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Ozone is strong oxidizing agent that is applied in aqueous form for sanitation. However, ozonated water is unstable and has a short half-life. Ultrafine bubble technology is promising to overcome these issues. Ultrafine bubble is nanoscale bubble and can exist in water for a considerable duration of time. This study aims to investigate the application of ozone ultrafine bubble water (OUFBW) as a disinfectant. We produced an OUFBW generator which generates OUFBW containing 4-6 ppm of ozone. Thereafter, we examined the bactericidal activity of the OUFBW against various pathogenic bacteria in oral cavity and upper airway, including antibiotic-susceptible and antibiotic-resistant Streptococcus pneumoniae, Pseudomonas aeruginosa, Streptococcus mutans, Streptococcus sobrinus, Fusobacterium nucleatum, Prevotella intermedia, and Porphyromonas gingivalis. Exposure of planktonic culture of these bacterial species to OUFBW reduced viable bacteria by > 99% within 30s. Additionally, OUFBW exerted bactericidal activity against S. pneumoniae and P. aeruginosa adhered to toothbrush and gauze, respectively. We also observed disruption of bacterial cell wall of S. pneumoniae exposed to OUFBW by transmission electron microscope. Additionally, OUFB did not show any significant cytotoxicity toward the human gingival epithelial cell line Ca9-22. These results suggest that OUFBW exhibits bactericidal activity against broad spectrum of bacteria and has low toxicity towards human cells.

DOI： 10.1371/journal.pone.0284115

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ABSTRACT

Objectives

To evaluate the relevance of serum immunoglobulin G (IgG) titers against periodontopathic bacteria to predict the clinical response to one-year treatment with biological disease-modifying antirheumatic drugs (bDMARDs) in rheumatoid arthritis (RA) patients.

Methods

Data were collected from 50 RA patients who had received conventional synthetic DMARDs, corticosteroids, or non-steroidal anti-inflammatory drugs before (baseline) and after one-year treatment with bDMARDs in a retrospective cohort study. Changes in rheumatologic conditions were compared between the two groups for low and high baseline IgG titers against Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans according to their median measurements.

Results

Twenty-five patients with low anti-P. gingivalis IgG titers showed significantly greater decreases in changes in the clinical disease activity index (CDAI) and swollen joint count than 25 patients with high anti-P. gingivalis IgG titers (p=0.04 for both). Bivariate and multivariate analyses revealed a significantly positive association of baseline anti-P. gingivalis IgG titers with CDAI changes (p=0.02 and p=0.002). However, post-treatment rheumatologic conditions were comparable between 25 patients each in the low and high baseline anti-A. actinomycetemcomitans IgG titer groups.

Conclusions

Baseline serum anti-P. gingivalis IgG titers are predictive of the clinical response to one-year treatment with bDMARDs in RA patients.

DOI： 10.1093/mr/roac093

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Publishing type：Research paper (scientific journal)   Publisher：Scientific Research Publishing, Inc.  

DOI： 10.4236/jfcmv.2022.103006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Elsevier BV  

OBJECTIVE: This study aimed to clarify the antibacterial mechanism and antibiofilm effect of soybean-derived peptide BCBS-11 against periodontopathic bacteria. DESIGN: The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of BCBS-11 against Porphyromonas gingivalis (P. gingivalis), Fusobacterium nucleatum (F. nucleatum), and Streptococcus mitis (S. mitis) were determined for the antibacterial mechanism. The effect of BCBS-11 on membrane permeability and depolarization activity were investigated using propidium iodide (PI) staining and 3, 3'-dipropylthiadicarbocyanine iodide (DiSC3-(5)) analysis. Monospecies and multispecies biofilms were cultured on 96-well plates. The amount of biofilm was determined using crystal violet staining to determine the inhibition of biofilm formation and the eradication of established biofilm using BCBS-11. The cytotoxicity of BCBS-11 was evaluated using 3-(4, 5-Dimethylthiazol-2-yl)- 2, 5-diphenyltetrazolium bromide (MTT) assay. RESULTS: The MIC and MBC indicated the bactericidal activity of BCBS-11 against P. gingivalis and F. nucleatum. The PI staining revealed that BCBS-11 disrupted the bacterial membrane integrity. The DiSC3-(5) analysis indicated that BCBS-11 depolarized the bacterial cytoplasmic membrane. These results indicate the antimicrobial action of BCBS-11 through membrane disruption and the collapse of membrane electrochemical gradient. BCBS-11 significantly inhibited the monospecies biofilm formation of P. gingivalis and F. nucleatum and also inhibited dual-species biofilm. BCBS-11 was not cytotoxic toward human oral epithelial cells. CONCLUSIONS: BCBS-11 inhibits the monospecies and multispecies biofilm formation of P. gingivalis and F. nucleatum, and their bactericidal activity results from membrane disruption.

DOI： 10.1016/j.archoralbio.2022.105497

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Neutrophil elastase (NE) functions as a host defense factor; however, excessive NE activity can potentially destroy human tissues. Although NE activity is positively correlated to gingival crevicular fluid and clinical attachment loss in periodontitis, the underlying mechanisms by which NE aggravates periodontitis remain elusive. In this study, we investigated how NE induces periodontitis severity and whether NE inhibitors were efficacious in periodontitis treatment. In a ligature-induced murine model of periodontitis, neutrophil recruitment, NE activity, and periodontal bone loss were increased in the periodontal tissue. Local administration of an NE inhibitor significantly decreased NE activity in periodontal tissue and attenuated periodontal bone loss. Furthermore, the transcription of proinflammatory cytokines in the gingiva, which was significantly upregulated in the model of periodontitis, was significantly downregulated by NE inhibitor injection. An in vitro study demonstrated that NE cleaved cell adhesion molecules, such as desmoglein 1, occludin, and E-cadherin, and induced exfoliation of the epithelial keratinous layer in three-dimensional human oral epithelial tissue models. The permeability of fluorescein-5-isothiocyanate-dextran or periodontal pathogen was significantly increased by NE treatment in the human gingival epithelial monolayer. These findings suggest that NE induces the disruption of the gingival epithelial barrier and bacterial invasion in periodontal tissues, aggravating periodontitis.

DOI： 10.1038/s41598-022-12358-3

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Periodontitis is one of the most common oral diseases resulting in gingival inflammation and tooth loss. Growing evidence indicates that it results from dysbiosis of the oral microbiome, which interferes with the host immune system, leading to bone destruction. Immune cells activate periodontal ligament cells to express the receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) and promote osteoclast activity. Osteocytes have active roles in periodontitis progression in the bone matrix. Local proteins are involved in bone regeneration through functional immunological plasticity. Here, we discuss the current knowledge of cellular and molecular mechanisms in periodontitis, the roles of local proteins, and promising synthetic compounds generating a periodontal regeneration effect. It is anticipated that this may lead to a better perception of periodontitis pathophysiology.

DOI： 10.3390/ijms23105540

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Laminin, a basement membrane heterotrimeric glycoprotein composed of α/β/γ subunits, has important tissue-specific functions in the control of cellular behavior. Our recent study showed the colocalization of CD163+ M2-like macrophages with Schwann cells in human dental pulp, leading us to hypothesize that the laminin isoform of Schwann cells is associated with CD163 expression. The present study investigated the distribution of laminin isoforms in human dental pulp and the underlying mechanisms that affect macrophage phenotypes. Immunofluorescence analysis indicated that blood vessels were exclusively positive for laminin α4 and α5, whereas laminin α2 was associated with Schwann cells. Unexpectedly, laminin α3/laminin-332 (α3β3γ2) was detected on lymphatic vessels. In intact and carious teeth, CD163+ cells were associated with laminin α2, whereas CD206 single-positive cells were present inside, outside, and along blood vessels. In vitro incubation of THP-1 macrophages in plates coated with laminin-211/511 or its functionally analogous E8 fragments of α-chain (E8-α) indicated that cell shapes differed between macrophages grown on laminin-211/E8-α2 and macrophages grown on laminin-511/E8-α5. Laminin-211/E8-α2-coated plates upregulated CD163 expression, compared with laminin-511/E8-α5-coated plates. Integrin α3- and integrin α6-neutralizing Abs altered the shape of THP-1 macrophages and upregulated mRNA levels of CD206 and CD163 in macrophages grown on laminin-511; the neutralizing Abs did not affect macrophages grown on laminin-211. These findings suggest that laminin isoforms differentially regulate macrophage behavior via distinct integrin-laminin affinities. Of note, laminin-332 is expressed by pulpal lymphatic vessels, the existence of which has been debated; laminin-211 might have a role in maintaining CD163 expression on macrophages.

DOI： 10.4049/immunohorizons.2100110

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Streptococcus pneumoniae is a causative pathogen of several human infectious diseases including community-acquired pneumonia. Pneumolysin (PLY), a pore-forming toxin, plays an important role in the pathogenesis of pneumococcal pneumonia. In recent years, the use of traditional natural substances for prevention has drawn attention because of the increasing antibacterial drug resistance of S. pneumoniae. According to some studies, green tea exhibits antibacterial and antitoxin activities. The polyphenols, namely the catechins epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC) are largely responsible for these activities. Although matcha green tea provides more polyphenols than green tea infusions, its relationship with pneumococcal pneumonia remains unclear. In this study, we found that treatment with 20 mg/mL matcha supernatant exhibited significant antibacterial activity against S. pneumoniae regardless of antimicrobial resistance. In addition, the matcha supernatant suppressed PLY-mediated hemolysis and cytolysis by inhibiting PLY oligomerization. Moreover, the matcha supernatant and catechins inhibited PLY-mediated neutrophil death and the release of neutrophil elastase. These findings suggest that matcha green tea reduces the virulence of S. pneumoniae in vitro and may be a promising agent for the treatment of pneumococcal infections.

DOI： 10.3390/antibiotics10121550

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OBJECTIVES: To assess whether periodontitis severity affects the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) for 1 year in rheumatoid arthritis (RA) patients. METHODS: Data were collected from 50 RA patients who had received corticosteroids, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 1 year of bDMARD therapy in a retrospective study. Rheumatologic conditions were compared between the two periodontitis severity groups according to the periodontal inflamed surface area (PISA) or Centers for Disease Control Prevention (CDC)/ American Academy of Periodontology (AAP) case definitions. RESULTS: Twenty-eight patients with no or mild periodontitis showed significantly greater decreases in changes in Clinical Disease Activity Index (CDAI) and tender and swollen joint count in comparison to 22 patients with moderate and severe periodontitis (p = 0.02, p = 0.01, and p = 0.03). Both bivariate and multivariate analyses revealed a significantly positive association between the baseline CDC/AAP definitions and CDAI changes (p = 0.005 and p = 0.0038). However, rheumatologic conditions were comparable between 25 patients each in the low and high PISA groups. CONCLUSIONS: Baseline periodontitis severity according to the CDC/AAP definitions is associated with the clinical response to bDMARDs for 1 year in RA patients.

DOI： 10.1093/mr/roab121

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<jats:sec><jats:title>Background &amp;amp; Aims</jats:title><jats:p>Periodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of <jats:italic>Porphyromonas gingivalis</jats:italic>, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>C57BL/6N mice were administered either vehicle, <jats:italic>P. gingivalis</jats:italic>, or <jats:italic>Prevotella intermedia</jats:italic>, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed <jats:italic>via</jats:italic> DNA microarray and quantitative polymerase chain reaction.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>CDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested <jats:italic>P. intermedia</jats:italic> and <jats:italic>P. gingivalis</jats:italic> were different.</jats:p></jats:sec><jats:sec><jats:title>Conclusions</jats:title><jats:p>Swallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.</jats:p></jats:sec>

DOI： 10.1021/acsomega.1c06891

DOI： 10.1093/pcp/pcac114

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PURPOSE: This study aimed to investigate the relationship between dental metal allergy, periodontitis, and palmoplantar pustulosis among patients from a dental metal allergy clinic over a period of 8 years. METHODS: This study included 436 patients who visited our dental metal allergy clinic between April 1, 2009 and March 31, 2016. Diagnoses of skin diseases, periodontal records, dental metal series patch test results, and electron probe microanalysis (EPMA) data were obtained from medical records. Relative risk (RR) values were estimated from these data. RESULTS: Of the 359 patients who underwent the patch test, 241 showed a positive reaction. Of the 187 patients who underwent EPMA, 113 had allergenic metals in their dental prostheses. These patients were suspected to have a dental metal allergy. Furthermore, 150 of the 436 patients were diagnosed with palmoplantar pustulosis (PPP). The RR of metal allergy between patients with PPP and healthy subjects was 3.88. The RR of periodontal disease between patients with PPP and PPP-negative patients in the national average was 2.54. CONCLUSIONS: In this study, both dental metal allergy and periodontitis showed a high RR for PPP.

DOI： 10.2186/jpr.JPR_D_20_00307

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OBJECTIVE: Food-derived bioactive peptides have been reported to exhibit various beneficial effects, including anti-microbial, anti-inflammatory, and anti-oxidant properties. Oxidative stress has been implicated in the development of several inflammatory diseases such as periodontal disease. However, the anti-oxidative effect of food-derived bioactive peptides in gingival epithelial cells (GECs) is unknown. Therefore, we examined the bioactivity of the peptides in GECs. DESIGN: Food-derived peptide fractionations derived from rice bran, rice endosperm, corn, and soy were screened for anti-oxidative effects using anti-oxidant response element (ARE)-luciferase-transfected HEK 293 cells. The induction of anti-oxidation-related genes and proteins in GECs by the fractions were examined by quantitative PCR and Western blotting, respectively. Then, the fraction-mediated anti-oxidative effects were examined by measuring intracellular reactive oxygen species (ROS) levels using flow cytometry. Furthermore, the anti-oxidative response-related cellular signaling pathways were analyzed via Western blotting. RESULTS: Although treatment with the food-derived peptides alone did not activate anti-oxidative responses, co-treatment with sulforaphane (SFN; a potent anti-oxidant) and certain food-derived peptides enhanced anti-oxidative responses in ARE-luciferase-transfected HEK 293 cells. The fractions augmented heme oxygenase-1 mRNA and protein expression in GECs. The percentage of ROS-positive cells was significantly decreased by co-treatment with SFN and peptide fractions derived from rice bran. Furthermore, the involvement of both nuclear factor erythroid 2-related factor 2 (Nrf2) and extracellular signal-regulated kinase (ERK) in the enhancement of anti-oxidative responses was demonstrated by Western blotting. CONCLUSIONS: Peptides derived from rice bran enhances SFN-induced anti-oxidative responses in GECs through ERK-Nrf2-ARE signaling.

DOI： 10.1016/j.archoralbio.2021.105215

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Objective The aim of the present study was to evaluate the association between the periodontal and serological parameters and the disease activity of rheumatoid arthritis (RA) and between the anti-agalactosyl immunoglobulin G (IgG) titer and periodontitis severity. The objective was also to assess the effect of supragingival scaling on the serological parameters in patients with RA.Background The periodontal and serological parameters in relation to the autoimmune inflammatory response have been linked to RA disease activity. However, the association of the anti-agalactosyl IgG titer with RA disease activity and periodontitis severity has not been elucidated.Methods The periodontal, rheumatologic, and serological data were collected from 127 patients with RA in a retrospective cohort study. Of the 127 patients, 21 had been randomly assigned to receive oral hygiene instruction and supragingival scaling. The anti-agalactosyl IgG titer was determined by an electrochemiluminescence immunoassay.Results The patients with a moderate to high RA disease activity showed significantly higher levels of probing depth (PD), clinical attachment level, anti-cyclic citrullinated peptide IgG, and anti-agalactosyl IgG titer and greater mean percentages of severe periodontitis than those with a low RA disease activity (p < .05 for all). Both univariate and multivariate analyses revealed a significantly positive correlation between the PD and RA disease activity (p = .009 and p = .001), between the anti-agalactosyl IgG titer and RA disease activity (p = .002 and p < .001), and between the anti-agalactosyl IgG titer and PD (p < .001 for both). Supragingival scaling significantly decreased the anti-agalactosyl IgG titer (p = 0.03).Conclusion The PD and anti-agalactosyl IgG titer are positively interrelated, both of which are correlated positively with RA disease activity and influenced by supragingival scaling in patients with RA.

DOI： 10.1111/jre.12867

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE RESEARCH  

Cells/colony motion determined by non-invasive, quantitative measurements using the optical flow (OF) algorithm can indicate the oral keratinocyte proliferative capacity in early-phase primary cultures. This study aimed to determine a threshold for the cells/colony motion index to detect substandard cell populations in a subsequent subculture before manufacturing a tissue-engineered oral mucosa graft and to investigate the correlation with the epithelial regenerative capacity. The distinctive proliferating pattern of first-passage [passage 1 (p1)] cells reveals the motion of p1 cells/colonies, which can be measured in a non-invasive, quantitative manner using OF with fewer full-screen imaging analyses and cell segmentations. Our results demonstrate that the motion index lower than 40 μm/h reflects cellular damages by experimental metabolic challenges although this value shall only apply in case of our culture system. Nonetheless, the motion index can be used as the threshold to determine the quality of cultured cells while it may be affected by any different culture conditions. Because the p1 cells/colony motion index is correlated with epithelial regenerative capacity, it is a reliable index for quality control of oral keratinocytes.

