased phospho-NF-κB (p-p65) and iNOS along with increased anti-dsDNA antibodies. Interestingly, sulforaphane treatment led to amelioration of TCE-mediated effects, resulting in Nrf2 activation and reduction in inflammatory and autoimmune responses. Our results show that TCE/DCAC mediates an impairment in Nrf2 regulation. Attenuation of TCE-mediated autoimmunity via activation of Nrf2 supports that antioxidants sulforaphane/tBHQ could be potential therapeutic agents for autoimmune diseases.

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Lithium Chloride Exerts Differential Effects on Dentinogenesis and Osteogenesis in Primary Pulp Cultures

Frontiers in Dental Medicine ◽

10.3389/fdmed.2021.649500 ◽

2021 ◽

Vol 2 ◽

Author(s):

Anushree Vijaykumar ◽

Mina Mina

Keyword(s):

Dental Pulp ◽

Osteoblast Differentiation ◽

Prolonged Treatment ◽

Odontoblast Differentiation ◽

Positive Effects ◽

Reparative Dentin ◽

Dentin Formation ◽

Reparative Dentin Formation

Wnt/β-catenin signaling is known to play essential roles in odontoblast differentiation and reparative dentin formation. Various Wnt activators including LiCl have been increasingly studied for their effectiveness to induce repair of the dentin-pulp complex. LiCl is a simple salt thought to activate Wnt/β-catenin signaling by inhibiting GSK3β. Previous in vitro and in vivo studies showed that LiCl increased odontoblast differentiation and enhanced reparative dentin formation. However, the underlying molecular and cellular mechanisms by which LiCl regulates odontoblast and osteoblast differentiation during reparative dentinogenesis are not well-understood. Our in vitro studies show that exposure of early dental pulp progenitors to LiCl increased the survival and the pool of αSMA+ progenitors, leading to enhanced odontoblast and osteoblast differentiation. The positive effects of LiCl in the differentiation of osteoblasts and odontoblasts from αSMA+ progenitors are mediated by Wnt/β-catenin signaling. Our results also showed that continuous and late exposure of dental pulp cells to LiCl increased the expression of odontoblast markers through Wnt/β-catenin signaling, and the number of odontoblasts expressing DMP1-Cherry and DSPP-Cerulean transgenes. However, unlike the early treatment, both continuous and late treatments decreased the expression of Bsp and the expression of BSP-GFPtpz transgene. These observations suggest that prolonged treatment with LiCl in more mature cells of the dental pulp has an inhibitory effect on osteoblast differentiation. The inhibitory effects of LiCl on osteogenesis and Bsp were not mediated through Wnt/β-catenin signaling. These observations suggest that the effects of LiCl, and GSK3β antagonists on reparative dentinogenesis involve multiple pathways and are not specific to Wnt/β-catenin signaling.

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IFN-mediated negative feedback supports bacteria class-specific macrophage inflammatory responses

eLife ◽

10.7554/elife.46836 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 2

Author(s):

Rachel A Gottschalk ◽

Michael G Dorrington ◽

Bhaskar Dutta ◽

Kathleen S Krauss ◽

Andrew J Martins ◽

...

Keyword(s):

Negative Feedback ◽

Molecular Mechanisms ◽

Cytokine Production ◽

Inflammatory Responses ◽

Type I ◽

Gram Negative Bacteria ◽

Gram Positive ◽

Gram Negative

Despite existing evidence for tuning of innate immunity to different classes of bacteria, the molecular mechanisms used by macrophages to tailor inflammatory responses to specific pathogens remain incompletely defined. By stimulating mouse macrophages with a titration matrix of TLR ligand pairs, we identified distinct stimulus requirements for activating and inhibitory events that evoked diverse cytokine production dynamics. These regulatory events were linked to patterns of inflammatory responses that distinguished between Gram-positive and Gram-negative bacteria, both in vitro and after in vivo lung infection. Stimulation beyond a TLR4 threshold and Gram-negative bacteria-induced responses were characterized by a rapid type I IFN-dependent decline in inflammatory cytokine production, independent of IL-10, whereas inflammatory responses to Gram-positive species were more sustained due to the absence of this IFN-dependent regulation. Thus, disparate triggering of a cytokine negative feedback loop promotes tuning of macrophage responses in a bacteria class-specific manner and provides context-dependent regulation of inflammation dynamics.

