The mechanisms of -derived outer membrane vesicles-induced neurotoxicity and microglia activation.

Background/purpose: Periodontitis is associated with various systemic diseases, potentially facilitated by the passage of outer membrane vesicles (Pg-OMVs). Several recent studies have suggested a connection between Pg-OMVs and neuroinflammation and neurodegeneration, but the precise causal relationship remains unclear. This study aimed to investigate the mechanisms underlying these associations using in vitro models.

Sirtuin 6 ameliorates arthritis through modulating cyclic AMP-responsive element binding protein/CCN1/cyclooxygenase 2 pathway in osteoblasts.

Introduction: CCN1 is an immediate-early gene product pivotal for arthritis progression. We have previously shown that sirtuin 6 (SIRT6) inhibited hypoxia-induced CCN1 expression in osteoblasts. Herein we examined the contribution of cyclic AMP-responsive element binding protein (CREB)/CRE to this suppressive action and the influence of CCN1 on cyclooxygenase (COX) 2 synthesis.

Metformin Reduces Bone Resorption in Apical Periodontitis Through Regulation of Osteoblast and Osteoclast Differentiation.

Introduction: We have previously demonstrated that auxiliary metformin therapy promotes healing of apical periodontitis. Here we aimed to investigate the effects of metformin on osteoblast differentiation and osteoclast formation in cultured cells and rat apical periodontitis.

Methods: Murine pre-osteoblasts MC3T3-E1 and macrophages RAW264.

The possible role of sirtuin 5 in the pathogenesis of apical periodontitis.

Objectives: We investigated the relation between expression of sirtuin 5 (SIRT5) in osteoblastic cells and progression of apical periodontitis. The role of SIRT5 in hypoxia-induced reactive oxygen species (ROS) formation and osteoblast apoptosis was also examined.

Materials And Methods: Progression of rat apical periodontitis was monitored by conventional radiography and microcomputed tomography.

Intracanal Metformin Promotes Healing of Apical Periodontitis via Suppressing Inducible Nitric Oxide Synthase Expression and Monocyte Recruitment.

Introduction: We have previously shown that intracanal metformin ameliorates apical periodontitis, partially by modulation of osteoblast apoptosis. The action of metformin on other cell types pertinent to the development of apical periodontitis needs to be examined. In the present study, we aimed to analyze whether its effects on the expression of inducible nitric oxide synthase (iNOS) and monocyte recruitment contribute to the therapeutic effect on apical periodontitis.

AKR1C1 controls cisplatin-resistance in head and neck squamous cell carcinoma through cross-talk with the STAT1/3 signaling pathway.

Background: Cisplatin is the first-line chemotherapy used against most upper aerodigestive tract carcinomas. In head and neck cancer, sensitivity to cisplatin remains the key issue in treatment response and outcome. Genetic heterogeneity and aberrant gene expression may be the intrinsic factors that cause primary cisplatin-resistance.

Metformin Ameliorates Periapical Lesions through Suppression of Hypoxia-induced Apoptosis of Osteoblasts.

Introduction: Intramuscular injection of metformin has been shown to inhibit the progression of periapical lesions in rats by decreasing the number of receptor activator of nuclear factor-κβ ligand- and tartrate-resistant acid phosphatase-positive cells. In this study, we investigated the effect of metformin on hypoxia-induced apoptosis of osteoblasts and the therapeutic activity of intracanal metformin in induced periapical lesions in rats.

Methods: The influence of metformin on hypoxia-induced mitochondrial superoxide production in human osteoblasts was examined by using MitoSOX (Invitrogen, Carlsbad, CA) fluorescence dye signaling.

Differential protective effects of connective tissue growth factor against Aβ neurotoxicity on neurons and glia.

Impaired clearance of amyloid-β peptide (Aβ) leads to abnormal extracellular accumulation of this neurotoxic protein that drives neurodegeneration in sporadic Alzheimer's disease (AD). Connective tissue growth factor (CTGF/CCN2) expression is elevated in plaque-surrounding astrocytes in AD patients. However, the role of CTGF in AD pathogenesis remains unclear.

Increased Expression of Glutaminase in Osteoblasts Promotes Macrophage Recruitment in Periapical Lesions.

Introduction: Recently, we have shown that tissue hypoxia stimulates the progression of periapical lesions by up-regulating glycolysis-dependent apoptosis of osteoblasts. Other facets of hypoxia-induced metabolic reprogramming in disease pathogenesis require further investigation. In this study, we examined the connection between hypoxia-augmented glutamine catabolism in osteoblasts and the development of periapical lesions.

