Cyclosporine br Experimental br Results br Discussion In thi

Experimental
Results
Discussion In this study, we performed molecular docking analysis and in vitro studies to determine whether genistein binds to HIF-1α in BC Cyclosporine and identify the residues involved in this interaction. We found that some functional groups (residues) mimic the binding of genistein and fit well to the active domain of HIF-1α. In particular, Thr183, Ser184, Asp201, Gln203, Arg238 residues play a significant function in the inhibitory interaction between genistein and HIF-1α. These key residues are located in the FIH-1 binding site of the HIF-1α protein. The FIH-1 molecule, characterized as the factor inhibiting HIF-1, attaches to HIF-1α, hydroxylates Asn803 and prevents the transactivation of downstream genetic targets including VEGF (Mahon et al., 2001). These results thus propose that genistein can exert its inhibitory function on HIF-1α by a similar mechanism to FIH-1, allowing it to bock the transactivation of downstream HIF-1α effectors. To confirm these results in vitro, we evaluated HIF-1α expression in BC cells treated with DFO with or without genistein and found that genistein decreased HIF-1α levels in cells treated with DFO or DMSO. As previous work has shown, DFO addition increases the levels of HIF-1α in breast cancer cells (El Guerrab et al., 2011). Based on these findings, we can thus conclude that DFO increased the levels of HIF-1α in our cells, as previously demonstrated, and that genistein administration countered this effect and reduced the upregulated HIF-1α expression. Our study is the first to report an interaction between genistein and HIF-1α in BC cells and to characterize the residues involved in this interaction. These results indicate that genistein might be an effective antagonist of HIF-1α in BC cells and that the development of FIH-1-like antagonists of HIF-1α could be a potential therapeutic strategy against cancers, such as BC. HIF-1α is a transcription factor produced by cells as a response to hypoxia. HIF-1 consists of an α and a β subunit that each comprises a helix-loop-helix region and Per-Arnt-Sim (PAS) region in its N-terminus (Hogenesch et al., 1997). Hypoxic conditions induce the translocation of cytoplasmic HIF-1α to the nucleus, inducing its heterodimerization with HIF-1β. The activated HIF-1α/β complex attaches to a particular DNA sequence in the enhancer domain of its gene targets, then recruits CREB binding protein (CBP), a co-activator, through its C terminal activation domain. It is modulated by Fe(II)-dependent hydroxylases and 2-oxoglutarate, including FIH-1, which block HIF-1α interaction with its co-activating molecules. Identifying potential inhibitors of HIF-1α, such as genistein and its analogues, is thus an attractive strategy for treating breast cancer, given the connection between genistein and estrogen.
Conclusion
Conflict of interest
Introduction Epilepsy is a chronic neurological disease causing transient brain dysfunction accompanied by a sudden abnormal discharge of brain neurons. Despite the rapid development of treatment, recent clinical data indicate that approximately 30% of epileptic patients, most of whom have temporal lobe epilepsy (TLE), are resistant to current therapies (Berg et al., 2010). Previous studies have demonstrated that temporal lobe epilepsy (TLE) is generally associated with neuronal loss in the hippocampus, hippocampal apoptosis and inflammatory responses (Curia et al., 2008). Additionally, studies performed during the prior decade have indicated that abnormal neurogenesis in the dentate gyrus (DG) is another main pathophysiological process during epilepsy contributing to increased neuronal excitotoxicity, astrogliosis and the formation of synaptic connections among mossy fibers (Jessberger et al., 2005, Parent, 2007, Curia et al., 2008). However, the mechanism underlying the abnormal neurogenesis in acute epilepsy has not been fully elucidated.