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Effect of experimentally induced marginal periodontitis and periodontal scaling on the dental pulp.

Experimental breakdown of the periodontal attachment apparatus was produced in six young adult monkeys to study the effect on the tissue of the dental pulp by (1) periodontitis, (2) scaling and plaque accumulation on exposed root dentin. Periodontal tissue breakdown was induced by the placement of ligatures around the neck of 92 permanent teeth. Subsequent plaque formation caused marked loss of periodontal tissue support, which after a period of 5--7 months amounted to 30--40% of the root length. One group of teeth received no further treatment. Other teeth were subjected to scaling and root planing. Following treatment, plaque was allowed to accumulate for 2, 10, and 30 days on the freshly planed root dentin surfaces. Histologic examination revealed that in comparison to teeth with normal periodontal conditions, 57% of the teeth exposed to periodontitis exhibited pathologic pulp tissue alterations. Secondary dentin formation and/or inflammatory cell infiltrates were observed within localized areas of the pulp subjacent to root surfaces exposed to periodontal tissue destruction. The changes within the pulp were of "mild" nature and only one tooth displayed signs of total pulp necrosis. Lateral canals communicating with both the pulp cavity and the exposed root surface were never detected. Teeth subjected to scaling and subsequent plaque accumulation in comparison with teeth with periodontitis alone exhibited no obvious aggravation or increased incidence of pathologic pulp reactions. The findings show that in the monkey (1) periodontal destruction limited to the cervical half of the root and (2) plaque accumulation on exposed root dentin does not cause severe alteration in the pulp of the roots involved.

Animals

The absence of proprioceptive nerve endings in the human periodontal ligament: the role of periodontal mechanoreceptors in the reflex control of mastication.

A review of the literature was conducted to determine the presence or absence of proprioceptive nerve endings in the human periodontal ligament. A histologic review of the periodontal ligament innervation concluded that nerve endings found were those mediating pain, pressure, or touch and that there is no histologic evidence of any "classic" proprioceptive nerve ending in the periodontal ligament. A summary is given concerning the precise role of nerve endings in the periodontal membrane, their afferent pathways, and the role of masticatory muscle proprioception, jaw reflexes, and the temporomandibular joint in the coordinated control of mastication and mandibular proprioception.

Afferent Pathways

Machine learning-based analysis of oral rinse samples to identify candidate proteomic signatures for severe periodontitis: a pilot study.

This pilot study investigated whether candidate protein signatures from oral rinse samples can distinguish patients with severe periodontitis (stage III/IV) and its subtypes, generalized and localized periodontitis, from non-periodontitis controls. Participants rinsed with phosphate-buffered saline, and samples were analyzed using a Proximity Extension Assay targeting 92 inflammatory and 92 immuno-oncology proteins. A machine learning approach using repeated nested cross-validation and SHAP was implemented to identify protein signatures. The study included 38 patients (18 with localized periodontitis and 20 with generalized periodontitis) and 16 controls. After data preprocessing, 54 samples and 141 proteins were retained. Proteins Gal-1, HGF, TNFSF14, CD27, and ARG1 distinguished periodontitis from controls (ROC-AUC = 0.85, 95% CI 0.82, 0.87). For generalized periodontitis, we found a protein signature including TNFSF14, Gal-1, STAMBP, MUC-16, S100A12, HGF, CASP-8, CD27, LAP TGF-β1, TNFRSF9, and uPA (ROC-AUC = 0.92, 95% CI 0.90, 0.94). For localized periodontitis, we identified ARG1 (ROC-AUC = 0.72, 95% CI 0.68, 0.76). No proteomic signature distinguishing generalized periodontitis from localized periodontitis was identified. This pilot study indicated that oral rinses are suitable for proteomic profiling, and there was a putative protein signature that could differentiate periodontitis, generalized periodontitis, and localized periodontitis from controls. These findings warrant validation in larger independent cohorts, including a clearly defined gingivitis group, before real-world non-invasive screening applications can be considered.

Humans

Gingival crevicular fluid: a new diagnostic aid in managing the periodontal patient.

