Biomineralization inspired 3D printed bioactive glass nanocomposite scaffolds orchestrate diabetic bone regeneration by remodeling micromilieu.

Type II diabetes mellitus (TIIDM) remains a challenging clinical issue for both dentists and orthopedists. By virtue of persistent hyperglycemia and altered host metabolism, the pathologic diabetic micromilieu with chronic inflammation, advanced glycation end products accumulation, and attenuated biomineralization severely impairs bone regeneration efficiency. Aiming to "remodel" the pathologic diabetic micromilieu, we 3D-printed bioscaffolds composed of Sr-containing mesoporous bioactive glass nanoparticles (Sr-MBGNs) and gelatin methacrylate (GelMA). Sr-MBGNs act as a biomineralization precursor embedded in the GelMA-simulated extracellular matrix and release Sr, Ca, and Si ions enhancing osteogenic, angiogenic, and immunomodulatory properties. In addition to angiogenic and anti-inflammatory outcomes, this innovative design reveals that the nanocomposites can modulate extracellular matrix reconstruction and simulate biomineralization by activating lysyl oxidase to form healthy enzymatic crosslinked collagen, promoting cell focal adhesion, modulating osteoblast differentiation, and boosting the release of OCN, the noncollagenous proteins (intrafibrillar mineralization dependent), and thus orchestrating osteogenesis through the Kindlin-2/PTH1R/OCN axis. This 3D-printed bioscaffold provides a multifunctional biomineralization-inspired system that remodels the "barren" diabetic microenvironment and sheds light on the new bone regeneration approaches for TIIDM.

The Role of TNF-α in the Pathogenesis of Temporomandibular Disorders.

Temporomandibular disorder (TMD) is an oral dentofacial disease that is related to multiple factors such as disordered dental occlusion, emotional stress, and immune responses. In the past decades, tumor necrosis factor-alpha (TNF-α), a pleiotropic cytokine, has provided valuable insight into the pathogenesis of TMD, particularly in settings associated with inflammation. It is thought that TNF-α participates in the pathogenesis of TMD by triggering immune responses, deteriorating bone and cartilage, and mediating pain in the temporomandibular joint (TMJ). Initially, TNF-α plays the role of "master regulator" in the complex immune network by increasing or decreasing the production of other inflammatory cytokines. Then, the effects of TNF-α on cells, particularly on chondrocytes and synovial fibroblasts, result in pathologic cartilage degradation in TMD. Additionally, multiple downstream cytokines induced by TNF-α and neuropeptides can regulate central sensitization and inflammatory pain in TMD. Previous studies have also found some therapies target TMD by reducing the production of TNF-α or blocking TNF-α-induced pathways. All this evidence highlights the numerous associations between TNF-α and TMD; however, they are currently not fully understood and further investigations are still required for specific mechanisms and treatments targeting specific pathways. Therefore, in this review, we explored general mechanisms of TNF-α, with a focus on molecules in TNF-α-mediated pathways and their potential roles in TMD treatment. In view of the high clinical prevalence rate of TMD and damage to patients' QOL, this review provides adequate evidence for studying links between inflammation and TMD in further research and investigation.

Biomechanical and biological responses of periodontium in orthodontic tooth movement: up-date in a new decade.

Nowadays, orthodontic treatment has become increasingly popular. However, the biological mechanisms of orthodontic tooth movement (OTM) have not been fully elucidated. We were aiming to summarize the evidences regarding the mechanisms of OTM. Firstly, we introduced the research models as a basis for further discussion of mechanisms. Secondly, we proposed a new hypothesis regarding the primary roles of periodontal ligament cells (PDLCs) and osteocytes involved in OTM mechanisms and summarized the biomechanical and biological responses of the periodontium in OTM through four steps, basically in OTM temporal sequences, as follows: (1) Extracellular mechanobiology of periodontium: biological, mechanical, and material changes of acellular components in periodontium under orthodontic forces were introduced. (2) Cell strain: the sensing, transduction, and regulation of mechanical stimuli in PDLCs and osteocytes. (3) Cell activation and differentiation: the activation and differentiation mechanisms of osteoblast and osteoclast, the force-induced sterile inflammation, and the communication networks consisting of sensors and effectors. (4) Tissue remodeling: the remodeling of bone and periodontal ligament (PDL) in the compression side and tension side responding to mechanical stimuli and root resorption. Lastly, we talked about the clinical implications of the updated OTM mechanisms, regarding optimal orthodontic force (OOF), acceleration of OTM, and prevention of root resorption.

