Sara Akeel

Georgia Health Sciences University, Augusta, GA, United States

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Publications (6)14.04 Total impact

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    ABSTRACT: 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.
    Experimental Eye Research 06/2014; · 3.03 Impact Factor
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    ABSTRACT: The ability of recombinant human bone morphogenetic protein 2 on absorbable collagen sponge (rhBMP2/ACS) to regenerate bone in segmental defect has been well characterized. However, clinical results of rhBMP2/ACS constructs in secondary reconstruction of large mandibular and craniofacial defects have not been consistent. We hypothesized that rhBMP2 delivery triggers an endogenous response in the soft tissues surrounding the defect, in the form of expression of BMP2 and vascular endothelial growth factor (VEGF). Such osteogenic response will occur only after immediate, as opposed to delayed, rhBMP2 delivery, suggesting a new explanation to the difference in bone regeneration between the two settings. A 35-mm segmental bone and periosteum defect was created on one side of the mandible in 16 dogs divided in three groups. Group 1 (Gp1, n=6) ACS was loaded with 8 mL of rhBMP2 (0.2 mg/mL). In Gp2 (n=5) the same dose of rhBMP2/ACS was delivered into the defect 4 weeks after surgery. In Gp3 (control; n=5) the defect was reconstructed using ACS loaded with 8 mL of buffer only (devoid of rhBMP2). Tissues were collected after 12 weeks of reconstruction in all groups. Direct measurement of physical dimensions of regenerates and bone morphometry was performed to evaluate bone regeneration. The mRNA expression of both BMP2 and VEGF in the soft tissue surrounding the defect was evaluated using real-time quantitative PCR. Both BMP2 and VEGF proteins were quantified in immunostained sections. Immunoflurescence colocalization of BMP2 and acetylated low density lipoprotein (AcLDL) was done to detect the source of BMP2. Immediate delivery yielded better bone regeneration. Both BMP2 and VEGF mRNA expression was upregulated only in Gp1 (+7.3, p=0.001; +1.53, p=0.001, respectively). BMP2 protein was significantly higher in the immediate reconstruction group; however, VEGF protein was undetected in the examined sections. Immediate delivery of rhBMP2 seemed to induce endogenous release of BMP2 from the surrounding soft tissues, an effect that was lacking in delayed delivery and may explain the variability of clinical results associated with BMP2 use. Colocalization of BMP2 and endothelial cells (ECs) suggested that ECs could be the source of endogenous BMP2.
    Tissue Engineering Part A 03/2012; 18(5-6):665-75. · 4.64 Impact Factor
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    ABSTRACT: Bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) have been reported in many studies to play a major role in the communication between endothelial cells and osteoblasts. The inflammatory reaction and relative hypoxia at the site of bone injury are the first stages of the fracture repair. rhBMP-2 has been used extensively in spinal fusion and reconstruction of maxillofacial bone defects with main complication is the formation of seroma. The aim of this study was to test whether rhBMP-2 regulates the expression of the angiogenic and inflammatory mediators in pre-osteoblasts via generating reactive oxygen species (ROS). rhBMP-2 effect on angiogenesis and inflammatory genes was assessed using normal human osteoblasts (NHOst). Angiogenesis genes were measured using angiogenic PCR array. VEGF and IL6 production were analysed using ELISA kit and real-time PCR. ROS production was assessed using dihydroethidine and dichlorofluorescein staining and lipid peroxidation. HIF-1α immunoreactivity was performed using immunofluorescence staining. There was an increase in the pro-angiogenic and -inflammatory genes as well as VEGF and IL6 protein expression in NHOst by rhBMP-2. This increase in VEGF and IL6 was blocked by the ROS scavenger N-acetyl cysteine (NAC). The regulatory effect of rhBMP-2 on angiogenesis and inflammation is mediated through a ROS-dependent mechanism, which involves upregulation of crucial angiogenic and inflammatory mediators such as VEGF and IL6. These findings highlight the need for future studies to identify new therapeutic targets downstream from rhBMP-2 to potentiate its beneficial effect or limit its complications such as seroma formation.
    Archives of oral biology 10/2011; 57(5):445-52. · 1.65 Impact Factor