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Anti-Inflammatory and Immunosuppressive Effects of the A2AAdenosine Receptor

The Scientific World JOURNAL ◽

10.1100/tsw.2011.22 ◽

2011 ◽

Vol 11 ◽

pp. 320-339 ◽

Cited By ~ 74

Author(s):

Gillian R. Milne ◽

Timothy M. Palmer

Keyword(s):

Molecular Mechanisms ◽

Immune Cell ◽

Inflammatory Responses ◽

Current Evidence ◽

Receptor Subtypes ◽

Protective Effects ◽

Stress Injury ◽

Anti Inflammatory

The production of adenosine represents a critical endogenous mechanism for regulating immune and inflammatory responses during conditions of stress, injury, or infection. Adenosine exerts predominantly protective effects through activation of four 7-transmembrane receptor subtypes termed A1, A2A, A2B, and A3, of which the A2Aadenosine receptor (A2AAR) is recognised as a major mediator of anti-inflammatory responses. The A2AAR is widely expressed on cells of the immune system and numerousin vitrostudies have identified its role in suppressing key stages of the inflammatory process, including leukocyte recruitment, phagocytosis, cytokine production, and immune cell proliferation. The majority of actions produced by A2AAR activation appear to be mediated by cAMP, but downstream events have not yet been well characterised. In this article, we review the current evidence for the anti-inflammatory effects of the A2AAR in different cell types and discuss possible molecular mechanisms mediating these effects, including the potential for generalised suppression of inflammatory gene expression through inhibition of the NF-κB and JAK/STAT proinflammatory signalling pathways. We also evaluate findings fromin vivostudies investigating the role of the A2AAR in different tissues in animal models of inflammatory disease and briefly discuss the potential for development of selective A2AAR agonists for use in the clinic to treat specific inflammatory conditions.

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Reducing miR485-3p ameliorates Alzheimer`s disease pathology by regulation of amyloid beta and neuro-inflammation

10.21203/rs.3.rs-19583/v1 ◽

2020 ◽

Author(s):

Han Seok Koh ◽

Hannah Jang ◽

SooKil Tae ◽

mi-sun Lee ◽

Jae-Woong Min ◽

...

Keyword(s):

Mouse Model ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Amyloid Β ◽

Neuronal Loss ◽

Precentral Gyrus ◽

Alzheimer Patient ◽

5Xfad Mice

Abstract Background Alzheimer`s disease (AD) is a progressive neurodegenerative disease worldwide. Accumulation of amyloid-β (Aβ), neurofibrillary tangles and neuroinflammation play the important neuro-pathology in patients with AD. miRNA is multifunctional and involved in physiological and pathological processes. Recently, microRNAs have been linked to neurodegenerative diseases. However, it is little known whether miRNA dysregulation contributes to AD pathology progression such as Aβ processing, phagocytosis and neuroinflammation. Here, we identify miR485-3p as a novel modulator of AD pathology in 5XFAD mice. Methods To study the role of miR485-3p in AD, we used in control or miR485-3p antisense oligonucleotides (miR485-3p ASO) injected 5XFAD mouse model. Changes of Aβ processing and clearance and inflammation were analyzed by biochemical method in vitro and in vivo. Result This study suggests that miR485-3p, a novel miRNA targeting SIRT1 may contribute to pathogenesis in an AD mouse. We found SIRT1 is significantly reduced in the precentral gyrus of Alzheimer patient`s and in 5XFAD mice. To determine whether the inhibition of miRNA 485-3p would affect AD pathology, we studied the effect of the antisense oligo in the brain of 5XFAD mice through direct intracerebral ventricular injection with miR485-3p ASO. We demonstrated that miR485-3p ASO significantly reduced Aβ plaque and amyloid biosynthetic enzyme. Importantly, the attenuation of Aβ plaques through miR485-3p ASO was mediated through Aβ phagocytic activity of glial cells, by which it can directly target CD36. MiR485-3p ASO also decreased inflammatory responses. Collectively, these responses inhibited neuronal loss caused by Aβ lead to improvements of cognitive impairment. Conclusion Our data provide evidence for the molecular mechanisms which underlie the miR485-3p ASO responses in an AD mouse model. These results suggest that attenuating miRNA 485-3p levels might represent a novel therapeutic approach in AD.

