Targeting SOX13 inhibits assembly of respiratory chain supercomplexes to overcome ferroptosis resistance in gastric cancer.

Therapeutic resistance represents a bottleneck to treatment in advanced gastric cancer (GC). Ferroptosis is an iron-dependent form of non-apoptotic cell death and is associated with anti-cancer therapeutic efficacy. Further investigations are required to clarify the underlying mechanisms. Ferroptosis-resistant GC cell lines are constructed. Dysregulated mRNAs between ferroptosis-resistant and parental cell lines are identified. The expression of SOX13/SCAF1 is manipulated in GC cell lines where relevant biological and molecular analyses are performed. Molecular docking and computational screening are performed to screen potential inhibitors of SOX13. We show that SOX13 boosts protein remodeling of electron transport chain (ETC) complexes by directly transactivating SCAF1. This leads to increased supercomplexes (SCs) assembly, mitochondrial respiration, mitochondrial energetics and chemo- and immune-resistance. Zanamivir, reverts the ferroptosis-resistant phenotype via directly targeting SOX13 and promoting TRIM25-mediated ubiquitination and degradation of SOX13. Here we show, SOX13/SCAF1 are important in ferroptosis-resistance, and targeting SOX13 with zanamivir has therapeutic potential.

A Bioinspired Gelatin-Amorphous Calcium Phosphate Coating on Titanium Implant for Bone Regeneration.

Biocompatible and bio-active coatings can enhance and accelerate osseointegration via chemical binding onto substrates. Amorphous calcium phosphate (ACP) has been shown as a precursor to achieve mineralization in vertebrates and invertebrates under the control of biological macromolecules. This work presents a simple bioinspired Gelatin-CaPO4 (Gel-CaP) composite coating on titanium surfaces to improve osseointegration. The covalently bound Gel-CaP composite is characterized as an ACP-Gel compound via SEM, FT-IR, XRD, and HR-TEM. The amorphous compound coating exhibits a nanometer range thickness and improved elastic modulus, good wettability, and nanometric roughness. The amount of grafted carboxyl groups and theoretical thickness of the coatings are also investigated. More importantly, MC3T3 cells, an osteoblast cell line, show excellent cell proliferation and adhesion on the Gel-CaP coating. The level of osteogenic genes is considerably upregulated on Ti with Gel-CaP coatings compared to uncoated Ti, demonstrating that Gel-CaP coatings possess a unique osteogenic ability. To conclude, this work offers a new perspective on functional, bioactive titanium coatings, and Gel-CaP composites can be a low-cost and promising candidate in bone regeneration.

Organized mineralized cellulose nanostructures for biomedical applications.

Cellulose is the most abundant naturally-occurring polymer, and possesses a one-dimensional (1D) anisotropic crystalline nanostructure with outstanding mechanical robustness, biocompatibility, renewability and rich surface chemistry in the form of nanocellulose in nature. Such features make cellulose an ideal bio-template for directing the bio-inspired mineralization of inorganic components into hierarchical nanostructures that are promising in biomedical applications. In this review, we will summarize the chemistry and nanostructure characteristics of cellulose and discuss how these favorable characteristics regulate the bio-inspired mineralization process for manufacturing the desired nanostructured bio-composites. We will focus on uncovering the design and manipulation principles of local chemical compositions/constituents and structural arrangement, distribution, dimensions, nanoconfinement and alignment of bio-inspired mineralization over multiple length-scales. In the end, we will underline how these cellulose biomineralized composites benefit biomedical applications. It is expected that this deep understanding of design and fabrication principles will enable construction of outstanding structural and functional cellulose/inorganic composites for more challenging biomedical applications.

A novel lineage of osteoprogenitor cells with dual epithelial and mesenchymal properties govern maxillofacial bone homeostasis and regeneration after MSFL.

Bone regeneration originates from proliferation and differentiation of osteoprogenitors via either endochondral or intramembranous ossification; and the regeneration capacities decline with age and estrogen loss. Maxillary sinus floor lifting (MSFL) is a commonly used surgical procedure for guiding bone regeneration in maxilla. Radiographic analysis of 1210 clinical cases of maxilla bone regeneration after MSFL revealed that the intrasinus osteogenic efficacy was independent of age and gender, however; and this might be related to the Schneiderian membrane that lines the sinus cavity. In view of the particularity of this biological process, our present study aimed to elucidate the underlying mechanism of MSFL-induced bone regeneration. We first established a murine model to simulate the clinical MSFL. By single-cell RNA-sequencing and flow cytometry-based bulk RNA-sequencing, we identified a novel Krt14+Ctsk+ subset of cells that display both epithelial and mesenchymal properties and the transcriptomic feature of osteoprogenitors. Dual recombinases-mediated lineage tracing and loss-of-function analyses showed that these Krt14+Ctsk+ progenitors contribute to both MSFL-induced osteogenesis and physiological bone homeostasis by differentiating into Krt14-Ctsk+ descendants which show robust osteogenic capacity. In addition, we detected a similar population of Krt14+Ctsk+ cells in human samples of Schneiderian membrane, which show a highly similar osteogenic potential and transcriptomic feature to the corresponding cells in mice. The identification of this Krt14+Ctsk+ population, featured by osteoprogenitor characteristics and dual epithelial-mesenchymal properties, provides new insight into the understanding of bone regeneration and may open more possibilities for clinical applications.

