A Mouse Model for Studying the Development of Apical Periodontitis with Age.
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ABSTRACT:
SUBMITTER: Goldman E
PROVIDER: S-EPMC8002842 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:In both humans and mice, the Glu-99-Lys (E99K) mutation in the cardiac actin gene (ACTC) results in little understood apical hypertrophic cardiomyopathy (AHCM). To determine how cross-bridge kinetics change with AHCM development, we applied sinusoidal length perturbations to skinned papillary muscle fibres from 2- and 5-month old E99K transgenic (Tg) and non-transgenic (NTg) mice, and studied tension and its transients. These age groups were chosen because our preliminary studies indicated that AHCM develops with age. Fibres from 5-month old E99K mice showed significant decreases in tension, stiffness, the rate of the medium-speed exponential process and its magnitude compared to non-transgenic control. The nucleotide association constants increased with age, and they were significantly larger in E99K compared to NTg. However, there were no large differences in the rates of the cross-bridge detachment step, the rates of the force generation step, or the phosphate association constant. Our result on force/cross-bridge demonstrates that the decreased active tension of E99K fibres was caused by a decreased amount of force generated per each cross-bridge. The effects were generally less or insignificant at 2 months. A pCa-tension study showed increased Ca2+-sensitivity (pCa50) with age in both the E99K and NTg sample groups, and pCa50 was significantly larger (but only for 0.05-0.06 pCa units) in E99K than in NTg groups. A significant decrease in cooperativity (nH) was observed only in 5-month old E99K mice. We conclude that the AHCM-causing ACTC E99K mutation is associated with progressive alterations in biomechanical parameters, with changes smaller at 2 months but larger at 5 months, correlating with the development of AHCM.
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Project description:Apical periodontitis caused by microbial infection in the dental pulp is characterized by inflammation, destruction of the pulpal and periradicular tissues, and alveolar bone resorption. We analyzed the chronological changes in microbiota using a pyrosequencing-based approach combined with radiologic and histopathologic changes in a rat apical periodontitis model. During the three-week observation, the pulp and periapical area showed a typical progress of apical periodontitis. A total of 27 phyla, 645 genera, and 1276 species were identified. The root apex had a lower bacterial species diversity than the pulp chamber. Proteobacteria, Firmicutes, Bacteroidetes, and Actinobacteria were dominant phyla in both the pulp chamber and root apex. Remarkably, bacterial communities showed a tendency to change in the root apex based on the disease progression. At the genus level, Escherichia, Streptococcus, Lactobacillus, Rodentibacter, and Bacteroidetes were dominant genera in the pulp chamber. The most abundant genera in the root apex were Bradyrhizobium, Halomonas, and Escherichia. The species Azospirillum oryzae increased in the pulp chamber, whereas the species Bradyrhizobium japonicum and Halomonas stevensii were highly observed in the root apex as the disease progressed. The experimental rat model of apical periodontitis demonstrated a relationship between the microbiota and the apical periodontitis progression.
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Project description:Apical periodontitis is an inflammatory disorder of periradicular tissues developed from endodontic infections. Understanding its pathophysiology and the underlying molecular mechanisms is key to the advancement of endodontics. MicroRNAs (miRNAs), a group of evolutionarily conserved small non-coding RNAs, may be phenotypically and functionally associated with the pathogenesis of apical periodontitis. Several studies have focused on the role of miRNAs in the pulp and periradicular biology, and they have demonstrated their essential functions, such as initiating odontogenic differentiation and promoting pro- or anti-inflammatory responses in pulpitis. Up to date, over 2,000 miRNAs have been discovered in humans; however, only few have been reported to associate with apical periodontitis. Therefore, identifying miRNAs involved in diseased apical tissues and conducting functional studies are important in expanding our current knowledge of pulp and periradicular biology and exploring novel therapeutic avenues. In this review, we revisit current models of apical periodontitis and miRNA biogenesis, analyze existing evidence of the involvement of miRNAs in diseased apical tissues, and discuss their diverse functions and potential values. Based on their sheer abundance, prolonged stability in biofluid, and relative ease of sampling, miRNAs may be a useful tool to be developed as diagnostic biomarkers for apical periodontitis. Furthermore, it can be used as therapeutic targets in conjunction with conventional endodontic therapies.
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Project description:BackgroundApical periodontitis (AP) is essentially an inflammatory disease of microbial etiology primarily caused by infection of the pulp and root canal system. Variation of the bacterial communities caused by AP, as well as their changes responding to dental therapy, are of utmost importance to understand the pathogensis of the apical periodontitis and establishing effective antimicrobial therapeutic strategies. This study aims to uncover the composition and diversity of microbiota associated to the root apex to identify the relevant bacteria highly involved in AP, with the consideration of root apex samples from the infected teeth (with/without root canal treatment), healthy teeth as well as the healthy oral.MethodsFour groups of specimens are considered, the apical part of root from diseased teeth with and without root canal treatment, and wisdom teeth extracted to avoid being impacted (tooth healthy control), as well as an additional healthy oral control from biofilm of the buccal mucosa. DNA was extracted from these specimens and the microbiome was examined through focusing on the V3-V4 hypervariable region of the 16S rRNA gene using sequencing on Illumina MiSeq platform. Composition and diversity of the bacterial community were tested for individual samples, and between-group comparisons were done through differential analysis to identify the significant changes.ResultsWe observed reduced community richness and diversity in microbiota samples from diseased teeth compared to healthy controls. Through differential analysis between AP teeth and healthy teeth, we identified 49 OTUs significantly down-regulated as well as 40 up-regulated OTUs for AP.ConclusionThis study provides a global view of the microbial community of the AP associated cohorts, and revealed that AP involved not only bacteria accumulated with a high abundance, but also those significantly reduced ones due to microbial infection.
