Detrimental actions of obesity-associated advanced glycation end-products on endometrial epithelial cell proliferation are alleviated by antioxidants.
Reprod Biomed Online
; 47(1): 35-50, 2023 07.
Article
em En
| MEDLINE
| ID: mdl-37142478
ABSTRACT
RESEARCH QUESTION Advanced glycation end-products (AGE) are elevated in the uterine environment of obese infertile women. Can the detrimental effects of AGE on endometrial epithelial cells be mitigated with therapeutics, and recapitulated in a more physiologically relevant primary model (organoids)? DESIGN:
Human endometrial epithelial cells (ECC-1) were exposed to AGE at concentrations physiologically representative of uterine fluid in lean or obese individuals, and three potential therapeutics 25 nmol/l receptor for AGE (RAGE) antagonist FPS-ZM1, 100 µmol/l metformin, or a combination of antioxidants (10 µmol/l N-acetyl-l-cysteine, 10 µmol/l N-acetyl-l-carnitine and 5 µmol/l α-lipoic acid). Real-time cell analysis (xCELLigence, ACEA Biosciences) determined the rate of adhesion and proliferation. The proliferation of organoid-derived cells and secretion of cytokines from organoids was characterized in the presence of AGE (nâ¯=â¯5). The uterine fluid of women undergoing assisted reproduction was profiled for AGE-associated inflammatory markers (nâ¯=â¯77).RESULTS:
ECC-1 proliferation was reduced by AGE from obese versus lean conditions and vehicle control (Pâ¯=â¯0.04 and P < 0.001, respectively), and restored to a proliferation corresponding to lean conditions by antioxidants. AGE influenced organoid derived primary endometrial epithelial cell proliferation in a donor-dependent manner. AGE increased the organoid secretion of the proinflammatory cytokine CXCL16 (Pâ¯=â¯0.006). Clinically, CXCL16 correlated positively to maternal body mass index (Râ¯=â¯0.264, Pâ¯=â¯0.021) and intrauterine glucose concentration (Râ¯=â¯0.736, P < 0.0001).CONCLUSIONS:
Physiologically relevant concentrations of AGE alter endometrial epithelial cell function. Antioxidants restore the rate of proliferation of AGE-treated endometrial epithelial (ECC-1) cells. Primary endometrial epithelial cells, cultured as organoids, demonstrate altered proliferation and CXCL16 secretion in the presence of AGE equimolar with the uterine fluid from obese individuals.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Uterinas
/
Infertilidade Feminina
Tipo de estudo:
Risk_factors_studies
Limite:
Female
/
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article