rgpA-Engineered/Functionalized DNA Vaccine as a Novel Prophylactic Vaccination to Prevent Porphyromonas gingivalis-Induced Periodontitis: An in Vivo Study.

BACKGROUND: Arg-gingipain A (rgpA) and Arg-gingipain B (rgpB) are crucial virulence factors associated with Porphyromonas gingivalis (P. gingivalis) and have been recognized as promising targets for antibacterial vaccines. Although vaccines containing rgpA have shown efficacy, the incorporation of rgpB, which lacks the haemagglutinin adhesin (HA) domain, diminishes the vaccine's effectiveness. This study aims to assess the immunogenicity of the functional HA domain of rgpA in mouse periodontitis models. METHODS: A total of 24 mice were randomly divided into four groups, each receiving different immune injections: group A received phosphate-buffered saline (PBS) as an empty control; group B received pVAX1 as a negative control (NC); group C received pVAX1-HA; and group D received pVAX1-rgpA. The mice were subjected to intramuscular injections every two weeks for a total of three administrations. Prior to each immunization, blood samples were collected for antibody detection under isoflurane anesthesia. Following the final immunization, periodontitis was induced two weeks later by using sutures soaked in a P. gingivalis solution. The mice were euthanized after an additional two-week period. To assess the safety of the procedure, major organs were examined through hematoxylin-eosin (HE) staining. Subsequently, the levels of IgG, IgG1, and IgG2a in the serum were quantified via enzyme-linked immunosorbent assay (ELISA). Additionally, the expression of inflammatory factors in the gingiva, including interleukin-6 (IL-6), interleukin-1ß (IL-1ß), and tumor necrosis factor alpha (TNF-α), was determined using quantitative real-time reverse transcript PCR (qRT-PCR). The extent of bone loss in periodontal tissues was evaluated using micro-computed tomography (micro-CT) and HE staining. RESULTS: HE staining of the organs confirmed the absence of vaccine-induced toxicity in vivo. After the second immunization, both the rgpA and HA groups displayed significantly higher specific IgG titers in comparison to the NC and PBS groups (p < 0.05). Furthermore, the rgpA and HA groups exhibited a noteworthy predominance of IgG1 antibodies after three immunization doses, while there was a noticeable reduction in IgG2a levels observed following ligation with P. gingivalis sutures, as opposed to the NC and PBS groups (p < 0.05). Additionally, both the HA and rgpA groups showed a significant decrease in the expression of inflammatory factors such as IL-6, IL-1ß, and TNF-α, as well as a reduction in bone loss around periodontitis-affected teeth, when compared to the NC and PBS groups (p < 0.05). CONCLUSIONS: The results of this study demonstrate that the rgpA-engineered/functionalized HA gene vaccine is capable of eliciting a potent prophylactic immune response against P. gingivalis-induced periodontitis, effectively serving as an immunogenic and protective agent in vivo.

Multifunctional Prosthesis Surface: Modification of Titanium with Cinnamaldehyde-Loaded Hierarchical Titanium Dioxide Nanotubes.

Orthopedic prostheses are the ultimate therapeutic solution for various end-stage orthopedic conditions. However, aseptic loosening and pyogenic infections remain as primary complications associated with these devices. In this study, a hierarchical titanium dioxide (TiO2 ) nanotube drug delivery system loaded with cinnamaldehyde for the surface modification of titanium implants, is constructed. These specially designed dual-layer TiO2 nanotubes enhance material reactivity and provide an extensive drug-loading platform within a short time. The introduction of cinnamaldehyde enhances the bone integration performance of the scaffold (simultaneously promoting bone formation and inhibiting bone resorption), anti-inflammatory capacity, and antibacterial properties. In vitro experiments have demonstrated that this system promoted osteogenesis by upregulating both Wnt/ß-catenin and MAPK signaling pathways. Furthermore, it inhibits osteoclast formation, suppresses macrophage-mediated inflammatory responses, and impedes the proliferation of Staphylococcus aureus and Escherichia coli. In vivo experiments shows that this material enhances bone integration in a rat model of femoral defects. In addition, it effectively enhances the antibacterial and anti-inflammatory properties in a subcutaneous implant in a rat model. This study provides a straightforward and highly effective surface modification strategy for orthopedic Ti implants.

