Bakuchiol Alleviates Hyperglycemia-Induced Diabetic Cardiomyopathy by Reducing Myocardial Oxidative Stress via Activating the SIRT1/Nrf2 Signaling Pathway

Abstract

Bakuchiol (BAK), a monoterpene phenol reported to have exerted a variety of pharmacological effects, has been related to multiple diseases, including myocardial ischemia reperfusion injury, pressure overload-induced cardiac hypertrophy, diabetes, liver fibrosis, and cancer. However, the effects of BAK on hyperglycemia-caused diabetic cardiomyopathy and its underlying mechanisms remain unclear. In this study, streptozotocin-induced mouse model and high-glucose-treated cell model were conducted to investigate the protective roles of BAK on diabetic cardiomyopathy, in either the presence or absence of SIRT1-specific inhibitor EX527, SIRT1 siRNA, or Nrf2 siRNA. Our data demonstrated for the first time that BAK could significantly abate diabetic cardiomyopathy by alleviating the cardiac dysfunction, ameliorating the myocardial fibrosis, mitigating the cardiac hypertrophy, and reducing the cardiomyocyte apoptosis. Furthermore, BAK achieved its antifibrotic and antihypertrophic actions by inhibiting the TGF-β1/Smad3 pathway, as well as decreasing the expressions of fibrosis- and hypertrophy-related markers. Intriguingly, these above effects of BAK were largely attributed to the remarkable activation of SIRT1/Nrf2 signaling, which eventually strengthened cardiac antioxidative capacity by elevating the antioxidant production and reducing the reactive oxygen species generation. However, all the beneficial results were markedly abolished with the administration of EX527, SIRT1 siRNA, or Nrf2 siRNA. In summary, these novel findings indicate that BAK exhibits its therapeutic properties against hyperglycemia-caused diabetic cardiomyopathy by attenuating myocardial oxidative damage via activating the SIRT1/Nrf2 signaling.

Quercetin Alleviates the Accumulation of Superoxide in Sodium Iodate-Induced Retinal Autophagy by Regulating Mitochondrial Reactive Oxygen Species Homeostasis through Enhanced Deacetyl-SOD2 via the Nrf2-PGC-1α-Sirt1 Pathway

“…This evidence pointed out that the promotion of the PGC1/Nrf2 signaling pathway accompanied by the occurrence of mitophagy was to eliminate the ROS-induced oxidative damage. However, the results were not consistent with the previous studies that proved the promotion of autophagy and the Nrf2-PGC1-Sirt1 signaling pathway accompanied by the attenuation of ROS in retinal degeneration [31,32,57]. Accumulating evidence has shown that Sirt1 plays a crucial role in cardiac protection in various cardiovascular diseases through a complex signaling network, including autophagy [58] and apoptosis [59].…”

“…PGC-1α was positively regulated by Sirt1, which is linked to autophagy [30]. Previous studies have also shown that Sirt1 can regulate mitochondrial ROS levels by deacetylating SOD2 [31]. Numerous studies have also clearly indicated that Sirt1 can exert antioxidative effects via the activation of Nrf2 [32].…”

SIRT1 is Required for Exercise-Induced Beneficial Effects on Myocardial Ischemia/Reperfusion Injury

“…Activation of the SIRT1/Nrf2 signaling pathway has been reported to promote the production of antioxidant. 39 , 40 Furthermore, regular exercise can stimulate the activation of Nrf2 to enhance the endogenous antioxidant ability to resist the destructive effect of reactive oxygen species. 20 Therefore, we explored the expression of Nrf2 and its downstream cytoprotective proteins through Western blotting.…”

NRF2-Related Epigenetic Modifications in Cardiac and Vascular Complications of Diabetes Mellitus

“…Recently, Gao et al found that long ncRNA (lncRNA) HOX transcript antisense RNA (HOTAIR) and Sirt1 were downregulated but miR-34a was upregulated in diabetic hearts and HG-stimulated H9c2 cells, while overexpression of lncRNA HOTAIR protected against DCM via increasing Sirt1 expression by sponging miR-34a (39). Furthermore, the Sirt1/NRF2 pathway was shown to play a role in improving DCM via alleviating myocardial oxidative stress (40). However, whether NRF2 can be regulated by the lncRNA HOTAIR/miR-34a/Sirt1 pathway in the treatment of DCM needs to be further explored.…”