Effect of thalidomide and rosiglitazone on the prevention of diabetic retinopathy in streptozotocin-induced diabetic rats

Sawada

et al. 2017

Sci Rep

The identification of the modes of action of bioactive compounds is a major challenge in chemical systems biology of diseases. Genome-wide expression profiling of transcriptional responses to compound treatment for human cell lines is a promising unbiased approach for the mode-of-action analysis. Here we developed a novel approach to elucidate the modes of action of bioactive compounds in a cell-specific manner using large-scale chemically-induced transcriptome data acquired from the Library of Integrated Network-based Cellular Signatures (LINCS), and analyzed 16,268 compounds and 68 human cell lines. First, we performed pathway enrichment analyses of regulated genes to reveal active pathways among 163 biological pathways. Next, we explored potential target proteins (including primary targets and off-targets) with cell-specific transcriptional similarity using chemical–protein interactome. Finally, we predicted new therapeutic indications for 461 diseases based on the target proteins. We showed the usefulness of the proposed approach in terms of prediction coverage, interpretation, and large-scale applicability, and validated the new prediction results experimentally by an in vitro cellular assay. The approach has a high potential for advancing drug discovery and repositioning.

Section: Resultsmentioning

confidence: 58%

Elucidating the modes of action for bioactive compounds in a cell-specific manner by large-scale chemically-induced transcriptomics

Sawada

et al. 2017

Sci Rep

“…In fact, the VEGF concentration in ocular fl uid was not higher in rosiglitazone-treated rats. 27 No remarkable worsening of diabetic macular edema by other thiazolidinediones, including pioglitazone and rosiglitazone, has been reported.…”

Section: Discussionmentioning

confidence: 99%

Effect of Thiazolidinedione on the Proliferation of Bovine Retinal Endothelial Cells Stimulated by Vascular Endothelial Cell Growth Factor

2007

“…Thalidomide prolonged also graft survival of donor corneas in eyes with previous neovascularization secondary to alkali injury [181]. In diabetic rats, daily oral administration of thalidomide blocked the increase of VEGF in ocular fluid and inhibited basement membrane thickening compared with untreated diabetic rats, thus indicating the potential action of this drug in preventing retinal neovascularization [182].…”

Section: Thalidomidementioning

confidence: 99%

Antineovascular Agents in the Treatment of Eye Diseases

Eichler¹,

Yafai²,

Wiedemann³

et al. 2006

CPD

Neovascularization is a common and potentially visually threatening complication of eye diseases such as diabetic retinopathy (DR) and age-related macular degeneration (AMD). An antiangiogenic therapy is aimed at inhibiting the growth of new blood vessels and should prevent onset or progression of neovascularization. Accumulated evidence indicates that growth factors, endothelial cell surface receptors, and extracellular matrix (ECM) proteins are major mediators of neovascularization and appealing targets for pharmacotherapeutical intervention. Vascular endothelial growth factor (VEGF) plays a critical role in the pathogenesis of retinal neovascularization (in linking tissue ischemia to angiogenesis), and is likely to contribute also significantly to choroidal neovascularization (CNV). Several antineovascular agents antagonize the function of VEGF, by blocking its proangiogenic activity. Indeed, VEGF targeting or disruption of VEGF signalling is the most effective strategy known so far in the pharmacological treatment of ocular neovascularization. Other compounds such as pigment epithelium-derived factor (PEDF) either aim at balancing the levels of pro-angiogenic and angiostatic molecules, target inflammation (cyclooxygenase inhibitors, steroids) or comprise modifiers of the ECM such as inhibitors of matrix metalloproteinases (MMPs) and agents that block the action of integrins. Vascular targeting agents (combretastatin) promote removal of newly formed vessels. This review provides an update on recent investigations directed at the pharmacotherapeutical management of ocular neovascular diseases, placing special emphasis on the underlying target molecules and relevant intracellular signalling pathways.