Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
From Gut to Brain: The roles of intestinal microbiota, immune system, and hormones in intestinal physiology and gut-brain-axis.
Khan MT, Zohair M, Khan A … +3 more , Kashif A, Mumtaz S, Muskan F
Mol Cell Endocrinol · 2025 Sep · PMID 40482955 · Publisher ↗
The intestine plays numerous roles in the normal physiology of our body. Gut-brain axis (GBA) is a complex communication network linking the gastrointestinal (GI) tract and central nervous system (CNS). This bidirectiona...
The intestine plays numerous roles in the normal physiology of our body. Gut-brain axis (GBA) is a complex communication network linking the gastrointestinal (GI) tract and central nervous system (CNS). This bidirectional system integrates endocrine, neural, and immune signals, impacting host metabolism and cognition. The gut microbiota, a critical component of the GBA, significantly impacts gut hormones, neurotransmission, neural development, and other components of gut-brain-axis. The microbiota-gut-brain axis facilitates communication via metabolites such as short chain fatty acids (SCFAs), and neurotransmitters such as dopamine, γ-amino butyric acid (GABA) and serotonin. The microbiota influences gut peptide production, including ghrelin, glucagon like pepetide-1 (GLP-1), serotonin, and cholecystokinin (CCK), thereby modulating nutrient absorption and immune responses. Gut hormones such as ghrelin, CCK, GLP-1, gastric inhibitory peptide (GIP), serotonin (5-HT), neurotensin, peptide YY (PYY) and melatonin play key roles in the GBA. These hormones play several roles including modulation of appetite and satiety, metabolism of nutrients such as lipid and glucose, insulin and glucagon secretion, and influence on gut inflammation, mood, learning and cognition. The interaction between gut microbiota and these hormones underscores their role in maintaining gut-brain homeostasis. Dysbiosis, or microbial imbalance, is linked to altered stress responses, anxiety, and depressive behaviors, highlighting the therapeutic potential of microbiota modulation. Despite the significant roles of gut hormones and microbiota in the GBA, literature on their cellular and molecular mechanisms is limited, and often based on animal models. This review synthesizes current understanding of hormones secreted by the intestine, their physiological effects and the cellular and molecular mechanisms of action underlying these effects, with a focus on their roles in the GBA. By elucidating these complex relationships, the review aims to advance research and clinical applications, offering insights into gastrointestinal and systemic health.
Aggressive pituitary tumours and pituitary carcinomas: molecular insights guiding management and the role of precision oncology.
Lamb LS, Sim HW, Ramus SJ … +1 more , McCormack AI
Mol Cell Endocrinol · 2025 Sep · PMID 40482954 · Publisher ↗
Aggressive pituitary neuroendocrine tumours and pituitary carcinomas are associated with high morbidity and mortality and have limited treatment options. Increased understanding of the molecular pathogenesis of pituitary...
Aggressive pituitary neuroendocrine tumours and pituitary carcinomas are associated with high morbidity and mortality and have limited treatment options. Increased understanding of the molecular pathogenesis of pituitary tumours has led to identification of molecular drivers of aggressive behaviour and prognostic markers, as well as identification of therapeutic targets. Mechanisms for pituitary tumourigenesis include chromosomal genomic instability, defective DNA repair, loss of cell cycle control, epigenetic changes, dysregulation of intracellular signalling pathways and alterations within the pituitary tumour immune microenvironment. Novel therapeutic treatment options including VEGF targeted therapies and immune checkpoint inhibitors have been used with varied responses. The application of precision oncology platforms to identify therapeutic targets is well described in other cancers and should be considered in the management of aggressive pituitary tumours and pituitary carcinomas. Histopathological analysis of established prognostic markers should be included in routine clinical practice.
NOC2L inhibits trophoblast ferroptosis in preeclampsia through the p53/SLC7A11 pathway.
Su F, Shi F, Yang C … +4 more , Zhao F, Geng X, Yang X, Zhao X
Mol Cell Endocrinol · 2025 Sep · PMID 40480436 · Publisher ↗
BACKGROUND: NOC2L is downregulated in preeclampsia (PE). However, the underlying functional mechanisms of NOC2L in the pathogenesis of PE remain unclear. METHODS: Cell viability, migration, and invasion were determined i...