IL13Rα2 as a crucial receptor for Chi3l1 in osteoclast differentiation and bone resorption through the MAPK/AKT pathway.

BACKGROUND: Previous research has revealed that the 18 glycoside hydrolase gene family (GH18) member Chitinase 3-like 1 (Chi3l1) can regulate osteoclast differentiation and bone resorption. However, its downstream receptors and molecular mechanisms during osteoclastogenesis have yet to be elucidated. METHODS: Initially, we conducted a comprehensive investigation to evaluate the effects of recombinant Chi3l1 protein or Chi3l1 siRNA on osteoclast differentiation and the RANKL-induced MAPK/AKT signaling pathways. Moreover, we used immunofluorescence and immunoprecipitation assays to identify IL13Rα2 as the downstream receptor of Chi3l1. Subsequently, we investigated the impact of IL13Rα2 recombinant protein or IL13Rα2-siRNA on osteoclast differentiation and the associated signaling pathways. Finally, we performed in vivo experiments to examine the effect of recombinant IL13Rα2 protein in an LPS-induced mouse model of cranial osteolysis. RESULTS: Our findings highlight that the administration of recombinant Chi3l1 protein increased the formation of osteoclasts and bolstered the expression of several osteoclast-specific genes (TRAP, NFATC1, CTR, CTSK, V-ATPase d2, and Dc-STAMP). Additionally, Chi3l1 significantly promoted the RANKL-induced MAPK (ERK/P38/JNK) and AKT pathway activation, whereas Chi3l1 silencing inhibited this process. Next, using immunofluorescence and co-immunoprecipitation assays, we identified IL13Rα2 as the binding partner of Chi3l1 during osteoclastogenesis. IL13Rα2 recombinant protein or IL13Rα2-siRNA also inhibited osteoclast differentiation, and IL13Rα2-siRNA attenuated the RANKL-induced activation of the MAPK (ERK/P38/JNK) and AKT pathways, similar to the effects observed upon silencing of Chi3l1. Moreover, the promoting effect of recombinant Chi3l1 protein on osteoclastogenesis and the activation of the MAPK and AKT pathways was reversed by IL13Rα2 siRNA. Finally, recombinant LI13Rα2 protein significantly attenuated the LPS-induced cranial osteolysis and the number of osteoclasts in vivo. CONCLUSIONS: Our findings suggested that IL13Rα2 served as a crucial receptor for Chi3l1, enhancing RANKL-induced MAPK and AKT activation to promote osteoclast differentiation. These findings provide valuable insights into the molecular mechanisms of Chi3l1 in osteoclastogenesis, with potential therapeutic implications for osteoclast-related diseases. Video Abstract.

A ROS-responsive microsphere capsule encapsulated with NADPH oxidase 4 inhibitor ameliorates macrophage inflammation and ferroptosis.

Inflammatory macrophages within the synovium play a pivotal role in the progression of arthritis inflammation. Effective drug therapy targeting inflammatory macrophages has long been a goal for clinicians and researchers. The standard approach for treating osteoarthritis (OA) involves systemic treatment and local injection. However, the high incidence of side effects associated with long-term drug administration increases the risk of complications in patients. Additionally, the rapid clearance of the joint cavity poses a biological barrier to the therapeutic effect. NADPH oxidase 4 (NOX4) is an enzyme protein regulating the cellular redox state by generating reactive oxygen species (ROS) within the cell. In this study, we designed and fabricated a hydrogel microsphere consisting of methyl methacrylate (MMA) and polyvinyl acetate (PVA) as the outer layer structure. We then loaded GLX351322 (GLX), a novel selective NOX4 inhibitor, into hydrogel microspheres through self-assembly with the compound polyethylene glycol ketone mercaptan (mPEG-TK) containing a disulfide bond, forming nanoparticles (mPEG-TK-GLX), thus creating a two-layer drug-loaded microspheres capsule with ROS-responsive and slow-releasing capabilities. Our results demonstrate that mPEG-TK-GLX@PVA-MMA effectively suppressed TBHP-induced inflammation, ROS production, and ferroptosis, indicating a promising curative strategy for OA and other inflammatory diseases in the future.

