Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
Hsp90α as a promising therapeutic target for suppressing tumor progression in Lactotroph PitNETs.
Wu J, Zhou Z, Ding C … +5 more , Sun H, Xia M, Zhou K, Zhang T, Li S
Mol Cell Endocrinol · 2026 Apr · PMID 41539368 · Publisher ↗
BACKGROUND: Aggressive Lactotroph Pituitary Neuroendocrine Tumors (Lactotroph PitNETs) usually exhibit invasive growth behavior and resistance to dopamine agonists, showing difficulty in radical treatment and a high recu...
BACKGROUND: Aggressive Lactotroph Pituitary Neuroendocrine Tumors (Lactotroph PitNETs) usually exhibit invasive growth behavior and resistance to dopamine agonists, showing difficulty in radical treatment and a high recurrence rate. Heat shock protein 90α(Hsp90α),a pivotal isoform of the heat shock protein 90(Hsp90) family, acts as a central chaperone that stabilizes numerous oncoproteins driving tumor progression, but its role in Lactotroph PitNETs remains unclear. OBJECTIVE: To study the effect of Hsp90α knockdown on the proliferation and invasiveness of Lactotroph PitNETs cells (MMQ). METHODS: Hsp90α and EGFR expression was compared between 18 aggressive and 22 Non-Aggressive human Lactotroph PitNETs by IHC and immunofluorescence. MMQ rat lactosomatotroph cells were transduced with lentiviral shRNA targeting Hsp90α(shHsp90α). Cell proliferation (CCK8),apoptosis (Annexin-V/7-AAD flow cytometry), Prolactin (PRL) secretion (ELISA), migration and invasion (Transwell) were assessed. Western blotting evaluated EGFR,PRL,AKT,ERK1/2,mTOR,p-AKT,p-ERK1/2 and p-mTOR. RESULTS: Aggressive Lactotroph PitNETs displayed higher Hsp90α and EGFR expression and showed a notable degree of spatial overlap. Hsp90α knockdown reduced EGFR,AKT,ERK1/2,mTOR,p-AKT,p-ERK1/2 and p-mTOR levels, decreased proliferation, increased apoptosis, lowered PRL secretion, and impaired migration and invasion. CONCLUSIONS: Hsp90α knockdown simultaneously destabilizes EGFR and its downstream AKT/mTOR and ERK axes, resulting in multi-modal suppression of Lactotroph PitNETs invasion. Targeting Hsp90α may offer a novel therapeutic strategy for Aggressive Lactotroph PitNETs refractory to standard medical therapy.
Developmental exposure to a mixture of propiconazole and glyphosate induces histopathological lesions in the prostate of postpubertal rats.
Gomez AL, Reato DG, Masat E … +2 more , Kass L, Altamirano GA
Mol Cell Endocrinol · 2026 Apr · PMID 41506592 · Publisher ↗
Pesticide mixture exposure during critical developmental windows is a growing public health concern, given their potential additive or synergistic effects on the male reproductive system. This study aimed to evaluate whe...
Pesticide mixture exposure during critical developmental windows is a growing public health concern, given their potential additive or synergistic effects on the male reproductive system. This study aimed to evaluate whether developmental exposure to a mixture of propiconazole (PRO) and glyphosate (GLY) alters the postpubertal rat prostate. Pregnant rats were orally exposed to vehicle (saline) or a mixture of PRO and GLY (4 mg PRO/kg/day and 3.7 mg GLY/kg/day) from gestation day 9 until weaning. On postnatal day 60, male offspring were euthanized, and the prostate and serum samples were collected. PROGLY-exposed rats exhibited changes in the ventral and dorsolateral prostate histoarchitecture, including epithelial and stromal remodeling and increased incidence of prostate lesions. In the ventral prostate, although the relative glandular area remained unchanged, PROGLY exposure exhibited increased epithelial height and decreased luminal acinar area. Also, hyperplastic and atrophic acini were more prevalent in these animals. PROGLY exposure reduced estrogen receptor beta (ESR2) protein level, particularly in hyperplastic and atrophic acini, without affecting androgen or estrogen receptor alpha. ESR2 decrease was associated with an increased cell proliferation index in hyperplastic acini and a reduction in serum testosterone level in PROGLY-exposed rats. Stromal alterations included increased smooth muscle cell layers and reduced vimentin-positive fibroblasts, with no evidence of myofibroblast presence. This study shows that developmental exposure to PROGLY disrupts normal ventral prostate architecture and hormone signaling in postpubertal rats. These findings highlight the potential long-term risks of combined pesticide exposure on male reproductive health and the importance of evaluating mixture effects.
Integrative advances in endocrine oncology: From unique glimpses to familiar themes.
Ezzat S
Mol Cell Endocrinol · 2026 Mar · PMID 41475654 · Publisher ↗
The field of endocrine oncology is benefiting from broad advances based on key insights in the pathogenesis of neoplasia. While traditionally regarded as unique and distinct entities from non-endocrine neoplasias, deeper...
