Development Of Periodontitis Research Articles

Pathobiont-responsive Th17 cells in gut-mouth axis provoke inflammatory oral disease and are modulated by intestinal microbiome.

Host immune response via Th17 cells against oral pathobionts is a key mediator in periodontitis development. However, where and how the Th17-type immune response is induced during the development of periodontitis is not well understood. Here, we demonstrate that gut translocation of the oral pathobiont Porphyromonas gingivalis (Pg) exacerbates oral pathobiont-induced periodontitis with enhanced Th17 cell differentiation. The oral pathobiont-responsive Th17 cells are differentiated in Peyer's patches and translocated systemically in the peripheral immune tissues. They are also capable of migrating to and accumulating in the mouth upon oral infection. Development of periodontitis via the oral pathobiont-responsive Th17 cells is regulated by the intestinal microbiome, and altering the intestinal microbiome composition with antibiotics affects the development of periodontitis. Our study highlights that pathobiont-responsive Th17 cells in the gut-mouth axis and the intestinal microbiome work together to provoke inflammatory oral diseases, including periodontitis.

The Strong Protective Action of Ce3+/F- Combined Treatment on Tooth Enamel and Epithelial Cells.

We studied the toxic effects of cerium and fluoride species on human dental pulp stem cells and epithelial cells of Cercopithecus aethiops as a surrogate for the human oral mucosa. The sequential use of CeCl3 and NH4F solutions in equimolar sub-toxic concentrations enabled the possible toxic effects of individual components to be avoided, ensuring the preservation of the metabolic activity of the cells due to the formation of CeF3 nanoparticles. Cerium fluoride nanoparticles and terbium-doped cerium fluoride nanoparticles exhibited neither cytotoxicity nor genotoxicity to dental pulp stem cells, even at high concentrations (10−4 M). In millimolar concentrations (from 10−5–10−6 M), these nanoparticles significantly increased the expression of genes responsible for the cell cycle, differentiation and proliferation. The formation of cerium fluoride on the surface of the mucous membrane and teeth provided protection against the development of carious lesions, periodontitis, ROS attacks and other inflammatory diseases of the oral cavity. Luminescent CeF3: Tb nanoparticles enabled the visualization of tooth enamel microcracks.

Role of fucoidan in stimulating osteoblast cells in alveolar bone loss

Alveolar bone loss is a characteristic of the development of periodontitis; its prevention is a major clinical challenge in the treatment of periodontal disease. Alveolar bone loss can significantly affect a patient's quality of life. In addressing the chal-lenges of recovering alveolar bone loss, fucoidan has attracted attention as a potential material due to its numerous biological activities, one of which is its potential to regulate osteogenic cell function so as to facilitate osteoblast cell proliferation and promote bone mineralization and development. This literature discusses the role of fucoidan, especially in stimulating osteo-blast cells in cases of alveolar bone loss.

Effect of Traditional Drug Therapy and its Combination with Soderm®-Forte and New Injectable Form of Rexod® on the Antioxidant-prooxidant Red Blood Cell System in Rats with Experimental Periodontitis

