Periodontitis, especially in its chronic form, is one of the leading causes of tooth loss, significantly affecting the quality of life in the modern era of aging society. Recent studies have revealed a potential correlation between periodontitis and various systemic diseases, including cardiovascular diseases and Alzheimer’s dementia (AD). With the body of epidemiologic evidence that links these separate disease entities, several lines of hypotheses have been postulated to provide mechanistic understandings that mostly comprises abnormal regulation of immunologic and inflammatory signaling. In this review, we revisit the experimental findings that describe virulence factors derived from Porphyromonas gingivalis, including gingipains and lipopolysaccharides, as well as their roles in the pathophysiology of AD. In addition, we address potential immunologic challenges imposed by this bacterial pathogen contributing to progression of AD.

Porphyromonas gingivalis, a major pathogen of chronic periodontitis, colonizes in subgingival crevice and affects surrounding oral tissues, especially in periodontitis patients. Oral cancer mainly occurs in old-aged persons, and are exposed to the P. gingivalis, released from periodontitis, one of the most common inflammatory disease of oral cavity. Thus oral cancer cells may be infected with P. gingivalis, and its biologic behavior are autologously and/or heterogeneously modulated by altering gene expression. Exosomes which are derived from cells contain not only coding genes but also non-coding RNAs such as long non-coding RNAs, miRNA, and piRNAs. Here, to investigate the effect of P. gingivalis on oral cancer cells and to gain insight into the crosstalk between inflammatory signal from tumor microenvironment and oral cancer, we observed miRNA profiles of exosomes from P. gingivalis–infected oral cancer cells. Upregulation of 6 miRNAs, miR-203-3p, miR-6516-3p, miR-483-5p, miR-1275, miR-8485, and miR-19a-3p, were observed whereas 14 miRNAs including let-7a-3p, miR-106a-5p were downregulated. In addition, KEGG pathway analysis using the upregulated- and downregulated- miRNAs showed association with cell adhesion molecules pathway and ECM-receptor interaction pathway, respectively. These findings suggest that P. gingivalis could modulate biologic behavior of oral cancer cells through changes of exosomal miRNAs.

Lysophosphatidic acid (LPA) is a bioactive lipid messenger involved in the pathogenesis of chronic inflammation and various diseases. Recent studies have shown an association between periodontitis and neuroinflammatory diseases such as Alzheimer’s disease, stroke, and multiple sclerosis. However, the mechanistic relationship between periodontitis and neuroinflammatory diseases remains unclear. The current study found that lysophosphatidic acid receptors 1 (LPAR1) and 6 (LPAR6) exhibited increased expression in primary microglia and astrocytes. The primary astrocytes were then treated using medium conditioned to mimic periodontitis through addition of Porphyromonas gingivalis lipopolysaccharides, and an increased nitric oxide (NO) production was observed. Application of conditioned medium from human periodontal ligament stem cells with or without LPAR1 knockdown showed a decrease in the production of NO and expression of inducible nitric oxide synthase and interleukin 1 beta. These findings may contribute to our understanding of the mechanistic link between periodontitis and neuroinflammatory diseases.

Periodontal disease is a chronic but treatable condition which often does not cause pain during the initial stages of the illness. Lack of awareness of symptoms can delay initiation of treatment and worsen health. The aim of this study was to develop and compare different risk prediction models for periodontal disease using machine learning algorithms. We obtained information on risk factors for periodontal disease from the Korea National Health and Nutrition Examination Survey (KNHANES) dataset. Principal component analysis and an auto-encoder were used to extract data on risk factors for periodontal disease. A synthetic minority oversampling technique algorithm was used to solve the problem of data imbalance. We used a combination of logistic regression analysis, support vector machine (SVM) learning, random forest, and AdaBoost to classify and compare risk prediction models for periodontal disease. In cases where we used principal component analysis (PCA) to extract risk factors, the recall was higher than the feature selection method in the logistic regression and support-vector machine learning models. AdaBoost’s recall was 0.98, showing the highest performance of both feature selection and PCA. The F1 score showed relatively high performance in Ada- Boost, logistic regression, and SVM learning models. By using the risk factors extracted from the research results and the predictive model based on machine learning, it will be able to help in the prevention and diagnosis of periodontal disease, and it will be used to study the relationship with various diseases related to periodontal disease.