The field of endocrine oncology is benefiting from broad advances based on key insights in the pathogenesis of neoplasia. While traditionally regarded as unique and distinct entities from non-endocrine neoplasias, deeper molecular profiling studies of endocrine tumors are now challenging this dogma. In this group of papers, experts from across the field provide their perspectives. Each group focuses on a different endocrine gland which they use as a model that highlights the spectrum of disease behavior. It is hoped that collective reflection on these vignettes will reveal new opportunities that can facilitate more effective detection and therapeutic approaches.
Toward intelligent hormonal diagnostics: Quantum dots reshaping endocrine disease detection.
Gemini-Piperni S, Aribigbola T, Murucci MD … +7 more , Bello ZM, Goldstein ADC, Olayinka OS, Dao TNP, Dezonne RS, Onikanni SA, Miranda-Alves L
Mol Cell Endocrinol · 2026 Mar · PMID 41453713 · Publisher ↗
Endocrine disorders necessitate diagnostic platforms capable of detecting rapid, low-abundance, fluctuating hormonal signals with high precision. Quantum dot (QD) technology has revolutionized this field by enabling mult...
Endocrine disorders necessitate diagnostic platforms capable of detecting rapid, low-abundance, fluctuating hormonal signals with high precision. Quantum dot (QD) technology has revolutionized this field by enabling multiplexed, ultrasensitive, and real-time biochemical profiling. Unlike traditional immunoassays limited to single-analyte detection and signal decay, QDs offer exceptional photostability, quantum-level sensitivity, and tunable emission, allowing simultaneous monitoring of various hormonal biomarkers related to thyroid, pancreatic, adrenal, and reproductive dysfunctions. Recent advancements have combined QDs with AI-assisted signal decoding, microfluidics, and wearable biosensor interfaces, creating intelligent systems capable of predicting trends rather than providing static measurements. Functionalized QDs engineered with aptameric, peptidic, or antibody-based recognition domains have shown promising diagnostic capabilities for insulin, estradiol, and thyroid hormones in complex biological samples. As biocompatible QD formulations continue to evolve, their integration with digital health platforms positions them as the next frontier in continuous endocrine monitoring, early disease detection, and personalized hormonal medicine. This review highlights key technological advancements, translational hurdles, and future directions necessary to propel QD-enabled endocrine diagnostics from the laboratory to clinical practice.
EGR1 promotes ferroptosis in endometriosis through transcriptional activation of HMOX1.
Yang F, Liu D, Hu L … +17 more , Tan H, Wei Y, Yang R, Huang B, Zou Q, Wu Q, He Y, Mai H, Lan X, Yan Y, Huang Z, Huang X, Fu Z, Deng Z, Huang Q, Yao S, Liang Y
Mol Cell Endocrinol · 2026 Mar · PMID 41422938 · Publisher ↗
Endometriosis (EM) affects approximately 10% of women of reproductive age and remains a prevalent estrogen-dependent gynecological disorder with limited therapeutic efficacy and high recurrence rates. Ferroptosis-an iron...
Endometriosis (EM) affects approximately 10% of women of reproductive age and remains a prevalent estrogen-dependent gynecological disorder with limited therapeutic efficacy and high recurrence rates. Ferroptosis-an iron-dependent, non-apoptotic form of regulated cell death driven by lipid peroxidation-has recently been recognized to play a paradoxical role in EM pathogenesis. To explore ferroptosis-related mechanisms in EM, this study integrated transcriptomic profiling from five Gene Expression Omnibus datasets (GSE6364, GSE7305, GSE11691, GSE23339, GSE51981) with machine learning algorithms and functional validation. Bioinformatic analysis identified 19 ferroptosis-related differentially expressed genes, with hub genes prioritized through protein-protein interaction network analysis. LASSO regression, support vector machine, and random forest models collectively identified EGR1, HMOX1, TIMP1, and FABP4 as robust diagnostic biomarkers, with strong performance in receiver operating characteristic analysis. Clinical validation confirmed significant upregulation of EGR1 and HMOX1 in ectopic endometrial tissues. Functional assays in 12Z endometriotic cells showed that EGR1 silencing partially attenuated erastin-induced ferroptosis by restoring mitochondrial membrane potential, reducing lipid peroxidation, and modulating key ferroptosis markers. Mechanistically, JASPAR analysis predicted EGR1 binding to conserved motifs in the HMOX1 promoter, which was validated using chromatin immunoprecipitation quantitative PCR and dual-luciferase reporter assays. Together, these results identify the EGR1/HMOX1 axis as a novel regulatory hub in EM-associated ferroptosis, offering new insights into diagnostic biomarkers. Therefore, targeting this axis may disrupt iron-redox crosstalk, offering a promising therapeutic avenue to mitigate endometriosis progression.
Estrogen therapies enhance mammary carcinogenesis in aging gerbil females under endocrine disruption.
