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In the last decades, the ortho-aesthetic-functional rehabilitation had significant advances with the advent of implantology. Despite the success in implantology surgeries, there is a percentage of failures mainly due to in loco infections, through bacterial proliferation, presence of fungi and biofilm formation, originating peri-implantitis. In this sense, several studies have been conducted since then, seeking answers to numerous questions that remain unknown. Thus, the present work aims to discuss the interaction between host-oral microbiome and the development of peri-implantitis. Peri-implantitis was associated with a diversity of bacterial species, being Porphiromonas gingivalis, Treponema denticola and Tannerella forsythia described in higher proportion of peri-implantitis samples. In a parallel role, the injury of peri-implant tissue causes an inflammatory response mediated by activation of innate immune cells such as macrophages, dendritic cells, mast cells, and neutrophils. In summary, the host immune system activation may lead to imbalance of oral microbiota, and, in turn, the oral microbiota dysbiosis is reported leading to cytokines, chemokines, prostaglandins, and proteolytic enzymes production. These biological processes may be responsible for implant loss.

Periodontitis is a chronic inflammatory disease that leads to the destruction of both soft and hard periodontal tissues. Complete periodontal regeneration in clinics using the currently available treatment approaches is still a challenge. Mesenchymal stem cells (MSCs) have shown promising potential to regenerate periodontal tissue in various preclinical and clinical studies. The poor survival rate of MSCs during in vivo transplantation and host immunogenic reaction towards MSCs are the main drawbacks of direct use of MSCs in periodontal tissue regeneration. Autologous MSCs have limited sources and possess patient morbidity during harvesting. Direct use of allogenic MSCs could induce host immune reaction. Therefore, the MSC-based indirect treatment approach could be beneficial for periodontal regeneration in clinics. MSC culture conditioned medium (CM) contains secretomes that had shown immunomodulatory and tissue regenerative potential in pre-clinical and clinical studies. MSC-CM contains a cocktail of growth factors, cytokines, chemokines, enzymes, and exosomes, extracellular vesicles, etc. MSC-CM-based indirect treatment has the potential to eliminate the drawbacks of direct use of MSCs for periodontal tissue regeneration. MSC-CM holds the tremendous potential of bench-to-bed translation in periodontal regeneration applications. This review focuses on the accumulating evidence indicating the therapeutic potential of the MSC-CM in periodontal regeneration-related pre-clinical and clinical studies. Recent advances on MSC-CM-based periodontal regeneration, existing challenges, and prospects are well summarized as guidance to improve the effectiveness of MSC-CM on periodontal regeneration in clinics.

Periodontitis is an inflammatory disease initiated by dysbiosis of the local microbial community. Periodontitis can result in destruction of tooth-supporting tissue; however, overactivation of the host immune response is the main reason for alveolar bone loss. Periodontal tissue cells, immune cells, and even further activated osteoclasts and neutrophils play pro-inflammatory or anti-inflammatory roles. Traditional therapies for periodontitis are effective in reducing the microbial quantities and improving the clinical symptoms of periodontitis. However, these methods are non-selective, and it is still challenging to achieve an ideal treatment effect in clinics using the currently available treatments and approaches. Exosomes have shown promising potential in various preclinical and clinical studies, including in the diagnosis and treatment of periodontitis. Exos can be secreted by almost all types of cells, containing specific substances of cells: RNA, free fatty acids, proteins, surface receptors and cytokines. Exos act as local and systemic intercellular communication medium, play significant roles in various biological functions, and regulate physiological and pathological processes in numerous diseases. Exos-based periodontitis diagnosis and treatment strategies have been reported to obtain the potential to overcome the drawbacks of traditional therapies. This review focuses on the accumulating evidence from the last 5 years, indicating the therapeutic potential of the Exos in preclinical and clinical studies of periodontitis. Recent advances on Exos-based periodontitis diagnosis and treatment strategies, existing challenges, and prospect are summarized as guidance to improve the effectiveness of Exos on periodontitis in clinics.

