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Metformin exhibits its therapeutic effect in the treatment of pre-eclampsia via modulating the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways.

Abstract

Metformin (Met) has been found to modify the methylation of H19 and to alter its expression. In addition, IL-27, one of the downstream factors in the H19 signaling pathway, plays an important role in the pathogenesis of pre-eclampsia (PE). In this study, we investigated the molecular mechanism underlying the therapeutic effect of Met in the management of PE both in vivo and in vitro. The role of H19 signaling pathway in PE was validated using online bioinformatics tools, luciferase assays, real-time PCR and Western Blot. A tail-cuff method was used to examine the blood pressures in PE rats with or without Met treatment. Cells exhibited a dose-dependent increase of H19 methylation, which inhibited the expression of H19. Additionally, upon the Met treatment, levels of miR-148-5p and miR-216-3p were both elevated in a dose-dependent manner while levels of p28 mRNA and EBI3 mRNA were both inhibited by Met treatment. Also, H19 was found to regulate the expression of miR-148a-5p and miR-216-3p, while P28 and EBI3 were respectively identified as target genes of miR-148a-5p and miR-216-3p. Therefore, the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways were implicated in the pathogenesis of PE. Met was implicated in the pathogenesis of PE via modulating the H19 signaling pathway. The methylation of H19 reduced H19 expression, which in turn could up-regulate the expression of miR-148-5p/miR-216-3p. And the expressions of subunits of IL-27, P28 and EBI3, were thus suppressed. Therefore, Met-induced inhibition of H19 also led to the reduction of IL-27 expression, TNF-α and IL-6 in vivo.

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  • Authors+Show Affiliations

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    Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

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    Department of Immunology, The Norman Bethune Medical Institute of Jilin University, Changchun, Jilin 130021, China.

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    Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

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    Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

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    Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

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    Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

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    Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, China.

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    Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, China. Electronic address: eclampsibe@yeah.net.

    Department of Obstetrics and Gynecology, The First Hospital of Jilin University, Changchun, Jilin 130021, China. Electronic address: yec8475@163.com.

    Source

    International immunopharmacology 74: 2019 Jun 13 pg 105693

    Pub Type(s)

    Journal Article

    Language

    eng

    PubMed ID

    31203154

    Citation

    Shu, Chang, et al. "Metformin Exhibits Its Therapeutic Effect in the Treatment of Pre-eclampsia Via Modulating the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 Signaling Pathways." International Immunopharmacology, vol. 74, 2019, p. 105693.
    Shu C, Yan D, Chen C, et al. Metformin exhibits its therapeutic effect in the treatment of pre-eclampsia via modulating the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways. Int Immunopharmacol. 2019;74:105693.
    Shu, C., Yan, D., Chen, C., Mo, Y., Wu, L., Gu, J., ... Dong, S. (2019). Metformin exhibits its therapeutic effect in the treatment of pre-eclampsia via modulating the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways. International Immunopharmacology, 74, p. 105693. doi:10.1016/j.intimp.2019.105693.
    Shu C, et al. Metformin Exhibits Its Therapeutic Effect in the Treatment of Pre-eclampsia Via Modulating the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 Signaling Pathways. Int Immunopharmacol. 2019 Jun 13;74:105693. PubMed PMID: 31203154.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Metformin exhibits its therapeutic effect in the treatment of pre-eclampsia via modulating the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways. AU - Shu,Chang, AU - Yan,Dongmei, AU - Chen,Chen, AU - Mo,Yanxiang, AU - Wu,Linlin, AU - Gu,Jishuang, AU - Shah,Neelam Kumari, AU - He,Jin, AU - Dong,Shuai, Y1 - 2019/06/13/ PY - 2019/03/26/received PY - 2019/05/16/revised PY - 2019/06/08/accepted PY - 2019/6/17/pubmed PY - 2019/6/17/medline PY - 2019/6/17/entrez KW - EBI KW - H19 KW - Hypertension KW - IL-27 KW - Metformin KW - P28 KW - PE KW - Pregnancy SP - 105693 EP - 105693 JF - International immunopharmacology JO - Int. Immunopharmacol. VL - 74 N2 - Metformin (Met) has been found to modify the methylation of H19 and to alter its expression. In addition, IL-27, one of the downstream factors in the H19 signaling pathway, plays an important role in the pathogenesis of pre-eclampsia (PE). In this study, we investigated the molecular mechanism underlying the therapeutic effect of Met in the management of PE both in vivo and in vitro. The role of H19 signaling pathway in PE was validated using online bioinformatics tools, luciferase assays, real-time PCR and Western Blot. A tail-cuff method was used to examine the blood pressures in PE rats with or without Met treatment. Cells exhibited a dose-dependent increase of H19 methylation, which inhibited the expression of H19. Additionally, upon the Met treatment, levels of miR-148-5p and miR-216-3p were both elevated in a dose-dependent manner while levels of p28 mRNA and EBI3 mRNA were both inhibited by Met treatment. Also, H19 was found to regulate the expression of miR-148a-5p and miR-216-3p, while P28 and EBI3 were respectively identified as target genes of miR-148a-5p and miR-216-3p. Therefore, the Met/H19/miR-148a-5p/P28 and Met/H19/miR-216-3p/EBI3 signaling pathways were implicated in the pathogenesis of PE. Met was implicated in the pathogenesis of PE via modulating the H19 signaling pathway. The methylation of H19 reduced H19 expression, which in turn could up-regulate the expression of miR-148-5p/miR-216-3p. And the expressions of subunits of IL-27, P28 and EBI3, were thus suppressed. Therefore, Met-induced inhibition of H19 also led to the reduction of IL-27 expression, TNF-α and IL-6 in vivo. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/31203154/Metformin_exhibits_its_therapeutic_effect_in_the_treatment_of_pre-eclampsia_via_modulating_the_Met/H19/miR-148a-5p/P28_and_Met/H19/miR-216-3p/EBI3_signaling_pathways L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(19)30645-9 DB - PRIME DP - Unbound Medicine ER -