Amorphous Precursor-Mediated Calcium Phosphate Coatings with Tunable Microstructures for Customized Bone Implants.

Calcium phosphate (CaP) is frequently used as coating for bone implants to promote osseointegration. However, commercial CaP coatings via plasma spraying display similar microstructures, and thus fail to provide specific implants according to different surgical conditions or skeletal bone sites. Herein, inspired by the formation of natural biominerals with various morphologies mediated by amorphous precursors, CaP coatings with tunable microstructures mediated by an amorphous metastable phase are fabricated. The microstructures of the coatings are precisely controlled by both polyaspartic acid and Mg2+ . The cell biological behaviors, including alkaline phosphatase activity, mineralization, and osteogenesis-related genes expression, on the CaP coatings with different microstructures, exhibit significant differences. Furthermore, in vivo experiments demonstrate the osseointegration in different types of rats and bones indeed favors different CaP coatings. This biomimetic strategy can be used to fabricate customized bone implants that can meet the specific requirements of various surgery conditions.

Trem2 mediated Syk-dependent ROS amplification is essential for osteoclastogenesis in periodontitis microenvironment.

Periodontitis is the sixth most prevalent diseases around the globe, which is closely related to many systemic diseases and affects general health. As the leading cause of tooth loss, periodontitis is characterized by irreversible alveolar bone loss and activated osteoclastogenic process, which might be closely related to the activated intracellular reactive oxygen species (ROS) in osteoclasts. Here, we demonstrated triggering receptor expressed on myeloid cells 2 (Trem2) as a key regulator of osteoclastogenesis with the regulation of intracellular ROS signals in periodontitis. In the present study, the expression of Trem2 was significantly upregulated in human alveolar bones diagnosed with chronic periodontitis, as assessed by RNA-seq. In the mice model of periodontitis, the alveolar bone resorption was impeded in the presence of the conditional knockout of Trem2 in osteoclasts. Furthermore, we identified Trem2/DAP12/Syk-dependent cascade as a vital intracellular signaling for the amplification of reactive oxygen species (ROS) signals in osteoclastogenesis, while the accumulation of soluble Aß42 oligomers (Aßo) in periodontitis microenvironment further strengthened the signals and enhanced osteoclastogenesis through direct interactions with Trem2. Collectively, Trem2 mediated ROS signal amplification cascade was crucial in the process of osteoclastogenesis in periodontitis, suggesting the potential of Trem2 as a target for the prevention and treatment of bone destruction in periodontitis.

Big data analysis of patients with periodontitis and factors influencing treatment behavior / 口腔疾病防治

Objective @#To study patient-related information and factors altering their decision making in periodontal treatment and treatment behavior via big data analysis of the electronic medical records and to guide better dental care service and improve periodontal treatment. @*Methods@# A retrospective study was performed in patients with periodontitis who visited the Affiliated Stomatological Hospital of Tongji University from 2014 to 2016. Based on the periodontal sequence treatment procedure, the treatment types were divided into six groups and were analyzed using multivariable regression analysis. Chi-square test was performed according to gender and age.@*Results@#Age, payment method, disease severity, exhibited statistically significant differences regarding their effects on patients’ treatment behavior (P ＜ 0.05). Men were more likely to have severe periodontitis than women (male 41.04%; female 31.85%), and use medical insurance more often as payment method (male 86.14%; female 83.74%) (P ＜ 0.05). Compared with the population under 35 years old, moderate and severe periodontitis accounted for a larger proportion (84.58%) in the population over 35 years old. The compliance of the population over 35 years old was poor. Less follow-up reviews were conducted (17.10%) and medical insurance was less often used (49.65%) in this population. The differences were statistically significant (P ＜ 0.05).@*Conclusion@#Moderate and severe periodontitis accounted for a larger proportion in the population over 35 years old. Patients over 35 years old tend to choose simpler treatments with lower compliance and frequency of revisits. This situation may be related to the lower proportion of medicare use in this population. The awareness and compliance of periodontal treatment protocols in people over 35 years old needs to be improved.

Coronectomy: A Useful Approach in Minimizing Nerve Injury Compared With Traditional Extraction of Deeply Impacted Mandibular Third Molars.

