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Frontiers in Cell and Developmental... 2023Curcumin has broad application prospects in the prevention and treatment of periodontal diseases. Periodontal ligament stem cell-derived extracellular vesicles...
Curcumin has broad application prospects in the prevention and treatment of periodontal diseases. Periodontal ligament stem cell-derived extracellular vesicles (PDLSC-EV) can effectively promote periodontal tissue regeneration and possess good drug delivery capability. Superior pharmacological effects can be exerted using PDLSC-EV as a curcumin carrier. In the present study, we constructed curcumin-primed PDLSCs-derived extracellular vesicles (Cur-PDLSC-EV) from cell culture supernatants of curcumin-pretreated PDLSCs by ultracentrifugation and investigated their effects on the proliferation, migration, and osteogenic ability of PDLSCs and the corresponding downstream molecular pathways. Both Cur-PDLSC-EV and PDLSC-EV promoted osteoblast proliferation and migration. Compared with PDLSC-EV, Cur-PDLSC-EV possessed a more potent pro-osteogenic ability. Moreover, the improved osteogenesis of Cur-PDLSC-EV was related to the activation of the Wnt/β-catenin signaling pathway. This study suggests that Cur-PDLSC-EV can promote osteogenic differentiation by activating Wnt/β-catenin, providing reference bases for the treatment of periodontal diseases.
PubMed: 37842095
DOI: 10.3389/fcell.2023.1225449 -
Journal of Periodontal Research Oct 2023To explore the mechanism of receptor-interacting protein 1 (RIP1)-mediated necroptosis during periodontitis progression.
OBJECTIVE
To explore the mechanism of receptor-interacting protein 1 (RIP1)-mediated necroptosis during periodontitis progression.
BACKGROUND
RIP3 and mixed lineage kinase domain-like protein (MLKL) have been detected to be upregulated in periodontitis models. Because RIP1 is involved in necroptosis, it might also play a role in the progression of periodontitis.
METHODS
An experimental periodontitis model in BALB/c mice was established by inducing oral bacterial infection. Western blotting and immunofluorescence analyses were used to detect RIP1 expression in the periodontal ligament. Porphyromonas gingivalis was used to stimulate L929 and MC3T3-E1. RIP1 was inhibited using small-interfering RNA. Western blotting, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA) analyses were used to detect the effect of necroptosis inhibition on the expression of damage-associated molecular patterns and inflammatory cytokines. Necrostatin-1 (Nec-1) was intraperitoneally injected to inhibit RIP1 expression in mice. Necroptosis activation and inflammatory cytokine expression in periodontal tissue were verified. Tartrate-resistant acid phosphatase staining was applied to observe osteoclasts in the bone tissues of different groups.
RESULTS
RIP1-mediated necroptosis was activated in mice with periodontitis. P. gingivalis induced RIP1-mediated necroptosis in L929 and MC3T3-E1 cells. After RIP1 inhibition, the expression levels of high mobility group protein B1 (HMGB1) and inflammatory cytokines were downregulated. After inhibiting RIP1 with Nec-1 in vivo, necroptosis was also inhibited, the expression levels of HMGB1 and inflammatory cytokines were downregulated, and osteoclast counts in the periodontal tissue decreased.
CONCLUSION
RIP1-mediated necroptosis plays a role in the pathological process of periodontitis in mice. Nec-1 inhibited necroptosis, alleviated inflammation in periodontal tissue, and reduced bone resorption in periodontitis.
Topics: Mice; Animals; HMGB1 Protein; Necroptosis; Periodontitis; Cytokines; Apoptosis
PubMed: 37334934
DOI: 10.1111/jre.13150 -
Scientific Reports Oct 2023Osteoimmune diseases, such as apical periodontitis, are prevalent, often painful, inflammatory conditions resulting in bone loss and reduced quality of life. There is...