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    ABSTRACT: Reconstruction of mandibular segmental bone defects is a challenging task. This study tests a new device used for reconstructing mandibular defects based on the principle of bone transport distraction osteogenesis. Thirteen beagle dogs were divided into control and experimental groups. In all animals, a 3-cm defect was created on one side of the mandible. In 8 control animals, the defect was stabilized with a reconstruction plate without further reconstruction and the animals were killed 2 to 3 months after surgery. The remaining 5 animals were reconstructed with a bone transport reconstruction plate, comprising a reconstruction plate with attached intraoral transport unit, and were killed after 1 month of consolidation. Clinical evaluation, cone-beam CT densitometry, three-dimensional histomorphometry, and docking site histology revealed significant new bone formation within the defect in the distracted group. The physical dimensions and architectural parameters of the new bone were comparable to the contralateral normal bone. Bone union at the docking site remains a problem.
    Annals of plastic surgery 09/2009; 63(4):441-8. · 1.29 Impact Factor
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    ABSTRACT: Objectives: The close proximity of osteoblasts and osteoclasts to the endothelial cells during bone formation suggests there is a cross-talk between these cells. Bone morphogenetic proteins (BMPs) and vascular endothelial growth factor (VEGF) have been reported in many studies to play a major role in this cell communication. VEGF, Superoxide and pro-inflammatory molecules such as IL-6 are important in modulating angiogenesis, a critical step in bone formation. Bone morphogenetic protein-2 (BMP-2) is well recognized for its ability to induce osteogenesis by different pathways. Our aim is to investigate whether BMP-2 enhances osteogenesis though superoxide overproduction and up-regulating VEGF, and pro-inflammatory molecules expression. Methods: The effect of BMP-2 on VEGF, IL-6 and superoxide production was evaluated in normal human osteoblasts cell line (NHOst). VEGF and IL-6 production were analyzed using ELISA kit and RT-PCR respectively. Superoxide generation was assessed using dihydroethidine staining method. Results: The superoxide generation, VEGF level and the expression of IL-6 mRNA were markedly increased in cultured NHOst by BMP-2 treatment compared to the control. Conclusion: Our data suggests that VEGF, superoxide and IL-6 production might play a role in mediating the effect of BMP-2 on osteogenesis. This will help us to identify new therapeutic targets downstream from BMP-2. Supported by a Predoctoral Fellowship from King Abdulaziz University, Jeddah, Saudi Arabia
    IADR General Session 2009; 04/2009
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    ABSTRACT: Recently, the authors have shown that NADPH oxidase is positively correlated with increased leukocyte adhesion and vascular leakage in diabetes and neovascularization in oxygen-induced retinopathy (OIR). Peroxisome proliferator-activated receptor gamma (PPARgamma) agonists have been shown to prevent vascular inflammation and leakage in an experimental model of diabetes. The goal of this study was to investigate whether there is a link between NADPH oxidase and PPARgamma that leads to vascular dysfunction in diabetic retina or OIR. Diabetes was induced with streptozotocin in wild-type mice or NOX2 knockout mice. One group of wild-type mice was treated with apocynin. Bovine retinal endothelial cells (BRECs) were treated with normal glucose (5 mM) or high glucose (25 mM) in the presence or absence of superoxide dismutase (SOD) or NADPH oxidase inhibitors (apocynin or diphenyleneiodonium [DPI]). Western blotting and immunofluorescence were used to evaluate PPARgamma expression. Activation of nuclear factor (NF)kappaB was measured using the transcription factor assay kit and Western blot analysis of phospho-NFkappaB. PPARgamma expression was also tested in OIR and lipopolysaccharide-induced retinal inflammation. Retinal expression of PPARgamma was suppressed in experimental models of diabetes, OIR, and retinal inflammation. This was associated with the activation of NFkappaB in the diabetic retina. These effects were prevented by apocynin or deletion of NOX2. PPARgamma expression was also suppressed in endothelial cells treated with high glucose, and this was prevented by apocynin, DPI, and SOD. Suppression of PPARgamma is involved in the pathogenesis of diabetic retinopathy and OIR. NADPH oxidase could be an upstream mediator of these changes.
    Investigative ophthalmology & visual science 10/2008; 50(2):878-84. · 3.43 Impact Factor