DOI： 10.1038/s41598-021-89073-y

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Objective This study aimed to evaluate the effects of ingested periodontal pathogens on experimental colitis in mice and to elucidate its underlying mechanisms.Background Inflammatory bowel disease (IBD) is defined as a chronic intestinal inflammation that results in damage to the gastrointestinal tract. Epidemiological studies have shown an association between IBD and periodontitis. Although a large number of ingested oral bacteria reach gastrointestinal tract constantly, the effect of ingested periodontal pathogens on intestinal inflammation is still unknown.Methods Experimental colitis was induced by inclusion of dextran sodium sulfate solution in drinking water of the mice. Major periodontal pathogens (Porphyromonas gingivalis, Prevotella intermedia, and Fusobacterium nucleatum) were administered orally every day during the experiment. The severity of colitis between the groups was compared. In vitro studies of the intestinal epithelial cell line were conducted to explore the molecular mechanisms by which periodontal pathogens affect the development of colitis.Results The oral administration of P. gingivalis significantly increased the severity of colitis when compared to other pathogens in the DSS-induced colitis model. The ingested P. gingivalis disrupted the colonic epithelial barrier by decreasing the expression of tight junction proteins in vivo. In vitro permeability assays using the intestinal epithelial cell line suggested the P. gingivalis-specific epithelial barrier disruption. The possible involvement of gingipains in the exacerbation of colitis was implied by using P. gingivalis lacking gingipains.Conclusion Porphyromonas gingivalis exacerbates gastrointestinal inflammation by directly interacting with the intestinal epithelial barrier in a susceptible host.

DOI： 10.1111/jre.12816

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Periodontal disease is a chronic inflammatory disease of the periodontal tissue. The periodontal inflamed surface area (PISA) is a proposed index for quantifying the inflammatory burden resulting from periodontitis lesions. This study aimed to investigate longitudinal changes in the periodontal status as evaluated by the PISA following the active periodontal treatment. To elucidate the prognostic factors of PISA, mixed-effect modeling was performed for clinical parameters, tooth-type, and levels of periodontal pathogens as independent variables. One-hundred-twenty-five patients with chronic periodontitis who completed the active periodontal treatment were followed-up for 24 months, with evaluations conducted at 6-month intervals. Five-times repeated measures of mean PISA values were 130+/-173, 161+/-276, 184+/-320, 175+/-417, and 209+/-469 mm(2). Changes in clinical parameters and salivary and subgingival periodontal pathogens were analyzed by mixed-effect modeling. Plaque index, clinical attachment level, and salivary levels of Porphyromonas gingivalis were associated with changes in PISA at the patient- and tooth-level. Subgingival levels of P. gingivalis and Prevotella intermedia were associated with changes in PISA at the sample site. For most patients, changes in PISA were within 10% of baseline during the 24-month follow-up. However, an increase in the number of bleeding sites in a tooth with a deep periodontal pocket increased the PISA value exponentially.

DOI： 10.3390/jcm10061165

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Macrolides are used to treat various infectious diseases, including periodontitis. Furthermore, macrolides are known to have immunomodulatory effects; however, the underlying mechanism of their action remains unclear. DEL-1 has emerged as an important factor in homeostatic immunity and osteoclastogenesis. Specifically, DEL-1 is downregulated in periodontitis tissues. Therefore, in the present study, we investigated whether the osteoclastogenesis inhibitory effects of erythromycin (ERM) are mediated through upregulation of DEL-1 expression. We used a ligature-induced periodontitis model in C57BL/6Ncrl wild-type or DEL-1-deficient mice and in vitro cell-based mechanistic studies to investigate how ERM inhibits alveolar bone resorption. As a result of measuring alveolar bone resorption and gene expression in the tooth ligation model, ERM treatment reduced bone loss by increasing DEL-1 expression and decreasing the expression of osteoclast-related factors in wild-type mice. In DEL-1-deficient mice, ERM failed to suppress bone loss and gene expression of osteoclast-related factors. In addition, ERM treatment downregulated osteoclast differentiation and calcium resorption in in vitro experiments with mouse bone marrow-derived macrophages. In conclusion, ERM promotes the induction of DEL-1 in periodontal tissue, which may regulate osteoclastogenesis and decrease inflammatory bone resorption. These findings suggest that ERM may exert immunomodulatory effects in a DEL-1-dependent manner.

DOI： 10.3390/antibiotics10030312

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The periodontal inflamed surface area (PISA) is a useful index for clinical and epidemiological assessments, since it can represent the inflammation status of patients in one contentious variable. However, calculation of the PISA is difficult, requiring six point probing depth measurements with or without bleeding on probing on 28 teeth, followed by data input in a calculation program. More simple methods are essential for screening periodontal disease or in epidemiological studies. In this study, we tried to establish a convenient partial examination method to estimate PISA. Cross-sectional data of 254 subjects who completed active periodontal therapy were analyzed. Teeth that represent the PISA value were selected by an item response theory approach. The maxillary second molar, first premolar, and lateral incisor and the mandibular second molar and lateral incisor were selected. The sum of the PISAs of these teeth was significantly correlated with the patient's PISA (R-2 = 0.938). More simply, the sum of the maximum values of probing pocket depth with bleeding for these teeth were also significantly correlated with the patient's PISA (R-2 = 0.6457). The simple model presented in this study may be useful to estimate PISA.

DOI： 10.3390/jcm10040723

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER JAPAN KK  

Japan Diabetes Complication and Prevention prospective (JDCP) study was conducted to examine the association between glycemic control and oral conditions in a large database of Japanese patients with diabetes. It included a total of 6099 patients with diabetes (range, 40-75 years) who had been treated as outpatients between 2007 and 2009. The mean number of present teeth at baseline was 19.8 and women with type 2 diabetes had fewer teeth than men with type 2 diabetes. Within the previous year, 17% of all patients had lost teeth. At baseline, 32% had experienced gingival swelling, 69% had brushed more than twice a day, 37% had used interdental cleaning aids, and 43% had undergone regular dental checkups. Multiple logistic regression analysis indicated that type 1 patients with HbA1c >= 7.0% were at higher risk of having fewer than 20 teeth (odds ratio [OR] 2.38; 95% confidence interval [CI] 1.25-4.78), and type 2 patients with HbA1c >= 8.0% also were at high risk of having fewer than 20 teeth (OR 1.16; 95% CI 1.00-1.34), after adjustment for nine possible confounding factors. In conclusion, patients with diabetes were found to be at high risk of tooth loss, and the poorer the glycemic control, the higher the risk of tooth loss in these patients.

DOI： 10.1007/s13340-020-00465-3

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Objective: Rice peptide has antibacterial properties that have been tested in planktonic bacterial culture. However, bacteria form biofilm at disease sites and are resistant to antibacterial agents. The aim of this study was to clarify the mechanisms of action of rice peptide and its amino acid substitution against periodontopathic bacteria and their antibiofilm effects.Design: Porphyromonas gingivalis and Fusobacterium nucleatum were treated with Amyl-1-18 rice peptide or its arginine-substituted analog, G12R, under anaerobic conditions. The amount of biofilm was evaluated by crystal violet staining. The integrity of the bacteria cytoplasmic membrane was studied in a propidium iodide (PI) stain assay and transmission electron microscopy (TEM).Results: Both Amyl-1-18 and G12R inhibited biofilm formation of P. gingivalis and F. nucleatum; in particular, G12R inhibited F. nucleatum at lower concentrations. However, neither peptide eradicated established biofilms significantly. According to the minimum inhibitory concentration and minimum bactericidal concentration against P. gingivalis, Amyl-1-18 has bacteriostatic properties and G12R has bactericidal activity, and both peptides showed bactericidal activity against F. nucleatum. PI staining and TEM analysis indicated that membrane disruption by G12R was enhanced, which suggests that the replacement amino acid reinforced the electostatic interaction between the peptide and bacteria by increase of cationic charge and alpha-helix content.Conclusions: Rice peptide inhibited biofilm formation of P. gingivalis and F. nucleatum, and bactericidal activity via membrane destruction was enhanced by amino acid substitution.

DOI： 10.1016/j.archoralbio.2020.104956

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Background & Aims: Periodontitis increases the risk of nonalcoholic fatty liver disease (NAFLD); however, the underlying mechanisms are unclear. Here, we show that gut dysbiosis induced by oral administration of Porphyromonas gingivalis, a representative periodontopathic bacterium, is involved in the aggravation of NAFLD pathology. Methods: C57BL/6N mice were administered either vehicle, P. gingivalis, or Prevotella intermedia, another periodontopathic bacterium with weaker periodontal pathogenicity, followed by feeding on a choline-deficient, l-amino acid-defined, high-fat diet with 60 kcal% fat and 0.1% methionine (CDAHFD60). The gut microbial communities were analyzed by pyrosequencing the 16S ribosomal RNA genes. Metagenomic analysis was used to determine the relative abundance of the Kyoto Encyclopedia of Genes and Genomes pathways encoded in the gut microbiota. Serum metabolites were analyzed using nuclear magnetic resonance-based metabolomics coupled with multivariate statistical analyses. Hepatic gene expression profiles were analyzed via DNA microarray and quantitative polymerase chain reaction. Results: CDAHFD60 feeding induced hepatic steatosis, and in combination with bacterial administration, it further aggravated NAFLD pathology, thereby increasing fibrosis. Gene expression analysis of liver samples revealed that genes involved in NAFLD pathology were perturbed, and the two bacteria induced distinct expression profiles. This might be due to quantitative and qualitative differences in the influx of bacterial products in the gut because the serum endotoxin levels, compositions of the gut microbiota, and serum metabolite profiles induced by the ingested P. intermedia and P. gingivalis were different. Conclusions: Swallowed periodontopathic bacteria aggravate NAFLD pathology, likely due to dysregulation of gene expression by inducing gut dysbiosis and subsequent influx of gut bacteria and/or bacterial products.

DOI： 10.3389/fimmu.2021.766170

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Objectives: We evaluated whether the periodontal inflamed surface area (PISA), a measure of the inflammatory burden posed by periodontitis, is associated with the clinical response to biological disease-modifying antirheumatic drugs (bDMARDs) in patients with rheumatoid arthritis (RA). Methods: We conducted a retrospective study that collected rheumatologic and periodontal data from 54 patients with RA who had received corticosteroid, conventional synthetic DMARDs, or non-steroidal anti-inflammatory drugs before (baseline) and after 6 months of bDMARD therapy. After the patients were divided into two groups based on high or low PISA according to the median measurements at baseline, the rheumatologic condition was compared between the groups. Results: The patients with a low PISA showed significantly lower values for the Clinical Disease Activity Index (CDAI) (p = .008), swollen joint count (p = .02), and patient's and evaluator's global assessment (p = .01 and p = .03) and significantly greater decreases in changes in the CDAI from baseline to 6 months than the patients with a high PISA (p = .01), although these values were comparable at baseline. Both univariate and multivariate analyses revealed a significantly positive correlation between the baseline PISA and changes in the CDAI (p = .04 and p < .001). Conclusion: The PISA is associated with the clinical response to bDMARDs in patients with RA.

DOI： 10.1080/14397595.2019.1680100

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Background: Previous studies have reported associations between nonalcoholic fatty liver disease, periodontitis, and obesity. Serum immunoglobulin G (IgG) antibody titer against Porphyromonas gingivalis, a major pathogen of periodontitis, is an established indicator of periodontal infection. However, the relationship between the antibody titer and liver enzyme levels has not been clarified yet. A study in the elderly was needed to evaluate the effect of long-term persistent bacterial infection on liver function. The objective of this study was to investigate the association between liver function and infection by P. gingivalis, and the effect of obesity on the association.Methods: A cross-sectional study was conducted in adult outpatients visiting Sado General Hospital, in Niigata Prefecture, Japan, from 2008 to 2010. The final participants included 192 men and 196 women (mean age 68.1 years). Multivariable logistic regression analyses were performed to assess the association between the serum IgG antibody titer and the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and gamma-glutamine transferase (GGT) levels.Results: In women, serum IgG antibody titers against P. gingivalis was associated with elevated ALT, but not with AST or GGT, independent of covariates (p = 0.015). No significant association was found between the antibody titer and the elevated liver enzymes in men. The effect of obesity on the relationship between antibody titer and liver enzyme levels was not statistically significant.Conclusions: A cross-sectional analysis of adult outpatients suggested an association between P. gingivalis infection and ALT levels in women. The effect of obesity on this association was not statistically significant.

DOI： 10.1016/j.heliyon.2020.e05531

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Background: The oral cavity serves as an entrance to the body and is therefore exposed to various exogenous stimuli, including mechanical forces, chemical agents, and bacterial components. The oral mucosa responds to these stimuli to maintain homeostasis and good oral health. The transient receptor potential vanilloid 1 (TRPV1) ion channel functions as an environment-sensing protein and is involved in a wide variety of cellular responses. Recent studies have revealed that epithelial TRPV1 ion channels in the oral cavity play pivotal roles in several pathophysiological conditions. In this review, we summarize the features of epithelial TRPV1 channels in the oral cavity and focus on their cellular function and pathogenicity with reference to related findings in other organs and tissues.Highlight: TRPV1 channels are widely expressed in epithelial cells in the oral cavity and play pivotal roles in fundamental cellular processes and disease progression.Conclusion: This review suggests that oral epithelial TRPV1 contributes to several cellular functions such as cell proliferation, barrier function, and inflammation. Further understanding of the characteristics of epithelial TRPV1 in the oral cavity may provide new insights into the prevention or treatment of diseases. (C) 2020 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.

DOI： 10.1016/j.job.2020.05.005

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC CLINICAL INVESTIGATION INC  

Macrolide antibiotics exert antiinflammatory effects; however, little is known regarding their immunomodulatory mechanisms. In this study, using 2 distinct mouse models of mucosal inflammatory disease (LPS-induced acute lung injury and ligature-induced periodontitis), we demonstrated that the antiinflammatory action of erythromycin (ERM) is mediated through upregulation of the secreted homeostatic protein developmental endothelial locus-1 (DEL-1). Consistent with the anti-neutrophil recruitment action of endothelial cell-derived DEL-1, ERM inhibited neutrophil infiltration in the lungs and the periodontium in a DEL-1-dependent manner. Whereas ERM (but not other antibiotics, such as josamycin and penicillin) protected against lethal pulmonary inflammation and inflammatory periodontal bone loss, these protective effects of ERM were abolished in Dell-deficient mice. By interacting with the growth hormone secretagogue receptor and activating JAK2 in human lung microvascular endothelial cells, ERM induced DEL1 transcription that was mediated by MAPK p38 and was CCAAT/enhancer binding protein-beta dependent. Moreover, ERM reversed IL-17-induced inhibition of DEL-1 transcription, in a manner that was dependent not only on JAK2 but also on P13K/AKT signaling. Because DEL-1 levels are severely reduced in inflammatory conditions and with aging, the ability of ERM to upregulate DEL-1 may lead to a novel approach for the treatment of inflammatory and aging-related diseases.

DOI： 10.1172/jci.insight.136706

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Purpose of Review: This review updates the current knowledge on nutrient supplements, which are reported as effective in maintaining the health of periodontal tissues or preventing diseases, as a complementary therapy to existing periodontal treatments. Recent Findings: The latest meta-analysis reported that green tea component might be used as a complementary method to existing periodontal treatments. New multifunctional food-derived components such as rice- and soybean-derived proteins and amino acids have also been reported recently. Summary: Several previous reports describe that nutritional supplements may help bacterial control and host immune regulation based on cellular or animal experiments, but evidence regarding most nutritional supplements is still insufficient to apply for prevention or treatment of periodontal disease. Complementary use of green tea extract, including catechin, potentially controlling the symptoms of periodontal disease combined with existing therapies could be beneficial, although randomized clinical trials and larger cohort studies are required properly.

DOI： 10.1007/s40496-020-00261-7

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Other Link： http://link.springer.com/article/10.1007/s40496-020-00261-7/fulltext.html

Language：Japanese   Publisher：(NPO)日本歯周病学会  

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

OBJECTIVE: The overall objective of this study was to investigate the effects of hinokitiol on periodontal bone loss in a murine model of experimental periodontitis and evaluate the anti-inflammatory activity of hinokitiol in vitro. DESIGN: Periodontitis was induced by tying a silk ligature around the maxillary second molar of mice for 8 days. Hinokitiol was injected once a day for 7 days into the palatal gingiva of the ligated molar. Periodontal bone loss was then assessed morphometrically in the maxillary second molar, and the number of tartrate-resistant acid phosphatase positive multinucleated giant cells around the molar was quantified. The bacterial load of the silk ligature was calculated by counting the number of colony-forming units, while the transcription levels of proinflammatory cytokine-related genes in the palatal gingiva were evaluated by real-time qPCR. The activity of hinokitiol against LPS-induced transcription of proinflammatory genes in RAW 264.7 macrophages was also examined. RESULTS: Local treatment with hinokitiol significantly inhibited the alveolar bone loss and osteoclast differentiation induced by tooth ligation. In addition, hinokitiol treatment decreased the oral bacterial load of the silk ligature and downregulated the mRNA levels of inflammatory cytokine-related genes, both in vitro and in vivo. CONCLUSION: The results indicated that hinokitiol exhibits antibacterial and anti-inflammatory activity and exerts a protective effect against periodontitis.

DOI： 10.1016/j.archoralbio.2020.104679

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Macrophages are immune cells with high plasticity that perform many functions related to tissue injury and repair. They are generally categorized as 2 functional phenotypes: M1 (proinflammatory) and M2 (anti-inflammatory and prohealing). To investigate the role of macrophages in human dental pulp, we examined the localization and distributional alterations of macrophages in healthy dental pulp as well as during the reparative process of pulp capping with mineral trioxide aggregate (MTA) and in cariously inflamed pulp of adult human teeth. We also quantified the populations of M1/M2 macrophages in healthy dental pulp by flow cytometric analysis. CD68+CD86+ cells (M1 phenotype) and CD68+CD163+ cells (M2 phenotype) were 2.11% ± 0.50% and 44.99% ± 2.22%, respectively, of 2.96% ± 0.41% CD68+ cells (pan-macrophages) in whole healthy dental pulp. Interestingly, M2 phenotype macrophages were associated with Schwann cells in healthy pulp, during mineralized bridge formation, and in pulp with carious infections in vivo. Furthermore, the M2 macrophages associated with Schwann cells expressed brain-derived neurotrophic factor (BDNF) under all in vivo conditions. Moreover, we found that plasma cells expressed BDNF. Coculture of Schwann cells isolated from human dental pulp and human monocytic cell line THP-1 showed that Schwann cells induced M2 phenotypic polarization of THP-1 cell-derived macrophages. The THP-1 macrophages that maintained contact with Schwann cells were stimulated, leading to elongation of their cell shape and expression of M2 phenotype marker CD163 in cocultures. In summary, we revealed the spatiotemporal localization of macrophages and potent induction of the M2 phenotype by Schwann cells in human dental pulp. M2 macrophages protect neural elements, whereas M1 cells promote neuronal destruction. Therefore, suppressing the neurodestructive M1 phenotype and maintaining the neuroprotective M2 phenotype of macrophages by Schwann cells may be critical for development of effective treatment strategies to maintain the viability of highly innervated dental pulp.