Background.The development of periodontitis is strongly linked with both periodontopathogenic microflora and antioxidant-proxidant system disorders, which determines the need for the combined use of antimicrobial and antioxidant agents.Objectives.A comparative evaluation of the antioxidant-prooxidant system of red blood cells in rats with experimental periodontitis against the background of the traditional drug therapy and its combination with Soderm®-Forte and new injectable form of Rexod®.Methods.The authors conducted a comparative study of the effect of traditional drug therapy (TDT) and its combination with Soderm®-Forte gel containing silver nanoparticles, recombinant human superoxide dismutase (Rexod®) and new injectable form (NIF) of Rexod® on the condition of the antioxidant-prooxidant system of red blood cells in rats with experimental periodontitis (EP). The experiments were performed on Wistar male rats of 210–230 g. EP was induced by ligature method. The rats were randomly divided into 5 comparable groups of 12 animals: group 1 — with intact periodontium; group 2 — with EP; group 3 — with EP, where TDT was used, including oral irrigation with chlorhexedine (0.05% solution) and application of Septo-Pack dento-gingival dressing; group 4 — with EP, TDT and Soderm®-Forte gel (applied into the periodontal pockets of the lower incisors); group 5 — with EP, TDT in combination with Soderm®-Forte gel and NIF of Rexod®, which was injected intraperitoneally at a dose of 8000 U/kg. Treatment of rats with EP (groups 3–5) was carried out for 12 days. The observation period for all animals lasted 42 days. The biochemical tests and the antioxidant-prooxidant index were used to assess the condition of antioxidant-prooxidant system. Statistical analysis of the obtained results was carried out with parametric and non-parametric methods of Microsoft Excel (Microsoft, USA), Analysis package and AtteStat, as well as Statistica 8.0 (StatSoft, USA) software.Results.The application of TDT against the developed EP caused a moderate positive correction of the indicators of Antioxidant protection system (APS). The enrichment of TDT for the EP animals with Soderm®-Forte and especially Soderm®-Forte in combination with NIF of Rexod® to enhance the APS potential caused more significant positive dynamics of the balance in the antioxidant-prooxidant system compared to TDT.Conclusion.The combination of TDT with Soderm®-Forte and NIF of Rexod® has the most significant positive corrective effect on the condition of antioxidant-prooxidant system of red blood cells in rats with EP in comparison with the complex of TDT with Soderm®-Forte and TDT used separately.

Periodontal disease and cancer risk: A nationwide population-based cohort study.

BackgroundAlthough emerging evidence suggests that periodontitis might increase the risk of cancer, comorbidity and lifestyle behaviors, such as smoking and body mass index (BMI), may have confounded this reported association. This study aimed to investigate whether chronic periodontitis is associated with cancer risk using a large, nationwide database.MethodsWe conducted a population-based, retrospective cohort study using data from the Korean National Health Insurance Cohort Database obtained between January 2003 and December 2015. We included 713,201 individuals without a history of cancer who were followed up to 10 years. Confounding factors included demographic factors (age, sex, income, and residential area), lifestyle behaviors (smoking history and BMI), and comorbidities, such as hypertension, diabetes, heart failure, and pulmonary disease, using the Charlson Comorbidity Index. Multivariable Cox regression analysis was applied to estimate the adjusted hazard ratio (aHR) for cancer risk.ResultsOf the 713,201 participants, 53,075 had periodontitis and were placed in the periodontitis group; the remaining 660,126 individuals were included as the control group. Overall, the cumulative incidence of cancer in the periodontitis group was 2.2 times higher than that in the control group. The periodontitis group had an increased risk of total cancer compared to the control group after adjusting for age, sex, comorbidities, BMI, and smoking history (aHR, 1.129; 95% confidence interval [CI], 1.089-1.171; P<0.0001). When examining specific cancer types, significant associations were also observed between periodontitis and stomach cancer (aHR, 1.136; 95% CI, 1.042-1.239; P=0.0037), colon cancer (aHR, 1.129; 95% CI, 1.029-1.239; P=0.0105), lung cancer (aHR, 1.127; 95% CI, 1.008-1.260; P=0.0353), bladder cancer (aHR, 1.307; 95% CI, 1.071-1.595; P=0.0085), thyroid cancer (aHR, 1.191; 95% CI, 1.085-1.308; P=0.0002), and leukemia (aHR, 1.394; 95% CI, 1.039-1.872; P=0.0270). There was no significant association between the development of secondary malignancy and periodontitis in cancer survivors who were alive 5 years after they were diagnosed with the primary malignancy.ConclusionsPeriodontal disease, including periodontitis, was associated with increased risk of cancer, which persisted after controlling for confounding factors. Further prospective research is warranted to establish a causal relationship.

Periodontitis prevalence in patients with ulcerative colitis and Crohn's disease - PPCC: A case-control study.

