Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway in human retinal endothelial cells by blocking the effect of AGE/RAGE

Giurdanella, Giovanni; Lazzara, Francesca; Caporarello, Nunzia; Lupo, Gabriella; Anfuso, Carmelina Daniela; Eandi, Chiara M; Leggio, Gian Marco; Drago, Filippo; Bucolo, Claudio; Salomone, Salvatore

doi:10.1016/j.bcp.2017.06.130

Cited by 51 publications

(49 citation statements)

References 48 publications

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“…According to the pathway map, the AGE-RAGE signaling pathway in diabetic complications pathway is also closely connected with the PI3K-Akt signaling pathway and VEGF. The PI3K-Akt signaling pathway is one of the most frequently studied pathways in DR [33][34][35]. The proliferation, migration and invasion of retinal vascular endothelial cells, retinal pericytes, retinal pigment epithelial cells and microglial cells can be regulated through this pathway [36][37][38][39].…”

Section: Discussionmentioning

confidence: 99%

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Yao

Xin

Zhan

et al. 2020

Preprint

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Background Compound Xueshuantong capsule (CXC) and Hexuemingmu tablet (HXMMT) are two important Chinese patent medicines (CPMs) frequently used to treat proliferative diabetic retinopathy (PDR), especially when complicated with vitreous hemorrhage (VH). However, a network pharmacology approach to understand the therapeutic mechanisms of these two CPMs in PDR has not been applied. The aim of the study was to identify differences in active ingredients between CXC and HXMMT and to comparatively predict and further analyze the molecular targets shared by these CPMs and PDR. Materials and methods The differentially expressed messenger RNAs (mRNAs) between normal retinal tissues in healthy individuals and active fibrovascular membranes in PDR patients were retrieved from the Gene Expression Omnibus database. The active ingredients of CXC and HXMMT and the targets of these ingredients were retrieved from the Traditional Chinese Medicine Systems Pharmacology database. The intersections of the CPM (CXC and HXMMT) targets and PDR targets were determined. Then, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed, and the ingredient-target networks, protein-protein interaction networks and KEGG-target (KEGG-T) networks were constructed. Results There CXC contains 4 herbal drugs in CXC, and HXMMT contains 19. Radix salviae is the only herbal drug common to both. CXC had 34 potential therapeutic targets in PDR, while HXMMT had these 34 and 10 additional targets. Both CPMs shared the following main processes: response to reactive oxygen species and oxidative stress, regulation of blood vessel diameter and size, vasoconstriction, smooth muscle contraction, hemostasis and blood coagulation. The shared pathways included the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, relaxin signaling pathway, IL-17 signaling pathway, etc. Conclusions Both CXC and HXMMT include components effective in treating PDR. Radix salviae, the only herbal drug common to both CPMs, contains many useful active ingredients. HXMMT has more therapeutic targets shared by different active ingredients and more abundant gene functions than CXC. Moreover, the AGE-RAGE signaling pathway in diabetic complications was the most significantly enriched pathway in both networks. However, these findings should be verified through further research.

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Section: Discussionmentioning

confidence: 99%

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Yao

Xin

Zhan

et al. 2020

Preprint

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“…There are little data describing the direct influence of SDX on ECs. In vitro experiments with various endothelial cell lines exposed to cytotoxic concentrations of glucose show that SDX can restore shredded glycocalyx, improve viability, decrease inflammation, reduce oxidative stress, and prevent senescence . In vivo, it has been shown that SDX reduces inflammation and IL‐6 concentration in serum in patients suffering from vascular disease, reduces the expression of VEGF and improves renal function in type 2 diabetic rats, restores glycocalyx in retinal and sublingual microcirculation in type 2 diabetic patients and in the balloon‐injury rat carotid artery model, and improves coronary microcirculatory function in diet‐induced obese rats .…”

Section: Discussionmentioning

confidence: 99%

“…Only a few papers describe the influence of SDX on angiogenesis and in vivo and in vitro experiments give opposite results, probably due to differences between models used in the research. Giurdanella et al . observed that SDX restored capability of in vitro cultured human retinal endothelial cells exposed to glucose cytotoxicity to form tube‐like structures, but the effect was independent of VEGF signaling.…”