DOI： 10.1177/0022034519894957

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Objective: Oxidative stress, which is defined as an imbalance between pro-oxidant and antioxidant systems, has been implicated in the development and/or progression of several inflammatory diseases, including periodontal disease. The reactive oxygen species (ROS) are the primary inducers of oxidative stress. In the induction of cytoprotective enzymes, the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling in antioxidant systems takes a main role. Notably, 10-oxo-trans-11-octadecenoic acid (KetoC), known as a bioactive metabolite generated by intestinal microorganisms, has been reported to have beneficial effects on several biological responses. Therefore, we investigated the antioxidant effect of KetoC on gingival epithelial cells (GECs) in this present study.Methods: An SV40-T antigen-transformed human gingival epithelial cell line (Epi4) was used for experiments. The alteration of anti-oxidative stress related genes was analyzed by qPCR. The cellular ROS levels were evaluated by flow cytometry. To explore its molecular mechanisms, ARE promotor activity was analyzed by luciferase assay; the involvement of mitogen-activated protein kinase (MAPK) and G protein-coupled receptor 120 (GPR120) were evaluated by Western blotting and luciferase assay, respectively.Results: KetoC significantly increased the expression of antioxidant-related genes in GECs. The level of ROS was significantly inhibited by the pretreatment of KetoC. Extracellular signal-regulated kinase (ERK) phosphorylation by KetoC promoted both the nuclear translocation of Nrf2 and its binding to the ARE in GECs. Further, GPR120 regulated the activation of KetoC induced-Nrf2-ARE signaling.Conclusion: KetoC exerts a protective function against the oxidative stress in GECs through GPR120-dependent ERK-Nrf2-ARE signaling.

DOI： 10.1016/j.archoralbio.2019.104602

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Language：Japanese  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J01092&link_issn=&doc_id=20200312150008&doc_link_id=%2Fdo1conde%2F2020%2F006301%2F008%2F0061-0072%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdo1conde%2F2020%2F006301%2F008%2F0061-0072%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

T follicular helper cells (T-FH) participate in germinal center (GC) development and are necessary for B cell production of high-affinity, isotype-switched antibodies. In a forward genetic screen, we identified a missense mutation in Prkd2, encoding the serine/threonine kinase protein kinase D2, which caused elevated titers of immunoglobulin E (IgE) in the serum. Subsequent analysis of serum antibodies in mice with a targeted null mutation of Prkd2 demonstrated polyclonal hypergammaglobulinemia of IgE, IgG1, and IgA isotypes, which was exacerbated by the T cell-dependent humoral response to immunization. GC formation and GC B cells were increased in Prkd2(-/-) spleens. These effects were the result of excessive cell-autonomous T-FH development caused by unrestricted Bcl6 nuclear translocation in Prkd2(-/-) CD4(+) T cells. Prkd2 directly binds to Bcl6, and Prkd2-dependent phosphorylation of Bcl6 is necessary to constrain Bcl6 to the cytoplasm, thereby limiting T-FH development. In response to immunization, Bcl6 repressed Prkd2 expression in CD4(+) T cells, thereby committing them to T(FH )development. Thus, Prkd2 and Bcl6 form a mutually inhibitory positive feedback loop that controls the stable transition from naive CD4(+) T cells to T-FH during the adaptive immune response.

DOI： 10.1126/sciimmunol.aaz0085

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The Japan Diabetes Complications and its Prevention (JDCP) prospective study was conducted to analyze the association between glycemic control and oral conditions in a large database of Japanese patients with diabetes. It included a total of 6,099 patients with diabetes (range, 40-75 years) who were treated as outpatients between 2007 and 2009. The mean number of teeth at baseline was 19.8 and women had fewer teeth than men in type 2 diabetes. Within the previous year, 17 % had lost teeth. At baseline, 32 % had experienced gingival swelling, 69 % brushed more than twice a day, 37 % used interdental devices, and 43 % received dental regular checkups. A multiple logistic regression analysis indicated that type 1 diabetic patients with HbAlc 7.0 % had a higher risk having fewer than 20 teeth (odds ratio [OR]: 2.38; 95 % confidence interval [CI]: 1.25-4.78), and type 2 diabetic patients with HbAlc 8.0 % also had a high risk having fewer than 20 teeth (OR: 1.16; 95 % CI: 1.00-1.34), after adjusting for 9 possible confounders. In conclusion, diabetic patients had a high risk of tooth loss and the poorer the glycemic control, the higher the risk of tooth loss.

DOI： 10.11213/tonyobyo.63.195

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Background The bioactive metabolite KetoC, generated by intestinal bacteria, exerts various beneficial effects. Nevertheless, its function in the pathogenesis of periodontitis remains unclear. Here, we investigated the effect of KetoC in a mouse model of periodontitis and explored the underlying mechanism. Methods Thirty-one 8-week-old male C57BL/6N mice were randomly divided into four groups (non-ligation, non-ligation + KetoC, ligation + Porphyromonas gingivalis, and ligation + P. gingivalis + KetoC) (n = 7/8 mice/group) and given a daily oral gavage of KetoC (15 mg/mL) or vehicle for 2 weeks. To induce periodontitis, a 5-0 silk ligature was placed on the maxillary left second molar on day 7, and P. gingivalis W83 (10(9) colony-forming unit [CFU]) was administered orally every 3 days. On day 14, all mice were euthanized. Alveolar bone destruction was determined from the level of the cemento-enamel junction to the alveolar bone crest. Moreover, bone loss level was confirmed from gingival tissue sections stained with hematoxylin and eosin. The presence of P. gingivalis was quantified using real-time polymerase chain reaction. In vitro, the bacteriostatic and bactericidal effects of KetoC were assessed by analyzing its suppressive activity on the proliferation of P. gingivalis and using a live/dead bacterial staining kit, respectively. A double-bond-deficient metabolite (KetoB) was then used to investigate the importance of double-bond structure in the antimicrobial activity of KetoC on P. gingivalis. Results In vivo, KetoC attenuated alveolar bone destruction and suppressed P. gingivalis in the periodontitis group. In vitro, KetoC (but not KetoB) downregulated the proliferation and viability of P. gingivalis in a dose-dependent manner. Conclusions KetoC reduced alveolar bone destruction in a periodontitis model via its antimicrobial function. Therefore, this bioactive metabolite may be valuable in clinical applications to support periodontal therapy.

DOI： 10.1002/JPER.19-0130

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BACKGROUND: Periodontitis is an inflammatory disease that results in alveolar bone resorption due to inflammatory cytokine production induced by bacterial antigens such as lipopolysaccharides (LPS). Here, the preventive effect of the Amyl-1-18 peptide derived from rice in an experimental model of periodontitis and the effect on the anti-inflammatory response were assessed. METHODS: Alveolar bone resorption, gene transcription of proinflammatory cytokines in the gingiva, and the endotoxin level in the oral cavity were evaluated after oral administration of the Amyl-1-18 peptide for 14 days using a ligature-induced periodontitis model in mice. Additionally, murine macrophages were incubated with LPS of Escherichia coli or Porphyromonas gingivalis in the presence of Amyl-1-18 to analyze the suppressive effects of Amyl-1-18 on the cell signaling pathways associated with proinflammatory cytokine production, including inflammasome activities. RESULTS: Oral administration of Amyl-1-18 suppressed alveolar bone resorption and gene transcription of interleukin (il)6 in the gingiva of the periodontitis model, and decreased endotoxin levels in the oral cavity, suggesting modulation of periodontal inflammation by inhibition of endotoxin activities in vivo. Also, Amyl-1-18 suppressed IL-6 production induced by LPS and recombinant IL-1β in macrophages in vitro but had no effect on inflammasome activity. CONCLUSIONS: The Amyl-1-18 peptide from rice inhibited alveolar bone destruction in mouse periodontitis model via suppressing inflammatory cytokine production induced by LPS. It was suggested that Amyl-1-18 peptide has anti-inflammatory property against LPS, not only by neutralization of LPS and subsequent inhibition of nuclear factor-κB signaling but also by inhibition of the IL-1R-related signaling cascade.

DOI： 10.1002/JPER.18-0630

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Language：English   Publisher：TAYLOR & FRANCIS INC  

The gingival epithelium acts as a physical barrier to separate the biofilm from the gingival tissue, providing the first line of defense against bacterial invasion in periodontal disease. Disruption of the gingival epithelial barrier, and the subsequent penetration of exogenous pathogens into the host tissues, triggers an inflammatory response, establishing chronic infection. Currently, more than 700 different bacterial species have been identified in the oral cavity, some of which are known to be periodontopathic. These bacteria contribute to epithelial barrier dysfunction in the gingiva by producing several virulence factors. However, some bacteria in the oral cavity appear to be beneficial, helping gingival epithelial cells maintain their integrity and barrier function. This review aims to discuss current findings regarding microorganism interactions and epithelial barrier function in the oral cavity, with reference to investigations in the gut, where this interaction has been extensively studied.

DOI： 10.1080/21688370.2019.1651158

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Tooth cusp is a crucial structure, since the shape of the molar tooth is determined by number, shape, and size of the cusp. Bone morphogenetic protein (Bmp) signaling is known to play a critical role in tooth development, including in initiation. However, it remains unclear whether Bmp signaling is also involved in cusp formation. To address this question, we examined cusp in two different transgenic mouse lines: mice with overexpression of Bmp4 (K14-Bmp4), and those with Bmp inhibitor, Noggin, (K14-Noggin) under keratin14 (K14) promoter. K14-Noggin mice demonstrated extra cusps, whereas reduced number of cusps was observed in K14-Bmp4 mice. To further understand how Bmps are expressed during cusp formation, we performed whole-mount in situ hybridisation analysis of three major Bmps (Bmp2, Bmp4, and Bmp7) in murine maxillary and mandibular molars from E14.5 to P3. The linear expressions of Bmp2 and Bmp4 were observed in both maxillary and mandibular molars at E14.5. The expression patterns of Bmp2 and Bmp4 became significantly different between the maxillary and mandibular molars at E16.5. At P3, all Bmps were expressed in all the cusp regions of the maxillary molar; however, the patterns differed. All Bmps thus exhibited dynamic temporo-spatial expression during the cusp formation. It could therefore be inferred that Bmp signaling is involved in regulating cusp formation.

DOI： 10.1016/j.gep.2019.04.002

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Language：English   Publisher：(NPO)日本歯周病学会  

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Aggregatibacter actinomycetemcomitans is considered to be associated with periodontitis. Leukotoxin (LtxA), which destroys leukocytes in humans, is one of this bacterium's major virulence factors. Amounts of neutrophil elastase (NE), which is normally localized in the cytoplasm of neutrophils, are reportedly increased in the saliva of patients with periodontitis. However, the mechanism by which NE is released from human neutrophils and the role of NE in periodontitis is unclear. In the present study, it was hypothesized that LtxA induces NE release from human neutrophils, which subsequently causes the breakdown of periodontal tissues. LtxA-treatment did not induce significant cytotoxicity against human gingival epithelial cells (HGECs) or human gingival fibroblasts (HGFs). However, it did induce significant cytotoxicity against human neutrophils, leading to NE release. Furthermore, NE and the supernatant from LtxA-treated human neutrophils induced detachment and death of HGECs and HGFs, these effects being inhibited by administration of an NE inhibitor, sivelestat. The present results suggest that LtxA mediates human neutrophil lysis and induces the subsequent release of NE, which eventually results in detachment and death of HGECs and HGFs. Thus, LtxA-induced release of NE could cause breakdown of periodontal tissue and thereby exacerbate periodontitis.

DOI： 10.1111/1348-0421.12672

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[This corrects the article DOI: 10.1016/j.heliyon.2018.e01111.].

DOI： 10.1016/j.heliyon.2019.e01210

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Objective: Food-derived peptides have been reported to exhibit antibacterial activity against periodontal pathogenic bacteria. However, no effect has been shown on inflammation and bone resorption in periodontal pathology. The overall objective of the current study was to investigate how rice peptides influence biological defense mechanisms against periodontitis-induced inflammatory bone loss, and identify their novel functions as a potential anti-inflammatory drug.Design: The expression of inflammatory and osteoclast-related molecules was examined in mouse macrophage derived RAW 264.7 cell cultures using qPCR. Subsequently, the effect of these peptides on inflammatory bone loss in mouse periodontitis was examined using a mouse model of tooth ligation. Briefly, periodontal bone loss was induced for 7 days in mice by ligating the maxillary second molar and leaving the contralateral tooth unligated (baseline control). The mice were microinjected daily with the peptide in the gingiva until the day before euthanization. One week after the ligation, TRAP-positive multinucleated cells (MNCs) were enumerated from five random coronal sections of the ligated sites in each mouse.Results: Rice peptides REP9 and REP11 significantly inhibited transcription activity of inflammatory and osteoclast-related molecules. Local treatment with the rice peptides, in mice subjected to ligature-induced periodontitis, inhibited inflammatory bone loss, explaining the decreased numbers of osteoclasts in bone tissue sections.Conclusion: Therefore, these data suggested that the rice peptides possess a protective effect against periodontitis.

DOI： 10.1016/j.archoralbio.2018.11.021

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Pro-protein convertase subtilisin/kexin type 9 (PCSK9), a secreted serine protease, regulates serum low-density lipoprotein (LDL) cholesterol levels by targeting the degradation of LDL receptor (LDLR) in the liver. Although previous reports describe elevated levels of PCSK9 in patients with periodontitis, the mechanisms that trigger this increase in serum PCSK9 levels and induce the related inflammatory response remain unclear. In an unc93b1-deficient mouse of Porphyromonas gingivalis infection, nucleic acid antigen recognition via Toll-like receptors was found to promote PCSK9 production, suggesting an indirect role for tumor necrosis factor-alpha as an inducer of PCSK9 in contrast to that reported in previous studies. Furthermore, PCSK9 production was independent of the TIR domain-containing adapter-inducing interferon-beta-dependent signaling pathway. These results indicate that changes in LDLR expression precede an increase in the serum PCSK9 level in the context of an infectious disease such as periodontitis.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Image-based cell/colony analyses offer promising solutions to compensate for the lack of quality control (QC) tools for noninvasive monitoring of cultured cells, a regulatory challenge in regenerative medicine. Here, the feasibility of two image analysis algorithms, optical flow and normalised cross-correlation, to noninvasively measure cell/colony motion in human primary oral keratinocytes for screening the proliferative capacity of cells in the early phases of cell culture were examined. We applied our software to movies converted from 96 consecutive time-lapse phase-contrast images of an oral keratinocyte culture. After segmenting the growing colonies, two indices were calculated based on each algorithm. The correlation between each index of the colonies and their proliferative capacity was evaluated. The software was able to assess cell/colony motion noninvasively, and each index reflected the observed cell kinetics. A positive linear correlation was found between cell/colony motion and proliferative capacity, indicating that both algorithms are potential tools for QC.

DOI： 10.1177/2041731419881528

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Objectives. Several serum biomarkers have been reported to increase in periodontitis patients as possible mediators linking periodontal inflammation to systemic diseases. However, the relationship between periodontitis and urine biomarkers is still unclear. The aim of this cross-sectional study was to investigate potential urine biomarkers of periodontitis in a Japanese population. Materials and Methods. This study included 108 male subjects, and microbiological and clinical parameters were evaluated as a periodontitis marker. The correlation between nine urine biomarkers (typically used to diagnose kidney disease) and periodontal parameters was analyzed. Based on the findings, beta(2)-microglobulin (beta(2)-MG) and neutrophil gelatinase-associated lipocalin (NGAL) were selected for comparison and multivariate regression analysis, and the Kruskal-Wallis test followed by Bonferroni correction was used to identify differences in their concentrations between the three periodontitis groups (severe, moderate, and no/mild periodontitis). Results. beta(2)-MG and NGAL exhibited a significant correlation with clinical parameters of periodontitis. The prevalence of clinical parameters such as bleeding on probing and number of sites with probing depth (PD) 6 mm were greater in the beta(2)-MG high group (>= 300 mu g/g creatinine) than in the normal group (P=0.017 and 0.019, respectively). Multivariate regression analysis indicated that the number of sites with PD >= 6 mm was independently associated with urine beta(2)-MG. Moreover, the number of sites with the clinical attachment level (CAL) 6 mm was greater in the NGAL high group (highest quartile) (P=0.041). Multivariate regression analysis showed that the number of sites with CAL >= 6 mm was associated independently with urine NGAL. Finally, beta(2)-MG was significantly higher in the severe periodontitis subjects compared to the no/mild periodontitis subjects. Conclusion. The significant association between urine beta(2)-MG or NGAL and periodontitis was revealed. These biomarkers can potentially be used to screen for or diagnose periodontitis.