Sirtuin 6 suppresses hypoxia-induced inflammatory response in human osteoblasts via inhibition of reactive oxygen species production and glycolysis-A therapeutic implication in inflammatory bone resorption.

Elevated glycolytic activity and redox imbalance induced by tissue hypoxia are common phenomena of chronic inflammation, including inflammatory bone diseases such as arthritis. However, relation between glycolysis and redox signaling in the inflammatory milieu is unclear. The histone deacetylase sirtuin 6 (SIRT6) is a crucial modulator of inflammation and glucose metabolism, and it is also involved in cellular protection against oxidative injury.

Sirtuin 6 modulates hypoxia-induced autophagy in nasal polyp fibroblasts via inhibition of glycolysis.

Background: To elucidate the interaction between hypoxia-induced autophagy and glycolysis in nasal polyp fibroblasts, and the regulatory role of Sirtuin 6 (SIRT6) in the pathogenesis of nasal polyp.

Objective: Through examining the expressions of lactate dehydrogenase (LDH), microtubule-associated protein II light chain 3 (LC3II) (an autophagy marker), and production of lactate under hypoxia, the interaction between autophagy and glycolysis was investigated. The role of SIRT6 on the hypoxia-induced autophagy and glycolysis was also examined.

Sirtuin 6 Modulates Hypoxia-induced Apoptosis in Osteoblasts via Inhibition of Glycolysis: Implication for Pathogenesis of Periapical Lesions.

Introduction: Osteoblast apoptosis is important in the regulation of inflammatory bone resorption. Hypoxia resulting from inflammation enhances glycolysis and apoptosis. Sirtuin 6 (SIRT6) is a modulator of glucose metabolism and apoptosis.

Simvastatin suppresses osteoblastic expression of Cyr61 and progression of apical periodontitis through enhancement of the transcription factor Forkhead/winged helix box protein O3a.

Introduction: In this study, the role of transcription factor Forkhead/winged helix box protein O3a (FoxO3a) in Cyr61 expression and its modulation by simvastatin were investigated in cultured murine osteoblasts and a rat model of induced apical periodontitis. We also examined the effects of simvastatin on the synthesis of chemokine CCL2 and chemotaxis of macrophages in vitro.

Methods: We assessed tumor necrosis factor (TNF)-α-stimulated expression of Cyr61 and phosphorylated inactive FoxO3a (p-FoxO3a) in MC3T3-E1 murine osteoblasts by Western analysis.

Simvastatin inhibits cysteine-rich protein 61 expression in rheumatoid arthritis synovial fibroblasts through the regulation of sirtuin-1/FoxO3a signaling.

Objective: To examine the role of sirtuin-1 (SIRT-1)/FoxO3a in the expression of cysteine-rich protein 61 (CYR-61) in rheumatoid arthritis synovial fibroblasts (RASFs) and the influence of simvastatin on this pathway, and to determine the relationship between disease progression and FoxO3a/CYR-61 signaling in synovial fibroblasts in vivo using a rat model of collagen-induced arthritis (CIA).

Methods: In RASFs, the expression of CYR-61 and SIRT-1, the localization of FoxO3a in the nucleus/cytoplasm, and the phosphorylation/acetylation of FoxO3a were examined by Western blotting. Secretion of CCL20 was assessed by enzyme-linked immunosorbent assay.

Epigallocatechin-3-gallate diminishes cytokine-stimulated Cyr61 expression in human osteoblastic cells: a therapeutic potential for arthritis.

Objective: To assess the effects of epigallocatechin-3-gallate (EGCG) on cytokine-induced Cyr61 synthesis in human osteoblastic cells and the associated signalling pathways. The therapeutic effect of EGCG on CIA in rats was also studied.

Methods: The expression of Cyr61 and NF-κB pathway molecules was examined by western blotting.

Simvastatin alleviates the progression of periapical lesions by modulating autophagy and apoptosis in osteoblasts.

Introduction: Autophagy is a process for recycling intracellular organelles as a survival mechanism. Apoptosis has important biological roles in the pathogenesis of many diseases. This study elucidated the effect of simvastatin on autophagy/apoptosis in MC3T3E1 murine osteoblastic cells and also the significance of this action on the progression of induced rat apical periodontitis.

Hypoxia induces cysteine-rich 61, vascular endothelial growth factor, and interleukin-8 expressions in human nasal polyp fibroblasts: An implication of neutrophils in the pathogenesis of nasal polyposis.