The aim of this questionnaire-based case-control study was to assess whether self-reported oral health and periodontitis in patients with ulcerative colitis (UC) and Crohn's disease (CD) differ from those in matched controls without inflammatory bowel disease (IBD). A survey including questions on general anamnestic information, IBD diagnosis, and oral health was distributed online. Self-perceived overall health of teeth and gums, severe periodontitis, and tooth loss were defined as outcome parameters. Analyses were based on answers from 1108 patients with IBD and 3429 controls. Patients with IBD reported significantly worse oral health and more periodontal problems compared to controls. Regression analyses corrected for relevant confounders showed significantly increased odds for fair or poor self-perceived overall health of teeth and gums (odds ratio [OR] 2.147 and 2.736, respectively) and for severe periodontitis (OR 1.739 and 2.574, respectively) for patients with UC and CD compared to controls; patients with CD presented additionally 91% higher odds for having &lt;20 remaining teeth. Patients with UC and CD have significantly increased odds for worse self-perceived oral health and severe periodontitis compared to controls, with the former being more severely affected and losing more teeth. It is strongly recommended that patients with IBD are kept under close surveillance to prevent periodontitis development and/or mitigate its progression.

Porphyromonas gingivalis-Helicobacter pylori co-incubation enhances Porphyromonas gingivalis virulence and increases migration of infected human oral keratinocytes

ABSTRACT Background Porphyromonas gingivalis is part of the subgingival biofilm and a keystone species in the development of periodontitis. Interactions between P.gingivalis and other bacteria in biofilms have been shown to affect bacterial virulence. Helicobacter pylori also inhabits the subgingival biofilm, but the consequences of interactions there with P.gingivalis remain unknown. Here, we investigated how the pre-incubation of P.gingivalis with H.pylori affects P.gingivalis virulence. Methods We assayed P.gingivalis internalization by oral keratinocytes (OKs), hemagglutination and biofilm formation to identify alterations in virulence after pre-incubation with H. pylori. Also, we evaluated viability and migration of OKs infected with P. gingivalis, as well as the role of toll-like receptor 4 (TLR4). In addition, we quantified the mRNA of genes associated with P.gingivalis virulence. Results Pre-incubation of P.gingivalis with H.pylori enhanced P.gingivalis biofilm formation, bacterial internalization into OKs and hemagglutination. Infection with pre-incubated P.gingivalis increased OK migration in a manner dependent on the O-antigen and linked to increased expression of the gingipain RgpB. Also, OK TLR4 participates in these events, because upon TLR4 knock-down, pre-incubated P.gingivalis no longer stimulated OK migration. Discussion We provide here for the first time insight to the consequences of direct interaction between P.gingivalis and H.pylori. In doing so, we shed light on the mechanism by which H. pylori presence in the oral cavity increases the severity or progression of periodontitis.

Role of PI3K in the bone resorption of apical periodontitis

BackgroundPhosphoinositide 3-kinase (PI3K) is located within cells, and is involved in regulating cell survival, proliferation, apoptosis and angiogenesis. The purpose of this study was to investigate the role of PI3K in the process of bone destruction in apical periodontitis, and provide reference data for the treatment of this disease.MethodsThe relative mRNA expression of PI3K, Acp5 and NFATc1 in the normal human periodontal ligament and in chronic apical periodontitis were analyzed by real-time quantitative polymerase chain reaction (RT-qPCR). A mouse model of apical periodontitis was established by root canal exposure to the oral cavity, and HE staining was used to observe the progress of apical periodontitis. Immunohistochemical staining was used to detect the expression of PI3K and AKT in different stages of apical periodontitis, while enzymatic histochemical staining was used for detection of osteoclasts. An Escherichia coli lipopolysaccharide (LPS)-mediated inflammatory environment was also established at the osteoclast and osteoblast level, and osteoclasts or osteoblasts were treated with the PI3K inhibitor LY294002 to examine the role of PI3K in bone resorption.ResultsThe expression of PI3K, Acp5 and NFATc1 genes in chronic apical periodontitis sample groups was significantly increased relative to healthy periodontal ligament tissue (P < 0.05). Mouse apical periodontitis was successfully established and bone resorption peaked between 2 and 3 weeks (P < 0.05). The expression of PI3K and Akt increased with the progression of inflammation, and reached a peak at 14 days (P < 0.05). The gene and protein expression of PI3K, TRAP and NFATc1 in osteoclasts were significantly increased (P < 0.05) in the E. coli LPS-mediated inflammatory microenvironment compared to the normal control group. Meanwhile in osteoblasts, the gene and protein expression of PI3K, BMP-2 and Runx2 were significantly reduced (P < 0.05) in the inflammatory microenvironment. With the addition of LY294002, expressions of bone resorption-related factors (TRAP, NFATc1) and bone formation-related factors (BMP-2, Runx2) significantly decreased (P < 0.05).ConclusionsUnder the inflammatory environment induced by LPS, PI3K participates in the occurrence and development of chronic apical periodontitis by regulating the proliferation and differentiation of osteoclasts and osteoblasts.

