The Antioxidant Effects of Isorhamnetin Contribute to Inhibit COX-2 Expression in Response to Inflammation: A Potential
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The Antioxidant Effects of Isorhamnetin Contribute to Inhibit COX-2 Expression in Response to Inflammation: A Potential Role of HO-1 Kyuhwa Seo,1 Ji Hye Yang,1 Sang Chan Kim,2 Sae Kwang Ku,2 Sung Hwan Ki,1 and Sang Mi Shin1,3
Abstract—Previously, we reported that isorhamnentin, a 3′-O-methylated metabolite of quercetin, reduced inducible nitric oxide synthase (iNOS) expression and NO production. The present study further investigated the underlying mechanism of anti-inflammatory and antioxidant effects of isorhamnentin. Administration of isorhamnetin decreased the number of cyclooxygenase-2 (COX-2) positive cells in rats with carrageenan-induced paw edema. Isorhamnetin also suppressed lipopolysaccharide (LPS)-induced expression of COX-2 in cells. It is well known that LPS-induced reactive oxygen species (ROS) production leads to COX-2 induction. Isorhamnetin decreased LPS-induced ROS production and apoptosis. In addition, the basal expression of heme oxygenase-1 (HO-1) was increased by isorhamnetin treatment in agreement with the increase in nuclear translocation of NF-E2-related factor-2 (Nrf2), an essential transcription factor for the regulation of HO-1 expression. Moreover, pretreatment of tin protoporphyrin IX (SnPP), a chemical inhibitor of HO-1, reversed the ability of isothamnetin to inhibit COX-2 expression. These results demonstrate that induction of HO-1 by isorhamnetin leads to a reduction in ROS production and its antioxidant property might contribute to the inhibition of COX-2 expression in response to inflammation. KEY WORDS: isorhamnetin; anti-inflammation; cyclooxygenase-2; reactive oxygen species; heme oxygenase-1.
INTRODUCTION Inflammation has been implicated in various diseases including sepsis, atherosclerosis, and cancer [1–3]. In K. Seo and J.H. Yang contributed equally to this work. 1
College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea Medical Research Center for Globalization of Herbal Formulation, College of Korean Medicine, Daegu Haany University, Gyeongsan, Gyeonsangbukdo 712-715, South Korea 3 To whom correspondence should be addressed at College of Pharmacy, Chosun University, Gwangju, 501-759, South Korea. E-mail: [email protected] 2
ABBREVIATIONS: AMPK, AMP-activated protein kinase; CO, Carbon monoxide; COX-2, Cyclooxygenase-2; DCFH-DA, 2′,7′-Dichlorofluorescein diacetate; HO-1, Heme oxygenase-1; IKK, IκB kinase; IκBα, Inhibitory κB α; iNOS, Inducible nitric oxide synthase; LPS, Lipopolysaccharide; MAPK, Mitogen-activated protein kinase; NAC, N-Acetyl cystein; NADPH oxidase, Nicotinamide adenine dinucleotide phosphate oxidase; NF-κB, Nuclear factor-kappaB; Nrf2, NF-E2-related factor-2; PGE2, Prostaglandin E2; PMA, Phorbol 12-myristate 13-acetate; PPARγ, Peroxisome proliferator-activated receptorγ; ROS, Reactive oxygen species; SnPP, Tin protoporphyrin IX; TLR, Toll-like receptor; TNFα, Tumor necrosis factor alpha
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