Background: The global burden of periodontal diseases remains high. Population

Oral disease remains a major public health burden worldwide. It is of great importance to integrate oral health into global health agenda via the common risk factor approach. The long-term sustainable strategy for global oral health should focus on health promotion and disease prevention through effective multidisciplinary teamwork.

An updated classification of the periodontal manifestations and conditions affecting the course of periodontitis and the periodontal attachment apparatus, as well as of developmental and acquired conditions, is introduced. Case definitions and diagnostic considerations are also presented.

Background A variety of systemic diseases and conditions can affect the course of periodontitis or have a negative impact on the periodontal attachment apparatus. Gingival recessions are highly prevalent and often associated with hypersensitivity, the development of caries and non‐carious cervical lesions on the exposed root surface and impaired esthetics. Occlusal forces can result in injury of teeth and periodontal attachment apparatus. Several developmental or acquired conditions associated with teeth or prostheses may predispose to diseases of the periodontium. The aim of this working group was to review and update the 1999 classification with regard to these diseases and conditions, and to develop case definitions and diagnostic considerations. Methods Discussions were informed by four reviews on 1) periodontal manifestions of systemic diseases and conditions; 2) mucogingival conditions around natural teeth; 3) traumatic occlusal forces and occlusal trauma; and 4) dental prostheses and tooth related factors. This consensus report is based on the results of these reviews and on expert opinion of the participants. Results Key findings included the following: 1) there are mainly rare systemic conditions (such as Papillon‐Lefevre Syndrome, leucocyte adhesion deficiency, and others) with a major effect on the course of periodontitis and more common conditions (such as diabetes mellitus) with variable effects, as well as conditions affecting the periodontal apparatus independently of dental plaque biofilm‐induced inflammation (such as neoplastic diseases); 2) diabetes‐associated periodontitis should not be regarded as a distinct diagnosis, but diabetes should be recognized as an important modifying factor and included in a clinical diagnosis of periodontitis as a descriptor; 3) likewise, tobacco smoking – now considered a dependence to nicotine and a chronic relapsing medical disorder with major adverse effects on the periodontal supporting tissues – is an important modifier to be included in a clinical diagnosis of periodontitis as a descriptor; 4) the importance of the gingival phenotype, encompassing gingival thickness and width in the context of mucogingival conditions, is recognized and a novel classification for gingival recessions is introduced; 5) there is no evidence that traumatic occlusal forces lead to periodontal attachment loss, non‐carious cervical lesions, or gingival recessions; 6) traumatic occlusal forces lead to adaptive mobility in teeth with normal support, whereas they lead to progressive mobility in teeth with reduced support, usually requiring splinting; 7) the term biologic width is replaced by supracrestal tissue attachment consisting of junctional epithelium and supracrestal connective tissue; 8) infringement of restorative margins within the supracrestal connective tissue attachment is associated with inflammation and/or loss of periodontal supporting tissue. However, it is not evident whether the negative effects on the periodontium are caused by dental plaque biofilm, trauma...

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Selected metallo-compounds exhibit potent activity against SARS-CoV-2 in vitro. Historically, metal compounds have been used as antimicrobial agents. However, their antiviral activities have not been explored extensively. Our earlier studies demonstrated that bismuth drugs and related compounds exhibit excellent antiviral activity against SARS-CoV 21. Building on these results, we selected six metal compounds-two bismuth(iii) citrate-based drugs (colloidal bismuth subcitrate (CBS) and RBC, two bismuth(iii) porphyrins (Bi(TPP) (TPP, tetraphenylporphyrinate) and Bi(TPyP) (TPyP, tetra(4-pyridyl)porphyrin)), one Au(i)-based drug (Auranofin), as well as its active derivative, chloro(triethylphosphine) gold(i) (Au(PEt 3)Cl)-to carry out a primary evaluation against SARS-CoV-2 in vitro (Extended Data Fig. 1). The 50% cytotoxicity concentrations (CC 50) of these compounds in monkey kidney Vero E6 cells were determined to be 3,254 ± 21 μM for CBS, 2,243 ± 43 μM for RBC, >400 μM for both Bi(TPP) and Bi(TPyP), 14.2 ± 1.3 μM for auranofin and 13.5 ± 1.8 μM for Au(PEt 3)Cl (Extended Data Fig. 2). The four bismuth(iii) compounds were prioritized for further evaluation of their CC 50 values in human colorectal Caco-2 cells because of their promisingly low cytotoxicity compared with the Au(i)-based drugs, resulting in similar CC 50 values ranging from 400 to 3,740 μM (Extended Data Fig. 2). To evaluate their antiviral potency, the half-maximal effective doses (EC 50) of the bismuth(iii) compounds were determined at low micromolar levels as 4.6 ± 0.4 µM for CBS, 2.3 ± 0.5 µM for RBC, 3.9 ± 1.2 µM for Bi(TPP) and 7.5 ± 0.9 µM for Bi(TPyP). Remarkably, addition of all four bismuth(iii) compounds at 1 h post infection (h.p.i.) reduced viral RNA loads in both Vero E6 and Caco-2 cells in a dose-dependent manner (Fig. 1). In non-toxic concentrations, CBS and RBC exhibited more potent anti-SARS-CoV-2 activity than Bi(TPP) and Bi(TPyP), as evidenced by the maximal ~2-log versus 1-log viral load reduction in the Vero E6 cell lysate (Fig. 1a-d), ~3-log versus ~2-log reduction in the Caco-2 cell lysate (Fig. 1e-h), ~4-log versus ~3-log reduction in the Vero E6 cell culture supernatant (Fig. 1i-l) and ~4-log versus ~3-log reduction in the Caco-2 cell culture supernatant (Fig. 1m-p). Importantly, bismuth(iii) drugs/compounds greatly inhibited SARS-CoV-2, as evidenced by the markedly decreased expression of viral nucleoprotein in the drug-treated cells when compared with the dimethyl sulfoxide (DMSO)-treated group (Fig. 2a-f). To investigate which steps of the SARS-CoV-2 replication cycle were interrupted by the selected drug compounds, we performed a time-of-drug-addition assay by treating virus-infected cells with each compound at different time points, followed by measurements of viral titre after 9 h.p.i., when the first round of progeny virions were detectable in the cell culture supernatant. (Fig. 2g,h). Intriguingly, addition of Bi(TPyP) during pre-treatment or co-incubation of cells significantly suppressed virus replication, whereas n...