Ruiz TFR, Silva SB, Grigio V … +5 more , Rahal P, Calmon MF, Vilamaior PSL, Leonel ECR, Taboga SR
Mol Cell Endocrinol · 2026 Mar · PMID 41419093 · Publisher ↗
Breast cancer is closely associated with the hormonal sensitization that the mammary gland (MG) undergoes. We evaluated the effects of endogenous (E2) and synthetic (EE2) estrogens, commonly used as hormonal therapies du...
Breast cancer is closely associated with the hormonal sensitization that the mammary gland (MG) undergoes. We evaluated the effects of endogenous (E2) and synthetic (EE2) estrogens, commonly used as hormonal therapies during menopause, in a context of a pro-carcinogenic environment of endocrine disruption. This scenario was modeled to mimic the menopausal involution of the MG during aging in the Mongolian gerbil experimental model under previous bisphenol A exposure, during pregnancy and lactation. Our findings revealed significant remodeling of the epithelial compartment, characterized by increased branching density and loss of normal features, including decreased CD117+ luminal cells and loss of E-cadherin expression. Hormonal therapy with E2 or EE2 led to the development of epithelial lesions, characterized by an increase in invasive microcarcinomas and a decrease in basal (p63+α-SMA-) and myoepithelial (p63+α-SMA+) progenitor cells, contributing to increased neoplastic invasiveness. These changes were orchestrated by overexpression of EZH2 and a decrease in BRCA1, indicating a poor prognosis, especially for EE2. Furthermore, an imbalance between proliferation (PH-H3 cells) and apoptosis (cleaved caspase 3) was observed in the MG of females treated with E2 and EE2. Additionally, distinct hormone receptor profiles were identified, with consistent upregulation of ERα and concomitant downregulation of ERβ and PR, particularly in EE2-treated MG. These alterations may contribute to the observed dysregulation of proliferation and apoptosis. Our results demonstrate that estrogenic hormonal therapies promote neoplastic progression of the aging MG previously subjected to endocrine disruption.
Endocrine programming of the pituitary-thyroid-adrenal axis: Sex-Specific effects of maternal malnutrition in rats.
Vieira ALS, Cordeiro GM, Andrade Felipe VA … +9 more , Fioretto MN, Barata LA, Pires MP, Vitali PM, Mattos R, Ribeiro IT, Maciel FA, Baptista HS, Justulin LA
Mol Cell Endocrinol · 2026 Mar · PMID 41407027 · Publisher ↗
The Developmental Origins of Health and Disease (DOHaD) concept highlights that early-life development can be influenced by environmental factors, leading to long-term metabolic programming in the offspring. Maternal Pro...
The Developmental Origins of Health and Disease (DOHaD) concept highlights that early-life development can be influenced by environmental factors, leading to long-term metabolic programming in the offspring. Maternal Protein Restriction (MPR) is a well-established model within this framework, inducing cellular stress and hormonal imbalances that disrupt basal metabolic regulation in descendants. We aim to investigate the consequences of MPR (6 %) on the metabolism and the pituitary-thyroid-adrenal axis of male and female postweaning rats. Systemically, there was a decrease in hormones T3 and T4 in the males and a decrease in T4 in the females. In the pituitary, we observed an increase in the Ppar a, Ppar g, and Neurod1 gene expression and a decrease in the Prl gene in the males of the GLLP group, while females exhibited a decrease in the Pomc and Ir gene expression. In the thyroid, male rats showed an increase in the Tshr and Ar gene expression. In gene expression of adrenal glands, we observed an increase in the expression of the Sts gene in males and a decrease in Cyp21a2 and Mao in females. In silico analyses demonstrated the potential sex-specific disturbance of MPR, mainly on developmental biology, endocrine response, endoplasmic reticulum, and endocytic pathways, indicating a risk scenario for endocrine diseases. Therefore, we conclude that MPR directly affects the early functioning of the pituitary-thyroid-adrenal axis in a sex-specific manner, highlighting its role in metabolic programming and the developmental origins of endocrine disorders.
Role of FKBP5 in adipose tissue function: Implications for obesity and insulin sensitivity.
Laterveer R, Hetty S, Mathioudaki A … +6 more , Lundqvist MH, Svensson MK, Sundbom M, Katsogiannos P, Eriksson JW, Pereira MJ
Mol Cell Endocrinol · 2026 Mar · PMID 41397645 · Publisher ↗
FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is a key regulator of glucocorticoid signaling and has been implicated in metabolism and insulin sensitivity, but its specific role in human adipose tissue rem...
FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is a key regulator of glucocorticoid signaling and has been implicated in metabolism and insulin sensitivity, but its specific role in human adipose tissue remains unclear. This study investigated the role of FKBP51 in human adipose tissue and its impact on glucose metabolism and insulin signaling. FKBP5 was measured in paired subcutaneous (SAT) and omental (OAT) adipose tissue samples from 56 subjects with and without obesity, and in SAT from individuals with obesity during weight loss up to 104 weeks post-bariatric surgery. Furthermore, FKBP51 knockdown adipocytes were used to study its effects on insulin signaling and glucose uptake. FKBP5 gene expression, but not protein expression, was significantly lower in obese individuals in both SAT and OAT compared to lean and overweight subjects, and it inversely correlated with insulin resistance measured by homeostatic model assessment of insulin resistance (HOMA-IR). After bariatric surgery, FKBP5 expression in SAT increased to levels similar to those in non-obese controls. Knockdown of FKBP5 in human adipocytes reduced GLUT1 gene expression and insulin-stimulated AKT Ser473 phosphorylation, however, maximal insulin-stimulated glucose uptake rate remained unchanged. Our findings suggest that FKBP5 levels in adipose tissue are reduced in obesity, and this decrease impairs insulin signaling in adipocytes without altering maximal glucose capacity, indicating a limited effect on glucose uptake under the tested conditions.
The in vivo metabolism of 11-oxyandrogens and 11-oxyprogesterones: novel pathways in the steroid metabolome.
Swart AC, Heyns B, Kidd M … +2 more , Pieters R, Atkin SL
Mol Cell Endocrinol · 2026 Mar · PMID 41391652 · Publisher ↗
The steroid metabolome remains incomplete as the metabolic pathways of the 11-oxyprogestogens and 11-oxyandrogens, biosynthesized in the adrenal and converted in the periphery, have never been characterized in vivo. This...
The steroid metabolome remains incomplete as the metabolic pathways of the 11-oxyprogestogens and 11-oxyandrogens, biosynthesized in the adrenal and converted in the periphery, have never been characterized in vivo. This study aims to identify these 11-oxy steroids in the human hair follicle. Hair segments provide a matrix representing one month of steroid production, unaffected by the circadian rhythm. Steroids were extracted from 37 segments using a novel automated method, and 52 steroids were analyzed using ultra-performance convergence chromatography-tandem mass spectrometry. Quantification of intermediates and end-products of 11-hydroxyprogesterone, 21-deoxycortisol, 11-hydroxyandrostenedione and 11-hydroxytestosterone identified nine novel 11-oxy steroids and showed: 11-hydroxyprogesterone metabolites >21-deoxycortisol metabolites: 170-1400 v. 190-540 pg/mg; 11-oxyandrogens > classical androgens: 600-1500 v. 110-350 pg/mg; active 11-oxyandrogens > active classical androgens: in females, 36.5 v. 1.3 pg/mg, and in males, 60.75 v. 11.7 pg/mg. The most abundant active androgen in both genders was 11-hydroxydihydrotestosterone; 11-ketodihydrotestosterone was detected in males only; 11-hydroxytestosterone levels were comparable, and 11-ketotestosterone levels were higher in males. The most abundant 11-oxyprogestogens in both genders were 11-ketoprogesterone (55.7-2173.8 pg/mg) and two metabolites, 11-oxo-17-hydroxyallopregnanolone (11KPdione) and 11,17-dihydroxyallopregnanolone (11OHPdiol). Metabolites included the neurosteroid, alfaxalone (11-ketoallopregnanolone), and another potential neurosteroid 11-hydroxyallopregnanolone. This is the first targeted study profiling the 11-oxyandrogens and the 11-oxyprogestogens and their respective metabolites in humans. Novel in vivo steroidogenic pathways have been confirmed, not necessarily linked to clinical conditions, having utility in clinical diagnostics reliant on the steroid metabolome.
CD36 may regulate glycolytic and steroidogenic processes but not the fatty acid uptake in bovine granulosa cells.
Tao X, Michaelis M, Brenmoehl J … +2 more , Vanselow J, Baddela VS
Mol Cell Endocrinol · 2026 Mar · PMID 41389983 · Publisher ↗
Postpartum metabolic stress increases non-esterified fatty acid (NEFA) concentration in follicular fluid, thereby impairing oocyte and granulosa cell (GC) function. CD36, a multifunctional scavenger receptor, is involved...
Postpartum metabolic stress increases non-esterified fatty acid (NEFA) concentration in follicular fluid, thereby impairing oocyte and granulosa cell (GC) function. CD36, a multifunctional scavenger receptor, is involved in the uptake of NEFAs in various cell types. This study examines lipid droplet (LD) accumulation and CD36 expression in GCs treated with oleate (OA), palmitate (PA), stearate (SA), and their combination. We also explored the role of CD36 in lipid uptake, glucose metabolism, and steroidogenesis in GCs. Flow cytometry analysis revealed that SA, OA, and the combined NEFA treatments resulted in significant LD accumulation, while PA had a minimal effect. Interestingly, CD36 expression mirrored the levels of LD accumulation in all treatments. However, SLC27A1, another highly expressed NEFA transporter, was upregulated by SA but was unchanged by PA and OA treatments. Combination of OA, PA, and SA has increased both CD36 and SLC27A1 expression. OA treatment induced a dose-dependent increase in LD accumulation and CD36 expression. However, CD36 knockdown did not affect either LD accumulation or triglyceride levels, indicating that CD36 is not essential for NEFA uptake, despite its increased expression. Previously, we showed that OA enhances glycolysis in GCs; here, we found that CD36 is involved in glucose metabolism as its silencing significantly reduced the extracellular acidification rate and mitochondrial membrane potential in GCs. Furthermore, CD36 knockdown significantly reduced progesterone production. These findings suggest that while CD36 is dispensable for NEFA uptake, it may play a regulatory role in maintaining glycolytic activity, mitochondrial function, and steroidogenesis in GCs under elevated NEFA levels.
