Danthron (Dantron)

Danthron attenuates experimental atherosclerosis by targeting foam cell formation

Exp Physiol 2021 Mar;106(3):653-662.33450102 10.1113/EP089021

New findings: What is the central question of this study? Does Danthron alleviate experimental atherosclerosis by inhibiting the formation of foam cells? What are the main findings and their importance? Danthron improved serum lipid profiles and significantly reduced the atherosclerotic plaque areas and lipid accumulation in the aortic root of ApoE-/- mice. Danthron inhibited foam cell formation in oxidized low-density lipoprotein-induced RAW264.7 macrophages. Furthermore, Danthron exerted its function in atherosclerosis at least partly through activating the AMP-activated protein kinase-sirtuin 1 signalling pathway. These findings suggest that Danthron has the potential to alleviate atherosclerosis. Abstract: Danthron, an ingredient isolated from Rheum palmatum L., has been revealed to reduce lipid accumulation in vitro. This study aimed to discover the effects of Danthron on the development of atherosclerosis and to delineate the underlying mechanisms. For in vivo studies, male ApoE-/- mice were fed a high-fat diet and orally treated with Danthron (30 or 60 mg/kg/day) for 12 weeks. For in vitro studies, RAW264.7 cells were induced by oxidized low-density lipoprotein (ox-LDL, 50 μg/ml) for 48 h and subsequently administered Danthron at appropriate concentrations for 24 h. AMP-activated protein kinase (AMPK) inhibitor compound C was added to ox-LDL-stimulated RAW264.7 cells 2 h before Danthron administration to confirm the role of the AMPK signalling pathway in the regulation by Danthron of foam cell formation. We found that Danthron improved serum lipid profiles, and significantly reduced atherosclerotic plaque areas and lipid accumulation in the aortic root of atherosclerotic mice. Moreover, Danthron upregulated the mRNA and protein expression of ATP-binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor α (LXRα), which play a crucial role in lipid metabolism, and activated the AMPK-sirtuin 1 (SIRT1) pathway. In an in vitro study, Danthron inhibited foam cell formation in ox-LDL-induced RAW264.7 macrophages with an increase in the expression of ABCA1, ABCG1 and LXRα as well as activation of the AMPK-SIRT1 pathway. Furthermore, compound C abolished the effects of Danthron on lipid accumulation and the protein expression of ABCA1/G1 and LXRα in vitro. Our results highlight that Danthron possesses potential benefits in alleviating experimental atherosclerosis by targeting foam cell formation by activating the AMPK-SIRT1 signalling pathway.

Danthron suppresses autophagy and sensitizes pancreatic cancer cells to doxorubicin

Toxicol In Vitro 2019 Feb;54:345-353.30389604 10.1016/j.tiv.2018.10.019

In contrast to the steady increase in survival observed for most cancer types, advances have been slow for pancreatic cancers. Current chemotherapy has limited benefits for patients with pancreatic cancer. Therefore, there is an urgent need for effective pancreatic cancer treatment strategies. At present, targeting the autophagic pathway is regarded as a promising new strategy for cancer treatment. Danthron (1,8-dihydroxyanthrquinone), a component from Rheum palmatum L. (polygonaceae), has several biological activities. However, the inhibition of autophagy by Danthron has never been recognized, previously.Here we find that Danthron may prevent autophagy, inhibit proliferation and induce apoptosis in pancreatic cancer cells in vitro. Autophagy induced by doxorubicin plays a protective role in pancreatic cancer cells and inhibition of autophagy by chloroquine or silencing autophagy protein 5 (Atg5) may chemosensitize pancreatic cancer cell lines to doxorubicin. Similarly, inhibition of autophagy by Danthron also enhances toxicity of doxorubicin to pancreatic cancer cells. These results indicate that Danthron has an anticancer effect and can sensitize the chemotherapeutic effect of doxorubicin on pancreatic cancer cells. These findings also suggest that inhibition of autophagy may be an effective way to promote the chemotherapy of pancreatic cancer.

Danthron ameliorates obesity and MAFLD through activating the interplay between PPARα/RXRα heterodimer and adiponectin receptor 2

Biomed Pharmacother 2021 May;137:111344.33581653 10.1016/j.biopha.2021.111344

Obesity and associated metabolic associated fatty liver diseases (MAFLD) are strongly associated with dysfunction of glucose and lipid metabolism. AMPKα and PPARα are key regulators in the lipid and glucose homeostasis, indicating that novel agents to activate them are promising therapeutic approaches for metabolic syndrome. Noticeably, as a natural anthraquinone derivative extracted from rhubarb, Danthron can activate AMPKα in vitro. However, the protective effect of Danthron on obesity and associated MAFLD in vivo, as well as the underlying mechanism remains unknown. In this study, obesity and associated MAFLD was induced in C57BL/6J mice by high fat diet (HFD), which were subjected to evaluations on the parameters of systematic metabolism. Simultaneously, the molecular mechanism of Danthron on lipid metabolism was investigated in 3T3-L1-derived adipocytes and HepG2 cells in vitro. In vivo, Danthron significantly attenuated the obesity and MAFLD by enhancing hepatic fatty acid oxidation, decreasing lipid synthesis, and promoting mitochondrial homeostasis. Mechanistically, Danthron significantly promoted combination of RXRα and PPARα, enhanced the binding of RXRα/PPARα heterodimer to the promoter of adiponectin receptor 2 (AdipoR2), by which activating the AMPKα and PPARα pathway. Moreover, PPARα and AdipoR2 can interplay in a loop style. Collectively, this study demonstrates that Danthron can substantially ameliorate obesity and associated hepatic steatosis via AdipoR2-mediated dual PPARα/AMPKα activation, which suggests that Danthron might be a novel therapeutic approach for inhibition of obesity and hepatic steatosis.

Danthron

Rep Carcinog 2011;12:128-9.21850139

Danthron activates AMP-activated protein kinase and regulates lipid and glucose metabolism in vitro

Acta Pharmacol Sin 2013 Aug;34(8):1061-9.23770982 PMC4003022

Aim: To discover the active compound on AMP-activated protein kinase (AMPK) activation and investigate the effects of the active compound 1,8-dihydroxyanthraquinone (Danthron) from the traditional Chinese medicine rhubarb on AMPK-mediated lipid and glucose metabolism in vitro. Methods: HepG2 and C2C12 cells were used. Cell viability was determined using MTT assay. Real-time PCR was performed to measure the gene expression. Western blotting assay was applied to investigate the protein phosphorylation level. Enzymatic assay kits were used to detect the total cholesterol (TC), triglyceride (TG) and glucose contents. Results: Danthron (0.1, 1, and 10 μmol/L) dose-dependently promoted the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC) in both HepG2 and C2C12 cells. Meanwhile, Danthron treatment significantly reduced the lipid synthesis related sterol regulatory element-binding protein 1c (SREBP1c) and fatty acid synthetase (FAS) gene expressions, and the TC and TG levels. In addition, Danthron treatment efficiently increased glucose consumption. The actions of Danthron on lipid and glucose metabolism were abolished or reversed by co-treatment with the AMPK inhibitor compound C. Conclusion: Danthron effectively reduces intracellular lipid contents and enhanced glucose consumption in vitro via activation of AMPK signaling pathway.