alitretinoin and Diabetes-Mellitus

An inflammatory response induced by high glucose is a cause of endothelial dysfunction in diabetes and is an important contributing link to atherosclerosis. Diabetes is an independent risk factor of atherosclerosis and activation of retinoid X receptor (RXR) has been shown to exert anti-atherogenic effects. In the present study, we examined the effects of the RXR ligands 9-cis-retinoic acid (9-cis-RA) and SR11237 on high glucose-induced inflammation in human umbilical endothelial vein endothelial cells (HUVECs) and explored the potential mechanism. Our results showed that the inflammation induced by high-glucose in HUVECs was mainly mediated by the activation of nuclear factor-B (NF- κB). High glucose-induced expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were in comparison, significantly decreased by treatment with RXR. The effect of RXR agonists was mainly due to the inhibition of NF-κB activation. Using pharmacological inhibitors and siRNA, we confirmed that nicotinamide adenine dinucleotide phosphate (NADPH) oxidase was an upstream activator of NF-κB. Furthermore, RXR agonists significantly inhibited high glucose-induced activation of NADPH oxidase and significantly decreased the production of reactive oxygen species (ROS). To explore whether the rapid inhibitory effects of RXR agonists were in fact mediated by RXR, we examined the effect of RXR downregulation by RXR siRNA. Our results showed that RXR siRNA largely abrogated the effects of RXR agonists, suggesting the requirement of RXR expression. Therefore, we have shown that RXR is involved in the regulation of NADPH oxidase- NF-κB signal pathway, as the RXR ligands antagonized the inflammatory response in HUVECs induced by high glucose.

Topics: Alitretinoin; Antineoplastic Agents; Atherosclerosis; Benzoates; Cells, Cultured; Diabetes Mellitus; Endothelium, Vascular; Gene Expression Regulation; Glucose; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; NADPH Oxidase 4; NADPH Oxidases; Reactive Oxygen Species; Retinoid X Receptors; Retinoids; RNA Interference; RNA, Small Interfering; Transcription Factor RelA; Tretinoin; Up-Regulation; Vascular Cell Adhesion Molecule-1

A novel furocoumarin derivative named oxyalloimperatorin (1), together with seventeen furocoumarins 2-18 were isolated from the radix of Angelica dahurica. The chemical structure of new metabolite was characterized by analysis of IR, NMR, and HR-ESI-MS spectroscopic data. Among the isolated compounds, 13, 16, and 18 (each at 20 μM) could significantly promote the gene transcriptional function of nuclear receptor RXRα. While 7-9, 13, 14, and the new structure 1 (each at 20 μM) showed significant reduction in RXRα gene transcriptional activities induced by 9-cis-retinoid acid. The findings indicated that these furocoumarin skeleton derivatives might hold beneficial effects on many intractable diseases, such as cancer and metabolic diseases, due to their potential activities on regulating the transcriptional activation function of RXRα.

Topics: Acetates; Alitretinoin; Angelica; Diabetes Mellitus; Furocoumarins; Gene Expression; Genes, Reporter; HEK293 Cells; Humans; Luciferases; Magnetic Resonance Spectroscopy; Mass Spectrometry; Neoplasms; Plant Extracts; Plant Roots; Plasmids; Retinoid X Receptor alpha; Transcriptional Activation; Transfection; Tretinoin