Revisiting the role of IL-1 signaling in the development of apical periodontitis.

Apical periodontitis (AP) develops as a result of an immune response to pulpal bacterial infection, and various cytokines are involved in the pathogenesis of AP, with Interleukin (IL)-1 being considered a key cytokine. The role of IL-1 in the pathogenesis of AP has been well studied. It is known that IL-1 expression in periapical lesions correlates closely with the development of AP. IL-1 is a potent bone-resorptive cytokine that induces osteoclast formation and activation. Hence, inhibiting its signaling with IL-1 receptor antagonist (IL-1RA) results in a reduction in periapical lesion size. On the other hand, IL-1 is also a central cytokine that combats bacterial infection by activating innate immune responses. Therefore, a complete loss of IL-1 signaling leads to a failure to limit bacterial dissemination and consequently exacerbates AP. In vivo, IL-1 expression is tightly regulated and its signaling is modulated to optimize the immune response. Obesity causes systemic low-grade chronic inflammation and increases the risk of cardiovascular, renal, and other disorders. In experimentally induced AP, obesity significantly increases periapical bone loss, albeit the underlying mechanism remains unclear. Recent technological innovations have enabled more comprehensive and detailed analyses than previously, leading to new insights into the role of IL-1RA in regulating IL-1 signaling, and modulating apical lesion progression in obesity. In this review, we provide a brief overview of the function of IL-1 in AP development, with special emphasis on the latest findings in normal weight and obese states.

Evaluation of the Progression of Periodontitis with the Use of Neural Networks.

Periodontitis is an inflammatory disease of the tissues surrounding the tooth that results in loss of periodontal attachment detected as clinical attachment loss (CAL). The mildest form of periodontal disease is gingivitis, which is a necessary condition for periodontitis development. We can distinguish also some modifying factors which have an influence on the rate of development of periodontitis from which the most important are smoking and poorly controlled diabetes. According to the new classification from 2017, we can identify four stages of periodontitis and three grades of periodontitis. Grades tell us about the periodontitis progression risk and may be helpful in treatment planning and motivating the patients. Artificial neural networks (ANN) are widely used in medicine and in dentistry as an additional tool to support clinicians in their work. In this paper, ANN was used to assess grades of periodontitis in the group of patients. Gender, age, nicotinism approximal plaque index (API), bleeding on probing (BoP), clinical attachment loss (CAL), and pocket depth (PD) were taken into consideration. There were no statistically significant differences in the clinical periodontal assessment in relation to the neural network assessment. Based on the definition of the sensitivity and specificity in medicine we obtained 85.7% and 80.0% as a correctly diagnosed and excluded disease, respectively. The quality of the neural network, defined as the percentage of correctly classified patients according to the grade of periodontitis was 84.2% for the training set. The percentage of incorrectly classified patients according to the grade of periodontitis was 15.8%. Artificial neural networks may be useful tool in everyday dental practice to assess the risk of periodontitis development however more studies are needed.

Interferon-gamma inducible protein 16 and type I interferon receptors expression in experimental apical periodontitis induced in wild-type mice.

