Melatonin has potent antioxidant, analgesic, and antinociceptive properties. However, the effects of melatonin against oxidative stress-induced cytotoxicity and inflammatory mediators in human chondrocytes remain poorly understood. This study examined the effects and underlying mechanism of melatonin in hydrogen peroxide (H(2) O(2) )-stimulated human chondrocytes and rabbit osteoarthritis (OA) model. Melatonin markedly inhibited hydrogen peroxide (H(2) O(2) )-stimulated cytotoxicity, iNOS, and COX-2 protein and mRNA expression, as well as the downstream products, NO and PGE(2) . Incubation of cells with melatonin decreased H(2) O(2) -induced Sirtuin 1 (SIRT1) mRNA and protein expression. SIRT1 inhibition by sirtinol or Sirt1 siRNA reversed the effects of melatonin on H(2) O(2) -mediated induction of pro-inflammatory cytokines (NO, PGE(2) , TNF-α, IL-1β, and IL-8) and the expression of iNOS, COX-2, and cartilage destruction molecules. Melatonin blocked H(2) O(2) -induced phosphorylation of PI3K/Akt, p38, ERK, JNK, and MAPK, as well as activation of NF-κB, which was reversed by sirtinol and SIRT1 siRNA. In rabbit with OA, intra-articular injection of melatonin significantly reduced cartilage degradation, which was reversed by sirtinol. Taken together, this study shows that melatonin exerts cytoprotective and anti-inflammatory effects in an oxidative stress-stimulated chondrocyte model and rabbit OA model, and that the SIRT1 pathway is strongly involved in this effect.

No abstract

Smartphone education with schema based assignment proved to be attractive in dental radiology, but students showed less satisfaction, and need to meet the requirements of evidence-based practice. Although the full use of smartphone education with schema is not recommended in dental education, we think that it could be try to use as a supplementary approach with traditional didactic method to facilitate student's exploration and self-study to cope with rapid change in educational environment.

Endoplasmic reticulum (ER) stress is closely connected to autophagy. When cells are exposed to ER stress, cells exhibit enhanced protein degradation and form autophagosomes. In this study, we demonstrate that the chemical chaperone, 4-phenylbutyric acid (4-PBA), regulates ER stressinduced cell death and autophagy in human gingival fibroblasts. We found that 4-PBA protected cells against thapsigargin-induced apoptotic cell death but did not affect the reduced cell proliferation. ER stress induced by thapsigargin was alleviated by 4-PBA through the regulation of several ER stress-inducible, unfolded protein response related proteins including GRP78, GRP94, C/EBP homologous protein, phospho-eIF-2α, eIF-2α, phospho-JNK1 (p46) and phospho-JNK2/3 (p54), JNK1, IRE-1α, PERK, and sXBP-1. Compared with cells treated with thapsigargin alone, cells treated with both 4-PBA and thapsigargin showed lower levels of Beclin-1, LC-3II and autophagic vacuoles, indicating that 4-PBA also inhibited autophagy induced by ER stress. This study suggests that 4-PBA may be a potential therapeutic agent against ER stress-associated pathologic situations.

No abstract

This is a case report of an extremely rare condition of atlanto-axial subluxation secondary to gouty arthritis, which mimicked rheumatoid arthritis at presentation. Gouty arthritis involving the spine is a rare condition. We highlight a case of gouty arthritis involving the atlanto-axial joint resulting in joint instability, subluxation, and neurological deficit. A 66-year-old obese woman who had a polyarticular disease for the previous 3 years presented with neck pain and progressive neurology. A 2-stage procedure was performed: posterior decompression and occipitocervical fusion followed by further anterior trans-oral decompression. However, after an initial neurological improvement, she succumbed to aspirational pneumonia and septicaemia. Atlanto-axial subluxation caused by gouty arthritis can present in the same way as rheumatoid arthritis. Therefore, the possibility of this as a differential diagnosis should be kept in mind.

High glucose leads to physio/pathological alterations in diabetes patients. We investigated collagen production in human gingival cells that were cultured in high concentrations of glucose. Collagen synthesis and secretion were increased when the cells were exposed to high concentrations of glucose. We examined endoplasmic reticulum (ER) stress response because glucose metabolism is related to ER functional status. An ER stress response including the expression of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), inositol requiring enzyme alpha (IRE-1α) and phosphoreukaryotic initiation factor alpha (p-eIF-2α) was activated in the presence of high glucose. Activating transcription factor 4 (ATF-4), a downstream protein of p-eIF-2α as well as a transcription factor for collagen, was also phosphorylated and translocalized into the nucleus. The chemical chaperone 4-PBA inhibited the ER stress response and ATF-4 phosphorylation as well as nuclear translocation. Our results suggest that high concentrations of glucose-induced collagen are linked to ER stress and the associated phosphorylation and nuclear translocation of ATF-4.

The molecular mechanisms controlling the differentiation of bone marrow stromal stem cells into osteoblasts remain largely unknown. In this study, we investigated whether bone marrow stromal antigen 2 (BST2) influences differentiation toward the osteoblasts lineage. BST2 mRNA expression in human alveolar-derived bone marrow stromal cells (hAD-BMSCs) increased during differentiation into osteoblasts. hAD-BMSCs differentiation into osteoblasts and the mRNA expression of the bone-specific markers alkaline phosphatase, collagen type α 1, bone sialoprotein, osteocalcin, and osterix were reduced by BST2 knockdown using siRNA. Furthermore, BST2 knockdown in hAD-BMSCs resulted in decreased RUNX2 mRNA and protein expression. We hypothesized that BST2 is involved in differentiation of into osteoblasts via the BMP2 signaling pathway. Accordingly, we evaluated the mRNA expression levels of BMP2, BMP receptors (BMPR1 and 2), and the downstream signaling molecules SMAD1, SMAD4, and p-SMAD1/5/8 in BST2 knockdown cells. BMP2 expression following the induction of differentiation was significantly lower in BST2 knockdown cells than in cells treated with a non-targeting control siRNA. Similar results were found for the knockdown of the BMP2 receptor- BMPR1A. We also identified significantly lower expression of SMAD1, SMAD4, and p-SMAD1/5/8 in the BST2 knockdown cells than control cells. Our data provide the first evidence that BST2 is involved in the osteogenic differentiation of bone marrow stromal cells via the regulation of the BMP2 signaling pathway.