Targeting OGF/OGFR signal to mitigate doxorubicin-induced cardiotoxicity.

Enkephalins are reportedly correlated with heart function. However, their regulation in the heart remains unexplored. This study revealed a substantial increase in circulating levels of opioid growth factor (OGF) (also known as methionine enkephalin) and myocardial expression levels of both OGF and its receptor (OGFR) in subjects treated with doxorubicin (Dox). Silencing OGFR through gene knockout or using adeno-associated virus serotype 9 carrying small hairpin RNA effectively alleviated Dox-induced cardiotoxicity (DIC) in mice. Conversely, OGF supplementation exacerbated DIC manifestations, which could be abolished by administration of the OGFR antagonist naltrexone (NTX). Mechanistically, the previously characterized OGF/OGFR/P21 axis was identified to facilitate DIC-related cardiomyocyte apoptosis. Additionally, OGFR was observed to dissociate STAT1 from the promoters of ferritin genes (FTH and FTL), thereby repressing their transcription and exacerbating DIC-related cardiomyocyte ferroptosis. To circumvent the compromised therapeutic effects of Dox on tumors owing to OGFR blockade, SiO2-based modifiable lipid nanoparticles were developed for heart-targeted delivery of NTX. The pretreatment of tumor-bearing mice with the assembled NTX nanodrug successfully provided cardioprotection against Dox toxicity without affecting Dox therapy in tumors. Taken together, this study provides a novel understanding of Dox cardiotoxicity and sheds light on the development of cardioprotectants for patients with tumors receiving Dox treatment.

Estrogen-induced Tgfbr1 and Bmpr1a Expression Repressed via Estrogen Receptor Beta in MC3T3-E1 Cells.

BACKGROUND: Estrogen, as an important hormone in human physiological process, is closely related to bone metabolism. The aim of this study was to investigate the mechanism of estrogen on osteoblasts metabolism in MC3T3-E1 cells. METHODS: We treated the MC3T3-E1 cells with different concentrations of ß-estradiol (0.01, 0.1, 1, and 10 nmol/L), observed the morphological changes of the cells, and detected the cell's proliferation and apoptosis of MC3T3-E1 cells. Two transcriptome libraries were constructed and sequenced. Quantitative real-time polymerase chain reaction (qRT-PCR) was performed to confirm the differentially expressed genes (DEGs), and then treated the MC3T3-E1 cells with estrogen receptor (ER) inhibitors α and ß, respectively, and then examined the expression of Tgfbr1 and Bmpr1a genes. The promoter of Tgfbr1 and Bmpr1a gene was analyzed, and the ER response elements were identified. Finally, ChIP was used to verify the binding of ER to Tgfbr1 and Bmpr1a promoter. RESULTS: In the high-concentration ß-estradiol treatment group (1 nmol/L and 10 nmol/L), there was no significant difference in the morphology of the cells under the microscope, 1 nmol/L and 10 nmol/L treated group appeared statistically significant difference in cell apoptosis and proliferation (P < 0.05 and P < 0.01, respectively). We found 460 DEGs compared with the control group. Among the DEGs, there were 66 upregulated genes and 394 downregulated genes. Gene ontology classification and Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that many bone metabolism-related biological processes and cell signaling pathways were disordered. The qRT-PCR verification showed that the expressions of Tgfbr1- and Bmpr1a-related genes in bone metabolism pathway in the 10 nmol/L treatment group were significantly decreased (P < 0.05). ER ß was involved in the inhibitory effect of Tgfbr1 and Bmpr1a genes. The bioinformatics of the promoter found that there were three ER response elements in the promoter of Tgfbr1, and there were two ER response elements in Bmpr1a promoter regions. ChIP experiments showed that estrogen could enhance the binding of ERs to Tgfbr1 and Bmpr1a genes. CONCLUSIONS: Estrogen can promote the apoptosis and proliferation of osteoblasts simultaneously, and the mechanism may be the joint action of transforming growth factor-beta, Wnt, mitogen-activated protein kinase, and nuclear factor-kappaB bone metabolism-related signaling pathway. Estrogen inhibits the expression of Tgfbr1 and Bmpr1a genes through ER ß and affects the metabolism of MC3T3-E1 osteoblasts.