DOI： 10.1155/2019/1394678

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The gingival epithelium acts as a physical barrier to separate the biofilm from the gingival tissue, providing the first line of defense against bacterial invasion in periodontal disease. Disruption of the gingival epithelial barrier, and the subsequent penetration of exogenous pathogens into the host tissues, triggers an inflammatory response, establishing chronic infection. Currently, more than 700 different bacterial species have been identified in the oral cavity, some of which are known to be periodontopathic. These bacteria contribute to epithelial barrier dysfunction in the gingiva by producing several virulence factors. However, some bacteria in the oral cavity appear to be beneficial, helping gingival epithelial cells maintain their integrity and barrier function. This review aims to discuss current findings regarding microorganism interactions and epithelial barrier function in the oral cavity, with reference to investigations in the gut, where this interaction has been extensively studied.

DOI： 10.1080/21688370.2019.1651158

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Blackwell Munksgaard  

Background and Objectives: Previous reports suggest that several serum biomarkers play roles in the pathogenesis, inflammatory response, and oxidative stress in periodontitis caused by bacterial infections, linking chronic periodontitis to atherosclerotic vascular disease (ASVD). The aim of this preliminary study was to investigate, in a Japanese cross-sectional community survey, potential serum biomarkers of periodontitis that are associated with ASVD and chronic periodontitis. Material and Methods: The study cohort included a total of 108 male subjects who underwent annual health examinations. Serum biomarkers (high-sensitivity C-reactive protein [hs-CRP], proprotein convertase subtilisin/kexin type 9 [PCSK9], interleukin-6, tumor necrosis factor-α, soluble CD14, myeloperoxidase, matrix metalloproteinase-3, adiponectin, total bilirubin [TBIL], and serum lipids) were analyzed to determine their association (if any) with periodontal parameters. Aortic stiffness was evaluated using the brachial-ankle aortic pulse wave velocity (PWV) index and the cardio-ankle vascular index (CAVI). Results: The concentrations of PCSK9 and hs-CRP were increased (P =.001 and.042, respectively), and the concentration of TBIL was decreased (P =.046), in subjects with periodontal disease (determined as a probing depth of ≥4 mm in at least one site) compared with periodontally healthy subjects. The ratio of low-density lipoprotein cholesterol (LDL-C) to high-density lipoprotein cholesterol and the concentrations of triglycerides, remnant-like particles-cholesterol, and oxidized LDL were elevated in subjects with periodontal disease compared with periodontally healthy subjects (P =.038,.007,.002, and.049, respectively). Multivariate regression analyses indicated that the number of sites with a pocket depth of ≥4 mm was associated with the concentration of PCSK9 and inversely associated with the concentration of TBIL independently (standardized β =.243, P =.040; standardized β = −.443, P =.0002; respectively). Analysis of receiver operating characteristic curves of PCSK9 indicated moderate accuracy for predicting the presence of disease sites (probing depth ≥ 4 mm) (area under the curve = 0.740). No significance in the values of PWV and CAVI was observed between subjects with periodontal disease and periodontally healthy subjects. Conclusion: In Japanese male subjects, the concentrations of serum PCSK9 and TBIL were correlated with periodontal parameters. Moreover, PCSK9 could be a candidate biomarker for diagnosing chronic periodontitis, and may also have potential to evaluate the risk for periodontitis to cause ASVD. Longitudinal studies of larger populations are necessary to confirm the exact association of periodontitis with increased serum PCSK9 and decreased TBIL.

DOI： 10.1111/jre.12533

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Several studies have demonstrated the remarkable properties of microbiota and their metabolites in the pathogenesis of several inflammatory diseases. 10-Hydroxy-cis-12-octadecenoic acid (HYA), a bioactive metabolite generated by probiotic microorganisms during the process of fatty acid metabolism, has been studied for its protective effects against epithelial barrier impairment in the intestines. Herein, we examined the effect of HYA on gingival epithelial barrier function and its possible application for the prevention and treatment of periodontal disease. We found that GPR40, a fatty acid receptor, was expressed on gingival epithelial cells; activation of GPR40 by HYA significantly inhibited barrier impairment induced by Porphyromonas gingivalis, a representative periodontopathic bacterium. The degradation of E-cadherin and beta-catenin, basic components of the epithelial barrier, was prevented in a GPR40-dependent manner in vitro. Oral inoculation of HYA in a mouse experimental periodontitis model suppressed the bacteria-induced degradation of E-cadherin and subsequent inflammatory cytokine production in the gingival tissue. Collectively, these results suggest that HYA exerts a protective function, through GPR40 signaling, against periodontopathic bacteria-induced gingival epithelial barrier impairment and contributes to the suppression of inflammatory responses in periodontal diseases.

DOI： 10.1038/s41598-018-27408-y

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Streptococcus pneumoniae is a leading cause of bacterial pneumonia. Our previous study suggested that S. pneumoniae autolysis-dependently releases intracellular pneumolysin, which subsequently leads to lung injury. In this study, we hypothesized that pneumococcal autolysis induces the leakage of additional intracellular molecules that could increase the pathogenicity of S. pneumoniae. Liquid chromatography tandem-mass spectrometry analysis identified that chaperone protein DnaK, elongation factor Tu (EF-Tu), and glyceraldehyde-3phosphate dehydrogenase (GAPDH) were released with pneumococcal DNA by autolysis. We demonstrated that recombinant (r) DnaK, rEF-Tu, and rGAPDH induced significantly higher levels of interleukin-6 and tumor necrosis factor production in peritoneal macrophages and THP-1-derived macrophage-like cells via toll-like receptor 4. Furthermore, the DNA-binding activity of these proteins was confirmed by surface plasmon resonance assay. We demonstrated that pneumococcal DnaK, EF-Tu, and GAPDH induced the production of proin-flammatory cytokines in macrophages, and might cause host tissue damage and affect the development of pneumococcal diseases.

DOI： 10.1016/j.cellimm.2018.01.006

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Calprotectin, an inflammation-related protein, is present in gingival crevicular fluid (GCF), and the determination of calprotectin is useful for diagnosing periodontal diseases. The authors have recently developed a novel immunochromatographic (IC) chip system to determine calprotectin levels in GCF. In the present study, the usefulness of this diagnostic system is investigated in patients with periodontal diseases.Methods: Thirty-six patients with periodontal diseases participated in this clinical test at multiple centers. Periodontitis sites (n = 118) and non-periodontitis (healthy) sites (n = 120) were selected after periodontal examination. GCF collection and periodontal examination were performed at baseline, after supragingival and subgingival scaling and root planing. Calprotectin levels in GCF were determined using a novel IC chip system and evaluated as a visual score and an IC reader value. Correlations between GCF calprotectin levels, clinical indicators, and changes in calprotectin levels by periodontal treatments were investigated. Receiver operating characteristic (ROC) analysis of IC reader value for GCF calprotectin was performed to predict periodontal diseases.Results: The visual score of GCF calprotectinwas highly correlated with the IC reader value. IC reader values of GCF calprotectin in the periodontitis group were higher than those of the healthy group at three dental examination stages, and they significantly decreased with periodontal treatments. Visual scores and IC reader values of GCF calprotectin were correlated to levels of clinical indicators. ROC analysis for GCF calprotectin showed an optimal cutoff value to predict periodontal diseases.Conclusion: Determination ofGCF calprotectin using a novel IC chip system is useful for diagnosis of periodontal diseases.

DOI： 10.1902/jop.2017.170206

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

GU-AG consensus sequences are used for intron recognition in the majority of cases of pre-mRNA splicing in eukaryotes. Mutations at splice junctions often cause exon skipping, short deletions, or insertions in the mature mRNA, underlying one common molecular mechanism of genetic diseases. Using N-ethyl-N-nitrosourea, a novel recessive mutation named seal was produced, associated with fragile bones and susceptibility to fractures (spine and limbs). A single nucleotide transversion (T. A) at the second position of intron 36 of the Col1a1 gene, encoding the type I collagen, alpha 1 chain, was responsible for the phenotype. Col1a1seal mRNA expression occurred at greatly reduced levels compared to the wild-type transcript, resulting in reduced and aberrant collagen fibers in tibiae of seal homozygous mice. Unexpectedly, splicing of Col1a1seal mRNA followed the normal pattern despite the presence of the donor splice site mutation, likely due to the action of a putative intronic splicing enhancer present in intron 25, which appeared to function redundantly with the splice donor site of intron 36. Seal mice represent a model of human osteogenesis imperfecta, and reveal a previously unknown mechanism for splicing "rescue."

DOI： 10.1038/s41598-017-10343-9

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Language：Japanese   Publisher：日本歯科医学教育学会  

歯学教育を改善するために、各大学歯学部・歯科大学においてさまざまな取り組みが行われている。なかでも、診療参加型の臨床実習を充実させることは重視されており、それぞれの歯学部・歯科大学は信頼される歯科医師を輩出するという最も大きな社会的命題を果たすべく努力を続けている。新潟大学歯学部では、卒業生の質の保証を目的に、臨床実習においてACCEPT Projectを立ち上げ、「ACKPIS」と称する方法を用いて学生の臨床能力を評価してきた。ACKPISは診療を自験する学生に対し、どのような専門領域においても必要不可欠となる6つの基本項目を、それぞれの専門処置を評価課題として確認するものである。今回、ACKPISの効果を検証するために、平成28年度の受検生にアンケート調査を行った。ACKPISの基本項目は、ADEAやGDCが提唱する歯科医師に求められるコンピテンシーの中にも該当する記述がみられ、国内外で医師に対して行われている臨床能力評価法同様、診療現場でのフィードバックを含んでいることから、歯学生の臨床能力を評価するために適当であると考えられた。また、アンケート結果から、受検した学生もACKPISの必要性や重要性を認識し、受検方法や合否判定の妥当性を認めていることが明らかになった。以上のことから、ACKPISは臨床実習中の学生の臨床能力を評価するための有用な方法となり得ることが示唆された。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2017&ichushi_jid=J02148&link_issn=&doc_id=20170510190001&doc_link_id=10.24744%2Fjdea.33.1_4&url=https%3A%2F%2Fdoi.org%2F10.24744%2Fjdea.33.1_4&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

The transient receptor potential vanilloid 1 (TRPV1) channel is abundantly expressed in peripheral sensory neurons where it acts as an important polymodal cellular sensor for heat, acidic pH, capsaicin, and other noxious stimuli. The oral cavity is densely innervated by afferent sensory neurons and is a highly specialized organ that protects against infections as well as physical, chemical, and thermal stresses in its capacity as the first part of the digestive system. While the function of TRPV1 in sensory neurons has been intensively studied in other organs, its physiological role in periodontal tissues is unclear. In this study we found that Trpv1(-/-) mice developed severe bone loss in an experimental model of periodontitis. Chemical ablation of TRPV1-expressing sensory neurons recapitulated the phenotype of Trpv1(-/-) mice, suggesting a functional link between neuronal TRPV1 signaling and periodontal bone loss. TRPV1 activation in gingival nerves induced production of the neuropeptide, calcitonin gene-related peptide (CGRP), and CGRP treatment inhibited osteoclastogenesis in vitro. Oral administration of the TRPV1 agonist, capsaicin, suppressed ligature-induced bone loss in mice with fewer tartrate-resistant acid phosphatase (TRAP)-positive cells in alveolar bone. These results suggest that neuronal TRPV1 signaling in periodontal tissue is crucial for the regulation of osteoclastogenesis via the neuropeptide CGRP.

DOI： 10.1038/srep29294

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Sitafloxacin (STFX) is a newly developed quinolone that has robust antimicrobial activity against periodontopathic bacteria. We previously reported that oral administration of STFX during supportive periodontal therapy was as effective as conventional mechanical debridement under local anesthesia microbiologically and clinically for 3 months. The aim of the present study was to examine the short-term and long-term microbiological and clinical effects of systemic STFX and azithromycin (AZM) on active periodontal pockets during supportive periodontal therapy. Fifty-one patients receiving supportive periodontal therapy were randomly allocated to the STFX group (200 mg/day of STFX for 5 days) or the AZM group (500 mg/day of AZM for 3 days). The microbiological and clinical parameters were examined until 12 months after the systemic administration of each drug. The concentration of each drug in periodontal pockets and the antimicrobial susceptibility of clinical isolates were also analyzed. The proportions of red complex bacteria, i.e., Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, which are the representative periodontopathic bacteria, were significantly reduced at 1 month and remained lower at 12 months than those at baseline in both the STFX and AZM groups. Clinical parameters were significantly improved over the 12-month period in both groups. An increase in the MIC of AZM against clinical isolates was observed in the AZM group. These results indicate that monotherapy with systemic STFX and AZM might be an alternative treatment during supportive periodontal therapy in patients for whom invasive mechanical treatment is inappropriate.

DOI： 10.1128/AAC.02575-15

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Other Link： http://orcid.org/0000-0002-7019-1872

Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Sitafloxacin (STFX) is a newly developed quinolone that has robust antimicrobial activity against periodontopathic bacteria. We previously reported that oral administration of STFX during supportive periodontal therapy was as effective as conventional mechanical debridement under local anesthesia microbiologically and clinically for 3 months. The aim of the present study was to examine the short-term and long-term microbiological and clinical effects of systemic STFX and azithromycin (AZM) on active periodontal pockets during supportive periodontal therapy. Fifty-one patients receiving supportive periodontal therapy were randomly allocated to the STFX group (200 mg/day of STFX for 5 days) or the AZM group (500 mg/day of AZM for 3 days). The microbiological and clinical parameters were examined until 12 months after the systemic administration of each drug. The concentration of each drug in periodontal pockets and the antimicrobial susceptibility of clinical isolates were also analyzed. The proportions of red complex bacteria, i.e., Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia, which are the representative periodontopathic bacteria, were significantly reduced at 1 month and remained lower at 12 months than those at baseline in both the STFX and AZM groups. Clinical parameters were significantly improved over the 12-month period in both groups. An increase in the MIC of AZM against clinical isolates was observed in the AZM group. These results indicate that monotherapy with systemic STFX and AZM might be an alternative treatment during supportive periodontal therapy in patients for whom invasive mechanical treatment is inappropriate. (This study has been registered with the University Hospital Medical Information Network-Clinical Trials Registry [UMIN-CTR] under registration number UMIN000007834.).

DOI： 10.1128/AAC.02575-15

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Objective: In periodontitis, chronic infection by periodontopathic bacteria induces uncontrolled inflammation, which leads to periodontal tissue destruction. Human gingival epithelial cells (HGECs) constitute a critical first line of defense against periodontopathic bacteria, both as a physical barrier and as regulators of inflammation. Resveratrol, a polyphenol found in grapes and red wine, reportedly has anti-inflammatory properties. Therefore, we investigated the effects of resveratrol on the Porphyromonas gingivalis-induced inflammatory responses of HGECs and their mechanism. Material and Methods: We stimulated the HGEC line, epi 4, with live or heat-killed P. gingivalis in the presence of resveratrol, and analyzed expressions of the interleukin-8, monocyte chemoattractant protein-1 and interleukin-1β genes. We determined the involvement of SIRT1 in the effect of resveratrol using sirtinol (a SIRT1 inhibitor) or SIRT1 knockdown. We also examined whether the effects were mediated by activation of AMP-activated kinase, suppression of reactive oxygen species, or inhibition of nuclear factor-κB (NF-κB). Results: Resveratrol treatment decreased the expression of inflammatory cytokines and slightly increased the expression of SIRT1. However, neither SIRT1 inhibition nor SIRT1 knockdown counteracted its anti-inflammatory effects. Although resveratrol did not affect AMP-activated kinase activation or reactive oxygen species production, it slightly suppressed NF-κB translocation when cells were stimulated with heat-killed P. gingivalis. Conclusion: Resveratrol suppressed the inflammatory responses of P. gingivalis-stimulated HGECs, probably by inhibiting NF-κB signaling but independent of SIRT1.

DOI： 10.1111/jre.12238

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SAGE PUBLICATIONS INC  

Transient receptor potential cation channel subfamily V member 1 (TRPV1), a member of the calcium-permeable thermosensitive transient receptor potential superfamily, is a sensor of thermal and chemical stimuli. TRPV1 is activated by noxious heat (> 43°C), acidic conditions (pH < 6.6), capsaicin, and endovanilloids. This pain receptor was discovered on nociceptive fibers in the peripheral nervous system. TRPV1 was recently found to be expressed by non-neuronal cells, such as epithelial cells. The oral gingival epithelium is exposed to multiple noxious stimuli, including heat and acids derived from endogenous and exogenous substances; however, whether gingival epithelial cells (GECs) express TRPV1 is unknown. We show that both TRPV1 mRNA and protein are expressed by GECs. Capsaicin, a TRPV1 agonist, elevated intracellular Ca2+ levels in the gingival epithelial cell line, epi 4. Moreover, TRPV1 activation in epi 4 cells accelerated proliferation. These responses to capsaicin were inhibited by a specific TRPV1 antagonist, SB-366791. We also observed GEC proliferation in capsaicin-treated mice in vivo. No effects were observed on GEC apoptosis by epithelial TRPV1 signaling. To examine the molecular mechanisms underlying this proliferative effect, we performed complementary (c)DNA microarray analysis of capsaicin-stimulated epi 4 cells. Compared with control conditions, 227 genes were up-regulated and 232 genes were down-regulated following capsaicin stimulation. Several proliferation-related genes were validated by independent experiments. Among them, fibroblast growth factor-17 and neuregulin 2 were significantly up-regulated in capsaicin-treated epi 4 cells. Our results suggest that functional TRPV1 is expressed by GECs and contributes to the regulation of cell proliferation.