The aim of this study was to evaluate the IFI16 and IFN-α/β receptors expression during the genesis and development of experimental apical periodontitis (AP) in mice teeth. Apical periodontitis was induced in the lower first molars of 40 C57BL/6 mice. They were divided according to the experimental periods 2, 7, 14, 21 and 42 days (n=8 per group). Five animals were used as a control group (without AP). Specimens were submitted to histological processing for description of the inflammatory process, immunostaining for the presence/absence and localization of IFI16 and IFN-α/β receptors (qualitative and semi-quantitative analysis) and tartrate-resistant acid phosphatase (TRAP) histoenzimology. The results showed a gradual development of AP over the experimental times. The expression of IFI16 was noticeably more exacerbated in the experimental early period (day 2) whilst the lowest expression was observed in the control group (p=.02). For IFN-α/β receptors, a higher intensity staining was observed 42 days after AP induction, that was statistically different from the control group (p=.02). In addition, the number of TRAP-positive cells was higher on the later periods (days 21 and 42; p < .001). IFI16 protein expression was highest during the early periods after AP induction in mice teeth, whilst IFN-α/β receptor expression was highest after AP became established.

Critical roles for CCR2 and the therapeutic potential of cenicriviroc in periodontitis: A pre-clinical study.

CCR2 plays important roles in many inflammatory and bone metabolic diseases, but its specific role in periodontitis is unknown. In the present study, we aimed to explore the role of CCR2 in the progression of periodontitis and evaluate the effect of cenicriviroc (CVC) on periodontitis. The expression of CCR2 was studied in patients with periodontitis and in ligation-induced murine model of periodontitis. The role of CCR2 in promoting inflammation and bone resorption in periodontitis was evaluated in Ccr2-/- mice and wild-type mice. The effect of CVC in the prevention and treatment of periodontitis was evaluated by systemic and local medication. Microcomputed tomography, haematoxylin and eosin staining, tartrate-resistant acid phosphatase staining, quantitative real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and flow cytometry were used for histomorphology, molecular biology, and cytology analysis, respectively. In this study, we demonstrated that CCR2 was highly expressed in human and murine periodontitis and that CCR2 deficiency was associated with decreased inflammatory monocyte and macrophage infiltration and inflammatory mediators, osteoclast number and alveolar bone resorption. Prevention and treatment with CVC significantly reduced the severity of periodontitis, regardless of whether it was administered systemically or locally. CCR2 plays an important role in the development and progression of periodontitis, and CVC is a potential drug for the prevention and treatment of periodontitis.

Genetic, Cellular and Molecular Aspects involved in Apical Periodontitis.

The development, establishment and repair of apical periodontitis (AP) is dependent of several factors, which include host susceptibility, microbial infection, immune response, quality of root canal treatment and organism's ability to repair. The understanding of genetic contributions to the risk of developing AP and presenting persistent AP has been extensively explored in modern Endodontics. Thus, this article aims to provide a review of the literature regarding the biochemical mediators involved in immune response signaling, osteoclastogenesis and bone neoformation, as the genetic components involved in the development and repair of AP. A narrative review of the literature was performed through a PUBMED/MEDLINE search and a hand search of the major AP textbooks. The knowledge regarding the cells, receptors and molecules involved in the host's immune-inflammatory response during the progression of AP added to the knowledge of bone biology allows the identification of factors inherent to the host that can interfere both in the progression and in the repair of these lesions. The main outcomes of studies evaluated in the review that investigated the correlation between genetic polymorphisms and AP in the last five years, demonstrate that genetic factors of the individual are involved in the success of root canal treatment. The discussion of this review gives subsides that may help to glimpse the development of new therapies based on the identification of therapeutic targets and the development of materials and techniques aimed at acting at the molecular level for clinical, radiographic and histological success of root canal treatment.