Periodontitis and periimplantitis are caused as a result of dental biofilm formation. This biofilm is composed of multiple species of pathogens. Therefore, controlling biofilm formation is critical for disease prevention. To inhibit biofilm formation, sugars can be used to interrupt lectin-involving interactions between bacteria or between bacteria and a host. In this study, we evaluated the effect of D-Arabinose on biofilm formation of putative periodontal pathogens as well as the quorum sensing activity and whole protein profiles of the pathogens. Crystal violet staining, confocal laser scanning microscopy, and scanning electron microscopy revealed that D-Arabinose inhibited biofilm formation of Porphyromonas gingivalis , Fusobacterium nucleatum , and Tannerella forsythia . D-Arabinose also significantly inhibited the activity of autoinducer 2 of F. nucleatum and the expression of representative bacterial virulence genes. Furthermore, D-Arabinose treatment altered the expression of some bacterial proteins. These results demonstrate that D-Arabinose can be used as an antibiofilm agent for the prevention of periodontal infections.

Lysophosphatidic acid (LPA) is a lipid messenger mediated by G protein-coupled receptors (LPAR1-6). It is involved in the pathogenesis of certain chronic inflammatory and autoimmune diseases. In addition, it controls the self-renewal and differentiation of stem cells. Recent research has demonstrated the close relationship between periodontitis and various diseases in the human body. However, the precise role of LPA in the development of periodontitis has not been studied. We identified that LPAR1 was highly expressed in human periodontal ligament stem cells (PDLSCs). In periodontitis-mimicking conditions with Porphyromonas gingivalis -derived lipopolysaccharide (Pg-LPS) treatment, PDLSCs exhibited a considerable reduction in the cellular viability and osteogenic differentiation potential, in addition to an increase in the inflammatory responses including tumor necrosis factor-α and interleukin-1β expression and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) activation. Of the various LPAR antagonists, pre-treatment with AM095, an LPAR1 inhibitor, showed a positive effect on the restoration of cellular viability and osteogenic differentiation, accompanied by a decrease in NF-κB signaling, and action against Pg-LPS. These findings suggest that the modulation of LPAR1 activity will assist in checking the progression of periodontitis and in its treatment.

Periodontitis is an inflammatory disease of the supportive tissues surrounding the teeth, and is characterized by irreversible destruction of the gingiva, periodontal ligament (PDL), and alveolar bone, which results in the loss of teeth. In the present study, we elucidated the correlation between periodontitis and apelin (APLN), an adipokine and a regulatory peptide, respectively, which are involved in inflammation and bone remodeling. The expression of APLN is negatively correlated with periodontitis progression in gingival tissue. In addition, treatment with TNF-α downregulated the expression of APLN in PDL cells and gingival fibroblasts, indicating the protective role played by APLN against periodontitis progression. The overexpression of APLN or treatment with exogenous APLN suppressed the TNF-α- mediated catabolic gene expression of MMP1, IL6 , and PTGS2 in PDL cells. Moreover, the inhibition of the APLNAPJ axis by ML221, an APJ inhibitor, induced catabolic gene expression in PDL cells. Thus, the results of this study provided evidence to support APLN as a regulatory factor of the inflammatory response during periodontitis.

