Melatonin levels in periodontitis vs. the healthy state: A systematic review and meta-analysis.

The aim was to provide a comprehensive qualitative and quantitative assessment of any potential differences in melatonin levels in periodontitis vs. the healthy state. The keyword combination "melatonin" AND "periodontitis" was searched in Web of Science, PubMed, and Scopus. Qualitative analysis and quantitative analysis were performed on articles satisfying the inclusion criteria. Only 14 studies were included in the systematic review, out of which only 10 had quantitative data compatible with a meta-analysis. Ten studies demonstrated low melatonin in periodontitis, three studies demonstrated an initial reduction in melatonin levels followed by elevation with worsening of periodontitis, and one study showed an elevation in melatonin levels in the transition from a healthy state to periodontitis. Grading of recommendations assessment, development, and evaluation revealed that all the included studies had low to very low overall evidence. The meta-analysis revealed a significant reduction (p < .0001) in salivary melatonin levels in chronic periodontitis (3.26 ± 3.44 pg/ml) compared with healthy controls (5.27 ± 5.39 pg/ml), with a mean difference of 2.65 ± 7.84 and a confidence interval of 1.94-3.36. The significantly lower salivary melatonin levels in periodontitis must be inferred with caution given the low quality of the included studies.

Mucous Membrane Pemphigoid: A Case Report with Oral and Ocular Presentation.

AIM: To describe the diagnosis and management of mucous membrane pemphigoid (MMP) with oral and ocular presentation. BACKGROUND: Mucous membrane pemphigoid constitutes a heterogeneous group of chronic, autoimmune vesiculobullous diseases characterized by blister formation that has a propensity to affect different mucous membranes of the body. The most commonly affected areas include the oral cavity, mucous membranes of the eyes, throat, genitalia, and nose. This disease usually affects elderly women with a peak incidence at around 50-70 years of age; however, rare cases have been diagnosed in children. The symptoms of MMP include recurrent blistering lesions which eventually rupture and occasionally heal with scarring that may lead to certain complications involving the eyes and throat regions. CASE DESCRIPTION: In this report, we describe a 66-year-old female patient who complained of oral and ocular lesions for a period of 2 years. Pain, burning mouth, and gingival inflammation were present. Ocular examination showed mild conjunctivitis with scar formation at the lateral canthus of the left eye. The patient also noticed periods of water-filled balloon-like formation in the gingiva that rupture spontaneously leaving sore spots. A biopsy was obtained from perilesional tissue and sent for histopathological examination, correlation of clinical and histological features directed us toward the diagnosis of MMP. The patient was treated for both oral and ocular lesions using topical corticosteroid therapy in conjunction with antifungal and antibacterial drugs. The response to local treatment was augmented via effective periodontal therapy to control the concurrent plaque-induced gingival inflammation and via using a customized application tray to sustain the drug efficacy. CONCLUSION: A multidisciplinary approach is often necessary in order to treat MMP lesions efficaciously. CLINICAL SIGNIFICANCE: Early diagnosis and effective treatment protocol using systemic or topical corticosteroid therapy along with other therapeutic means including periodontal therapy, good oral hygiene practice, and timely follow-up are very useful in preventing long-term complications due to this disease.

Future Drug Targets in Periodontal Personalised Medicine-A Narrative Review.

Periodontal disease is an infection-driven inflammatory disease characterized by the destruction of tooth-supporting tissues. The establishment of chronic inflammation will result in progressive destruction of bone and soft tissue changes. Severe periodontitis can lead to tooth loss. The disease has complex pathogenesis with an interplay between genetic, environmental, and host factors and pathogens. Effective management consists of plaque control and non-surgical interventions, along with adjuvant strategies to control inflammation and disrupt the pathogenic subgingival biofilms. Recent studies have examined novel approaches for managing periodontal diseases such as modulating microbial signaling mechanisms, tissue engineering, and molecular targeting of host inflammatory substances. Mounting evidence suggests the need to integrate omics-based approaches with traditional therapy to address the disease. This article discusses the various evolving and future drug targets, including proteomics, gene therapeutics, vaccines, and nanotechnology in personalized periodontal medicine for the effective management of periodontal diseases.