Osteoimmune diseases, such as apical periodontitis, are prevalent, often painful, inflammatory conditions resulting in bone loss and reduced quality of life. There is growing evidence that the nociceptive fibers densely innervating affected tissues regulate disease progression; therefore, we hypothesized that nociceptors regulate the transcriptomic profile of the periapical osteolytic lesion in a mouse model of apical periodontitis. Male control and nociceptor-ablated mice underwent pulp exposures, and after 0, 7, or 14 days, total RNA from periapical tissues was submitted for sequencing and bioinformatic analysis. Pulp exposure triggers the differential expression of hundreds of genes over the course of infection. At 14 days post pulp exposure, 422 genes, including Tnf, Il1a, and Il1b, were differentially expressed between nociceptor-ablated and control mice with greater enrichment of biological processes related to inflammation in nociceptor-ablated mice. Nociceptor ablation regulates the transcriptomic profile of periapical lesions in a mouse model of apical periodontitis, shifting the gene expression profile to a greater enrichment of inflammatory genes, suggesting nociceptors play a role in the kinetics of the immune response. This newly uncovered neuro-immune axis and its mechanisms in apical periodontitis can be an important therapeutic target for the treatment of this prevalent disease.
Topics: Male; Mice; Animals; Transcriptome; Nociceptors; Quality of Life; Periapical Periodontitis; Periapical Tissue
PubMed: 37845223
DOI: 10.1038/s41598-023-44648-9 -
International Journal of Nanomedicine 2023Periodontitis is a chronic inflammatory disease that causes alveolar bone loss. Diabetes is one of the most important factors contributing to periodontitis. Exosomes...
INTRODUCTION
Periodontitis is a chronic inflammatory disease that causes alveolar bone loss. Diabetes is one of the most important factors contributing to periodontitis. Exosomes derived from mesenchymal stem cells (MSCs-Exo) have been reported to promote bone regeneration. This study aimed to examine the function and mechanism of exosomes derived from periodontal ligament stem cells (PDLSCs-Exo) in regulating periodontal regeneration in diabetic periodontitis.
METHODS
Exosomes derived from normal-glucose-cultured PDLSCs (NG-PDLSCs-Exo) and high-glucose-preconditioned PDLSCs (HG-PDLSCs-Exo) were used. Their effects on RAW264.7 cells were investigated by TRAP staining and quantitative real time-polymerase chain reaction (qRT-PCR). The role of exosomal miR-31-5p in osteoclast differentiation was tested using qRT-PCR, double luciferase analysis, and Western blotting. We investigated the effects of these two types of PDLSCs-Exo on alveolar bone loss in vivo in mice with experimental periodontitis.
RESULTS
PDLSCs-Exo were transferred to RAW264.7, and HG-PDLSCs-Exo inhibited osteoclast formation to a lesser extent than NG-PDLSCs-Exo. Further studies revealed the effect of PDLSCs-Exo on osteoclastogenesis via the miR-31-5p/eNOS signaling pathway. In mice with experimental periodontitis, PDLSCs-Exo reduced alveolar bone destruction and decreased the number of osteoclasts on the alveolar bone surface.
CONCLUSION
Our results suggest that exosomal miR-31-5p derived from PDLSCs regulates alveolar bone regeneration by targeting eNOS.
Topics: Animals; Mice; Alveolar Bone Loss; Exosomes; Periodontal Ligament; Stem Cells; Disease Models, Animal; Glucose; MicroRNAs
PubMed: 37746047
DOI: 10.2147/IJN.S409664 -
BioRxiv : the Preprint Server For... Oct 2023Periodontal health is dependent on a symbiotic relationship of the host immune response with the oral microbiota. Pathologic shifts of the microbial plaque elicit an...
