Background: Paeonol (2'-hydroxy-4'-methoxyacetophenone) is thought to possess a broad range of clinically curative effects that are likely mediated by its anti-inflammatory and antioxidant activities. Aims: To elucidate the efficacy of paeonol's anti-inflammatory and antioxidant activities and the underlying mechanism of paeonol in advanced oxidation protein product (AOPP) stimulation of THP-1 macrophages. Materials and Methods: After incubating cells with AOPP plus paeonol, nitric oxide (NO) production and the levels of inducible NO synthase (iNOS), receptor for advanced glycation end products (RAGE), CD36, scavenger receptor (SR)-A, and SR-B1 were calculated. Moreover, THP-1 macrophages were preincubated with paeonol, the free radical scavenger N-acetylcysteine (NAC), NADPH oxidase inhibitors [apocynin, diphenylene iodonium (DPI)], and the specific inhibitor of nuclear factor-κB pyrrolidine dithiocarbamate (PDTC) prior to incubation with AOPP, and the levels of intracellular reactive oxygen species (ROS) production and tumor necrosis factor-a (TNF-a), interleukin (IL)-1ß, IL-6, and monocyte chemotactic protein 1 (MCP-1) were determined. Results: Paeonol increased NO production and the mRNA level of iNOS, whereas it decreased ROS production. ROS production was also effectively attenuated by apocynin, DPI, NAC, and PDTC. Furthermore, these inhibitors and paeonol could downregulate the mRNA and protein levels of proinflammatory cytokines (TNF-a, IL-1ß, IL-6, and MCP-1). Paeonol significantly reduced the expression levels of RAGE and CD36 but increased the expression levels of SR-A and SR-B1. Conclusions: These results indicate that paeonol can decrease proinflammatory cytokines in THP-1 macrophages, likely through RAGE-, CD36-, SR-A-, and SR-B1-mediated signals involving NADPH oxidase-dependent ROS generation. This suggests that paeonol can be used as a therapeutic agent for diseases contributing to oxidative stress injury.

Keywords:
Paeonol, THP-1 macrophages, Advanced oxidation protein product, Oxidative stress, Inflammation
1.
Witko-Sarsat V, Friedlander M, Capeillere-Blandin C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jungers P, Descamps-Latscha B: Advanced oxidation protein products as a novel marker of oxidative stress in uremia. Kidney Int 1996;49:1304-1313.
2.
Alderman CJ, Shah S, Foreman JC, Chain BM, Katz DR: The role of advanced oxidation protein products in regulation of dendritic cell function. Free Radic Biol Med 2002;32:377-385.
3.
Li HY, Hou FF, Zhang X, Chen PY, Liu SX, Feng JX, Liu ZQ, Shan YX, Wang GB, Zhou ZM, Tian JW, Xie D: Advanced oxidation protein products accelerate renal fibrosis in a remnant kidney model. J Am Soc Nephrol 2007;18:528-538.
4.
Hartmann S, Schönemeyer A, Sonnenburg B, Vray B, Lucius R: Cystatins of filarial nematodes up-regulate the nitric oxide production of interferon-γ-activated murine macrophages. Parasite Immunol 2002;24:253-262.
5.
Chou TC: Anti-inflammatory and analgesic effects of paeonol in carrageenan-evoked thermal hyperalgesia. Br J Pharmacol 2003;139:1146-1152.
6.
Lambeth JD, Krause KH, Clark RA: NOX enzymes as novel targets for drug development. Semin Immunopathol 2008;30:339-363.
7.
Li Q, Verma IM: NF-κB regulation in the immune system. Nat Rev Immunol 2002;2:725-734.
8.
Usui HK, Shikata K, Sasaki M, Okada S, Matsuda M, Shikata Y, Ogawa D, Kido Y, Nagase R, Yozai K, Ohga S, Tone A, Wada J, Takeya M, Horiuchi S, Kodama T, Makino H: Macrophage scavenger receptor-A-deficient mice are resistant against diabetic nephropathy through amelioration of microinflammation. Diabetes 2007;56:363-372.
9.
El Khoury J, Hickman SE, Thomas CA, Cao L, Silverstein SC, Loike JD: Scavenger receptor-mediated adhesion of microglia to β-amyloid fibrils. Nature 1996;382:716-719.
10.
