Bone morphogenetic protein 2: a potential new player in the pathogenesis of diabetic retinopathy.

Diabetic retinopathy (DR) is one of the most common complications of diabetes mellitus. Vision loss in DR principally occurs due to breakdown of the blood-retinal barrier (BRB), leading to macular edema, retinal detachment and inner retinal and vitreous hemorrhage. Several growth factors have been shown to play crucial role in the development of these vascular changes; however, the cellular and molecular mechanisms of DR are not yet fully revealed. In the current study we investigated the role of bone morphogenetic protein-2 (BMP2) in DR. We examined the changes in the protein levels of BMP2 in human vitreous and retina in addition to the mouse retina of streptozotocin-induced diabetes. To detect the source of BMP2 during diabetes, human retinal endothelial cells (hRECs) were subjected to high glucose (HG) for 5 days and levels of BMP2 protein were analyzed in conditioned media of these cells relative to control. We also evaluated the effect of BMP2 on the levels of VEGF in cultured rat Müller cells (rMC1). In addition, we tested the pro-inflammatory effects of BMP2 by examining its effect on leukocyte adhesion to cultured hRECs, and levels of adhesion molecules and cytokines production. Finally, the effect of different concentrations of BMP2 on permeability of confluent monolayer of hRECs was evaluated using FITC-Dextran flux permeability assay and by measuring Transcellular Electrical Resistance (TER) using Electric Cell-substrate Impedance Sensing (ECIS). Our results show, for the first time, the up-regulation of BMP2 in diabetic human and mouse retinas in addition to its detection in vitreous of patients with proliferative DR (72 ± 7 pg/ml). In vitro, hRECs showed upregulation of BMP2 in HG conditions suggesting that these cells are a potential source of BMP2 in diabetic conditions. Furthermore, BMP2 induced VEGF secretion by Müller cells in-vitro; and showed a dose response in increasing permeability of cultured hRECs. Meanwhile, BMP2 pro-inflammatory effects were recognized by its ability to induce leukocyte adhesion to the hRECs, intercellular adhesion molecule-1 (ICAM-1) and upregulation of interleukin-6 and 8 (IL-6 and IL-8). These results show that BMP2 could be a contributing growth factor to the development of microvascular dysfunction during DR via enhancing both pro-angiogenic and inflammatory pathways. Our findings suggest BMP2 as a potential therapeutic target to prevent/treat DR.

The Impact of Sinus Floor Elevation Techniques on Sinus Membrane Perforation: A Systematic Review and Network Meta-analysis.

Purpose: To compare the risk of sinus membrane perforation (SMP) among lateral window sinus floor elevation (LSFE) and transcrestal sinus floor elevation (TSFE) techniques in prospective and retrospective studies for patients who underwent sinus augmentation for dental implant placement. Materials and Methods: A database search was conducted to screen the literature published from January 1960 to August 2021. The associations between SMP and surgical techniques as well as other clinical factors were evaluated via network meta-analysis. The impact of SMP on vertical ridge gain and implant survival was also evaluated. Results: Eighty-five studies with 5,551 SFE procedures were included. In LSFE techniques, using rotary burs showed the highest risk of SMP (surface under the cumulative ranking area [SUCRA] = 0.0745). In TSFE techniques, using reamers had the lowest risk of SMP (SUCRA = 0.9444). Increased SMP prevalence was significantly associated with reduced implant survival rate (odds ratio [OR] = 0.45 per 10% increase of SMP rate [95% credible interval (CreI): 0.21, 0.71], P < .001). Conclusions: With the inherent limitations, this network meta-analysis suggested that some techniques within either the LSFE or TSFE group may reduce SMP risk. Additional randomized controlled trials and better assessment of SMP are required to directly compare the risk of SMP between LSFE and TSFE.

Complications of sinus floor elevation procedure and management strategies: A systematic review.