BACKGROUND: NOC2L is downregulated in preeclampsia (PE). However, the underlying functional mechanisms of NOC2L in the pathogenesis of PE remain unclear. METHODS: Cell viability, migration, and invasion were determined in hypoxia-stimulated HTR-8/SVneo cells in CCK-8, wound healing, and Transwell assays. The levels of GSH, MDA and Fe were measured using specific commercial kits. Lipid ROS levels were determined through C11-BODIPY staining. The protein levels were analyzed via western blotting. Additionally, a rat model of PE was used to examine the influence of NOC2L on the progression of PE and the associated ferroptosis. RESULTS: NOC2L overexpression increased the viability of hypoxia-treated trophoblast cells and increased the levels of GSH, SLC7A11, and GPX4 while simultaneously reducing Fe, MDA, and lipid ROS levels. Furthermore, both NOC2L overexpression and ferrostatin-1 application facilitated trophoblast migration and invasion. In contrast, NOC2L knockdown exacerbated the hypoxia-induced increase in ferroptosis and inhibited cell migratory and invasive capabilities. Notably, treatment with PFT-α, a p53 inhibitor, abolished the influence of NOC2L silencing on trophoblast cell functions. NOC2L overexpression was associated with improved blood pressure and urinary protein concentration, reduced pathological damage in the placenta, alterations in ferroptosis-related markers, and an increased survival rate in rat fetuses. CONCLUSION: NOC2L inhibits trophoblast ferroptosis through the p53/SLC7A11 signaling pathway, potentially preventing the progression of PE.
Structural comparison of androstenediol recognition by the human estrogen receptor ligand binding domains.
Pederick JL, Bruning JB
Mol Cell Endocrinol · 2025 Sep · PMID 40480435 · Publisher ↗
Estrogen receptors α (ERα) and β (ERβ) are ligand-regulated transcription factors that control important biological processes in humans. The endogenous steroid androstenediol possesses estrogenic activity, despite being...
Estrogen receptors α (ERα) and β (ERβ) are ligand-regulated transcription factors that control important biological processes in humans. The endogenous steroid androstenediol possesses estrogenic activity, despite being a precursor of the primary androgen, testosterone. While androstenediol is an agonist of both ERs, it is ∼ 3-fold selective for ERβ. Additionally, it has been reported that androstenediol can repress proinflammatory responses of the central nervous system (CNS) in an ERβ-dependent manner, but the primary estrogen, estradiol (E2), cannot. As no structural characterization of the interaction between ERα or ERβ with androstenediol has been reported, the basis of ERβ selectivity, and whether this is responsible for the anti-inflammatory effects of androstenediol, remains unclear. To address these gaps in knowledge we determined crystal structures of the human ER LBDs (hERα and hERβ) complexed with androstenediol and coactivator-derived peptide. This revealed that androstenediol stabilizes the active conformation of both receptors in the same manner as E2. The binding mode of androstenediol between the hERα and hERβ LBDs is extremely similar, suggesting that subtle differences in the van der Waals interactions mediated by non-conserved residues of the ligand binding pocket confer selectivity toward hERβ. Finally, in both receptors the coactivator-derived peptide occupied the activation function 2 (AF2) surface, as observed for previous agonist-bound hER structures. Therefore, as androstenediol does not induce any distinct structural changes within the hERβ LBD compared to E2, this suggests that the hERβ-dependent anti-inflammatory effects of androstenediol on the CNS are mediated by other factors.
White beans (Phaseolus vulgaris L.) in diet reduces hypothalamic pro-inflammatory cytokines improving insulin resistance in small litter grown rats.
Alves EV, Alves TV, Barrozo Junior LS … +9 more , Ribeiro MVF, Nunes AFF, Ricken CLRDS, Borkenhagen IR, Cavalheiro BVT, Dias G, Oliveira R, Bomfim GF, de Oliveira JC
Mol Cell Endocrinol · 2025 Sep · PMID 40436331 · Publisher ↗
In the present study we were interested in studying the effect of white beans (Phaseolus vulgaris L.) as diet supplementation on glucose-insulin and metabolic homeostasis in early overfeeding rats. Small litter (SL) was...
In the present study we were interested in studying the effect of white beans (Phaseolus vulgaris L.) as diet supplementation on glucose-insulin and metabolic homeostasis in early overfeeding rats. Small litter (SL) was adjusted to 3 pups on post-natal day 3, while normal litter (NL) was kept with 8 pups. The milk collection and milk intake were performed, and the rat-offspring when weaned (at 22 days old), were fed a standard (NL-SD and SL-SD groups) or a white bean (2.5 % w/w) supplemented diet (NL-WB and SL-WB groups). Body weight, food and water intake were measured from weaning until adulthood (100 days old). Glucose and insulin tolerance, and intracerebroventricular insulin (10 mmol/L) tests were performed to assess peripheral and central insulin-glucose homeostasis in adult rats. Blood, hypothalamus, visceral fat pad and lean mass were collected. Milk from SL mothers displays high content of glucose, cholesterol, triglycerides and energy (P < 0.05). Milk consumption by SL rat-offspring, in early stage of suckling, was higher than NL rats (P<0.05). At adulthood, SL-SD rats were obese, hyperphagic, dyslipidemic, hyperglycemic, glucose intolerant and IR (P < 0.05). At adulthood, SL-SD rats displayed central IR and higher hypothalamic pro-inflammatory (TNF-α, 43.5 %; IL-6, 78.5 % and IL-1β, 50.1 %, P < 0.05) cytokine. The habitual ingestion of white beans-dietary supplementation prevented all those metabolic disruptions. In summary, white beans-dietary supplementation prevented obesity and glucose-insulin homeostasis deregulation in early overfeeding rats, avoiding hypothalamic inflammatory cytokines high levels and improving insulin sensitivity.
