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Background: Gonadotropin precisely controls mammalian reproductive activities. Systematic analysis of the mechanisms by which epigenetic modifications regulate the synthesis and secretion of gonadotropin can be useful for more precise regulation of the animal reproductive process. Previous studies have identified many differential m6A modifications in the GnRH-treated adenohypophysis. However, the molecular mechanism by which m6A modification regulates gonadotropin synthesis and secretion remains unclear. Results: Herein, it was found that GnRH can promote gonadotropin synthesis and secretion by promoting the expression of FTO. Highly expressed FTO binds to Foxp2 mRNA in the nucleus, exerting a demethylation function and reducing m6A modification. After Foxp2 mRNA exits the nucleus, the lack of m6A modification prevents YTHDF3 from binding to it, resulting in increased stability and upregulation of Foxp2 mRNA expression, which activates the cAMP/PKA signaling pathway to promote gonadotropin synthesis and secretion. Conclusions: Overall, the study reveals the molecular mechanism of GnRH regulating the gonadotropin synthesis and secretion through FTO-mediated m6A modification. The results of this study allow systematic interpretation of the regulatory mechanism of gonadotropin synthesis and secretion in the pituitary at the epigenetic level and provide a theoretical basis for the application of reproductive hormones in the regulation of animal artificial reproduction. [ABSTRACT FROM AUTHOR]

Mastitis affects the milk quality and yield and is the most expensive disease in dairy cows. Elucidation of the pathogenesis of mastitis is of great importance for disease control. As a medium of intercellular communication, exosomes play key roles in various inflammatory diseases by regulating macrophage polarization. However, the molecular factors in exosomes that mediate the intercellular communication between mammary epithelial cells and macrophages during mastitis remain to be further explored. In this study, we isolated and identified mammary epithelial cell-derived exosomes from a lipopolysaccharide (LPS)/lipoteichoic acid (LTA)-induced mastitis cell model, and we demonstrated that exosomes from LPS/LTA-stimulated mammary epithelial cells promote M1-type macrophage polarization in vivo and in vitro. Based on the results of high-throughput sequencing, we constructed a differential miRNA (microRNA) expression profile of exosomes and demonstrated that miR-221-3p was highly expressed. Furthermore, in vivo and in vitro experiments, combined with coculture experiments and fluorescence tracing, showed that high miR-221-3p expression promoted M1-type macrophage polarization, demonstrating the transcellular role of miR-221-3p. Mechanistically, dual luciferase reporter gene assays and rescue assays showed that miR-221-3p regulated macrophage polarization by targeting Igf 2 bp 2. The results of this study will deepen our understanding of the pathogenesis of mastitis, and the molecular regulatory axis that was established in this study is expected to be a target for mastitis treatment.

Skin cutaneous melanoma (SKCM) is one of the most malignant and aggressive forms of cancer. Investigating the mechanisms of carcinogenesis further could lead to the discovery of prognostic biomarkers that could be used to guide cancer treatment. In this study, we conducted integrative bioinformatics analyses of TCGA database, STRING, cBioPortal, TRRUST, The Human Protein Atlas, and DGIdb to determine which hub genes contributed to tumor progression and the cancer-associated immunology of SKCM. The results show that immune-related 873 differential genes grouped SKCM samples into subtypes. The initial results showed that the optimal number of clusters was two subgroups. Further analysis showed that there were significant differences in survival rate and immune infiltration level between the two subgroups. Subsequently, obtaining the different genes between groups, construct PPI to screen 6 hub genes (HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DRA, HLA-DRB1, HLA-DRB5). In total, 6 MHC class II molecules were significantly related to overall survival. We then analyzed the expression of these genes along with their mutation landscapes, transcription factor regulation, and drug regulatory networks. In summary, our study identified 6 MHC class II molecules (HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DRA, HLA-DRB1, HLA-DRB5) as important biomarkers in the occurrence and progression of SKCM tumors. Their expression levels are closely related to prognosis and immune infiltration and can help us better understand the tumorigenesis of SKCM., Competing Interests: None., (AJCR Copyright © 2022.)