Radiation-induced surge of macrophage foam cell formation, oxidative damage, and cytokine release is attenuated by a nanoformulation of curcumin

Abstract

<p><b>Purpose:</b> We examined the potential of a dendrosomal nanoformulation of curcumin (DNC) for intervention of ionizing radiation (IR)-induced damage (particularly leading to atherosclerosis), employing an irradiated THP-1 macrophage model.</p> <p><b>Materials and methods:</b> Differentiated THP-1 macrophages were irradiated and treated with curcumin or DNC nanoformulation (and oxidized low density lipoprotein, ox-LDL, to promote foam cells). Chemical, biochemical, and genetics tools including viability and apoptosis, multiple ELISA, real-time PCR, Western blotting, enzyme activity, and fluorimetry assays were employed to illustrate IR damage as well as the DNC intervention potential.</p> <p><b>Results:</b> DNC <i>per se</i> at 10 μM exerted no cytotoxic effects on macrophages. However, it caused apoptosis in 2 Gy-irradiated macrophages which were treated with ox-LDL, chiefly through a caspase-dependent pathway involving caspase-3. Concurrently, 10 μM DNC prevented the IR-induced rise in lipid accumulation (72% decrease compared to IR control, <i>p</i> < .0001), dil-oxLDL uptake (78% decrease, <i>p</i> < .005), protein and mRNA expression of cholesterol influx genes, CD36 and SR-A, NF-κB activation (81% less binding activity, <i>p</i> < .001; and lower nuclear presence of p65), cytokine (monocyte chemoattractant protein-1 and interleukin-1β) release, reactive oxygen species (ROS), and oxidative damage to DNA (37% decrease in 8-OHdG, <i>p</i> < .05) and lipids (62% decrease in 8-isoprostane, <i>p</i> < .005). DNC facilitated the uptake of curcumin in irradiated macrophages, increased glutathione peroxidase expression and activity, restored glutathione (GSH) level, and upregulated the expression of a cholesterol efflux gene, ABCA1. Two other antioxidants, resveratrol and N-acetyl cycteine (NAC), could simulate some of the beneficial effects of DNC against IR-induced CD36 expression and lipid accumulation, which were obviated by buthionine sulfoximine (BSO) pre-treatment of macrophages. However, some modulatory effects of DNC, particularly on lipid accumulation and the expression of SR-A and ABCA1 genes, seemed to be independent of its antioxidant effect, since they were still observed in BSO-pretreated macrophages, depleted of GSH.</p> <p><b>Conclusions:</b> DNC treatment suppresses IR-induced oxidative damage, inflammation, and foam cell formation in macrophages through multiple mechanisms.</p