Disease-associated SNP variants of THRβ: Insights into the molecular determinants of aberrant receptor function.
Rehman G, Srivastav AK, Rizvi S … +2 more , Chhabra A, Tyagi RK
Mol Cell Endocrinol · 2025 Sep · PMID 40419015 · Publisher ↗
Thyroid hormone receptor beta (THRβ) is a ligand-modulated transcription factor that regulates thyroid hormone (T)-mediated genomic actions. It regulates the hypothalamus-pituitary-thyroid axis and various metabolic proc...
Thyroid hormone receptor beta (THRβ) is a ligand-modulated transcription factor that regulates thyroid hormone (T)-mediated genomic actions. It regulates the hypothalamus-pituitary-thyroid axis and various metabolic processes, primarily in the liver and kidney. Research has shown that genetic variations, mainly single nucleotide polymorphism (SNP) in the THRB gene, may be linked to diseases like resistance to thyroid hormone, thyroid-related cancers, neurological and mental disorders. Despite this revelation, a significant gap remains in understanding the impact of SNPs on THRβ cellular function and disease etiology. Thus, the present study investigated the disease-associated missense THRβ-SNPs using both in silico analysis and cell-based assays. The study was initiated with computational analysis of disease-associated THRβ variants to predict the effects of SNPs on receptor conformation, structure, stability, and function. The molecular docking and simulation approach then evaluated the impact of these variants on interactions with T and RXR. Following this, an extensive investigation was conducted into the dynamics and functioning of these receptor variants to address the underlying deviations in their cellular functioning by assessing receptor-subcellular localization, response to T hormone, transcriptional functions, interaction with heterodimeric partner RXR, and receptor-chromatin interactions encountered in healthy and disease states. The study emphasizes that the structural and conformational integrity of THRβ is essential for its normal function, and critical deviations are associated with several metabolic/endocrine disease states. A comprehensive analysis of these disease-associated THRβ variants suggests the prospects of personalized medicine and the development of SNP-based genomic tests. The findings may also facilitate the discovery of novel small-molecule modulators to treat thyroid-related diseases linked to THRβ dysfunction, improving diagnosis and management of disease conditions.
The lysosome-associated SLAMF7 inhibits the development of ovarian cancer by promoting lysosomal damage.
Zou W, Fang X, Qian Z … +1 more , Nie L
Mol Cell Endocrinol · 2025 Sep · PMID 40414453 · Publisher ↗
Ovarian cancer (OC) is one of the most severe cancers worldwide. Recent research suggests that the lysosomal pathway could be applied for early disease screening, prognosis evaluation, and adjuvant therapy. However, whet...
Ovarian cancer (OC) is one of the most severe cancers worldwide. Recent research suggests that the lysosomal pathway could be applied for early disease screening, prognosis evaluation, and adjuvant therapy. However, whether lysosome-related genes were applied for immune and prognosis prediction in OC remains unclear. RNA sequencing datasets, including clinical information of OC patients, were collected from TCGA and GEO databases. Lysosome-related prognostic genes and functional pathways in OC were identified using the lysosome dataset. The prognostic value of the most significant lysosome-related gene, SLAMF7, was estimated using Kaplan-Meier survival analysis. Differences in genomic mutations, tumor microenvironment immune infiltration, and drug resistance were evaluated in the high/low SLAMF7 of OC patients. The effect of SLAMF7 overexpression on the malignant characteristics of OC was assessed using OC cell lines (HEY A8 and OVCAR3 cells) and a xenograft mouse model. Based on the functional prediction of lysosome-related genes, T cell activation, immune receptor activity, and lysosomal pathways were significantly enriched in OC. Dimensionality reduction analysis using the random survival forest method confirmed that SLAMF7 was the most significantly different lysosome-related prognostic gene in OC. SLAMF7 was downregulated in OC cells and was associated with poor prognosis in OC patients. Low SLAMF7 expression was positively associated with chemotherapy sensitivity, immune infiltration, and function in OC patients. Overexpression of SLAMF7 promoted the pro-CTSB and LAMP1 expression, and inhibited CTSD expression in HEY A8 and OVCAR3 cells. Overexpression of SLAMF7 inhibited proliferation and formation of subcutaneous tumors in nude mice. The lysosome-related gene SLAMF7 is downregulated in OC and could serve as a prognostic biomarker. Overexpression of SLAMF7 inhibited the malignant of OC cells and tumor formation.
Androgen receptor plays critical role in regulating cervical cancer cell migration.