Corrigendum: Case Report: Surgical treatment of a primary giant epithelioid hemangioendothelioma of the spine with total en-bloc spondylectomy.

[This corrects the article DOI: 10.3389/fonc.2023.1109643.].

[Evaluation of low intensity Nd: YAG laser and traditional drugs in the treatment of myofascial pain].

PURPOSE: To evaluate the efficacy of low intensity Nd: YAG laser and traditional drugs in the treatment of myofascial pain (MP). METHODS: Eighty patients with MP were divided into laser group(n=40) and traditional medicine group(n=40) according to the principle of randomization and double-blindness. The patients in the laser group were treated with low intensity Nd :YAG laser(1 064 nm, 8 J/cm2, 250 mW) , with an interval of 48 h between the two laser treatments. The whole course of treatment was 10 times. Patients in the traditional medicine group uesd celecoxib capsules, 1 capsulet each time(0.2 g), twice a day for 2 weeks. Before and after each treatment, mouth opening, protrusion excursion, lateral movement of the affected side and lateral movement of the contralateral side were measured, and pain visual analogue scores (VAS) were measured and recorded. The data were statistically analyzed with SPSS 22.0 software package. RESULTS: Patients in laser group had significantly improved mandibular function and movement status(P＜0.05) and pain symptoms(P＜0.05); patients in traditional medicine group had the same significant improvement on mandibular functional movement status(P＜0.05) and pain symptoms (P＜0.05). The total effective rate of the two groups had no significant difference(P＞0.05). The VAS score of patients in laser group was lower than that of traditional medicine group, but the difference was not significant(P＞0.05). CONCLUSIONS: Low intensity Nd: YAG laser and traditional medicine can effectively relieve the symptoms of myofascial pain and improve mandibular function and movement. Laser treatment has the advantages of short course of treatment, high efficiency, no pain and fewer side effects, which is worthy of clinical application.

Dlk2 interacts with Syap1 to activate Akt signaling pathway during osteoclast formation.

Excessive osteoclast formation and bone resorption are related to osteolytic diseases. Delta drosophila homolog-like 2 (Dlk2), a member of the epidermal growth factor (EGF)-like superfamily, reportedly regulates adipocyte differentiation, but its roles in bone homeostasis are unclear. In this study, we demonstrated that Dlk2 deletion in osteoclasts significantly inhibited osteoclast formation in vitro and contributed to a high-bone-mass phenotype in vivo. Importantly, Dlk2 was shown to interact with synapse-associated protein 1 (Syap1), which regulates Akt phosphorylation at Ser473. Dlk2 deletion inhibited Syap1-mediated activation of the AktSer473, ERK1/2 and p38 signaling cascades. Additionally, Dlk2 deficiency exhibits increased bone mass in ovariectomized mice. Our results reveal the important roles of the Dlk2-Syap1 signaling pathway in osteoclast differentiation and osteoclast-related bone disorders.

Xl019, a novel JAK inhibitor, suppressed osteoclasts differentiation induced by RANKL through MAPK signaling pathway.

Inbonemetabolism,osteoclastsare the only cellscapableofresorbingbone. Hyperactivity of osteoclasts may lead to osteolytic disease like osteoporosis and arthritis. Although there are several drugs for the treatment of osteolytic diseases, they have limitations and a variety of side effects. An inhibitor of Janus kinase (JAK), XL019, has shown promising results in the treatment of myelofibrosis and other cancers. But whether it can functionally impact osteoclast activity has not been proven. In this study, the effects of XL019 on osteoclastogenesis and the mechanism pathway were investigated in vitro. It was found that XL019 could impair osteoclasts formation, interfere with bone resorption ability and downregulate the osteoclast-specific genes and proteins expression. Furthermore, Western blot and molecular docking studies demonstrated that XL019 inhibited RANKL-induced osteoclastogenesis by suppressing MAPK signaling. A molecular docking analysis explained how XL019 binds to MAPK pathway factors. In addition, titanium particles induced calvarial osteolysis in mice further confirming its beneficial effect on bone homeostasis in vivo. In conclusion, this study demonstrates that Osteoclastactivity canbeeffectivelyinhibitedby XL019viaMAPK signalingpathway,making it a promising alternative pharmacologicaltreatmentfor bone metabolicdisorders.

