Bioinformatics and integrated pharmacology network to identify the therapeutic targets and potential molecular mechanism of alpha-lipoic acid on primary ovarian insufficiency.

Women experiencing primary ovarian insufficiency (POI) are more likely to experience infertility, and its incidence is increasing worldwide annually. Recently, the role of alpha-lipoic acid (ALA) in the treatment of POI has been reported. However, details of the potential pharmacological targets and related molecular pathways of ALA remain unclear and need to be elucidated. Thus, this study aims to elucidate the potential therapeutic target and related molecular mechanism of ALA on POI. First, the potential targets of POI and ALA-related targets were downloaded from online public databases. Subsequently, the overlapped target genes between POI and ALA were acquired, and gene ontology (GO), Kyoto encyclopedia of genes and genomes (KEGG) analysis, protein-protein interaction (PPI) networks were performed and constructed. Finally, molecular docking was performed to verify protein-to-protein effect. A total of 152 potential therapeutic targets were identified. The biological processes of the intersecting targets were mainly involved in the cellular response to peptides, response to xenobiotic stimuli, and response to peptide hormones. The highly enriched pathways were the cAMP, PI3K/AKT, estrogen, progesterone mediated oocyte maturation, and apoptosis signaling pathways. The top 10 hub targets for ALA in the treatment of POI were STAT3, STAT1, CASP3, MTOR, PTGS2, CASP8, HSP90AA1, PIK3CA, MAPK1, and ESR1. The binding between ALA and all top hub targets were verified using the molecular docking analysis. In summary, using the systematic integrated pharmacology network and bioinformatics analysis, this study illustrated that ALA participates in the treatment of POI via multiple targets and multiple pathways mechanisms.

The Role of Prolactin in Amniotic Membrane Regeneration: Therapeutic Potential for Premature Rupture of Membranes.

Premature rupture of membranes (PROM) is defined as rupture of fetal membranes before the onset of labor. Prolactin (PRL) is secreted by decidual membranes and accumulated significantly in the amniotic fluid during pregnancy. PRL could ameliorate inflammation and collagen degradation in fetal membranes. However, the role of PRL in amniotic membrane is not well characterized. We isolated human amniotic epithelial stem cells (hAESCs) from human fetal membranes to study the effect of PRL on proliferation, migration, and antioxidative stress. Amniotic pore culture technique (APCT) model was constructed to evaluate the tissue regeneration effect in vitro. The potential targets and pathways of PRL acting in amnion via integrated bioinformatic methods. PRL had a dose-dependent effect on hAESCs in vitro. PRL (500 ng/mL) significantly improved the viability of hAESCs and inhibited cell apoptosis, related to the upregulation of CCN2 expression and downregulation of Bax, Caspase 3, and Caspase 8. PRL accelerated migration process in hAESCs via downregulation of MMP2, MMP3, and MMP9. PRL attenuated the cellular damage and mitochondrial dysfunction induced by hydrogen peroxide in hAESCs. PRL accelerated the healing process in the APCT model significantly. The top 10 specific targets (IGF1R, SIRT1, MAP2K1, CASP8, MAPK14, MCL1, NFKB1, HIF1A, MTOR, and HSP90AA1) and signaling pathways (such as HIF signaling pathway) were selected using an integrated bioinformatics approach. PRL improves the viability and antioxidative stress function of hAESCs and the regeneration of ruptured amniotic membranes in vitro. Thus, PRL has great therapeutic potential for prevention and treatment of ruptured membranes.

Investigating the regenerative effects of folic acid on human amniotic epithelial stem cells and amniotic pore culture technique (APCT) model in vitro using an integrated pharmacological-bioinformatic approach.

INTRODUCTION: Disruption of fetal membranes before the onset of labor is referred to as premature rupture of membranes (PROM). Lack of maternal folic acid (FA) supplementation reportedly leads to PROM. However, there is a lack of information on the location of FA receptors in the amniotic tissue. Additionally, the regulatory role and potential molecular targets of FA in PROM in vitro have rarely been investigated. METHODS: The three FA receptors (folate receptor α isoform [FRα], transporter of reduced folate [RFC], and proton-coupled folate transporter [PCFT]) in human amniotic epithelial stem cells (hAESCs) and amniotic tissue were localized using immunohistochemistry and immunocytochemistry staining. Effect and mechanism analyses of FA were performed in hAESCs and amniotic pore culture technique (APCT) models. An integrated pharmacological-bioinformatics approach was utilized to explore the potential targets of FA for the treatment of PROM. RESULTS: The three FA receptors were widely expressed in human amniotic tissue, especially in the hAESC cytoplasm. FA stimulated the amnion regeneration in the in vitro APCT model. This mimics the PROM status, in which cystathionine-ß-synthase, an FA metabolite enzyme, may play an important role. The top ten hub targets (STAT1, mTOR, PIK3R1, PTPN11, PDGFRB, ABL1, CXCR4, NFKB1, HDAC1, and HDAC2) of FA for preventing PROM were identified using an integrated pharmacological-bioinformatic approach. DISCUSSION: FRα, RFC, and PCFT are widely expressed in human amniotic tissue and hAESCs. FA aids the healing of ruptured membrane.