Regulation of adhesion molecules expression in TNF-α-stimulated brain microvascular endothelial cells by tanshinone IIA: involvement of NF-κB and ROS generation.

Pro-inflammatory cytokine-mediated expression of cell surface adhesion molecules plays a key role in endothelial cell injury, leading to vascular inflammation and the development of many cerebrovascular diseases. Thus, antiinflammatory agents targeting these adhesion molecules may represent potential drugs for the prevention and treatment of cerebrovascular diseases. The present study explored the effects of tanshinone IIA (Tan IIA), an active ingredient present in the Salvia miltiorrhiza root, on the expression of cellular adhesion molecules in TNF-α-stimulated brain microvascular endothelial cells (BMVECs). Treatment with Tan IIA was found to suppress the expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), resulting in inhibition of TNF-α-induced adhesion of neutrophils to BMVECs in a dose-dependent manner. In addition, Tan IIA significantly inhibited TNF-α-induced production of reactive oxygen species (ROS), which was accompanied by decreased malondialdehyde (MDA) levels. Treatment with Tan IIA also inhibited nuclear factor-kappa B (NF-κB) activation. Together, these results suggest that Tan IIA regulates TNF-α-induced expression of VCAM-1 and ICAM-1 through inhibition of NF-κB activation and ROS generation in BMVECs.

Tang C ，Xue HL ，Bai CL ，Fu R ... -  《-》

Chloroform extract of aged black garlic attenuates TNF-α-induced ROS generation, VCAM-1 expression, NF-κB activation and adhesiveness for monocytes in human umbilical vein endothelial cells.

Aged black garlic is a type of fermented garlic (Allium sativum) which has been used in Oriental countries for a long time because of various biological properties of garlic derivatives. The current study explored the potential of the chloroform extract of aged black garlic (CEABG) in attenuating the activities of adhesion molecules in tumor necrosis factor-α (TNF-α)-stimulated human umbilical vein endothelial cells (HUVECs). The study was performed on HUVECs that were pretreated with 30 μg/mL of CEABG before TNF-α treatment. Treatment of HUVECs with CEABG significantly inhibited TNF-α-induced reactive oxygen species (ROS) formation. HUVECs treated with CEABG showed markedly suppressed TNF-α-induced mRNA expression of VCAM-1, but little alteration in ICAM-1 and E-selectin mRNA expression. CEABG treatment also significantly decreased the TNF-α-induced cell surface and total protein expression of VCAM-1 without affecting ICAM-1 and E-selectin expression. In addition, treatment of HUVECs with CEABG markedly reduced THP-1 monocyte adhesion to TNF-α-stimulated HUVECs. Furthermore, CEABG significantly inhibited NF-κB transcription factor activation in TNF-α-stimulated HUVECs. The data provide new evidence of the antiinflammatory properties of CEABG that may have a potential therapeutic use for the prevention and treatment of vascular diseases such as atherosclerosis through mechanisms involving the inhibition of VCAM-1 expression and NF-κB activation in vascular endothelial cells.

Lee EN ，Choi YW ，Kim HK ，Park JK ，Kim HJ ，Kim MJ ，Lee HW ，Kim KH ，Bae SS ，Kim BS ，Yoon S ... -  《-》

The anti-atherosclerotic effect of tanshinone IIA is associated with the inhibition of TNF-α-induced VCAM-1, ICAM-1 and CX3CL1 expression.

Tanshinone IIA is one of the major diterpenes in Salvia miltiorrhiza. The inhibitory effect of Tanshinone IIA on atherosclerosis has been reported, but the underlying mechanism is not fully understood. The present study aimed to study the anti-atherosclerosis effect of Tanshinone IIA on the adhesion of monocytes to vascular endothelial cells and related mechanism. Results showed that Tanshinone IIA, at the concentrations without cytotoxic effect, dose-dependently inhibited the adhesion of THP-1 monocytes to the TNF-α-stimulated human vascular endothelial cells. The expressions of cell adhesion molecules including VCAM-1, ICAM-1 and E-selectin were induced by TNF-α in HUVECs at both the mRNA and protein levels. The mRNA and protein expressions of VCAM-1 and ICAM-1, but not E-selectin, were both significantly suppressed by Tanshinone IIA in a dose dependent manner. In addition, the TNF-α-induced mRNA expression of fractalkine/CX3CL1 and the level of soluble fractalkine were both reduced by Tanshinone IIA. We also found that Tanshinone IIA significantly inhibited TNF-α-induced nuclear translocation of NF-κB which was resulted from the inhibitory effect of Tanshinone IIA on the TNF-α-activated phosphorylation of IKKα, IKKβ, IκB and NF-κB. As one of the major components of Salvia miltiorrhiza, Tanshinone IIA alone exerted more potent effect on inhibiting the adhesion of monocytes to vascular endothelial cells when compared with Salvia miltiorrhiza. All together, these results demonstrate a novel underlying mechanism for the anti-inflammatory effect of Tanshinone IIA by modulating TNF-α-induced expression of VCAM-1, ICAM-1 and fractalkine through inhibition of TNF-α-induced activation of IKK/NF-κB signaling pathway in human vascular endothelial cells.

Chang CC ，Chu CF ，Wang CN ，Wu HT ，Bi KW ，Pang JH ，Huang ST ... -  《-》

A novel cyclin-dependent kinase inhibitor down-regulates tumor necrosis factor-alpha (TNF-alpha)-induced expression of cell adhesion molecules by inhibition of NF-kappaB activation in human pulmonary epithelial cells.

BAI (a novel cyclin-dependent kinase (CDK) inhibitor, 2-[1,1'-biphenyl]-4-yl-N-[5-(1,1-dioxo-1lambda(6)-isothiazolidin-2-yl)-1H-indazol-3-yl] acetamide) is known to have anti-proliferative activity, but the mechanism responsible for it remains unclear. We here investigated the functional effect of BAI on airway inflammation and its action mechanism. BAI down-regulated the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in human lung epithelial A549 cells stimulated with tumor necrosis factor-alpha: (TNF-alpha), resulting in the suppression of leukocyte adhesion to lung epithelial A549 cells. In addition, BAI inhibited TNF-alpha-induced expression of adhesion molecules (ICAM-1 and VCAM-1) protein and mRNA in a dose-dependent manner. BAI inhibited nuclear factor-kappaB (NF-kappaB) activity and nuclear translocation of NF-kappaB. Furthermore, BAI potently inhibits the TNF-alpha-induced increase in ROS generation in A549 cells, suggesting that inhibition of ROS generation is maybe involved in the BAI-mediated inhibition of TNF-alpha-induced ICAM-1 down-regulation to A549 cells. Taken together, these results suggest that BAI inhibits cell adhesion through inhibition of ICAM-1 and VCAM-1 expressions, at least in part, by inhibition of ROS generation and down-regulation of NF-kappaB activity.

Oh JH ，Park EJ ，Park JW ，Lee J ，Lee SH ，Kwon TK ... -  《-》

4-O-methylgallic acid down-regulates endothelial adhesion molecule expression by inhibiting NF-kappaB-DNA-binding activity.

Lee G ，Na HJ ，Namkoong S ，Jeong Kwon H ，Han S ，Ha KS ，Kwon YG ，Lee H ，Kim YM ... -  《EUROPEAN JOURNAL OF PHARMACOLOGY》