Periodontal health is dependent on a symbiotic relationship of the host immune response with the oral microbiota. Pathologic shifts of the microbial plaque elicit an immune response that eventually leads to the recruitment and activation of osteoclasts and matrix metalloproteinases and the eventual tissue destruction that is evident in periodontal disease. Once the microbial stimulus is removed, an active process of inflammatory resolution begins. The goal of this work was to use scRNAseq to demonstrate the unique cellular immune response across three distinct conditions of periodontal health, disease, and resolution using mouse models. Periodontal disease was induced using a ligature model. Resolution was modeled by removing the ligature and allowing the mouse to recover. Immune cells (Cd45+) were isolated from the periodontium and analyzed via scRNAseq. Gene signature shifts across the three conditions were characterized and shown to be largely driven by macrophage and neutrophils during the periodontal disease and resolution conditions. Resolution of periodontal disease was characterized by the differential regulation of unique gene subsets. Clustering analysis characterized multiple cellular subpopulations within B Cells, macrophages, and neutrophils that demonstrated differential expansion and contraction across conditions of periodontal health, disease, and resolution. Interestingly, we identified a transcriptionally distinct macrophage subpopulation that expanded during the resolution condition and demonstrated an immunoregulatory gene signature. We identified a cell surface marker for this resolution-associated macrophage subgroup (Cd74) and validated the expansion of this subgroup during resolution via flow cytometry. This work presents a robust immune cell atlas for study of the immunological changes in the oral mucosa during three distinct conditions of periodontal health, disease, and resolution and it improves our understanding of the cellular and molecular markers that characterize health from disease for the development of future diagnostics and therapies.
PubMed: 37904993
DOI: 10.1101/2023.10.18.562816 -
Photodermatology, Photoimmunology &... Jan 2024Periodontitis, a chronic infectious disease, is primarily caused by a dysbiotic microbiome, leading to the destruction of tooth-supporting tissues and tooth loss.... (Review)
Review
BACKGROUND
Periodontitis, a chronic infectious disease, is primarily caused by a dysbiotic microbiome, leading to the destruction of tooth-supporting tissues and tooth loss. Photodynamic therapy (PDT), which combines excitation light with photosensitizers (PS) and oxygen to produce antibacterial reactive oxygen species, is emerging as a promising adjuvant treatment for periodontitis.
METHODS
This review focuses on studies examining the antibacterial effects of PDT against periodontal pathogens. It also explores the impact of PDT on various aspects of periodontal health, including periodontal immune cells, human gingival fibroblasts, gingival collagen, inflammatory mediators, cytokines in the periodontium, vascular oxidative stress, vascular behavior, and alveolar bone health. Clinical trials assessing the types of PSs and light sources used in PDT, as well as its effects on clinical and immune factors in gingival sulcus fluid and the bacterial composition of dental plaque, are discussed.
RESULTS
The findings indicate that PDT is effective in reducing periodontal pathogens and improving markers of periodontal health. It has shown positive impacts on periodontal immune response, tissue integrity, and alveolar bone preservation. Clinical trials have demonstrated improvements in periodontal health and alterations in the microbial composition of dental plaque when PDT is used alongside conventional treatments.
CONCLUSIONS
PDT offers a promising adjunctive treatment for periodontitis, with benefits in bacterial reduction, tissue healing, and immune modulation. This article highlights the potential of PDT in periodontal therapy and emphasizes the need for further research to refine its clinical application and efficacy.