On the whole, the studies on GCF have demonstrated that the flow of this fluid is sufficiently indicative of the inflammatory state that it can be used under a variety of clinical conditions to monitor and control gingival inflammation. Since gingivitis is extremely common, and since some cases of gingivitis presumably do not progress to periodontitis, the question could be posed whether or not a concerted effort to control inflammation (i.e. trying to achieve a GCF flow as near to zero as possible) would be clinically significant. Until there is evidence to the contrary, the answer must be "yes", since few cases are known where periodontitis occurs without being preceded by gingivitis. In other words, the control of all gingivitis, if feasible, should prevent most cases of periodontitis. Although control of all gingivitis would mean the treatment of many cases that would not progress to periodontal breakdown, such efforts would be worth-while if most periodontal destruction were prevented. Even the early destructive lesion exhibiting little or no inflammation may soon be identified, mainly because the minute volume of fluid collected from the gingival crevice can now be measured accurately. Accordingly, the concentration of various constituents in the GCF can be determined, which should lead to the development of tests to differentiate between pockets undergoing active destruction with minimal inflammation from the majority of active lesions that are intimately involved with frank inflammation. Thus, a clinician would measure sub-clinical gingival inflammation by measuring GCF flow, then differentiate destructive from quiescent lesions by analyzing the GCF sample for some constituent(s), chemical or microbial (Listgarten et al. 1975) indicative of the periodontal destructive process. Monitoring the flow of GCF might be of value in other clinical situations. For example, one could monitor the response of gingival tissues to various restorative and prosthetic procedures (Strauss et al. 1975) to ensure that these procedures do not aggravate the periodontal tissues and induce gingivitis or periodontitis. The education of the patient should be easier since patients can read their own numbers on the GCF meter at each examination and self-evaluate their personal periodontal condition and the effectiveness of their home care. Even the education of the dental student should be easier since he or she would have the means of self-evaluating the effectiveness of treatment, and not be as dependent upon the subjective assessment of his efforts by an instructor. Finally, monitoring GCF for various components could provide the dentist with a valuable means of easily screening patients for systemic disease. Obviously, this area of investigation is in its infancy, but does promise an exciting future for the oral diagnostician.

Ammonia

GWAS for Periodontitis Phenotypes Using Multi-Ancestry All of Us Research Platform.

Periodontitis is a multifactorial inflammatory disease whose pathogenesis is associated with intricate interactions between genetic and environmental factors. Leveraging electronic health records data from the All of Us Research Program, we stratified periodontitis by clinically relevant dimensions: stage, grade, and extent. Based on these phenotypes, we performed a multi-ancestry genome-wide association study, focusing on predominant ancestry populations of African, European, and Admixed American. Our study cohort comprised 3,881 periodontitis patients and a control group of 10,760 patients with dental caries and without periodontitis. Ancestry-specific GWAS revealed significant genetic associations (P<5&#xd7;10-8) in periodontitis grade phenotypes at the LINC00294 and CLMN loci in the African ancestry population and also confirmed via the multi-ancestry meta-analysis. In addition, the XYLT1 locus emerged as a significant signal associated with periodontitis grade phenotype in the admixed American GWAS. Our GWAS comparing periodontitis to dental caries in the admixed American population identified several significant loci, including RABGAP1L, previously linked to immune regulation, DCHS2, a cadherin-related gene involved in bone mineralization and tissue morphogenesis, and OSTM1, known to be crucial for bone remodeling. The findings of our study highlight the potential of integrating EHR and genomic data from large-scale biobanks to achieve informative dental phenotyping, uncover novel molecular insights into periodontal disease, and personalize treatment approaches.

Journal Article

Cross-kingdom dynamics of the subgingival bacteriome and mycobiome: A pilot study on the effects of a novel HA-H&#x2082;O&#x2082;-Glycine formulation to treat periodontitis.

OBJECTIVES: Traditional periodontal therapy primarily focuses on bacterial biofilm control; however, recent evidence also suggests a critical role for the oral mycobiome. This study evaluated the clinical and ecological impact of a novel mouthwash formulation containing hyaluronic acid (HA), hydrogen peroxide (H2O2), and glycine on periodontal patients METHODS: This prospective, randomized split-mouth trial included 13 adult participants with periodontitis treated with HA-H2O2-glycine formula (BMG0703A) used twice a day for seven days. Subgingival plaque samples were collected from periodontal pocket and healthy control sites at baseline (T0) and one-week post-treatment (T1). Microbial and fungal communities were characterized using Next-Generation Sequencing (NGS) of the 16S rRNA and ITS2 regions. Linear Mixed Models (LMM) and Spearman correlation were used to assess taxonomic shifts and cross-kingdom relationships. RESULTS: Sequencing revealed a promising ecological shift: the bacteriome shifted from anaerobic dominance (Olsenella, Peptostreptococcus) toward a health-associated aerobic profile, with Rothia near-doubling (11.91% to 22.68%). The mycobiome underwent a "normalization" effect: Candida abundance decreased significantly (22.8% to 9.1%), while fungal Shannon diversity in pockets returned to healthy-site levels. Inter-kingdom analysis identified antagonistic relationships between expanding commensal bacteria and opportunistic fungi, suggesting that the intervention may help re-establish a protective bacterial niche. CONCLUSIONS: The HA-H2O2-glycine formulation seems to facilitate a rapid, cross-kingdom modulation of the subgingival niche. By reducing anaerobic pathogens and normalizing the mycobiome it appear to induce short-term changes, suggesting potential as adjunctive strategy in periodontal management. CLINICAL SIGNIFICANCE: The present work underlines the possible cross-Kingdom effects of a novel compound.

