title: MC-002 exhibits positive effects against platelets aggregation and endothelial dysfunction through thromboxane A2 inhibition.
abstract: BACKGROUND
  Thromboxane A2 (TXA2) induces platelet aggregation and vasoconstriction, and agents that inhibit TXA2 production or interaction with receptors may exert potential application in stroke therapy.
  
  
  OBJECTIVE
  To illustrate the platelet aggregation antagonistic and endothelial protective effect of (E) - 3 - (3 - methoxy - 4 - ((3, 5, 6 - trimethylpyrazin - 2 - yl) methoxy) phenyl) sodium acrylate (MC-002) through TXA2 inhibition and underline mechanisms.
  
  
  METHODS
  Platelets aggregation and thoracic aorta ring contraction of rabbits were induced by U46619. Human umbilical vein endothelial cells (HUVECs) were further applied to explore the protective effect of MC-002 on endothelium when exposed to tumor necrosis factor - α (TNF-α). MTT method was used to assess cell damage, and ELISA analysis was exerted to estimate nitrogen monoxide (NO), endothelin-1 (ET-1), thromboxane B2 (TXB2) and 6-keto-prostaglandin F1α (6-keto-PGF1α) releasing. Fluorescence spectrophotometry was conducted to determine intracellular calcium concentration ([Ca(2+)]i), and western blotting method was applied to evaluate the protein expressions of intracellular adhesion molecule-1 (ICAM-1), P-selectin and nuclear factor-kappa B (NF-κB).
  
  
  CONCLUSIONS
  TXA2 analog U46619 mediated obvious platelet aggregation and vasoconstriction. MC-002 inhibited platelet aggregation through administration in vivo and incubation with platelet in vitro, and relaxed aorta ring in endothelium dependent manner. MC-002 alleviated cell damage, [Ca(2+)]i overload, ET-1 overexcretion and TXB2 activation, but improved NO availability reduction in HUVECs treated with TNF-α. Furthermore, MC-002 downregulated ICAM-1, P-selectin and NF-κB overexpression induced by TNF-α. In conclusion, MC-002 exerted antiplatelet aggregation effect through TXA2 inhibition and relieved inflammatory injury of endothelial cells through NF-κB signal pathway.
authors: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors: Weirong
authors: W
authors: Fang
authors: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors: Jie
authors: J
authors: Wei
authors: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors: Dan
authors: D
authors: Han
authors: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, P. R. China.
authors: Xi
authors: X
authors: Chen
authors: Hefei Yigong Medicine Co., Ltd., Hefei 230088, P. R. China.
authors: Guangwei
authors: G
authors: He
authors: Hefei Yigong Medicine Co., Ltd., Hefei 230088, P. R. China.
authors: Qiang
authors: Q
authors: Wu
authors: Hefei Yigong Medicine Co., Ltd., Hefei 230088, P. R. China.
authors: Shaoxing
authors: S
authors: Chu
authors: State Key Laboratory of Natural Medicines, Department of Physiology, China Pharmaceutical University, Nanjing 210009, P. R. China. Electronic address: yunmanlicpu@hotmail.com.
authors: Yunman
authors: Y
authors: Li
mesh_terms: D000179:Acrylates / Q000494:pharmacology; D000818:Animals; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011448:Prostaglandin Antagonists / Q000494:pharmacology*; D011714:Pyrans / Q000494:pharmacology*; D011817:Rabbits; D011897:Random Allocation; D044244:Receptors, Thromboxane A2, Prostaglandin H2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000179:Acrylates; D010975:Platelet Aggregation Inhibitors; D011448:Prostaglandin Antagonists; D011714:Pyrans; D044244:Receptors, Thromboxane A2, Prostaglandin H2; D013928:Thromboxane A2
keywords: Inflammation; MC-002; Platelet aggregation; TXA(2)