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Chemical Inhibition of NRF2 Transcriptional Activity Influences Colon Function and Oestrogen Receptor Expression in

Aleksandra Piechota-Polanczyk1, Zanya Mariwani2, Jakub Fichna3

  • 1Department of Cell Cultures and Genomic Analysis, Medical University of Lodz, 90-752 Lodz, Poland.

International Journal of Molecular Sciences
|January 8, 2025
PubMed

Insights

Chemical inhibition of NRF2 transcriptional activity (TA) impacts female mouse colon contractility and goblet cell numbers. NRF2 TA also influences oestrogen receptor signaling in the female colon.

Area of Science:

  • Gastroenterology
  • Endocrinology
  • Molecular Biology

Background:

  • NRF2 (Nuclear factor erythroid 2-related factor 2) is a transcription factor regulating cellular responses to oxidative stress.
  • Oestrogen receptors (ERs) play crucial roles in various physiological processes, including those in the colon.
  • Age-related changes in NRF2 activity and ER signaling may affect colon function in females.

Purpose of the Study:

  • To investigate the effect of NRF2 transcriptional activity (TA) inhibition on distal colon contractions in female mice.
  • To determine if NRF2 TA inhibition impacts oestrogen receptor signaling in an age-dependent manner.
  • To explore the relationship between NRF2 TA, colon contractility, and goblet cell numbers.

Main Methods:

  • Female mice (3 and 6 months old) were treated with ML385 (NRF2 inhibitor) or vehicle for 7 days.
  • Colon functionality was assessed using a bead expulsion test.
  • Serum oestradiol levels and colon tissue (histology for ERα, ERβ, GPR30, goblet cells) were analyzed.

Main Results:

  • ML385 treatment significantly downregulated NRF2 TA and impacted colon contractility (p < 0.05).
  • Younger females showed increased goblet cell numbers and ERα expression with ML385 treatment.
  • ML385 downregulated GPR30 in older mice, while basal GPR30 was higher in older mice's epithelial layer.

Conclusions:

  • ML385 decreases NRF2 TA in the female mouse colon, affecting contractility and goblet cell counts.
  • NRF2 TA influences oestrogen receptor expression (ERα, GPR30) in the female colon.
  • These findings suggest a link between NRF2, oestrogen signaling, and colon function in female mice, potentially varying with age.
Keywords:
ML385NRF2colonoestrogen receptors

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