DNA damage-inducible transcript 3 deficiency promotes bone resorption in murine periodontitis models.

BACKGROUND AND OBJECTIVE: Periodontitis is a multifactorial inflammatory disease that leads to the destruction of supporting structures of the teeth. DNA damage-inducible transcript 3 (DDIT3) plays crucial roles in cell survival and differentiation. DDIT3 regulates bone mass and osteoclastogenesis in femur. However, the role of DDIT3 in periodontitis has not been elucidated. This research aimed to explore the role and mechanisms of DDIT3 in periodontitis. METHODS: DDIT3 gene knockout (KO) mice were generated using a CRISPR/Cas9 system. Experimental periodontitis models were established to explore the role of DDIT3 in periodontitis. The expression of DDIT3 in periodontal tissues was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC). The alveolar bone phenotypes were observed by micro-CT and stereomicroscopy. The inflammation levels and osteoclast activity were examined by histological staining, immunostaining, and qRT-PCR. Bone marrow-derived macrophages (BMMs) were isolated to confirm the effects of DDIT3 on osteoclast formation and function in vitro. RESULTS: The increased expression of DDIT3 in murine inflamed periodontal tissues was detected. DDIT3 knockout aggravated alveolar bone loss and enhanced expression levels of inflammatory cytokines in murine periodontitis models. Increased osteoclast formation and higher expression levels of osteoclast-specific markers were observed in the inflamed periodontal tissues of KO mice. In vitro, DDIT3 deficiency promoted the formation of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated osteoclasts and the bone resorption activity of mature osteoclasts. CONCLUSIONS: Our results demonstrate that DDIT3 deletion aggravated alveolar bone loss in experimental periodontitis through enhanced inflammatory reactions and osteoclastogenesis. The anti-inflammation and the inhibition of bone loss by DDIT3 in murine periodontitis provides a potential novel therapeutic strategy for periodontitis.

Biomechanical Analysis of Different Framework Design, Framework Material and Bone Density in the Edentulous Mandible With Fixed Implant-Supported Prostheses: A Three-Dimensional Finite Element Study.

PURPOSE: The objective of this finite element study was to investigate the effect of different framework designs, framework materials, and bone densities on the stress distribution of fixed implant-supported prostheses for edentulous mandibles. MATERIALS AND METHODS: Under the condition of 2-mm cortical bone, 16 models were created in the edentulous mandible to simulate different framework designs (1-piece or 3-piece frameworks) with different framework material (pure titanium, zirconia, polyetheretherketone, or carbon fiber-reinforced polyetheretherketone) in-high or low-density trabecular bone. Then, vertical loading and oblique loading at 75° were applied to the anterior and posterior regions. The stress distribution and stress concentration region of implant and peri-implant bone with different combinations were compared by finite element analysis. RESULTS: The use of the 1-piece zirconia framework in high-density trabecular bone improved stress distribution on implants and peri-implant bone. The region of stress concentration is located in the buccal cervix of the distal implants and the distobuccal portion of the cortical bone in all models. To improve the stress distribution on fixed implant-supported dentures for edentulous mandibles, the 1-piece framework and zirconia represent the better combination. CONCLUSION: Under the condition of 2-mm cortical bone thickness, the full-arch zirconia framework had minimum von Mises stress on implants and peri-implant bone in all models, and high trabecular bone density greatly decreased the stress on cortical bone.

An Opto- and Thermal-Rewrite PCM/CNF-IR 780 Energy Storage Nanopaper with Mechanical Regulated Performance.

In spite of efforts to fabricate self-assembled energy storage nanopaper with potential applications in displays, greenhouses, and sensors, few studies have investigated their multiple stimuli-sensitivities. Here, an opto- and thermal-rewrite phase change material/cellulose nanofibril (PCM/CNF) energy storage nanopaper with mechanical regulated performance is facilely fabricated, through 5 min sonication of PCMs and CNFs in an aqueous system. The combination of PCM and CNF not only guarantees the recyclability of PCM without leakage, but also offers nanopaper adaptive properties by leveraging the mobility and optical variation accompanying solid-to-liquid transition of PCM. Besides, trace near-infrared (NIR) dye (IR 780) in it imparts a PCM-embedded nanopaper photothermal effect to modulate the local transparency via time- and position-controlled laser exposure, leading to a reusable opto-writing nanopaper. Furthermore, since the synergistic effect of stick-and-slip function attributes from PCMs and pore structures are produced by calcium ions, the PCM/CNF energy storage nanopaper exhibits excellent mechanically regulated performance from rigid to flexible, which greatly enriches their application in energy-efficient smart buildings and displays.

