Psoralens are well-known furocoumarins belonging to the class of photosensitizers used for their activity in the treatment of various chronic inflammatory skin diseases. They are characterized by a differently substituted tricyclic aromatic skeleton, derived from condensation of a coumarin nucleus with a furan ring1. Recently, it was established that 4,6,4’-trimethyl-angelicin (TMA) is a strong inhibitor of the expression of the IL-8 gene in bronchial epithelial cells in which the inflammatory response has been challenged with P. aeruginosa2, the most common bacterium found in the airways of patients affected by Cystic Fibrosis (CF); moreover TMA, in addition to its anti-inflammatory and CFTR potentiator activities, also displays CFTR corrector properties3. These findings suggested us to analyze new synthetic derivatives of TMA in order to evaluate their biological activities on human bronchial epithelial CF IB3-1 cells. In inflammatory processes that involve CF patients NF-κB transcription factor plays a crucial role. In fact, the expression of many genes encoding for cytokines, chemokines, adhesion molecules, and other proteins involved in inflammation, is regulated by NF-κB. Analogues able to inhibit NF-κB/DNA interaction at lower concentration than TMA were selected to investigate their biological activity on IB3-1 cells induced with TNF-α. In this biological system NF-κB IL-8 gene expression was investigated. Some analogues showed similar activity (33-38% of inhibition of IL-8 expression) to the lead compound TMA. Other analogues displayed higher activities, in particular the most interesting compounds showing relevant anti-inflammatory effects are nine and they were found to cause 56-83% reduction of IL-8 mRNA expression at low concentrations (1-10 μM), without changes in cell proliferation pattern, demonstrating their potential interest for a possible anti-inflammatory therapy of CF.
Anti-inflammatory activity of novel 4,6,4’-trimethylangelicin’s analogues: effects on the NF-kB activity and IL-8 expression in Cystic Fibrosis IB3-1 cells
Lampronti, I;Milani, R;Gambari, R;Cabrini, G;
2016
Abstract
Psoralens are well-known furocoumarins belonging to the class of photosensitizers used for their activity in the treatment of various chronic inflammatory skin diseases. They are characterized by a differently substituted tricyclic aromatic skeleton, derived from condensation of a coumarin nucleus with a furan ring1. Recently, it was established that 4,6,4’-trimethyl-angelicin (TMA) is a strong inhibitor of the expression of the IL-8 gene in bronchial epithelial cells in which the inflammatory response has been challenged with P. aeruginosa2, the most common bacterium found in the airways of patients affected by Cystic Fibrosis (CF); moreover TMA, in addition to its anti-inflammatory and CFTR potentiator activities, also displays CFTR corrector properties3. These findings suggested us to analyze new synthetic derivatives of TMA in order to evaluate their biological activities on human bronchial epithelial CF IB3-1 cells. In inflammatory processes that involve CF patients NF-κB transcription factor plays a crucial role. In fact, the expression of many genes encoding for cytokines, chemokines, adhesion molecules, and other proteins involved in inflammation, is regulated by NF-κB. Analogues able to inhibit NF-κB/DNA interaction at lower concentration than TMA were selected to investigate their biological activity on IB3-1 cells induced with TNF-α. In this biological system NF-κB IL-8 gene expression was investigated. Some analogues showed similar activity (33-38% of inhibition of IL-8 expression) to the lead compound TMA. Other analogues displayed higher activities, in particular the most interesting compounds showing relevant anti-inflammatory effects are nine and they were found to cause 56-83% reduction of IL-8 mRNA expression at low concentrations (1-10 μM), without changes in cell proliferation pattern, demonstrating their potential interest for a possible anti-inflammatory therapy of CF.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