Porphyromonas gingivalis (Pg), Aggregatibacter actinomycetemcomitans (Aa), Tannerella forsythia (Tf), Prevotella intermedia (Pi), and Fusobacterium nucleatum (Fn) are major periodontal pathogens. Lipopolysaccharides (LPSs) from periodontal bacteria play an important role in periodontal pathogenesis by stimulating host cells to produce inflammatory cytokines. In this study, highly pure LPSs from the five major periodontopathogens were prepared, and their monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-α (TNF-α)-inducing activities were compared in human umbilical vein endothelial cells (HUVECs) and THP-1 macrophagic cells, respectively. In HUVECs, LPSs from Aa and Fn were potent stimulators for MCP-1 induction; however, LPSs from Pg, Pi, and Tf were much weaker MCP-1 inducers. In THP-1 cells, LPSs from Pg, Aa, and Fn were relatively strong inducers of TNF-α, whereas LPSs from Pi and Tf produced little activity. The Toll-like receptor (TLR)2/TLR4 dependency of various LPSs was also determined by measuring NF-κB reporter activity in TLR2- or TLR4-expressing 293 cells. LPSs from Aa, Fn, and Tf stimulated only TLR4; however, LPSs from Pg and Pi stimulated both TLR2 and TLR4. These results suggest that LPSs from major periodontal bacteria differ considerably in their cell-stimulating activity.

Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin's lymphoma, and usually showed painless neck swelling, fever, sweat, and weight loss. Although about 5% of all lymphomas appeared in the oral area, the primary maxillofacial lymphomas were rare and sometimes clinically tended to be misdiagnosed such as chronic periodontitis, osteomyelitits, etc. This study demonstrated three cases of primary DLBCL mimicking localized osteomyelitis at mandible or maxilla. A series of histological and immunohistochemical examination using different biomarkers of lymphoreticular cells were performed to characterize the neoplastic cells of DLBCL. The first case occurred in a 45 years old male exhibiting mandibular osteomyelitis and neck swelling. The second case simply showed a gingival swelling at left upper premolar area in a 55 years old male. And the third case is from an 84 years old female who felt numbness at left lower lip and had severe periodontitis involving regional alveolar bone resorption. All of three cases had experienced no systemic manifestation of lymphoreticular malignancy before the diagnosis of oral lymphoma. Immunostainings of CD3, CD20, TNFα, BCL-2, Ki-67, PCNA, and c-Myc were strongly positive in these tumor cells, while those of p53 and CD31 were slightly positive, and CD56 immunoreaction was negative. These three cases were diagnosed as DLBCL and referred to the hemato-oncology unit for treatment. Therefore, every chronic granulomatous periodontal lesion hardly cured by simple medical treatment should be carefully explored through pathological examination, and it was presumed that DLBCL is closely related to the chronic inflammatory periodontal lesions recruiting mucosa-associated lymphoid cells in older patients. It was also suggested that DLBCL be differentially diagnosed from T-cell lymphoma, Burkitt’s lymphoma, and Hodgkin’s disease, etc. with immunohistochemical determination of tumor cell subtypes as soon as possible in order to be treated with appropriate therapy.

The purpose of this study is to determine if natural extracts could be used as an additive in oral health food made with Weissella cibaria CMU (oraCMU). Natural extracts of green tea, mulberry leaf, licorice, and propolis, which are reported to have antimicrobial activities, were selected and used in this study. The minimum inhibitory concentrations (MIC) of extracts on periodontal pathogens such as Fusobacterium nucleatum and Porphyromonas gingivalis and their synergy effects with oraCMU by the fractional inhibitory concentrations methods were measured. From the results obtained, all the extracts showed no effect on the growth of oraCMU. Green tea extract showed the best antibacterial activity with MIC of 1.8 mg/ml against both F. nucleatum and P. gingivalis. In addition, green tea extract had a synergistic effect with oraCMU against F. nucleatum. Therefore, these results suggested that green tea extract is available as an additive in oral health food made with oraCMU.

Quorum sensing (QS) is a cell density-dependent communication mechanism between bacteria through small signaling molecules. When the number of QS signaling molecules reaches a threshold, they are transported back into the cells or recognized by membrane-bound receptors, triggering gene expression which affects various phenotypes including bioluminescence, virulence, adhesion, and biofilm formation. These phenotypes are beneficial for bacterial survival in harsh environments. This review summarizes the application of QS inhibitors for control of biofilm formation and virulence expression of periodontal pathogens.

