Therapeutic Effect of a Novel M1 Macrophage-Targeted Nanodrug in Chronic Periodontitis Mice.

Chronic periodontitis is a chronic, progressive, and destructive disease. Especially, the large accumulation of advanced glycation end products (AGEs) in a diseased body will aggravate the periodontal tissue damage, and AGEs induce M1 macrophages. In this project, the novel nanodrugs, glucose-PEG-PLGA@MCC950 (GLU@MCC), are designed to achieve active targeting with the help of glucose transporter 1 (GLUT1) which is highly expressed in M1 macrophages induced by AGEs. Then, the nanodrugs release MCC950, which is a kind of NLRP3 inhibitor. These nanodrugs not only can improve the water solubility of MCC950 but also exhibit superior characteristics, such as small size, stability, innocuity, etc. In vivo experiments showed that GLU@MCC could reduce periodontal tissue damage and inhibit cell apoptosis in periodontitis model mice. In vitro experiments verified that its mechanism of action might be closely related to the inhibition of the NLRP3 inflammatory factor in M1 macrophages. GLU@MCC could effectively reduce the damage to H400 cells caused by AGEs, decrease the expression of NLRP3, and also obviously reduce the M1-type macrophage pro-inflammatory factors such as IL-18, IL-1ß, caspase-1, and TNF-α. Meanwhile, the expression of anti-inflammatory factor Arg-1 in the M2 macrophage was increased. In brief, GLU@MCC would inhibit the expression of inflammatory factor NLRP3 and exert antiperiodontal tissue damage in chronic periodontitis via GLUT1 in the M1 macrophage as the gating target. This study provides a novel nanodrug for chronic periodontitis treatment.

Novel truncating mutations in CTNND1 cause a dominant craniofacial and cardiac syndrome.

CTNND1 encodes the p120-catenin (p120) protein, which has a wide range of functions, including the maintenance of cell-cell junctions, regulation of the epithelial-mesenchymal transition and transcriptional signalling. Due to advances in next-generation sequencing, CTNND1 has been implicated in human diseases including cleft palate and blepharocheilodontic (BCD) syndrome albeit only recently. In this study, we identify eight novel protein-truncating variants, six de novo, in 13 participants from nine families presenting with craniofacial dysmorphisms including cleft palate and hypodontia, as well as congenital cardiac anomalies, limb dysmorphologies and neurodevelopmental disorders. Using conditional deletions in mice as well as CRISPR/Cas9 approaches to target CTNND1 in Xenopus, we identified a subset of phenotypes that can be linked to p120-catenin in epithelial integrity and turnover, and additional phenotypes that suggest mesenchymal roles of CTNND1. We propose that CTNND1 variants have a wider developmental role than previously described and that variations in this gene underlie not only cleft palate and BCD but may be expanded to a broader velocardiofacial-like syndrome.

DYNC1H1-related disorders: A description of four new unrelated patients and a comprehensive review of previously reported variants.

Heterozygous variants in the DYNC1H1 gene have been associated chiefly with intellectual disability (ID), malformations in cortical development (MCD), spinal muscular atrophy (SMA), and Charcot-Marie-Tooth axonal type 20 (CMT), with fewer reports describing other intersecting phenotypes. To better characterize the variable syndromes associated with DYNC1H1, we undertook a detailed analysis of reported patients in the medical literature through June 30, 2019. In sum we identified 200 patients from 143 families harboring 103 different DYNC1H1 variants, and added reports for four unrelated patients identified at our center, three with novel variants. The most common features associated with DYNC1H1 were neuromuscular (NM) disease (largely associated with variants in the stem domain), ID with MCD (largely associated with variants in the motor domain), or a combination of these phenotypes. Despite these trends, exceptions are noted throughout. Overall, DYNC1H1 is associated with variable neurodevelopmental and/or neuromuscular phenotypes that overlap. To avoid confusion DYNC1H1 disorders may be best categorized at this time by more general descriptions rather than phenotype-specific nomenclature such as SMA or CMT. We therefore propose the terms: DYNC1H1-related NM disorder, DYNC1H1-related CNS disorder, and DYNC1H1-related combined disorder. Our single center's experience may be evidence that disease-causing variants in this gene are more prevalent than currently recognized.