Section: Discussionmentioning

confidence: 99%

Sulodexide inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures

Niderla-Bielińska

Bartkowiak

Ciszek

et al. 2018

Fundamemntal Clinical Pharma

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Sulodexide (SDX) is a mixed drug containing low‐molecular‐weight heparin sulfate and dermatan sulfate. It exerts mild anticoagulant action but can also affect leukocytes, macrophages, and cell–cell adhesion and may interact with growth factors although its direct influence on endothelial cells is not well described. Clinically, SDX is used for the treatment of cardiovascular diseases, where it exerts anti‐inflammatory and endothelial protective effects. The aim of this study was to determine the influence of SDX on tubule formation and angiogenesis‐related proteins’ mRNA expression in endothelial cell line C166 and mouse proepicardial explants. C166 cells and explants were stimulated with a proangiogenic cocktail containing bFGF/VEGF‐A120/VEGF‐A164 enriched with SDX. After stimulation, the number and morphology of tubules stained with anti‐CD31 antibody were examined under confocal microscope and expression of mRNA for VEGF‐A, VEGF‐B, VEGF‐C, bFGF, IGF‐1, Dll4, and Notch1 was measured with real‐time PCR. In C166 cell line, there was no difference in tubule formation and mRNA expression, but in proepicardial explants, we observed reduction in tubule number and in mRNA level for DLL4 and Notch1 after SDX administration. In conclusion, SDX indirectly inhibits angiogenesis in mouse proepicardial explant cultures but has no direct effect on the C166 endothelial cell line.

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“…Nevertheless, ERK1-2/cPLA 2 /COX-2 can be activated as a downstream pathway of VEGF, but they can also be activated in another pathway directly downstream of AGE-RAGE interaction. Thus, with blockade of RAGE, we may expect an entire reversion of HG-induced cPLA2 phosphorylation and PGE2 release, while with VEGF blockade we may expect only a partial reversion [33]. This may be one of the reasons for the failure of current anti-VEGF medication in eye diseases that needs however further confirmation.…”

Section: Angiogenesismentioning

confidence: 99%

“…However, in diabetes, certain inflammatory stimulates target ECs, resulting in hyperpermeability [15]. Therefore, the ensuing impairment of BRB further induces macular edema and vascular hemorrhage, compromising retina integrity [33]. Previous researches in vitro have verified that the accumulation of AGEs in the blood greatly contributes to the disruption and exacerbation of the retinal vascular permeability in DM.…”

Section: Endothelial Dysfunctionmentioning

confidence: 99%

Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

Chen

et al. 2018

Cell Physiol Biochem

159

106

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Diabetic retinopathy (DR) is a common and devastating microvascular complication of diabetes and a major cause of acquired blindness in young adults. Advanced glycation end products (AGEs) accumulated under hyperglycemic conditions are thought to play an important role in the pathogenesis of DR. AGEs can exert their deleterious effects by acting directly to induce aberrant crosslinking of extracellular matrix proteins, to increase vascular stiffness, altering vascular structure and function. Moreover, AGEs binding to the receptor for AGEs (RAGE) evokes intensive intracellular signaling cascades that leading to endothelial dysfunction, elaboration of key proinflammatory cytokines and proangiogenic factors, mediating pericyte apoptosis, vascular inflammation and angiogenesis, as well as breakdown of the inner blood-retinal barrier (BRB), the end result of all these events is damage to the neural and vascular components of the retina. Elucidation of AGE-induced mechanisms will help in the understanding of the complex cellular and molecular pathogenesis associated with DR. Novel anti-AGEs agents or AGE crosslink “breakers” are being investigated, it is hoped that in next few years, some of these promising therapies will be successfully applied in clinical context, aiming to reduce the major economical and medical burden caused by DR.

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Sulodexide prevents activation of the PLA2/COX-2/VEGF inflammatory pathway in human retinal endothelial cells by blocking the effect of AGE/RAGE

Cited by 51 publications

References 48 publications

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Network Pharmacology-based Approach to Comparatively Predict the Active Ingredients and Molecular Targets of Compound Xueshuantong Capsule and Hexuemingmu Tablet in the Treatment of Proliferative Diabetic Retinopathy

Sulodexide inhibits angiogenesis via decreasing Dll4 and Notch1 expression in mouse proepicardial explant cultures

Involvement of Advanced Glycation End Products in the Pathogenesis of Diabetic Retinopathy

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