BACKGROUND/OBJECTIVES Unregulated inflammatory responses caused by hyperglycemia may induce diabetes complications. Hesperetin, a bioflavonoid, is a glycoside in citrus fruits and is known to have antioxidant and anticarcinogenic properties. However, the effect of inflammation on the diabetic environment has not been reported to date. In this study, we investigated the effect of hesperetin on proinflammatory cytokine secretion and its underlying mechanistic regulation in THP-1 macrophages with co-treatment LPS and hyperglycemic conditions. MATERIALS/METHODS THP-1 cells differentiated by PMA (1 μM) were cultured for 48 h in the presence or absence of hesperetin under normoglycemic (5.5 mM/L glucose) or hyperglycemic (25 mM/L glucose) conditions and then treated with LPS (100 ng/mL) for 6 h before harvesting. Inflammation-related proteins and mRNA levels were evaluated by enzyme-linked immunosorbent assay, western blot, and quantitative polymerase chain reaction analyses. RESULTS Hesperetin (0–100 μM, 48 h) treatment did not affect cell viability. The tumor necrosis factor-α and interleukin-6 levels increased in cells co-treated with LPS under hyperglycemic conditions compared to normoglycemic conditions, and these increases were decreased by hesperetin treatment. The TLR2/4 and MyD88 activity levels increased in cells co-treated with LPS under hyperglycemic conditions compared to normoglycemic conditions; however, hesperetin treatment inhibited the TLR2/4 and MyD88 activity increases. In addition, nuclear factor-κB (NF-κB) and Acetyl-NF-κB levels increased in response to treatment with LPS under hyperglycemic conditions compared to normoglycemic conditions, but those levels were decreased when treated with hesperetin. SIRT3 and SIRT6 expressions were increased by hesperetin treatment. CONCLUSIONS Our results suggest that hesperetin may be a potential agent for suppressing inflammation in diabetes.

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Foam cell formation characterized by lipid accumulation is a hallmark of the early stages of atherosclerosis. Foam cells form fatty streaks of plaques in the arteries and lead to atherosclerosis. 3,3′-Diindolylmethane (DIM) is a dietary agent derived from cruciferous vegetables such as broccoli and cauliflower. DIM has been shown to exhibit anti-cancer and anti-inflammatory properties. But the inhibitory effects of DIM on foam cell formation are not fully understood. In this study, we investigated the effect of DIM on cholesterol efflux and lipid accumulation in THP-1 foam cells and its underlying molecular mechanism. We exposed a THP-1 derived macrophage to oxidized low-density lipoprotein (Ox-LDL, 0 μg/mL) and lipopolysaccharides (LPS, 500 ng/mL) to initiate foam cell formation and carried out an analysis using MTT assay and western blotting. DIM decreased the expression of cluster of differentiation 36, lectin-like oxidized low-density lipoprotein receptor-1, and nuclear factor-κB, while it increased liver X receptor α, peroxisome proliferator-activated receptor-γ, and ATP-binding cassette cholesterol transporter A1 expressions compared to the co-treatment of Ox-LDL and LPS. Taken together, DIM inhibited foam cell formation via the induction of cholesterol efflux and lipid accumulation. Also, DIM inhibited the inflammation induced by foam cells. Thus, DIM may be a potent candidate for the treatment and prevention of inflammation and atherosclerosis.