Abstract
Chronic inflammation and oxidative stress lead to a multitude of adverse cellular responses in target organs of chronic diabetic complications. Curcumin, a highly investigated phytochemical, has been shown to exhibit both anti-inflammatory and antioxidant activities. However, the clinical application of curcumin has been greatly limited due to a poor pharmacokinetic profile. To overcome these limitations, we have generated analogs of curcumin to enhance bioavailability and offer a preferable pharmacokinetic profile. Here, we explored the effects of two mono-carbonyl curcumin analogs, L2H21 and L50H46, in alleviating indices of inflammation and oxidative stress in cell culture and mouse model of diabetic complications. Our results show that L2H21 and L50H46 normalize inflammatory mediators (IL-6 and TNF-α), extracellular matrix proteins (FN and COL4α1), vasoactive factors (VEGF and ET-1) and a key transcriptional coactivator (p300) in cultured human retinal microvascular endothelial cells (HRECs) and dermal-derived microvascular endothelial cells (HMVECs) challenged with high levels of glucose. These curcumin analogs also reduced glucose-induced oxidative DNA damage as evidenced by 8-OHdG labeling. We further show that treatment of streptozotocin-induced diabetic mice with curcumin analogs prevents cardiac and renal dysfunction. The preservation of target tissue function was associated with normalization of pro-inflammatory cytokines and matrix proteins. Collectively, our results show that L2H21 and L50H46 offer the anti-inflammatory and antioxidant activities as has been reported for curcumin, and may provide a clinically applicable therapeutic option for the treatment of diabetic complications.
Highlights
As the incidence of diabetes rises globally, the risk of sustaining considerable organ damage and developing secondary complications remain at an all-time high
We and others have shown that glucose-induced upregulation of p300 can regulate the expression of genes for extracellular matrix (ECM) proteins and vasoactive factors in endothelial cells [11, 12]
We found statistically significant differences between L50H46 and curcumin treatments for FN expressions in human retinal microvascular endothelial cells (HRECs) (P = 0.0419); while, in HMVECs, differences existed between L2H21 and curcumin treatments for vascular endothelial growth factor (VEGF)-A (P = 0.0464)
Summary
As the incidence of diabetes rises globally, the risk of sustaining considerable organ damage and developing secondary complications remain at an all-time high. High levels of glucose in diabetes induce multiple biochemical pathways in vascular cells, including increased oxidative stress, generation of advanced glycation end-products, excess synthesis of extracellular matrix, altered protein kinase C activity, increased vascular permeability, and endothelial cell apoptosis [2, 3]. We and others have shown that glucose-induced upregulation of p300 can regulate the expression of genes for extracellular matrix (ECM) proteins and vasoactive factors in endothelial cells [11, 12]. These studies underscore the discovery and development of therapeutic agents that combat diabetes-induced oxidative stress and inflammatory responses
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