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Ravinarayanan Haribalaganesh Sardarpasha Sheikpranbabu Banumathi Elayappan Deepak Venkataraman Sangiliyandi Gurunathan 《Angiogenesis》2009,12(4):381-389
Pigment epithelium–derived factor (PEDF) is a well-known protease inhibitor for angiogenesis in the eye, suggesting that loss
of PEDF in eye is implicated in the pathogenesis of proliferative diabetic retinopathy. Since the role of PEDF in diabetic
retinopathy is unclear, the effect of PEDF on different types of cells constituting the blood vessel has to be checked. Here,
we have investigated the effects of PEDF under hyperglycemic conditions in retinal pericytes, isolated from goat’s eye and
used to analyze the signaling pathway involved. High glucose increased the apoptotic cell death and intracellular reactive
oxygen species generation, which was blocked on the addition of PEDF. PEDF was found to inhibit the apoptotic cell death and
protect the cells via activating the PI3K/Akt pathway, which was analyzed with dominant negative Akt and constitutively active
Akt–transfected cells. These results demonstrate that PEDF protects pericytes against the high glucose–induced apoptosis and
dysfunction. 相似文献
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Kalishwaralal K Sheikpranbabu S BarathManiKanth S Haribalaganesh R Ramkumarpandian S Gurunathan S 《Angiogenesis》2011,14(1):29-45
The purpose of this study was to investigate the effect of gold nanoparticles on the signaling cascade related to angiogenesis
and vascular permeability induced by Vascular Endothelial Growth Factor (VEGF) in Bovine retinal endothelial cells (BRECs).
The effect of VEGF and gold nanoparticles on cell viability, migration and tubule formation was assessed. PP2 (Src Tyrosine
Kinase inhibitor) was used as the positive control and the inhibitor assay was performed to compare the effect of AuNPs on
VEGF induced angiogenesis. The transient transfection assay was performed to study the VEGFR2/Src activity during experimental
conditions and was confirmed using western blot analysis. Treatment of BRECs with VEGF significantly increased the cell proliferation,
migration and tube formation. Furthermore, gold nanoparticles (500 nM) significantly inhibited the proliferation, migration
and tube formation, in the presence of VEGF in BRECs. The gold nanoparticles also inhibited VEGF induced Src phosphorylation
through which their mode of action in inhibiting angiogenic pathways is revealed. The fate of the gold nanoparticles within
the cells is being analyzed using the TEM images obtained. The potential of AuNPs to inhibit the VEGF165-induced VEGFR-2 phosphorylation
is also being confirmed through the receptor assay which elucidates one of the possible mechanism by which AuNPs inhibit VEGF
induced angiogenesis. These results indicate that gold nanoparticles can block VEGF activation of important signaling pathways,
specifically Src in BRECs and hence modulation of these pathways may contribute to gold nanoparticles ability to block VEGF-induced
retinal neovascularization. 相似文献
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Sangiliyandi Gurunathan Kyung-Jin Lee Kalimuthu Kalishwaralal Sardarpasha Sheikpranbabu Ramanathan Vaidyanathan Soo Hyun Eom 《Biomaterials》2009,30(31):6341-6350
Angiogenesis is an important phenomenon involved in normal growth and wound healing processes. An imbalance of the growth factors involved in this process, however, causes the acceleration of several diseases including malignant, ocular, and inflammatory diseases. Inhibiting angiogenesis through interfering in its pathway is a promising methodology to hinder the progression of these diseases. The function and mechanism of silver nanoparticles (Ag-NPs) in angiogenesis have not been elucidated to date. PEDF is suggested to be a potent anti-angiogenic agent. In this study, we postulated that Ag-NPs might have the ability to inhibit angiogenesis, the pivotal step in tumor growth, invasiveness, and metastasis. We have demonstrated that Ag-NPs could also inhibit vascular endothelial growth factor (VEGF) induced cell proliferation, migration, and capillary-like tube formation of bovine retinal endothelial cells like PEDF. In addition, Ag-NPs effectively inhibited the formation of new blood microvessels induced by VEGF in the mouse Matrigel plug assay. To understand the underlying mechanism of Ag-NPs on the inhibitory effect of angiogenesis, we showed that Ag-NPs could inhibit the activation of PI3K/Akt. Together, our results indicate that Ag-NPs can act as an anti-angiogenic molecule by targeting the activation of PI3K/Akt signaling pathways. 相似文献
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Aim
This study investigated the effects of pigment epithelium-derived factor (PEDF) on advanced glycation end-product (AGE)-induced cytotoxicity in porcine retinal pericytes and the signalling mechanism involved.Methods
Retinal pericytes were isolated from porcine eyes and characterized by immunocytochemistry. The effect of AGEs and PEDF on cell proliferation was determined by bromodeoxyuridine (BrdU) assay. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was analyzed by luminescence assay. Reactive oxygen species (ROS), nitric oxide (NO), superoxide dismutase (SOD) and glutathione peroxidase (GSH) were determined by biochemical assays. Induction of apoptosis was determined by caspase-3 colorimetric assay and DNA fragmentation analysis. Src activity was assessed by transient transfection analysis, and the status of Src phosphorylation at Y419 was analyzed by a competitive ELISA method.Results
AGEs significantly increased intracellular ROS generation in pericytes via NADPH oxidase and induced cell death via caspase-3 enzyme activation, whereas PEDF increased cell proliferation in a dose-dependent manner. In addition, PEDF inhibited AGE-induced ROS generation by increasing levels of SOD and GSH, and also blocked the activation of caspase-3. Furthermore, PEDF induced cell survival via the Src pathway by Src phosphorylation at Y419, as evidenced by a pharmacological inhibitor and Src mutants.Conclusion
These results suggest that PEDF abrogates AGE-induced oxidative stress and apoptosis in retinal pericytes via the Src pathway, thereby suggesting that PEDF is an effective therapeutic agent for the treatment of loss of pericytes in early diabetic retinopathy. 相似文献8.
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