Bone marrow transplantation attenuates inflammation and improves glycemic control in type 2 non-obese diabetic Goto-Kakizaki rats.
de Oliveira Borges JC, Correa IS, Gimenes GM … +15 more , de Araújo Ferreira L, de Moura Silva MAR, Pauferro JRB, Lobato TB, Alves ACDA, Pereira ACG, Souza KO, Dos Santos CS, Levada-Pires AC, Pithon-Curi TC, Marzuca-Nassr GN, Hirabara SM, Curi R, Gorjão R, Masi LN
Mol Cell Endocrinol · 2026 Mar · PMID 41389982 · Publisher ↗
Chronic hyperglycemia induces changes in the bone marrow (BM) microenvironment, favoring the expansion and differentiation of stem cells toward a pro-inflammatory profile. Since leukocyte recruitment plays a key role in...
Chronic hyperglycemia induces changes in the bone marrow (BM) microenvironment, favoring the expansion and differentiation of stem cells toward a pro-inflammatory profile. Since leukocyte recruitment plays a key role in chronic inflammation during the onset of type 2 diabetes mellitus (T2DM), the aim of this study was to evaluate the influence of bone marrow transplantation (BMT) on glycemic control and inflammatory markers in Goto-Kakizaki (GK) rats transplanted after weaning. GK rats are spontaneously non-obese, T2DM animals. We performed BMT from normoglycemic Wistar (WT) rats to GK animals (aged 28 days), previously immunosuppressed with busulfan (20 mg/kg) and cyclophosphamide (150 mg/kg). The mRNA expression of pro-inflammatory cytokines IL-1β and IL-7 was increased in the BM of weaned GK rats, and it was reduced in the BM mononuclear cells (BMMCs) 100 days after BMT. Hepatic cytokine levels were also evaluated by flow cytometry to calculate the Inflammatory Marker Index (based on IFN-γ, TNF-α, IL-6, and IL-10), which was decreased in transplanted GK rats. Moreover, transplanted GK rats also showed reduced fasting glucose evaluated at 30, 60, and 90 days after transplantation. BMT also induced a significant decrease in plasma insulin and attenuated insulin resistance (HOMA-IR). Overall, BMT in just-weaned GK rats, characterized by an elevated inflammatory profile in the BM and liver, culminated in improvement of glycemic control compared with non-transplanted GK animals. In conclusion, modulation of the BM microenvironment emerges as a novel therapeutic avenue for managing non-obese T2DM and preventing its complications.
Prenatal perfluorooctanoic sulfonate exposure is associated with polycystic ovary syndrome-like and related traits in female offspring mice.
Urrutia-Lopez C, González-Carranza L, Barajas-Salinas A … +11 more , Bonilla E, Rodriguez-Mercado JJ, Aviles A, Langley E, Reyes-Grajeda JP, Casillas F, Lopez A, Casas E, Betancourt M, González-Torres MC, Bahena-Ocampo I
Mol Cell Endocrinol · 2026 Mar · PMID 41386421 · Publisher ↗
Polycystic Ovary Syndrome (PCOS), is the most common female endocrine disorder affecting women of reproductive age. Its prevalence is estimated to be up to 13 % worldwide. This heterogeneous clinical condition is charact...
Polycystic Ovary Syndrome (PCOS), is the most common female endocrine disorder affecting women of reproductive age. Its prevalence is estimated to be up to 13 % worldwide. This heterogeneous clinical condition is characterized by marked clinical and/or biochemical hyperandrogenism, ovulatory dysfunction, and frequent development of polycystic ovaries. Several studies have focused on the relationship between endocrine-disrupting pollutants and PCOS development. Perfluorooctanesulfonate (PFOS) is ubiquitously detected in the environment. Exposure to endocrine-disrupting chemicals, including PFOS, during early fetal development may lead to alterations similar to the PCOS phenotype. Using mice as a model, we compared the effects of prenatal exposure to PFOS or dihydrotestosterone (a model of PCOS induction). After analyzing steroid status, we detected delayed pubertal onset accompanied by increased testosterone concentrations in adulthood, as well as altered estrous cycles with a longer metestrus phase. At this point, two of three Rotterdam criteria have been confirmed as PCOS features. Finally, we identified endocrine disruption in the ovaries from adult females prenatally exposed to PFOS, as evidenced by altered expression of genes involved in steroidogenesis pathways, as well as altered expression of gonadotropin hormone receptors, and Amh signaling. These data support a role of PFOS in endocrine disruption and in promoting development of PCOS symptom development.
