Novel oxicam nonsteroidal compound XK01 attenuates inflammation by suppressing the NF-κB and MAPK pathway in RAW264.7 macrophages
Jixiang Wang,
Jiawang Tan,
Qianmei Hu,
Siyu Mao,
Hongting Chen,
Weiyi Luo,
Xing Feng
Affiliations
Jixiang Wang
The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
Jiawang Tan
The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
Qianmei Hu
The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
Siyu Mao
The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
Hongting Chen
College of Letters & Science, University of California, Berkeley, CA, 94720, USA
Weiyi Luo
The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China
Xing Feng
The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013, China; Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, School of Medicine, Hunan Normal University, Engineering Research Center of Reproduction and Translational Medicine of Hunan Province, Changsha, China; Corresponding author. The Key Laboratory of Study and Discovery of Small Targeted Molecules of Hunan Province, and Department of Pharmacy, School of Medicine, Hunan Normal University, Hunan, 410013 China.
Traditional non-steroidal anti-inflammatory drugs (NSAIDs) show serious adverse effects during clinical use, which limits their usage. Oxicams (e.g., piroxicam, meloxicam) are widely used as NSAIDs. However, selectivity to cyclooxygenase (COX) 2 may cause cardiovascular problems considering the long-term use of the drugs. Therefore, it is important to develop new non-steroidal compounds as anti-inflammatory drugs. In the present study, we evaluated the anti-inflammatory activity of a newly developed nonsteroidal drug XK01. Our data showed that XK01 reduced the contents of nitric oxide (NO) and reactive oxygen species (ROS)and inhibited the transcription levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and IL-1β in a dose-dependent manner in lipopolysaccharide (LPS)-stimulated mouse RAW264.7 macrophages. XK01 showed no significant inhibitory effect on COX-1, but inhibited the expression of COX-2. At molecular level, XK01 prevented the translocation of p65 protein from the cytoplasm to the nucleus and inhibited the phosphorylation of p65, IκB, and MAPKs proteins. And high concentration of XK01 also inhibited the phosphorylation of JNK, p38 and ERK, showing stronger effect than that of meloxicam. In addition, the anti-inflammatory activity of XK01 was further validated in Xylene-induced mouse ear swelling model. Thus, this study verified that XK01 inhibits the expression of inflammatory mediators and COX-2, and exhibits potential anti-inflammatory effects via suppressing the NF-κB and MAPK pathway.
