IRE1α regulates macrophage polarization in type 2 diabetic periodontitis through promoting endoplasmic reticulum stress.

OBJECTIVES: The aim of this study was to investigate the effect of 4µ8c, an inhibitor targeting the endoplasmic reticulum stress-associated factor IRE1α, on macrophage polarization in an experimental model of diabetic periodontitis through ex vivo experiments. MATERIALS AND METHODS: Local alveolar bone parameters were evaluated using Micro-CT following intraperitoneal administration of 4µ8c in mice with experimental diabetic periodontitis. Surface markers indicating macrophage polarization were identified using immunofluorescence. In vitro experiments were performed employing bone marrow-derived macrophages and gingival fibroblasts. Macrophage polarization was determined using flow cytometry. Principal impacted signaling pathways were identified through Western blot analysis. RESULTS: Results from both in vitro and in vivo experiments demonstrated that 4µ8c mitigated alveolar bone resorption and inflammation in mice with diabetic periodontitis. Furthermore, it modulated macrophage polarization towards the M2 phenotype and augmented M2 macrophage polarization through the MAPK signaling pathway. CONCLUSIONS: These findings suggest that inhibiting IRE1α can modulate macrophage polarization and alleviate ligature-induced diabetic periodontitis via the MAPK signaling pathway. This unveils a novel mechanism, offering a scientific foundation for the treatment of experimental diabetic periodontitis.

Clostridium butyricum MIYAIRI 588 alleviates periodontal bone loss in mice with diabetes mellitus.

The gut microbiota is a bridge linking periodontitis and systemic diseases, such as diabetes mellitus (DM). The probiotic Clostridium butyricum MIYAIRI 588 (CBM588) is reportedly an effective therapeutic approach for gut dysbiosis. Here, in a mouse model, we explored the therapeutic effect of CBM588 on periodontal bone destruction in DM and DM-associated periodontitis (DMP), as well as the underlying mechanism. Micro-computed tomography revealed that DM and DMP both aggravated periodontal bone destruction, which was alleviated by intragastric supplementation with CBM588. Moreover, 16S rRNA sequencing and untargeted metabolite analysis indicated that CBM588 ameliorated DMP-triggered dysbiosis and led to reduced oxidative stress associated with elevated 4-hydroxybenzenemethanol (4-HBA) in serum. Furthermore, in vitro and in vivo experiments found that the metabolite 4-HBA promoted nuclear factor erythroid 2-related factor 2 (Nrf2) signaling activation and modulated the polarization of macrophages, thus ameliorating inflammatory bone destruction in DMP. Our study demonstrates the protective effects of CBM588 in DM-induced mice, with and without ligature-induced periodontitis. The mechanism involves regulation of the gut microbiota and restoration of the integrity of the gut barrier to alleviate oxidative damage by elevating serum 4-HBA. This study suggests the possibility of CBM588 as a therapeutic adjuvant for periodontal treatment in diabetes patients.

Increased serum α-tocopherol acetate mediated by gut microbiota ameliorates alveolar bone loss through the STAT3 signalling pathway in diabetic periodontitis.

AIM: To evaluate whether and how gut microbiota-meditated metabolites regulate alveolar bone homeostasis in diabetic periodontitis (DP). MATERIALS AND METHODS: Lactobacillus casei (L. casei) was employed as a positive modulator of gut microbiota in DP mice. The destruction of alveolar bone was evaluated. Untargeted metabolomics was conducted to screen out the pivotal metabolites. A co-housing experiment was conducted to determine the connection between the gut microbiota and alpha-tocopherol acetate (α-TA). α-TA was applied to DP mice to investigate its effect against alveolar bone loss. Human periodontal ligament cells (hPDLCs) and human gingival fibroblasts (HGFs) were extracted for the in vitro experiment. Transcriptomic analysis and immunohistochemistry were performed to detect the major affected signalling pathways. RESULTS: Positive regulation of the gut microbiota significantly attenuated alveolar bone loss and increased the serum α-TA level. The alteration in gut microbiota composition could affect the serum α-T (the hydrolysates of α-TA) level. α-TA could alleviate alveolar bone destruction in DP mice and α-T exert beneficial effects on hPDLCs and HGFs. Mechanistically, the STAT3 signalling pathway was the pivotal pathway involved in the protective role of α-TA. CONCLUSIONS: The gut microbiota-α-TA-STAT3 axis plays an important role in the regulation of diabetic alveolar bone homeostasis.