Humans

The immunopathogenesis of progressive chronic inflammatory periodontal disease.

Natural, humoral and cellular immune mechanisms have all been implicated in the pathogenesis of chronic inflammatory periodontal disease. However, confusion still exists as to the role played by each of these immunological mechanisms. Recently, characterization of the cell types within the progressive lesion has been established, in which four recognizable zones were described. Immediately subjacent to the epithelium lining the periodontal pocket both polymorphonuclear leukocytes (PMN's) and macrophages were seen, while cells deeper in the tissues had the morphological appearance of lymphocytes. The majority of these lymphocytes had a B-cell phenotype although a few T-cells and macrophages were found. On the advancing front of the lesion the cells had the morphological appearance of plasma cells, the majority of which contained IgG. Other cells found in this region had the morphology of plasma cells yet contained no cytoplasmic immunoglobulin, but they did contain substantial amounts of lysosomal enzymes. Similar cells have previously been described in periodontal disease; their frequent association with fibroblasts may suggest that they are important in the pathogenesis. Deposits of IgG and fibrin were found in the fibrous tissue band surrounding the lesion. These results are reviewed and, although the zones described were not anatomically distinct, by describing the lesion in this way it was possible to establish a convenient model to explain the immunopathogenesis of progressive chronic inflammatory periodontal disease. In this respect, progressive chronic inflammatory periodontal disease in man should be considered as a B-cell lesion.

Animals

Blastogenic response of human lymphocytes to oral bacterial antigens: comparison of individuals with periodontal disease to normal and edentulous subjects.

Cell-mediated immunity in humans to antigens derived from oral plaque bacteria was investigated by using the lymphocyte blastogenesis assay. Subjects with varying severities of periodontal disease including normal, gingivitis, periodontitis, and edentulous were compared. Mononuclear leukocytes were separated from peripheral blood and cultured with antigens prepared by sonication of Actinomyces viscosus (AV), Actinomyces naeslundii (AN), Veillonella alcalescens (VA), Leptotrichia buccalis (LB), Bacteroides melaninogenicus (BM), and homologous dental plaque (DP). The lymphocyte response of subjects with gingivitis or periodontitis was significantly greater than that of normal subjects to antigens of AV, AN, and DP, but did not differ from the response of edentulous subjects. Periodontitis subjects were significantly more reactive than edentulous and normal subjects in response to VA, LB, and BM. These findings suggest that the tested gram-negative bacteria and the host response they evoke are associated with advanced periodontal destruction.

Actinomyces

Deciphering the molecular nexus of BTG2 in periodontitis and diabetic kidney disease.

OBJECTIVE: To investigate the role of BTG2 in periodontitis and diabetic kidney disease (DKD) and its potential underlying mechanism. METHODS: Gene expression data for periodontitis and DKD were acquired from the Gene Expression Omnibus (GEO) database. Differential expression analysis identified co-expressed genes between these conditions. The Nephroseq V5 online nephropathy database validated the role of these genes in DKD. Pearson correlation analysis identified genes associated with our target gene. We employed Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) networks to elucidate potential mechanisms. Expression levels of BTG2 mRNA were examined using quantitative polymerase Chain Reaction (qPCR) and immunofluorescence assays. Western blotting quantified proteins involved in epithelial-to-mesenchymal transition (EMT), apoptosis, mTORC1 signaling, and autophagy. Additionally, wound healing and flow cytometric apoptosis assays evaluated podocyte migration and apoptosis, respectively. RESULTS: Analysis of GEO database data revealed BTG2 as a commonly differentially expressed gene in both DKD and periodontitis. BTG2 expression was reduced in DKD compared to normal conditions and correlated with proteinuria. GSEA indicated enrichment of BTG2 in the EMT and mTORC1 signaling pathways. The PPI network highlighted BTG2's relevance to S100A9, S100A12, and FPR1. Immunofluorescence assays demonstrated significantly lower BTG2 expression in podocytes under high glucose (HG) conditions. Reduced BTG2 expression in HG-treated podocytes led to increased levels of EMT markers (&#x3b1;-SMA, vimentin) and the apoptotic protein Bim, alongside a decrease in nephrin. Lower BTG2 levels were associated with increased podocyte mobility and apoptosis, as well as elevated RPS6KB1 and mTOR levels, but reduced autophagy marker LC3. CONCLUSION: Our findings suggest that BTG2 is a crucial intermediary gene linking DKD and periodontitis. Modulating autophagy via inhibition of the mTORC1 signaling pathway, and consequently suppressing EMT, may be pivotal in the interplay between periodontitis and DKD.