Background Porphyromonas gingivalis is a major pathogen of periodontal disease that affects a majority of adults worldwide. Increasing evidence shows that periodontal disease is linked to various systemic diseases like diabetes and cardiovascular disease, by contributing to increased systemic levels of inflammation. Lipopolysaccharides (LPS), as a key virulent attribute of P. gingivalis, possesses significant amount of lipid A heterogeneity containing tetra- (LPS1435/1449) and penta-acylated (LPS1690) structures. Hitherto, the exact molecular mechanism of P. gingivalis LPS involved in periodontal pathogenesis remains unclear, due to limited understanding of the specific receptors and signaling pathways involved in LPS-host cell interactions.Methodology/Principal FindingsThis study systematically investigated the effects of P. gingivalis LPS1435/1449 and LPS1690 on the expression of TLR2 and TLR4 signal transduction and the activation of pro-inflammatory cytokines IL-6 and IL-8 in human gingival fibroblasts (HGFs). We found that LPS1435/1449 and LPS1690 differentially modulated TLR2 and TLR4 expression. NF-κB pathway was significantly activated by LPS1690 but not by LPS1435/1449. In addition, LPS1690 induced significant expression of NF-κB and p38 MPAK pathways-related genes, such as NFKBIA, NFKB1, IKBKB, MAP2K4 and MAPK8. Notably, the pro-inflammatory genes including GM-CSF, CXCL10, G-CSF, IL-6, IL-8 and CCL2 were significantly upregulated by LPS1690 while down-regulated by LPS1435/1449. Blocking assays confirmed that TLR4-mediated NF-κB signaling was vital in LPS1690-induced expression of IL-6 and IL-8 in HGFs.Conclusions/SignificanceThe present study suggests that the tetra- and penta-acylated lipid A structures of P. gingivalis LPS differentially activate TLR4-mediated NF-κB signaling pathway, and significantly modulate the expression of IL-6 and IL-8 in HGFs. The ability to alter the lipid A structure of LPS could be one of the strategies carried-out by P. gingivalis to evade innate host defense in gingival tissues, thereby contributing to periodontal pathogenesis.

Summary The oral and intestinal host tissues both carry a heavy microbial burden. Although commensal bacteria contribute to healthy intestinal tissue structure and function, their contribution to oral health is poorly understood. A crucial component of periodontal health is the recruitment of neutrophils to periodontal tissue. To elucidate this process, gingival tissues of specific‐pathogen‐free and germ‐free wild‐type mice and CXCR2KO and MyD88KO mice were examined for quantitative analysis of neutrophils and CXCR2 chemoattractants (CXCL1, CXCL2). We show that the recruitment ofneutrophils to the gingival tissue does not require commensal bacterial colonization but is entirely dependent on CXCR2 expression. Strikingly, however, commensal bacteria selectively upregulate the expression of CXCL2, but not CXCL1, in a MyD88‐dependent way that correlates with increased neutrophil recruitment as compared with germ‐free conditions. This is the first evidence that the selective use of chemokine receptor ligands contributes to neutrophil homing to healthy periodontal tissue.