Discovery of cinnamamide-barbiturate hybrids as a novel class of Nrf2 activator against myocardial ischemia/reperfusion injury

Wei, Bo; Zhang, Ji; Li, Nannan; Yang, Longhua; Xu, Xue-Li; Shi, Yangyang; Liu, Shaohui; Chen, Yajing

doi:10.1016/j.bioorg.2022.105828

Cited by 6 publications

(1 citation statement)

References 27 publications

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“…Studies have discovered that cinnamamide-barbituric acid derivatives exhibit high antioxidant activities, excellent free radical scavenging activity, and considerable protective benefits against H2O2 induced injury in HTT2 cells (Chen et al, 2017). Based on the above research, our group previously combined trans-and cis-cinnamamide to produce cinnamamide derivative intermediate A with good antioxidant property, which could further convert to cinnamamide-barbituric acid derivative 7w after nuclear fusion cyclization of barbituric acid with strong cardioprotective activity, as demonstrated by increased cell viability in cardiomyocytes subjected to H2O2 and improved cardiac function in MIR rats (Wei et al, 2022). 17 cinnamamide-barbituric acid derivatives were optimized and synthesized on the basis of compound 7w.…”

Section: Introductionmentioning

confidence: 99%

Cardioprotective effect of Cinnamamide derivative compound 10 against myocardial ischemia-reperfusion through regulating cardiac autophagy via Sirt1

Xue,

Liu,

et al. 2023

Preprint

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Background and Purpose: Our previous research discovered that cinnamamide derivatives are a new type of potential cardioprotective agents myocardial ischemia-reperfusion (MIR) injury, among which Compound 10 exhibits wonderful beneficial action in vitro. However, the exact mechanism of Compound 10 still needs to be elucidated. Experimental Approach: The protective effect of Compound 10 was determined by detecting the cell viability and LDH leakage rate in H9c2 cells subjected to H2O2. Alterations of electrocardiogram, echocardiography, cardiac infarct area, histopathology and serum myocardial zymogram were tested in MIR rats. Additionally, the potential mechanism of Compound 10 was explored through PCR. Network pharmacology and Western blotting was conducted to monitor levels of proteins related to autophagic flux and mTOR, autophagy regulatory substrate, induced by Compound 10 both in vitro and in vivo, as well as expressions of Sirtuins family members. Key Results: Compound 10 significantly ameliorated myocardial injury, as demonstrated by increased cell viability, decreased LDH leakage in vitro, and declined serum myocardial zymogram, ST elevation, cardiac infarct area and improved cardiac function and microstructure of heart tissue in vivo. Importantly, Compound 10 markedly enhanced the obstruction of autophagic flux and inhibited excessive autophagy initiation against MIR by decreased P-mTOR and increased LAMP2. Furthermore, Sirt1 knockdown hindered Compound 10’s regulation on mTOR, leading to interrupted cardiac autophagic flux. Conclusions and Implications: Compound 10 exerted cardioprotective effects on MIR by reducing excessive autophagy and improving autophgic flux blockage. Our work would take a novel insight in seeking effective prevention and treatment strategies against MIR injury. Keywords: Myocardial ischemia-reperfusion; Cinnamamide derivatives; Autophagic flux; Sirt1; mTOR;

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Section: Introductionmentioning

confidence: 99%