Transglutaminase2 (TGM2) is a multi-functional calcium dependent enzyme that affects angiogenesis, apoptosis, differentiation, attachment, and changes in the extracellular matrix. However, its function in periodontal tissue has not yet been studied. The aim of this study was to investigate the association of the TGM2 expression and the modulation of inflammatory mediators in inflamed periodontal ligament (PDL) cells induced by pro-inflammatory cytokines such as Interleukin-1β and the Tumor necrosis factor-α. The expression of TGM2 was increased in the inflamed periodontal tissue and PDL cells. Over-expressed TGM2 in the PDL cells increased expression of MMP1, MMP3, IL-6, CXCL8, and PTGS2. Conversely, inhibition of TGM2 activity using LDN27219, a TGM2 inhibitor, resulted in decreased expression of MMP1, MMP3, IL-6, and CXCL8. The mRNA expression was confirmed by RT-PCR and quantified by qRT-PCR. Protein levels were also confirmed by immunofluoroscence staining. These results suggest that TGM2 plays an important role in the regulation of inflammatory mediators which exacerbate tissue damage in inflamed periodontal tissue.

Transient receptor potential melastatin 8 (TRPM8) plays a crucial role in innocuous cool sensation, acute cold pain and cold-induced hyperalgesia during pathologic conditions. To help understand TRPM8-mediated cold perception in the dental pulp and periodontal tissues, we examined the distribution of TRPM8-immunopositive (+) axons in molar and incisor pulp and periodontal tissues using transgenic mice expressing a genetically encoded axonal tracer in TRPM8+ neurons. In the radicular pulp of the molar teeth, a small number of TRPM8+ axons were observed. TRPM8+ axons branched frequently and extensively in the core of coronal pulp, forming a network in the peripheral pulp. Some TRPM8+ axons ascended between odontoblasts and were observed in the dentinal tubule. TRPM8+ axons were linear-shaped in the radicular pulp, whereas many TRPM8+ axons showed portions shaped like beads connected with thin axonal stands at the peripheral pulp. TRPM8 was densely expressed in the bead portions. In the incisor pulp, TRPM8+ axons were occasionally observed in the core of the coronal pulp and rarely observed at the peripheral pulp. TRPM8+ axons were occasionally observed and showed a linear shape rather than a bead-like appearance in the periodontal ligament and lamina propria of the gingival tissue. These findings, showing differential distribution of TRPM8+ axons between radicular and coronal portions of the molar pulp, between incisor and molar pulp, and between dental pulp and periodontal tissues, may reflect differential cold sensitivity in these regions.

Flavonoid myricetin, usually found in tea and medicinal plants, has antioxidant and anti-inflammatory effects. Our objectives in this study were to verify the effects of myricetin on periodontal ligament fibroblasts (PDLFs) under inflammatory conditions and to observe its effects on osteoclast generation and on cytokine expression in RAW264.7 cells. To determine the effects of myricetin on PDLFs, we examined the expression and activity of proteolytic enzymes, including MMP-1, MMP-2, and MMP-8, which all play an important role in chronic periodontitis. We observed the effects of myricetin on intracellular signal transduction to verify the molecular mechanism involved. By measuring the formation of TRAP–positive multinucleated cells and the expression and activity of MMP-8, we were able to assess the effects of myricetin on osteoclast generation. In addition, by measuring the secretion of IL-6 and NO, we could evaluate the effects of myricetin on inflammatory mediators. We found that Myricetin had no effect on the viability of the PDLFs in the presence of inflammation, but it did decrease both the expression of MMP-1 and MMP-8 and the enzyme activity of MMP-2 and MMP-8 in these fibroblasts. Myricetin also decreased the lipopolysaccharide-stimulated phosphorylation of JNK, p38 signaling, IKKB, AKT, and p65RelA in the PDLFs. In the RAW264.7 cells, myricetin inhibited both the expression and the activity of MMP-8. Furthermore, Myricetin not only suppressed the generation of LPS-stimulated osteoclasts, but it also slightly inhibited LPS-stimulated degradation of IkB and decreased the release of LPS-induced IL-6 and NO. These findings suggest that myricetin alleviates the tissue-destructive processes that occur during periodontal inflammation.

