title: Ethyl-p-methoxycinnamate isolated from Kaempferia galanga inhibits inflammation by suppressing interleukin-1, tumor necrosis factor-α, and angiogenesis by blocking endothelial functions.
abstract: OBJECTIVE
  The present study aimed to investigate the mechanisms underlying the anti-inflammatory and anti-angiogenic effects of ethyl-p-methoxycinnamate isolated from Kaempferia galanga.
  
  
  METHODS
  The anti-inflammatory effects of ethyl-p-methoxycinnamate were assessed using the cotton pellet granuloma assay in rats, whereby the levels of interleukin-1 and tumor necrosis factor-α were measured in the animals' blood. In addition, the levels of interleukin, tumor necrosis factor, and nitric oxide were measured in vitro using the human macrophage cell line (U937). The analgesic effects of ethyl-p-methoxycinnamate were assessed by the tail flick assay in rats. The anti-angiogenic effects were evaluated first by the rat aortic ring assay and, subsequently, by assessing the inhibitory effects of ethyl-p-methoxycinnamate on vascular endothelial growth factor, proliferation, migration, and tube formation in human umbilical vein endothelial cells.
  
  
  RESULTS
  Ethyl-p-methoxycinnamate strongly inhibited granuloma tissue formation in rats. It prolonged the tail flick time in rats by more than two-fold compared with the control animals. The inhibition of interleukin and tumor necrosis factor by ethyl-p-methoxycinnamate was significant in both in vivo and in vitro models; however, only a moderate inhibition of nitric oxide was observed in macrophages. Furthermore, ethyl-p-methoxycinnamate considerably inhibited microvessel sprouting from the rat aorta. These mechanistic studies showed that ethyl-p-methoxycinnamate strongly inhibited the differentiation and migration of endothelial cells, which was further confirmed by the reduced level of vascular endothelial growth factor.
  
  
  CONCLUSIONS
  Ethyl-p-methoxycinnamate exhibits significant anti-inflammatory potential by inhibiting pro-inflammatory cytokines and angiogenesis, thus inhibiting the main functions of endothelial cells. Thus, ethyl-p-methoxycinnamate could be a promising therapeutic agent for the treatment of inflammatory and angiogenesis-related diseases.
authors: Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmacology, Pulau Penang, Malaysia, Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmacology, Pulau Penang, Malaysia.
authors: Muhammad Ihtisham
authors: MI
authors: Umar
authors: Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmacology, Pulau Penang, Malaysia, Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmacology, Pulau Penang, Malaysia.
authors: Mohd Zaini
authors: MZ
authors: Asmawi
authors: Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Pulau Penang, Malaysia, Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, Pulau Penang, Malaysia.
authors: Amirin
authors: A
authors: Sadikun
authors: Amin Malik Shah Abdul
authors: AM
authors: Majid
authors: Universiti Sains Malaysia, School of Pharmaceutical Sciences, EMAN Testing and Research Laboratories, Pulau Penang, Malaysia, Universiti Sains Malaysia, School of Pharmaceutical Sciences, EMAN Testing and Research Laboratories, Pulau Penang, Malaysia.
authors: Fouad Saleih R
authors: FS
authors: Al-Suede
authors: Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmacology, Pulau Penang, Malaysia, Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmacology, Pulau Penang, Malaysia.
authors: Loiy Elsir Ahmed
authors: LE
authors: Hassan
authors: Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmacology, Pulau Penang, Malaysia, Universiti Sains Malaysia, School of Pharmaceutical Sciences, Department of Pharmacology, Pulau Penang, Malaysia.
authors: Rabia
authors: R
authors: Altaf
authors: Universiti Sains Malaysia, School of Pharmaceutical Sciences, EMAN Testing and Research Laboratories, Pulau Penang, Malaysia, Universiti Sains Malaysia, School of Pharmaceutical Sciences, EMAN Testing and Research Laboratories, Pulau Penang, Malaysia.
authors: Mohamed B Khadeer
authors: MB
authors: Ahamed
mesh_terms: D000704:Analysis of Variance; D020533:Angiogenesis Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000302:isolation & purification / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002934:Cinnamates / Q000494:pharmacology*; D004797:Enzyme-Linked Immunosorbent Assay; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007375:Interleukin-1 / Q000032:analysis; D008297:Male; D010936:Plant Extracts / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015203:Reproducibility of Results; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000187:drug effects; D020298:U937 Cells / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis / Q000187:drug effects*; D030521:Zingiberaceae / Q000737:chemistry*
chemical_list: D020533:Angiogenesis Inhibitors; D000893:Anti-Inflammatory Agents; D002934:Cinnamates; D007375:Interleukin-1; D010936:Plant Extracts; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C531364:ethyl 4-methoxycinnamate