Vascular cell adhesion molecule inhibition

Selective inhibition of tumor necrosis factor-induced vascular cell adhesion molecule-1 gene expression by a novel flavonoid. Lack of effect on trascriptional factor NF-kB Arteriosclerosis, Thrombosis and Vascular Biology 16, 1501-8. 

Natalizumab (Tysabri ) is a recombinant humanized IgG4 mAb that binds to the a4-integrin subunit of a4(31 (VLA-4) and oA M (LPAM-1) integrins expressed on the surface of all leukocytes except neutrophils, and inhibits the a4-mediated adhesion of leukocytes to their respective receptors.103 104 The receptor for a4pi, vascular cell adhesion molecule-1 (VCAM-1), is expressed on activated endothelial cells and is... 

Halichlorine (1) (Fig. 11.1) is an alkaloid which was isolated from the marine sponge H. okadai Kadota (Kuramoto et ah, 1996). This compound was revealed to be a novel alkaloid containing an azaspiro[4.5]decane skeleton clarified by detailed spectroscopic analyses. The absolute stereostructure was confirmed by many synthetic studies (Arimoto et ah, 1998 Clive et ah, 2005 Liu et ah, 2009 Trauner et ah, 1999). Halichlorine was shown to inhibit the induction of vascular cell adhesion molecule-1 (VCAM-1) in cultured human umbilical vein endothelial cells. Drugs that block the inflammatory stimuli-induced expression of VCAM-1 may be useful for treating atherosclerosis, coronary artery diseases, angina, and noncardiovascular inflammatory diseases (Kock et ah, 1995). We introduce here the recent aspects of the biological and physiological activities of halichlorine. 

The quinolizidine alkaloid halichlorine (203), isolated from the marine sponge Halichondria okadai, inhibits the induction of vascular cell adhesion molecule-1 (VCAM-1) at IC50 7 pg/ml, which may be useful for treating atherosclerosis, coronary artery diseases, angina and noncardiovascular inflammatory diseases [161]. 

Three novel related marine alkaloids, halichlorine (1148) from the sponge Halichondria okadai (1177, 1178) and pinnaic acid (1149) and tauropinnaic acid (1150) from the bivalve Pinna muricata (1179), have been the objects of much synthetic interest in view of their pronounced biological activity (inhibition of the vascular cell adhesion molecule-1) (1180). Synthesis of these alkaloids led to both revision and confirmation of the original structures (1181,1182). The syntheses of the previously known chlorine-containing cylindricines have been reviewed (1183). 

Inhibits expression of vascular cell adhesion molecule-1 and E-selectin independently of heme oxygenase-1 expression [155]... 

Expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) is known to be elevated at sites of inflammation. Studies have been conducted into the effects of EGCG and TF-3 on the expression of these adhesion molecules induced by interleukin-ip (IL-lp) in cultured human umbilical vein endothelial cells (HUVECs). Both compounds significantly inhibited IL-ip-induced protein expression of VCAM and ICAM in dose-dependent manners and were associated with reduced adhesion of leukocytes to HUVECs. The m-RNA level of VCAM-1 was also inhibited by these tea polyphenolics, as was the NF-KB-dependent transcriptional activity induced by IL-lp. It is concluded that these molecules exhibit anti-inflammatory and anti-invasion properties, probably via a route involving blockage of IkB kinase. 

By the same token, a flavonoid, 2-(3-amino-phenyl)-8-methoxy-chromene-4-one, markedly inhibited TNF-alpha induced vascular cell adhesion molecule-1 (VCAM-1) in a concentration-dependent fashion of human aortic endothelial cells, but had no effect on intercellular adhesion molecule-1 (ICAM-1) [192]. 

Other mechanisms, apart from PPARy modulation, have been reported and proposed to explain the observed protective effects exerted by nitroalkenes. An important pro-inflammatory pathway regulated by NO2-FA is the translocation to the nucleus of the nuclear factor-kappa B (NF-kB) transcription factor (Cui et al. 2006 Rudolph et al. 2010). NF-kB remains inactive in the cytosol bounded to the IkB repressor both NO2-LA and NO2-OA modulate the release of the transcription factor by nitroalkylating the NF-KB-p65 protein subunit leading to a decrease on lipopoly-saccharide-induced secretion of pro-inflammatory cytokines in macrophages (e.g. IL-6, TNFa, MCP-1). Similar mechanisms were reported for the inhibition of the expression of the vascular cell adhesion molecule 1 (VCAM-1) as well as monocyte rolling and adhesion (Cui et al. 2006). 

Tumour necrosis factor-a-induced vascular cell adhesion molecule-1 (VCAM-1) expression on endothelial cells is inhibited by NO-donors, 8-Br-cGMP and flow-induced endothelial NO release (Tsao et al. 1996). NO and nitrovasodilators also inhibited the IL-1-induced increase in intercellular adhesion molecule-1 (ICAM-1) and VCAM-1, an effect blocked by haemoglobin inhibition of NO (De Caterina etal. 1995, Takahashi etal. 1996). Ko-KURA et al. (2000) exposed human umbilical vein... 

Inhibition by niacin of inflammatory and oxidative pathways may exert anti-atherosclerotic effects. In cultured human aortic endothelial cells, niacin increased cellular levels of nicotinamide adenine dinucleotide phosphate (reduced) (NADPH) and glutathione, regulators of redox reactions, and reduced production of reactive oxygen species. Niacin inhibited monocyte adhesion through the inhibition of tumour necrosis factor-alpha (TNF-a) induced expression of vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein-1 (MCP-1) (Ganji et al. 2009). Persistent increases in plasma adiponectin, an adipokine with anti-inflammatory properties, were found after 6 months of niacin treatment in humans (Linke et al. 2009). 

Chai H, Wang Q, Huang L, Xie T, Fu Y (2008) Ginsenoside Rbl inhibits tumor necrosis factor-alpha induced vascular cell adhesion molecule-1 expression in human endothelial cells. Biol Pharm Bull 31 2050-2056... 

Stannard AK, Riddell DR, Sacre SM, et al. Cell-derived apolipoiuotein E (ApoE) particles inhibit vascular cell adhesion molecule-1 (VCAM-1) expression inhuman endothelial cells. 7 flioZ Chem 2001 276 46,011-46,016. 

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