Pulp treatment is extremely common in endodontics, with the main purpose of eliminating clinical symptoms and preserving tooth physiological function. However, the effect of dental pulp treatment is closely related to the methods and materials used in the process of treatment. Plenty of studies about calcium silicate-based bioceramics which are widely applied in various endodontic operations have been reported because of their significant biocompatibility and bioactivity. Although most of these materials have superior physical and chemical properties, the differences between them can also have an impact on the success rate of different clinical practices. Therefore, this review is focused on the applications of several common calcium silicate-based bioceramics, including Mineral trioxide aggregate (MTA), Biodentine, Bioaggregate, iRoot BP Plus in usual endodontic treatment, such as dental pulp capping, root perforation repair, regenerative endodontic procedures (REPs), apexification, root-end filling and root canal treatment (RCT). Besides, the efficacy of these bioceramics mentioned above in human trials is also compared, which aims to provide clinical guidance for their clinical application in endodontics.

Background Restoration of salivary gland function in Sjogren’s syndrome (SS) is still a challenge. Dental pulp stem cells (DPSCs) derived exosomes had shown anti-inflammatory, anti-oxidative, immunomodulatory, and tissue function restorative abilities. However, the salivary gland function restoration potential of DPSCs-derived exosomes (DPSC-Exos) during SS has not been investigated yet. Methods DPSC-Exos was isolated by ultracentrifugation methods and characterized. Salivary gland epithelial cells (SGEC) were treated with interferon-gamma (IFN-γ) to mimic SS in vitro and cultured with or without DPSC-Exos. SGEC survival and aquaporin 5 (AQP5) expression were analyzed. mRNA sequencing and bioinformatics analysis were performed in IFN-γ vs. DPSC-Exos+ IFN-γ treated SGEC. Non-obese diabetic (NOD)/ltj female mice (SS model), were intravenously administered with DPSC-Exos, and salivary gland functions and SS pathogenicity were analyzed. Furthermore, the mRNA sequencing and bioinformatics predicted mechanism of the therapeutic effect of DPSC-Exos was further investigated both in vitro and in vivo using RT-qPCR, Western blot, immunohistochemistry, immunofluorescence, flowcytometry analysis. Results DPSC-Exos partially rescued IFN-γ triggered SGEC death. IFN-γ inhibited AQP5 expression in SGEC and DPSC-Exos reversed this effect. Transcriptome analysis showed GPER was the upregulated DEG in DPSC-Exos-treated SGEC with a positive correlation with salivary secretion-related DEGs. Pathway enrichment analysis revealed that DEGs were mainly attributed to estrogen 16 alpha-hydroxylase activity, extracellular exosome function, cAMP signaling, salivary secretion, and estrogen signaling. Intravenous injection of DPSC-Exos in NOD/ltj mice alleviated the SS syndrome as indicated by the increased salivary flow rate, attenuated glandular inflammation, and increased AQP5 expression. GPER was also upregulated in the salivary gland of DPSC-Exos-treated NOD/ltj mice compared with the PBS-treated NOD/ltj mice. IFN-γ+DPSC-Exos-treated SGEC showed higher expression of AQP5, p-PKA, cAMP, and intracellular Ca 2+ levels compared with IFN-γ-treated SGEC. These effects were reversed by the inhibition of GPER. Conclusions Our results showed that DPSC-Exos revitalize salivary gland epithelial cell function during SS via the GPER-mediated cAMP/PKA/CREB pathway suggesting the possible therapeutic potential of DPSC-Exos in SS-treatment.

Background and objective Progranulin (PGRN), a multifunctional growth factor, plays indispensable roles in the regulation of cancer, inflammation, metabolic diseases, and neurodegenerative diseases. Nevertheless, its immune regulatory role in periodontitis is insufficiently understood. This study attempts to explore the regulatory effects of PGRN on macrophage polarization in periodontitis microenvironment. Methods Immunohistochemical (IHC) and multiplex immunohistochemical (mIHC) stainings were performed to evaluate the expression of macrophage-related markers and PGRN in gingival samples from periodontally healthy subjects and periodontitis subjects. RAW264.7 cells and bone marrow-derived macrophages (BMDMs) were polarized towards M1 or M2 macrophages by the addition of LPS or IL-4, respectively, and were treated with or without PGRN. Real-time fluorescence quantitative PCR (qRT-PCR), immunofluorescence staining (IF), enzyme-linked immunosorbent assay (ELISA), and flow cytometry were used to determine the expressions of M1 and M2 macrophage-related markers. Co-immunoprecipitation was performed to detect the interaction between PGRN and tumor necrosis factor receptor 2 (TNFR2). Neutralizing antibody was used to block TNFR2 to confirm the role of TNFR2 in PGRN-mediated macrophage polarization. Results The IHC and mIHC staining of human gingival slices showed a significant accumulation of macrophages in the microenvironment of periodontitis, with increased expressions of both M1 and M2 macrophage markers. Meanwhile, PGRN was widely expressed in the gingival tissue of periodontitis and co-expressed mainly with M2 macrophages. In vitro experiments showed that in RAW264.7 cells and BMDMs, M1 markers (CD86, TNF-α, iNOS, and IL-6) substantially decreased and M2 markers (CD206, IL-10, and Arg-1) significantly increased when PGRN was applied to LPS-stimulated macrophages relatively to LPS stimulation alone. Besides, PGRN synergistically promoted IL-4-induced M2 markers expression, such as CD206, IL-10, and Arg1. In addition, the co-immunoprecipitation result showed the direct interaction of PGRN with TNFR2. mIHC staining further revealed the co-localization of PGRN and TNFR2 on M2 macrophages (CD206+). Blocking TNFR2 inhibited the regulation role of PGRN on macrophage M2 polarization. Conclusions In summary, PGRN promotes macrophage M2 polarization through binding to TNFR2 in both pro- and anti-inflammatory periodontal microenvironments.