Enhanced bone regeneration via local low-dose delivery of PTH1-34 in a composite hydrogel.

Introducing bone regeneration-promoting factors into scaffold materials to improve the bone induction property is crucial in the fields of bone tissue engineering and regenerative medicine. This study aimed to develop a Sr-HA/PTH1-34-loaded composite hydrogel system with high biocompatibility. Teriparatide (PTH1-34) capable of promoting bone regeneration was selected as the bioactive factor. Strontium-substituted hydroxyapatite (Sr-HA) was introduced into the system to absorb PTH1-34 to promote the bioactivity and delay the release cycle. PTH1-34-loaded Sr-HA was then mixed with the precursor solution of the hydrogel to prepare the composite hydrogel as bone-repairing material with good biocompatibility and high mechanical strength. The experiments showed that Sr-HA absorbed PTH1-34 and achieved the slow and effective release of PTH1-34. In vitro biological experiments showed that the Sr-HA/PTH1-34-loaded hydrogel system had high biocompatibility, allowing the good growth of cells on the surface. The measurement of alkaline phosphatase activity and osteogenesis gene expression demonstrated that this composite system could promote the differentiation of MC3T3-E1 cells into osteoblasts. In addition, the in vivo cranial bone defect repair experiment confirmed that this composite hydrogel could promote the regeneration of new bones. In summary, Sr-HA/PTH1-34 composite hydrogel is a highly promising bone repair material.

Case report: Surgical treatment of a primary giant epithelioid hemangioendothelioma of the spine with total en-bloc spondylectomy.

Background: Epithelioid hemangioendothelioma (EHE) is an extremely uncommon malignant neoplasm that originates from vascular endothelial or pre-endothelial cells. In this report, we present the case of patient who was diagnosed with a primary giant EHE of the spine and underwent treatment with total en-bloc spondylectomy (TES). Case presentation: A 43-year-old male patient with a history of he presented to our hospital with chronic and progressive back pain. Physical examination revealed weakened sensation of acupuncture and touch on the left costal arch, while relatively normal neurological functions were preserved. Radiological examinations identified a giant destructive soft tissue lesion occupying the T8 vertebral region, with moderate destruction of the pedicle and lamina, as well as the 7th left rib. A preoperative biopsy of the 8th vertebra resulted in a diagnosis of epithelioid hemangioendothelioma(EHE). Postoperative immunohistochemical and pathological reports confirmed the presence of EHE in the left ribs and T8 ribs. The patient underwent resection of the 7th left rib and posterior pedicle screw fixation with 8 pairs of screws and a titanium mesh cage. Subsequently, thoracic en bloc spondylectomy was performed on the T8 vertebra. The patient did not receive radiation or chemotherapy following surgery. Over a period of 3 years, the patient remained free of disease and relapse. Conclusion: The use of transarterial embolization with spherical embolic agents (TES) has been demonstrated to be a safe, effective, and reliable treatment option for hepatic epithelioid hemangioendothelioma (EHE). Nevertheless, it is crucial to conduct long-term follow-up of this patient in order to assess their clinical outcome.

GLX351322, a Novel NADPH Oxidase 4 Inhibitor, Attenuates TMJ Osteoarthritis by Inhibiting the ROS/MAPK/NF-κB Signaling Pathways.

As a degenerative disease in joints, temporomandibular joint osteoarthritis (TMJOA) is characterized by progressive cartilage degradation, subchondral bone remodeling, and chronic synovitis, severely undermining functions and quality of life in patients. NADPH oxidase 4 (NOX4) contributes to reactive oxygen species (ROS) production and inflammatory pathway activation in osteoarthritis, which has attracted increasing attention in research in recent years. GLX351322 (GLX), a novel NOX4 inhibitor, exerts a protective effect on chondrocytes. However, whether it has a therapeutic effect on ROS production and inflammatory responses in synovial macrophages remains to be evaluated. In this study, we examined the effect of GLX on LPS-induced ROS production and inflammatory responses in vitro and on complete Freund's adjuvant (CFA)-induced TMJ inflammation in vivo. We found that GLX could depress LPS-induced intracellular ROS production and inflammatory response without cytotoxicity by inhibiting the ROS/MAPK/NF-κB signaling pathways. In line with in vitro observations, GLX markedly attenuated the synovial inflammatory reaction in the TMJ, thus protecting the condylar structure from severe damage. Taken together, our results suggest that GLX intervention or NOX4 inhibition is a promising curative strategy for TMJOA and other inflammatory diseases.

