Kasimanickam Ramanathan, Ferreira Joao, Kasimanickam Vanmathy
College of Veterinary Medicine, Washington State University, Pullman, WA 99164, USA.
School of Veterinary Medicine and Animal Science, São Paulo State University-UNESP, Botucatu 18618-81, SP, Brazil.
Curr Issues Mol Biol. 2025 Aug 11;47(8):643. doi: 10.3390/cimb47080643.
Postpartum metritis in dairy cows compromises reproductive performance and leads to substantial economic losses. This study investigated the molecular mechanisms underlying metritis by integrating high-throughput circulating microRNA (miRNA) profiling with systems-level bioinformatics. Previously, 30 differentially expressed miRNAs, 16 upregulated and 14 downregulated, were identified in metritis-affected cows compared to healthy controls. Building on these findings, this study predicted miRNA target genes and constructed regulatory networks involving miRNAs, mRNAs, circRNAs, lncRNAs, and snRNAs, alongside protein-protein interaction networks. Functional annotation and KEGG pathway analysis revealed that upregulated miRNAs influenced genes involved in immune activation, apoptosis, and metabolism, while downregulated miRNAs were associated with angiogenesis, immune suppression, and tissue repair. Hub genes such as AKT3, VEGFA, and HIF1A were central to immune and angiogenic signaling, whereas UBE3A and ZEB1 were linked to immune inhibition. Interferon-stimulated genes (e.g., ISG15, RSAD2, CXCL chemokines) were shown to regulate solute carriers, contributing to immune dysregulation. Key pathways included PI3K-Akt, NF-κB, JAK-STAT, insulin resistance, and T cell receptor signaling. Noncoding RNAs such as NEAT1, KCNQ1OT1, and XIST, along with miRNAs like bta-miR-15b and bta-miR-148a, emerged as pro-inflammatory regulators, while bta-miR-199a-3p appeared to exert immunosuppressive effects. These findings offer new insights into the complex regulatory networks driving metritis and suggest potential targets for improving fertility in dairy cows.
奶牛产后子宫炎会影响繁殖性能，并导致巨大的经济损失。本研究通过将高通量循环微小RNA（miRNA）分析与系统水平的生物信息学相结合，研究了子宫炎的分子机制。此前，与健康对照相比，在患子宫炎的奶牛中鉴定出30个差异表达的miRNA，其中16个上调，14个下调。基于这些发现，本研究预测了miRNA靶基因，并构建了涉及miRNA、mRNA、环状RNA（circRNA）、长链非编码RNA（lncRNA）和小核RNA（snRNA）的调控网络以及蛋白质-蛋白质相互作用网络。功能注释和KEGG通路分析表明，上调的miRNA影响参与免疫激活、细胞凋亡和代谢的基因，而下调的miRNA与血管生成、免疫抑制和组织修复相关。诸如AKT3、VEGFA和HIF1A等枢纽基因在免疫和血管生成信号传导中起核心作用，而UBE3A和ZEB1与免疫抑制有关。干扰素刺激基因（如ISG15、RSAD2、CXCL趋化因子）被证明可调节溶质载体，导致免疫失调。关键通路包括PI3K-Akt、NF-κB、JAK-STAT、胰岛素抵抗和T细胞受体信号传导。诸如NEAT1、KCNQ1OT1和XIST等非编码RNA，以及bta-miR-15b和bta-miR-148a等miRNA，成为促炎调节因子，而bta-miR-199a-3p似乎发挥免疫抑制作用。这些发现为驱动子宫炎的复杂调控网络提供了新见解，并为提高奶牛繁殖力提出了潜在靶点。