Hypoxia, a dynamic tool to amplify the gingival mesenchymal stem cells potential for neurotrophic factor secretion.

Gingival mesenchymal stem cells (GMSCs) have significant regenerative potential. Their potential applications range from the treatment of inflammatory diseases, wound healing, and oral disorders. Preconditioning these stem cells can optimize their biological properties. Hypoxia preconditioning of MSCs improves stem cell properties like proliferation, survival, and differentiation potential. This research explored the possible impact of hypoxia on the pluripotent stem cell properties that GMSCs possess. We evaluated the morphology, stemness, neurotrophic factors, and stemness-related genes. We compared the protein levels of secreted neurotrophic factors between normoxic and hypoxic GMSC-conditioned media (GMSC-CM). Results revealed that hypoxic cultured GMSC's had augmented expression of neurotrophic factors BDNF, GDNF, VEGF, and IGF1 and stemness-related gene NANOG. Hypoxic GMSCs showed decreased expression of the OCT4 gene. In hypoxic GMSC-CM, the neurotrophic factors secretions were significantly higher than normoxic GMSC-CM. Our data demonstrate that culturing of GMSCs in hypoxia enhances the secretion of neurotrophic factors that can lead to neuronal lineage differentiation.

Monocyte Differentiation into Destructive Macrophages on In Vitro Administration of Gingival Crevicular Fluid from Periodontitis Patients.

BACKGROUND: Periodontitis is an inflammatory condition of the tooth-supporting structures initiated and perpetuated by pathogenic bacteria present in the dental plaque biofilm. In periodontitis, immune cells infiltrate the periodontium to prevent bacterial insult. Macrophages derived from monocytes play an important role in antigen presentation to lymphocytes. However, they are also implicated in causing periodontal destruction and bystander damage to the host tissues. OBJECTIVES: The objective of the present study was to quantify the cytokine profile of gingival crevicular fluid (GCF) samples obtained from patients with periodontitis. The study further aimed to assess if GCF of periodontitis patients could convert CD14+ monocytes into macrophages of destructive phenotype in an in vitro setting. The secondary objectives of the study were to assess if macrophages that resulted from GCF treatment of monocytes could affect the synthetic properties, stemness, expression of extracellular matrix proteins, adhesion molecules expressed by gingival stem cells, gingival mesenchymal stromal cells, and osteoblasts. METHODS: GCF, blood, and gingival tissue samples were obtained from periodontitis subjects and healthy individuals based on specific protocols. Cytokine profiles of the GCF samples were analyzed. CD14+ monocytes were isolated from whole blood, cultured, and treated with the GCF of periodontitis patients to observe if they differentiated into macrophages. Further, the macrophages were assessed for a phenotype by surface marker analysis and cytokine assays. These macrophages were co-cultured with gingival stem cells, epithelial, stromal cells, and osteoblasts to assess the effects of the macrophages on the synthetic activity of the cells. RESULTS: The GCF samples of periodontitis patients had significantly higher levels of IFN gamma, M-CSF, and GM-CSF. Administration of the GCF samples to CD14+ monocytes resulted in their conversion to macrophages that tested positive for CD80, CD86, and CD206. These macrophages produced increased levels of IL-1ß, TNF-α, and IL-6. Co-culture of the macrophages with gingival stem cells, epithelial cells, and stromal cells resulted in increased cytotoxicity and apoptotic rates to the gingival cells. A reduced expression of markers related to stemness, extracellular matrix, and adhesion namely OCT4, NANOG, KRT5, POSTN, COL3A1, CDH1, and CDH3 were seen. The macrophages profoundly affected the production of mineralized nodules by osteoblasts and significantly reduced the expression of COL1A1, OSX, and OCN genes. CONCLUSION: In periodontitis patients, blood-derived monocytes transform into macrophages of a destructive phenotype due to the characteristic cytokine environment of their GCF. Further, the macrophages affect the genotype and phenotype of the resident cells of the periodontium, aggravate periodontal destruction, as well as jeopardize periodontal healing and resolution of inflammation.