DOI： 10.1177/0022034514552826

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Objective: Elderly people exhibit increased susceptibility to a number of autoimmune and infectious diseases, such as periodontitis. Although aging is reportedly associated with a decline in immune function, age-related alterations in periodontal tissue have remained elusive. In the present study, we comprehensively analyzed the effect of aging on the expression of selected genes using mouse gingival fibroblasts. Material and Methods: Gingival fibroblasts derived from young (8 wk of age) and old (≥ 24 mo of age) C57BL/6 mice were stimulated with Porphyromonas gingivalis lipopolysaccharide or live P. gingivalis strain W83. Expression of cytokines/chemokines, innate immune receptors, growth factors, matrix metalloproteinases, tissue inhibitors of metalloproteinases and osteoclastogenesis-related molecules were evaluated using real-time polymerase chain reaction and ELISA for interleukin-6 and transforming growth factor-β1. Results: Gingival fibroblasts derived from old mice exhibited decreased gene expression of Il-6, Cxcl1, Tlr2, Tlr4, Irak3 (IRAK-M), Kgf, Timp1, Timp3 and Rankl under resting conditions, whereas the expression levels of Tgfβ1, Mmp3, Mmp13 and Opg were increased. Age-related differences were also detected at the protein level. Although P. gingivalis W83 upregulated Vegf, Fgf-2 and Bmp2 expression in both young and old gingival fibroblasts, the stimulatory effect on these genes was significantly lower in old gingival fibroblasts. Conclusion: Our findings demonstrated that aging altered the expression of a number of genes in gingival fibroblasts. Thus, alterations in the balance of these molecules could play a critical role in periodontitis progression in the elderly. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

DOI： 10.1111/jre.12134

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Objective: T and B cells are known to be involved in the disease process of periodontitis. However, the role of natural killer T cells in the pathogenesis of periodontitis has not been clarified. Materials and Methods: To examine the role of these cells, C57BL/6J (wild-type), CD1d-/- and α-galactosylceramide (αGC)-stimulated wild-type mice were orally infected with Porphyromonas gingivalis strain W83. Results: Apart from CD1d-/- mice, the level of alveolar bone resorption was elevated by the infection and was further accelerated in αGC-stimulated mice. The infection induced elevated levels of serum amyloid A and P. gingivalis-specific IgG in the sera, although the degree of elevation was much smaller in the CD1d-/- mice. Infection-induced RANKL elevation was only observed in αGC-stimulated mice. Although the cytokines produced by splenocytes were mainly T-helper 1 type in wild-type mice, those in αGC-stimulated mice were predominantly T-helper 2 type. In the liver, the infection demonstrated no effect on the gene expression for interferon-γ, interleukin-4 and RANKL except αGC-stimulated mice in which the infection upregulated the gene expressions. Conclusion: This study is the first to show that natural killer T cells upregulated systemic and local inflammatory responses induced by oral infection with P. gingivalis, thereby contributing to the progression of alveolar bone resorption. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

DOI： 10.1111/jre.12080

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Language：English   Publisher：NATURE PUBLISHING GROUP  

DOI： 10.1038/ni.2734

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GENETICS SOC AM  

Linkage between transmembrane proteins and the spectrin-based cytoskeleton is necessary for membrane elasticity of red blood cells. Mutations of the proteins that mediate this linkage result in various types of hemolytic anemia. Here we report a novel N-ethyl-N-nitrosourea-induced mutation of ankyrin-1, named hema6, which causes hereditary spherocytosis in mice through a mild reduction of protein expression. The causal mutation was traced to a single nucleotide transition located deep into intron 13 of gene Ank1. In vitro minigene splicing assay revealed two abnormally spliced transcripts containing cryptic exons from fragments of Ank1 intron 13. The inclusion of cryptic exons introduced a premature termination codon, which leads to nonsense-mediated decay of the mutant transcripts in vivo. Hence, in homozygous mice, only wild-type ankyrin-1 is expressed, albeit at 70% of the level in wild-type mice. Heterozygotes display a similar hereditary spherocytosis phenotype stemming from intermediate protein expression level, indicating the haploinsufficiency of the mutation. Weakened linkage between integral transmembrane protein, band 3, and underlying cytoskeleton was observed in mutant mice as the result of reduced high-affinity binding sites provided by ankyrin-1. Hema6 is the only known mouse mutant of Ank1 allelic series that expresses full-length canonical ankyrin-1 at a reduced level, a fact that makes it particularly useful to study the functional impact of ankyrin-1 quantitative deficiency.

DOI： 10.1534/g3.113.007013

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：PERGAMON-ELSEVIER SCIENCE LTD  

Objective: Biomarkers in gingival crevicular fluid (GCF) have been investigated; however, measurements were limited by the small sample volume available. The aim of this study was to determine the levels of 40 different cytokines and chemokines in GCF samples.Design: Eleven patients with generalised chronic periodontitis participating in a supportive periodontal therapy programme with remaining probing pocket depths (PDs) of >5 mm were enrolled. One healthy and two diseased sites were sampled in each subject. Forty biomarkers in GCF were examined using a multiplex bead immunoassay. Porphyromonas gingivalis from the diseased sites was quantified by real-time polymerase chain reaction.Results: Twenty-six biomarkers were detected in the GCF samples using the multiplex bead immunoassay. The levels of nine biomarkers were significantly different between the diseased and healthy sites after adjustment with Bonferroni's correction. The level of 26 biomarkers in diseased sites was compared between bleeding on probing (BOP)-positive and BOP-negative sites. Interleukin (IL)-1 beta and interferon-inducible protein (IP)-10 levels were significantly higher in BOP-positive diseased sites than BOP-negative diseased sites after adjustment for multiple comparisons (IL-1 beta, p = 0.0007, IP-10; p = 0.0009). In addition, the levels of IL-1 beta in GCF were found to be strongly correlated with the P. gingivalis ratio (r = 0.646, p = 0.0012).Conclusion: IL-1 beta levels in GCF correlate with the PDs, BOP and the presence of P. gingivalis in subgingival plaque. Multiplex bead assays can be useful in GCF studies. These findings can help in identifying new diagnostic methods in the diagnosis of periodontal disease. (C) 2012 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2012.11.012

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BACKGROUND: We present a compendium of N-ethyl-N-nitrosourea (ENU)-induced mouse mutations, identified in our laboratory over a period of 10 years either on the basis of phenotype or whole genome and/or whole exome sequencing, and archived in the Mutagenetix database. Our purpose is threefold: 1) to formally describe many point mutations, including those that were not previously disclosed in peer-reviewed publications; 2) to assess the characteristics of these mutations; and 3) to estimate the likelihood that a missense mutation induced by ENU will create a detectable phenotype. FINDINGS: In the context of an ENU mutagenesis program for C57BL/6J mice, a total of 185 phenotypes were tracked to mutations in 129 genes. In addition, 402 incidental mutations were identified and predicted to affect 390 genes. As previously reported, ENU shows strand asymmetry in its induction of mutations, particularly favoring T to A rather than A to T in the sense strand of coding regions and splice junctions. Some amino acid substitutions are far more likely to be damaging than others, and some are far more likely to be observed. Indeed, from among a total of 494 non-synonymous coding mutations, ENU was observed to create only 114 of the 182 possible amino acid substitutions that single base changes can achieve. Based on differences in overt null allele frequencies observed in phenotypic vs. non-phenotypic mutation sets, we infer that ENU-induced missense mutations create detectable phenotype only about 1 in 4.7 times. While the remaining mutations may not be functionally neutral, they are, on average, beneath the limits of detection of the phenotypic assays we applied. CONCLUSIONS: Collectively, these mutations add to our understanding of the chemical specificity of ENU, the types of amino acid substitutions it creates, and its efficiency in causing phenovariance. Our data support the validity of computational algorithms for the prediction of damage caused by amino acid substitutions, and may lead to refined predictions as to whether specific amino acid changes are responsible for observed phenotypes. These data form the basis for closer in silico estimations of the number of genes mutated to a state of phenovariance by ENU within a population of G3 mice.

DOI： 10.1186/1756-0500-5-577

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

BACKGROUND: Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL) cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models. METHODS: We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver. RESULTS: P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP)2 (human homologue of Srebf2), whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection. CONCLUSIONS: P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies are required to elucidate how infection regulates Srebf2 expression and subsequently influences lipid metabolism.

DOI： 10.1186/1476-511X-11-121

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BMC  

Background: Periodontal disease is suggested to increase the risk of atherothrombotic disease by inducing dyslipidemia. Recently, we demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9), which is known to play a critical role in the regulation of circulating low-density lipoprotein (LDL) cholesterol levels, is elevated in periodontitis patients. However, the underlying mechanisms of elevation of PCSK9 in periodontitis patients are largely unknown. Here, we explored whether Porphyromonas gingivalis, a representative periodontopathic bacterium, -induced inflammatory response regulates serum PCSK9 and cholesterol levels using animal models.Methods: We infected C57BL/6 mice intraperitoneally with Porphyromonas gingivalis, a representative strain of periodontopathic bacteria, and evaluated serum PCSK9 levels and the serum lipid profile. PCSK9 and LDL receptor (LDLR) gene and protein expression, as well as liver X receptors (Lxrs), inducible degrader of the LDLR (Idol), and sterol regulatory element binding transcription factor (Srebf)2 gene expression, were examined in the liver.Results: P. gingivalis infection induced a significant elevation of serum PCSK9 levels and a concomitant elevation of total and LDL cholesterol compared with sham-infected mice. The LDL cholesterol levels were significantly correlated with PCSK9 levels. Expression of the Pcsk9, Ldlr, and Srebf2 genes was upregulated in the livers of the P. gingivalis-infected mice compared with the sham-infected mice. Although Pcsk9 gene expression is known to be positively regulated by sterol regulatory element binding protein (SREBP)2 (human homologue of Srebf2), whereas Srebf2 is negatively regulated by cholesterol, the elevated expression of Srebf2 found in the infected mice is thought to be mediated by P. gingivalis infection.Conclusions: P. gingivalis infection upregulates PCSK9 production via upregulation of Srebf2, independent of cholesterol levels. Further studies are required to elucidate how infection regulates Srebf2 expression and subsequently influences lipid metabolism.

DOI： 10.1186/1476-511X-11-121

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Language：Japanese   Publisher：(公社)日本歯科医師会  

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-BLACKWELL  

Background and Objective: Periodontal infection affects atherosclerotic diseases, such as coronary heart diseases. Mouse models have revealed that oral infection with Porphyromonas gingivalis induces changes in inflammatory- and lipid metabolism-related gene expression, regardless of the development of atherosclerotic lesions. However, the serum protein expression profile in the oral infection model has not been investigated. The present study aimed to analyse the effect of oral infection with P. gingivalis on the expression levels of multiple cytokines in the serum in apolipoproteinE-deficient mice by using a cytokine antibody array. Material and Methods: C57BL/6.KOR-Apoe shl mice were orally infected with P. gingivalis five times at 3day intervals and were then killed. Splenocytes were isolated and analysed for proliferative activity and immunoglobulinG (IgG) production in response to in vitro restimulation with P. gingivalis. The expression levels of various cytokines in the sera were analysed using a mouse antibody array glass chip. Results: Splenocytes from P. gingivalis-infected mice demonstrated significantly greater proliferation and IgG production in response to P. gingivalis compared with those from sham-infected mice. Antibody array analysis revealed the selective upregulation of matrix metalloproteinase 3, intercellular adhesion molecule 1, insulin-like growth factor binding protein 2 and chemokine (C-X-C motif) ligand 7 and the downregulation of interleukin-17, tumor necrosis factor-α and L-selectin. Conclusion: These data demonstrate that oral infection with P. gingivalis induces alterations in systemic cytokine production. These cytokines could play roles in the development not only of periodontitis but also of atherosclerosis. © 2011 John Wiley & Sons A/S.

DOI： 10.1111/j.1600-0765.2011.01441.x

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Objective: The present study was designed to investigate whether titres of antibody to two strains of Porphyromonas gingivalis, FDC381 and SU63, are associated with serum high-sensitivity C-reactive protein (hs-CRP) levels in Japanese periodontitis patients.Design: Forty-nine patients with moderate to advanced periodontitis and 40 periodontally healthy control subjects were included in this study. hs-CRP levels and antibody titres to P. gingivalis were measured at baseline and reassessment 3-4 months after periodontal treatment in periodontitis patients as well as at the time of examination in the periodontally healthy subjects. Further, the effect of periodontal therapy, including surgical treatment and use of antibacterials on both markers, was analysed in patients.Results: hs-CRP levels and antibody titres to P. gingivalis were higher in periodontitis patients than in control subjects, and they significantly decreased following periodontal treatment (p < 0.005). Also, a significant decrease in hs-CRP levels as a result of periodontal treatment was found in patients with hs-CRP levels >1 mgl(-1) at baseline (p < 0.005). Probing depth, clinical attachment level, and alveolar bone loss in patients were significantly associated with a higher antibody titre to both strains of P. gingivalis (p < 0.05), but were not related to hs-CRP levels. No relationship was observed between hs-CRP levels and tertiles as defined by titres of antibody to P. gingivalis strains FDC381 and SU63.Conclusions: Our data indicate that hs-CRP levels were independent of antibody titres to P. gingivalis in Japanese periodontitis patients. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2011.11.008

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Background: Periodontal disease increases the risk of atherothrombotic disease, and high concentrations of low density lipoprotein (LDL) cholesterol are considered to be involved: however, the underlying mechanisms are largely unknown. Recent studies demonstrated that proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a critical role in circulating LDL cholesterol concentrations. The aim of the present study is to analyze serum PCSK9 concentrations and their relation to lipoprotein concentrations in periodontitis patients.Methods: Sera were obtained from 40 periodontitis patients and 30 control subjects. PCSK9 concentrations, high-sensitivity C-reactive protein (hs-CRP), IL-6, TNF-alpha and Porphyromonas gingivalis antibodies were measured by ELISA, and lipid profiles were determined by a commercial laboratory.Results: Periodontitis patients demonstrated significantly higher serum antibody titer to P. gingivalis and hs-CRP concentrations than control subjects, suggesting infection with P. gingivalis and a systemic inflammatory response. PCSK9 concentrations in periodontitis patients were significantly higher than those in control subjects. However, the concentrations of total and LDL cholesterols were not significantly different between periodontitis patients and control subjects. Moreover, no correlations were observed between PCSK9 concentrations and lipid profiles.Conclusion: Periodontal infection upregulates PCSK9 production. However, further studies are required to elucidate how periodontal infection affects PCSK9 concentrations and subsequent lipid metabolism. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.cca.2011.09.023

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Background: Epidemiological studies have suggested periodontitis as a risk factor for ischemic heart disease. High sensitive C-reactive protein (hs-CRP), a predictor of cardiovascular risk, is elevated in periodontitis patients. Therefore, local infection-induced elevation of systemic CRP could account for the relationship between the 2 diseases. However, the underlying mechanism of CRP production in the periodontal tissues has not been fully elucidated. Therefore, the aim of the present study was to clarify the mechanism of CRP production in periodontal tissues.Methods: Gene expression of CRP in gingival biopsies was analysed by quantitative PCR. Human gingival epithelial cells (HGECs), human gingival fibroblasts (HGFBs), and human coronary artery endothelial cells (HCAECs) were characterized for CRP-producing ability by incubating with interleukin (IL)-1 beta, IL-6, soluble IL-6 receptor (sIL-6R), and Porphyromonas gingivalis strain W83.Results: Gene expression of CRP is significantly elevated in periodontitis lesions compared with gingivitis lesions. HCAECs, but not HGECs and HGFBs, produced CRP in response to IL-6 and IL-1 beta in the presence of sIL-6R. In contrast to IL-6, the effect of IL-1 beta on CRP production was indirect via induction of IL-6. IL-1 beta was produced by HGECs and HGFBs with stimulation of P. gingivalis antigens.Conclusion: These results suggest that CRP induced locally by periodontal infection may play another role in the pathogenesis of periodontal disease, and to a much lesser extent, has the potential to modulate systemic CRP level by extra-hepatic CRP production. (C) 2011 Elsevier Ltd. All rights reserved.

DOI： 10.1016/j.archoralbio.2011.04.010

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The role of interleukin (IL)-17 in cellular communication in inflammation has been well described, and a positive correlation between the severity of periodontitis and the level of IL-17 was reported. Although epithelial cells are a major target of IL-17, little is known about the effect of IL-17 on the production of chemokines by human gingival epithelial cells (HGECs). We evaluated the effects of IL-17 on the expression of CXCL8 and CCL2 by HGECs using quantitative real-time PCR and ELISA. In addition, the role of the nuclear factor (NF)-kappa B signalling pathway in the IL-17-mediated expression of chemokines was assessed using a specific inhibitor. Stimulation with IL-17 up-regulated the expression of CXCL8 mRNA but not of CCL2 mRNA in HGECs, whereas tumour necrosis factor-alpha (TNF-alpha) elevated the expression of mRNA for both chemokines. Stimulation with IL-17 up-regulated the secretion of CXCL8 protein, but not the secretion of CCL2 protein. The effect of IL-17 on CXCL8 production was suppressed using an anti-IL-17R Ig, suggesting a role for a specific receptor-ligand interaction. Inhibition of the NF-kappa B signalling pathway demonstrated that NF-kappa B activation is required for the CXCL8 expression in HGECs. In conclusion, IL-17 is involved in the regulation of the innate immune response in HGECs by inducing CXCL8 production.