Therapeutic potentials and modulatory mechanisms of fatty acids in bone.

Bone metabolism is a lifelong process that includes bone formation and resorption. Osteoblasts and osteoclasts are the predominant cell types associated with bone metabolism, which is facilitated by other cells such as bone marrow mesenchymal stem cells (BMMSCs), osteocytes and chondrocytes. As an important component in our daily diet, fatty acids are mainly categorized as long-chain fatty acids including polyunsaturated fatty acids (LCPUFAs), monounsaturated fatty acids (LCMUFAs), saturated fatty acids (LCSFAs), medium-/short-chain fatty acids (MCFAs/SCFAs) as well as their metabolites. Fatty acids are closely associated with bone metabolism and associated bone disorders. In this review, we summarized the important roles and potential therapeutic implications of fatty acids in multiple bone disorders, reviewed the diverse range of critical effects displayed by fatty acids on bone metabolism, and elucidated their modulatory roles and mechanisms on specific bone cell types. The evidence supporting close implications of fatty acids in bone metabolism and disorders suggests fatty acids as potential therapeutic and nutritional agents for the treatment and prevention of metabolic bone diseases.

Metabolic gene NR4A1 as a potential therapeutic target for non-smoking female non-small cell lung cancer patients.

BACKGROUND: Although cigarette smoking is considered one of the key risk factors for lung cancer, 15% of male patients and 53% of female patients with lung cancer are non-smokers. Metabolic changes are critical features of cancer. Therapeutic target identification from a metabolic perspective in non-small cell lung cancer (NSCLC) tissue of female non-smokers has long been ignored. RESULTS: Based on microarray data retrieved from Affymetrix expression arrays E-GEOD-19804, we found that the downregulated genes in non-smoking female NSCLC patients tended to participate in protein/amino acid and lipid metabolism, while upregulated genes were more involved in protein/amino acid and carbohydrate metabolism. Combining nutrient metabolic co-expression, protein-protein interaction network construction and overall survival assessment, we identified NR4A1 and TIE1 as potential therapeutic targets for NSCLC in female non-smokers. To accelerate the drug development for non-smoking female NSCLC patients, we identified nilotinib as a potential agonist targeting NR4A1 encoded protein by molecular docking and molecular dynamic stimulation. We also show that nilotinib inhibited proliferation and induced senescence of cells in non-smoking female NSCLC patients in vitro. CONCLUSIONS: These results not only uncover nutrient metabolic characteristics in non-smoking female NSCLC patients, but also provide a new paradigm for identifying new targets and drugs for novel therapy for such patients.

Screening of novel histone deacetylase 7 inhibitors through molecular docking followed by a combination of molecular dynamics simulations and ligand-based approach.

Histone acetylation/deacetylation is a key mechanism for transcription regulation which plays an important role in control of gene expression, tissue growth, and development. In particular, histone deacetylase 7 (HDAC7), a member of class IIa HDACs, is crucial to maintain cell homeostasis, and HDAC7 has emerged as a new target for cancer therapy. In this study, molecular docking was applied to screen candidate inhibitors and 21 compounds were found. Following the 50 ns molecular dynamics simulations and binding free energy calculation, ZINC00156160, ZINC01703144, ZINC04293665, and ZINC13900201 were identified as potential HDAC7 inhibitors, which would provide a sound starting point for further studies involving molecular modeling coupled with biochemical experiments. Meanwhile, similarity computation and substructure search were combined, and then we found that compounds sharing common backbone "CC(=O)N[C@@H](CSc1ccccc1)C(=O)O" could be efficient to inhibit the bioactivity of HDAC7. Then comparative molecular similarity indices analysis (CoMSIA) techniques were implemented to investigate the relationship between properties of the substituent group and bioactivities of small molecules. The CoMSIA model exhibited powerful predictivity, with satisfactory statistical parameters such as q2 of 0.659, R2 of 0.952, and F of 268.448. Contour maps of the CoMSIA model gave insight into the feature requirements of the common backbone for the HDAC7 inhibitory activity. Finally, details of designing novel HDAC7 inhibitors were confirmed by a combination of receptor-based docking and ligand-based structure-activity relationship. Communicated by Ramaswamy H. Sarma.