Ultrasmall PtAu2 nanoclusters activate endogenous anti-inflammatory and anti-oxidative systems to prevent inflammatory osteolysis.

Rationale: Inflammatory osteolysis, characterized by abundant immune cell infiltration and osteoclast (OC) formation, is a common complication induced by bacterial products and/or wear particles at the bone-prosthesis interface that severely reduces long-term stability after implantation. Molecular nanoclusters are ultrasmall particles with unique physicochemical and biological properties that have great potential as theranostic agents for treating inflammatory diseases. Methods: In this study, heterometallic PtAu2 nanoclusters with sensitive nitric oxide-responsive phosphorescence turn-on characteristics and strong binding interactions with cysteine were designed, making them desirable candidates for the treatment of inflammatory osteolysis. Results: PtAu2 clusters exhibited satisfactory biocompatibility and cellular uptake behavior, with potent anti-inflammatory and anti-OC activities in vitro. In addition, PtAu2 clusters alleviated lipopolysaccharide-induced calvarial osteolysis in vivo and activated nuclear factor erythroid 2-related factor 2 (Nrf2) expression by disrupting its association with Kelch-like ECH-associated protein 1 (Keap1), thereby upregulating the expression of endogenous anti-inflammatory and anti-oxidative products. Conclusion: Through the rational design of novel heterometallic nanoclusters that activate the endogenous anti-inflammatory system, this study provides new insights into the development of multifunctional molecular therapeutic agents for inflammatory osteolysis and other inflammatory diseases.

Balancing the antibacterial and osteogenic effects of double-layer TiO2 nanotubes loaded with silver nanoparticles for the osseointegration of implants.

The improvement of Ag nanoparticles (AgNPs), in particular, loaded titania nanotubes, includes not only the antibacterial effect but also balancing the side effects from the antibacterial effect and osteogenesis properties, which can lead to an increased success rate of implants. Herein, based on the various needs of the graft to inhibit bacteria at different stages in vivo, we used a special osteogenic honeycomb-like "large tube over small tube" double-layered nanotube structure and created ultra-small-sized silver nanoparticles uniformly loaded on the surface and the interior of double-layer nanotubes by an optimized sputter coating method to ensure the time-dependent controllable release of antibacterial Ag ions from grafts and achieve the balance of the antibacterial effect and osteogenesis properties. The release of Ag+ from DNT-Ag8 was determined by inductively coupled plasma spectrometry. The release rate of Ag was slow; it was 30% on the first day and plateaued by the 19th day. Porphyromonas gingivalis adhesion and live bacteria were less abundant on the surface of DNT-Ag8, reaching an antibacterial efficiency of 55.6% in vitro. DNT-Ag8 shows a significantly higher antibacterial effect in a rat model infected with Staphylococcus aureus. An in vitro study demonstrated that DNT-Ag8 had no adverse effects on the adhesion, viability, proliferation, ALP staining, or activity assays of rat BMSCs. In contrast, it increased the expression of osteogenic genes. In vivo, DNT-Ag8 promoted bone-implant osseointegration in a beagle mandibular tooth loss model. This study demonstrated that the uniform loading of small-diameter silver nanoparticles using a honeycomb bilayer nanotube template structure is a promising method for modifying titanium surfaces to improve both bacteriostasis and osseointegration.

Novel Titanium Implant: A 3D Multifunction Architecture with Charge-Trapping and Piezoelectric Self-Stimulation.

Implant-associated infection and inflammation are the main causes of implant failure, causing irreversible damage and significantly increasing clinical risks and economic losses. In this study, a 3D multifunctional architecture is constructed that consisted of hierarchical TiO2 nanotubes (NTs) and electrospun polyvinylidene fluoride nanofiber layers on the surface of a titanium implant. The movement of bacteria through the nanofiber layer is facilitated by its appropriate pore sizes and electrostatic interactions to reach the NT layer where the bacteria are killed by positive charge traps. In contrast, the macrophages tend to adhere to the nanofiber layer. The mechanical interactions between the macrophages and piezoelectric nanofibers generate a self-stimulated electric field that regulated an anti-inflammatory phenotype. This study provides a new method for multifunctional implant materials with antibacterial, piezoelectrically self-stimulated anti-inflammatory, and osteointegration properties that are driven by electrical stimulation.