Background: The purpose of this article was to elucidate the roles of neutrophils and angiogenesis factors in the pathogenesis of nasal polyposis. The effect of hypoxia on the expressions of angiogenesis factors as cysteine-rich 61 (Cyr61) and vascular endothelial growth factor (VEGF) and neutrophil chemoattractant as interleukin (IL)-8 in nasal polyp fibroblasts (NPFs), and the role of nuclear factor kappa B (NF-kappaB) in this reaction were investigated. The action of Cyr61 on the synthesis of VEGF and IL-8 in NPFs was also examined.

Highly efficient release of lovastatin from poly(lactic-co-glycolic acid) nanoparticles enhances bone repair in rats.

Lovastatin exhibits higher thermal stability and lower degradation rate than simvastatin. However, the amount of research studying a lovastatin delivery device has been far less than similar research on simvastatin. As a consequence, a high lovastatin release rate system has not been developed.

Major histocompatibility complex class II transactivator inhibits cysteine-rich 61 expression in osteoblastic cells and its implication in the pathogenesis of periapical lesions.

Introduction: Osteoblastic expression of cysteine-rich 61 (Cyr61) correlates with the severity of periapical lesion-associated bone loss, but the regulatory mechanism of Cyr61 expression was not known.

Methods: In the study we examined the effect of major histocompatibility complex class II transactivator (CIITA) on tumor necrosis factor (TNF)-alpha-induced Cyr61 synthesis in U2OS human osteoblastic cells by Western blot analysis. In a rat model of bacteria-induced apical periodontitis, we assessed the relation between osteoblastic expressions of CIITA/Cyr61 and disease progression by radiographic and immunohistochemistry studies.

Simvastatin inhibits cytokine-stimulated Cyr61 expression in osteoblastic cells: a therapeutic benefit for arthritis.

Objective: To examine the effects of proinflammatory cytokines on Cyr61 expression in osteoblastic cells and the modulatory action of simvastatin, to assess the role of CREB in Cyr61 induction, and to investigate the relationship of osteoblastic expression of Cyr61 to disease progression in experimental arthritis.

Methods: Cyr61 expression and CREB phosphorylation at serine 133 were examined by Western blotting. Promoter activity of Cyr61 was assessed by luciferase assay with promoter deletion/mutagenesis and forced expression/gene silencing of CREB.

Simvastatin as a novel strategy to alleviate periapical lesions.

Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are widely used cholesterol-lowering agents that also possess anti-inflammatory activities. Cysteine-rich 61 (Cyr61) and CCL2 are potential osteolytic mediators in inflammatory bone diseases. The study assessed the effect of simvastatin on tumor necrosis factor alpha (TNF- alpha)-induced synthesis of Cyr61 and CCL2 in MG-63 human osteoblastic cells.

Oncostatin M-induced CCL2 transcription in osteoblastic cells is mediated by multiple levels of STAT-1 and STAT-3 signaling: an implication for the pathogenesis of arthritis.

Objective: To examine the roles of STATs 1 and 3 in CCL2 production in human osteoblastic cells and their influences on arthritis development.

Methods: The expression of CCL2 in primary human osteoblasts and U2OS human osteoblastic cells was examined by Northern blotting and enzyme-linked immunosorbent assay. The roles of STAT-1/3 and c-Fos were assessed using short hairpin RNAs (shRNA) to silence their functions.

An extract of green tea, epigallocatechin-3-gallate, reduces periapical lesions by inhibiting cysteine-rich 61 expression in osteoblasts.

Recent investigations indicate that epigallocatechin-3-gallate (EGCG), the major polyphenol of green tea, has anti-inflammatory properties. This study assessed the effect of EGCG on oncostatin M (OSM)-induced synthesis of cysteine-rich 61 (Cyr61), a potential osteolytic mediator, in MG-63 human osteoblastic cells. The therapeutic effect of EGCG in apical periodontitis in rats was also examined.

Epigallocatechin-3-gallate diminishes CCL2 expression in human osteoblastic cells via up-regulation of phosphatidylinositol 3-Kinase/Akt/Raf-1 interaction: a potential therapeutic benefit for arthritis.

Objective: To assess the effects of epigallocatechin-3-gallate (EGCG) on oncostatin M (OSM)-induced CCL2 synthesis and the associated signaling pathways in human osteoblastic cells. The therapeutic effect of EGCG on collagen-induced arthritis (CIA) in rats was also studied.

Methods: CCL2 and c-Fos messenger RNA expression was analyzed by Northern blotting.