Myricitrin Attenuates High Glucose-Induced Apoptosis through Activating Akt-Nrf2 Signaling in H9c2 Cardiomyocytes

Zhang, Bin; Chen, Yaping; Shen, Qiang; Liu, Guiyan; Ye, Jingxue; Sun, Guibo; Sun, Xiaobo

doi:10.3390/molecules21070880

Cited by 44 publications

(31 citation statements)

References 40 publications

(53 reference statements)

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“…Western blot analysis showed that myricitrin increased the Bcl-2/Bax ratio compared with the H/R group. These data demonstrated that myricitrin effectively inhibits H/R-induced apoptosis and provides further evidence supporting its anti-apoptotic role (Qin et al, 2015;Zhang et al, 2016). Myricitrin interacts with proteins, such as PI-3 kinase, nitric oxide synthase (NOS), PKCα, and PKCε (Pereira et al, 2011;Schwanke et al, 2013;Qin et al, 2015).…”

Section: Discussionsupporting

confidence: 53%

Myricitrin Protects Cardiomyocytes from Hypoxia/Reoxygenation Injury: Involvement of Heat Shock Protein 90

Wang¹,

Sun²,

Du³

et al. 2017

Front. Pharmacol.

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Modulation of oxidative stress is therapeutically effective in ischemia/reperfusion (I/R) injury. Myricitrin, a naturally occurring phenolic compound, is a potent antioxidant. However, little is known about its effect on I/R injury to cardiac myocytes. The present study was performed to investigate the potential protective effect of myricitrin against hypoxia/reoxygenation (H/R)-induced H9c2 cardiomyocyte injury and its underlying mechanisms. Myricitrin pretreatment improved cardiomyocyte viability, inhibited ROS generation, maintained the mitochondrial membrane potential, reduced apoptotic cardiomyocytes, decreased the caspase-3 activity, upregulated antiapoptotic proteins and downregulated proapoptotic proteins during H/R injury. Moreover, the potential targets of myricitrin was predicted using Discovery Studio software, and heat shock protein 90 (Hsp90) was identified as the main disease-related target. Further mechanistic investigation revealed that 17-AAG, a pharmacologic inhibitor of Hsp90, significantly blocked the myricitrin-induced cardioprotective effect demonstrated by increased apoptosis and ROS generation. These results suggested that myricitrin provides protection to H9c2 cardiomyocytes against H/R-induced oxidative stress and apoptosis, most likely via increased expression of Hsp90.

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Section: Discussionsupporting

confidence: 53%

Myricitrin Protects Cardiomyocytes from Hypoxia/Reoxygenation Injury: Involvement of Heat Shock Protein 90

Wang¹,

Sun²,

Du³

et al. 2017

Front. Pharmacol.

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“…Our group previously found that Myr could prevent endothelial cell apoptosis by activating PI3K/Akt signaling. It was further verified in our laboratory that Myr could also suppress H9c2 cell apoptosis induced by high glucose16. In addition, Myr was reported to possess anti-inflammatory and anti-fibrotic properties17.…”

mentioning

confidence: 70%

“…Additionally, the ERK signaling pathway is reported to be involved in DCM, wherein ERK is significantly phosphorylated and inhibits Nrf2 signaling, resulting in cell hypertrophy1240. Furthermore, our previous studies have confirmed that phosphorylation of Akt regulates Nrf2 activation and HO-1 expression1641. However, the impacts of Myr on Akt and ERK signaling in the diabetic heart were unclear.…”