Computer-aided identification of a novel pyruvate kinase M2 activator compound.

OBJECTIVES: The aim of this study was to obtain antitumour molecules targeting to activate PKM2 through adequate computational methods combined with biological activity experiments. METHODS: The structure-based virtual screening was utilized to screen effective activator targeting PKM2 from ZINC database. Molecular dynamics simulations were performed to evaluate the stability of the small molecule-binding PKM2 complex systems. Then, cell survival experiments, glutaraldehyde crosslinking reaction, western blot, and qPCR experiments were used to detect the effects of top hits on various cancer cells and the targeting specificity of PKM2. RESULTS: Two small molecules in 1,5-2H-pyrrole-dione were obtained after virtual screening. In vitro experiments demonstrated that ZINC08383544 specifically activated PKM2 and affected the expression of upstream and downstream genes of PKM2 during glycolysis, leading to the inhibition of tumour cell growth. These results indicate that ZINC08383544 conforms to the characteristics of PKM2 activator and is potential to be a novel PKM2 activator as antitumour drug. DISCUSSION: This work proves that ZINC08383544 promotes the formation of PKM2 tetramer, effectively blocks PKM2 nuclear translocation, and inhibits the growth of tumour, and ZINC08383544 may be a novel activator of PKM2. This work may provide a good choice of drug or molecular fragments for the antitumour strategy targeting PKM2. Screening of targeted drugs by combination of virtual screening and bioactivity experiments is a rapid method for drug discovery.

Wnt signaling in bone metastasis: mechanisms and therapeutic opportunities.

Bone metastasis frequently occurs in advanced cancer patients, who will develop osteogenic/osteolytic bone lesions in the late stage of the disease. Wnt signaling pathway, which is mainly grouped into the ß-catenin dependent pathway and ß-catenin independent pathway, is a well-organized cascade that has been reported to play important roles in a variety of physiological and pathological conditions, including bone metastasis. Regulation of Wnt signaling in bone metastasis involves multiple stages, including dissemination of primary tumor cells to bone, dormancy and outgrowth of metastatic tumor cells, and tumor-induced osteogenic and osteolytic bone destruction, suggesting the importance of Wnt signaling in bone metastasis pathology. In this review, we will introduce the involvement of Wnt signaling components in specific bone metastasis stages and summarize the promising Wnt modulators that have shown potential as bone metastasis therapeutics, in the hope to maximize the therapeutic opportunities of Wnt signaling for bone metastasis.

In silico identification of potential inhibitors targeting Streptococcus mutans sortase A.

Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans (S. mutans) utilizes sortase A (SrtA) to anchor surface proteins to the cell wall and forms a biofilm to facilitate its adhesion to the tooth surface. Some plant natural products, especially several flavonoids, are effective inhibitors of SrtA. However, given the limited number of inhibitors and the development of drug resistance, the discovery of new inhibitors is urgent. Here, the high-throughput virtual screening approach was performed to identify new potential inhibitors of S. mutans SrtA. Two libraries were used for screening, and nine compounds that had the lowest scores were chosen for further molecular dynamics simulation, binding free energy analysis and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties analysis. The results revealed that several similar compounds composed of benzofuran, thiadiazole and pyrrole, which exhibited good affinities and appropriate pharmacokinetic parameters, were potential inhibitors to impede the catalysis of SrtA. In addition, the carbonyl of these compounds can have a key role in the inhibition mechanism. These findings can provide a new strategy for microbial infection disease therapy.