Clinical use of the anti-cancer drug doxorubicin (DOX) is largely limited due to its severe cardiotoxicity. Dysregulation of autophagy is implicated in DOX-induced cardiotoxicity (DIC). Prior studies have indicated that Beclin1 and lysosomal-associated membrane proteins-1 (LAMP1) are critical mediators of autophagy. In this work, by assessing autophagic flux in a DOX-stimulated H9C2 model, we observed autolysosome accumulation caused by interruption of autolysosome degradation. Tanshinone IIA (TSA) is a well-known small molecule that exerts impressive cardioprotective effects on heart failure. Here, we investigated the regulation of TSA in DOX-treated zebrafish, mice, and H9C2 models. Results demonstrated that TSA remarkably improved heart function and reversed pathological changes in vivo, while TSA restored autophagic flux by promoting autolysosome degradation and autophagosome formation. Further experiments demonstrated that these effects were mediated through upregulation of Beclin1 and LAMP1. The mTOR agonist MHY1485 was shown to abrogate the effect of TSA via the UNC-51-like kinase 1 (ULK1)-Beclin1/TFEB-LAMP1 signaling pathway in vitro, demonstrating that TSA protects against DIC by promoting autophagy via the Beclin1/LAMP1 signaling pathway. We further employed a U87 model to assess whether TSA would compromise the antitumor activity of DOX. Intriguingly, the co-treatment of TSA was able to synergistically inhibit proliferative activity. Collectively, in this study we uncover the novel insight that TSA is able to reduce the cardiotoxicity of DOX without compromising antitumor activity.

Atherosclerosis is a chronic and complex disease caused by lipid disorder, inflammation, and other factors. It is closely related to cardiovascular diseases, the chief cause of death globally. Peroxisome proliferator-activated receptors (PPARs) are valuable anti-atherosclerosis targets that showcase multiple roles at different pathological stages of atherosclerosis and for cell types at different tissue sites. Considering the spatial and temporal characteristics of the pathological evolution of atherosclerosis, the roles and pharmacological and clinical studies of PPARs were summarized systematically and updated under different pathological stages and in different vascular cells of atherosclerosis. Moreover, selective PPAR modulators and PPAR-pan agonists can exert their synergistic effects meanwhile reducing the side effects, thereby providing novel insight into future drug development for precise spatial-temporal therapeutic strategy of anti-atherosclerosis targeting PPARs. Key Scientific Concepts of Review: Based on the spatial and temporal characteristics of atherosclerosis, we have proposed the importance of stage- and cell type-dependent precision therapy. Initially, PPARs improve endothelial cells' dysfunction by inhibiting inflammation and oxidative stress and then regulate macrophages' lipid metabolism and polarization to improve fatty streak. Finally, PPARs reduce fibrous cap formation by suppressing the proliferation and migration of vascular smooth muscle cells (VSMCs). Therefore, research on the cell type-specific mechanisms of PPARs can provide the foundation for space-time drug treatment. Moreover, pharmacological studies have demonstrated that several drugs or compounds can exert their effects by the activation of PPARs. Selective PPAR modulators (that specifically activate gene subsets of PPARs) can exert tissue and cell-specific effects. Furthermore, the dual- or pan-PPAR agonist could perform a better role in balancing efficacy and side effects. Therefore, research on cells/tissue-specific activation of PPARs and PPAR-pan agonists can provide the basis for precision therapy and drug development of PPARs.

Retinoid X receptors (RXRs) are members of ligand-dependent transcription factors whose effects on a diversity of cellular processes, including cellular proliferation, the immune response, and lipid and glucose metabolism. Knock out of RXRα causes a hypoplasia of the myocardium which is lethal during fetal life. In addition, the heart maintains a well-orchestrated balances in utilizing fatty acids (FAs) and other substrates to meet the high energy requirements. As the master transcriptional regulators of lipid metabolism, RXRs become particularly important for the energy needs of the heart. Accumulating evidence suggested that RXRs may exert direct beneficial effects in the heart both through heterodimerization with other nuclear receptors (NRs) and homodimerization, thus standing as suitable targets for treating in cardiovascular diseases. Although compounds that target RXRs are promising drugs, their use is limited by toxicity. A better understanding of the structural biology of RXRs in cardiovascular disease should enable the rational design of more selective nuclear receptor modulators to overcome these problems. Here, this review summarizes a brief overview of RXRs structure and versatility of RXR action in the control of cardiovascular diseases. And we also discussed the therapeutic potential of RXR ligand.

Background: Gamabufotalin (Ga) is a primary bioactive bufadienolide extracted from Venenum Bufonis. It has been identified to exert anti-fibrotic and anti-inflammatory properties; however, its anti-fibrotic effect and underlying mechanism in heart failure (HF) remain undetermined.Purpose: This study aimed to evaluate the cardioprotective and anti-fibrotic properties of Ga in LADL-induced HF rats and isoproterenol (ISO)-induced HF mice. Furthermore, the molecular target and signaling mechanisms associated with Ga were investigated.Methods: In vivo cardiac function and fibrosis rate were assessed by echocardiography, histopathology, and Western blotting. For in vitro analysis, primary cardiac fibroblasts (CFs) were first stimulated with TGF-β1 and then evaluated for proliferation and migration using CCK-8, EdU, wound healing, and Transwell assays. Molecular docking and rescue assays were carried out using the TGFBR1 agonist SRI. Moreover, a Smad2/3 nuclear translocation assay was performed to identify the key target and mechanism.Results: The data revealed that Ga significantly improved cardiac function, alleviated myocardial hypertrophy and fibrosis, and inhibited activation of TGFBR1/Smad signaling in two HF models. In vitro, Ga (20 nM) inhibited TGF-β1-induced CF proliferation and migration, decreased Smad2/3 phosphorylation and nuclear translocation, and downregulated fibrotic markers. Ga directly targeted TGFBR1, whereas its anti-fibrotic effects were reversed by SRI-mediated TGFBR1 activation.Conclusion: This study revealed that Ga alleviates myocardial fibrosis and improves heart function by directly suppressing TGFBR1 and blocking downstream Smad2/3 signaling. These results suggest that Ga could serve as an anti-fibrotic agent for HF and provide pharmacological evidence for the modern application of toad venom–derived compounds.