A longitudinal evaluation of oxidative stress - mitochondrial dysfunction - ferroptosis genes in anthracycline-induced cardiotoxicity.

BACKGROUND: Antineoplastic medications, including doxorubicin, idarubicin, and epirubicin, have been found to adversely affect the heart due to oxidative stress - mitochondrial dysfunction - ferroptosis (ORMFs), which act as contributing attributes to anthracycline-induced cardiotoxicity. To better understand this phenomenon, the time-resolved measurements of ORMFS genes were analyzed in this study. METHODS: The effect of three anthracycline drugs on ORMFs genes was studied using a human 3D cardiac microtissue cell model. Transcriptome data was collected over 14 days at two doses (therapeutic and toxic). WGCNA identified key module-related genes, and functional enrichment analysis investigated the biological processes quantified by ssGSEA, such as immune cell infiltration and angiogenesis. Biopsies were collected from heart failure patients and control subjects. GSE59672 and GSE2965 were collected for validation. Molecular docking was used to identify anthracyclines's interaction with key genes. RESULTS: The ORMFs genes were screened in vivo or in vitro. Using WGCNA, six co-expressed gene modules were grouped, with MEblue emerging as the most significant module. Eight key genes intersecting the blue module with the dynamic response genes were obtained: CD36, CDH5, CHI3L1, HBA2, HSD11B1, OGN, RPL8, and VWF. Compared with control samples, all key genes except RPL8 were down-regulated in vitro ANT treatment settings, and their expression levels varied over time. According to functional analyses, the key module-related genes were engaged in angiogenesis and the immune system pathways. In all ANT-treated settings, ssGSEA demonstrated a significant down-regulation of angiogenesis score and immune cell activity, including Activated CD4 T cell, Immature B cell, Memory B cell, Natural killer cell, Type 1 T helper cell, and Type 2 T helper cell. Molecular docking revealed that RPL8 and CHI3L1 show significant binding affinity for anthracyclines. CONCLUSION: This study focuses on the dynamic characteristics of ORMFs genes in both human cardiac microtissues and cardiac biopsies from ANT-treated patients. It has been highlighted that ORMFs genes may contribute to immune infiltration and angiogenesis in cases of anthracycline-induced cardiotoxicity. A thorough understanding of these genes could potentially lead to improved diagnosis and treatment of the disease.

Effects of Dimethyl Phthalate (DMP) on Serum Sex Hormone Levels and Apoptosis in C57 Female Mice.

BACKGROUND: The effects of dimethyl phthalate (DMP) on the reproductive system of mammal females are unclear because no studies have been conducted on this topic. METHODS: In this study, 40 C57 female mice were used as experimental subjects and evenly divided into 8 groups, which were fed with mixed DMP (0, 0.5, 1, and 2 g/kg bw/day) and corn oil. After 20 days and 40 days of gavage, the mice were weighed and their individual ovary organ coefficients measured. RESULTS: Changes were discovered on progesterone, estradiol, follicle-stimulating hormone and luteinizing hormone in mouse serum, and on the apoptosis rate of ovarian granulosa cells. CONCLUSIONS: Prolonged exposure to DMP led to decreased secretion of FSH hormones and increased secretion of E2 and LH hormones. Furthermore, DMP interfered with the pituitary-ovary axis and increased the apoptosis rate of ovarian granulosa cells. Therefore, prolonged exposure to DMP is likely to have negative effects on reproduction and development.