Role of ferroptosis-related genes in periodontitis based on integrated bioinformatics analysis

BackgroundCell survival or death is one of the key scientific issues of inflammatory response. To regulate cell death during the occurrence and development of periodontitis, various forms of programmed cell death, such as pyroptosis, ferroptosis, necroptosis, and apoptosis, have been proposed. It has been found that ferroptosis characterized by iron-dependent lipid peroxidation is involved in cancer, degenerative brain diseases and inflammatory diseases. Furthermore, NCOA4 is considered one of ferroptosis-related genes (FRGs) contributing to butyrate-induced cell death in the periodontitis. This research aims to analyze the expression of FRGs in periodontitis tissues and to explore the relationship between ferroptosis and periodontitis.MethodGenes associated with periodontitis were retrieved from two Gene Expression Omnibus datasets. Then, we normalized microarray data and removed the batch effect using the R software. We used R to convert the mRNA expression data and collected the expression of FRGs. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), transcription factor (TF) and protein-protein interaction (PPI) network analyses were used. In addition, we constructed a receiver operating characteristic curve and obtained relative mRNA expression verified by quantitative reverse-transcription polymerase chain reaction (PCR).ResultsEight and 10 FRGs related to periodontitis were upregulated and downregulated, respectively. GO analysis showed that FRGs were enriched in the regulation of glutathione biosynthetic, glutamate homeostasis, and endoplasmic reticulum-nucleus signaling pathway. The top TFs included CEBPB, JUND, ATF2. Based on the PPI network analysis, FRGs were mainly linked to the negative regulation of IRE1-mediated unfolded protein response, regulation of type IIa hypersensitivity, and regulation of apoptotic cell clearance. The expression levels of NCOA4, SLC1A5 and HSPB1 using PCR were significantly different between normal gingival samples and periodontitis samples. Furthermore, the diagnostic value of FRGs for periodontitis were “Good”.ConclusionsWe found significant associations between FRGs and periodontitis. The present study not only provides a new possible pathomechanism for the occurrence of periodontitis but also offers a new direction for the diagnosis and treatment of periodontitis.

Expression of Concern

This article refers to:Abnormal expression of long noncoding RNA FGD5-AS1 affects the development of periodontitis through regulating miR-142-3p/SOCS6/NF-κB pathway

Metabolomics in Periodontal Disease - A Mini Review

Periodontitis is the most common oral disease. It is a chronic disease that is characterised by the destruction of the tissues. It is caused by multifactorial aetiology. Variation in host metabolism and microbes results in the development of periodontitis. Saliva provides us with a protective role of lubrication, neutralizing the pH, mineralising the bones and fighting microbes in a diseased oral cavity. We need to identify metabolites in saliva to know the aetiology and stage of periodontitis. Some metabolites may help in the diagnosis and treatment of periodontitis. Various classes of the biochemicals like amino acids, lipids, carbohydrates, nuclear peptides, dipeptides are changed in periodontitis. Most importantly, there is an increase in the levels of protease, glycosidase and lipase activity in chronic periodontal disease that forms the most favourable time for the growth of bacteria. There is a deficiency in contempered screening methods. Therefore, we should understand the arising need for metabolites for better diagnosis and treatment of periodontitis.