Developmental programming: gestational exposure to excess testosterone disrupts maternal steroid homeostasis and perturbs the steroid-lipid relationship in sheep.
Saadat N, Saeed R, Pallas B … +3 more , Vyas AK, Auchus RJ, Padmanabhan V
Mol Cell Endocrinol · 2026 Mar · PMID 41297875 · Full text
Gestational hyperandrogenism may disrupt the steroid and lipid metabolism homeostatic balance that is important for pregnancy progression. We hypothesized that excess gestational testosterone would disrupt the maternal s...
Gestational hyperandrogenism may disrupt the steroid and lipid metabolism homeostatic balance that is important for pregnancy progression. We hypothesized that excess gestational testosterone would disrupt the maternal steroid profile and the steroid-lipid relationship. Using sheep, we investigated maternal delta-4 (Δ4) and delta-5 (Δ5) steroids and the steroid-lipidome relationship in gestational testosterone excess (n = 12, 100 mg T-propionate days 30-90 of gestation twice-weekly intramuscularly) and control (n = 5, vehicle) Suffolk sheep. Steroids were measured using liquid chromatography-tandem mass spectrometry and lipids by shotgun lipidomics. Principal component analysis showed clear separation of control and the gestational testosterone excess groups. The main impact of testosterone excess was on the Δ5 pathway, with reductions in 17-OH pregnenolone, androstenediol, allopregnanolone, and androsterone. In the Δ4 pathway only a trend for reduced androstenedione and a large magnitude increase in corticosterone and decrease in 11-deoxycorticosterone was observed. Dimensionality reduction partial least squares regression models revealed disruptive impact of testosterone-excess on the steroid-lipid relationship prevailing in controls namely with lipid biosynthesis and metabolism and enrichment in cholesterol biosynthetic, circadian clock and transcriptional regulatory, and liver steatosis pathways. Disrupted steroid-lipid associations in the gestational testosterone excess group showed linkage to complex disease-profiles centering on lipid metabolism and transport, cholesterol, and of relevance to hyperlipidemia, gestational diabetes, and hypertension in the enrichment analysis. Fewer lipid species were associated with individual steroids in gestational testosterone excess group, indicative of loss of the majority of the homeostatic steroid-lipid associations. This study provides a novel screening insight into the steroid-lipid relationship that prevails during normal pregnancy and the disruptive impact of hyperandrogenism in perturbing this homeostasis.
In vitro activation of brown adipocyte thermogenesis by fermented hypholomine B-enriched Sanghuangporus sanghuang mycelia through FNDC5/Irisin pathway.
Li IC, Chan YE, Lin YL … +5 more , Wu TY, Wu LY, Tsai CY, Lin HT, Chen CC
Mol Cell Endocrinol · 2026 Feb · PMID 41285360 · Publisher ↗
In the face of the global obesity epidemic (globesity), we present the first comprehensive investigation of fermented Sanghuangporus sanghuang mycelia extract (SS-IM1) and its novel bioactive compound hypholomine B in br...
In the face of the global obesity epidemic (globesity), we present the first comprehensive investigation of fermented Sanghuangporus sanghuang mycelia extract (SS-IM1) and its novel bioactive compound hypholomine B in brown adipose tissue activation. Using HEK293 cells with FNDC5 promoter-EGFP constructs and differentiated 3T3-L1 adipocytes, we demonstrate that both compounds significantly enhance FNDC5 expression and irisin secretion. We reveal distinct mechanistic profiles: SS-IM1 showed superior efficacy in irisin induction and thermogenesis activation, while isolated hypholomine B demonstrated unprecedented potency in reducing lipid accumulation. Seahorse analysis revealed enhanced mitochondrial respiration and UCP1-mediated proton leak, confirming their thermogenic effects. Furthermore, we discovered that SS-IM1 uniquely enhanced glucose uptake through GLUT4 upregulation. These findings not only elucidate novel molecular mechanisms underlying the anti-obesity effects of S. sanghuang but also establish hypholomine B as a promising first-in-class therapeutic candidate for addressing the worldwide challenges of obesity and metabolic disorders.
Androgen deprivation induces distinct muscle-specific transcriptional changes to genes regulating glucose, lipid, and amino acid metabolism.
Ayers-Creech WA, Steiner JL, Laskin GR … +1 more , Gordon BS
Mol Cell Endocrinol · 2026 Feb · PMID 41274596 · Publisher ↗
BACKGROUND: Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered am...