Extracellular vesicles derived from human dental mesenchymal stem cells stimulated with low-intensity pulsed ultrasound alleviate inflammation-induced bone loss in a mouse model of periodontitis.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) have emerged as a new mode of intercellular crosstalk and are responsible for many of the therapeutic effects of MSCs. To promote the application of MSC-EVs, recent studies have focused on the manipulation of MSCs to improve the production of EVs and EV-mediated activities. The current paper details an optimization method using non-invasive low-intensity pulsed ultrasound (LIPUS) as the stimulation for improving oral MSC-EV production and effectiveness. Stem cells from apical papilla (SCAP), a type of oral mesenchymal stem cell, displayed intensity-dependent pro-osteogenic and anti-inflammatory responses to LIPUS without significant cytotoxicity or apoptosis. The stimuli increased the secretion of EVs by promoting the expression of neutral sphingomyelinases in SCAP. In addition, EVs from LIPUS-induced SCAP exhibited stronger efficacy in promoting the osteogenic differentiation and anti-inflammation of periodontal ligament cells in vitro and alleviating oral inflammatory bone loss in vivo. In addition, LIPUS stimulation affected the physical characteristics and miRNA cargo of SCAP-EVs. Further investigations indicated that miR-935 is an important mediator of the pro-osteogenic and anti-inflammatory capabilities of LIPUS-induced SCAP-EVs. Taken together, these findings demonstrate that LIPUS is a simple and effective physical method to optimize SCAP-EV production and efficacy.

Systemic antibiotics increase microbiota pathogenicity and oral bone loss.

Periodontitis is the most widespread oral disease and is closely related to the oral microbiota. The oral microbiota is adversely affected by some pharmacologic treatments. Systemic antibiotics are widely used for infectious diseases but can lead to gut dysbiosis, causing negative effects on the human body. Whether systemic antibiotic-induced gut dysbiosis can affect the oral microbiota or even periodontitis has not yet been addressed. In this research, mice were exposed to drinking water containing a cocktail of four antibiotics to explore how systemic antibiotics affect microbiota pathogenicity and oral bone loss. The results demonstrated, for the first time, that gut dysbiosis caused by long-term use of antibiotics can disturb the oral microbiota and aggravate periodontitis. Moreover, the expression of cytokines related to Th17 was increased while transcription factors and cytokines related to Treg were decreased in the periodontal tissue. Fecal microbiota transplantation with normal mice feces restored the gut microbiota and barrier, decreased the pathogenicity of the oral microbiota, reversed the Th17/Treg imbalance in periodontal tissue, and alleviated alveolar bone loss. This study highlights the potential adverse effects of long-term systemic antibiotics-induced gut dysbiosis on the oral microbiota and periodontitis. A Th17/Treg imbalance might be related to this relationship. Importantly, these results reveal that the periodontal condition of patients should be assessed regularly when using systemic antibiotics in clinical practice.

A rational synthesis of ultrasmall palladium-based alloys with superhydrophilicity as biocompatible agents and recyclable catalysts.

As essential controlling parameters, the local surface area (size distribution) and polarity property of the surface molecules can determine the catalytic activity and biocompatibility directly. Here, ultrasmall palladium-based alloys (FePd, FePdCo, and FePdCu NCs) were developed to serve as artificial degradation catalysts with superhydrophilicity (SPh), biocompatibility, and reusability, which were referred to as "biocatalysts". As synthesized in aqueous solvent with negative surface potential while dispersing in water medium, because of the surface biological molecules effect. The obtained alloys illustrated a size distribution of about 3.5 nm. Additionally, owing to SPh property, these alloys could be stored in water up to 30 days without any precipitation and retained their monodisperse morphology in colloidal solutions. The cytotoxicity assessment of the alloys by exposing to L-929 cells over 3 days indicated that it maintained cell viability of >80% even up to 390 µg mL-1 (concentration of alloys). Furthermore, they exhibited an obvious enhancement in the catalytic performance for degrading Rhodamine B (RhB) and 4-nitrophenol (4-NP). The recyclable utilization of biocatalysts demonstrates durable stability even after 8 reduction cycles.

A Natural Hydrogel with Prohealing Properties Enhances Tendon Regeneration.

Tendon regeneration and reduction of peritendinous adhesion remain major clinical challenges. This study addresses these challenges by adopting a unique hydrogel derived from the skin secretion of Andrias davidianus (SSAD) and taking advantage of its biological effects, adhesiveness, and controllable microstructures. The SSAD-derived hydrogel contains many cytokines, which could promote tendon healing. In vitro, leach liquid of SSAD powder could promote tendon stem/progenitor cells migration. In vivo, the SSAD-derived hydrogel featuring double layers possesses strong adhesiveness and could reconnect ruptured Achilles tendons of Sprague-Dawley rats without suturing. The intimal SSAD-derived hydrogel, with a pore size of 241.7 ± 21.0 µm, forms the first layer of the hydrogel to promote tendon healing, and the outer layer SSAD-derived hydrogel, with a pore size of 3.3 ± 1.4 µm, reducing peritendinous adhesion by serving as a dense barrier. Additionally, the SSAD-derived hydrogel exhibits antioxidant and antibacterial characteristics, which further contribute to the reduction of peritendinous adhesion. In vivo studies suggest that the SSAD-derived hydrogel reduces peritendinous adhesion, increases collagen fiber deposition, promotes cell proliferation, and improves the biomechanical properties of the regenerated tendons, indicating better functional restoration. The SSAD-derived bilayer hydrogel may be a feasible biomaterial for tendon repair in the future.