Cardiac sirtuin1 deficiency exacerbates ferroptosis in doxorubicin-induced cardiac injury through the Nrf2/Keap1 pathway.

Doxorubicin (DOX), a broad-spectrum chemotherapeutic agent for various cancers, has limited clinical application because of its serious cardiotoxicity, which is due to different mechanisms, including cardiac ferroptosis and oxidative stress. Some drugs, such as berberine or dioscin, show efficacy in impeding DOX-induced cardiotoxicity by activating Sirtuin 1 (Sirt1). However, there is no direct evidence to clarify the role of Sirt1 in DOX-induced cardiomyopathy and its underlying role in cardiac ferroptosis. In this study, C57BL/6 and cardiac-specific Sirt1-/- knockout mice were used as a DOX-induced cardiotoxicity model. We found that cardiac Sirt1 was downregulated, oxidative stress was increased and ferroptosis were obviously enhanced, as reflected by decreased Glutathione peroxidase 4 (GPX4) and increased Heme oxygenase 1 (Hmox-1), exposure to DOX treatment in mice and H9c2 cells compared with the control. And Sirt1 activation was resistant to cardiac injury induced by DOX, as observed the improvement of cardiac dysfunction, and the reduction of cardiac fibrosis. However, cardiac Sirt1 deficiency aggravated Dox-induced cardiac dysfunction and cardiac remodeling, further downregulated GPX4, upregulated Hmox-1 expression and increased ROS level. In addition, Sirt1-siRNA exacerbated DOX-induced cardiotoxicity in H9c2 cells, which is similar to the results obtained in vivo. Furthermore, DOX decrease Nrf2 translocation from the cytosol to the nucleus, and Sirt1 deficiency further restrain the process, as well as the downstream Keap1 pathways, in DOX-induced cardiotoxicity. This study provides direct evidence that Sirt1 plays a protective role in DOX-induced cardiotoxicity by mediating ferroptosis reduction via the Nrf2/Keap1 pathway.

Di-n-hexyl phthalate causes Leydig cell hyperplasia in rats during puberty.

Di-n-hexyl phthalate (DNHP) is commonly used as a plasticizer. However, whether DNHP influences Leydig cell development during puberty remains unexplored. In this study, DNHP (0, 10, 100, and 1000 mg/kg) was administered via gavage to 35-day-old male Sprague-Dawley rats for 21 days. Serum levels of testosterone, luteinizing hormone, follicle-stimulating hormone, Leydig cell number, the expression of Leydig and Sertoli cell genes and proteins were investigated. DNHP significantly increased serum testosterone levels at 10 mg/kg but lowered its level at 1000 mg/kg. DNHP significantly increased luteinizing hormone levels at 1000 mg/kg without affecting follicle-stimulating hormone levels. DNHP increased Leydig cell number at all doses but down-regulated the expression of Lhcgr, Hsd3b1, Hsd17b3, and Hsd11b1 in Leydig cell per se at 1000 mg/kg. DNHP elevated phosphorylation of ERK1/2 and GSK-3ß at 10 mg/kg but decreased SIRT1 and PGC-1α levels at 1000 mg/kg. In conclusion, DNHP exposure causes Leydig cell hyperplasia possibly via stimulating phosphorylation of ERK1/2 and GSK-3ß signaling pathways.