Radiologic outcomes of temporomandibular joint disk repositioning by suturing through an open incision in adolescent patients with anterior disk displacement.

PURPOSE: To investigate the efficacy and stability of temporomandibular joint disk repositioning by suturing through an open incision in adolescents with anterior disk displacement (ADD). METHODS: Patients (aged 10-18 years) diagnosed with ADD and operated for disc repositioning between June 2019 and January 2021 were included in this study. Magnetic resonance imaging (MRI) and cephalometric films before and 1 year after surgery were collected from all patients. The surgical success rate was defined as the primary outcome variable. Changes of condylar height, mandibular asymmetry, and retrognathia were defined as the secondary outcome variables. RESULTS: One hundred and four patients (167 joints) with a mean age of 14.6 ± 1.81 years were included in this study. Postoperative MRIs showed that all disks had been repositioned with an overall success rate of 94%. Statistically significant differences were found in the improvement of condylar height (P < .001), mandibular asymmetry (P < .001), and retrognathia (P < .001) after 1 year of follow-up. The relapse rate in patients <15 years (8.57%) was higher than that of patients older than 15 years (4.12%), although this was not statistically significant (P = .387). CONCLUSIONS: For juvenile patients, disk repositioning by suturing through an open incision was an effective treatment. Early surgery can promote condylar regeneration and alleviate maxillofacial deformity in juvenile patients.

[Influence of bilateral coronoidectomy on temporomandibular joint stress distribution after costochondral graft reconstruction: a finite element analysis].

PURPOSE: To explore the effect of bilateral coronoidectomy on stress distribution after reconstruction of temporomandibular joint (TMJ) by costochondral graft. METHODS: Ten groups of models were established to simulate costochondral graft reconstruction with simultaneously different distances (0, 2, 4, 6, 8 mm) of mandibular advancement, with or without coronoidectomy. Force and stress distribution in the rib-cartilage area were analyzed by finite element analysis. RESULTS: In the process of bilateral joint reconstruction with simultaneously mandible advancement ranging from 0 mm to 8 mm, when the coronoid processes were retained, the forward deformation of the cartilage occurred and the shear force decreased in turn, from 113.2 N to 26.7 N on the left side and from 133.7 N to 1.9 N on the right side. When the coronoid processes were removed, the cartilage deformed backward and the shear force increased successively, from 94.6 N to 188.5 N on the left and 70.1 N to 157.7 N on the right. The stress in the neck was obviously concentrated when mandible advanced 8 mm. CONCLUSIONS: Coronoidectomy has an important impact on stress distribution in the TMJ area, and keeping the coronoid process is beneficial to maintain the mechanical balance. Bilateral CCG reconstruction with coronoidectomy for lengthy mandible advancement (≥ 8 mm) may lead to prominent increase in shear force beyond CCG resistance, resulting in a costal-cartilage junction fracture.

KLF9 and EPYC acting as feature genes for osteoarthritis and their association with immune infiltration.

BACKGROUND: Osteoarthritis, a common degenerative disease of articular cartilage, is characterized by degeneration of articular cartilage, changes in subchondral bone structure, and formation of osteophytes, with main clinical manifestations including increasingly serious swelling, pain, stiffness, deformity, and mobility deficits of the knee joints. With the advent of the big data era, the processing of mass data has evolved into a hot topic and gained a solid foundation from the steadily developed and improved machine learning algorithms. Aiming to provide a reference for the diagnosis and treatment of osteoarthritis, this paper using machine learning identifies the key feature genes of osteoarthritis and explores its relationship with immune infiltration, thereby revealing its pathogenesis at the molecular level. METHODS: From the GEO database, GSE55235 and GSE55457 data were derived as training sets and GSE98918 data as a validation set. Differential gene expressions of the training sets were analyzed, and the LASSO regression model and support vector machine model were established by applying machine learning algorithms. Moreover, their intersection genes were regarded as feature genes, the receiver operator characteristic (ROC) curve was drawn, and the results were verified using the validation set. In addition, the expression spectrum of osteoarthritis was analyzed by immunocyte infiltration and the co-expression correlation between feature genes and immunocytes was construed. CONCLUSION: EPYC and KLF9 can be viewed as feature genes for osteoarthritis. The silencing of EPYC and the overexpression of KLF9 are associated with the occurrence of osteoarthritis and immunocyte infiltration.