EFFECTIVENESS OF MATRIX METALLOPROTEINASES INHIBITORS FOR PREVENTIVE TREATMENT OF GENERALIZED PERIODONTITIS

Generalized periodontitis is one of the most widespread human stomatological diseases; it is diagnosed in 11.0 % of the world's population. Despite the recognition of the microbial factor as leading in its etiopathogenesis, antimicrobial treatment of gingivitis, added with removal of dental plaque, does not prevent the further development of periodontitis. Dysbacteriosis causes inflammation which leads to an increase of proteolysis products. They are a nutrient medium for periodontal pathogenic microflora, they contribute to its growth. So, the use of anti-inflammatory drugs, such as matrix metalloproteinase inhibitors, is promising for preventive treatment of generalized periodontitis.&#x0D; The aim of the work is to conduct a clinical trial of complex treatment which includes matrix&#x0D; metalloproteinase inhibitors in patients with diffuse gingivitis and generalized periodontitis of chronic course.&#x0D; Materials and methods of the research. 60 patients with chronic course of diffuse gingivitis and generalized periodontitis of initial, I and II stages, were treated. The effectiveness of the treatment was evaluated in the early and distant term (after 1 year) according to data of the clinical and radiological examination, computer tomography, biochemical examination of oral fluid for matrix metalloproteinases-8 and -9 (MMP-8, -9) and immunohistochemical study of gingival biopsies for cytoplasmic expression of matrix metalloproteinase-1 (MMP-1).&#x0D; Results of the research. According to the data of the clinical examination, complete elimination of inflammatory symptoms in periodontal tissues was achieved in 93.3% of patients in the comparison group in 12-14 days and in 96.7% in the base group in 10-12 days. In patients in whom the developed therapeutic scheme was used, the best dynamics of the index assessment of the state of hygiene, gingiva and periodontal complex was established. The main difference between the research groups was the preservation of obtained results in 1 year after treatment in patients of the base group (p ˂ 0.05). In particular, a year later, the results of bone mineral density measurement for patients of the base group did not change from baseline, while in the comparison group there was their significant decrease (p ˂ 0.05), indicating the progression of inflammatory-destructive process in periodontal tissues.&#x0D; After treatment, a significant reduction in the level of MMP-8 and MMP-9 in the oral fluid of patients of both groups was achieved (p ˂ 0.05). In patients of the base group, in contrast to the comparison, these results were the same in the distant term (p ˂ 0.05). When assessing the cytoplasmic expression of MMP-1 in epithelial and stromal cells after treatment, zero result was in 96.7% of patients in the base group and in 80.0% – in the comparison group, and after 1 year – in 90.0% vs 63.3% respectively.&#x0D; It should be noted that the differences between the base and comparison groups were most observed for patients with gingivitis and generalized periodontitis of initial stage without destructive processes in periodontal tissues. It suggests the greatest effectiveness of the proposed treatment in the early stages of pathological process.&#x0D; Thus, based on the fact that the activity of matrix metalloproteinases characterizes the course of the inflammatory process in periodontal tissues, a decrease in their level according to biochemical and immunohistochemical studies in the base group against the comparison indicates a better anti-inflammatory effect of the developed treatment to prevent the progression of generalized periodontitis.&#x0D; Conclusion. The obtained results allow recommending the use of matrix metalloproteinase inhibitors as a preventive pathogenetic treatment for the patients with chronical course of gingivitis and generalized periodontitis of the initial stage, to inhibit the inflammatory component of the pathological process.&#x0D; Prospects for further research. It should be studied the indication for repeated courses of matrix metalloproteinase inhibitors in patients with periodontal disease.

The Periodontal Pathogen Fusobacterium nucleatum Exacerbates Alzheimer's Pathogenesis via Specific Pathways.

Alzheimer’s Disease (AD) is the most common form of dementia in older adults and has a devastating impact on the patient’s quality of life, which creates a significant socio-economic burden for the affected individuals and their families. In recent years, studies have identified a relationship between periodontitis and AD. Periodontitis is an infectious/inflammatory disease that destroys the supporting periodontal structure leading to tooth loss. Dysbiosis of the oral microbiome plays a significant role in the onset and development of periodontitis exhibiting a shift to overgrowth of pathobionts in the normal microflora with increasing local inflammation. Fusobacterium nucleatum is a common pathogen that significantly overgrows in periodontitis and has also been linked to various systemic diseases. Earlier studies have reported that antibodies to F. nucleatum can be detected in the serum of patients with AD or cognitive impairment, but a causal relationship and a plausible mechanism linking the two diseases have not been identified. In this study, we conducted both in vivo and in vitro experiments and found that F. nucleatum activates microglial cells causing morphological changes, accelerated proliferation and enhanced expression of TNF-α and IL-1β in microglial cells. In our in vivo experiments, we found that F. nucleatum-induced periodontitis resulted in the exacerbation of Alzheimer’s symptoms in 5XFAD mice including increased cognitive impairment, beta-amyloid accumulation and Tau protein phosphorylation in the mouse cerebrum. This study may suggest a possible link between a periodontal pathogen and AD and F. nucleatum could be a risk factor in the pathogenesis of AD. We are currently further identifying the pathways through which F. nucleatum modulates molecular elements in enhancing AD symptoms and signs. Data are available via ProteomeXchange with identifier PXD033147.

