Byung Joo Lee

Rosmarinic acid suppresses retinal neovascularization via cell cycle arrest with increase of p21WAF1 expression.

Pathological angiogenesis is the most common cause of blindness at all ages including retinopathy of prematurity, diabetic retinopathy, and age-related macular degeneration. Despite advances in therapy, retinopathy of prematurity remains the most sight-threatening vaso-proliferative retinopathy in children. Herein, we demonstrated that rosmarinic acid has an anti-angiogenic activity to retinal neovascularization in a mouse model of retinopathy of prematurity, which is related to cell cycle arrest with increase of p21(WAF1). Rosmarinic acid significantly inhibited the proliferation of retinal endothelial cells in a dose-dependent manner, and inhibited in vitro angiogenesis of tube formation. Interestingly, the anti-proliferative activity of rosmarinic acid on retinal endothelial cells was related to G2/M phase cell cycle arrest in a dose-dependent manner. With treatment of rosmarinic acid, retinal endothelial cells in G2/M phase increased whereas those in G0/G1 and S phases decreased, which was accompanied by increase of p21(WAF1) expression in a dose-dependent manner. Moreover, rosmarinic acid effectively suppressed retinal neovascularization in a mouse model of retinopathy of prematurity, and showed no retinal toxicity. These data suggest rosmarinic acid could be a potent inhibitor of retinal neovascularization and may be applied in the treatment of other vasoproliferative retinopathies.

Anti―angiogenic effect of caffeic acid on retinal neovascularization

Pathological angiogenesis is the most common cause of vision loss at all ages including retinopathy of prematurity (ROP), diabetic retinopathy, and age-related macular degeneration. ROP is a proliferative disease of the retinal vasculature in premature infants. Herein, we demonstrated caffeic acid (CA) has the anti-angiogenic activity to retinal endothelial cells and retinal neovascularization in a mouse model of ROP, which might be related to the suppression of ROS-induced VEGF expression. CA effectively inhibited VEGF-induced proliferation of retinal endothelial cells in concentration-dependent manner. In addition, VEGF-induced migration and tube formation of retinal endothelial cells were completely inhibited. This anti-angiogenic activity of CA on retinal endothelial cells was related to the anti-oxidant activity: the inhibitory activity of CA to H(2)O(2)-induced reactive oxygen species production and VEGF expression. Interestingly, CA significantly suppressed retinal neovascularization in oxygen-induced retinopathy as the animal model of ROP without retinal cytotoxicity. These data suggests that CA could be a potent anti-angiogenic agent for retinal neovascularization, and be applied in the treatment of other vaso-proliferative retinopathies.

Tissue factor is involved in retinoblastoma cell proliferation via both the Akt and extracellular signal-regulated kinase pathways.

Tissue factor (TF) is known to play a role in tumor progression. In retinoblastoma, the expression and role of TF has not been determined yet. Herein, we demonstrated for the first time that TF is closely related to the proliferation of retinoblastoma cells, which could be therefore effectively suppressed by blockade of the TF pathway. TF was selectively expressed on the areas of highly mitogenic activity in an orthotopic transplantation mouse model of retinoblastoma. In addition, the levels of TF expression in retinoblastoma cells were elevated after FGF2 treatment, whereas the proliferative effect of FGF2 on retinoblastoma cells was significantly inhibited by blockade of the TF pathway via TF pathway inhibitor (TFPI). Interestingly, retinoblastoma cells cultured with FGF2 showed increased phosphorylation of both Akt and ERK1/2. Addition of TFPI nearly abolished the FGF2-induced phosphorylation of Akt and ERK1/2 in retinoblastoma cells. Therefore, our data suggest that TF expression in retinoblastoma cells is closely related to tumor cell proliferation and TFPI has the potential to inhibit retinoblastoma cell proliferation via the inhibition of both Akt and ERK1/2 activation.

Surgical outcomes after intraocular lens implantation for posterior lenticonus–related cataract according to preoperative lens status

Purpose To address the surgical outcomes of pediatric patients with cataracts associated with posterior lenticonus who required cataract extraction and intraocular lens (IOL) implantation according to preoperative lens status. Setting Department of Ophthalmology, Seoul National University Children’s Hospital, Seoul, South Korea. Design Comparative case series. Methods Patients who had cataract extraction and IOL implantation for posterior lenticonus were divided into 2 groups according to the preoperative lens status. Clinical features and visual outcomes in both groups were comparatively analyzed. Results Forty‐seven eyes of 43 patients were studied. Thirty‐five eyes had lens opacities localized to the posterior pole, and 12 eyes presented with total opacity of the lens. Preexisting posterior capsule defect was identified intraoperatively in 11 eyes with total lens opacity. Eyes with preexisting posterior capsule defects more frequently required ciliary sulcus fixation of the IOL (P=.01). The mean follow‐up after cataract extraction was 66.9 months ± 35.9 (SD). The mean final corrected distance visual acuity of patients with total opacity (0.37 ± 0.57 logMAR) was better than that of patients with posterior polar opacity (0.56 ± 0.50 logMAR), with borderline significance (P=.05). Conclusions A preexisting posterior capsule defect, found most often in eyes that presented with total lens opacity, could be an obstacle to capsular bag fixation of the IOL. Posterior lenticonus patients with total lens opacity had marginally significantly better visual outcomes than patients with posterior polar opacity. Financial Disclosure No author has a financial or proprietary interest in any material or method mentioned.

