title: [Acetyl-11-keto-beta-boswellic acid and arsenic trioxide regulate the productions and activities of matrix metalloproteinases in human skin fibroblasts and human leukemia cell line THP-1].
abstract: OBJECTIVE
  In order to reveal the treatment mechanism of Chinese medicine with the effect of activating blood and resolving putridity, we selected acetyl-11-keto-beta-boswellic acid (AKBA) and arsenic trioxide (ATO), the main monomeric components of frankincense and arsenolite which are two most commonly used Chinese medicine with effect of activating blood and resolving putridity. We combined AKBA and ATO as a compound, and explored its regulatory role in productions and activities of matrix metalloproteinase (MMP)-1, MMP-2 and MMP-9 in human skin fibroblasts (HSFbs) and human acute monocytic leukemia cell line THP-1 in inflammatory state.
  
  
  METHODS
  In order to simulate the inflammatory micro-environment of chronic wounds, we established 3 cell models: HSFb model activated by tumor necrosis factor-alpha (TNF-α), THP-1 cell model activated by phorbol-12-myristate-13-acetate (PMA) and HSFb-THP-1 cell coculture system. AKBA and ATO were cocultured with these cell models. Enzyme-linked immunosorbent assay (ELISA), gelatin zymography assay and reverse transcription-polymerase chain reaction (RT-PCR) were used to test the secretions, activities and mRNA expressions of MMP-1, MMP-2 and MMP-9. In the study of the regulatory mechanism of AKBA and ATO on MMPs, AKBA and ATO were cocultured with the cell models. ELISA was used to test the secretions of TNF-α and interleukin-1beta (IL-β) and Western blot was used to test the phosphorylation levels of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and p38 mitogen-activated proteinkinase (p38MAPK).
  
  
  RESULTS
  Compound of AKBA and ATO inhibited MMP-1, MMP-2 and MMP-9 mRNA expressions, secretions and activities respectively in HSFbs and THP-1 cells in inflammatory state (P<0.05, P<0.01). Also compound of AKBA and ATO inhibited secretions of TNF-α and IL-1β in THP-1 cells and cell coculture system (P<0.01). It also decreased the phosphorylation of ERK1/2 and p38 MAPK in HSFbs and THP-1 cells (P<0.05, P<0.01).
  
  
  CONCLUSIONS
  The combined use of AKBA and ATO which in line with the rule of activating blood and resolving putridity inhibits fibroblasts and inflammatory cells in producing MMPs in inflammatory state through inhibiting the release of inflammatory factors and MAPK cascade pathway.
authors.affiliation: Beijing Institute of Chinese Medicine, Beijing Hospital of Chinese Medicine, Capital Medical University, Beijing 100010, China.
authors.forename: Ya-hui
authors.initials: YH
authors.lastname: Liang
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Jing-xia
authors.initials: JX
authors.lastname: Zhao
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.forename: Qi-fu
authors.initials: QF
authors.lastname: Huang
mesh_terms: D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000008:administration & dosage / Q000494:pharmacology*; D045744:Cell Line, Tumor; D005347:Fibroblasts / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects* / Q000378:metabolism; D010087:Oxides / Q000008:administration & dosage / Q000494:pharmacology*; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D001152:Arsenicals; D010087:Oxides; D014315:Triterpenes; C094432:acetyl-11-ketoboswellic acid; D020782:Matrix Metalloproteinases; D000077237:Arsenic Trioxide