Epigenetics in susceptibility, progression, and diagnosis of periodontitis.

Periodontitis is characterized by irreversible destruction of periodontal tissue. At present, the accepted etiology of periodontitis is based on a three-factor theory including pathogenic bacteria, host factors, and acquired factors. Periodontitis development usually takes a decade or longer and is therefore called chronic periodontitis (CP). To search for genetic factors associated with CP, several genome-wide association study (GWAS) analyses were conducted; however, polymorphisms associated with CP have not been identified. Epigenetics, on the other hand, involves acquired transcriptional regulatory mechanisms due to reversibly altered chromatin accessibility. Epigenetic status is a condition specific to each tissue and cell, mostly determined by the responses of host cells to stimulations by local factors, like bacterial inflammation, and systemic factors such as nutrition status, metabolic diseases, and health conditions. Significantly, epigenetic status has been linked with the onset and progression of several acquired diseases. Thus, epigenetic factors in periodontal tissues are attractive targets for periodontitis diagnosis and treatments. In this review, we introduce accumulating evidence to reveal the epigenetic background effects related to periodontitis caused by genetic factors, systemic diseases, and local environmental factors, such as smoking, and clarify the underlying mechanisms by which epigenetic alteration influences the susceptibility of periodontitis.

Enterococcus faecalis-Induced Macrophage Necroptosis Promotes Refractory Apical Periodontitis.

ABSTRACTThe persistence of residual bacteria, particularly Enterococcus faecalis, contributes to refractory periapical periodontitis, which still lacks effective therapy. The role of receptor-interacting protein kinase 3 (RIPK3)- and mixed lineage kinase domain-like protein (MLKL)-mediated necroptosis, a highly proinflammatory form of regulated cell death, has recently drawn much attention. However, the role of necroptosis in the pathogenesis of refractory periapical periodontitis remains unclear. We investigated whether the RIPK3/MLKL signaling pathway was activated in periapical lesion specimens obtained from patients diagnosed with refractory periapical periodontitis. RIPK3-deficient mice were then used to determine the role of necroptosis under this condition in vivo. We found that the phosphorylation levels of RIPK3 and MLKL were elevated in periapical lesion specimens of patients with refractory periapical periodontitis. In addition, necroptosis was induced in an E. faecalis-infected refractory periapical periodontitis mouse model, in which inhibition of necroptosis by RIPK3 deficiency could markedly alleviate inflammation and bone destruction. Moreover, double-labeling immunofluorescence suggested that macrophage necroptosis may be involved in the development of refractory periapical periodontitis. Then, we established an in vitro macrophage infection model with E. faecalis. E. faecalis infection was found to induce necroptotic cell death in macrophages through the RIPK3/MLKL signaling pathway, which was markedly alleviated by the RIPK3- or MLKL-specific inhibitor. Our study revealed that RIPK3/MLKL-mediated macrophage necroptosis contributes to the development of refractory periapical periodontitis and suggests that inhibitors or treatments targeting necroptosis represent a plausible strategy for the management of refractory periapical periodontitis.IMPORTANCE Oral infectious diseases represent a major neglected global population health challenge, imposing an increasing burden on public health and economy. Refractory apical periodontitis (RAP), mainly caused by Enterococcus faecalis, is a representative oral infectious disease with considerable therapeutic challenges. The interplay between E. faecalis and the host often leads to the activation of programmed cell death. This study identifies an important role of macrophage necroptosis induced by E. faecalis in the pathogenesis of RAP. Manipulating RIPK3/MLKL-mediated necroptosis may represent novel therapeutic targets, not only for RAP but also for other E. faecalis-associated infectious diseases.