BACKGROUND: Androgens such as testosterone regulate whole-body metabolic homeostasis. Low androgen levels lead to undesirable shifts in metabolism including lower glucose oxidation, greater lipid reliance, and altered amino acid metabolism. Skeletal muscle is a primary site regulating fuel substrate metabolism, but whether all muscles contribute to the undesirable metabolic shifts in response to low androgen levels is unclear. METHODS AND RESULTS: Male mice underwent sham or castration surgery and muscles were harvested 7, 14-, 21-, 28-, or 49-days post-surgery. The content of genes related to glucose, lipid, and amino acid metabolism were assessed in the tibialis anterior (TA) and gastrocnemius muscles. The content of genes related to glucose metabolism were altered in a manner consistent with lower rates of oxidation in both the TA and gastrocnemius following castration although the magnitudes of change were generally more pronounced in the TA. Genes related to lipid oxidation were altered in a manner consistent with higher oxidation rates only in the TA following castration. Genes related to amino acid catabolism were paradoxically unaltered or even lower in both muscles in response to castration. CONCLUSION: These findings indicate that the TA undergoes more pronounced transcriptional changes related to glucose and lipid metabolism compared to the gastrocnemius, likely contributing more to whole-body metabolic shifts during androgen deprivation.
Brain derived neurotrophic factor promotes oocyte maturation through the TrkB-MAPK-PI3K pathway in zebrafish.
Uju C, Unniappan S
Mol Cell Endocrinol · 2026 Feb · PMID 41248839 · Publisher ↗
Brain-derived neurotrophic factor (BDNF) was previously reported as a positive modulator of zebrafish reproduction, yet the mechanism of action of BDNF that elicits this function is unknown. We hypothesized that the pro-...
Brain-derived neurotrophic factor (BDNF) was previously reported as a positive modulator of zebrafish reproduction, yet the mechanism of action of BDNF that elicits this function is unknown. We hypothesized that the pro-reproductive effects of BDNF in female zebrafish are mediated by TrkB signaling. In zebrafish liver (ZFL) cells, a TrkB antagonist (ANA-12) blocked the stimulatory effect of BDNF on transcript abundance of vitellogenin (vtg1, 2, 4, and 7) and steroidogenic factor 1 (sf-1). No changes were observed in hepatocyte nuclear factor 4 alpha, specificity protein 1, cAMP response element-binding protein 1a, or forkhead box L2. Blocking the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K), and phospholipase C gamma (PLC-γ) pathways significantly attenuated BDNF-induced upregulation of vtg and sf-1 transcripts. Total vtg protein was increased by BDNF, an effect that was blunted when TrkB, MAPK, PI3K, or PLC-γ were blocked. The estrogen receptor alpha (Esrα) fluorescence immunoreactivity in the ZFL cells treated with BDNF was significantly reduced in the presence of ANA-12. In the zebrafish follicles, BDNF-induced oocyte maturation was attenuated by TrkB, MAPK-, and PI3K inhibitors, but not a PLC-γ blocker. Similarly, the positive effects of BDNF on maturation-related genes 3β-hydroxysteroid dehydrogenase 2 enzyme (3bhsd2), cytochrome P450 family 17, hyaluronan synthase 2, luteinizing hormone receptor, and prostaglandin synthase 2 were significantly attenuated when TrkB, MAPK, or PI3K was blocked. PLC-γ inhibition prevented the BDNF-induced upregulation of 3bhsd1 in the oocytes. This study demonstrates that BDNF promotes vitellogenesis via the TrkB-MAPK/PI3K/PLC-γ signaling pathways. Meanwhile, BNDF enhances oocyte maturation through the TrkB-MAPK/PI3K pathways in zebrafish.
Role of visfatin on early embryogenesis in normal weight and obese mice. Studies on siRNA induced knockdown model.
Kurowska P, Honda S, Tanaka G … +4 more , Yuwei G, Minami N, Rak A, Ikeda S
Mol Cell Endocrinol · 2026 Feb · PMID 41241247 · Publisher ↗
Visfatin/Nampt, an adipokine upregulated in obesity, has been implicated in oocyte maturation, but its role in early embryogenesis remains poorly understood. This study investigated visfatin/Nampt function during preimpl...
Visfatin/Nampt, an adipokine upregulated in obesity, has been implicated in oocyte maturation, but its role in early embryogenesis remains poorly understood. This study investigated visfatin/Nampt function during preimplantation development in normal-weight and high-fat diet-induced obese mice. Nampt mRNA expression was examined in embryos from the 1-cell to the blastocyst stage, and siRNA-mediated Nampt silencing was performed at the 1-cell stage. Embryo development was assessed by cleavage and blastocyst formation rates, while molecular effects were evaluated via qPCR analysis of maternal-effect and proliferation/apoptosis, differentiation genes, immunofluorescence detection of pluripotency/differentiation markers, and transcriptome profiling (RNA-seq). The functional reproductive outcomes, including implantation rates, offspring number, and ovarian gene expression (qPCR) in the progeny, were also analyzed. Nampt expression decreases during early embryogenesis. Nampt silencing impaired blastocyst formation in obese mice and altered lineage marker expression, increasing NANOG in normal-weight embryos and reducing GATA6-positive cells in obese embryos. Transcriptomic analysis of normal-weight blastocysts revealed 73 upregulated and 24 downregulated genes enriched in pathways regulating apoptosis, energy metabolism, and development. Although the implantation rates and offspring numbers were unchanged, offspring from Nampt-silenced embryos presented altered ovarian gene expression linked to steroidogenesis and oogenesis. This work provides the first transcriptomic analysis of blastocysts following siRNA-mediated Nampt silencing and demonstrates that visfatin/Nampt modulates early lineage allocation in a manner dependent on maternal metabolic status. These findings extend visfatin research beyond oocyte maturation and highlight its potential contribution to embryonic programming.
