Background Heart failure (HF) is a common cardiovascular syndrome. Tanshinone IIA (Tan IIA) is a pharmacologically active monomer that exerts a significant cardioprotective effect in the clinic; however, the specific mechanisms are not fully understood. Purpose We mainly investigated the protective effects of Tan IIA on doxorubicin (DOX)-induced HF. Methods In an in vitro study, H9C2 and HL-1 cells were cultured and treated with DOX and Tan IIA for 24 h, we investigated the mechanism underlying Tan IIA-mediated protection. In an in vivo study, a model of DOX-induced HF was established in C57BL/6 mice that were divided into the six groups randomly: a control group, a DOX group, DOX groups treated with Tan IIA (DOX+Tan IIA) at dosages of 2.5, 5 and 10 mg/kg/day and DOX groups treated with N-acetylcysteine (NAC) at dosages of 200 mg/kg/day. Result The results demonstrated that Tan IIA significantly increased cell viability and protected against DOX-induced apoptosis. RNA-sequencing showed that the genes expression associated with the apoptotic signaling pathway was altered by Tan IIA. Among the differentially expressed genes, death-domain associated protein (DAXX), which plays an critical role in apoptotic signaling, exhibited increased expression under Tan IIA treatment. In addition, RNA interference was used to silence the expression of DAXX, which abolished Tan IIA-mediated protection against DOX-induced apoptosis; this effect was associated with extracellular signal-regulated protein kinase 1/2 (ERK1/2) and mitogen-activated protein kinase (MEK) expression. In the in vivo study, the echocardiography results revealed that heart function was rescued by Tan IIA, and the histomorphology results showed that Tan IIA prevented myocardial structural alteration and myofibril disruption. Furthermore, Tan IIA induced the expressions of DAXX, p-ERK1/2 and p-MEK. Tan IIA also inhibited apoptosis by suppressing the expression of cleaved caspase-8, p-P38 and cleaved caspase-3. Conclusion Our results provide novel interpretations into the important role of DAXX in DOX-induced cardiotoxicity and show that Tan IIA may be a novel agent strategy for HF treatment via activating the DAXX/MEK/ERK1/2 pathway.
Juan Deng,Juan Qin,Guolin Song,Chenghai Li,Wentao Tang,Yilin Tang,Xinfang Xiao,Liu Wu,Sicheng He,Yiqing Zhou,Junfen Li,Yan Wang
The potential of low-intensity pulsed ultrasound (LIPUS) in regulating ovarian function has been demonstrated; however, there is a lack of scientific evidence regarding the long-term efficacy of LIPUS in treating ovarian injury and understanding its regulatory mechanisms. In this study, 4-vinylcyclohexene diepoxide (VCD) was used to induce ovarian injury in rats, and LIPUS was applied to target the damaged ovarian tissues. The research aimed to investigate the long-term protective effect of LIPUS against ovum toxicity induced by VCD and elucidate the associated molecular mechanisms. During the experiment, HE staining was employed for observing the morphology and structure of the ovary, while protein sequencing was utilized for identifying and confirming the molecular mechanism through which LIPUS restores the damaged ovarian structure. The long-term effectiveness of LIPUS in protecting against ovarian injury was evaluated through ELISA, estrous cycle monitoring, fertility testing, and behavioral analysis. The results indicated that LIPUS effectively restored the structure of damaged ovaries. Both in vivo and in vitro studies revealed that this protective effect may be attributed to LIPUS inhibiting apoptosis of ovarian granulosa cells (GCs) by regulating Daxx-mediated ASK1/JNK signaling pathway. Subsequent functional tests demonstrated significant improvements in sex hormone secretion and regulation of estrous cycle within 6 cycles following LIPUS treatment. Additionally, there was a notable increase in offspring numbers after mating. Behavioral analysis revealed that LIPUS effectively alleviated menopausal symptoms resulting from ovarian injury including mood fluctuations, cognitive behavior changes, and reduced muscle excitability levels. These findings suggest that beneficial effects of LIPUS may help reduce VCD-induced ovarian damage with long-term efficacy.
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