Engineered extracellular vesicles with sequential cell recruitment and osteogenic functions to effectively promote senescent bone repair.

Senescent mandibular bone repair poses a formidable challenge without a completely satisfactory strategy. Endogenous cell recruitment and osteogenic differentiation are two sequential stages in bone regeneration, and disruptions in these two processes present significant obstacles to senescent bone repair. To address these issues, engineered extracellular vesicles (EV) with sequential stem cell recruitment and osteogenic functions were developed.

Advances in magnesium-containing bioceramics for bone repair.

Reconstruction of bone defects or fractures caused by ageing, trauma and tumour resection is still a great challenge in clinical treatment. Although autologous bone graft is considered as gold standard, the source of natural bone is limited. In recent years, regenerative therapy based on bioactive materials has been proposed for bone reconstruction.

DNA Tetrahedron Delivering miR-21-5p Promotes Senescent Bone Defects Repair through Synergistic Regulation of Osteogenesis and Angiogenesis.

Compromised osteogenesis and angiogenesis is the character of stem cell senescence, which brought difficulties for bone defects repairing in senescent microenvironment. As the most abundant bone-related miRNA, miRNA-21-5p plays a crucial role in inducing osteogenic and angiogenic differentiation. However, highly efficient miR-21-5p delivery still confronts challenges including poor cellular uptake and easy degradation.

Mesoporous bioactive glass scaffolds for the delivery of bone marrow stem cell-derived osteoinductive extracellular vesicles lncRNA promote senescent bone defect repair by targeting the miR-1843a-5p/Mob3a/YAP axis.

Bone repair in elderly patients poses a huge challenge due to the age-related progressive decline in regenerative abilities attributed to the senescence of bone marrow stem cells (BMSCs). Bioactive scaffolds have been applied in bone regeneration due to their various biological functions. In this study, we aimed to fabricate functionalized bioactive scaffolds through loading osteoinductive extracellular vesicles (OI-EVs) based on mesoporous bioactive glass (MBG) scaffolds (10 particles/scaffold) and to investigate its effects on osteogenesis and senescence of BMSCs.

Mandible-First Sequencing Increase Surgical Accuracy for Patients With Skeletal Class II Malocclusion Concomitant With Unstable Condyle-Fossa Relation.

The aim of this study was to explore whether mandible-first sequencing increases the surgical accuracy in bimaxillary orthognathic surgery for patients with skeletal class II malocclusion concomitant with the unstable condyle-fossa relation. A retrospective evaluation of 19 patients who had undergone virtually planned double-splint orthognathic surgery with different operation sequences was performed: maxilla-first (n=9) or mandible-first (n=10) surgery. The centroid position, translational, and rotational differences in the maxilla were evaluated by comparing the virtual plans with actual results.

Magnesium-containing bioceramics stimulate exosomal miR-196a-5p secretion to promote senescent osteogenesis through targeting /MAPK signaling axis.

Stem cell senescence is characterized by progressive functional dysfunction and secretory phenotypic changes including decreased proliferation, dysfunction of osteogenic and angiogenic differentiation, increased secretion of the senescence-associated secretory phenotype (SASP), which bring difficulties for bone repair. Rescuing or delaying senescence of aged bone marrow mesenchymal stem cells (O-BMSCs) was considered as effective strategy for bone regeneration in aging microenvironment. Magnesium (Mg) ion released from bioceramics was reported to facilitate bone regeneration via enhancing osteogenesis and alleviating senescence.

Compromised osteogenic effect of exosomes internalized by senescent bone marrow stem cells endocytoses involving clathrin, macropinocytosis and caveolae.

Stem cell senescence leads to progressive functional declines and disrupts the physiological homeostasis of bone environment. Stem cell-derived exosomes are emerging as promising therapeutical approaches to treat diverse aging-related osseous diseases. Herein, a previously reported osteoinductive exosome (OI-exo) was applied as a therapeutic agent for bone repair in aging individuals and its internalization mechanisms in senescent bone marrow stem cells (BMSCs) were explored.

Evaluation of the transdentinal capability of the intrinsic antibacterial cetylpyridinium chloride/cholesterol sterosomes in vitro and in vivo.

Aim: Dentinal tubules serve as disease-causing channels for infiltration and penetration of bacteria and their by-products; which are regarded as the major driver of pathogenesis in pulpal inflammation and infection. In this study, we aimed to evaluate the transdentinal potential of nanoscale cetylpyridinium chloride/cholesterol (CPC/Chol) sterosomes, which are a recently developed type of cationic non-phospholipid liposomal nanocarrier; as well as their intrinsic and universal antibacterial activity.

Methodology: Cetylpyridinium chloride/cholesterol sterosomes were formulated, with a hydrodynamic diameter of 134 ± 4 nm, a low polydisperse index of 0.