Periodontitis

Interleukin-23 Receptor and Interleukin-17 Receptor A: Splice Variants, Isoforms and Their Relationship With Periodontitis-A Systematic Review and Bioinformatic Analysis.

This systematic review aimed to: (1) identify the splicing variants of IL23R and IL17RA reported in the literature; (2) perform a multiple alignment analysis to describe the isoforms of IL-23R and IL-17RA; and (3) compare the expression levels of IL-23R, IL-17RA, and their soluble isoforms (sIL-23R and sIL-17RA) in patients with periodontitis and periodontally healthy individuals. The study protocol followed PRISMA guidelines and was registered in PROSPERO (CRD420251267367). Six databases (PubMed, ScienceDirect, Scopus, Web of Science, EBSCO, and Google Scholar) were searched without restrictions on year or language. The descriptors used were: 'Interleukin-23 Receptor,' 'IL-23R,' 'Interleukin-17 Receptor A' 'IL-17RA,' 'Alternative Splicing,' 'Splice Variants,' 'Isoforms,' and 'Periodontitis.' The bioinformatics analysis was performed using CLUSTALW (V.1.83), InterPro and DeepTMHMM. Risk of bias was assessed with the QUIN and JBI tools for cross-sectional studies. Of 104 articles, four in&#xa0;vitro studies and eight cross-sectional studies were included. Qualitative analysis revealed that to date there are 32 splicing variants of the IL23R gene, while only one splicing variant has been reported for IL17RA. CLUSTALW, InterPro and DeepTMHMM analysis showed that these splicing variants result in 23 isoforms which can be soluble forms, complete intracellular peptides, truncated extracellular or intracellular peptides, or complete structures with truncated extracellular and/or intracellular domains. All studies had a low risk of bias. IL-23R and IL-17RA exhibit structural diversity resulting from alternative splicing, with IL-23R demonstrating significantly greater isoform complexity. However, the biological significance of these isoforms in periodontitis remains unclear and requires further investigation.

Humans

Molecular and Genomic Mechanisms Linking Diabetes Mellitus and Periodontitis: From Pathogenesis to Translational Opportunities.

Diabetes mellitus and periodontitis are bidirectionally associated chronic disorders linked through metabolic dysregulation, host inflammation, microbial dysbiosis, and impaired tissue remodeling. This review summarizes clinical, molecular, cellular, genomic, epigenomic, transcriptomic, and microbial evidence concerning the mechanisms underlying this relationship and their potential translational relevance. Chronic hyperglycemia is associated with advanced glycation end product signaling through the receptor for advanced glycation end products, mitogen-activated protein kinase/nuclear factor-&#x3ba;B activation, reactive oxygen species production, oxidative stress, and NLR family pyrin domain-containing 3 inflammasome activation, which may contribute to enhanced cytokine responses and periodontal tissue injury. Diabetes is also associated with altered neutrophil and macrophage function, increased T helper 17/interleukin-17 signaling, and an elevated receptor activator of nuclear factor-&#x3ba;B ligand/osteoprotegerin ratio, thereby favoring osteoclastogenesis and alveolar bone loss. Conversely, periodontal inflammation and microbial products may contribute to systemic low-grade inflammation, insulin resistance, and metabolic dysregulation. Multi-omics studies have identified shared susceptibility loci, regulatory networks, and disease-associated cell states, although their causal and clinical significance remains incompletely defined. These findings suggest potential roles for integrated medical-dental care, glycemic screening in dental settings, periodontal inflammation control, host-modulatory therapies, and regenerative biomaterials. Further longitudinal and experimental studies are needed to determine their clinical applicability.

Humans

Light and ultrastructural relationship between oxytalan fibers in the periodontal ligament of the guinea pig.

