Weixin Li1, Mingchai Wu2, Longguang Tang3, Yong Pan3, Zhiguo Liu3, Chunlai Zeng4, Jingying Wang3, Tiemin Wei5, Guang Liang6. 1. Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China; Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. 2. Department of Pharmacy, The Third Affiliated Hospital of Wenzhou Medical University, Wenzou, Zhejiang, China. 3. Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. 4. Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China. 5. Department of Cardiology, The 5th Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang, China. Electronic address: lswtm@sina.com. 6. Chemical Biology Research Center, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, China. Electronic address: wzmcliangguang@163.com.
Abstract
BACKGROUND: Alleviating the oxidant stress associated with myocardial ischemia reperfusion has been demonstrated as a potential therapeutic approach to limit ischemia reperfusion (I/R)-induced cardiac damage. Curcumin, a natural compound with anti-oxidative activity, exerts beneficial effect against cardiac I/R injury, but poor chemical and metabolic stability. Previously, we have designed and synthesized a series of mono-carbonyl analogues of curcumin (MACs) with high stability. This study aims to find new anti-oxidant MACs and to demonstrate their effects and mechanisms against I/R-induced heart injury. METHODS: H9c2 cells challenged with H2O2 or TBHP were used for in vitro bio-screening and mechanistic studies. The MDA, H2O2 and SOD levels in H9C2 cells were determined, and the cell viability was assessed by MTT assay. Myocardial I/R mouse models administrated with or without the compound were used for in vivo studies. RESULTS: The in vitro cell-based screening showed that curcumin analogues 8d and 14p exhibited strong anti-oxidative effects. Pre-treatment of H9c2 cells with 14p activated Nrf2 signaling pathway, attenuated H2O2-increased MDA and SOD level, followed by the inhibition of TBHP-induced cell death and Bax/Bcl-2-caspase-3 pathway activation. Silencing Nrf2 significantly reversed the protective effects of 14p. In in vivo animal model of myocardial I/R, administration of low dose 14p (10mg/kg) reduced infarct size and myocardial apoptosis to the same extent as the high dose curcumin (100mg/kg). CONCLUSION: These data support the novel curcumin analogue 14p as a promising antioxidant to decrease oxidative stress and limit myocardial ischemia reperfusion injury via activating Nrf2.
BACKGROUND: Alleviating the oxidant stress associated with myocardial ischemia reperfusion has been demonstrated as a potential therapeutic approach to limit ischemia reperfusion (I/R)-induced cardiac damage. Curcumin, a natural compound with anti-oxidative activity, exerts beneficial effect against cardiac I/R injury, but poor chemical and metabolic stability. Previously, we have designed and synthesized a series of mono-carbonyl analogues of curcumin (MACs) with high stability. This study aims to find new anti-oxidant MACs and to demonstrate their effects and mechanisms against I/R-induced heart injury. METHODS: H9c2 cells challenged with H2O2 or TBHP were used for in vitro bio-screening and mechanistic studies. The MDA, H2O2 and SOD levels in H9C2 cells were determined, and the cell viability was assessed by MTT assay. Myocardial I/R mouse models administrated with or without the compound were used for in vivo studies. RESULTS: The in vitro cell-based screening showed that curcumin analogues 8d and 14p exhibited strong anti-oxidative effects. Pre-treatment of H9c2 cells with 14p activated Nrf2 signaling pathway, attenuated H2O2-increased MDA and SOD level, followed by the inhibition of TBHP-induced cell death and Bax/Bcl-2-caspase-3 pathway activation. Silencing Nrf2 significantly reversed the protective effects of 14p. In in vivo animal model of myocardial I/R, administration of low dose 14p (10mg/kg) reduced infarct size and myocardial apoptosis to the same extent as the high dose curcumin (100mg/kg). CONCLUSION: These data support the novel curcumin analogue 14p as a promising antioxidant to decrease oxidative stress and limit myocardial ischemia reperfusion injury via activating Nrf2.
Authors: Johant Lakey-Beitia; Andrea M Burillo; Giovanni La Penna; Muralidhar L Hegde; K S Rao Journal: J Alzheimers Dis Date: 2021 Impact factor: 4.472