Serotonin promotes aggressive features in breast cancer cells by modulating proliferation and migration, hormone receptors and HER2 expression.
Paixão LP, Nascimento Junior JXD, Espírito Santo MESFD … +9 more , Imbroisi Filho R, Bernardo Leandro JG, Mundim D, Branco JR, Santos LE, Ferreira ST, Pizzatti L, Sola-Penna M, Zancan P
Mol Cell Endocrinol · 2026 Feb · PMID 41177387 · Publisher ↗
Serotonin (5-HT), a key regulator of epithelial homeostasis, plays a paradoxical role in breast cancer progression. This study investigates the impact of 5-HT signaling on hormone receptor expression, cell proliferation,...
Serotonin (5-HT), a key regulator of epithelial homeostasis, plays a paradoxical role in breast cancer progression. This study investigates the impact of 5-HT signaling on hormone receptor expression, cell proliferation, therapeutic response, and tumor aggressiveness in breast cancer cells. We demonstrate that 5-HT activates transcriptional factors in MCF-7 cells, collectively enhancing cancer hallmarks such as sustained proliferation and invasiveness. Notably, 5-HT downregulates mRNA expression of estrogen receptor (ER), progesterone receptor (PR), and HER2, inducing a phenotype reminiscent of triple-negative breast cancer. Despite these phenotypic changes, acute 5-HT treatment does not impair the effectiveness of tamoxifen in vitro. In vivo, administration of fluoxetine, a selective serotonin reuptake inhibitor, accelerates tumor growth and increases malignancy in a murine model. These findings underscore the ability of 5-HT to reprogram hormone receptors expression profiles and to promote a more aggressive cancer phenotype.
Melatonin administration protects the right ventricle from adrenergic stress via anti-inflammatory and anti-apoptotic mechanisms.
Zimmer A, de Oliveira VR, Fernandes TRG … +10 more , Santos R, Turck P, de Mello Palma V, Visioli F, Fernandes E, Tasca S, Carraro CC, Belló-Klein A, da Rosa Araujo AS, de Castro AL
Mol Cell Endocrinol · 2026 Jan · PMID 41173208 · Publisher ↗
BACKGROUND: Adrenergic overload is a central feature of cardiovascular diseases, contributing to right ventricular (RV) injury. Although widely studied, limited data are available on melatonin's impact on the RV and extr...
BACKGROUND: Adrenergic overload is a central feature of cardiovascular diseases, contributing to right ventricular (RV) injury. Although widely studied, limited data are available on melatonin's impact on the RV and extracardiac tissues. OBJECTIVE: To investigate the effects of melatonin on RV remodeling, inflammation, and oxidative stress in the lung and gastrocnemius muscle of rats subjected to isoproterenol (ISO)-induced adrenergic stress. METHODS: Male Wistar rats were divided into Control, ISO, and ISO + melatonin groups. ISO (5 mg/kg, s.c.) was administered for 7 days, and ISO + M received ISO plus melatonin (10 mg/kg/day, gavage). Control animals received saline (s.c) and the non-treated groups received only saline by gavage. Cardiac function and hypertrophy was assessed by echocardiography and morphometric analyses, respectively. RV inflammation and fibrosis were examined histologically, while protein expression in the RV (TLR4, NF-κB, Bax) and lungs (eNOS, ETAR) was analyzed by western blotting. Oxidative stress markers (ROS, TBARS, sulfhydryl groups, nitrite) were measured in lung and gastrocnemius. RESULTS: ISO reduced cardiac output and heart rate, effects preserved by melatonin. RV hypertrophy induced by ISO was not prevented, but inflammatory infiltrate, fibrosis, and upregulation of TLR4, NF-κB, and Bax were attenuated by melatonin. In the lungs, no significant alterations were observed, except for increased nitrite levels in ISO + M. Gastrocnemius oxidative stress was unchanged. CONCLUSIONS: Melatonin attenuates RV inflammation and apoptosis under adrenergic overload without preventing hypertrophy or markedly affecting lungs and skeletal muscle, supporting its potential as adjunctive therapy in cardiac diseases.
Corrigendum to "The impact of mineralocorticoid and glucocorticoid receptor interaction on corticosteroid transcriptional outcomes" [Molecul. Cell. Endocrinol. 594 (2024) 112389].
Alvarez de la Rosa D, Ramos-Hernández Z, Weller-Pérez J … +2 more , Johnson TA, Hager GL
Mol Cell Endocrinol · 2026 Jan · PMID 41152100 · Publisher ↗
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