Genetic Polymorphisms of NLRP3 (rs4612666) and CARD8 (rs2043211) in Periodontitis and Cardiovascular Diseases.

BACKGROUND: The existing data show that inflammasomes play a role in periodontal disease pathogenesis. However, their role in the pathogenesis of periodontitis and coronary heart disease remains unclear. This study had the objective of assessing NLRP3 (rs4612666) and CARD8 (rs2043211) gene polymorphisms in dental plaque and blood of generalized chronic periodontitis (CP) patients in the presence and absence of coronary heart disease (CHD). METHODS: A total of 70 subjects were divided into two groups, including CP and CP + CHD subjects. Demographic variables, periodontal, and cardiac parameters were recorded from both groups. Subgingival plaque and blood samples were obtained from both groups and were subjected to further molecular analysis for NLRP3 (rs4612666) and CARD8 (rs2043211) expression and allele change using conventional polymerase chain reaction (PCR) and gene sequencing (Sanger's method). RESULTS: Amongst the demographic variables, age, and monthly income were statistically significant between the two groups. Plaque index (PI), clinical attachment level (CAL), high-density lipoprotein (HDL), and low density-lipoprotein (LDL) exhibited statistically significant levels between the two groups. NLRP3 (rs4612666) and CARD8 (rs2043211) genes showed a statistically significant association of allele change (frequency) among the groups. In general, when all of the parameters were compared to the allele change of the genes, statistically significant relationships were found between the two groups. CONCLUSIONS: The present study expressed an allele change of the investigated genes which could profoundly affect the pathobiology of the two diseases under investigation.

Melatonin as a Topical/Systemic Formulation for the Management of Periodontitis: A Systematic Review.

OBJECTIVES: To qualitatively and quantitatively review the use of melatonin as a topical/systemic formulation for the management of periodontitis. MATERIALS AND METHODS: PubMed; Scopus; and Web of Science databases were searched using the MesH terms "melatonin" and "periodontitis". Title and abstracts were screened to eliminate irrelevant and duplicate articles. The full text data of the screened articles were assessed using the selection criteria. RESULTS: Of 176 identified articles (PubMed-66; Scopus-56; Web of Science-52; Cross-reference-2), only 12 studies qualified to be included in the systematic review. Four studies assessed the independent effect of 1% topical melatonin formulation while 8 articles assessed the adjunctive use of systemic melatonin formulation (1-10 mg) following scaling and root planing (SRP). All studies showed an improvement in periodontal parameters such as pocket depth, clinical attachment loss, periodontal disease index, community periodontal index, gingival bleeding scores, and prognostic marker levels in saliva and serum. A meta-analysis of data from 2 studies revealed that 1-2 mg (systemic) melatonin supplementation reduced pocket depth; although the difference was not statistically significant and hence cannot be interpreted or used for conclusive evidence. Risk of Bias Assessment tool (RoBANS) and Cochrane Collaboration RoB tool elicited a high risk of bias in the included studies. GRADE (recommendation assessment, development, and evaluation) inferred a weak recommendation for the use of melatonin in periodontitis management. CONCLUSIONS: Melatonin supplementation (topical and systemic) in periodontitis patients improved key periodontal parameters including pocket depth and clinical attachment loss. CLINICAL RELEVANCE: Melatonin could be a potential host modulatory agent for periodontitis management; although the data from the present review should be interpreted carefully due to the associated high risk of bias.

miRNA-146a and miRNA-126 as Potential Biomarkers in Patients with Coronary Artery Disease and Generalized Periodontitis.

The present study aims to compare the levels of micro-RNA-146a and micro-RNA-126 in oral subgingival plaque and coronary plaque from artery walls in patients with coronary artery disease who suffer from generalized periodontitis. A total of 75 participants were selected and grouped into three categories of 25 patients each: GP+CAD, GP, and HP groups. GP+CAD consisted of patients diagnosed with generalized periodontitis (GP) and coronary artery disease (CAD). The GP+CAD group was further divided into two groups-GP+CADa: where subgingival plaque samples were collected; GP+CADb group: where coronary plaque samples were collected while the patient underwent a coronary artery bypass grafting surgery. The GP group consisted of 25 patients diagnosed with only generalized periodontitis. The HP group consisted of 25 systemically and periodontally healthy controls. miRNA-146a and miRNA126 levels were assessed in subgingival plaque (SP) samples from all groups. Results revealed that miRNA-146a was expressed at higher levels and miRNA-126 was downregulated in the GP+CAD group. microRNAs in subgingival plaque samples showed a significant correlation with the coronary plaque samples in the GP+CAD group. miRNA-146a and miRNA-126 were present in coronary artery disease patients with periodontitis. These micro-RNAs may serve as risk biomarkers for coronary artery disease and generalized periodontitis.

