Effects of metformin on the uterus of d‐galactose‐induced aging mice: Histomorphometric, immunohistochemical localization (B‐cell lymphoma 2, Bcl2‐associated X protein, and active capase3), and oxidative stress study

Abstract

D-galactose (DG)-induced rodent aging model has widely been used for the study of age-related dysfunctions of various organs, including gonads and uterus. Antidiabetic drug metformin has gained an attention as antiaging drug in model organism and human but its effect on uterus has not been studied in relation to induced aging. Therefore, we investigated the effect of metformin on uterus of DG-induced aging mice model. Mice were randomly divided into three groups, that is, control (CN), DG-induced aging model and aging model treated with metformin. Histomorphometric results showed significantly decreased number of uterine glands, endometrial thickness, and increased luminal epithelium height in aging model. Furthermore, metformin resumed the number of uterine glands, endometrial thickness, and luminal epithelium height up to CN group. Metformin has also significantly decreased the ageassociated oxidative stress (malondialdehyde and lipid hydroperoxide). Superoxide dismutase was significantly decreased in both treated groups compared to the CN group. However, catalase and glutathione peroxidase enzymes were significantly increased by metformin compared to the aging model. Immunostaining of active caspase3 and BAX were intense in the endometrium of aging model compare to CN-and metformin-treated groups. Localization of B-cell lymphoma 2 (Bcl2) showed intense immunostaining in the uterus of CN-and metformin-treated groups, with mild immunostaining in aging model. Our observations suggested that metformin treatment might be helpful for management of age-associated uterine dysfunctions.Moreover, it may be concluded that metformin might ameliorate uterine dysfunctions by reducing oxidative stress, suppressing apoptosis, and increasing the survival/ antiapoptotic protein Bcl2.

Molecular Landscape of Pelvic Organ Prolapse Provides Insights into Disease Etiology

“…Metformin inhibits the TGFB1-induced synthesis of type 1 collagen by fibroblasts through suppressing SMAD3 phosphorylation [ 46 , 47 , 48 ] (a protein that has been found to be upregulated in POP tissues [ 49 ]). Furthermore, metformin may have a (more) directly beneficial effect on cells from the urogenital tract (and hence on POP) as it was found to reduce estradiol-induced EMT [ 50 ], inflammation [ 51 ], and age-associated dysfunction [ 52 ] of uterine cells. Therefore, since metformin also specifically suppresses TGFB1 responses in fibroblast cell lines [ 17 ], we used fibroblasts from patients to assess if the drug could affect TGFB1 signaling in a direction that might have a beneficial effect on POP (or POP development).…”

Expression and localization of apelin and apelin receptor protein in the oviduct of letrozole‐induced hyperandrogenized mice

“…For the thickness of different regions of oviduct, several serial transverse sections were used to measure the thickness (µm) of oviductal walls of ampulla and isthmus regions. Four random perpendicular axes are drawn in the mucosal fold, muscularis, and lumen layers of both regions at 10× magnification (Machado‐Neves et al, 2019; Rempuia et al, 2022). To measure the thickness of lumen, mucosal fold, and muscularis layers, the axes were drawn on each layer to observe the change in the diameter in control and PCOS groups of oviduct.…”

Antiaging effects of dietary supplements and natural products

“…The protein activities of Bax and caspase-3 (the most critical apoptosis-executing protease during apoptosis, which cleaves the Bcl-2 protein and triggers apoptosis upon activation) are elevated and Bcl-2 activity is reduced in senescent mouse cells ( Rempuia et al, 2022 ). Athyrium multidentatum (Doll.)…”