PURPOSE: A surgical procedure to minimize the incidence of inferior alveolar nerve injury (IANI) in deeply impacted mandibular third molars (IMTMs) has been proposed. Our study compared the near-term outcomes between coronectomy and traditional extraction of IMTMs and evaluated the long-term complications after coronectomy using cone-beam computed tomography (CBCT). PATIENTS AND METHODS: A prospective study was performed of patients with IMTMs at high-risk of IANI using radiographic examination and CBCT. The patients were divided into 2 groups: a coronectomy group and an extraction group. The short-term outcomes, including IANI and other conditions, such as bleeding, pain, and swelling, were assessed in both groups 1 week after surgery. The coronectomy patients were evaluated at 3, 6, 12, and 36 months after the procedure. The primary long-term complications assessed included root migration, secondary included inflammation, socket healing, and eruption. Relevant factors affecting the outcomes (ie, age, gender, root morphology, impacted depth, impacted angle) were also analyzed. The data were analyzed using SPSS Statistics, version 20.0 (IBM Corp, Armonk, NY). RESULTS: A total of 110 IMTMs (55 in the coronectomy group and 55 in the extraction group) in 92 patients (49 men and 43 women) were included in CBCT assessment. IANI was found in 6 patients in the extraction group and no patient in the coronectomy group (P < .05). After 6 months, 2 patients still presented with light numbness. After coronectomy, the roots had migrated quickly during the initial 6 months and had become stable 1 year after surgery; 90.9% of the roots had migrated away from the mandibular nerve canal at 6 months postoperatively. No infection had occurred within the 3-year follow-up period. CONCLUSIONS: Coronectomy should be considered superior to traditional extraction in the management of the risk of IANI, with few additional complications occurring during follow-up. It could be used as a useful and safe clinical treatment of IMTMs with a high risk of IANI.

Dual micelles-loaded gelatin nanofibers and their application in lipopolysaccharide-induced periodontal disease.

INTRODUCTION: Combined therapies utilizing inhibitors to remove pathogens are needed to suppress lipopolysaccharide (LPS)-induced periodontal disease. We prepared a novel, multi-agent delivery scaffold for periodontal treatment. METHODS: In this study, we synthesized SP600125 (a JNK inhibitor) and SB203580 (a p38 inhibitor) drug-loaded poly(ethylene glycol)-block-caprolactone copolymer via dialysis method. The physical property of micelles was characterized through dynamic light scattering and transmission electron microscopy. The cell growth and LPS-induced MMP-2 and MMP-13 expression were evaluated through CCK-8, real-time PCR and Western blot assay. The release of SP600125 and SB203580 from different scaffolds was estimated. Microcomputed tomography and histology were used for evaluating the effect of the micelles-loaded nanofibers on the treatment of class II furcation defects in dogs. RESULTS: The drug was then successfully incorporated into gelatin fibers during electrospinning process. We confirmed that the micelles had spherical structure and an average particle size of 160 nm for SP600125-micelles (SP-Ms) and 150 nm for SB203580-micelles (SB-Ms). The nanofiber scaffold showed excellent encapsulation capability, in vitro drug-release behavior, and cell compatibility. Real-time PCR and Western blot assay further indicated that LPS-induced MMP-2 and MMP-13 expression was significantly inhibited by the scaffold. CONCLUSION: The results suggested that the dual drug-loaded system developed in this study might become a highly effective therapy for periodontal disease.

Alterations of oral microbiota distinguish children with autism spectrum disorders from healthy controls.

Altered gut microbiota is associated with autism spectrum disorders (ASD), a group of complex, fast growing but difficult-to-diagnose neurodevelopmental disorders worldwide. However, the role of the oral microbiota in ASD remains unexplored. Via high-throughput sequencing of 111 oral samples in 32 children with ASD and 27 healthy controls, we demonstrated that the salivary and dental microbiota of ASD patients were highly distinct from those of healthy individuals. Lower bacterial diversity was observed in ASD children compared to controls, especially in dental samples. Also, principal coordinate analysis revealed divergences between ASD patients and controls. Moreover, pathogens such as Haemophilus in saliva and Streptococcus in plaques showed significantly higher abundance in ASD patients, whereas commensals such as Prevotella, Selenomonas, Actinomyces, Porphyromonas, and Fusobacterium were reduced. Specifically, an overt depletion of Prevotellaceae co-occurrence network in ASD patients was obtained in dental plaques. The distinguishable bacteria were also correlated with clinical indices, reflecting disease severity and the oral health status (i.e. dental caries). Finally, diagnostic models based on key microbes were constructed, with 96.3% accuracy in saliva. Taken together, this study characterized the habitat-specific profile of the oral microbiota in ASD patients, which might help develop novel strategies for the diagnosis of ASD.