Bose S, Das S, Maity S … +6 more , Raychaudhuri D, Banerjee T, Paul M, Mukhopadhyay A, Chakrabarti O, Chakrabarti S
Mol Cell Endocrinol · 2025 Sep · PMID 40409531 · Publisher ↗
Cervical cancer (CC) is the second most common cancer among women in India and the fourth worldwide. While major genes and pathways have been studied, further research is needed to identify newer candidates for targeted...
Cervical cancer (CC) is the second most common cancer among women in India and the fourth worldwide. While major genes and pathways have been studied, further research is needed to identify newer candidates for targeted therapy in metastatic disease. This study used a graph-theory-based network analysis to identify important interacting proteins (IIPs) with maximum connectivity, high centrality scores, and significant global and local network perturbation scores. Among the identified IIPs, the Androgen receptor (AR) emerged as one of the crucial yet understudied regulator in cervical cancer. Patient samples, ex vivo, and in vitro experiments showed significant downregulation of AR in cervical cancer. Ligand-dependent overexpression of AR reduced cancer cell migration while failed to induce apoptosis in CC cell lines. Downregulation of mesenchymal markers and restoration of epithelial markers upon exogenous expression of AR suggested its potential in reversing invasive properties of cervical cancer cells. AR overexpression followed by activation upregulated its downstream target PTEN and downregulated pPI3K levels, which in turn restored GSK3β activity by interfering with AKT phosphorylation, probably leading to degradation of mesenchymal markers in cervical cancer cells. Further studies showed that AR reduced cell motility by hindering focal adhesion formation and Actin filament assembly. An increased G-Actin ratio suggested AR disrupted cytoskeletal dynamics through altering the RhoA/ROCK1/LIMK1/CFL1 pathway eventually impeding cervical cancer cell spread.
Açaí seed extract mitigates intestinal and hypothalamic alterations in obese mice.
de Moraes Arnoso BJ, de Araújo CA, Ramundo GD … +8 more , de Bem GF, Ognibene DT, Fontes-Dantas FL, Martins BC, Daleprane JB, de Souza MO, Resende AC, da Costa CA
Mol Cell Endocrinol · 2025 Sep · PMID 40409530 · Publisher ↗
Obesity is a significant health concern, significantly contributing to increased morbidity and mortality by disrupting multiple physiological systems. It is strongly associated with metabolic dysfunctions, including impa...
Obesity is a significant health concern, significantly contributing to increased morbidity and mortality by disrupting multiple physiological systems. It is strongly associated with metabolic dysfunctions, including impaired glycemic homeostasis, compromised intestinal barrier integrity, and gut microbiota imbalances, all exacerbating the risk of chronic diseases. The hydroalcoholic extract of açaí seeds (ASE), rich in phenolic compounds, has demonstrated beneficial effects on obesity and hyperglycemia; however, its impacts on gut health and gut-hypothalamus communication remain unclear. This study aimed to investigate the therapeutic effect of ASE in intestinal and hypothalamic alterations associated with obesity and compare it with Metformin. Male C57BL/6 mice were fed a high-fat or standard diet for 14 weeks. The ASE (300 mg/kg/day) and Metformin (300 mg/kg/day) treatments started in the tenth week until the fourteenth week, totaling four weeks of treatment. Our data show that the treatment with ASE and Metformin reduced body weight, ameliorated lipid profile, hyperglycemia, and plasma hyperleptinemia, and decreased the oxidative damage in the gut by reducing immunostaining of 8-isoprostane and NOX-4 expression, and improved the intestinal parameters and hypothalamic gene expression. Obesity-induced dysbiosis in the HF group was marked by reduced Proteobacteria and elevated LPS plasma levels, which were improved by treatments with ASE and Metformin. These findings suggest that ASE and Metformin are promising strategies to counteract the adverse effects of obesity on intestinal health and gut-hypothalamus communication, though they act through distinct mechanisms. Therefore, we can suggest that ASE is a promising natural product for treating the intestinal alterations associated with obesity.
Dehydroepiandrosterone (DHEA)-induced autophagy protects against lipotoxicity in hepatic cells.
Gupta P, Tewari A, Rajak S … +4 more , Shahi A, Yadav A, Raza S, Sinha RA
Mol Cell Endocrinol · 2025 Sep · PMID 40409529 · Publisher ↗
Dehydroepiandrosterone (DHEA), a precursor of sex hormones, has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH), with studies suggest...
Dehydroepiandrosterone (DHEA), a precursor of sex hormones, has been implicated in the pathogenesis of non-alcoholic steatohepatitis (NASH) or metabolic dysfunction-associated steatohepatitis (MASH), with studies suggesting a strong correlation between DHEA levels and disease severity. In this study, we demonstrated that DHEA alleviated lipotoxicity-induced hepatic damage by promoting autophagy. Our findings demonstrate that DHEA-induced autophagy is mediated by estrogen receptor alpha (ER-α) and androgen receptor (AR) activation and protects hepatic cells against palmitate-induced apoptosis, steatosis, and inflammasome activation. DHEA treatment in a murine NASH model induced significant autophagy in the liver, further supporting the hepatoprotective role of DHEA. Collectively, our results identified DHEA as a pro-autophagic hormone with therapeutic potential for the treatment of lipotoxicity in NASH.