Mitochondria-targeted supramolecular coordination container encapsulated with exogenous itaconate for synergistic therapy of joint inflammation.

Rationale: Inflammatory macrophages and osteoclasts (OCs) play critical roles in joint inflammation, which feature the excessive production of reactive oxygen species (ROS), resulting in synovial inflammation and bone erosion. Scavenging ROS, especially by modulating mitochondrial metabolic activity, could be a desirable strategy for the management of inflammatory joints. This study aimed to develop a mitochondria-targeted supramolecular drug delivery system with exogenous and endogenous ROS-scavenging activities for the treatment of joint inflammation. Methods: In this study, we utilized a zinc-based metal-organic supercontainer (MOSC) as a proton sponge and electron reservoir with outstanding proton binding capacity, extracellular ROS-scavenging ability, and biocompatibility to establish an efficient supramolecular nanocarrier for endo/lysosomal escape and mitochondrial targeting. 4-Octyl itaconate (4-OI), an itaconate derivative, served as the loaded guest for the construction of a synergistic therapeutic system for inflammatory macrophages and OCs. Results: After the effective encapsulation of 4-OI, 4-OI@Zn-NH-pyr not only exhibited potent ROS-scavenging capacity, but also reduced ROS production by mediating mitochondrial respiration in inflammatory macrophages. Regarding its anti-inflammatory efficacy, 4-OI@Zn-NH-pyr ameliorated the inflammatory reaction by activating nuclear factor erythroid 2-related factor 2 (Nrf2), thus increasing the production of antioxidants, apart from the inhibition of NF-κB pathways. Additionally, receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and function was remarkably suppressed by 4-OI@Zn-NH-pyr. Consistent with in vitro observations, 4-OI@Zn-NH-pyr efficiently inhibited synovial inflammation and subchondral bone destruction in an acute arthritis model. Conclusion: By using MOSCs that are highly reactive to ROS as drug-loaded matrices for the first time, this study provides an avenue for the management of severe joint inflammation by designing synergistic supramolecular drug-delivery systems with subcellular targeting and ROS-scavenging capacity.

Titanium Nanobowl-Based Nest-Like Nanofiber Structure Prepared at Room Temperature and Pressure Promotes Osseointegration of Beagle Implants.

Nest-like nanofiber structures have potential applications in surface modifications of titanium implants. In this study, nest-like nanofiber structures were prepared on a titanium surface at room temperature and pressure by using the nanobowl template-assisted method combined with alkali etching. The characterization and biocompatibility of this material were analyzed by cellular adhesion, death, CCK-8, ALP, and RT-PCR assays in vitro, and osseointegration was evaluated by micro-CT and fluorescent labeling in vivo. The results showed that this nest-like nanofiber structure has a firmer and asperate surface than nanotubes, which leads to better cellular adhesion, proliferation, and differentiation capacity. In a beagle alveolar bone implant model, the nest-like nanofiber structure showed a better osseointegration capacity. In conclusion, this nest-like nanofiber structure has potential applications in dental implantology.

[Retracted] Silencing XIAP suppresses osteosarcoma cell growth, and enhances the sensitivity of osteosarcoma cells to doxorubicin and cisplatin.

Following the publication of this paper, it was drawn to the Editors' attention by a concerned reader that the western blotting data featured in Figs. 2B and 4D, the flow cytometric data in Fig. 4A and the tumour images shown in Fig. 6A were strikingly similar to data appearing in different form in other articles at different research institutes. Owing to the fact that the contentious data in the above article were already under consideration for publication, or had already been published, elsewhere prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. After having been in contact with the authors, they agreed with the decision to retract the paper. The Editor apologizes to the readership for any inconvenience caused. [the original article was published in Oncology Reports 33: 1177­1184, 2015; DOI: 10.3892/or.2014.3698].