DOI： 10.1111/j.1600-0722.2011.00842.x

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Background: Recent studies have suggested that periodontal disease increases the risk of atherothrombotic disease. Atherosclerosis has been characterized as a chronic inflammatory response to cholesterol deposition in the arteries. Although several studies have suggested that certain periodontopathic bacteria accelerate atherogenesis in apolipoprotein E-deficient mice, the mechanistic link between cholesterol accumulation and periodontal infection-induced inflammation is largely unknown.Methodology/Principal Findings: We orally infected C57BL/6 and C57BL/6. KOR-Apoe(shl) (B6.Apoeshl) mice with Porphyromonas gingivalis, which is a representative periodontopathic bacterium, and evaluated atherogenesis, gene expression in the aorta and liver and systemic inflammatory and lipid profiles in the blood. Furthermore, the effect of lipopolysaccharide (LPS) from P. gingivalis on cholesterol transport and the related gene expression was examined in peritoneal macrophages. Alveolar bone resorption and elevation of systemic inflammatory responses were induced in both strains. Despite early changes in the expression of key genes involved in cholesterol turnover, such as liver X receptor and ATP-binding cassette A1, serum lipid profiles did not change with short-term infection. Long-term infection was associated with a reduction in serum high-density lipoprotein (HDL) cholesterol but not with the development of atherosclerotic lesions in wild-type mice. In B6.Apoeshl mice, long-term infection resulted in the elevation of very low-density lipoprotein (VLDL), LDL and total cholesterols in addition to the reduction of HDL cholesterol. This shift in the lipid profile was concomitant with a significant increase in atherosclerotic lesions. Stimulation with P. gingivalis LPS induced the change of cholesterol transport via targeting the expression of LDL receptor-related genes and resulted in the disturbance of regulatory mechanisms of the cholesterol level in macrophages.Conclusions/Significance: Periodontal infection itself does not cause atherosclerosis, but it accelerates it by inducing systemic inflammation and deteriorating lipid metabolism, particularly when underlying hyperlidemia or susceptibility to hyperlipidemia exists, and it may contribute to the development of coronary heart disease.

DOI： 10.1371/journal.pone.0020240

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Aim: Limited epidemiological studies have investigated the relationship between ischemic vascular disease and periodontitis in non-Western populations. We investigated this relationship in a Japanese cohort by measuring serum titers of antibodies to periodontopathic bacteria.Methods: As part of the Tokamachi-Nakasato cohort study, we followed up 7021 participants regarding cardiovascular events over 5 years, and observed 99 ischemic vascular events: 66 cerebral infarctions and 33 cases of ischemic heart disease (IHD). For a nested case-control study, we selected 495 sex-and age-matched control subjects. Conditional logistic regression analysis was used to estimate the odds ratios (OR) and 95% confidence intervals (CI) of ischemic vascular events associated with antibody titers to Porphyromonas gingivalis FDC381 and SU63. Multivariable models were adjusted for traditional cardiovascular risk factors using propensity scores.Results: The highest tertile category of antibody titers to P. gingivalis FDC381 in men was significantly associated with an increased risk of cerebral infarction in only the crude model. The 2nd and 3rd tertile categories of antibody titers to P. gingivalis SU63 were significantly associated with an increased risk of cerebral infarction in men (multivariable ORs (95% CIs) were 7.12 (1.51-33.5) and 9.03 (1.97-41.5), respectively). The association was not appreciably modified when we further adjusted for serum high-sensitivity C-reactive protein levels. Antibody titers to P. gingivalis were not dose-dependently associated with the risk of IHD.Conclusion: High serum antibody titers to P. gingivalis SU63 could be a predictor of cerebral infarction in Japanese men independent of traditional risk factors and inflammation.

DOI： 10.5551/jat.6957

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Takahashi N, Honda T, Domon H, Nakajima T, Tabeta K, Yamazaki K. Interleukin-1 receptor-associated kinase-M in gingival epithelial cells attenuates the inflammatory response elicited by Porphyromonas gingivalis. J Periodont Res 2010; 45: 512-519. © 2010 John Wiley & Sons A/S Background and Objective: Recent studies have revealed that negative regulatory molecules, including interleukin-1 receptor-associated kinase-M (IRAK-M), control the overactivation of Toll-like receptor (TLR) signaling. The role of IRAK-M in human gingival epithelial cells (HGECs), which express TLRs, remains unclear. The present study examined the role of IRAK-M on interleukin-8 and macrophage chemoattractant protein-1 (MCP-1) expression in HGECs stimulated with Porphyromonas gingivalis and TLR ligands. Material and Methods: Primary HGECs and an SV40 T-antigen-immortalized HGEC line (epi 4) were stimulated with live or heat-killed P. gingivalis, P. gingivalis lipopolysaccharide or the synthetic lipopeptide PAM3CSK4, and subsequent expression of IRAK-M, interleukin-8 and MCP-1 was evaluated at the mRNA and protein levels. The effects of IRAK-M on interleukin-8 and MCP-1 expressions were evaluated by IRAK-M-specific RNA interference (RNAi)-based loss-of-function assay. Results: All tested stimulants up-regulated the expression of IRAK-M in HGECs. The P. gingivalis lipopolysaccharide or PAM3CSK4 increased MCP-1 expression, whereas live P. gingivalis down-regulated the MCP-1 expression in HGECs. However, IRAK-M RNAi increased the expression of MCP-1 irrespective of up- or down-regulation mediated by the respective stimulants. Interleukin-8 gene expression, up-regulated by all tested stimulants, was further enhanced by IRAK-M RNAi. In contrast, IRAK-M RNAi had no effect on the interleukin-8 protein levels, irrespective of the stimulant, indicating that post-translational modification, not IRAK-M, controls interleukin-8 protein expression. Conclusion: Interleukin-1 receptor-associated kinase-M appeared to have distinct regulatory roles on the interleukin-8 and MCP-1 produced by HGECs, further suggesting an important role for interleukin-8 in the immune reponse to periodontopathic bacteria. © 2010 John Wiley & Sons A/S.

DOI： 10.1111/j.1600-0765.2009.01266.x

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Bacterial fimbriae are an important pathogenic factor. It has been demonstrated that fimbrial protein encoded by fimA gene (FimA fimbriae) of Porphyromonas gingivalis not only contributes to the abilities of bacterial adhesion and invasion to host cells, but also strongly stimulates host innate immune responses. However, FimA fimbriae separated from P. gingivalis ATCC 33277 using a gentle procedure showed very weak proinflammatory activity compared with previous reports. Therefore, in the present study, biological characteristics of FimA fimbriae were further analyzed in terms of proinflammatory activity in macrophages. Macrophages differentiated from THP-1 cells were stimulated with native, heat-denatured, or either proteinase- or lipoprotein lipase-treated FimA fimbriae of P. gingivalis ATCC 33277. Stimulating activities of these FimA fimbriae were evaluated by TNF-alpha-inducing activity in the macrophages. To clarify the mode of action of FimA fimbriae, anti-Toll-like receptor (TLR) 2 blocking antibody was added prior to stimulation. Weak stimulatory activity of native FimA fimbriae was enhanced by heat treatment and low-dose proteinase K treatment. Higher dose of proteinase K treatment abrogated this up-regulation. The activity of treated FimA fimbriae was suppressed by anti-TLR2 antibody, and more substantially by lipoprotein lipase treatment. These results suggest that lipoproteins or lipopeptides associated with FimA fimbriae could at least in part account for signaling via TLR2 and subsequent TNF-alpha production in macrophages.

DOI： 10.1016/j.bbrc.2010.06.040

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Background and Objective: Although an elevation in the concentration of high-sensitivity C-reactive protein (hs-CRP) as a result of periodontal infection may account for an increased risk of developing coronary heart disease (CHD), the effect of periodontal infection on the level of hs-CRP in an otherwise healthy Japanese population has not yet been reported. The aim of the present study was to confirm, on a larger scale, our previous pilot study findings that both chronic periodontitis and subsequent periodontal treatment alter the serum levels of C-reactive protein (CRP), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Material and Methods: The concentrations of serum hs-CRP, IL-6 and TNF-α were measured in 78 periodontitis patients at baseline and at re-assessment, and in 40 periodontally healthy subjects at the time of examination. Results: The concentrations of hs-CRP and IL-6 in the sera of periodontitis patients were significantly higher than those in control subjects. By contrast, the concentration of TNF-α was significantly lower in periodontitis patients than in control subjects. Whereas periodontal treatment decreased the levels of serum hs-CRP and IL-6, no such effect was observed for TNF-α. When the patients were subdivided into four groups according to their initial concentration of hs-CRP, only the CRP and IL-6 concentrations of the highest quartile group showed a significant reduction following periodontal treatment. No significant difference in the initial clinical parameters was observed in any quartile. Conclusion: Although periodontal infection does affect the concentration of hs-CRP and IL-6 in serum, a subgroup of patients exist who are highly susceptible to an increased risk of CHD associated with periodontitis, suggesting that there may be subjects who have an elevated risk of CHD independent of susceptibility to periodontal tissue destruction per se. © 2009 John Wiley & Sons A/S.

DOI： 10.1111/j.1600-0765.2009.01209.x

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Background: Individuals with periodontitis have elevated serum levels of IL-6 and C-reactive protein and have been reported to have a significantly increased risk of developing cardiovascular disease. The transcription factor early growth response factor 1 (Egr-1) has been shown to play an important role in the development and progression of atherosclerosis. However, it is not known whether periodontal infection affects the expression of Egr-1 and subsequent endothelial cells expression of monocyte chemoattractant protein (MCP)-1, a key molecule of leukocyte chemoattraction into vessels. Methods: Human coronary artery endothelial cells (HCAECs) were stimulated with either sonicated extracts from Porphyromonas gingivalis strains 381 or SU63, or a combination of IL-6 and soluble IL-6 receptor (IL-6/sIL-6R). The expression of Egr-1, and subsequently MCP-1, was then analyzed. The role of Egr-1 on MCP-1 expression was analyzed by siRNA transfection. Results: Both P. gingivalis anti-gens and IL-6/sIL-6R stimulations upregulated the expression of Egr-1, with a more robust effect by IL-6/sIL-6R. Increased expression of Egr-1 coincided with MCP-1 production, and Egr-1 downregulation by siRNA suppressed this effect. Conclusion: These results clearly suggest that periodontal infection has the potential to affect HCAECs and hence contribute to the development of subsequent atherosclerosis. Copyright (C) 2009 S. Karger AG, Basel

DOI： 10.1159/000265568

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The accumulating knowledge about host-pathogen interactions in infectious diseases shows how the immune system interfaces with pathogens, and thus, helps us in understanding the pathogenesis of diseases and improving their treatment. Purified antigens are indispensable while investigating the immune response in both innate and acquired immunities. It is ideal to use native antigens purified from the host organisms in native conditions that sustain their biological activity completely. However, purification of native antigens, especially on a large scale, is technically difficult and generally time consuming. Purifying protein as a peptide-tagged fusion protein is an effective approach. Purification of a recombinant protein engineered to incorporate a polyhistidine tag at either the carboxyl or amino terminus is an established method, and it can be easily modified to obtain optimal results under different conditions. Heat-shock proteins were highly conserved during evolution and are highly homologous between prokaryotic and eukaryotic cells. Their molecular mimicry might have roles in the pathogenesis of chronic inflammatory diseases. We successfully generated histidine-tagged recombinant heat-shock proteins from the periodontopathogens, Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. The recombinant proteins allowed us to evaluate the immune response to these antigens in periodontitis patients.

DOI： 10.1007/978-1-60761-820-1_21

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ROCKEFELLER UNIV PRESS  

Toll-like receptors (TLRs) 3, 7, and 9 recognize microbial nucleic acids in endolysosomes and initiate innate and adaptive immune responses. TLR7/9 in dendritic cells (DCs) also respond to self-derived RNA/DNA, respectively, and drive autoantibody production. Remarkably, TLR7 and 9 appear to have mutually opposing, pathogenic or protective, impacts on lupus nephritis in MRL/lpr mice. Little is known, however, about the contrasting relationship between TLR7 and 9. We show that TLR7 and 9 are inversely linked by Unc93B1, a multiple membrane-spanning endoplasmic reticulum (ER) protein. Complementation cloning with a TLR7-unresponsive but TLR9-responsive cell line revealed that amino acid D34 in Unc93B1 repressed TLR7-mediated responses. D34A mutation rendered Unc93B1-deficient DCs hyperresponsive to TLR7 ligand but hyporesponsive to TLR9 ligand, with TLR3 responses unaltered. Unc93B1 associates with and delivers TLR7/9 from the ER to endolysosomes for ligand recognition. The D34A mutation up-regulates Unc93B1 association with endogenous TLR7 in DCs, whereas Unc93B1 association with TLR9 was down-regulated by the D34A mutation. Consistently, the D34A mutation up-regulated ligand-induced trafficking of TLR7 but down-regulated that of TLR9. Collectively, TLR response to nucleic acids in DCs is biased toward DNA-sensing by Unc93B1.

DOI： 10.1084/jem.20082316

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Background: A genome-association study is a powerful toot for analyzing small gene effects in complex diseases such as chronic periodontitis (CP), although the cost of analysis is prohibitive. We designed a study using the DNA pooling method, which could be a breakthrough in lowering such costs. This study was conducted to assess the genetic association in severe CP in a Japanese population.Methods: We adopted a DNA pooling method by genotyping 454 densely spaced microsatellite (MS) markers in chromosome 19 as a pilot study, with the possibility of future use in a whole-genome study. This can reduce the high cost and technical burden, which is generally unavoidable in a genomic association study. Pooled DNA samples from 300 case subjects, 300 control subjects, and 200 systemically healthy subjects were screened by genotyping MS markers. The case-control association in the candidate region was analyzed by individual typing of MS and single nucleotide polymorphisms (SNPs).Results: The single MS marker allele 17 of 1902G31 was isolated in association with severe CP (P = 0.0012 for 2 x 2; P<0.046 for 2 x m, where m refers to the number of polymorphic alleles observed in a population). No other SNP or MS polymorphism hypothesized to affect biologic functions in the critical region was found in the linkage disequilibrium block analysis.Conclusions: We efficiently isolated the susceptible locus for severe CP in chromosome 19 and identified a useful marker to evaluate the risk for disease. This approach can be applied to a whole-genome study in severe CP. J Periodontol 2009;80:663-671.

DOI： 10.1902/jop.2009.080516

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BACKGROUND: Endoplasmic reticulum (ER) stress is the cell response by activation of the unfolded protein response (UPR) pathway in a variety of conditions such as infection and aging. The UPR may be associated with the pathogenesis of periodontal disease because of the induction of apoptosis and activation of nuclear factor-kappaB (NF-kappaB), a transcription factor for pro-inflammatory cytokines. However, the relationship between ER stress and periodontal disease is yet to be determined. METHODS: The expression of UPR-related molecules was analyzed by real-time polymerase chain reaction and immunohistochemistry, respectively and compared between gingivitis and periodontitis. The gene expressions were also analyzed for macrophages stimulated with lipopolysaccharides (LPS) from Escherichia coli (E. coli), and Porphyromonas gingivalis (P. gingivalis) or IFN-gamma. RESULTS: The expression levels of UPR-related genes and HSP60 were significantly higher in periodontitis compared with gingivitis lesions. However, LPS from P. gingivalis but not E. coli or IFN-gamma failed to up-regulate the gene expression in macrophage. CONCLUSIONS: An inflammatory response may have profound effect on the UPR response, particularly in periodontitis patients. Considering the histological nature of periodontitis and the link between UPR and inflammatory responses via NF-kappaB, ER stress in B cells could be another pathological mechanism underlying periodontal disease.

DOI： 10.1016/j.cca.2008.12.007

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Alveolar macrophages are the first line of host defence against mycobacteria, but an insufficient host response allows survival of bacteria within macrophages. We aimed to investigate the role of Toll-like receptor 9 (TLR9) activation in macrophage defence against mycobacteria. Human in vitro differentiated macrophages as well as human and mouse alveolar macrophages showed TLR9 mRNA and protein expression. The cells were markedly activated by DNA isolated from attenuated mycobacterial strains (H37Ra and Mycobacterium bovis BCG) as assessed by measuring cytokine expression by real-time PCR, whereas synthetic phosphorothioate-modified oligonucleotides had a much lower potency to activate human macrophages. Intracellular replication of H37Ra was higher in macrophages isolated from TLR9-deficient mice than in macrophages from wild-type mice, whereas H37Rv showed equal survival in cells from wild-type or mutant mice. Increased bacterial survival in mouse macro-phages was accompanied by altered cytokine production as determined by Luminex bead assays. In vivo infection experiments also showed differential cytokine production in TLR9-deficient mice compared to wild-type animals. Both human monocyte-derived macrophages as well as human alveolar macrophages showed reduced activation upon treatment with DNA isolated from bacteria from virulent (M. bovis and H37Rv) compared to attenuated mycobacteria. We suggest attenuated TLR9 activation contributes to the insufficient host response against virulent mycobacteria. Copyright (C) 2008 S. Karger AG, Basel

DOI： 10.1159/000142731

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BACKGROUND: A number of different theories have been postulated to explain the progression of gingivitis to periodontitis in the context of the Th1/Th2 paradigm. However, no consistent results have been obtained. Th17, a new T-cell subset producing IL-17, which is implicated in many aspect of inflammatory tissue destruction, overcomes many of the discrepant findings in the studies related to the Th1/Th2 hypothesis. We compared the gene expression profile of Th17-related molecules in gingivitis and periodontitis lesions showing distinct clinical entities. METHODS: Gingival tissue samples were obtained from 23 gingivitis and 24 periodontitis tissues. The gene expression was measured by using quantitative real-time PCR for IL-17A, IL-17F, CCR4, CCR6, IL-12 p35 and IL-23 p19. The difference of gene expressions between gingivitis and periodontitis was analyzed by Mann-Whitney U-test. Correlations between each gene expression were also analyzed. RESULTS: The expression level of IL-17A was higher than that of IL-17F and a significant difference in expression between gingivitis and periodontitis was observed only for IL-17A. CCR4 and CCR6 tended to be higher in periodontitis compared with gingivitis, although the differences were not statistically significant. Whereas the gene expression of IL-12 p35 was significantly higher in periodontitis compared with gingivitis, that of IL-23 p19 was not different between the two diseases. CONCLUSION: This study demonstrates the elevated expression of IL-17 and IL-12 in periodontitis, i.e., the tissue destruction form of periodontal diseases, as compared with gingivitis, and provides new insight into the T-cell mediated immunopathogenesis of periodontal disease.