Biomechanical analysis of inclined and cantilever design with different implant framework materials in mandibular complete-arch implant restorations.

STATEMENT OF PROBLEM: Inclined distal implants with posterior framework cantilevers are an alternative to straight implants for the treatment of edentulous jaws, avoiding grafting procedures and utilizing pre-existing bone. However, little is known about the implant, framework, and peri-implant bone stresses exerted by this design. PURPOSE: The purpose of this finite element analysis study was to assess the biomechanical properties of the inclined versus straight design, with different implant framework material to generate implant-supported complete-arch fixed mandibular prostheses. MATERIAL AND METHODS: A finite element model of the edentulous mandible was generated by using 4 implants in 2 distinct configurations: the inclined design and the straight design. Different framework materials were tested: pure titanium, cobalt-chromium alloy, type IV gold alloy, zirconia, polyetheretherketone (PEEK), and carbon fiber-reinforced polyetheretherketone (CFR-PEEK). A 300-N load at a 75-degree angle was applied to the occlusal plane from the lingual side of the buccal cusps of the 2 premolars and the first molar teeth. Subsequently, stresses on the implant, surrounding bone, and framework were measured and analyzed quantitatively and qualitatively. RESULTS: In terms of implant configurations, the inclined design demonstrated less stress on the posterior cortical bone, implants, and framework than the straight design. Comparing the framework materials, zirconia and metal exhibited reduced cortical bone and implants stresses but elevated framework stress when compared with the polymeric frameworks. CONCLUSIONS: From a biomechanical viewpoint, in edentulous patients with excessive posterior alveolar bone resorption, the inclined design exhibited more favorable stress distribution around the posterior implants than the straight design. In implant-supported complete-arch fixed mandibular prostheses, zirconia and metal, particularly cobalt-chromium alloy, distributed the stresses more effectively to the implants and supporting bone than polymeric materials.

Programmable Assembly of Multivalent DNA-Protein Superstructures for Tumor Imaging and Targeted Therapy.

Programmable DNA materials hold great potential in biochemical and biomedical researches, yet the complicated synthesis, and the low stability and targeting efficacy in complex biological milieu limit their clinical translations. Here we show a one-pot assembly of DNA-protein superstructures as drug vehicles with specifically high affinity and stability for targeted therapy. This is achieved by biomimetic assembly of programmable polymer DNA wire into densely packed DNA nanosphere with an alkaline protein, protamine. Multivalent DNA nanostructures encoded with different types and densities of aptamers exhibit high affinity to targeted cells through polyvalent interaction. Our results show high cancer cell selectivity, reduced side effect, excellent therapeutic efficacy, and sensitive tumor imaging in both subcutaneous and orthotopic non-small-cell lung cancer murine models. This biomimetic assembly approach provides practical DNA nanomaterials for further clinical trials and may advance oligonucleotide drug delivery.

Evaluation of 1-Piece Versus 3-Piece Framework Designs for the Edentulous Mandible with Fixed Implant-Supported Prostheses: A Clinical, Occlusal and Biomechanical Study.

PURPOSE: This study aims to evaluate the clinical, occlusal and biomechanical performance of 1-piece and 3-piece designs for implant-supported fixed dentures in the edentulous mandible. MATERIALS AND METHODS: A total of 65 patients with edentulous mandibles who underwent fixed implant-supported restorations were recruited and subsequently assigned to 1 of 2 groups based on the framework design (1-piece or 3-piece). The participants underwent clinical and occlusal examination using a periodontal probe, T-Scan III system, and electromyography 12 months after prosthesis delivery. Two mandibular finite element models were created to evaluate stress values and their distribution during function. RESULTS: Ninety-five point four percent (n = 62) of participants in the follow-up period underwent clinical and occlusal examination after prosthesis delivery. Clinical examination revealed a trend towards increased inflammation around the implants in the 1-piece prostheses. Occlusal parameters indicated that the 1-piece design was superior for the masticatory system than the 3-piece design. Biomechanical analysis revealed the highest stress values in the posterior region of the 3-piece design. CONCLUSIONS: On the basis of ease of ensuring oral hygiene, when compared to the 3-piece design, the 1-piece framework design might be the superior therapy for restoring an edentulous mandible, based on occlusal and biomechanical outcomes.

The risk of periodontitis for peripheral vascular disease: a systematic review.