Evaluation of Related Factors of Maxillary Sinusitis After Le Fort I Osteotomy Based on Computed Tomography: A Retrospective Case-Control Study.

Maxillary sinusitis is 1 of the postoperative complications of the Le Fort I osteotomy, this study investigated the related factors of maxillary sinusitis after Le Fort I osteotomy. A total of 23 cases, 92 controls, and 11 related factors were included in this case-control study with a 1:4 case-control ratio. The risk factors for maxillary sinusitis after Le Fort I were examined by least absolute shrinkage and selection operator multivariate conditional logistic regression and least absolute shrinkage and selection operator multivariate linear regression.

Effects of autologous concentrated growth factor on gingival thickness in periodontal accelerated osteogenic orthodontics: a 6-month randomized controlled trial.

Background: Earlier studies have not given clear results of concentrated growth factor (CGF) on gingival thickness (GT) in periodontal accelerated osteogenic orthodontics (PAOO). This randomized controlled trial aimed to evaluate the effects of CGF on GT in patients with thin gingival phenotype undergoing PAOO.

Methods: Forty four patients presenting 264 anterior mandibular teeth were recruited and randomly allocated to one of the groups: test-positioning of autologous CGF after PAOO or control-positioning of a collagen membrane after PAOO.

A new method for individual condylar osteotomy and repositioning guides used in patients with severe deformity secondary to condylar osteochondroma.

Background: Mandibular condylar osteochondroma (OC) could lead to facial morphologic and functional disturbances, such as facial asymmetry, malocclusion, and temporomandibular joint dysfunction. However, after condylar OC resection, the inaccurate reposition of the neocondyle still needs to be solved. The purpose of this study was to explore the feasibility of the condylar osteotomy and repositioning guide to reposition the neocondyle in the treatment of patients with severe deformity secondary to condylar OC.

Amyotrophic lateral sclerosis: Protein chaperone dysfunction revealed by proteomic studies of animal models.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects motor neurons and causes progressive muscle weakness and atrophy. The etiology and pathogenesis of ALS are largely unknown and no effective treatment is presently available. About 10% of patients have the familial or inherited form of the disease (fALS), among which 20% is linked to mutations with Cu(2+)/Zn(2+) superoxide dismutase (mSOD1).

Immune modulation and tolerance induction by RelB-silenced dendritic cells through RNA interference.

Dendritic cells (DC), the most potent APCs, can initiate the immune response or help induce immune tolerance, depending upon their level of maturation. DC maturation is associated with activation of the NF-kappaB pathway, and the primary NF-kappaB protein involved in DC maturation is RelB, which coordinates RelA/p50-mediated DC differentiation. In this study, we show that silencing RelB using small interfering RNA results in arrest of DC maturation with reduced expression of the MHC class II, CD80, and CD86.

Calcium mediated excitotoxicity in neurofilament aggregate-bearing neurons in vitro is NMDA receptor dependant.

We have previously shown that the co-localization of neuronal nitric oxide synthase (nNOS) with neurofilament (NF) aggregates in motor neurons derived from transgenic mice over-expressing the human low molecular weight NF protein (hNFL+/+) is associated with a deregulation of calcium influx via the N-methyl-d-aspartate (NMDA) receptor, resulting in apoptosis. Because the absence of the GluR2 subunit of the alpha-amino-3-hydroxy-5-methyl-4-isoazolepropionic acid (AMPA) receptor confers calcium permeability and has been implicated in the process of excitotoxicity in ALS, we have examined the role of the AMPA receptor in this model. GluR2 protein expression and mRNA were examined in hNFL+/+ and wild-type motor neurons (wt).

14-3-3 protein binds to the low molecular weight neurofilament (NFL) mRNA 3' UTR.

We have previously reported that altered stability of low molecular weight neurofilament (NFL) mRNA in lumbar spinal cord homogenates in amyotrophic lateral sclerosis (ALS) is associated with altered expression of trans-acting 3' UTR mRNA binding proteins. We have identified two hexanucleotide motifs as the main cis elements and, using LC/MS/MS of peptide digests of NFL 3' UTR interacting proteins from human spinal cord, observed that 14-3-3 proteins interact with these motifs. 14-3-3 beta, zeta, tau, gamma, and eta isoforms were found to be expressed in human spinal cord.

Neuronal tissue-specific ribonucleoprotein complex formation on SOD1 mRNA: alterations by ALS SOD1 mutations.

Amyotrophic lateral sclerosis (ALS) is a fatal disease of unknown etiology. Mutations in copper/zinc superoxide dismutase (SOD1) are the most commonly associated genetic abnormality. Given that SOD1 is ubiquitously expressed, the exclusive vulnerability of motor neurons is one of the most puzzling issues in ALS research.

Activated microglial supernatant induced motor neuron cytotoxicity is associated with upregulation of the TNFR1 receptor.