The interfaces and the relationships between collagen and oxytalan fibers were observed under light and electron microscopy. Guinea pig periodontal ligament was prepared for light and electron microscopy with perfusion using Peter's buffered formalin for light microscopy and GTA-S-collidine and OSO4 for electron microscopic studies. The tissue for light microscopy was stained with a modified Gomori's aldehyde fuchsin technique, in which pre-oxidization with potassium monopersulfate was carried out before staining so as to demonstrate the oxytalan fibers. EM tissues were routinely stained with lead citrate and uranyl acetate. Two different structural relationships were observed. First, the subcomponents of the collagen and oxytalan fiber types interweave with each other; and, second, some of these two-fiber subcomponents appear attached to each other. These relationships and the known orientation of oxytalan fibers as seen in the periodontal ligament provide insight as to the function of oxytalan fibers. The oxytalan fibers may provide increased structural integrity and increased distribution of forces over a wider area of the periodontal ligament. Because of their close relationship to blood and lymph vessels in the periodontal ligament, they may also help to stabilize these elements by the same structural relationships to collagen fibers.

Animals

The role of Bacteroides melaninogenicus and other anaerobes in periodontal infections.

Recent taxonomic and anatomical studies of dental plaque associated with periodontal health and disease have demonstrated that differences in the microbial populations in plaque may be responsible for the initiation and progression of disease. The consistent isolation of large numbers of anaerobic and capnophilic bacteria from the depths of periodontal lesions has suggested an important role for these organisms. Bacteria that have been isolated include Capnocytophaga (Bacteroides ochraceus), other species of Bacteroides, Fusobacterium, Selenomonas, spirochetes, Campylobacter, Veillonella, Actinomyces, Propionibacterium, Peptococcus, and other genera. The periodontopathic potential of oral strains of Bacteroides melaninogenicus has been explored in a number of investigations because these organisms are consistently isolated from periodontal lesions. Studies of B. melaninogenicus have included purification of a capsular substance, characterization of the lipopolysaccharide and a variety of toxic substances and lytic enzymes, and ecologic aspects of its colonization. Understanding of the nature and pathogenic mechanisms of the oral microbiota may lead to control of this pandemic infection.

Bacteroides Infections

Longitudinal study of experimentally induced periodontal disease in Macaca arctoides: relationship between microflora and alveolar bone loss.

Macaca arctoides monkeys develop periodontal disease, and they harbor a periodontopathic indigenous flora largely similar to that of humans. This study showed that various Haemophilus isolates and H2O2-splitting asaccharolytic Bacteroides melaninogenicus strains constituted major segments of the monkey periodontal microflora. These organisms have not been previously identified among human isolates. Furthermore, the present data revealed that asaccharolytic B. melaninogenicus strains increased in proportion from a few percent to about 66% of the total isolates concomitant with the development of a significant loss of alveolar bone mass. Hence, this study strongly implicates B. melaninogenicus subsp. asaccharolyticus and closely related strains as important pathogens in actively destructive periodontal disease.

Alveolar Process

Autoradiographic study of 3-h-proline incorporation by rat periodontal ligament, gingival connective tissue and dental pulp.

The rates of 3-H-proline incorporation by the rat periodontal ligament, the gingival connective tissue and the dental pulp were studied by autoradiography. The rate of 3-H-proline incorporation by the periodontal ligament was 2.8 times higher than by the gingival connective tissue and 5 times higher than by the dental pulp. These differences were significant (p smaller than 0.01). The pattern of 3-H-proline incorporation by the periodontal ligament was significantly different (p smaller than 0.01) from that by the gingival connective tissue and the dental pulp. The latter two tissues exhibited a similar pattern of 3-H-proline incorporation. The ratio of the rates of 3-H-proline incorporation by the three tissues did not correlate with the ratio of the cellular densities in the same three tissues.

Animals

IgG subclasses in human periodontal disease. II. Cytophilic and membrane IgG subclass immunoglobulins.

Lymphocyte membrane-associated IgG subclass antibodies in human periodontal disease were studied to ascertain the relative presence of cytophilic IgG antibodies and the membrane Fc receptors which bind them. The experimental approach correlated the effect of incubating gingiva in tissue culture medium to remove cytophilic antibodies with the changes in the number of Fc receptors detectable after washing. The evidence indicated that the majority of lymphocytes in mild gingivitis lesions lacked cytophilic IgG antibodies as well as Fc recetors. In severe gingivitis, the number of IgG subclass bearing lymphocytes increased to about half of the total lymphoid population, while the percentage of Fc receptor bearing cells remained quite low (12.3 % +/- 3.2, S.E.). The majority of IgG subclass bearing lymphocytes had membrane IgG which serve as receptors for antigen; such cells are classically defined as bone marrow (B) derived lymphocytes and serve as the progenitor for plasma cells. Gingival specimens for patients with periodontitis were found to contain the highest percentage of Fc receptor bearing lymphocytes (38.3% +/- 12.6 S.E.) and cytophilic IgG antibodies. The findings indicate that the clinical stages of human periodontal disease are characterized by different populations of infiltrating lymphocytes.

Gingiva