Deep RNA analyses for BeWo cells and placentae of HIV positive pregnant women treated with lopinavir/ritonavir

IF 2.8 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology Pub Date : 2025-06-27 DOI:10.1016/j.reprotox.2025.108980

Shi Zou , Wei Guo , Miao Tan , Xuechen Yu , Jinli Liu , Qian Du , Yuting Tan , Yingjie Wu , Songjie Wu , Yanan Zhu , Yong Feng , Ke Liang

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引用次数: 0

Abstract

Introduction

Combination antiretroviral therapy (cART) based on protease inhibitor lopinavir /ritonavir (LPV/r) is the first-line regimen for HIV-infected pregnant women to prevent mother-to-child transmission (MTCT) in China. Studies have indicated a correlation between LPV/r and adverse pregnancy outcomes (APOs). However, a knowledge gap exists regarding the potential mechanisms.

Methods

In this study, the transcriptomics and proteomics analyses were performed to investigate the genes in BeWo cells and human placentae exposed to LPV/r. BeWo cells were treated with LPV/r with different concentrations for 24 h, then the mRNAs were sequenced. We also adopted proteomics sequencing between human placentae exposed to LPV/r and non-LPV/r based antiretroviral regimens. Flow cytometry analysis, real-time PCR and immunohistochemistry were performed to verified our sequencing results.

Results

A Total 800–4000 differentially expressed genes (DEGs) after LPV/r treatment in Bewo cells were identified compared to the vehicle control. There were 321 differentially expressed proteins (DEPs) in the LPV/r group of human placentae. Comprehensive analysis of the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) terms in transcriptomics and proteomics analyses demonstrated that LPV/r may result in APOs via active apoptosis, Endoplasmic reticulum (ER) stress, oxidative stress and lipid metabolism. Expression up-regulation of BAX (Bcl2 Associated X Protein), C-FOS (Cellular oncogene fos), P53 (Tumor suppressor protein p53) and down- regulation of MDM2 (Mouse double minute 2 homolog) by LPV/r may be the key genes for APOs.

Conclusions

Apoptosis by LPV/r may be the most important factor for APOs. The deep analysis provides important clues for understanding the mechanisms for the APOs were attributed to LPV/r.

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洛匹那韦/利托那韦治疗的HIV阳性孕妇BeWo细胞和胎盘的深度RNA分析。

基于蛋白酶抑制剂洛匹那韦/利托那韦（LPV/r）的抗逆转录病毒联合治疗（cART）是中国hiv感染孕妇预防母婴传播（MTCT）的一线治疗方案。研究表明LPV/r与不良妊娠结局（APOs）之间存在相关性。然而，关于潜在机制存在知识缺口。方法：采用转录组学和蛋白质组学方法研究LPV/r暴露的BeWo细胞和人胎盘的相关基因。用不同浓度的LPV/r处理BeWo细胞24h，然后对mrna进行测序。我们还对暴露于LPV/r和非LPV/r抗逆转录病毒方案的人类胎盘进行了蛋白质组学测序。流式细胞术分析、实时PCR和免疫组织化学验证了我们的测序结果。结果：与对照相比，经LPV/r处理的Bewo细胞共鉴定出800-4000个差异表达基因（DEGs）。人胎盘LPV/r组存在321个差异表达蛋白（DEPs）。基因本体（GO）和京都基因与基因组百科全书（KEGG）转录组学和蛋白质组学分析的综合分析表明，LPV/r可能通过主动凋亡、内质网（ER）应激、氧化应激和脂质代谢导致APOs。LPV/r上调BAX （Bcl2相关X蛋白）、C-FOS（细胞癌基因fos）、P53（肿瘤抑制蛋白P53）和下调MDM2（小鼠双分钟2同源物）的表达可能是APOs的关键基因。结论：LPV/r凋亡可能是APOs发生的重要因素。深入分析为理解LPV/r引起的apo机制提供了重要线索。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Reproductive toxicology 生物-毒理学

CiteScore

6.50

自引率

3.00%

发文量

131

审稿时长

45 days

期刊介绍： Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.