Transcriptomic characterization of the synergy between human induced pluripotent stem cells-derived liver- and pancreas-on-chip coculture.
Essaouiba A, Jellali R, Poulain S … +5 more , Kim SH, Danoy M, Legallais C, Sakai Y, Leclerc E
Mol Cell Endocrinol · 2025 Sep · PMID 40409528 · Publisher ↗
Interactions between the liver and pancreas are key features of the carbohydrate and lipid homeostasis in healthy and pathological patients. To investigate the crosstalk between the two organs, we have developed an organ...
Interactions between the liver and pancreas are key features of the carbohydrate and lipid homeostasis in healthy and pathological patients. To investigate the crosstalk between the two organs, we have developed an organ-on-chip coculture model derived from human induced pluripotent stem cells. The presence of pancreatic-derived tissue in the culture environment contributed to increase the CYP3A4 activity, the glycogen storage, and the expression of genes related to lipids, bile acids and sterol metabolism in the liver derived tissue. Concomitantly, the presence of liver cells led to increase the C-peptide secretion in pancreas. The coculture with liver modulated the pancreatic differentiation by increasing the activity of important transcription factors (REST, MAFB, PBX1) and by downregulating several hormone encoding genes (INS, GCG, TTR). The liver also stimulated the expression of genes involved in the response to inflammation in pancreas (via TGFβ/SMAD pathway). In parallel we observed a pancreatic cell reorganization coupled with the activation of the cell proliferation related transcription factor (SCRT1) and the upregulation of cellular remodeling genes (FLNA, FLNB, FN1, COL4A5). Finally, the pancreatic lipid genes were also upregulated in presence of the liver tissue. Overall, our results reflect a complex synergy between both tissues. We believe that those results are an encouraging step toward the development of relevant human model using advanced organ-on-chip technology and stem cells sources.
Embryo-derived human chorionic gonadotropin promotes human decidualization through activating epithelial prostaglandin F2α secretion.
Jin DD, He YY, Ran F … +3 more , Yang HY, Yan GJ, Yang ZM
Mol Cell Endocrinol · 2025 Sep · PMID 40398806 · Publisher ↗
Decidualization of endometrial stromal cells is important for pregnancy in rodents and humans. Dysfunction of decidualization can lead to implantation failure and recurrent miscarriage. Although the amount of PGF2α in ut...
Decidualization of endometrial stromal cells is important for pregnancy in rodents and humans. Dysfunction of decidualization can lead to implantation failure and recurrent miscarriage. Although the amount of PGF2α in uterine fluid increases during embryo implantation, what stimulates the production of PGF2α in the uterus and whether PGF2α is involved in embryo implantation and decidualization are still unknown. In our study, human chorionic gonadotropin (hCG), an embryo-derived protein, stimulates human endometrial epithelial cells to increase the levels of PGF2α synthesis-related enzymes (cPLA2, COX-1, COX-2, and AKR1C3) and to secrete PGF2α. Epithelial PGF2α induces EREG and HB-EGF secretion by activating ADAM17. The level of IGFBP1, a marker of human in vitro decidualization, is significantly increased by EREG or HB-EGF. PGF2α is also able to increase the IGFBP1 level in humans during in vitro decidualization. Our results indicate that hCG stimulates uterine epithelial PGF2α production to induce in vitro decidualization through EREG and HB-EGF.
The interplay between FOXO1 and glucocorticoid signaling in promoting the terminal differentiation of somatotropes.
Das P, Stallings CE, Abubakar RA … +4 more , Mojahed N, Guha S, Abou-Jabal D, Ellsworth BS
Mol Cell Endocrinol · 2025 Sep · PMID 40381980 · Full text
Glucocorticoids play a pivotal role in terminal differentiation of pituitary somatotropes. However, the mechanisms for this remain poorly understood. Here we demonstrate that loss of the forkhead transcription factor, FO...
Glucocorticoids play a pivotal role in terminal differentiation of pituitary somatotropes. However, the mechanisms for this remain poorly understood. Here we demonstrate that loss of the forkhead transcription factor, FOXO1, severely impairs glucocorticoid-induced expression of the gene encoding growth hormone (Gh1) both in vitro and in vivo. The mechanism appears to involve glucocorticoid induction of Foxo1 expression, nuclear localization, and increased binding associated with the Gh1 gene. An additional mechanism includes stabilization of the glucocorticoid receptor, NR3C1, possibly through FOXO1 induction of the chaperone protein, HSP90. Together these data suggest that glucocorticoid signaling and FOXO1 cooperate to promote Gh1 expression, an essential aspect of somatotrope terminal differentiation.
The role of aldosterone on the endothelial dysfunction induced by female hormone deficiency.
