A novel clinically relevant antagonistic interplay between prolactin and oncogenic YAP-CCN2 pathways as a differentiation therapeutic target in breast cancerLiu, Moamer, Gomes da Silva
et alCell Death Dis (2025) 16 (1), 221
Abstract: Cellular differentiation limits cellular plasticity allowing cells to attain their specialized functional characteristics and phenotypes, whereas loss of differentiation is a hallmark of cancer. Thus, characterizing mechanisms underlying differentiation is key to discover new cancer therapeutics. We report a novel functional antagonistic relationship between the prolactin (PRL)/prolactin receptor (PRLR) differentiation pathway and YAP-CCN2 oncogenic pathway in normal mammary epithelial cells and breast cancer cells that is essential for establishing/maintaining acinar morphogenesis, cell-cell junctions and the intracellular localization of apical-basal polarity protein complexes (Par, Crumb and Scrib). Importantly, using CRISPR knockout of the PRLR in MCF7, HR+ breast cancer cells, further revealed that the negative relationship between PRL/PRLR pathway and YAP-CCN2 pathway is critical in suppressing luminal-to-basal stem-like lineage plasticity. Furthermore, the clinical relevance of this interplay was evaluated using bioinformatics approaches on several human datasets, including samples from normal breast epithelium, breast cancer, and 33 other cancer types. This analysis revealed a positive correlation between PRLR and the YAP suppressor Hippo pathway and a co-expression gene network driving favourable patients' survival outcomes in breast cancer. The therapeutic potential of this interplay was also evaluated in vitro using MDA-MB-231 cells, a preclinical model of human triple-negative breast cancer, where treatment with PRL and Verteporfin, an FDA-approved pharmacological YAP-inhibitor, alone or their combination suppressed the expression of the mesenchymal marker vimentin and the stem cell marker CD44 as well as reduced their Ki67 proliferative marker expression. Collectively, our results emphasize the pro-differentiation role of PRL/PRLR pathway in mammary and breast cancer cells and highlight that promoting PRL/PRLR signaling while inhibiting the YAP-CCN2 oncogenic pathway can be exploited as a differentiation-based combination therapeutic strategy in breast cancer.© 2025. The Author(s).
Carvedilol and clomiphene combination therapy alleviates inflammation and redox imbalance in experimental PCOS: role of Nrf2/HMOX-1 and NfkB signalingAyodeji, Odetayo, Akintoye
et alNiger J Physiol Sci (2024) 39 (2), 259-266
Abstract: Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenemia, irregular menstrual cycle, and small cysts on the ovaries. This condition can be morphological or biochemical (elevated testosterone). Elevated testosterone (hyperandrogenemia) is the hallmark of PCOS, which can inhibit follicular development, anovulation, or cause irregular menstrual changes. Unfortunately, there is no cure for PCOS, and available treatment options are restricted to mitigating its symptoms. This study was, however, designed to investigate the synergistic effect of clomiphene (CLO) and carvedilol (CAL) on PCOS-induced female infertility. Thirty female Wistar rats were randomized into 5 groups (n= 6/group) control, PCOS, PCOS+ CLO, PCOS+CAL, and PCOS+ CLO+CAL. The administration was once daily via the oral route and lasted for 15 days. Clomiphene and carvedilol synergistically ameliorated PCOS-induced elevated serum gonadotropin-releasing hormone, luteinizing hormone (LH), testosterone and prolactin, and decreased follicle stimulating hormone (FSH), estrogen and progesterone. This was accompanied by the downregulation of PCOS-induced overexpression of ovarian LH, androgen, and FSH receptors. It was also accompanied by a decrease in inflammatory markers such as ovarian interleukin 1 beta and Nuclear factor kappa B (NF-κB) and apoptosis markers such as ovarian caspase 3 and an increase in ovarian Nuclear factor erythroid-2-related factor 2 (Nrf2), Heme Oxygenase 1 (HO 1 or HMO-1), catalase and glutathione reductase. This study shows that carvedilol and clomiphene combination therapy alleviates inflammation and redox imbalance in experimental PCOS.
