RESUMEN
Background: Intrauterine growth restriction (IUGR) and preeclampsia (PE) are intricately linked with specific maternal health conditions, exhibit shared placental abnormalities, and play pivotal roles in precipitating preterm birth (PTB) incidences. However, the molecular mechanism underlying the association between PE and IUGR has not been determined. Therefore, we aimed to analyze the data of females with PE and those with PE + IUGR to identify the key gene(s), their molecular pathways, and potential therapeutic interactions. Methods: In this study, a comprehensive relationship analysis of both PE and PE + IUGR was conducted using RNA sequence datasets. Using two datasets (GSE148241 and GSE114691), differential gene expression analysis via DESeq2 through R-programming was performed. Gene set enrichment analysis was performed using ClusterProfiler, proteinâprotein interaction (PPI) networks were constructed, and cluster analyses were conducted using String and MCODE in Cytoscape. Functional enrichment analyses of the resulting subnetworks were performed using ClueGO software. The hub genes were identified under both conditions using the CytoHubba method. Finally, the most common hub protein was docked against a library of bioactive flavonoids and PTB drugs using the PyRx AutoDock tool, followed by molecular dynamic (MD) simulation analysis. Pharmacokinetic analysis was performed to determine the ADMET properties of the compounds using pkCSM. Results: We identified eight hub genes highly expressed in the case of PE, namely, PTGS2, ENG, KIT, MME, CGA, GAPDH, GPX3, and P4HA1, and the network of the PE + IUGR gene set demonstrated that nine hub genes were overexpressed, namely, PTGS2, FGF7, FGF10, IL10, SPP1, MPO, THBS1, CYBB, and PF4. PTGS2 was the most common hub gene found under both conditions (PE and PEIUGR). Moreover, the greater (-9.1 kcal/mol) molecular binding of flavoxate to PTGS2 was found to have satisfactory pharmacokinetic properties compared with those of other compounds. The flavoxate-bound PTGS2 protein complex remained stable throughout the simulation; with a ligand fit to protein, i.e., a RMSD ranging from â¼2.0 to 4.0 Å and a RMSF ranging from â¼0.5 to 2.9 Å, was observed throughout the 100 ns analysis. Conclusion: The findings of this study may be useful for treating PE and IUGR in the management of PTB.
RESUMEN
Sumoylation is the Post-translational modification gaining most of the research interest recently. Sumoylation is involved in various crucial functions of the cell such as regulation of cell cycle, DNA damage repair, apoptosis, etc. Oncology is advancing in radiotherapy, targeted chemotherapy, various forms of immunotherapy and targeted gene therapy. Researches are being conducted to prove its connotation with a variety of cancers and inhibitors are being developed to obstruct the fatal effect caused by misbalance of the SUMO-catalytic cycle. It has been shown that up-regulation of certain enzymes of Sumoylation correlates with cancer incidence in most of the cases. However, in some cases, down-regulation also associates with cancer invasion such as underexpression of UBC9 in initial stage breast cancer. This can aid in future study, treatment, and diagnosis of a variety of cancers including breast cancer, prostate cancer, lung adenocarcinoma, melanoma, multiple myeloma, etc. Various mechanistic assays are being developed and used to identify potential inhibitors against the dysregulated proteins of Sumoylation. This review summarizes the normal roles of the enzymes involved in the SUMOcatalytic cycle, their misbalanced regulation leading to tumorigenesis and nearly all the potent inhibitors identified to date, while after detailed studied it was observed that ML-792 could be a promising inhibitor in treating cancers by inhibiting Sumoylation enzymes.