Guo ZJ, Niu HX, Hou FF, Zhang L, Fu N, Nagai R, Lu X, Chen BH, Shan YX, Tian JW, Nagaraj RH, Xie D, Zhang X: Advanced oxidation protein products activate vascular endothelial cells via a RAGE-mediated signaling pathway. Antioxid Redox Signal 2008;10:1699-1712.
11.
Witko-Sarsat V, Gausson V, Nguyen AT, Touam M, Drueke T, Santangelo F, Descamps-Latscha B: AOPP-induced activation of human neutrophil and monocyte oxidative metabolism: a potential target for N-acetylcysteine treatment in dialysis patients. Kidney Int 2003;64:82-91.
12.
Witko-Sarsat V, Friedlander M, Nguyen KT, Capeillere-Blandin C, Nguyen AT, Canteloup S, Dayer JM, Jungers P, Drueke T, Descamps-Latscha B: Advanced oxidation protein products as novel mediators of inflammation and monocyte activation in chronic renal failure. J Immunol 1998;161:2524-2532.
13.
Mosmann T: Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 1983;65:55-63.
14.
Cortas NK, Wakid NW: Determination of inorganic nitrate in serum and urine by a kinetic cadmium-reduction method. Clin Chem 1990;36:1440-1443.
15.
Bass DA, Parce JW, Dechatelet LR, Szejda P, Seeds MC, Thomas M: Flow cytometric studies of oxidative product formation by neutrophils: a graded response to membrane stimulation. J Immunol 1983;130:1910-1917.
16.
Kishimoto Y, Tani M, Uto-Kondo H, Iizuka M, Saita E, Sone H, Kurata H, Kondo K: Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages. Eur J Nutr 2010;49:119-126.
17.
Asamitsu K, Tetsuka T, Kanazawa S, Okamoto T: RING finger protein AO7 supports NF-κB-mediated transcription by interacting with the transactivation domain of the p65 subunit. J Biol Chem 2003;278:26879-26887.
18.
Garcia X, Stein F: Nitric oxide. Semin Pediatr Infect Dis 2006;17:55-57.
19.
Bogdan C: Nitric oxide and the immune response. Nat Immunol 2001;2:907-916.
20.
Xie QW, Kashiwabara Y, Nathan C: Role of transcription factor NF-κB/Rel in induction of nitric oxide synthase. J Biol Chem 1994;269:4705-4708.
21.
Wilder RL: Adrenal and gonadal steroid hormone deficiency in the pathogenesis of rheumatoid arthritis. J Rheumatol Suppl 1996;44:10-12.
22.
Trikha M, Corringham R, Klein B, Rossi JF: Targeted anti-interleukin-6 monoclonal antibody therapy for cancer: a review of the rationale and clinical evidence. Clin Cancer Res 2003;9:4653-4665.
23.
MacDermott RP: Chemokines in the inflammatory bowel diseases. J Clin Immunol 1999;19:266-272.
24.
Frangogiannis NG, Smith CW, Entman ML: The inflammatory response in myocardial infarction. Cardiovasc Res 2002;53:31-47.
25.
Stanimirovic D, Satoh K: Inflammatory mediators of cerebral endothelium: a role in ischemic brain inflammation. Brain Pathol 2000;10:113-126.
26.
Ross R: Atherosclerosis is an inflammatory disease. Am Heart J 1999;138:S419-S420.
27.
Iwao Y, Nakajou K, Nagai R, Kitamura K, Anraku M, Maruyama T, Otagiri M: CD36 is one of important receptors promoting renal tubular injury by advanced oxidation protein products. Am J Physiol Renal Physiol 2008;295:F1871-F1880.
28.
Zhou LL, Cao W, Xie C, Tian J, Zhou Z, Zhou Q, Zhu P, Li A, Liu Y, Miyata T, Hou FF, Nie J: The receptor of advanced glycation end products plays a central role in advanced oxidation protein products-induced podocyte apoptosis. Kidney Int 2012;82:759-770.
29.
Shi XY, Hou FF, Niu HX, Wang GB, Xie D, Guo ZJ, Zhou ZM, Yang F, Tian JW, Zhang X: Advanced oxidation protein products promote inflammation in diabetic kidney through activation of renal nicotinamide adenine dinucleotide phosphate oxidase. Endocrinology 2008;149:1829-1839.
30.
Zhong ZM, Bai L, Chen JT: Advanced oxidation protein products inhibit proliferation and differentiation of rat osteoblast-like cells via NF-κB pathway. Cell Physiol Biochem 2009;24:105-114.
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2014
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