Topics: Humans; Photochemotherapy; Dental Plaque; Periodontitis; Photosensitizing Agents; Anti-Bacterial Agents
PubMed: 38288767
DOI: 10.1111/phpp.12946 -
Journal of Nanobiotechnology Jan 2024Periodontitis is a chronic inflammatory disease caused by the local microbiome and the host immune response, resulting in periodontal structure damage and even tooth... (Review)
Review
Periodontitis is a chronic inflammatory disease caused by the local microbiome and the host immune response, resulting in periodontal structure damage and even tooth loss. Scaling and root planning combined with antibiotics are the conventional means of nonsurgical treatment of periodontitis, but they are insufficient to fully heal periodontitis due to intractable bacterial attachment and drug resistance. Novel and effective therapeutic options in clinical drug therapy remain scarce. Nanotherapeutics achieve stable cell targeting, oral retention and smart release by great flexibility in changing the chemical composition or physical characteristics of nanoparticles. Meanwhile, the protectiveness and high surface area to volume ratio of nanoparticles enable high drug loading, ensuring a remarkable therapeutic efficacy. Currently, the combination of advanced nanoparticles and novel therapeutic strategies is the most active research area in periodontitis treatment. In this review, we first introduce the pathogenesis of periodontitis, and then summarize the state-of-the-art nanotherapeutic strategies based on the triple concerto of antibacterial activity, immunomodulation and periodontium regeneration, particularly focusing on the therapeutic mechanism and ingenious design of nanomedicines. Finally, the challenges and prospects of nano therapy for periodontitis are discussed from the perspective of current treatment problems and future development trends.
Topics: Humans; Periodontitis; Periodontium; Anti-Bacterial Agents; Regeneration; Immunomodulation; Immunity
PubMed: 38178140
DOI: 10.1186/s12951-023-02261-y -
Cellular Signalling Aug 2023Orthodontic treatment in older adults is more difficult than in younger adults, partially due to delayed osteogenesis caused by senescence of human periodontal ligament...
Orthodontic treatment in older adults is more difficult than in younger adults, partially due to delayed osteogenesis caused by senescence of human periodontal ligament stem cells (hPDLSCs). The production of brain-derived neurotrophic factor (BDNF) which regulates the differentiation and survival of stem cells decreases with age. We aimed to investigate the relationship between BDNF and hPDLSC senescence and its effects on orthodontic tooth movement (OTM). We constructed mouse OTM models using orthodontic nickel‑titanium springs and compared the responses of wild-type (WT) and BDNF mice with or without addition of exogenous BDNF. In vitro, hPDLSCs subjected to the mechanical stretch were used to simulate the cell stretch environment during OTM. We extracted periodontal ligament cells from WT and BDNF mice to evaluate their senescence-related indicators. The application of orthodontic force increased BDNF expression in the periodontium of WT mice, while the mechanical stretch increased BDNF expression in hPDLSCs. Osteogenesis-related indicators, including RUNX2 and ALP decreased and cellular senescence-related indicators such as p16, p53 and β-galactosidase increased in BDNF mice periodontium. Furthermore, periodontal ligament cells extracted from BDNF mice exhibited more senescent compared with cells from WT mice. Application of exogenous BDNF decreased the expression of senescence-related indicators in hPDLSCs by inhibiting Notch3, thereby promoting osteogenic differentiation. Periodontal injection of BDNF decreased the expression of senescence-related indicators in periodontium of aged WT mice. In conclusion, our study showed that BDNF promotes osteogenesis during OTM by alleviating hPDLSCs senescence, paving a new path for future research and clinical applications.
Topics: Animals; Humans; Mice; Brain-Derived Neurotrophic Factor; Cell Differentiation; Cells, Cultured; Cellular Senescence; Osteogenesis; Periodontal Ligament; Stem Cells; Tooth Movement Techniques
PubMed: 37211081
DOI: 10.1016/j.cellsig.2023.110724 -
International Immunopharmacology Aug 2023Several substances that have anti-inflammatory, antiproteinase, and anti-infective properties have been evaluated as modulators of the inflammatory response in...
PURPOSE
Several substances that have anti-inflammatory, antiproteinase, and anti-infective properties have been evaluated as modulators of the inflammatory response in periodontal disease. However, evidence for the anti-inflammatory and antioxidative activities of bromelain is limited. This study evaluated the impact of systemically administered bromelain on the progression of experimental periodontitis.