Halitosis is a bad odor in mouth. The etiology of halitosis is multifactorial including intra-oral and extra-oral causes. It affects social interactions in many people. The aim of this study is to investigate an association between recognition group and non-recognition group by evaluating halitosis level and systemic factors. Nineteen participants who visited Department of Periodontology of Seoul National University Bundang Hospital were enrolled. Volatile sulfur a compounds (VSCs) were measured by Oral ChromaⓇ, a questionnaire was requested and oral exam was carried out in all subjects. Female is more sensitive than male for oral malodor. VSCs level of hydrogen sulfide(H2S) and methyl mercaptan(CH3SH) in male is higher than that in female. Participants who gave appeal dry mouth seem to recognize halitosis.

Subcutaneous emphysema is a rare but serious side effect of dental and oral surgery procedures. The condition is characterized by air being forced underneath the tissue, leading to swelling, crepitus on palpation, and with potential to spread along the fascial planes to the periorbital, mediastinal, pericardial, and/or thoracic spaces. A wide range of causes have been documented for the origin of subcutaneous emphysema during dental treatment including: crown preparations, other operative procedures, endodontic therapy, extractions, as well as oral surgery procedures. The patient was a 58-year-old woman who presented to the Seoul Saint mary’s hospital emergency department with a chief complaint of facial edema, dyspnea and chest discomfort after periodontal treatment using an air-flow equipment in local dental clinic. During treatment in the emergency department, oxygen therapy and intravenous injection of steroid and anti-histamine was done. it was noted that the patient had pain and swelling on left lower molar region, pus discharging on same site. Severe edema was observed on periorbital region to neck with heatness. An audible crepitus sound was heard during palpation on facial area. Neck CT scan and antibiotic therapy was done, as symptom suggesting dental abscess is observed. 3 hours after injection of antibiotics, the patient’s symptom was relieved, but she felt chest discomfort continuously. CT scan with constrast depicted confluent and extensive soft tissue emphysematous changes involving face and deep neck spaces and pneumomediastinum. The patient was refered to thoracic surgery department, oxygen therapy was decided continuously. After 10 hours, patient’s chief complaint was resolved, and discharged. After 1 week, all symptom was disappear and follow-up neck CT scan finding was disappearance of edema and pnuemomediastinum. We report a case of cervical subcutaneous emphysema and pneumomediastinum occurring after periodontal treatment using an air-flow equipment and case on the diagnosis and treatment of subcutaneous emphysema and pneumomediastinum, along with a review of the literature.

The purpose of this study was to synthetically examine the relationship between systemic diseases and periodontal diseases. The data of the Fifth Korea National Health and Nutrition Examination Survey were used. SPSS 18.0 for Windows was applied for statistical analysis. The surveyed data were analyzed by using independent sample t-test for the difference between Body Mass Index and clinical test according to the existence of periodontal disease, and X2test for the relationship between periodontal disease and systemic disease. Multiple logistic regression analysis was used in order to figure out the influence upon the existence of periodontal disease prevalence among general characteristics and relevant factors to systemic disease. As results, the value of high density lipoprotein (HDL) and HBA1C were statistically significant, depending on the presence of periodontal disease. As for the relationship between periodontal disease and systemic disease, hypertension (odds ratio 1.362, p<.05), cardiovascular disease (odds ratio 2.118, p<.05), arthritis (odds ratio 1.289, p<.05) and cirrhosis (odds ratio 6.124, p<.05) were statistically significant. In conclusion, the majority of the systemic diseases such as cardiovascular system, diabetes, and liver diseases have been considered to have relationship with periodontal disease. To strengthen oral health education is needed to enhance systemic health as well as oral health. Moreover, basic biological research should be followed to support this surveyed study.