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Cissus subtetragona Planch. Ameliorates Inflammatory Responses in LPS-induced Macrophages, HCl/EtOH-induced Gastritis, and LPS-induced Lung Injury via Attenuation of Src and TAK1

Molecules ◽

10.3390/molecules26196073 ◽

2021 ◽

Vol 26 (19) ◽

pp. 6073

Author(s):

Laily Rahmawati ◽

Nur Aziz ◽

Jieun Oh ◽

Yo Han Hong ◽

Byoung Young Woo ◽

...

Keyword(s):

Acute Lung Injury ◽

Lung Injury ◽

Mouse Models ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Raw264.7 Cells ◽

Acute Gastritis ◽

Anti Inflammatory

Several Cissus species have been used and reported to possess medicinal benefits. However, the anti-inflammatory mechanisms of Cissus subtetragona have not been described. In this study, we examined the potential anti-inflammatory effects of C. subtetragona ethanol extract (Cs-EE) in vitro and in vivo, and investigated its molecular mechanism as well as its flavonoid content. Lipopolysaccharide (LPS)-induced macrophage-like RAW264.7 cells and primary macrophages as well as LPS-induced acute lung injury (ALI) and HCl/EtOH-induced acute gastritis mouse models were utilized. Luciferase assays, immunoblotting analyses, overexpression strategies, and cellular thermal shift assay (CETSA) were performed to identify the molecular mechanisms and targets of Cs-EE. Cs-EE concentration-dependently reduced the secretion of NO and PGE2, inhibited the expression of inflammation-related cytokines in LPS-induced RAW264.7 cells, and decreased NF-κB- and AP-1-luciferase activity. Subsequently, we determined that Cs-EE decreased the phosphorylation events of NF-κB and AP-1 pathways. Cs-EE treatment also significantly ameliorated the inflammatory symptoms of HCl/EtOH-induced acute gastritis and LPS-induced ALI mouse models. Overexpression of HA-Src and HA-TAK1 along with CETSA experiments validated that inhibited inflammatory responses are the outcome of attenuation of Src and TAK1 activation. Taken together, these findings suggest that Cs-EE could be utilized as an anti-inflammatory remedy especially targeting against gastritis and acute lung injury by attenuating the activities of Src and TAK1.

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Capsular polysaccharide correlates with immune response to the human gut microbe Ruminococcus gnavus

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2007595118 ◽

2021 ◽

Vol 118 (20) ◽

pp. e2007595118

Author(s):

Matthew T. Henke ◽

Eric M. Brown ◽

Chelsi D. Cassilly ◽

Hera Vlamakis ◽

Ramnik J. Xavier ◽

...

Keyword(s):

Immune Response ◽

Molecular Mechanisms ◽

Capsular Polysaccharide ◽

Inflammatory Responses ◽

Cell Wall Polysaccharide ◽

Proinflammatory Responses ◽

Gut Microbe ◽

Inflammatory Bowel

Active inflammatory bowel disease (IBD) often coincides with increases of Ruminococcus gnavus, a gut microbe found in nearly everyone. It was not known how, or if, this correlation contributed to disease. We investigated clinical isolates of R. gnavus to identify molecular mechanisms that would link R. gnavus to inflammation. Here, we show that only some isolates of R. gnavus produce a capsular polysaccharide that promotes a tolerogenic immune response, whereas isolates lacking functional capsule biosynthetic genes elicit robust proinflammatory responses in vitro. Germ-free mice colonized with an isolate of R. gnavus lacking a capsule show increased measures of gut inflammation compared to those colonized with an encapsulated isolate in vivo. These observations in the context of our earlier identification of an inflammatory cell-wall polysaccharide reveal how some strains of R. gnavus could drive the inflammatory responses that characterize IBD.

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Effects of Eicosapentaenoic Acid on Arterial Calcification

International Journal of Molecular Sciences ◽

10.3390/ijms21155455 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5455

Author(s):

Yukihiro Saito ◽

Kazufumi Nakamura ◽

Hiroshi Ito

Keyword(s):

Clinical Trials ◽

Eicosapentaenoic Acid ◽

Cardiovascular Events ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Density Lipoprotein ◽

Clinical Situation ◽

Arterial Calcification

Arterial calcification is a hallmark of advanced atherosclerosis and predicts cardiovascular events. However, there is no clinically accepted therapy that prevents progression of arterial calcification. HMG-CoA reductase inhibitors, statins, lower low-density lipoprotein-cholesterol and reduce cardiovascular events, but coronary artery calcification is actually promoted by statins. The addition of eicosapentaenoic acid (EPA) to statins further reduced cardiovascular events in clinical trials, JELIS and REDUCE-IT. Additionally, we found that EPA significantly suppressed arterial calcification in vitro and in vivo via suppression of inflammatory responses, oxidative stress and Wnt signaling. However, so far there is a lack of evidence showing the effect of EPA on arterial calcification in a clinical situation. We reviewed the molecular mechanisms of the inhibitory effect of EPA on arterial calcification and the results of some clinical trials.