Gingival crevicular fluid infiltrating CD14+ monocytes promote inflammation in periodontitis.

Periodontitis is a condition that occurs because of inflammation-mediated tissue degeneration. Many studies have been conducted to identify inflammatory molecules in periodontitis, but the well-defined role of cells from the immune system in the progression of periodontitis as well as in gingival tissue degeneration has not been appropriately established. The objective of the present study was to characterize the monocytes isolated from the gingival crevicular fluid (GCF) in patients with periodontitis. GCF was obtained from periodontitis patients and healthy controls. Cytokine levels of CCL2 were evaluated by ELISA in GCF samples. CD14+ monocytes were separated using magnetic sorting from GCF. RT-qPCR was performed to assess the gene expression. Cytometric bead array analysis was performed to analyze the levels of cytokines and chemokines in the secretome of cells. CD14+ monocytes from GCF secreted higher levels of CCL2 and showed elevated expression of genes responsible for monocyte migration. Additionally, upon lipopolysaccharide stimulation, these monocytes secreted higher levels of inflammatory cytokines and chemokines. This investigation aids in understanding the inflammatory microenvironment of periodontitis by characterizing GCF in terms of infiltrated CD14+ monocytes, cytokines, and molecules secreted by these monocytes, which are specific for cellular differentiation.

Necrotizing periodontal diseases in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: A review.

Human immunodeficiency virus-infected patients have depleted CD4 lymphocyte counts and are susceptible to a plethora of infections of bacterial, viral, and fungal etiology. In addition to a wide range of systemic manifestations, human immunodeficiency virus-infected patients also display several characteristic oral manifestations. Studies have shown a correlation between some of the oral manifestations and CD4 lymphocyte counts which in turn is an independent prognostic indicator. To tackle the human immunodeficiency virus numerous drugs have been discovered and implemented. To overcome any potential resistance, human immunodeficiency virus patients are prescribed highly active antiretroviral therapy, wherein a combination of antiretroviral regimens are used. Studies have shown that in addition to controlling the viral activity, the treatment regimen, has a significant effect on the oral manifestations of the human immunodeficiency virus-infected patients. The present paper highlights the effects of highly active antiretroviral therapy on periodontal diseases in human immunodeficiency virus-infected individuals.

Viability of Quercetin-Induced Dental Pulp Stem Cells in Forming Living Cellular Constructs for Soft Tissue Augmentation.

Autogenous gingival grafts used for root coverage or gingival augmentation procedures often result in donor site morbidity. Living cellular constructs as an exogenous alternative have been proven to be associated with lower morbidity. With the available background information, the present study aims to assess if quercetin-induced living cell constructs, derived from dental pulp stem cells, have the potential to be applied as a tool for soft tissue augmentation. The characterized dental pulp stem cells (positive for CD73, CD90, and negative for CD34, HLA-DR) were expanded in Dulbecco's Modified Eagle's medium (DMEM) supplemented with 10 mM quercetin. The handling properties of the quercetin-induced dental pulp stem cell constructs were assessed by visual, and tactile sensation. A microscopic characterization using hematoxylin and eosin staining, and qRT-PCR-based analysis for stemness-associated genes (OCT4, NANOG, SOX2, and cMyc) was also performed. Dental pulp stem cells without quercetin administration were used as the control. Dental pulp stem cell constructs induced by quercetin easily detached from the surface of the plate, whereas there was no formation in the control cells. It was also simple to transfer the induced cellular construct on the flattened surface. Microscopic characterization of the constructs showed cells embedded in a tissue matrix. Quercetin also increased the expression of stemness-related genes. The use of quercetin-induced DPSC living constructs for soft tissue augmentation could provide an alternative to autogenous soft tissue grafts to lower patient morbidity and improve esthetic outcomes.