Periodontitis is the sixth most prevalent chronic disease globally and places significant burdens on societies and economies worldwide. Behavioral modification, risk factor control, coupled with cause-related therapy have been the “gold standard” treatment for managing periodontitis. Given that host inflammatory and immunological responses play critical roles in the pathogenesis of periodontitis and impact treatment responses, several adjunctive strategies aimed at modulating host responses and improving the results of periodontal therapy and maintenance have been proposed. Of the many pharmacological host modulators, we focused on non-steroidal anti-inflammatory drugs (NSAIDs), due to their long history and extensive use in relieving inflammation and pain and reducing platelet aggregation. NSAIDs have been routinely indicated for treating rheumatic fever and osteoarthritis and utilized for the prevention of cardiovascular events. Although several efforts have been made to incorporate NSAIDs into the treatment of periodontitis, their effects on periodontal health remain poorly characterized, and concerns over the risk–benefit ratio were also raised. Moreover, there is emerging evidence highlighting the potential of NSAIDs, especially aspirin, for use in periodontal regeneration. This review summarizes and discusses the use of NSAIDs in various aspects of periodontal therapy and regeneration, demonstrating that the benefits of NSAIDs as adjuncts to conventional periodontal therapy remain controversial. More recent evidence suggests a promising role for NSAIDs in periodontal tissue engineering and regeneration.

Periodontal ligament fibroblasts (PDLFs) play a crucial role in the etiology of periodontitis and periodontal tissue regeneration. In healthy periodontal tissues, PDLFs maintain the homeostasis of periodontal soft and hard tissues as well as the local immune microenvironment. PDLFs also have the potential for multidirectional transdifferentiation and are involved in periodontal tissue regeneration. On the other hand, PDLFs can become dysfunctional and acquire an inflammatory phenotype to secret various inflammatory cytokines when affected by pathological factors. These cytokines further trigger immune and inflammatory events, and lead to destruction of periodontal soft and hard tissues as well as damage to the regenerative potential of PDLFs. This review summarizes the physiological functions of PDLFs. Meanwhile, this review also highlights recent insights into the pathological mechanisms driving the development of periodontitis through dysfunctional PDLFs and the negative impact on periodontal tissue regeneration. Additionally, this paper summarizes strategies for targeting PDLFs to treat periodontitis, involving blocking multiple stages of the inflammatory response induced by PDLFs and promoting the multidirectional transdifferentiation of PDLFs. Future research directions are proposed to address important questions that have not yet been answered in this field. This article provides a reference for understanding the important role of PDLFs in the pathological mechanisms of periodontitis and for developing new strategies for targeting PDLFs in periodontitis treatment. Graphical Abstract