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The Impact of Acute or Chronic Alcohol Intake on the NF-κB Signaling Pathway in Alcohol-Related Liver Disease

International Journal of Molecular Sciences ◽

10.3390/ijms21249407 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9407

Author(s):

Aleksander J. Nowak ◽

Borna Relja

Keyword(s):

Liver Disease ◽

Signaling Pathway ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Current Knowledge ◽

In Vivo Studies ◽

Related Liver Disease ◽

The Impact

Ethanol misuse is frequently associated with a multitude of profound medical conditions, contributing to health-, individual- and social-related damage. A particularly dangerous threat from this classification is coined as alcoholic liver disease (ALD), a liver condition caused by prolonged alcohol overconsumption, involving several pathological stages induced by alcohol metabolic byproducts and sustained cellular intoxication. Molecular, pathological mechanisms of ALD principally root in the innate immunity system and are especially associated with enhanced functionality of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway. NF-κB is an interesting and convoluted DNA transcription regulator, promoting both anti-inflammatory and pro-inflammatory gene expression. Thus, the abundancy of studies in recent years underlines the importance of NF-κB in inflammatory responses and the mechanistic stimulation of inner molecular motifs within the factor components. Hereby, in the following review, we would like to put emphasis on the correlation between the NF-κB inflammation signaling pathway and ALD progression. We will provide the reader with the current knowledge regarding the chronic and acute alcohol consumption patterns, the molecular mechanisms of ALD development, the involvement of the NF-κB pathway and its enzymatic regulators. Therefore, we review various experimental in vitro and in vivo studies regarding the research on ALD, including the recent active compound treatments and the genetic modification approach. Furthermore, our investigation covers a few human studies.

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Replacement Therapy for the Prevention of Dental Disease

Advances in Dental Research ◽

10.1177/08959374870010010301 ◽

1987 ◽

Vol 1 (1) ◽

pp. 119-125 ◽

Cited By ~ 29

Author(s):

J.D. Hillman ◽

S.S. Socransky

Keyword(s):

Dental Caries ◽

Replacement Therapy ◽

Periodontal Diseases ◽

Oral Bacteria ◽

Periodontal Pathogens ◽

Wild Type ◽

Laboratory Rats ◽

Natural Variant

Certain laboratory-derived and naturally occurring oral bacteria are promising effector strains for the replacement therapy of dental infectious diseases. In the case of dental caries, several types of low-acid-producing mutants of Streptococcus mutans and a natural variant of S. salivarius have been found that are virtually non-cariogenic. Laboratory rats can be readily and persistently infected with these micro-organisms. Once infected, the animals become much more resistant to infection by wild-type (disease-causing) strains of S. mutans. Thus, in the laboratory rat, replacement therapy has proved successful in providing lifelong resistance to dental caries following a single application of an effector strain. Attempts to extend these findings to humans have required a search for effector strains that can both colonize well and, in addition, displace indigenous, wild-type strains of S. mutans. A mutant of a strain of S. mutans producing a bacteriocin-like molecule has been found that appears to be well-suited for this purpose. Replacement therapy may also find a practical application in the prevention and cure of certain periodontal diseases. Hydrogen peroxide-producing streptococci are invariably found in plaque taken from healthy gingiva; they are rarely found in samples from active disease sites of patients with juvenile or refractory periodontitis. In vitro, peroxide production by these streptococci inhibits the growth of Actinobacillus actinomycetemcomitans and several other presumed periodontal pathogens. Bacterial interactions of this sort have also been directly demonstrated to occur in vivo. Thus, natural inhibitors in plaque may be essential for maintenance of periodontal health. Patients lacking such inhibitors may be treated by replacement therapy to restore the composition of their plaque flora to one that is conducive to health.

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