METHODS
Four equal groups of 32 Wistar albino rats were created as follows (n = 8): control, periodontitis + saline, periodontitis + 5 mg/kg/day bromelain, and periodontitis + 10 mg/kg/day bromelain. To quantify the resorption of bone and bone volume/tissue volume, bone surface / bone volume, and connectivity, lower jawbones were fixed and then scanned using microcomputed tomography (micro CT). Blood samples were taken to measure the macrophage colony-stimulating factor(M-CSF) concentrations, receptor activator of nuclear factor kappa-Β ligand (RANKL), osteoprotegerin (OPG), tumor necrosis factor-alpha (TNF-α), matrix metalloproteinase-8 (MMP-8), interleukin-6(IL-6), glutathione peroxidase (GPx), superoxide dismutase (SOD), and malondialdehyde (MDA). Histopathological assessments were made to examine the tissue.
RESULTS
Treatment with bromelain improved the healing of the periodontium by decreasing the number of leukocytes and ligament deterioration in the gingival connective tissue and by supporting reintegration with alveolar bone. Bromelain used in ligature-induced periodontitis reduced alveolar bone (AB) resorption as measured by microCT; reduced inflammatory parameters such as IL-6 and TNF-α; regulated oxidative-antioxidative processes by increasing GPx and SOD and reducing MDA levels; and regulated AB modeling by decreasing M-CSF, RANKL, and MMP-8 and increasing OPG levels.
CONCLUSION
Bromelain may be an option in periodontal therapy by regulating cytokine levels, improving the healing process, and reducing bone resorption and oxidative stress.
Topics: Rats; Animals; Rats, Wistar; Matrix Metalloproteinase 8; Macrophage Colony-Stimulating Factor; Tumor Necrosis Factor-alpha; Interleukin-6; Bromelains; X-Ray Microtomography; Periodontitis; Antioxidants; Anti-Inflammatory Agents; Glutathione Peroxidase; Bone and Bones
PubMed: 37290321
DOI: 10.1016/j.intimp.2023.110446 -
Biofabrication Aug 2023Gingival connective tissue and its vasculature play a crucial role in the host's immune response against the periodontal microbiome and serve as a bridge between the...
Gingival connective tissue and its vasculature play a crucial role in the host's immune response against the periodontal microbiome and serve as a bridge between the oral and systemic environments. However, there is a lack of representative models that mimic the complex features of vascularized gingival connective tissue and its interaction with the periodontal microbiome, hindering our understanding of periodontal health and disease. Towards this pursuit, we present the characterization of vascularized gingival connective tissue equivalents (CTEs) as a model to study the interactions between oral biofilm colonizers and gingival tissues in healthy and diseased states. Whole-mount immunolabeling and label-free confocal reflectance microscopy of human fibrin-based matrix embedded with gingival fibroblasts and microvascular endothelial cells demonstrated the generation of bi-cellular vascularized gingival CTEs. Next, we investigated the response of the vascularized gingival CTEs to early, intermediate, and late oral biofilm colonizers. Despite colonization, the early colonizers did not elicit any significant change in the production of the cytokines and chemokines by the CTEs representative of the commensal and homeostatic state. In contrast, intermediate and late colonizers representing a transition to a diseased state exhibited connective tissue and vascular invasion, and elicited a differential immune response accompanied by increased monocyte migration. The culture supernatants produced by the vascularized gingival CTEs in response to early and intermediate colonizers polarized macrophages towards an immunomodulatory M2-like phenotype which activates and protects the host, while the late colonizers polarized towards a pro-inflammatory M1-like phenotype. Lastly,analysis showed a high strength of associations between the proteins and transcripts investigated with periodontitis and vascular diseases. In conclusion, the vascularized gingival CTEs provide a biomimeticplatform to study host-microbiome interactions and innate immune response in periodontal health and diseased states, which potentially paves the way toward the development and assessment of novel periodontal therapeutics.
Topics: Humans; Endothelial Cells; Host Microbial Interactions; Gingiva; Periodontitis; Connective Tissue
PubMed: 37473752
DOI: 10.1088/1758-5090/ace935