Xanthohumol Analogues And Magnolol Alleviate Oxidative Stress-mediated Injuries Of PC12 Cells

Reactive oxygen species(ROS)are produced from various physiological processes and have been proven to be essential messenger molecules involved in diverse signaling pathways.However,massive accumulation of ROS resulting from the imbalance between ROS formation and elimination leads to oxidative stress,which has been entangled in neurodegenerative disorders.The nuclear factor erythroid 2-related factor 2(Nrf2),a master transfaction factor controlling a series of cytoprotective genes,is closely associated with scavenging the reactive oxygen species and maintaining the intracellular redox balance.Accumulating evidence has indicated that activation of Nrf2 is efficient to block or retard oxidative stress-mediated neurodegenerative disorders.Small molecules that contribute directly or indirectly to the Nrf2 activation thus are promising therapeutic agents.Based on the regulation of intracellular redox,we devoted to discover and screen small molecules with neuroprotection.Furthermore,the underlying molecular mechanism was explored.Our studies would establish experimental and theoretical basis for the development of effective neuroprotective agents.The main content of this thesis was summarized as follows:1.A brief of Kelch-like ECH-associated protein 1(Keap1)-Nrf2-antioxidant response elements(ARE)signaling pathway was displayed in Chapter 1.The diseases involved in Nrf2 and progress in the development of Nrf2 activators were also summarized.2.Based on previous studies on xanthohumol,we screened xanthohumol analogues and two analogues(11 and 12)were disclosed to possess low cytotoxicity and rescue PC12 cells from the hydrogen peroxide-or 6-hydroxydopamine-induced injury.Molecular mechanism studies demonstrated that compounds 11 and 12 are potent Nrf2 activators by promoting the nuclear accumulation of Nrf2 and enhancing the cellular antioxidant defense system.More importantly,genetically silencing the Nrf2 expression shut down the observed cytoprotection conferred by both compounds,supporting the critical involvement of Nrf2 for the cellular actions of the compounds 11 and 12.In addition,the structure-activity relationship disclosed here will provide guidance for the development of xanthohumol analogues.3.Magnolol,a naturally occurring substance isolated from the bark of the Magnolia officinalis(the traditional Chinese medicine known as houpo),possesses abundant pharmacological functions.Our study demonstrated that magnolol upregulated the expression of ARE-driven target genes against hydrogen peroxide-or 6-hydroxydopamine-induced neurotoxicity by activating Nrf2.More importantly,our results have deepened the insight of molecular mechanisms of magnolol neuroprotection,suggesting that magnolol could be a potential neuroprotective agent for the prevention and treatment of neurodegenerative diseases.