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© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Recurrent pregnancy loss (RPL) occurs in approximately 5% of women. Despite an abundance of evidence, the molecular mechanism of RPL’s pathology remains unclear. Here, we report the protective role of polo-like kinase 1 (PLK1) during RPL. We aimed to construct an RPL network utilizing GEO datasets and identified hub high-traffic genes. We also investigated whether the expressions of PLK1 were altered in the chorionic villi collected from women with RPL compared to those from healthy early pregnant women. Gene expression differences were evaluated using both pathway and gene ontology (GO) analyses. The identified genes were validated using in vivo and in vitro models. Mice with PLK1-overexpression and PLK1-knockdown in vitro models were produced by transfecting certain plasmids and si-RNA, respectively. The apoptosis in the chorionic villi, mitochondrial function, and NF-κB signaling activity was evaluated. To suppress the activation of PLK1, the PLK1 inhibitor BI2536 was administered. The HTR-8/SVneo and JEG-3 cell lines were chosen to establish an RPL model in vitro. The NF-κB signaling, Foxo signaling, PI3K/AKT, and endometrial cancer signaling pathways were identified via the RPL regulatory network. The following genes were identified: PLK1 as hub high-traffic gene and MMP2, MMP9, BAX, MFN1, MFN2, FOXO1, OPA1, COX15, BCL2, DRP1, FIS1, TRAF2, and TOP2A. Clinical samples were examined, and the results demonstrated that RPL patients had tissues with decreased PLK1 expression in comparison to women with normal pregnancies (p < 0.01). In vitro, PLK1 knockdown induced the NF-κB signaling pathway and apoptosis activation while decreasing cell invasion, migration, and proliferation (p < 0.05). Furthermore, the in vivo model proved that cell mitochondrial function and chorionic villi development are both hampered by PLK1 suppression. Our findings revealed that the PLK1/TRAF2/NF-κB axis plays a crucial role in RPL-induced chorionic villi dysfunction by regulating mitochondrial dynamics and apoptosis and might be a potential therapeutic target in the clinic.

Details

Title
Designing Effective Multi-Target Drugs and Identifying Biomarkers in Recurrent Pregnancy Loss (RPL) Using In Vivo, In Vitro, and In Silico Approaches
Author
Ramírez-Coronel, Andrés Alexis 1   VIAFID ORCID Logo  ; Rostami, Amirabbas 2 ; Younus, Laith A 3 ; Arias Gonzáles, José Luis 4 ; Methaq Hadi Lafta 5 ; Amin, Ali H 6 ; Saadoon, Mohammed Abdulkadhim 7 ; Salman, Hayder Mahmood 8 ; Bahrami, Abolfazl 9   VIAFID ORCID Logo  ; Rossa Feilei 10 ; Akhavan-Sigari, Reza 11 

 Epidemiology and Biostatistics Group, Research Group in Educational Statistics, National University of Education (UNAE), Azogues 030102, Ecuador; Azogues Campus Nursing Career, Health and Behavior Research Group (HBR), Psychometry and Ethology Laboratory, Catholic University of Cuenca, Cuenca 010109, Ecuador; Psychology Group, University of Palermo, Buenos Aires 60301, Argentina; Epidemiology and Biostatistics Research Group, CES University, Medellín 050001, Colombia 
 Department of Internal Medicine, Faculty of General Medicine, Yerevan State Medical University, Yerevan 375010, Armenia 
 Department of Clinical Laboratory Sciences, Faculty of Pharmacy, Jabir Ibn Hayyan Medical University, Al Najaf Al Ashraf 54001, Iraq 
 Pontificia Universidad Católica Del Peru, Lima 15001, Peru 
 Iraqi Ministry of Education, Baghdad 10011, Iraq 
 Deanship of Scientific Research, Umm Al-Qura University, Makkah 21955, Saudi Arabia; Zoology Department, Faculty of Science, Mansoura University, Mansoura 35516, Egypt 
 Directorate General of Education Karkh 1, Ministry of Education, Baghdad 10011, Iraq 
 Department of Computer Science, Al-Turath University College Al Mansour, Baghdad 10011, Iraq 
 Biomedical Center for Systems Biology Science Munich, Ludwig-Maximilians-University, 80333 Munich, Germany 
10  Department of Cell Biology, Tuebingen University, 72072 Tuebingen, Germany 
11  Department of Neurosurgery, University Medical Center, 72072 Tuebingen, Germany; Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw, 04080 Warszawa, Poland 
First page
879
Publication year
2023
Publication date
2023
Publisher
MDPI AG
e-ISSN
22279059
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2791584213
Copyright
© 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.