Background Micro-RNAs (miRNAs) have been reported to play an important role during orthodontic tooth movement (OTM) through the regulation of periodontal soft and hard tissue homeostasis and functions. The aim of the present study was to assess the effects of miRNAs on OTM and to evaluate possible predictors that influenced the overall OTM amount at a 3-month follow-up. Methods Through a split-mouth design, 21 healthy patients (mean age 13.2 ± 1.8 years) were enrolled in the present study. Clinical parameters and gingival crevicular fluid (GCF) sampling were performed on both compression and tension sides of a random canine to be distalized (test groups) at baseline and at 1 h, 1 day, 1 month and at 3-month after OTM, while the contralateral canine served as a control group. miRNAs − 7a-3p, -7a-2-3p, -7a-5p, -21-3p, -21-5p, -100-3p, -100-5p, -125b-2-3p, -125b-5p, -200b-3p, and − 200b-5p expression was analyzed using a real-time quantitative polymerase chain reaction (RT-PCR). Data were analyzed to assess miRNAs change following OTM. Spearman test, two-way ANOVA and a multivariate regression model were established to evaluate the correlation among miRNAs and clinical parameters and to explore possible predictors of OTM amount at 3-month follow-up. Results At 3-month follow-up, there was an increase of miRNA-7a-2-3p, -21-5p, -100-5p, a decrease of miRNA-125b-5p, 200b-3p and − 200b-5p in the compression side and an increase of miRNA-7a-3p, 100-5p in the tension side ( p  < 0.05). The two-way ANOVA revealed that OTM determined, on the compression side, a significant upregulation on miRNA-7a-3p ( p  = 0.017), -7a-2-3p ( p  = 0.023), -21-5p ( p  = 0.007), -100-5p ( p  = 0.025) and a significant downregulation of miRNA-125b-2-3p ( p  = 0.019) and − 200b-5p ( p  = 0.017). The multivariate model highlighted that high baseline miRNA-7a2-3p ( p  = 0.025), -21-5p ( p  = 0.014), -200b-3p ( p  = 0.041), young age ( p  = 0.042), lower bleeding on probing (BOP) ( p  = 0.021) and miRNA-125b-2-3p ( p  = 0.021) levels were significant predictors of OTM at 3-month follow-up. Conclusions In the present study, OTM significantly impacted the expression of the miRNAs analyzed, in both the tension and compression side of traction tooth at 3-month follow-up. High baseline miRNA-7a2-3p, -21-5p, -200b-3p, and lower miRNA-125b-2-3p, together with younger age and lower BOP, were significant predictors of OTM amount at 3-month follow-up. Trial registration ClinicalTrials.gov NCT06023433 (retrospectively registered).

Background Recent research has established the correlation between gut microbiota and periodontitis via oral-gut axis. Intestinal dysbiosis may play a pivotal bridging role in extra-oral inflammatory comorbidities caused by periodontitis. However, it is unclear whether the link is merely correlative or orchestrated by causative mechanistic interactions. This two-sample Mendelian randomization (MR) study was performed to evaluate the potential bidirectional causal relationships between gut microbiota and periodontitis. Materials and Methods A two-sample MR analysis was performed using summary statistics from genome-wide association studies (GWAS) for gut microbiota (n = 18,340) and periodontitis (cases = 12,251; controls = 22,845). The inverse-variance weighted (IVW) method was used for the primary analysis, and we employed sensitivity analyses to assess the robustness of the main results. The PhenoScanner database was then searched for pleiotropy SNPs associated with potential confounders. In order to identify the possibly influential SNPs, we further conducted the leave-one-out analysis. Finally, a reverse MR analysis was performed to evaluate the possibility of links between periodontitis and genetically predicted gut microbiota alternation. Results 2,699 single nucleotide polymorphisms (SNPs) associated with 196 microbiota genera were selected as instrumental variables (IVs). IVW method suggested that order Enterobacteriales (OR: 1.35, 95% CI 1.10–1.66), family Bacteroidales S24.7group (OR: 1.22, 95% CI 1.05–1.41), genus Lachnospiraceae UCG008 (OR: 1.16, 95% CI 1.03–1.31), genus Prevotella 7 (OR: 1.11, 95% CI 1.01–1.23), and order Pasteurellales (OR: 1.12, 95% CI 1.00–1.26) may be associated with a higher risk of periodontitis, while genus Ruminiclostridium 6 may be linked to a lower risk (OR: 0.82, 95% CI 0.70–0.95). The sensitivity and heterogeneity analyses yielded no indication of horizontal pleiotropy or heterogeneity. Only the association between order Enterobacteriales and the likelihood of periodontitis remained consistent across all alternative MR approaches. In the reverse MR analysis, four microbiota genera were genetically predicted to be down-regulated in periodontitis, whereas two were predicted to be up-regulated. Conclusions The present MR analysis demonstrated the potential bidirectional causal relationships between gut microbiota and periodontitis. Our research provided fresh insights for the prevention and management of periodontitis. Future research is required to support the finding of our current study.