Marcarini WD, Marques VB, Teixeira AC … +8 more , Ferreira NS, Nunes DO, Costa AKN, Ferreira KKS, Tostes RC, Ribeiro EH, Padilha AS, Stefanon I
Mol Cell Endocrinol · 2025 Aug · PMID 40379081 · Publisher ↗
Inhibition of the renin-angiotensin system prevents vascular dysfunction induced by estrogen deficiency in rats. However, the role of aldosterone in ovarian hormone deficiency-related vascular dysfunction is unclear. The...
Inhibition of the renin-angiotensin system prevents vascular dysfunction induced by estrogen deficiency in rats. However, the role of aldosterone in ovarian hormone deficiency-related vascular dysfunction is unclear. Therefore, we aimed to investigate the role of the aldosterone pathway in the endothelial dysfunction observed in isolated resistance and conduit arteries in a model of endogenous female hormone deficiency. Female Wistar rats (8 weeks old) underwent bilateral ovariectomy (Ovx) and were randomly assigned to receive daily treatment with spironolactone (Ovx Spi, 80 mg/kg), placebo (Ovx) and Sham treatment with spironolactone (Sham Spi, 80 mg/kg) or placebo (Sham group) for 60 days. In isolated aortic rings, but not mesenteric resistance arteries, Ovx increased vascular reactivity to phenylephrine that was prevented by spironolactone. Incubation with L-NAME increased the phenylephrine response in the isolated aorta in all groups, but this effect was smaller in Ovx rats. The muted response in the Ovx rats was restored by spironolactone. Apocynin, catalase, SOD, tiron and ML-171 attenuated the vascular reactivity to phenylephrine in the aorta of Ovx rats, but this effect was prevented by spironolactone. Corroborating these findings, the reduction of nitric oxide, and the increases in superoxide anion, hydrogen peroxide, NOX4 and NOX2 protein expression in aorta of Ovx rats were prevented by spironolactone. Therefore, spironolactone treatment prevented endothelial dysfunction in aorta from Ovx rats by increasing nitric oxide bioavailability and reducing NADPH oxidase-derived ROS production, suggesting a potential role of the pathway in the vascular dysfunction produced by female hormone deficiency in rats.
Hepatic estrogen-related receptor gamma is a key regulator of GDF15 production in acute and chronic liver injury.
Jung YS, Radhakrishnan K, Noh JR … +3 more , Kim YH, Lee CH, Choi HS
Mol Cell Endocrinol · 2025 Sep · PMID 40379080 · Publisher ↗
AIMS: Growth differentiation factor 15 (GDF15) is a stress-induced hepatokine with emerging roles in liver injury. Estrogen-related receptor γ (ERRγ), a nuclear receptor regulating mitochondrial function and metabolic st...
AIMS: Growth differentiation factor 15 (GDF15) is a stress-induced hepatokine with emerging roles in liver injury. Estrogen-related receptor γ (ERRγ), a nuclear receptor regulating mitochondrial function and metabolic stress, has also been implicated in various liver injury conditions. However, the regulatory interplay between ERRγ and GDF15 remains unclear. This study investigates the molecular mechanisms underlying GDF15 expression and secretion in the liver, focusing on the role of ERRγ during acute and chronic liver injury. MATERIALS AND METHODS: Wild-type and hepatocyte-specific ERRγ knockout (ERRγ-LKO) mice were administered with a single dose of carbon tetrachloride (CCl) or fed an alcohol-containing diet for 4 weeks to establish acute or chronic liver injury models, respectively. ERRγ was overexpressed through an adenoviral construct (Ad-ERRγ). The ERRγ-specific inverse agonist GSK5182 was employed to inhibit the transactivation of ERRγ. The luciferase reporter assays were used to assess the binding of ERRγ protein to the regulatory region of GDF15 gene. KEY FINDINGS: Hepatic ERRγ and GDF15 gene expression, and GDF15 protein secretion were significantly elevated in both acute and chronic liver injury. Adenovirus-mediated overexpression of ERRγ is sufficient to substantially increase hepatic GDF15 expression and secretion. Genetic ablation of ERRγ expression or pharmacological inhibition of ERRγ transactivation substantially inhibited the upregulation of hepatic GDF15 expression and production in both acute and chronic liver injury. Furthermore, reporter assays showed that ERRγ, but not ERRα or ERRβ, directly binds to and activates the GDF15 gene promoter. SIGNIFICANCE: Our findings highlight the crucial role of ERRγ in transcriptional regulation of GDF15 gene expression and production in response to liver damage. Understanding the regulatory mechanisms of GDF15 expression could lead to new therapeutic targets for protecting the liver from various types of injuries and associated diseases.
c-Jun regulates postpartum β-cell apoptosis and survival downstream of prolactin signaling.
