Inhibition of PKM2 suppresses osteoclastogenesis and alleviates bone loss in mouse periodontitis.

BACKGROUND: Chronic periodontitis triggers an increase in osteoclastogenesis, with glycolysis playing a crucial role in this process. Pyruvate kinase M2 (PKM2) is a critical enzyme involved in glycolysis and pyruvate metabolism. Yet, the precise function of PKM2 in osteoclasts and their formation remains unclear and requires further investigation. METHODS: Bioinformatics was used to investigate critical biological processes in osteoclastogenesis. In vitro, osteoclastogenesis was analyzed using tartrate-resistant acid phosphatase (TRAP) staining, phalloidin staining, quantitative real­time PCR (RT-qPCR), and Western blotting. Small interfering RNA (siRNA) of PKM2 and Shikonin, a specific inhibitor of PKM2, were used to verify the role of PKM2 in osteoclastogenesis. The mouse model of periodontitis was used to assess the effect of shikonin on bone loss. Analyses included micro computed tomography, immunohistochemistry, flow cytometry, TRAP staining and HE staining. RESULTS: Bioinformatic analysis revealed a significant impact of glycolysis and pyruvate metabolism on osteoclastogenesis. Inhibition of PKM2 leads to a significant reduction in osteoclastogenesis. In vitro, co-culture of the heat-killed Porphyromonas gingivalis significantly promoted osteoclastogenesis, concomitant with an increased PKM2 expression in osteoclasts. Shikonin weakened the promoting effect of porphyromonas gingivalis on osteoclastogenesis. In vivo experiments demonstrated that inhibition of PKM2 by shikonin alleviated bone loss induced by periodontitis, suppressed excessive osteoclastogenesis in alveolar bone, and reduced tissue inflammation to some extent. CONCLUSION: PKM2 inhibition by shikonin, a specific inhibitor of this enzyme, attenuated osteoclastogenesis and bone resorption in periodontitis. Shikonin appears to be a promising therapeutic agent for treating periodontitis.

The relationship between third molar agenesis and craniofacial morphology: a systematic review and meta-analysis.

BACKGROUND: Agenesis of third molar agenesis has a higher incidence than other tooth development anomalies. Previous research identified a potential correlation between third molar agenesis and specific craniofacial morphology; however, no systematic review and meta-analysis on this topic currently exists. OBJECTIVE: The objective of this systematic review and meta-analysis was to evaluate the association between third molar agenesis and craniofacial sagittal and vertical morphology. SEARCH METHODS: An electronic search was conducted on PubMed, Embase, Web of Science, and the Cochrane Library without restrictions on publication year or language; this was supplemented by the manual retrieval of relevant literature. SELECTION CRITERIA: Cross-sectional studies that compared craniofacial morphology using angular and linear measurements obtained from lateral cephalography between patients with third molar agenesis and those without were included. DATA COLLECTION AND ANALYSIS: The quality assessment of the enrolled articles was evaluated by the Joanna Briggs Institute critical appraisal tool. Meta-analysis and sensitivity analysis were performed by Review Manager software (The Cochrane Collaborative, version 5.4, Cochrane IMS). RESULTS: A total of seven studies were included. Meta-analysis demonstrated that the ANB (mean differences (MD) = -0.75, 95% CI: -1.31 to -0.19, P < 0.01), palate length (ANS-PNS, MD = -1.68, 95% CI: -2.24 to -1.11, P < 0.01), and mandibular length (Go-Pog, MD = -0.36, 95% CI: -0.59 to -0.13, P < 0.01) were smaller in patients with third molar agenesis. With regard to vertical craniofacial morphology, the mandibular plane angle (MP-FH; MD = -1.88, 95% CI: -3.45 to -0.31, P = 0.02), gonial angle (gonial angle; MD = -1.73, 95% CI: -2.69 to -0.77, P < 0.01) and lower face height (lower face heigh angle; MD = -1.36, 95% CI: -1.94 to -0.77, P < 0.01) were smaller in patients with third molar agenesis, indicating a flatter or brachyfacial skeletal pattern. CONCLUSIONS: The results of this study suggest that third molar agenesis maybe associated with a reduced maxillary length and a flatter mandible. However, these findings need to be interpreted with caution due to inconsistencies in the certainty of evidence. CLINICAL TRIAL REGISTRATION: PROSPERO (CRD42023448226).

Influence of differences in mandibular incisor inclination on skeletal stability after orthognathic surgery in patients with skeletal Class III malocclusion.

OBJECTIVE: The preoperative inclination angle of mandibular incisors was crucial for surgical and postoperative stability while the effect of proclined mandibular incisors on skeletal stability has not been investigated. This study aimed to evaluate the effects of differences in presurgical mandibular incisor inclination on skeletal stability after orthognathic surgery in patients with skeletal Class III malocclusion. METHODS: A retrospective cohort study of 80 consecutive patients with skeletal Class III malocclusion who underwent bimaxillary orthognathic surgery was conducted. According to incisor mandibular plane angle (IMPA), patients were divided into 3 groups: retroclined inclination (IMPA < 87°), normal inclination (87° ≤ IMPA < 93°) and proclined inclination (IMPA ≥ 93°). Preoperative characteristics, surgical changes and postoperative stability were compared based on lateral cephalograms obtained 1 week before surgery (T0), 1 week after surgery (T1), and at 6 to 12 months postoperatively (T2). RESULTS: The mandible demonstrated a forward and upward relapse in all three groups. No significant differences in skeletal relapse were observed in the 3 groups of patients. However, the proclined inclination group showed a negative overbite tendency postoperatively compared with the other two groups and a clinically significant mandibular relapse pattern. Proclined IMPA both pre- and postoperatively was correlated with mandibular relapse. CONCLUSION: Sufficient presurgical mandibular incisor decompensation was of crucial importance for the maintenance of skeletal stability in patients with skeletal Class III malocclusion who subsequently underwent orthognathic surgery.

Design, synthesis, and structure-activity relationship of tropane muscarinic acetylcholine receptor antagonists.

Novel tropane derivatives were characterized as muscarinic acetylcholine receptor antagonists (mAChRs). Through optimization of the structure-activity relationship around the tropane scaffold, the quaternary ammonium salt 34 was identified as a very potent M(3) mAChR antagonist. The compound was functionally active and displayed greater than 24 h duration of action in a mouse model of bronchoconstriction.

Discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide as an efficacious inhaled muscarinic acetylcholine receptor antagonist for the treatment of COPD.

Design and syntheses of a novel series of muscarinic antagonists are reported. These efforts have culminated in the discovery of (3-endo)-3-(2-cyano-2,2-diphenylethyl)-8,8-dimethyl-8-azoniabicyclo[3.2.1]octane bromide (4a) as a potent and pan-active muscarinic antagonist as well as a functionally active compound in a murine model of bronchoconstriction. The compound has also displayed pharmacokinetic characteristics suitable for inhaled delivery.