Protective effect of alizarin on vascular endothelial dysfunction via inhibiting the type 2 diabetes-induced synthesis of THBS1 and activating the AMPK signaling pathway.

BACKGROUND: In this study, we investigated the protective effects of alizarin (AZ) on endothelial dysfunction (ED). AZ has inhibition of the type 2 diabetes mellitus (T2DM)-induced synthesis of thrombospondin 1 (THBS1). Adenosine 5'-monophosphate- activated protein kinase (AMPK), particularly AMPKα2 isoform, plays a critical role in maintaining cardiac homeostasis. PURPOSE: The aim of this study was to investigate the ameliorative effect of AZ on vascular injury caused by T2DM and to reveal the potential mechanism of AZ in high glucose (HG)-stimulated human umbilical vein endothelial cells (HUVECs) and diabetic model rats. STUDY DESIGN: HUVECs, rats and AMPK-/- transgenic mice were used to investigate the mitigating effects of AZ on vascular endothelial dysfunction caused by T2DM and its in vitro and in vivo molecular mechanisms. METHODS: In type 2 diabetes mellitus rats and HUVECs, the inhibitory effect of alizarin on THBS1 synthesis was verified by immunohistochemistry (IHC), immunofluorescence (IF) and Western blot (WB) so that increase endothelial nitric oxide synthase (eNOS) content in vitro and in vivo. In addition, we verified protein interactions with immunoprecipitation (IP). To probe the mechanism, we also performed AMPKα2 transfection. AMPK's pivotal role in AZ-mediated prevention against T2DM-induced vascular endothelial dysfunction was tested using AMPKα2-/- mice. RESULTS: We first demonstrated that THBS1 and AMPK are targets of AZ. In T2DM, THBS1 was robustly induced by high glucose and inhibited by AZ. Furthermore, AZ activates the AMPK signaling pathway, and recoupled eNOS in stressed endothelial cells which plays a protective role in vascular endothelial dysfunction. CONCLUSIONS: The main finding of this study is that AZ can play a role in different pathways of vascular injury due to T2DM. Mechanistically, alizarin inhibits the increase in THBS1 protein synthesis after high glucose induction and activates AMPKα2, which increases NO release from eNOS, which is essential in the prevention of vascular endothelial dysfunction caused by T2DM.

PAE ameliorates doxorubicin-induced cardiotoxicity via suppressing NHE1 phosphorylation and stimulating PI3K/AKT phosphorylation.

Doxorubicin (DOX), a broad-spectrum anti-tumor drug, has severe cardiotoxic side effects that limit its clinical application. Perillaldehyde (PAE) is the main component of volatile oil extracted from the stems and leaves of Herbaceous plant-perilla, which demonstrates antioxidant, anti-inflammatory, hypolipidemic, and other health functions. The present study aimed to explore the protective effect of perillaldehyde on DOX-induced cardiotoxicity in rats and to confirm its possible mechanism. The results showed that PAE could significantly improve cardiac function, alleviate myocardial fibrosis, and attenuate oxidative stress and inflammatory responses in DOX-induced cardiotoxicity in rats. Mechanistically, PAE could DOX-induced cardiotoxicity, which is related to its regulation of the PI3K/Akt signaling pathway and inhibition of NHE1 phosphorylation. Therefore, the finding demonstrates that perillaldehyde may be a promising cardioprotective agent for the prevention and treatment of cardiotoxicity caused by DOX.