Alizarin attenuates oxidative stress-induced mitochondrial damage in vascular dementia rats by promoting TRPM2 ubiquitination and proteasomal degradation via Smurf2.

BACKGROUND: Alizarin (AZ) is a natural anthraquinone with anti-inflammatory and moderate antioxidant properties. PURPOSE: In this study, we characterized the role of AZ in a rat model of vascular dementia (VaD) and explored its underlying mechanisms. METHODS: VaD was induced by bilateral common carotid artery occlusion. RESULTS: We found that AZ attenuated oxidative stress and improved mitochondrial structure and function in VaD rats, which led to the improvement of their learning and memory function. Mechanistically, AZ reduced transient receptor potential melastatin 2 (TRPM2) expression and activation of the Janus-kinase and signal transducer activator of transcription (JAK-STAT) pathway in VaD rats. In particular, the reduction in the expression of TRPM2 channels was the key to the attenuation of the oxidative stress-induced mitochondrial damage, which may be achieved by increasing the expression of the E3 ubiquitin ligase, Smad-ubiquitination regulatory factor 2 (Smurf2); thereby increasing the ubiquitination and degradation levels of TRPM2. CONCLUSION: Our results suggest that AZ is an effective candidate drug for ameliorating VaD and provide new insights into the current clinical treatment of VaD.

Perillaldehyde improves diabetic cardiomyopathy by upregulating miR-133a-3p to regulate GSK-3ß.

Diabetic cardiomyopathy (DCM) is part of the most important causes of death from cardiovascular disease. Perillaldehyde (PAE), a major component of the herb perilla, has been shown to ameliorate doxorubicin-induced cardiotoxicity, but it is unclear whether PAE exerts beneficial effects on DCM. Exploring the potential molecular mechanisms of PAE for the treatment of DCM through network pharmacology and molecular docking. The SD rat type 1 diabetes model was established by a single intraperitoneal injection of streptozotocin (60 mg/kg), the cardiac function indexes of each group were detected by echocardiography; the morphological changes, apoptosis, protein expression of P-GSK-3ß (S9), collagen I (Col-Ⅰ), collagen III (Col-Ⅲ) and alpha-smooth muscle actin (α-SMA), and miR-133a-3p expression levels were detected. An DCM model of H9c2 cells was established in vitro and transfected with Mimic and Inhibitor of miR-133a-3p. The results showed that PAE ameliorated cardiac dysfunction, reduced fasting glucose and cardiac weight index, and improved myocardial injury and apoptosis in DCM rats. It reduced high glucose-induced apoptosis, promoted migration and improved mitochondrial division injury in H9c2 cells. PAE decreased P-GSK-3ß (S9), Col-Ⅰ, Col-Ⅲ and α-SMA protein expression and upregulated miR-133a-3p expression levels. After miR-133a-3p Inhibitor treatment, the expression of P-GSK-3ß (S9) and α-SMA expression were significantly increased; after miR-133a-3p Mimic treatment, the expression of P-GSK-3ß (S9) and α-SMA decreased significantly in H9c2 cells. It suggests that the mechanism of action of PAE to improve DCM may be related to the upregulation of miR-133a-3p and inhibition of P-GSK-3ß expression.