BACKGROUND/OBJECTIVES: Resveratrol, a natural polyphenol, has multiple functions in cellular responses including apoptosis, survival, and differentiation. It also participates in the regulation of inflammatory response and oxidative stress. MicroRNA-Let-7A (miR-Let7A), known as a tumor suppressor miRNA, was recently reported to play a crucial role in both inflammation and apoptosis. Therefore, we examined involvement of miR-Let7A in the modulation of inflammation and cell survival/apoptosis regulated by resveratrol. MATERIALS/METHODS: mRNA expression of pro-/anti-inflammatory cytokines and sirtuin 1 (SIRT1), and protein expression of apoptosis signal-regulating kinase 1 (ASK1), p-ASK1, and caspase-3 and cleaved caspase-3 were measured, and cell viability and Hoechst/PI staining for apoptosis were observed in Lipopolysaccharide (LPS)-stimulated human THP-1 macrophages with the treatment of resveratrol and/or miR-Let7A overexpression. RESULTS: Pre-treatment with resveratrol (25-200 µM) resulted in significant recovery of the reduced cell viabilities under LPS-induced inflammatory condition and in markedly increased expression of miR-Let7A in non-stimulated or LPS-stimulated cells. Increased mRNA levels of tumor necrosis factor-α and interleukin (IL)-6 induced by LPS were significantly attenuated, and decreased levels of IL-10 and brain-derived neurotrophic factor were significantly restored by resveratrol and miR-Let7A overexpression, respectively, or in combination. Decreased expression of IL-4 mRNA by LPS stimulation was also significantly increased by miR-Let7A overexpression co-treated with resveratrol. In addition, decreased SIRT1 mRNA levels, and increased p-ASK1 levels and PI-positive cells by LPS stimulation were significantly restored by resveratrol and miR-Let7A overexpression, respectively, or in combination. CONCLUSIONS: miR-Let7A may be involved in the inflammatory response and cell survival/apoptosis modulated by resveratrol in human THP-1 macrophages.
Apoptosis ; Brain-Derived Neurotrophic Factor ; Caspase 3 ; Cell Survival ; Cytokines ; Humans ; Inflammation ; Interleukin-10 ; Interleukin-4 ; Interleukins ; Macrophages* ; MAP Kinase Kinase Kinase 5 ; MicroRNAs ; Necrosis ; Oxidative Stress ; RNA, Messenger ; Sirtuin 1

Diabetes and impaired fasting glucose are associated with incidence of cerebro-/cardio-vascular diseases. This study hypothesized that fasting glycemic status may reflect cerebrovascular risk in non-diabetic Koreans. Fasting glycemic status, lipid profiles, oxidative stress, and inflammation markers were measured in non-diabetic subjects (healthy controls, n = 112 and stroke n = 41). Systolic blood pressure, fasting glucose, glycated hemoglobin (HbA1C), triglycerides, high sensitivity C-reactive protein (hs-CPR), interleukin-6, and tumor necrosis factor-alpha were higher, and high density lipoprotein (HDL)-cholesterols were lower in patients with stroke than healthy controls. Fasting glucose positively correlated with hs-CRP, interleukin-6, tumor necrosis factor-alpha, oxidized low density lipoprotein (LDL) and malondialdehyde. The significances continued or at least turned to a trend after adjustments for confounding factors. Multiple regression analyses revealed that fasting glucose was mainly associated with cerebrovascular risk (beta'-coefficient = 0.284, p < 0.0001) together with age, systolic blood pressure, total cholesterol, hs-CRP, body mass index, dietary poly unsaturated fatty acid/saturated fatty acid (PUFA/SFA), and HbA1C (r2 = 0.634, p = 0.044). The subjects were subdivided by their fasting glucose levels [normal fasting glucose: 70-99 mg/dL, n = 91 [NFG-control] and n = 27 [NFG-stroke]; higher fasting glucose: 100-125 mg/dL, n = 21 [HFG-control] and n = 14 [HFG-stroke]). In both controls and stroke patients, HFG groups show higher triglyceride, total- and LDL-cholesterol and lower HDL-cholesterol than NFG groups. Control-HFG group showed significantly higher levels of oxidative stress and inflammation than control-NFG group. Stroke-HFG group also showed significantly higher inflammatory levels than stroke-NFG group, moreover the highest among the groups. Additionally, stroke-NFG group consumed higher PUFA/SFA than stroke-HFG group. Fasting glucose may be a useful indicator for cerebrovascular risk in non-diabetic individuals which may be mediated by oxidative stress and inflammation status.
Blood Pressure ; Body Mass Index ; C-Reactive Protein ; Cholesterol ; Fasting* ; Glucose* ; Hemoglobin A, Glycosylated ; Humans ; Incidence ; Inflammation* ; Interleukin-6 ; Lipoproteins ; Malondialdehyde ; Oxidative Stress* ; Stroke ; Triglycerides ; Tumor Necrosis Factor-alpha