Chung JY, Ruiz-Otero N, Banerjee RR
Mol Cell Endocrinol · 2025 Sep · PMID 40350071 · Full text
Pregnancy and postpartum states drive dynamic expansion and regression of maternal β-cell mass. Little is known about what regulates postpartum regression. We recently profiled murine islets from late gestation and early...
Pregnancy and postpartum states drive dynamic expansion and regression of maternal β-cell mass. Little is known about what regulates postpartum regression. We recently profiled murine islets from late gestation and early postpartum to identify regulators of β-cell apoptosis or survival. One hit was c-Jun, a transcription factor which regulates proliferation, apoptosis, and survival in various tissues. Here, we examine c-Jun regulation and function during gestation and postpartum and in murine and human islets. To examine the regulation of c-Jun within β-cells we used a mouse genetic model lacking β-cell prolactin receptor (PRLR) and stimulation of human and murine cultured islets with recombinant prolactin. Knockdown of c-Jun in MIN6 cells was accomplished using siRNA and lentiviral-shRNA, or in islets using pharmacologic inhibitors. We found that c-Jun expression in β-cells is temporally restricted to late gestation and early postpartum and requires PRLR signaling. Moreover, c-Jun expression was mutually exclusive with apoptotic β-cells identified by TUNEL staining. Prolactin treatment induces c-Jun expression downstream of MAPK/ERK signaling in both murine and human islets. Inhibition of c-Jun blocks prolactin-mediated survival of β-cells following pro-apoptotic stress, via the pro-survival factors Bcl2l1 (Bcl-xL) and Birc5 (Survivin). Finally, islets from pregnant donors exhibit increased c-Jun expression in β-cells, while absent in β-cells from donors with gestational diabetes (GDM). Together, our findings indicate that c-Jun contributes to pro-survival effects of lactogens downstream of PRLR/MAPK signaling in β-cells. c-Jun regulation is conserved in human islets and pregnancy and dysregulated in GDM.
Selective steroid receptor modulators, degraders and PROTACs: Therapeutic strategies in management of endocrine-related cancers.
Tripathi A, Chhabra A, Rizvi S … +1 more , Tyagi RK
Mol Cell Endocrinol · 2025 Aug · PMID 40339978 · Publisher ↗
Endocrine-related disorders are highly prevalent globally, affecting millions of people. Such diseases are multifactorial in origin and are influenced by the complex interplay of genetics, lifestyle, and environmental fa...
Endocrine-related disorders are highly prevalent globally, affecting millions of people. Such diseases are multifactorial in origin and are influenced by the complex interplay of genetics, lifestyle, and environmental factors. Recurring disruptions in the endocrine homeostasis can lead to a cascade of endocrine-related cancers. It is well known that nuclear receptors (NRs), particularly estrogen receptor and androgen receptor malfunctioning promote the oncogenesis of breast cancer and prostate cancer, respectively. However, existing therapeutics against these diseases, including aromatase inhibitors, (anti-) hormonal therapy, etc., often yield limited success, prompting to explore alternative methods of disease management. Additionally, drug resistance is prominent in cancer patients undergoing multidrug therapy. Currently, novel drug design strategies targeting NRs are being implemented for the discovery of a new generation of small molecule modulators, including selective NR modulators (SNuRMs) and degraders (SNuRDs). Moreover, proteolysis-targeting chimeras (PROTACs) as NR degraders, are also being developed primarily to overcome drug resistance, enhance protein selectivity, and mitigate off-target toxicity. This review highlights recent advancements in SNuRMs and SNuRDs for managing NRs-associated endocrine/metabolic disorders. Furthermore, we discuss the therapeutic potential of PROTAC degraders as a stand-alone strategy for receptor-mediated disease intervention, offering new avenues for precision medicine.
Estrogen increases Setdb1 cytoplasmic localization to stabilize Serpinh1 and improve protein homeostasis in osteoblasts.
Han C, Wang P, Ye J … +8 more , Wang R, Shi X, Hu G, Hu X, Shen J, Zhang M, Zhang X, Wu Y
Mol Cell Endocrinol · 2025 Aug · PMID 40324678 · Publisher ↗
Estrogen regulates osteoblast activity at the epigenetic level. Setdb1 is an epigenetic regulator that functions in skeleton homeostasis maintenance. Setdb1 shows nuclear and cytoplasm localization in cells; however, the...