Section: Discussionmentioning

confidence: 96%

Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

Zhang

Shen

Chen

et al. 2017

Sci Rep

Self Cite

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Diabetic cardiomyopathy (DCM) has been increasingly considered as a main cause of heart failure and death in diabetic patients. At present, no effective treatment exists to prevent its development. In the present study, we describe the potential protective effects and mechanisms of myricitrin (Myr) on the cardiac function of streptozotosin-induced diabetic mice and on advanced glycation end products (AGEs)-induced H9c2 cardiomyocytes. In vitro experiments revealed that pretreatment with Myr significantly decreased AGEs-induced inflammatory cytokine expression, limited an increase in ROS levels, and reduced cell apoptosis, fibrosis, and hypertrophy in H9c2 cells. These effects are correlated with Nrf2 activation and NF-κB inhibition. In vivo investigation demonstrated that oral administration of Myr at 300 mg/kg/day for 8 weeks remarkably decreased the expression of enzymes associated with cardiomyopathy, as well as the expression of inflammatory cytokines and apoptotic proteins. Finally, Myr improved diastolic dysfunction and attenuated histological abnormalities. Mechanistically, Myr attenuated diabetes-induced Nrf2 inhibition via the regulation of Akt and ERK phosphorylation in the diabetic heart. Collectively, these results strongly indicate that Myr exerts cardioprotective effects against DCM through the blockage of inflammation, oxidative stress, and apoptosis. This suggests that Myr might be a potential therapeutic agent for the treatment of DCM.

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“…Several transcription factors are involved in the regulation of bile acid transporter expression (Jansen, 2018;Jigorel et al, 2006;Tanaka et al, 2009;Trauner et al, 2017;Weerachayaphorn et al, 2009;Weerachayaphorn et al, 2012;Zollner et al, 2010). One of these, nuclear factor-E2-related factor 2 (Nrf2), is activated by rapamycin (Klempner et al, 2013;Yao et al, 2016;Zhang et al, 2016a;Zhang et al, 2016b). To evaluate the possible role of Nrf2 in the mechanism by which rapamycin alters the expression of bile acid transporters, we compared the actions of rapamycin on H4IIE cells with those of oltipraz, an established activator of Nrf2 (Weerachayaphorn et al, 2009).…”

Section: Effects Of Rapamycin On the Expression Of Mrna Encoding Bilementioning

confidence: 99%

Evidence that decreased expression of sinusoidal bile acid transporters accounts for the inhibition by rapamycin of bile flow recovery following liver ischemia

Afroz

Jonkman

Jin

et al. 2018

European Journal of Pharmacology

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Rapamycin is employed as an immunosuppressant following organ transplant and, in patients with hepatocellular carcinoma, to inhibit cancer cell regrowth following liver surgery. Preconditioning the liver with rapamycin to induce the expression of antioxidant enzymes is a potential strategy to reduce ischemia reperfusion (IR) injury. However, pre-treatment with rapamycin inhibits bile flow, especially following ischemia. The aim was to investigate the mechanisms involved in this inhibition. In a rat model of segmental hepatic ischemia and reperfusion, acute administration of rapamycin by intravenous injection did not inhibit the basal rate of bile flow. Pre-treatment of rats with rapamycin for 24 h by intraperitoneal injection inhibited the expression of mRNA encoding the sinusoidal influx transporters Ntcp, Oatp1 and 2 and the canalicular efflux transporter Bsep, and increased expression of canalicular Mrp2. Dose-response curves for the actions of rapamycin on the expression of Bsep and Ntcp in cultured rat hepatocytes were biphasic, and monophasic for effects on Oatp1. In cultured tumorigenic H4IIE liver cells, several bile acid transporters were not expressed, or were expressed at very low levels compared to hepatocytes. In H4IIE cells, rapamycin increased expression of Ntcp, Oatp1 and Mrp2, but decreased expression of Oatp2. It is concluded that the inhibition of bile flow recovery following ischemia observed in rapamycin-treated livers is principally due to inhibition of the expression of sinusoidal bile acid transporters. Moreover, in tumorigenic liver tissue the contribution of tumorigenic hepatocytes to total liver bile flow is likely to be small and is unlikely to be greatly affected by rapamycin.

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Myricitrin Attenuates High Glucose-Induced Apoptosis through Activating Akt-Nrf2 Signaling in H9c2 Cardiomyocytes

Cited by 44 publications

References 40 publications

Myricitrin Protects Cardiomyocytes from Hypoxia/Reoxygenation Injury: Involvement of Heat Shock Protein 90

Myricitrin Protects Cardiomyocytes from Hypoxia/Reoxygenation Injury: Involvement of Heat Shock Protein 90

Myricitrin Alleviates Oxidative Stress-induced Inflammation and Apoptosis and Protects Mice against Diabetic Cardiomyopathy

Evidence that decreased expression of sinusoidal bile acid transporters accounts for the inhibition by rapamycin of bile flow recovery following liver ischemia

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