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Project description:Apical periodontitis (AP) is a painful inflammatory disease resulting from tooth infection that affects millions worldwide with a marked impact on quality of life and is accompanied by bone loss surrounding the affected tooth. There is growing evidence that the nociceptive fibers densely innervating teeth regulate the disease progression, in addition to their sensorial function. We hypothesized that nociceptors regulate the transcriptomic profile of the periapical osteolytic lesion in a mouse model of AP. Male control (Nav1.8 cre+/-) and nociceptor-ablated (Nav1.8cre+/- DTAlox+/-) mice were generated and underwent pulp exposure procedures on all 4 first molars and at 8 weeks of age. At either 0, 7, or 14 days after pulp exposure, periapical tissues were dissected from mice (n=3-4/strain/time point). Total RNA was extracted from the pooled periapical lesions from each animal and submitted for total RNA sequencing and bioinformatic analysis. We found that pulp exposure triggers the differential expression of hundreds of genes within the periapical lesion over the course of infection with marked differences between in both control and mice with nociception ablation. Importantly, at 14 days post pulp-exposure, 422 genes were differentially expressed between nociceptor-ablated and control mice with greater enrichment of biological processes related to inflammation, specifically immune cell chemotaxis and migration, compared to control mice. Among these inflammatory markers, TNFα, IL-1α, and IL-1β, that are known to play a crucial role in AP were significantly upregulated in nociceptor-ablated mice. In conclusion, nociceptor-ablation regulates the transcriptomic profile of periapical lesions in a mouse model of AP, 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 AP can potentially be an important therapeutic target for the treatment of this prevalent disease.
2023-12-31 | GSE205195 | GEO
Project description:Vascular progenitor cells are desirable in a variety of therapeutic strategies; however, the lineage commitment of endothelial and smooth muscle cell from a common progenitor is not well-understood. Here, we report the generation of the first dual reporter mouse embryonic stem cell (mESC) lines designed to facilitate the study of vascular endothelial and smooth muscle development in vitro. These mESC lines express green fluorescent protein (GFP) under the endothelial promoter, Tie-2, and Discomsoma sp. red fluorescent protein (RFP) under the promoter for alpha-smooth muscle actin (α-SMA). The lines were then characterized for morphology, marker expression, and pluripotency. The mESC colonies were found to exhibit dome-shaped morphology, alkaline phosphotase activity, as well as expression of Oct 3/4 and stage-specific embryonic antigen-1. The mESC colonies were also found to display normal karyotypes and are able to generate cells from all three germ layers, verifying pluripotency. Tissue staining confirmed the coexpression of VE (vascular endothelial)-cadherin with the Tie-2 GFP+ expression on endothelial structures and smooth muscle myosin heavy chain with the α-SMA RFP+ smooth muscle cells. Lastly, it was verified that the developing mESC do express Tie-2 GFP+ and α-SMA RFP+ cells during differentiation and that the GFP+ cells colocalize with the vascular-like structures surrounded by α-SMA-RFP cells. These dual reporter vascular-specific mESC permit visualization and cell tracking of individual endothelial and smooth muscle cells over time and in multiple dimensions, a powerful new tool for studying vascular development in real time.
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Project description:Apical periodontitis is an inflammatory reaction at the apex of an infected tooth. Its microbiota resembles that of marginal periodontitis and may induce local and systemic antibodies binding to bacteria- and host-derived epitopes. Our aim was to investigate the features of the adaptive immune response in apical periodontitis. The present Parogene cohort (n = 453) comprises patients with cardiac symptoms. Clinical and radiographic oral examination was performed to diagnose apical and marginal periodontitis. A three-category endodontic lesion score was designed. Antibodies binding to the bacteria- and host-derived epitopes were determined from saliva and serum, and bacterial compositions were examined from saliva and subgingival samples. The significant ORs (95% CI) for the highest endodontic scores were observed for saliva IgA and IgG to bacterial antigens (2.90 (1.01-8.33) and 4.91 (2.48-9.71)/log10 unit), saliva cross-reacting IgG (2.10 (1.48-2.97)), serum IgG to bacterial antigens (4.66 (1.22-10.1)), and Gram-negative subgingival species (1.98 (1.16-3.37)). In a subgroup without marginal periodontitis, only saliva IgG against bacterial antigens associated with untreated apical periodontitis (4.77 (1.05-21.7)). Apical periodontitis associates with versatile adaptive immune responses against both bacterial- and host-derived epitopes independently of marginal periodontitis. Saliva immunoglobulins could be useful biomarkers of oral infections including apical periodontitis-a putative risk factor for systemic diseases.
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