Evaluation of Stress Distribution during Insertion of Tapered Dental Implants in Various Osteotomy Techniques: Three-Dimensional Finite Element Study.

Conventional osteotomy techniques can, in some cases, induce higher stress on bone during implant insertion as a result of higher torque. The aim of the present study was to evaluate and compare the stress exerted on the underlying osseous tissues during the insertion of a tapered implant using different osteotomy techniques through a dynamic finite element analysis which has been widely applied to study biomedical problems through computer-aided software. In three different types of osteotomy techniques, namely conventional (B1), bone tap (B2), and countersink (B3), five models and implants designed per technique were prepared, implant insertion was simulated, and stress exerted by the implant during each was evaluated. Comparison of stress scores on the cortical and cancellous bone at different time points and time intervals from initiation of insertion to the final placement of the implant was made. There was a highly statistically significant difference between B1 and B2 (p = 0.0001) and B2 and B3 (p = 0.0001) groups. In contrast, there was no statistically significant difference in the stress scores between B1 and B3 (p = 0.3080) groups at all time points of implant placement. Overall, a highly significant difference was observed between the stresses exerted in each technique. Within the limitations of our study, bone tap significantly exerted lesser stresses on the entire bone than conventional and countersink type of osteotomy procedures. Considering the stress distribution at the crestal region, the countersink showed lower values in comparison to others.

Comparison of RANKL and osteoprotegerin levels in the gingival crevicular fluid of young cigarette- and waterpipe-smokers and individuals using electronic nicotine delivery systems.

OBJECTIVE: The aim of the present observational case-control study was to compare the levels of Receptor activator of NF-kappa B ligand (RANKL) and osteoprotegerin (OPG) in the gingival crevicular fluid (GCF) of cigarette- and waterpipe-smokers and electronic-nicotine-delivery-systems (ENDS)-users. METHODS: Demographic data was collected using a questionnaire. Clinical periodontal parameters (plaque index [PI], bleeding on probing [BOP], probing depth [PD] and clinical attachment loss [CAL]) were measured; and GCF samples were collected from the deepest periodontal pocket of the mandibular right first molar. The GCF volume was determined and levels of RANKL and OPG were determined. Group comparisons were performed and P < 0.05 was considered statistically significant. RESULTS: One hundred and twenty male individuals (30 cigarette-smokers, 30 waterpipe users, 30 ENDS-users and 30 non-smokers) were included. Scores of PI (P < 0.01) and PD (P < 0.01) were significantly higher among cigarette- and waterpipe smokers, and ENDS-users than non-smokers. The GCF volume was significantly higher among cigarette- (0.92 ±â€¯0.05 µl) (P < 0.01) and waterpipe-smokers (0.66 ±â€¯0.08 µl) (P < 0.001) and ENDS-users (0.62 ±â€¯0.03 µl) (P < 0.01) than non-smokers (0.21 ±â€¯0.007 µl). The GCF RANKL levels were significantly higher among cigarette- (14.9 ±â€¯8.2 pg/ml) (P < 0.001) and waterpipe-smokers (12.6 ±â€¯8.8 pg/ml) (P < 0.01) and ENDS-users (11.5 ±â€¯8.4 pg/ml) (P < 0.01) than non-smokers (3.5 ±â€¯0.7 pg/ml). The GCF OPG levels were significantly higher among cigarette- (95.9 ±â€¯7.2 pg/ml) (P < 0.001) and waterpipe-smokers (86.6 ±â€¯5.8 pg/ml) (P < 0.01) and ENDS-users (77.5 ±â€¯3.4 pg/ml) (P < 0.05) than non-smokers (21.5 ±â€¯10.7 pg/ml). There was no significant difference in GCF RANKL and OPG levels among cigarette- and waterpipe smokers, ENDS users. CONCLUSION: Cigarette- and waterpipe smoking and ENDS usage is associated with an increased expression of RANKL and OPG in the GCF.