Details
| Original language | English |
|---|---|
| Article number | 1173 |
| Journal | Pharmaceuticals (Basel, Switzerland) |
| Volume | 15 |
| Issue number | 10 |
| Publication status | Published - 21 Sept 2022 |
Abstract
Inflammation mediators enhance the activity of connexin (Cx) hemichannels, especially in the epithelial and endothelial tissues. As potential release routes for injury signals, such as (oligo)nucleotides, Cx hemichannels may contribute to long-lasting inflammation. Specific inhibition of Cx hemichannels may therefore be a mode of prevention and treatment of long-lasting, chronic sterile inflammation. The activity of Cx hemichannels was analysed in N2A and HeLa cells transfected with human Cx26 and Cx46 as well as in Calu-3 cells, using dye uptake as functional assay. Moreover, the possible impacts of the bioactive phenolic agents CVB2-61 and CVB4-57 on the barrier function of epithelial cells was analysed using Calu-3 cells. Both agents inhibited the dye uptake in N2A cells expressing Cx26 (>5 µM) and Cx46 (>20 µM). In Calu-3 cells, CVB2-61 and CVB4-57 reversibly inhibited the dye uptake at concentrations as low as 5 µM, without affecting the gap junction communication and barrier function, even at concentrations of 20 µM. While CVB2-61 or CVB4-57 maintained a reduced dye uptake in Calu-3 cells, an enhancement of the dye uptake in response to the stimulation of adenosine signalling was still observed after removal of the agents. The report shows that CVB2-61 and CVB4-57 reversibly block Cx hemichannels. Deciphering the mechanisms of the interactions of these agents with Cx hemichannels could allow further development of phenolic compounds to target Cx hemichannels for better and safer treatment of pathologies that involve Cx hemichannels.
Keywords
- Calu-3 cells, connexin channels, curcuminoids, dye uptake, inflammation signals, polyphenols, transepithelial electrical resistance (TEER)
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)
- Drug Discovery
- Biochemistry, Genetics and Molecular Biology(all)
- Molecular Medicine
- Pharmacology, Toxicology and Pharmaceutics(all)
- Pharmaceutical Science
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In: Pharmaceuticals (Basel, Switzerland), Vol. 15, No. 10, 1173, 21.09.2022.
Research output: Contribution to journal › Article › Research › peer review
}
TY - JOUR
T1 - The Bioactive Phenolic Agents Diaryl Ether CVB2-61 and Diarylheptanoid CVB4-57 as Connexin Hemichannel Blockers
AU - Dierks, Anne
AU - Vanucci-Bacqué, Corinne
AU - Schäfer, Anne-Marie
AU - Lehrich, Tina
AU - Ruhe, Frederike
AU - Schadzek, Patrik
AU - Bedos-Belval, Florence
AU - Ngezahayo, Anaclet
N1 - Funding Information: We thank Vicky Kawalek for the GNOME-LP/ DT macro and Frank Koepke and Helma Feierabend for technical support. The publication of this article was funded by the Open Access Fund of the Leibniz Universität Hannover. Funding Information: This research was funded by the PhD Completion Grant programme of Hochschulbüro für ChancenVielfalt, Leibniz Universität Hannover.
PY - 2022/9/21
Y1 - 2022/9/21
N2 - Inflammation mediators enhance the activity of connexin (Cx) hemichannels, especially in the epithelial and endothelial tissues. As potential release routes for injury signals, such as (oligo)nucleotides, Cx hemichannels may contribute to long-lasting inflammation. Specific inhibition of Cx hemichannels may therefore be a mode of prevention and treatment of long-lasting, chronic sterile inflammation. The activity of Cx hemichannels was analysed in N2A and HeLa cells transfected with human Cx26 and Cx46 as well as in Calu-3 cells, using dye uptake as functional assay. Moreover, the possible impacts of the bioactive phenolic agents CVB2-61 and CVB4-57 on the barrier function of epithelial cells was analysed using Calu-3 cells. Both agents inhibited the dye uptake in N2A cells expressing Cx26 (>5 µM) and Cx46 (>20 µM). In Calu-3 cells, CVB2-61 and CVB4-57 reversibly inhibited the dye uptake at concentrations as low as 5 µM, without affecting the gap junction communication and barrier function, even at concentrations of 20 µM. While CVB2-61 or CVB4-57 maintained a reduced dye uptake in Calu-3 cells, an enhancement of the dye uptake in response to the stimulation of adenosine signalling was still observed after removal of the agents. The report shows that CVB2-61 and CVB4-57 reversibly block Cx hemichannels. Deciphering the mechanisms of the interactions of these agents with Cx hemichannels could allow further development of phenolic compounds to target Cx hemichannels for better and safer treatment of pathologies that involve Cx hemichannels.
AB - Inflammation mediators enhance the activity of connexin (Cx) hemichannels, especially in the epithelial and endothelial tissues. As potential release routes for injury signals, such as (oligo)nucleotides, Cx hemichannels may contribute to long-lasting inflammation. Specific inhibition of Cx hemichannels may therefore be a mode of prevention and treatment of long-lasting, chronic sterile inflammation. The activity of Cx hemichannels was analysed in N2A and HeLa cells transfected with human Cx26 and Cx46 as well as in Calu-3 cells, using dye uptake as functional assay. Moreover, the possible impacts of the bioactive phenolic agents CVB2-61 and CVB4-57 on the barrier function of epithelial cells was analysed using Calu-3 cells. Both agents inhibited the dye uptake in N2A cells expressing Cx26 (>5 µM) and Cx46 (>20 µM). In Calu-3 cells, CVB2-61 and CVB4-57 reversibly inhibited the dye uptake at concentrations as low as 5 µM, without affecting the gap junction communication and barrier function, even at concentrations of 20 µM. While CVB2-61 or CVB4-57 maintained a reduced dye uptake in Calu-3 cells, an enhancement of the dye uptake in response to the stimulation of adenosine signalling was still observed after removal of the agents. The report shows that CVB2-61 and CVB4-57 reversibly block Cx hemichannels. Deciphering the mechanisms of the interactions of these agents with Cx hemichannels could allow further development of phenolic compounds to target Cx hemichannels for better and safer treatment of pathologies that involve Cx hemichannels.
KW - Calu-3 cells
KW - connexin channels
KW - curcuminoids
KW - dye uptake
KW - inflammation signals
KW - polyphenols
KW - transepithelial electrical resistance (TEER)
UR - http://www.scopus.com/inward/record.url?scp=85140899492&partnerID=8YFLogxK
U2 - 10.3390/ph15101173
DO - 10.3390/ph15101173
M3 - Article
C2 - 36297285
VL - 15
JO - Pharmaceuticals (Basel, Switzerland)
JF - Pharmaceuticals (Basel, Switzerland)
SN - 1424-8247
IS - 10
M1 - 1173
ER -