We have previously reported that supernatant derived from LPS-activated BV-2 cells, an immortalized microglial cell line, induces death of NSC-34 cells (a motor neuron hybridoma) through a TNFalpha and nitric oxide synthase (NOS) dependant mechanism. In this study, we have observed that LPS-activated BV-2 supernatant induces NSC-34 cell death in association with an upregulation of the TNF receptor 1 (TNFR1) expression on NSC-34 cells, both at the transcription level and at the cell surface protein level. The upregulation of TNFR1 receptor was independent of TNFalpha, and could be partly inhibited by the inhibition of iNOS activation in the BV-2 cells.

Mutant copper-zinc superoxide dismutase binds to and destabilizes human low molecular weight neurofilament mRNA.

The mechanism by which mutated copper-zinc superoxide dismutase (SOD1) causes familial amyotrophic lateral sclerosis is believed to involve an adverse gain of function, independent of the physiological antioxidant enzymatic properties of SOD1. In this study, we have observed that mutant SOD1 (G41S, G85A, and G93A) but not the wild type significantly reduced the stability of the low molecular weight neurofilament mRNA in a dosage-dependent manner. We have also demonstrated that mutant SOD1 but not the wild type bound directly to the neurofilament mRNA 3'-untranslated region and that the binding was necessary to induce mRNA destabilization.

Induction of RNA interference in dendritic cells.

Dendritic cells (DC) reside at the center of the immunological universe, possessing the ability both to stimulate and inhibit various types of responses. Tolerogenic/regulatory DC with therapeutic properties can be generated through various means of manipulations in vitro and in vivo. Here we describe several attractive strategies for manipulation of DC using the novel technique of RNA interference (RNAi).

Intermediate filament steady-state mRNA levels in amyotrophic lateral sclerosis.

We have examined the steady-state levels of intermediate filament mRNA in amyotrophic lateral sclerosis using the RNAse protection assay (NFL, NFM, NFH; corrected against GAPDH) or by PCR (peripherin, alpha-internexin, nestin, and vimentin; corrected against beta-actin). Significant elevations of NFL and peripherin mRNA levels were observed within the ALS cervical and lumbar spinal cord, with all other IF mRNA levels being comparable between control and ALS cases. These findings suggest that disturbances in both NFL and peripherin expression, independently known to contribute to the generation of motor neuron dysfunction in transgenic mice, are evident in ALS.

Cytoplasmic retention sites in p190RhoGEF confer anti-apoptotic activity to an EGFP-tagged protein.

p190RhoGEF is a large multi-functional protein with guanine nucleotide exchange (GEF) activity. The C-terminal region of p190RhoGEF is a highly interactive domain that binds multiple factors, including proteins with anti-apoptotic activities. We now report that transfection of EGFP-tagged p190RhoGEF protects Neuro 2a cells from stress-induced apoptosis and that anti-apoptotic activity is localized to cytoplasmic retention sequences (CRS-1 and CRS-2) in the C-terminal region of p190RhoGEF.

Selective loss of trans-acting instability determinants of neurofilament mRNA in amyotrophic lateral sclerosis spinal cord.

Neurofilament (NF) aggregates in motor neurons are a key neuropathological feature of amyotrophic lateral sclerosis (ALS). We have previously observed an alteration in the stoichiometry of NF subunit steady state mRNA levels in ALS spinal motor neurons using in situ hybridization and proposed that this led to aggregate formation. We have now examined the levels of NF mRNA in whole tissue homogenates of spinal cord using the RNase protection assay and real time reverse transcriptase-PCR and observed significant elevations of NF mRNA level in ALS.

Binding of p190RhoGEF to a destabilizing element on the light neurofilament mRNA is competed by BC1 RNA.

The enhancement of RNA-mediated motor neuron degeneration in transgenic mice by mutating a major mRNA instability determinant in a light neurofilament (NF-L) transgene implicates cognate RNA binding factors in the pathogenesis of motor neuron degeneration. p190RhoGEF is a neuron-enriched guanine exchange factor (GEF) that binds to the NF-L-destabilizing element, to c-Jun N-terminal kinase-interactive protein-1 (JIP-1), and to 14-3-3 and may link neurofilament expression to pathways affecting neuronal homeostasis. This study was undertaken to identify additional RNA species that bind p190RhoGEF and could affect interactions of the exchange factor with NF-L transcripts.

Untranslated element in neurofilament mRNA has neuropathic effect on motor neurons of transgenic mice.

Studies of experimental motor neuron degeneration attributable to expression of neurofilament light chain (NF-L) transgenes have raised the possibility that the neuropathic effects result from overexpression of NF-L mRNA, independent of NF-L protein effects (Cañete-Soler et al., 1999). The present study was undertaken to test for an RNA-mediated pathogenesis.