title: Anti-inflammatory effects of novel curcumin analogs in experimental acute lung injury.
abstract: BACKGROUND
  Acute lung injury (ALI) and its most severe form acute respiratory distress syndrome (ARDS) have been the leading cause of morbidity and mortality in intensive care units (ICU). Currently, there is no effective pharmacological treatment for acute lung injury. Curcumin, extracted from turmeric, exhibits broad anti-inflammatory properties through down-regulating inflammatory cytokines. However, the instability of curcumin limits its clinical application.
  
  
  METHODS
  A series of new curcumin analogs were synthesized and screened for their inhibitory effects on the production of TNF-α and IL-6 in mouse peritoneal macrophages by ELISA. The evaluation of stability and mechanism of active compounds was determined using UV-assay and Western Blot, respectively. In vivo, SD rats were pretreatment with c26 for seven days and then intratracheally injected with LPS to induce ALI. Pulmonary edema, protein concentration in BALF, injury of lung tissue, inflammatory cytokines in serum and BALF, inflammatory cell infiltration, inflammatory cytokines mRNA expression, and MAPKs phosphorylation were analyzed. We also measured the inflammatory gene expression in human pulmonary epithelial cells.
  
  
  RESULTS
  In the study, we synthesized 30 curcumin analogs. The bioscreeening assay showed that most compounds inhibited LPS-induced production of TNF-α and IL-6. The active compounds, a17, a18, c9 and c26, exhibited their anti-inflammatory activity in a dose-dependent manner and exhibited greater stability than curcumin in vitro. Furthermore, the active compound c26 dose-dependently inhibited ERK phosphorylation. In vivo, LPS significantly increased protein concentration and number of inflammatory cells in BALF, pulmonary edema, pathological changes of lung tissue, inflammatory cytokines in serum and BALF, macrophage infiltration, inflammatory gene expression, and MAPKs phosphorylation . However, pretreatment with c26 attenuated the LPS induced increase through ERK pathway in vivo. Meanwhile, compound c26 reduced the LPS-induced inflammatory gene expression in human pulmonary epithelial cells.
  
  
  CONCLUSIONS
  These results suggest that the novel curcumin analog c26 has remarkable protective effects on LPS-induced ALI in rat. These effects may be related to its ability to suppress production of inflammatory cytokines through ERK pathway. Compound c26, with improved chemical stability and bioactivity, may have the potential to be further developed into an anti-inflammatory candidate for the prevention and treatment of ALI.
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. ya-li000@163.com.
authors.forename: Yali
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. liangdandan90@163.com.
authors.forename: Dandan
authors.initials: D
authors.lastname: Liang
authors.affiliation: The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. luckydlily@163.com.
authors.forename: Lili
authors.initials: L
authors.lastname: Dong
authors.affiliation: The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. 228302061@qq.com.
authors.forename: Xiangting
authors.initials: X
authors.lastname: Ge
authors.affiliation: The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. 18368719239@163.com.
authors.forename: Fengli
authors.initials: F
authors.lastname: Xu
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. 932927513@qq.com.
authors.forename: Wenbo
authors.initials: W
authors.lastname: Chen
authors.affiliation: The 2nd Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. yuanrongdai2000@163.com.
authors.forename: Yuanrong
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. huameng@yahoo.com.
authors.forename: Huameng
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China. top_zoupeng@163.com.
authors.forename: Peng
authors.initials: P
authors.lastname: Zou
authors.affiliation: School of Environmental and Biological Engineering, Nanjing University of Science and Technology, Nanjing, Jiangsu, 210094, China. shulin_yang@126.com.
authors.forename: Shulin
authors.initials: S
authors.lastname: Yang
authors.affiliation: Chemical Biology Research Center at School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China. wzmcliangguang@163.com.
authors.forename: Guang
authors.initials: G
authors.lastname: Liang
mesh_terms: D055371:Acute Lung Injury / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002478:Cells, Cultured; D003474:Curcumin / Q000031:analogs & derivatives / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008070:Lipopolysaccharides; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011654:Pulmonary Edema / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D012333:RNA, Messenger / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000893:Anti-Inflammatory Agents; C508585:IL1B protein, human; C508600:IL6 protein, human; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D015850:Interleukin-6; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C577686:interleukin-6, mouse; D020928:Mitogen-Activated Protein Kinases; D003474:Curcumin