AIM: This systematic review aimed to investigates the types and incidences of complications following sinus floor elevations (SFE) along with their prevention and management strategies. MATERIALS AND METHODS: Electronic database and hand search were conducted to screen the literature published from January 1960 to June 2021. The selected studies had to report well-described SFE techniques, complications during, and post-SFE. Data extraction included types of SFE techniques, complications, and their treatment strategies. RESULTS: A total of 74 studies with 4411 SFE procedures met the inclusion criteria. Different SFE techniques demonstrated varying patterns for both complications and complication rates. Postoperative pain, swelling, and edema were widely reported. The most common complications that required intervention following Lateral SFE (LSFE) were sinus membrane perforation (SMP), wound dehiscence, graft exposure and failure, and sinusitis. LSFE had more SMPs and sinusitis cases compared with a transcrestal SFE (TSFE). The presence of benign paroxysmal positional vertigo following TSFE was significant in certain selected studies. CONCLUSION: Given the inherent limitations, this systematic review showed distinct features of complications in SFE using varying techniques. Treatment planning for these procedures should incorporate strategies to avoid complication occurrence.

Caspase-14 expression impairs retinal pigment epithelium barrier function: potential role in diabetic macular edema.

We recently showed that caspase-14 is a novel molecule in retina with potential role in accelerated vascular cell death during diabetic retinopathy (DR). Here, we evaluated whether caspase-14 is implicated in retinal pigment epithelial cells (RPE) dysfunction under hyperglycemia. The impact of high glucose (HG, 30 mM D-glucose) on caspase-14 expression in human RPE (ARPE-19) cells was tested, which showed significant increase in caspase-14 expression compared with normal glucose (5 mM D-glucose + 25 mM L-glucose). We also evaluated the impact of modulating caspase-14 expression on RPE cells barrier function, phagocytosis, and activation of other caspases using ARPE-19 cells transfected with caspase-14 plasmid or caspase-14 siRNA. We used FITC-dextran flux assay and electric cell substrate impedance sensing (ECIS) to test the changes in RPE cell barrier function. Similar to HG, caspase-14 expression in ARPE-19 cells increased FITC-dextran leakage through the confluent monolayer and decreased the transcellular electrical resistance (TER). These effects of HG were prevented by caspase-14 knockdown. Furthermore, caspase-14 knockdown prevented the HG-induced activation of caspase-1 and caspase-9, the only activated caspases by HG. Phagocytic activity was unaffected by caspase-14 expression. Our results suggest that caspase-14 contributes to RPE cell barrier disruption under hyperglycemic conditions and thus plays a role in the development of diabetic macular edema.

12/15-Lipoxygenase-derived lipid metabolites induce retinal endothelial cell barrier dysfunction: contribution of NADPH oxidase.

The purpose of the current study was to evaluate the effect of 12/15-lipoxygenase (12/15-LOX) metabolites on retinal endothelial cell (REC) barrier function. FITC-dextran flux across the REC monolayers and electrical cell-substrate impedance sensing (ECIS) were used to evaluate the effect of 12- and 15-hydroxyeicosatetreanoic acids (HETE) on REC permeability and transcellular electrical resistance (TER). Effect of 12- or 15-HETE on the levels of zonula occludens protein 1 (ZO-1), reactive oxygen species (ROS), NOX2, pVEGF-R2 and pSHP1 was examined in the presence or absence of inhibitors of NADPH oxidase. In vivo studies were performed using Ins2(Akita) mice treated with or without the 12/15-LOX inhibitor baicalein. Levels of HETE and inflammatory mediators were examined by LC/MS and Multiplex Immunoassay respectively. ROS generation and NOX2 expression were also measured in mice retinas. 12- and 15- HETE significantly increased permeability and reduced TER and ZO-1 expression in REC. VEGF-R2 inhibitor reduced the permeability effect of 12-HETE. Treatment of REC with HETE also increased ROS generation and expression of NOX2 and pVEGF-R2 and decreased pSHP1 expression. Treatment of diabetic mice with baicalein significantly decreased retinal HETE, ICAM-1, VCAM-1, IL-6, ROS generation, and NOX2 expression. Baicalein also reduced pVEGF-R2 while restored pSHP1 levels in diabetic retina. Our findings suggest that 12/15-LOX contributes to vascular hyperpermeability during DR via NADPH oxidase dependent mechanism which involves suppression of protein tyrosine phosphatase and activation of VEGF-R2 signal pathway.