Periodontitis is one of the risk factors associated with peripheral artery disease. This meta-analysis evaluates how periodontitis contributes to the pathogenesis and progression of peripheral artery disease. We systematically searched electronic databases Ovid Medline, Embase, Cochrane Library and Pubmed. Grey literature was also searched via Google Scholar. All studies evaluating the relationship between the incidence of periodontitis and peripheral artery disease were included. Subgroup analyses of carotid artery disease and lower extremity arterial disease were also conducted. Odds ratios (OR) and 95% confidence intervals (CI) were pooled and analyzed. The I² statistic was used to evaluate heterogeneity. Within a total of 25 studies, including 22,090 participants based on eligibility criteria, the incidence of peripheral artery disease was significantly higher among those with periodontitis (OR: 1.60, 95% CI 1.41-1.82, P < 0.001, I² = 80.5%). In subgroup analysis, periodontitis was still a risk for lower extremity arterial disease (OR: 3.00, 95% CI 2.23-4.04, P < 0.001, I² = 0%) and carotid artery disease (OR: 1.39, 95% CI 1.24-1.56, P < 0.001, I² = 79.4%). Periodontitis is significantly associated with the incidence of lower extremity arterial disease and carotid artery disease.

A multifunctional cascade enzyme system for enhanced starvation/chemodynamic combination therapy against hypoxic tumors.

Starvation therapy has shown promise as a cancer treatment, but its efficacy is often limited when used alone. In this work, a multifunctional nanoscale cascade enzyme system, named CaCO3@MnO2-NH2@GOx@PVP (CMGP), was fabricated for enhanced starvation/chemodynamic combination cancer therapy. CMGP is composed of CaCO3 nanoparticles wrapped in a MnO2 shell, with glucose oxidase (GOx) adsorbed and modified with polyvinylpyrrolidone (PVP). MnO2 decomposes H2O2 in cancer cells into O2, which enhances the efficiency of GOx-mediated starvation therapy. CaCO3 can be decomposed in the acidic cancer cell environment, causing Ca2+ overload in cancer cells and inhibiting mitochondrial metabolism. This synergizes with GOx to achieve more efficient starvation therapy. Additionally, the H2O2 and gluconic acid produced during glucose consumption by GOx are utilized by MnO2 with catalase-like activity to enhance O2 production and Mn2+ release. This process accelerates glucose consumption, reactive oxygen species (ROS) generation, and CaCO3 decomposition, promoting the Ca2+ release. CMGP can alleviate tumor hypoxia by cycling the enzymatic cascade reaction, which increases enzyme activity and combines with Ca2+ overload to achieve enhanced combined starvation/chemodynamic therapy. In vitro and in vivo studies demonstrate that CMGP has effective anticancer abilities and good biosafety. It represents a new strategy with great potential for combined cancer therapy.

Carcinogenesis promotion in oral squamous cell carcinoma: KDM4A complex-mediated gene transcriptional suppression by LEF1.

Oral squamous cell carcinoma (OSCC) is the most prevalent cancer of the mouth, characterised by rapid progression and poor prognosis. Hence, an urgent need exists for the development of predictive targets for early diagnosis, prognosis determination, and clinical therapy. Dysregulation of lymphoid enhancer-binding factor 1 (LEF1), an important transcription factor involved in the Wnt-ß-catenin pathway, contributes to the poor prognosis of OSCC. Herein, we aimed to explore the correlation between LEF1 and histone lysine demethylase 4 A (KDM4A). Results show that the KDM4A complex is recruited by LEF1 and specifically binds the LATS2 promoter region, thereby inhibiting its expression, and consequently promoting cell proliferation and impeding apoptosis in OSCC. We also established NOD/SCID mouse xenograft models using CAL-27 cells to conduct an in vivo analysis of the roles of LEF1 and KDM4A in tumour growth, and our findings show that cells stably suppressing LEF1 or KDM4A have markedly decreased tumour-initiating capacity. Overall, the results of this study demonstrate that LEF1 plays a pivotal role in OSCC development and has potential to serve as a target for early diagnosis and treatment of OSCC.

In vitro Antibacterial Activity of an FDA-Approved H+-ATPase Inhibitor, Bedaquiline, Against Streptococcus mutans in Acidic Milieus.

