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ZLJ-6, a novel COX/5-LOX inhibitor, attenuates TNF-α-induced endothelial E-selectin, ICAM-1 and VCAM-1 expression and monocyte-endothelial interactions via a COX/5-LOX-independent mechanism.
Vascul Pharmacol. 2011 Nov-Dec; 55(5-6):135-42.VP

Abstract

Nonsteroidal anti-inflammatory drugs (NSAIDs) are previously found to possess prostaglandin and leukotriene-independent anti-inflammatory effect. The aim of the present study was to investigate the prostaglandin and leukotriene-independent anti-inflammatory effect of an imidazolone COX/5-LOX inhibitor ZLJ-6 and the underlying mechanism. Pretreatment human umbilical vein endothelial cells (HUVECs) with ZLJ-6 (3, 10 and 30 μM) concentration-dependently decreased TNF-α-induced monocyte-endothelial interactions in both static and dynamic conditions whereas no effect was found after pretreatment with the COX-2 inhibitor celecoxib (30 μM), 5-LOX inhibitor zileuton (30 μM) and the combination of them. ZLJ-6 also attenuated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cytoadhesion molecule-1 (VCAM-1) on TNF-α-induced HUVECs. A further analysis indicated that ZLJ-6 attenuated TNF-α-induced nuclear translocation of NF-κB, IκB phosphorylation, IκB kinase β (IKKβ) activity, and subsequent NF-κB-DNA complex formation, suggesting that NF-κB pathway was involved in TNF-α-induced inflammation. However, ZLJ-6 did not affect TNF-α-induced extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 phosphorylation. Taken together, our results indicated that ZLJ-6 potently inhibited TNF-α-induced monocyte-endothelial interactions and adhesion molecule (E-selectin, ICAM-1 and VCAM-1) expression and these effects were mediated by NF-κB signaling pathway rather than its primary pharmacological target COX-2 or 5-LOX.

Authors+Show Affiliations

Department of Pharmacology, China Pharmaceutical University, Nanjing, 210009, PR China.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21777697

Citation

Chen, Li, et al. "ZLJ-6, a Novel COX/5-LOX Inhibitor, Attenuates TNF-α-induced Endothelial E-selectin, ICAM-1 and VCAM-1 Expression and Monocyte-endothelial Interactions Via a COX/5-LOX-independent Mechanism." Vascular Pharmacology, vol. 55, no. 5-6, 2011, pp. 135-42.
Chen L, Zhao Q, Wang XL, et al. ZLJ-6, a novel COX/5-LOX inhibitor, attenuates TNF-α-induced endothelial E-selectin, ICAM-1 and VCAM-1 expression and monocyte-endothelial interactions via a COX/5-LOX-independent mechanism. Vascul Pharmacol. 2011;55(5-6):135-42.
Chen, L., Zhao, Q., Wang, X. L., You, R., Zhang, Y. H., Ji, H., & Lai, Y. S. (2011). ZLJ-6, a novel COX/5-LOX inhibitor, attenuates TNF-α-induced endothelial E-selectin, ICAM-1 and VCAM-1 expression and monocyte-endothelial interactions via a COX/5-LOX-independent mechanism. Vascular Pharmacology, 55(5-6), 135-42. https://doi.org/10.1016/j.vph.2011.07.003
Chen L, et al. ZLJ-6, a Novel COX/5-LOX Inhibitor, Attenuates TNF-α-induced Endothelial E-selectin, ICAM-1 and VCAM-1 Expression and Monocyte-endothelial Interactions Via a COX/5-LOX-independent Mechanism. Vascul Pharmacol. 2011 Nov-Dec;55(5-6):135-42. PubMed PMID: 21777697.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - ZLJ-6, a novel COX/5-LOX inhibitor, attenuates TNF-α-induced endothelial E-selectin, ICAM-1 and VCAM-1 expression and monocyte-endothelial interactions via a COX/5-LOX-independent mechanism. AU - Chen,Li, AU - Zhao,Qian, AU - Wang,Xu-Liang, AU - You,Ran, AU - Zhang,Yi-Hua, AU - Ji,Hui, AU - Lai,Yi-Sheng, Y1 - 2011/07/12/ PY - 2011/03/17/received PY - 2011/06/01/revised PY - 2011/07/06/accepted PY - 2011/7/23/entrez PY - 2011/7/23/pubmed PY - 2013/5/2/medline SP - 135 EP - 42 JF - Vascular pharmacology JO - Vascul Pharmacol VL - 55 IS - 5-6 N2 - Nonsteroidal anti-inflammatory drugs (NSAIDs) are previously found to possess prostaglandin and leukotriene-independent anti-inflammatory effect. The aim of the present study was to investigate the prostaglandin and leukotriene-independent anti-inflammatory effect of an imidazolone COX/5-LOX inhibitor ZLJ-6 and the underlying mechanism. Pretreatment human umbilical vein endothelial cells (HUVECs) with ZLJ-6 (3, 10 and 30 μM) concentration-dependently decreased TNF-α-induced monocyte-endothelial interactions in both static and dynamic conditions whereas no effect was found after pretreatment with the COX-2 inhibitor celecoxib (30 μM), 5-LOX inhibitor zileuton (30 μM) and the combination of them. ZLJ-6 also attenuated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cytoadhesion molecule-1 (VCAM-1) on TNF-α-induced HUVECs. A further analysis indicated that ZLJ-6 attenuated TNF-α-induced nuclear translocation of NF-κB, IκB phosphorylation, IκB kinase β (IKKβ) activity, and subsequent NF-κB-DNA complex formation, suggesting that NF-κB pathway was involved in TNF-α-induced inflammation. However, ZLJ-6 did not affect TNF-α-induced extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinases (JNK) and p38 phosphorylation. Taken together, our results indicated that ZLJ-6 potently inhibited TNF-α-induced monocyte-endothelial interactions and adhesion molecule (E-selectin, ICAM-1 and VCAM-1) expression and these effects were mediated by NF-κB signaling pathway rather than its primary pharmacological target COX-2 or 5-LOX. SN - 1879-3649 UR - https://www.unboundmedicine.com/medline/citation/21777697/ZLJ_6_a_novel_COX/5_LOX_inhibitor_attenuates_TNF_α_induced_endothelial_E_selectin_ICAM_1_and_VCAM_1_expression_and_monocyte_endothelial_interactions_via_a_COX/5_LOX_independent_mechanism_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1537-1891(11)00069-3 DB - PRIME DP - Unbound Medicine ER -