N-retinylidene-N-retinylethanolamine degradation in human retinal pigment epithelial cells via memantine- and ifenprodil-mediated autophagy.

N-methyl-D-aspartate (NMDA) receptors are ionic glutamine receptors involved in brain development and functions such as learning and memory formation. NMDA receptor inhibition is associated with autophagy activation. In this study, we investigated whether the NMDA receptor antagonists, memantine and ifenprodil, induce autophagy in human retinal pigment epithelial cells (ARPE-19) to remove Nretinylidene- N-retinylethanolamine (A2E), an intracellular lipofuscin component. Fluorometric analysis using labeled A2E (A2E-BDP) and confocal microscopic examination revealed that low concentrations of NMDA receptor antagonists, which did not induce cytotoxicity, significantly reduced A2E accumulation in ARPE-19 cells. In addition, memantine and ifenprodil activated autophagy in ARPE-19 cells as measured by microtubule-associated protein 1A/1B-light chain3-II formation and phosphorylated p62 protein levels. Further, to understand the correlation between memantine- and ifenprodil-mediated A2E degradation and autophagy, autophagy-related 5 (ATG5) was depleted using RNA interference. Memantine and ifenprodil failed to degrade A2E in ARPE-19 cells lacking ATG5. Taken together, our study indicates that the NMDA receptor antagonists, memantine and ifenprodil, can remove A2E accumulated in cells via autophagy activation in ARPE-19 cells.

Screw-and-cement-retained prosthesis versus cement-retained prosthesis: Which is more appropriate for the upper premolar area?

Background/purpose: The narrow alveolar ridge in the maxillary premolars area limits the angle of implant placement and the shape of the prosthesis. The aim of this study was to evaluate which implant prosthesis, screw-and-cement-retained prosthesis (SCRP) or cement-retained prosthesis (CRP), was more suitable for the maxillary premolar area. Materials and methods: We conducted virtual implantation on 58 implant images from 47 patients obtained using cone beam computed tomography (CBCT). The width and buccal inclination of the alveolar bone, the angulation of the implant fixture, and the angulation of abutment were measured and calculated. Results: We determined that SCRP was feasible in 52% and 78.8% of first and second premolar areas, respectively. There was a positive relationship between the feasibility of SCRP and the premolar region in general (P = 0.031), although SCRP was more likely to be a possibility in the second premolar area. On multiple logistic regression analysis, the difference in the angle between the axis of the prosthesis and the axis of the alveolar bone (RA) was significantly associated with the type of prosthesis (P = 0.001). The RA was significantly higher for CRP implants (OR = 1.885; 95% CI: 1.31 to 2.70). Conclusion: SCRP is not always feasible in the maxillary premolar area, especially in the first premolar area. If the difference between the angle of the axis of the prosthesis and the axis of the alveolar bone is large, it may be necessary for the clinician to consider CRP in the treatment planning stage.

NMDA Receptor Antagonists Degrade Lipofuscin via Autophagy in Human Retinal Pigment Epithelial Cells.

Background and Objectives: Age-related macular degeneration is a slow-progressing disease in which lipofuscin accumulates in the retina, causing inflammation and apoptosis of retinal pigment epithelial (RPE) cells. This study aimed to identify N-methyl-D-aspartate (NMDA) signaling as a novel mechanism for scavenging N-retinylidene-N-retinylethanolamine (A2E), a component of ocular lipofuscin, in human RPE cells. Materials and Methods: A2E degradation assays were performed in ARPE-19 cells using fluorescently labeled A2E. The autophagic activity in ARPE-19 cells was measured upon blue light (BL) exposure, after A2E treatment. Autophagy flux was determined by measuring LC3-II formation using immunoblotting and confocal microscopy. To determine whether autophagy via the NMDA receptor is involved in A2E clearance, ATG5-deficient cells were used. Results: Ro 25-6981, an NR2B-selective NMDA receptor antagonist, effectively cleared A2E. Ro 25-6981 reduced A2E accumulation in the lysosomes of ARPE-19 cells at sub-cytotoxic concentrations, while increasing the formation of LC3-II and decreasing p62 protein levels in a concentration-dependent manner. The autophagic flux monitored by RFP-GFP-LC3 and bafilomycin A1 assays was significantly increased by Ro 25-6981. A2E clearance by Ro 25-6981 was abolished in ATG5-depleted ARPE-19 cells, suggesting that A2E degradation by Ro 25-6981 was mediated by autophagy. Furthermore, treatment with other NMDA receptor antagonists, CP-101,606 and AZD6765, showed similar effects on autophagy activation and A2E degradation in ARPE-19 cells. In contrast, glutamate, an NMDA receptor agonist, exhibited a contrasting effect, suggesting that both the activation of autophagy and the degradation of A2E by Ro 25-6981 in ARPE-19 cells occur through inhibition of the NMDA receptor pathway. Conclusions: This study demonstrates that NMDA receptor antagonists degrade lipofuscin via autophagy in human RPE cells and suggests that NMDA receptor antagonists could be promising new therapeutics for retinal degenerative diseases.

Exploring dentists' strategies for overcoming failure in daily dental practice.

OBJECTIVE: This study aimed to explore the strategies used by dentists to overcome failure in their daily practice. METHODS: In-depth interviews and qualitative description were used in the study. Fifteen dentists with more than 5 years of clinical practice experience participated. After consent was obtained, the interview was audio-recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: All participants had experienced failure during dental practice and used various strategies for overcoming it. Seven strategies were identified. These related to the dentists themselves (reflecting, learning, correcting), colleague dentists (asking, referring), patients (communicating), and advances in dentistry (adopting). CONCLUSIONS: Strategies for overcoming failure are related to multiple factors. Dentists need to comprehensively consider various strategies to achieve the best outcome when faced with failure. As lifelong learners, dentists need to continually develop competencies for overcoming failure. CLINICAL SIGNIFICANCE: Failures occur in everyday life, and clinical dentistry is no exception. Therefore, strategies for overcoming failure will help ensure patient safety and provide high-quality dental care.