BACKGROUND: Dental caries is an acid-related disease. Current anti-caries agents mainly focus on the bacteriostatic effect in a neutral environment and do not target acid-resistant microorganisms related to caries in acidic milieus. OBJECTIVES: To assess the in vitro antibacterial activities of bedaquiline against oral pathogens in acidic milieus. METHODS: Streptococcus mutans, Streptococcus sanguinis, and Streptococcus salivarius were used to prepare the mono-/multiple suspension and biofilm. The MIC and IC50 of bedaquiline against S. mutans were determined by the broth microdilution method. Bedaquiline was compared regarding (i) the inhibitory activity in pH 4-7 and at different time points against planktonic and biofilm; (ii) the effect on the production of lactic acid, extracellular polysaccharide, and pH of S. mutans biofilm; (iii) the cytotoxicity effects; and (iv) the activity on H+-ATPase enzyme of S. mutans. RESULTS: In pH 5 BHI, 2.5 mg/L (IC50) and 4 mg/L (MIC) of bedaquiline inhibited the proliferation and biofilm generation of S. mutans and Mix in a dose-dependent and time-dependent manner, but it was invalid in a neutral environment. The lactic acid production, polysaccharide production, and pH drop range reduced with the incorporation of bedaquiline in a pH 5 environment. Its inhibitory effect (>56 mg/L) against H+-ATPase enzyme in S. mutans and its non-toxic effect (<10 mg/L) on periodontal ligament stem cells were also confirmed. CONCLUSION: Bedaquiline is efficient in inhibiting the proliferation and biofilm generation of S. mutans and other oral pathogens in an acidic environment. Its high targeting property and non-cytotoxicity also promote its clinical application potential in preventing caries. Further investigation of its specific action sites and drug modification are warranted.

Enhanced Immunostimulatory Activity of a Cytosine-Phosphate-Guanosine Immunomodulator by the Assembly of Polymer DNA Wires and Spheres.

Unmethylated cytosine-phosphate-guanosine (CpG) oligodeoxynucleotides are immunostimulatory nucleic acids wildly utilized as adjuvants or for vaccines to treat diseases. However, there is a lack of simple and efficient vectors for CpG oligodeoxynucleotide delivery with long-lasting immune stimulation. Herein, self-assembled polymer wires consisting of CpG motifs by hybridization chain reaction were constructed with excellent biocompatibility and immunostimulatory activity. The designed polymer DNA wires acted as programmable multivalent immunoadjuvants and triggered immune response, stimulated pro-inflammatory cytokine secretion, and induced the apoptosis of cancer cells. More strikingly, polymer nanospheres assembled from the polymer DNA wires and cationic poly-l-lysine further improved cellular uptake and continuously stimulate the lysosomal Toll-like receptor 9 of immune cells, thereby remarkably enhancing the activation of immune cells. These results demonstrated that self-assembled polymer DNA nanoassemblies with multivalent CpG could trigger strong immune response and further induce cancer cell death.

Multifunctional siRNA-Laden Hybrid Nanoplatform for Noninvasive PA/IR Dual-Modal Imaging-Guided Enhanced Photogenetherapy.

Small interfering RNA (siRNA)-induced gene therapy has been recognized as a promising avenue for effective cancer treatment, while easy enzymatic degradation, poor transfection efficiency, nonspecific biodistribution, and uncontrolled release hinder its extensive clinical applications. Zeolitic imidazolate frameworks-8 (ZIF-8) have emerged as promising drug carriers without an in-depth exploration in programmable siRNA delivery. Herein, we report a multifunctional PDAs-ZIF-8 (PZ) nanoplatform for delivering siRNA with combined photothermal therapy (PTT) and gene therapy (GT) via the noninvasive guidance of photoacoustic (PA)/near-infrared (IR) dual-modal imaging. The ingenious PZ nanocarriers mediated the tumor-specific accumulation of therapeutic siRNA without undesired degradation and preleakage. The pH-responsive ZIF-8 decomposed in an acidic tumor microenvironment that was accompanied by the release of siRNA payloads for cleaving target mRNA in gene silencing therapy. Meanwhile, the polydopamine nanoparticles (PDAs) could simultaneously serve as a powerful noninvasive PA/IR imaging contrast agent and versatile photothermal agent for diagnosis-guided photogenetherapy. The systematic in vitro and in vivo experimental explorations demonstrated that our PDAs-siRNA-ZIF-8 (PSZ) could greatly enhance the therapeutic efficiency as compared with the corresponding PTT or GT monotherapy. This work holds great potential to advance the development of more intelligent diagnosis and therapeutic strategies, thus supplying promising smart nanomedicines in the near future.

