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D H received funding from the Doctorate Program MOLIN (FWF, W1241) and the Medical University of Graz. J B-M received funding from the Doctorate Program DP-iDP (FWF, DOC 31-B26) and the Medical University of Graz. A M-M and G D are supported by funds of the Oesterreichische Nationalbank (Anniversary Fund, project number: 17950).

Analysis of institutional authors

Majali-Martinez, AlejandroAuthor

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November 17, 2021
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Different regulation of IRE1 alpha and eIF2 alpha pathways by oxygen and insulin in ACH-3P trophoblast model

Publicated to:Reproduction. 162 (1): 1-10 - 2021-07-01 162(1), DOI: 10.1530/REP-20-0668

Authors: Tandl, Veronika; Hoch, Denise; Bandres-Meriz, Julia; Nikodijevic, Sanela; Desoye, Gernot; Majali-Martinez, Alejandro

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Med Univ Graz, Dept Obstet & Gynecol, Graz, Austria - Author

Abstract

Endoplasmic reticulum (ER)-stress activates the unfolded protein response (UPR), which plays a (patho)physiological role in the placenta. Oxygen and hyperinsulinemia are major regulators of placental development. Thus, we hypothesized that oxygen, insulin and their interplay modulate ER-stress in early pregnancy. Using the human first-trimester trophoblast cell line ACH-3P, we quantified mRNA and protein of several members of UPR by RT-qPCR and Western blotting, respectively. ER-stress induction using tunicamycin and brefeldin A resulted in increased CHOP (4.6-fold change; P <= 0.001), XBP1 expression (1.7- and 1.3-fold change, respectively; P <= 0.001 and P < 0.05) and XBP1 splicing (7.9- and 12.8-fold change, respectively; P <= 0.001). We subsequently analyzed the effect of oxygen (6.5%, 2.5%), insulin (0.1-10 nM) and their interaction using ANCOVA adjusted for cell passage as co-variate. Although GRP78 protein remained unaffected, low oxygen (2.5% O-2) increased IRE1 alpha phosphorylation (+52%; P < 0.05) and XBP1 splicing (1.8-fold change; P <= 0.001) after 24 h, while eIF2 alpha protein and CHOP expression were downregulated (-28%; P < 0.05 and -24%; P <= 0.001; respectively). eIF2oc phosphorylation was also reduced after 48 h by low oxygen (-61%; P < 0.05) but increased in the presence of insulin (+46%; P <= 0.01). These changes were not PERK-mediated, since PERK phosphorylation and total protein were not altered. Overall, our results suggest that IRE1 alpha and eIF2 alpha UPR-pathways are differentially regulated by oxygen and insulin in early pregnancy.

Keywords

Atf6CancerCell fateEndoplasmic reticulum stressEndoplasmic-reticulum stressEndoribonucleasesEr stressErn1 protein, humanEukaryotic initiation factor-2FemaleGene expression regulationGene-expressionHuman placentaHumansHypoglycemic agentsInsulinIre1OxygenPhosphorylationPregnancyProtein serine-threonine kinasesSensorTrophoblastsUnfolded protein response

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Reproduction due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2021, it was in position 9/39, thus managing to position itself as a Q1 (Primer Cuartil), in the category Developmental Biology.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2025-07-19:

  • WoS: 2
  • Scopus: 2
  • Europe PMC: 2

Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2025-07-19:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 6.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 7 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 1.35.
  • The number of mentions on the social network X (formerly Twitter): 2 (Altmetric).

It is essential to present evidence supporting full alignment with institutional principles and guidelines on Open Science and the Conservation and Dissemination of Intellectual Heritage. A clear example of this is:

  • The work has been submitted to a journal whose editorial policy allows open Open Access publication.

Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: Austria.

There is a significant leadership presence as some of the institution’s authors appear as the first or last signer, detailed as follows: Last Author (MAJALI MARTINEZ, ALEJANDRO).