DOI： 10.1016/j.cca.2008.06.003

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Language：Japanese   Publisher：(公社)日本歯科医師会  

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Introduction: In addition to bacteria, viruses have been reportedly implicated in periodontitis. However, the available data are confined to Toll-like receptor 2 (TLR2) and TLR4, which recognize bacterial products in periodontitis. In the present study, we investigated the expression levels of TLR5, -7, and -9 messenger RNAs (mRNAs) in addition to those of TLR2 and -4, and compared gingivitis and periodontitis. Interferon-α1 (IFN-α1), which is important for the antiviral response, was also compared. Methods: Gene expression was analyzed using quantitative real-time polymerase chain reaction for 59 periodontitis and 27 gingivitis tissue samples together with viral serology in some patients. The presence of plasmacytoid dendritic cells (pDCs), a robust producer of IFN-α, was immunohistochemically analyzed in an additional seven periodontitis and two gingivitis specimens. Results: The expression levels of TLR2, -4, -7, and -9 were significantly higher in periodontitis lesions than gingivitis lesions. The expression level of TLR5 was comparable to levels of TLR2 and -4; however, no significant difference was found between gingivitis and periodontitis. Although the expression of IFN-α1 mRNA was higher in periodontitis lesions compared with gingivitis lesions, the level was quite low. Only a few pDCs were found in some periodontitis specimens. No difference was found for antibody-positivity between gingivitis and periodontitis. Conclusion: This is the first study to show that a variety of TLRs are up-regulated in periodontitis lesions compared with gingivitis lesions, suggesting that diverse microbial and possibly viral antigens are involved in the pathogenic mechanisms for periodontal diseases. However, the ligands recognized by the various TLRs in periodontal lesions remain to be determined. © 2007 The Authors.

DOI： 10.1111/j.1399-302X.2007.00377.x

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Mutations in the melanocortin-4 receptor (MC4R) are associated with early-onset obesity in humans. Furthermore, a null Mc4r allele in mice leads to severe obesity due to hyperphagia and decreased energy expenditure. As part of independent N-ethyl-N-nitrosourea (ENU) mutagenesis screens, two obesity mutants, Fatboy and Southbeach, were isolated. Mapping revealed linkage to the melanocortin-4 receptor (Mc4r) and sequencing found single amino acid changes in Mc4r for each line. Expression of the mutant receptors in HEK 293 cells revealed defects in receptor signaling. The mutated Fatboy receptor (I194T) shows an increase in the effective concentration necessary for 50% of maximal signaling (EC50) when stimulated with alpha-MSH. Based on competitive binding, I194T is expressed on the cell surface at lower levels than the nonmutated receptor. In contrast, Southbeach (L300P) displays minimal receptor signaling when stimulated with the natural ligand alpha-MSH or the synthetic agonist NDP-alpha-MSH. Cell surface binding is absent, which usually indicates a lack of cell surface expression. However, antibody binding to Flag-tagged receptors by flow cytometry analysis and immunofluorescence demonstrates that L300P is translocated to the plasma membrane at a level comparable to the wild-type receptor. These results indicate a correlation with remaining receptor activity and the severity of the obesity in the mice homozygous for the mutations. Southbeach has less receptor activity and becomes more obese. These mutants will serve as good models for the variability in phenotype in humans carrying mutations in the MC4R gene.

DOI： 10.1007/s00335-006-0073-z

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Language：English   Publisher：BENTHAM SCIENCE PUBL LTD  

The identification of the TLRs as key sensors of microbial infection has presented a series of new targets for drug development. The TLRs are linked to the most powerful inflammatory pathways in mammals. The question arises from the start: do we wish to stimulate TLR signaling in order to eradicate specific infections and/or neoplastic diseases? Or do we wish to block TLR signaling to treat inflammatory diseases? If we accept that it would be useful to modulate TLR signaling, the next step is to identify the correct molecular target(s) for the task. Perhaps it might even be possible to exercise selectivity, modulating some aspects of TLR signaling and not others. Classical and reverse genetic analyses offer insight into the possibilities that exist, and point to specific checkpoints within signaling pathways at which modulation might normally be imposed. © 2006 Bentham Science Publishers Ltd.

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ASSOC ADVANCEMENT SCIENCE  

Herpes simplex virus-1 (HSV-1) encephalitis (HSE) is the most common form of sporadic viral encephalitis in western countries. Its pathogenesis remains unclear, as it affects otherwise healthy patients and only a small minority of HSV-1-infected individuals. Here, we elucidate a genetic etiology for HSE in two children with autosomal recessive deficiency in the intracellular protein UNC-93B, resulting in impaired cellular interferon-alpha/beta and -lambda antiviral responses. HSE can result from a single-gene immunodeficiency that does not compromise immunity to most pathogens, unlike most known primary immunodeficiencies. Other severe infectious diseases may also reflect monogenic disorders of immunity.

DOI： 10.1126/science.1128346

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：CELL PRESS  

Here, we describe a previously unrecognized pathway for activation of antigen-specific adaptive immune responses that was independent of Toll-Interleukin 1 Receptor signaling and directed toward detection of antigens expressed by apoptotic cells. This pathway is represented within Flt-3 Ligand-derived dendritic cells (DCs) that represent immature lymphoid DCs, but not within GM-CSF-treated bone marrow-derived dendritic cells. Exposure of these DCs to apoptotic cells resulted in production of type I interferon and favored the development of cytotoxic T cell responses. The N-Ethyl-N-Nitrosourea-induced germline mutation 3d (Unc3b1(3d/3d)) abolished both MHC class I and 11 responses elicited by this pathway, whereas a null allele of Cd36 selectively abolished class 11 responses. We propose that this mode of adaptive immune activation evolved to permit the sensitive detection of intracellular microbial infections, particularly viral infections, which frequently induce apoptotic cell death, but may also be important in transplantation, autoimmunity, and vaccine development.

DOI： 10.1016/j.immuni.2006.03.024

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

Here we have identified 'triple D' (3d), a recessive N-ethyl-N-nitrosourea-induced mutation and phenotype in which no signaling occurs via the intracellular Toll-like receptors 3, 7 and 9 (sensors for double-stranded RNA, single-stranded RNA and unmethylated DNA, respectively). The 3d mutation also prevented cross-presentation and diminished major histocompatibility complex class II presentation of exogenous antigen; it also caused hypersusceptibility to infection by mouse cytomegalovirus and other microbes. By positional identification, we found 3d to be a missense allele of Unc93b1, which encodes the 12-membrane-spanning protein UNC-93B, a highly conserved molecule found in the endoplasmic reticulum with multiple paralogs in mammals. Innate responses to nucleic acids and exogenous antigen presentation, which both initiate in endosomes, thus seem to depend on an endoplasmic reticulum-resident protein, which suggests communication between these organellar systems.

DOI： 10.1038/ni1297

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Language：English   Publishing type：Part of collection (book)   Publisher：ELSEVIER ACADEMIC PRESS INC  

The inflammatory response to microbes-and host perception of microbes in general-is largely initiated by a single class of receptors, named for their similarity to the prototypic Toll receptor of Drosophila. The mammalian Toll-like receptors (TLRs) are ultimately responsible for most phenomena associated with infection. This includes both "good" effects of infection (e.g., the induction of lasting specific immunity to an infectious agent) and "bad" effects of infection (systemic inflammation and shock). Although they are essential for host defense, no other endogenous proteins can match their lethal potential. The TLR complexes transduce the toxicity of lipopolysaccharide (LPS), cysteinyl lipopeptides, and many other molecules of microbial origin. The identification of the TLRs as the key conduit to host awareness of microbial infection was a victory for reductionism, proving that the complexity of infectious inflammation as a phenomenon belies the simplicity of its origins. It was achieved by a classical genetic approach, proceeding from phenotype to gene. Further analysis of the signaling pathways activated by the TLRs has depended on both classical and reverse genetic methods. Additional work will ultimately disclose the extent to which sterile inflammatory diseases are mediated by aberrations in these pathways.

DOI： 10.1016/S0065-2776(06)91005-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER ACADEMIC PRESS INC  

The inflammatory response to microbes--and host perception of microbes in general--is largely initiated by a single class of receptors, named for their similarity to the prototypic Toll receptor of Drosophila. The mammalian Toll-like receptors (TLRs) are ultimately responsible for most phenomena associated with infection. This includes both "good" effects of infection (e.g., the induction of lasting specific immunity to an infectious agent) and "bad" effects of infection (systemic inflammation and shock). Although they are essential for host defense, no other endogenous proteins can match their lethal potential. The TLR complexes transduce the toxicity of lipopolysaccharide (LPS), cysteinyl lipopeptides, and many other molecules of microbial origin. The identification of the TLRs as the key conduit to host awareness of microbial infection was a victory for reductionism, proving that the complexity of infectious inflammation as a phenomenon belies the simplicity of its origins. It was achieved by a classical genetic approach, proceeding from phenotype to gene. Further analysis of the signaling pathways activated by the TLRs has depended on both classical and reverse genetic methods. Additional work will ultimately disclose the extent to which sterile inflammatory diseases are mediated by aberrations in these pathways.

DOI： 10.1016/S0065-2776(06)91005-0

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：WILEY-V C H VERLAG GMBH  

A viable hypomorphic allele of mouse retinoid X receptor alpha (Rxralpha) was created by random germline mutagenesis. The mutation (I273N) alters the ligand binding and heterodimerization domain, and causes a 90% decline in ligand-inducible transactivation. Homozygotes develop progressive alopecia and dermal cysts, and progressive exaggeration of Th1 and loss of Th2 responses to antigen. Th1 skewing is directly caused by aberrant function of both antigen-presenting cells and naïve CD4 T cells; the predominant Th1 response to antigen is attributable to decreased suppression of regulatory T cells in mutant mouse. Dietary depletion of vitamin A in Th2-prone wild-type mice mimics the immune phenotype caused by the mutation. Hence, RXRalpha plays an important post-developmental role in the regulation of adaptive immune responses, and provides a plausible link between nutritional environment and the type of adaptive response that results from immunization.

DOI： 10.1002/eji.200535366

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：SPRINGER  

The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as "Toll-like receptors" (TLRs), of which ten representatives are encoded in the human genome. The sensing role of the TLRs first came to light when one member of this family, TLR4, was shown to serve the detection of endotoxin (lipopolysaccharide; LPS) in mice. This discovery was based upon positional cloning of a spontaneous mutation affecting a locus known as Lps. The recognition specificities of other TLRs have since been established by reverse genetic methods. The understanding of the biochemical circuitry that maintains the innate capacity for immune recognition and response has loomed as the next hurdle in the field. A total of five adapter proteins with cytoplasmic domain homology to the TLRs are known to exist in mammals. These proteins are not entirely promiscuous in their interaction with TLRs, but rather, show preferential association with individual family members, giving a particular character to the signals that distinct micro-organisms initiate. The adaptive immune response is dependent upon upregulation of costimulatory molecules (UCM) such as CD80 and CD86. Very recently, it has been shown that this upregulation is dependent upon an adapter encoded by a locus known as Lps2, known as Trif or Ticam-1, and upon type I interferon receptor signaling. LPS and dsRNA both signal via Trif, but dsRNA has an accessory pathway for UCM, that is independent of both Trif/Ticam-1 and the known dsRNA receptor, TLR3. Other key innate immunity genes have also been disclosed by germline mutagenesis, and are discussed in the present review.

DOI： 10.1007/0-387-24180-9_4

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER SCIENCE BV  

The innate immune system senses pathogens largely through signals initiated by a collection of phylogenetically related proteins known as "Toll-like receptors" (TLRs), of which 10 representatives are encoded in the human genome. Our understanding of the sensing role played by the TLRs began with the positional cloning of a spontaneous mutation (Lps(d)) in the gene encoding the mammalian lipopolysaccharide (LPS) receptor. Other key innate immunity proteins have been disclosed by germline mutagenesis, and are discussed in the present review.

DOI： 10.1016/j.micinf.2004.08.017

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL MUNKSGAARD  

Individuals with periodontitis have been reported to have a significantly increased risk of developing coronary heart disease. Several studies have demonstrated that the immune response to heat shock protein 60 (HSP60) may be involved in the pathogenesis of both atherosclerosis and chronic periodontitis. To investigate this possible link between these diseases, cellular and humoral immune responses to HSP60 in atherosclerosis patients were compared with those in periodontitis patients and healthy subjects using human and Porphyromonas gingivalis HSP60 (GroEL) as antigens. Antibody levels to both human and P. gingivalis HSP60s were the highest in atherosclerosis patients, followed by periodontitis patients and healthy subjects. Clonal analysis of the T cells clearly demonstrated the presence of not only human HSP60- but also P. gingivalis GroEL-reactive T-cell populations in the peripheral circulation of atherosclerosis patients. Furthermore, these HSP60-reactive T cells seemed to be present in atherosclerotic lesions in some patients. These results suggest that T-cell clones with the same specificity may be involved in the pathogenesis of the different diseases.

DOI： 10.1111/j.0902-0055.2004.00134.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATL ACAD SCIENCES  

Several subsets of dendritic cells have been shown to produce type I IFN in response to viral infections, thereby assisting the natural killer cell-dependent response that eliminates the pathogen. Type I IFN production can be induced both by unmethylated CpG-oligodeoxynucleotide and by double-stranded RNA. Here, we describe a codominant CpG-ODN unresponsive phenotype that results from an N-ethyl-N-nitrosourea-induced missense mutation in the Tlr9 gene (Tlr9(CpG1)). Mice homozygous for the Tlr9(CpG1) allele are highly susceptible to mouse cytomegalovirus infection and show impaired infection-induced secretion of IFN-alpha/beta and natural killer cell activation. We also demonstrate that both the Toll-like receptor (TLR) 9 --> MyD88 and TLR3 --> Trif signaling pathways are activated in vivo on viral inoculation, and that each pathway contributes to innate defense against systemic viral infection. Whereas both pathways lead to type I IFN production, neither pathway offers full protection against mouse cytomegalovirus infection in the absence of the other. The Tlr9(CpG1) mutation alters a leucine-rich repeat motif and lies within a receptor domain that is conserved within the evolutionary cluster encompassing TLRs 7, 8, and 9. In other TLRs, including three mouse-specific TLRs described in this paper, the affected region is not represented. The phenotypic effect of the Tlr9(CpG1) allele thus points to a critical role for TLR9 in viral sensing and identifies a vulnerable amino acid within the ectodomain of three TLR proteins, essential for a ligand response.

DOI： 10.1073/pnas.0400525101

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：GENETICS SOC AM  

In the course of a large-scale program of ENU mutagenesis, we isolated a dominant mutation, called Velvet. The mutation was found to be uniformly lethal to homozygotes, which do not survive E13.5. Mice heterozygous for the Velvet mutation are born with eyelids open and demonstrate a wavy coat and curly vibrissae. The mutation was mapped to the proximal end of chromosome 11 by genome-wide linkage analysis. On 249 meioses, the locus was confined to a 2.7-Mb region, which included the epidermal growth factor receptor gene (Egfr). An A --> G transition in the Egfr coding region of Velvet mice was identified, causing the amino acid substitution D833G. This substitution alters an essential triad of amino acids (DFG --> GFG) that is normally required for coordination of the ATP substrate. As such, kinase activity is at least mostly abolished, but quaternary structure of the receptor is presumably maintained, accounting for the dominant effect. Velvet is the first known dominant representative of the Egfr allelic series that is fully viable, a fact that makes it particularly useful for developmental studies.

DOI： 10.1534/genetics.166.1.331

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：INT AMER ASSOC DENTAL RESEARCHI A D R/A A D R  

It has been reported that there is a relationship between a single-nucleotide polymorphism (SNP) in the promoter region of the CD14 gene at position -159 (C→T) and infectious diseases. The aim of the present study was to test the hypthesis that expression of this SNP correlates with periodontal disease in a Japanese population. The CD14 genotype was determined in 163 subjects with periodontitis and in 104 age- and gender-matched control subjects without periodontitis. The genotype distribution and allele frequency within the periodontitis patients were not significantly different from those of control subjects. There was, however, a significant difference in the genotype distribution between young patients (< 35 yrs) and older patients (≥ 35 yrs). These findings suggest that CD14 -159C/T polymorphism is not related to the development of periodontitis in a Japanese population, but that, within the periodontitis subjects, expression of the SNP may be related to early disease activity.

DOI： 10.1177/154405910308200808

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：NATURE PUBLISHING GROUP  

In humans, ten Toll-like receptor (TLR) paralogues sense molecular components of microbes, initiating the production of cytokine mediators that create the inflammatory response. Using N-ethyl-N-nitrosourea, we induced a germline mutation called Lps2, which abolishes cytokine responses to double-stranded RNA and severely impairs responses to the endotoxin lipopolysaccharide (LPS), indicating that TLR3 and TLR4 might share a specific, proximal transducer. Here we identify the Lps2 mutation: a distal frameshift error in a Toll/interleukin-1 receptor/resistance (TIR) adaptor protein known as Trif or Ticam-1. TrifLps2 homozygotes are markedly resistant to the toxic effects of LPS, and are hypersusceptible to mouse cytomegalovirus, failing to produce type I interferons when infected. Compound homozygosity for mutations at Trif and MyD88 (a cytoplasmic TIR-domain-containing adaptor protein) loci ablates all responses to LPS, indicating that only two signalling pathways emanate from the LPS receptor. However, a Trif-independent cell population is detectable when TrifLps2 mutant macrophages are stimulated with LPS. This reveals that an alternative MyD88-dependent 'adaptor X' pathway is present in some, but not all, macrophages, and implies afferent immune specialization.