Estrogen regulates osteoblast activity at the epigenetic level. Setdb1 is an epigenetic regulator that functions in skeleton homeostasis maintenance. Setdb1 shows nuclear and cytoplasm localization in cells; however, the subcellular distribution of Setdb1 and the role of cytoplasmic Setdb1 in osteoblasts are largely unknown. Here, immunofluorescence staining and immunoblotting analysis showed that the distribution of Setdb1 in the cytoplasm increased upon β-estradiol treatment by increasing nuclear Setdb1 stability in osteoblasts. In β-estradiol-treated MC3T3-E1 cells, knocking-down Atf7ip expression enhanced Setdb1 cytoplasmic localization, but the cytoplasmic distribution of Setdb1 decreased in cells treated with the Setdb1 inhibitor (R,R)-59. Moreover, ovariectomized (OVX) mice lacking Atf7ip in mature osteoblasts showed better bone microstructure than the OVX controls. The proteomic analysis of the cytoplasmic binding of Setdb1 showed that cytoplasmic Setdb1 in osteoblasts mainly functioned to regulate protein homeostasis. Setdb1 binds to Serpinh1, a regulator of pro-collagen folding and maturation, and enhances Serpinh1 stability. Interrupting Setdb1 cytoplasmic localization by treating the cells with Leptomycin B (LMB) or (R,R)-59 led to an accumulation of unfolded protein and the elicitation of endoplasmic reticulum (ER) stress. The findings revealed a previously unrecognized role of cytoplasmic Setdb1 in the regulation of β-estradiol-mediated osteoblast homeostasis, which could enhance the understanding of estrogen's mechanism of action in regulating osteoblasts.
Interactive effects of light at night and high fructose intake on the central circadian clock and endocrine outputs in rats.
Zeman M, Stefanik P, Rumanova VS … +1 more , Okuliarova M
Mol Cell Endocrinol · 2025 Aug · PMID 40311860 · Publisher ↗
Light pollution is an increasing global environmental risk factor that contributes to the recent burden of metabolic diseases. The underlying mechanisms are not understood, but disruption of circadian control of physiolo...
Light pollution is an increasing global environmental risk factor that contributes to the recent burden of metabolic diseases. The underlying mechanisms are not understood, but disruption of circadian control of physiological and behavioural processes may be involved. The negative consequences of chronodisruption can be augmented by co-exposure to high energy intake. Therefore, we investigated the individual and combined effects of artificial light at night (ALAN) and 10 % fructose in drinking water on the central clock in the suprachiasmatic nuclei (SCN) of the hypothalamus and circadian hormonal outputs in male rats. After 10 weeks of ALAN exposure and high fructose intake, the clockwork in the SCN was attenuated as indicated by eliminated day/night differences in the core clock gene Per1. Additionally, ALAN suppressed the daily variability and fructose induced upregulation of a gamma-aminobutyric acid-synthesising enzyme (GAD65), potentially affecting inhibitory neurotransmission in the SCN. ALAN and fructose additively inhibited plasma melatonin levels revealing excessive fructose intake as a chronodisruptive factor that can be potentiated by ALAN. In contrast to melatonin, daytime plasma testosterone concentrations were increased by high fructose and supressed by ALAN. Furthermore, high fructose intake elevated the plasma levels of two adipokines, leptin and adiponectin, but this response was absent specifically during the daytime in rats exposed to ALAN, indicating that ALAN reduced adipose tissue responsiveness. Our results document the complex consequences of ALAN and high fructose intake on endocrine control mechanisms that can have a long-term negative impact on metabolic health.
The environmental contaminants, tributyltin and bisphenol S, alone or in combination, harm the hypothalamus-pituitary-gonadal axis and uterus.
de Sousa Anselmo D, Cunha Azeredo DB, Junior RR … +7 more , Lopes de Souza L, Lisboa PC, Graceli JB, de Brito Gitirana L, Freitas Ferreira AC, Paiva-Melo FD, Miranda-Alves L
Mol Cell Endocrinol · 2025 Aug · PMID 40306609 · Publisher ↗
Endocrine disrupting-chemicals (EDCs) are chemical compounds found in the environment that can have adverse impacts on human health. Among these agents are tributyltin (TBT) and bisphenol S (BPS). TBT is used in anti-fou...
Endocrine disrupting-chemicals (EDCs) are chemical compounds found in the environment that can have adverse impacts on human health. Among these agents are tributyltin (TBT) and bisphenol S (BPS). TBT is used in anti-fouling paints, and its indiscriminate use has health repercussions. BPS is found in plastic products and marketed as a safe alternative to bisphenol A (BPA). Little is known about the effects resulting from interactions between different EDCs on the organisms. The aim of this study was to analyze changes induced by exposure to these compounds in hypothalamic-pituitary-gonadal (HPG) axis and uterus. We divided four groups: Control, TBT 100 ng kg.day, BPS 50 μg kg.day, and the group simultaneously exposed to TBT and BPS. Rats were gavaged for 15 days and euthanized in the estrus phase. All EDCs groups showed uterus with cellular hyperplasia, glandular degeneration, increased epithelial thickness, and vacuolization. In the ovaries, there was an increase in atretic follicles in all EDCs groups. In the hypothalamus, the group exposed to the mixture showed an increase in the GnRH gene. In the blood, all EDCs groups had reduced levels of FSH and LH. Additionally, the BPS and mixture groups exhibited reduced levels of prolactin. Therefore, we suggest that exposure to these agents may contribute to damage to the female reproductive system, and that doses considered safe by regulatory agencies need to be reassessed.
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