Lissencephaly and Mild Cerebellar Vermis Hypoplasia in a Case of Microcephaly and Chorioretinal Dysplasia

Purpose: Microcephaly and chorioretinal dysplasia is a very rare syndrome, characterized by microcephaly, chorioretinal dysplasia, mental retardation, and is phenotypically classified according to the presence of lymphedema. Among previously described patients, there has been no association with brain anomaly other than simple microcephaly, except for one case that presented with micro-lissencephaly, who had lymphedema. Methods: Herein, we describe a case of microcephaly and chorioretinal dysplasia without lymphedema who was shown to have lissencephaly and cerebellar vermis hypoplasia. His head circumference at birth was 28u2009cm (below -3SD) and both fundi showed pigmentary retinopathy with multiple punched-out lesions and retinal vascular attenuation. Results: Magnetic resonance imaging of the brain showed lissencephaly accompanied by inferior cerebellar vermis hypoplasia. Conclusions: These results show that microcephaly and chorioretinal dysplasia can be accompanied by lissencepahly, thus brain imaging should be considered in evaluating these patients.

Nuclear expression of p53 in mature tumor endothelium of retinoblastoma

The present study aimed to investigate the p53 expression pattern in tumor cells and in mature tumor vascular endothelium of retinoblastoma. Nuclear p53 accumulation was observed in most of the tumor cells in both the human and orthotopic retinoblastoma animal models using SNUOT-Rb1 and Y79 cells. In the orthotopic animal model, some of the tumor vascular endothelium also demonstrated nuclear p53 immunoreactivity, and the ratio of p53 positivity among the total mature tumor vascular endothelium was slightly higher in the Y79 cell model when compared with the SNUOT-Rb1 cell model. In addition, in the human retinoblastoma specimens, 32.9% of the tumor vascular endothelium showed p53 nuclear staining. In conclusion, some of the mature tumor vascular endothelium in both the human and orthotopic models of retinoblastoma share the same cytogenetic abnormality (an abnormal nuclear accumulation of p53) with retinoblastoma cells.

Chronological Changes in Tip Cells during Sprouting Angiogenesis of Development of the Retinal Vasculature in Newborn Mice

ABSTRACT Purpose: To investigate a sequential chronological change in tip cells during the development of the retinal vasculature in newborn mice. Materials and Methods: Newborn C57BL/6 mice were used for this study. To elucidate the patterns in the developing retinal vasculature, histology, and immunohistochemistry—antiplatelet endothelial cell adhesion molecule-1, anticollagen type IV, isolectin IB4—were performed on sections of mouse retina on postnatal days (P)-4, -8, and -12. Staining patterns of isolectin IB4-stained arterial and venous tip cells were compared in retinal wholemounts, in which the numbers and characteristics of tip cells were compared between arteries and veins on P-4, -6, and -8. In addition, vascular densities and branching patterns were compared between arterial and venous vascular forefront areas. Results: Tip cells in the superficial vascular plexus were observed until P-8. The number of tip cells was highest on P-6, decreasing dramatically from P-6 to P-8 (P-4, 165.2 ± 10.1, n = 17; P-6, 183.8 ± 19.4, n = 15; P8, 21.4 ± 6.4, n = 15) (p < 0.05, respectively, t-test). There was a greater number of tip cells in veins versus arteries on P-4 and P-6 (P-4, 91.0 ± 9.2 veins versus 74.2 ± 10.4 arteries; P-6, 104.0 ± 10.2 veins versus 79.8 ± 11.3 arteries) (p < 0.05, respectively). Arterial tip cells had thinner and longer sprouts compared with venous tip cells (basal thickness: 15.7 ± 8.7 veins versus 9.9 ± 3.5 μm arteries) (length, 20.3 ± 9.1 veins versus 37.1 ± 13.2 μm arteries on P-4) (p < 0.05, respectively). Vessel areas and densities of vascular branch points were significantly higher around veins compared to arteries (vessel areas: 58.9 ± 1.2% veins versus 40.8 ± 1.9% arteries; vascular branch points, 1371.9 ± 136.7/mm2 veins versus 1046.7 ± 175.5/mm2 arteries) (p < 0.05, respectively). Conclusion: The number of tip cells increased to a greater extent in the superficial vascular plexus of veins versus arteries until P-6. Consequently, there are more vessel areas and vascular branch points near retinal veins versus arteries. Arterial tip cells are longer and thinner than the shorter and thicker venous tip cells.