DOI： 10.1038/nature01889

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS AS  

A phenotype-driven approach led to the first understanding of precisely what the Toll-like receptors (TLR) did, when it was determined that the mammalian endotoxin (lipopolysaccharide; LPS) receptor is encoded by TLR4. The TLRs are the primary sensors of the innate immune system, and without them, small inocula of microorganisms pose a major threat to the host, growing unchecked for a long period before they are recognized. Mutations that affect innate immune sensing may account for a substantial fraction of sepsis, and a highly significant excess of mutations in TLR4 has been identified in patients with systemic meningococcal disease. As such, it is important to understand the pathways that are responsible for innate immune sensing, including the signaling intermediates utilized by the TLRs. Random germline mutagenesis identified a locus, Lps2, which is required for normal responses to double-stranded RNA and LPS. Hence, a single transducer was found to serve both the TLR3 and TLR4 response pathways. The Lps2 mutation was found to ablate entirely the MyD88-independent pathway for LPS sensing, indicating that two and only two branches of the LPS sensing pathway exist in macrophages, and homozygotes for the mutation were resistant to LPS, but markedly susceptible to infection with mouse cytomegalovirus. Remarkably, Lps2 mutant mice entirely failed to produce type I interferons in response to a viral infection. It would appear that Lps2 is the most proximal component of a signal integration system required for innate immune responses to both viral and bacterial diseases. Positional cloning revealed that the TIR adapter protein Trif/Ticam-1 is structurally altered by the Lps2 mutation. This adapter is responsible for shared effects of responses to viral and bacterial pathogens.

DOI： 10.1080/00365540310016295

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Language：Japanese   Publisher：日本バイオフィルム学会  

動脈硬化症患者7名より動脈硬化組織,末梢血を採取し,歯周疾患と動脈硬化症の両疾患に関与すると報告されている60kDa heat shock protein(hsp60)とPorphyromonas gingivalis(Pg)のヒトhspホモローグであるGroELに対する動脈硬化患者における免疫応答について検索した.検討した7名中1名を除いて,PgまたはA.actinomycetemcomitans GroELとhsp60において反応する抗体産生が認められた.さらに分析結果より,歯周炎と動脈硬化症の疫学的因果関係を裏付ける可能性も考えられた

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Heat shock protein 60s (hsp60) are remarkably immunogenic, and both T-cell and antibody responses to hsp60 have been reported in various inflammatory conditions. To clarify the role of hsp60 in T-cell responses in periodontitis, we examined the proliferative response of peripheral blood mononuclear cells (PBMC), as well as the cytokine profile and T-cell clonality, for periodontitis patients and controls following stimulation with recombinant human hsp60 and Porphyromonas gingivalis GroEL. To confirm the infiltration of hsp60-reactive T-cell clones into periodontitis lesions, nucleotide sequences within complementarity-determining region 3 of the T-cell receptor (TCR) beta-chain were compared between hsp60-reactive peripheral blood T cells and periodontitis lesion-infiltrating T cells. Periodontitis patients demonstrated significantly higher proliferative responses of PBMC to human hsp60, but not to P. gingivalis GroEL, than control subjects. The response was inhibited by anti-major histocompatibility complex class II antibodies. Analysis of the nucleotide sequences of the TCR demonstrated that human hsp60-reactive T-cell clones and periodontitis lesion-infiltrating T cells have the same receptors, suggesting that hsp60-reactive T cells accumulate in periodontitis lesions. Analysis of the cytokine profile demonstrated that hsp60-reactive PBMC produced significant levels of gamma interferon (IFN-gamma) in periodontitis patients, whereas P. gingivalis GroEL did not induce any skewing toward a type1 or type2 cytokine profile. In control subjects no significant expression of IFN-gamma or interleukin 4 was induced. These results suggest that periodontitis patients have human hsp60-reactive T cells with a type 1 cytokine profile in their peripheral blood T-cell pools.

DOI： 10.1128/IAI.70.5.2492-2501.2002

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL PUBLISHING LTD  

Heat shock protein 60 (hsp60) has been increasingly recognized as an important molecule in infectious and autoimmune diseases. We have demonstrated previously that serum antibodies to both human hsp60 and Porphyromonas gingivalis GroEL were elevated in periodontitis patients compared with healthy subjects. In order to clarify the relative importance of hsp60 in the inflammatory response in periodontal disease, the stimulatory effect of human and bacterial hsp60 on the production of tumour necrosis factor-α (TNF-α) was examined in phorbol myristate acetate (PMA)-stimulated THP-1 cells. As bacterial hsp60s, recombinant P. gingivalis and Actinobacillus actinomycetemcomitans GroEL was used. Human hsp60 but not P. gingivalis or A. actinomycetemcomitans GroEL demonstrated stimulatory activity similar to lipopolysaccharide (LPS) derived from the bacteria. The activity of hsp60 was inhibited by anti-CD14 and anti-Toll-like receptor 4 (TLR4) antibodies, suggesting that both CD14 and TLR4 mediate hsp60 signalling. Immunohistochemical analysis demonstrated that hsp60 is abundantly expressed in periodontitis lesions. Therefore, it is postulated that periodontopathic bacteria stimulate the cells in the periodontium to up-regulate the expression of hsp60, which in turn may stimulate macrophage and possibly other cells to produce proinflammatory cytokines. These mechanisms may be involved in the chronicity and tissue destruction of periodontal disease.

DOI： 10.1046/j.1365-2249.2002.01723.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

Background: IL-10 is an anti-inflammatory cytokine, which may modulate disease expression in chronic inflammatory periodontal disease. 3 dimorphic polymorphisms within the IL-10 gene promoter have recently been identified and appear to influence regulation of its expression. Aim: The aim of the present study was to investigate whether the promoter polymorphisms are associated with adult periodontitis (AP) and generalized early-onset periodontitis (G-EOP). Methods: Genomic DNA was obtained from 34 AP patients, 18 G-EOP patients and 52 controls. The promoter region between -506 and -1140 was amplified by polymerase chain reaction, and polymorphisms were detected by nucleotide sequencing. Results: The haplotype frequencies in Japanese were quite different from those of Caucasian and were even slightly different from those of southern Chinese with systemic lupus erythematosus. We found no significant difference in allele or haplotype frequencies between patients and controls. Conclusions: IL-10 production may be regulated within the complex cytokine network in chronic inflammatory periodontal disease, rather than the gene polymorphisms. © Munksgaard, 2001.

DOI： 10.1034/j.1600-051x.2001.028009828.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：MUNKSGAARD INT PUBL LTD  

Recent evidence suggests that molecular mimicry between bacterial and human heat shock protein 60 (hsp60) is involved in various conditions of autoimmune and infectious diseases. Many periodontopathic bacteria have been reported to express GroEL-like protein that is homologous to human hsp60. In this study, the presence of antibodies to the hsp60 of Actinobacillus actinomycetemcomitans in the sera of periodontitis patients and periodontally healthy control subjects was evaluated by enzyme-linked immunosorbent assay using a recombinant A. actinomycetemcomitans GroEL as an antigen. Furthermore, their cross-reactivity with Escherichia coli GroEL and Mycobacterium bovis BCG hsp65 was examined. The mean values of antibody were 0.624 (range 0.088-1.113) and 0.728 (range 0.217-1.296) in control subjects and periodontitis patients, respectively. The antibody levels to A. actinomycetemcomitans after absorption with E. coli GroEL and M. bovis BCG clearly decreased in both control subjects and periodontitis patients. The remaining antibody levels to A. actinomycetemcomitans GroEL after absorption with M. bovis BCG hsp65 were higher than those with E. coli GroEL, indicating higher cross-reactivity with E. coli GroEL. These results suggest that not only periodontitis patients but also periodontally healthy subjects may be infected with A. actinomycetemcomitans but that the part of the antibody could be derived from the cross-reactivity with E. coli GroEL. Any relationship of the antibody to the disease, however, remains to be determined.

DOI： 10.1034/j.1399-302X.2001.016005290.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER ACAD PERIODONTOLOGY  

Background: Early-onset periodontitis (EOP) is considered to have a genetic basis, which has not been clearly defined. The tumor necrosis factor-alpha (TNF-α) gene polymorphism as one of the genetic factors may influence the expression of several chronic inflammatory diseases. The aim of the present study was to evaluate whether the polymorphisms in the 5′-flanking region of the TNF-α gene are associated with Japanese EOP patients. Methods: Forty-six Japanese, generalized EOP (G-EOP) patients and 104 Japanese healthy subjects were identified according to established clinical criteria. Twenty healthy subjects were analyzed by nucleotide sequence to screen polymorphisms of the 5′-flanking region of the TNF-α gene. Then, all subjects were analyzed by polymerase chain reaction and sequence-specific oligonucleotide probe (SSOP) methods. Results: We determined 5 single nucleotide polymorphisms at positions -1031 (T/C), -863 (C/A), -857 (C/T), -308 (G/A), and -238 (G/A) in the 5′-flanking region of the TNF-α gene. There were no significant differences in the genotype and allele frequency when we compared G-EOP patients to healthy subjects. Because the frequency of polymorphic alleles at positions -308 and -238 was very low in this study population, we demonstrated the existence of 4 detected haplotypes and 6 detected genotypes concerning 3 single nucleotide polymorphisms (-1031, -863, and -857). The frequency of the H1/H3 (TCC/TCT)-detected genotype tended to decrease in G-EOP patients compared to healthy subjects, but was not statistically significant. Conclusion: These findings suggest there is no significant association between polymorphisms in the 5′-flanking region of the TNF-α gene and susceptibility to G-EOP in Japanese patients.

DOI： 10.1902/jop.2001.72.11.1554

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC MICROBIOLOGY  

Gingival fibroblasts produce proinflammatory cytokines in response to lipopolysaccharide (LPS) from periodontopathic bacteria. Recently it has become evident that the human homologue of Drosophila Toll can transduce intracellular signaling by LPS stimulation. Toll-like receptors (TLRs) have been identified in myeloid cells; however, their role in nonmyeloid cells such as gingival fibroblasts has not been fully elucidated. Here, we report that human gingival fibroblasts constitutively express TLR2 and TLR4 and that their levels of expression are increased by stimulation with LPS from Porphyromonas gingivalis. Upregulated expression of interleukin-6 gene and protein in fibroblasts stimulated with LPS is inhibited by anti-TLR4 antibody. These findings suggest that TLRs may confer responsiveness to LPS in gingival fibroblasts.

DOI： 10.1128/IAI.68.6.3731-3735.2000

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The presence of antibodies to the 60-kD human and Porphyromonas gingivalis GroEL hsp60 in the sera and inflamed gingival tissues of periodontitiS patients was examined. In order to obtain the antigens, recombinant plasmids carrying human hsp60 and P. gingivalis GroEL genes were constructed and expressed as histidine-tagged recombinant proteins. Immunoreactivities of these proteins were confirmed by MoAbs specific to mammalian hsp60 and cross-reactive with both mammalian and bacterial hsp60. Western blot analysis clearly demonstrated that the number of periodontitis patients showing a positive response to P. gingivalis GroEL was higher than the number of periodontally healthy subjects. Furthermore, anti-P. gingivalis GroEL antibody was detected in all samples of gingival tissue extracts. For human hsp60, a higher frequency of seropositivity was found in the periodontitis patients than in the healthy subjects. In addition, the periodontitis patients demonstrated stronger reactivity compared with the healthy subjects. Quantitative analysis of serum antibodies by ELISA also demonstrated that the levels of antibodies in the sera of patients were significantly higher than those of control subjects. In the gingival tissue extracts, seven out of 10 patients demonstrated a positive response to human hsp60 and tso of these demonstrated strong positivity. Affinity-purified serum antibodies to human hsp60 and P. gingivalis GroEL from selected patients reacted with P. gingivalis GroEL and human hsp60, respectively, suggesting cross-reactivity of antibodies. These results suggest that molecular mimicry between GroEL of the periodontopathic bacterium P. gingivalis and autologous human hsp60 may play some role in immune mechanisms in periodontitis.

DOI： 10.1046/j.1365-2249.2000.01216.x

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：BLACKWELL SCIENCE LTD  

Chronic inflammatory periodontal diseases are characterized by a cellular infiltrate and are similar in many respects to other chronic inflammatory diseases. While periodontopathic bacteria have been recognized as the principal causative agent and the immune response to these bacteria is thought to be responsible for the tissue destruction, the full aetiological spectrum is still incompletely understood. In addition to many cell types such as polymorphonuclear leucocytes and macrophages, T cells have been implicated in pathogenesis and are considered to have regulatory roles in progression of the disease. Based on our recent studies demonstrating biased expression of several Vβ families in periodontitis tissues, the aim of this study was to characterize further the T cells relevant to the disease process by reverse transcription-polymerase chain reaction-single-strand conformation polymorphism (RT-PCRSSCP) and subsequent nucleotide sequence analysis of complementarity-determining region 3 (CDR3) of the TCR β-chain. In spite of the likely involvement of numerous bacteria, the present study has clearly shown the oligoclonality of infiltrating T cells in periodontitis lesions in contrast to low clonality of peripheral blood T cells as evidenced by the appearance of distinct bands in gingival tissue samples and smear pattern of peripheral blood on SSCP gels. These were confirmed by the DNA sequencing of the CDR3 of Vβ16 of selected samples. The analysis of deduced amino acid sequences demonstrated amino acid motifs in the CDR3 region of the periodontitis lesion-derived sequences from each patient. The results indicate that gingival tissue-infiltrating T cells recognizing a limited number of antigens or epitopes are involved in the disease process.

DOI： 10.1046/j.1365-2249.2000.01179.x

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Language：Japanese   Publisher：(NPO)日本歯科保存学会  

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Language：Japanese   Publisher：(NPO)日本顎咬合学会  

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Language：Japanese   Publisher：神奈川歯科大学学会  

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Language：Japanese   Publisher：新潟歯学会  

2017年、アメリカ歯周病学会とヨーロッパ歯周病学連盟の合同ワークショップにおいて、歯周病の新しい分類体系が発表された。新分類では、病変の重症度と複雑度をステージ、歯周炎の進行リスクをグレードを用いて評価することが提示された。歯周病のバイオマーカーとして、hCRP(高感度C反応性蛋白質)、PCSK9(プロ蛋白質転換酵素サブチリシン/ケキシン9型)の応用が期待されている。

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Language：Japanese   Publisher：(NPO)日本歯周病学会  

世界中で猛威を振い続ける新型コロナウイルスの感染経路のひとつにエアロゾル感染がある。歯周治療で頻用される超音波スケーラーから発生するエアロゾルが交差感染のリスクとして懸念されているが,そのエアロゾル特性については十分に知られていない。本研究の目的は,微粒子可視化システムを用いた流体工学的検討と,感水試験紙およびパーティクルカウンターを用いた模擬臨床試験から,超音波スケーラーから発生するエアロゾル特性およびエアロゾル感染予防策を検討することである。流体工学的検討から,超音波スケーラーから発生するエアロゾルの平均粒子径は約40μmで,液滴速度が3m/sであった。また感水試験紙を用いた模擬臨床試験から,超音波スケーラーの向きによるエアロゾルの飛散距離の違いが観察された。パーティクルカウンターを用いた解析において,1-10μmの粒径のエアロゾル飛散量は距離とともに減少し,口腔内外バキュームの使用によりエアロゾル量が大幅に減少することが確認された。これらのことから,超音波スケーラーから様々な粒子径のエアロゾルが発生するが,吸引装置の適切な使用によって超音波スケーラーから発生するエアロゾルを介した交差感染リスクを抑制できる可能性が示唆された。(著者抄録)

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2021&ichushi_jid=J01095&link_issn=&doc_id=20220124250001&doc_link_id=%2Fcp9perlo%2F2021%2F006304%2F001%2F0171-0182%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcp9perlo%2F2021%2F006304%2F001%2F0171-0182%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：新潟歯学会  

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Language：Japanese   Publisher：(一社)日本口腔検査学会  

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Language：Japanese   Publisher：(一社)日本糖尿病学会  

JDCP studyベースライン時の糖尿病患者6,099名(1型6%,2型94%,61.1±8.1歳)の病態と口腔所見の関係を検討した.現在歯数は平均19.8本,2型糖尿病で男性より女性の方が少なかった.1年間の歯の喪失者,歯肉腫脹既往者,口腔清掃回数2回以上,歯間清掃用具使用者,歯科定期健診者の割合は,それぞれ17%,32%,69%,37%,43%であった.関連9因子を説明変数,現在歯数(20歯未満,20歯以上)を従属変数とした多重ロジスティック回帰分析では,1型糖尿病でHbA1c 7.0%以上になると20歯未満となるオッズ比(OR)は2.38(95%CI 1.25-4.78),2型糖尿病でHbA1c 8.0%以上になると20歯未満となるORは1.16(95%CI 1.00-1.34)となった.糖尿病患者では,現在歯数が少なく血糖コントロール状態の悪化に伴い歯の喪失リスクが高くなった.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J00926&link_issn=&doc_id=20200518400005&doc_link_id=10.11213%2Ftonyobyo.63.195&url=https%3A%2F%2Fdoi.org%2F10.11213%2Ftonyobyo.63.195&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_2.gif

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Language：English   Publishing type：Book review, literature introduction, etc.   Publisher：Elsevier Ltd  

The relationship between poor oral health and systemic diseases has been increasingly recognized over the past two decades. Atherosclerosis is an important basal component of atherosclerotic cardiovascular disease (ACVD), which is the primary cause of death worldwide, including Japan. The accumulation of multiple individual epidemiological studies has paved the way for subsequent systematic reviews that have demonstrated that periodontitis can be considered as an emerging risk factor for ACVD. Although the causal mechanisms by which periodontitis accelerates ACVD have not been fully elucidated, plausible evidence regarding the inflammatory response due to inflammatory mediators and bacterial etiologies, and the recognition of altered lipid metabolism in patients with periodontitis suggest that infection with periodontopathic bacteria can influence atherogenesis in vitro and in vivo. Animal model studies have strengthened this evidence. However, there have been a lack of interventional studies that show the effects of periodontal treatment on the future risk of ACVD; this lack of evidence critically weakens the importance of the relationship between the two diseases. This review presents a summary of the current evidence and biological plausibility that link periodontitis to ACVD. © 2014 Japanese Association for Dental Science.

DOI： 10.1016/j.jdsr.2014.03.001

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