Abstract
Background: Preeclampsia (PE) is a serious risk to the health of pregnant women and fetuses during pregnancy, and there is no effective treatment for this condition. Although many reports have confirmed the therapeutic effects of peptides in diseases, the role of peptides in PE remains poorly understood.Methods: A differentially expressed peptide in PE (AEDPPE) is derived from heat-shock protein beta-1 (HSPB1), amino acids 100 to 109 (DVNHFAPDEL), which we identified in a previous study. We synthesized AEDPPE and investigated its effect on HTR-8/SVneo cell function using a Cell Counting Kit-8, flow cytometric assay, and Transwell and wound-healing assays. Quantitative reverse transcription-PCR and ELISA were used to determine cytokine expression. Pull-down assay, mass spectrometry, Western blot analysis, and immunofluorescence were used to explore the potential targets and signaling pathways regulated by AEDPPE. Finally, we assessed the effect of AEDPPE in the lipopolysaccharide (LPS)-induced PE-like rat model.Results: AEDPPE significantly promoted the migration and invasion of HTR-8/SVneo cells, and it decreased the expression of interleukins 1 beta (IL-1β), interleukin 6 (IL-6), and interleukin 8 (IL-8). These functions performed by AEDPPE remained evident after injury to HTR-8/SVneo cells with tumor necrosis factor-alpha (TNF-α), and AEDPPE reversed the elevated sFlt-1/PlGF ratio induced by TNF-α. AEDPPE may exert these biological effects by binding to heat-shock protein 90β (HSP 90β) and, thus, affect the NF-κB signaling pathway. In an LPS-induced PE-like rat model, AEDPPE significantly improved PE symptoms and fetal rat outcomes.Conclusion: Our study showed that AEDPPE enhanced trophoblast migration and invasion and reduced inflammatory cytokine expression, and we hypothesized that these actions involved the NF-κB signaling pathway. The use of AEDPPE may thus develop into a novel modality in the treatment of PE.
Highlights
Preeclampsia (PE) is a serious risk to the health of pregnant women and fetuses during pregnancy, and there is no effective treatment for this condition
The CCK-8 assay showed that AEDPPE did not exert an effect on the proliferation of HTR8/SVneo cells (Figure 2A), and flow cytometric results showed that AEDPPE did not affect the apoptotic rate of the various treatment groups (Figure 2B)
Using qRTPCR and Western blotting analyses, we demonstrated that tumor necrosis factor-α (TNF-α) significantly downregulated MMP-2 mRNA and protein expression, whereas AEDPPE upregulated its expression; this may be how AEDPPE promoted the migration and invasiveness of HTR-8/SVneo cells (Figures 3G,H)
Summary
Preeclampsia (PE) is a serious risk to the health of pregnant women and fetuses during pregnancy, and there is no effective treatment for this condition. Recent studies have shown that the expression of soluble FMS-like tyrosine kinase 1 (sFlt-1), placental growth factor (PlGF), and other factors changes; and that these factors play an important role in different pathogenic processes [12, 13]. In addition to these factors, tumor necrosis factor-α (TNF-α); interleukins 1 beta (IL-1β), 6 (IL6), and 8 (IL-8); and other inflammation-related factors are increased in the serum of patients with PE [14, 15]. As no drugs have been shown to affect disease progression [16], there is an urgent need for such pharmaceutical agents in the treatment of PE
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