The purpose of this study was to synthetically examine the relationship between systemic diseases and periodontal diseases. The data obtained from the Fifth Korea National Health and Nutrition Examination Survey were used. SPSS 18.0 for Windows was applied for statistical analysis. The surveyed data were analyzed by using independent sample t-test for the difference between Body Mass Index and clinical test according to the existence of periodontal disease, and X2 test for the relationship between periodontal disease and systemic disease. Multiple logistic regression analysis was used in order to figure out the influence upon the periodontal disease prevalence among general characteristics and systemic diseases. As results, the values of high density lipoprotein (HDL) and HBA1C were statistically significant, depending on the presence of periodontal disease. As for the relationship between periodontal disease and systemic disease, hypertension (odds ratio 1.362, p<.05), cardiovascular disease (odds ratio 2.118, p<.05), arthritis (odds ratio 1.289, p<.05) and cirrhosis (odds ratio 6.124, p<.05) were statistically significant. According to Multiple logistic regression analysis, gender (odds ratio 1.24, p<.05), alcohol intake (odds ratio 1.25, p<.05), cardiovascular diseases (odds ratio 1.56, p<.05), and liver cirrhosis (odds ratio 1.17, p<.05) were related to the prevalence of periodontal diseases. In conclusion, the systemic diseases such as cardiovascular system, diabetes, and liver diseases revealed to have relationship with periodontal disease. To strengthen oral health education is needed to enhance systemic health as well as oral health. Moreover, basic biological research should be followed to support this surveyed study.

Glucosamine is commonly taken by the elderly without prescription as a nutritional supplement to attenuate the progression or symptoms of osteoarthritis. Previous studies demonstrated that glucosamine shows anti-inflammatory effects in tissues such as blood vessels and the heart. However, there have been few reports about the effects of glucosamine on oral inflammatory diseases. Therefore, in this study, the effects of glucosamine on lipopolysaccharide (LPS)-induced inflammatory responses were investigated using human periodontal ligament fibroblasts (HPDLFs). HPDLFs were incubated in the presence and absence of glucosamine (10 mM) for 24 h, followed by treatment with E. coli LPS (100 ng/ml) or vehicle. Quantitative RT-PCR and ELISA results showed that LPS exposure significantly increased the levels of IL-6 and IL-8 mRNA and protein, while the effect was significantly suppressed by glucosamine treatment. Glucosamine did not attenuate, but slightly increased, the LPS-induced activation of mitogen activated kinases (ERK, p38, JNK). However, it suppressed the LPS-induced increase in the DNA binding affinity and transcriptional activity of NF-κB. These results suggest that glucosamine exerts anti-inflammatory effects on HPDLFs exposed to LPS via inhibition of NF-κB activity, necessitating further studies using animal periodontitis models.

Minimal inhibitory concentration (MIC) is the lowest concentration of antibiotics that inhibits the visible growth of a microorganism. It has been reported that sub-MIC of antibiotics may result in morphological alterations along with biochemical and physiological changes in bacteria. The purpose of this study was to examine morphological changes of periodontal pathogens after treatment with sub-MIC antibiotics. Aggregatibacter actinomycetemcomitans, Fusobacterium nucleatum, and Porphyromonas gingivalis were used in this study. The MIC for amoxicillin, doxycycline, metronidazole, penicillin, and tetracycline were determined by broth dilution method. The bacterial morphology was observed with bright field microscope after incubating with sub-MIC antibiotics. The length of A. actinomycetemcomitans and F. nucleatum were increased after incubation with metronidazole; penicillin and amoxicillin. P. gingivalis were increased after incubating with metronidazole and penicillin. However, F. nucleatum showed decreased length after incubation with doxycycline and tetracycline. In this study, we observed that sub-MIC antibiotics can affect the morphology of periodontal pathogens.