[Gnathology in implant-supported fixed restoration in edentulous mandible].

OBJECTIVE: This study aims to investigate the occlusal and myoelectric characteristics of implant-supported fixed denture in the mandibular region and provide reference for the design of fixed restoration. METHODS: Sixty edentulous patients with implant-supported fixed denture were selected and divided into three groups: group A, 20 cases with implant-supported fixed restoration in the maxillary region; group B, 20 cases with natural dentition, and group C, 20 cases with removable partial denture. The T-scan 8.0 digital occlusion analysis system was used to evaluate the occlusal characteristics of patients in the three groups at intercuspal, protrusion, and left and right lateral positions. Electromyography was used to analyze the myoelectric amplitude and bilateral asymmetry index of the anterior temporalis and masseter of the three groups in different states such as resting and clenching. The relationship between occlusion and myoelectricity was also investigated. RESULTS: In the occlusion analysis by T-scan, the occlusion time, the balance of left and right bite force, the left and right asymmetry of the occlusion center, the trajectory of central occlusion force, and the disclusion time were higher in group C than in groups A and B (P<0.05). No significant differences were observed in the anterior and posterior asymmetry of the occlusion center and percentage of bite force at anterior region among the three groups. In the analysis of myoelectricity, the myoelectric amplitude at resting state and the asymmetry index of masticatory muscles in group C were higher than those in groups A and B (P<0.05). The myoelectric amplitude during clenching in groups A and B groups was higher than that in group C (P<0.05). CONCLUSIONS: In implant-supported fixed restoration at edentulous mandibular, when maxillary includes the removable partial denture, degree of occlusal instability and left and right asymmetry of occlusion center are greater than those with the natural dentition and implant-supported fixed denture at maxillary. The myoelectricity is closely related to occlusion. The removable partial denture can increase the myoelectric activity and reduce the potential of the masticatory muscle. The asymmetry of bilateral myoelectricity is related to the occlusion imbalance.

Stimuli-responsive multifunctional metal-organic framework nanoparticles for enhanced chemo-photothermal therapy.

Construction of stimuli-responsive multifunctional nanoparticles is critical for nanotherapeutic delivery. Though metal-organic frameworks (MOFs) have been emerged as promising delivery vehicles, the therapeutic efficacy of MOFs in cancer treatment is limited by the lack of a general approach for the preparation of stimuli-responsive multifunctional MOFs. We show that the combination of a versatile coating material polydopamine with MOFs enables facile integration of different functional therapeutics, obtaining stimuli-responsive multifunctional MOFs with extensive photothermal efficiency and outstanding capability to abrogate tumors by chemo-photothermal therapy. Exemplary MOFs including ZIF-8, UiO-66, and MIL-101 were utilized to prepare stimuli-responsive multifunctional MOFs to illustrate the generality of the strategy. This approach enables targeted drug delivery and stimuli-responsive release of multi-therapeutics and allows combination therapy with excellent in vitro and in vivo antitumor activity. Taking into account the diversity of MOFs and different functional molecules, this work provides flexible access to programmable MOF nanoparticles for specific biological applications.

Versatile Catalytic Deoxyribozyme Vehicles for Multimodal Imaging-Guided Efficient Gene Regulation and Photothermal Therapy.

Catalytic deoxyribozyme has great potential for gene regulation, but the poor efficiency of the cleavage of mRNA and the lack of versatile DNAzyme vehicles remain big challenges for potent gene therapy. By the rational designing of a diverse vehicle of polydopamine-Mn2+ nanoparticles (MnPDA), we demonstrate that MnPDA has integrated functions as an effective DNAzyme delivery vector, a self-generation source of DNAzyme cofactor for catalytic mRNA cleavage, and an inherent therapeutic photothermal agent as well as contrast agent for photoacoustic and magnetic resonance imaging. Specifically, the DNAzyme-MnPDA nanosystem protects catalytic deoxyribozyme from degradation and enhances cellular uptake efficiency. In the presence of intracellular glutathione, the nanoparticles are able to in situ generate free Mn2+ as a cofactor of DNAzyme to effectively trigger the catalytic cleavage of mRNA for gene silencing. In addition, the nanosystem shows high photothermal conversion efficiency and excellent stability against photothermal processing and degradation in complex environments. Unlike previous DNAzyme delivery vehicles, this vehicle exhibits diverse functionalities for potent gene regulation, allowing multimodal imaging-guided synergetic gene regulation and photothermal therapy both in vitro and in vivo.