Liquid chromatography-inductively coupled plasma mass spectrometry analysis of peptides labelled with ClickZip mass tagsMyšková, David, Šedinová
et alAnal Chim Acta (2025) 1350, 343853
Abstract: Lipidated anorexigenic peptides are highly promising compounds for the treatment of obesity and related diseases. However, their exact mechanism of action still remains unknown. We labelled a lipidated analogue of an anorexigenic prolactin-releasing peptide (palm11-PrRP31) with an extremely stable ClickZip lanthanide tag, facilitating tracking of the peptide within the organism. We then employed a separation method based on liquid chromatography combined with inductively coupled plasma mass spectrometry (LC-ICP-MS). This technique involved the use of an unconventional mobile phase containing 5 % 1,2-hexanediol in H2O (v/v) with the addition of 2 % formic acid. Using a rapid. 6-min analysis, we were able to quantify the ClickZip tag - and thus indirectly the fate of the labelled peptides in the living organism - independently of free Ln3+ ions. The detection limits for the various lanthanide chemical forms were extremely low, ranging between 0.9 and 3.4 ng/L. We demonstrated the suitability of the method for analysing real biological samples like blood plasma, and confirmed the accuracy of our results. Prior to LC-ICP-MS analysis, we optimised a process involving the microwave-assisted digestion of liver samples to preserve the integrity of the ClickZip tag. We also identified several metabolites of the labelled peptides in the liver, urine, and blood plasma, highlighting the utility of the method for revealing the mechanism of action behind the labelled lipopeptides.Copyright © 2025 Elsevier B.V. All rights reserved.
Cafeteria Diet-Induced Obesity Alters Uterine Function by Disrupting Insulin and Sex Steroid Actions in RatsSrinivasan, Raghavendhira, Iqbal Khan
et alJ Nutr (2025)
Abstract: The cafeteria diet (CAFD) model leads to obesity in rats, disrupting glucose metabolism, hormonal balance and ovarian function, which results in macrosomic offspring. Insulin and ovarian hormones are essential for uterine growth, but there is limited research on how CAFD-induced obesity affects uterine function by modulating hormonal levels.This study assesses how CAFD-induced obesity impacts uterine function in adult female rats by analysing ovarian steroids, insulin levels, and uterine responses.Post-weaning female Sprague-Dawley rats (22 days), were divided into a control group fed standard chow and an obese group fed energy-dense snacks (CAFD) and standard chow for 32 weeks. Body weight, food intake, energy intake, and estrous cycles were monitored during the experiment. After the experimental period, the uterine tissues were evaluated histologically, and protein expression was analysed using Western blotting and immunofluorescence. Serum hormone levels were assessed by ELISA, and uterine oxidative stress markers (SOD, CAT, GSH, LPO, and vitamin C) were measured using spectrophotometric methods.CAFD-fed rats exhibited increased body weight, BMI, and abdominal girth, along with hyperglycaemia, extended estrous cycles averaging 8.9 days and 40% reduction in uterine weight (p<0.05). The expression of PCNA was elevated (p<0.001), with a significant increase in uterine cell proliferation. Obese rats showed lower levels of SOD, GSH, and vitamin C, while levels of LPO and CAT were higher in uteri (p<0.05). Exposure to CAFD significantly reduced serum levels of prolactin, progesterone, and estradiol. Moreover, progesterone receptor and its target molecules (IHH, PPARγ, PRLR) were upregulated, while estrogen receptor-α (p<0.001) and its responsive molecules (VEGF, HOXA11) were downregulated (p<0.05).Consumption of CAFD caused obesity, leading to hyposecretion of ovarian steroids, insulin and oxidative stress in the uterus, which affected the uterine milieu by altering the expression of key molecules involved in uterine function.Copyright © 2025 American Society for Nutrition. Published by Elsevier Inc. All rights reserved.
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