Molecular And Cellular Endocrinology[JOURNAL]
Sun
200 papers
Comparative analysis of melatonin and sildenafil in a rat model of pulmonary arterial hypertension: Insights into oxidative stress, inflammation, and mitochondrial biogenesis.
Tasca S, Türck P, Drosdowski D … +4 more , Campos Carraro C, Belló-Klein A, Luz de Castro A, da Rosa Araujo AS
Mol Cell Endocrinol · 2026 Jun · PMID 41679692 · Publisher ↗
Pulmonary artery hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to the augmented afterload of the right ventricle (RV), hypertrophy, and heart failure. Oxidative stress and inflam...
Pulmonary artery hypertension (PAH) is characterized by increased pulmonary vascular resistance, leading to the augmented afterload of the right ventricle (RV), hypertrophy, and heart failure. Oxidative stress and inflammation in the RV may be involved in the physiopathology of PAH. Because of their antioxidant properties, melatonin and sildenafil could be possible therapeutic agents for the treatment of PAH. Therefore, the present study evaluated the protective effects of melatonin against oxidative stress, inflammation, and mitochondrial biogenesis in the RV of rats with PAH. Wistar rats were divided into four groups: control (CTR), monocrotaline (MCT), monocrotaline treated with sildenafil (MCT + SIL), and monocrotaline treated with melatonin (MCT + MEL). PAH was induced using a single dose of MCT (60 mg/kg, i. p.). Sildenafil citrate (50 mg/kg/day) and melatonin (10 mg/kg/day) were then administered by gavage, beginning on the first day of the experimental protocol. On the day 21, echocardiographic, morphometric, oxidative/nitrosative stress and Western blotting analyses were performed. Animals that received melatonin or sildenafil demonstrated an increased tricuspid annular plane systolic excursion (TAPSE) when compared with non-treated animals, indicating an improvement in RV contractility. Both melatonin and sildenafil treatment decreased lipid peroxidation (LPO) and reestablished sulfhydryl levels. Melatonin administration decreased the protein expression level of nuclear factor kappa beta (NF-κB), while sildenafil decreased xanthine oxidase expression. Both treatments increased peroxisome proliferator activated receptor gamma co-activator 1 alpha (PGC-1α) expression. Based on our findings, melatonin showed a protective effect similar to sildenafil in the RV of a rats model of PAH.
Thyroid hormones drive central nervous system remodelling during flatfish metamorphosis.
Olvera A, Carballo C, Lazcano I … +3 more , Orozco A, Manchado M, Power DM
Mol Cell Endocrinol · 2026 Jun · PMID 41679691 · Publisher ↗
Flatfish metamorphosis is an abrupt post-embryonic transformation driven by thyroid hormones (THs), in which a bilaterally symmetric pelagic larvae becomes an asymmetric benthic juvenile. While the craniofacial changes a...
Flatfish metamorphosis is an abrupt post-embryonic transformation driven by thyroid hormones (THs), in which a bilaterally symmetric pelagic larvae becomes an asymmetric benthic juvenile. While the craniofacial changes associated with eye migration during metamorphosis are well documented, the role of THs in central nervous system (CNS) remodelling remains poorly understood. Here we investigated the role of THs on CNS remodelling during metamorphosis of the flatfish, Solea senegalensis, by integrating high-throughput transcriptomic analysis with experimental manipulation of TH availability using an inhibitor of hormone synthesis, methimazole (MMI) or exogenous T4. Transcriptome profiling revealed 567 differentially expressed gene transcripts associated with TH-levels involved in CNS development, neuronal and glial differentiation, migration, myelination and metabolism. Key CNS-related factors such as klf9, sox9, mbp, and plp were strongly down-regulated in MMI-treated larvae. Cell proliferation assays further demonstrated increased interocular neural proliferation under hypothyroidism, consistent with impaired differentiation. Region-specific analyses of the head and body uncovered distinct patterns of TH signalling involving dio2, dio3, thra, thrb, and mct8, underscoring the spatial complexity of endocrine regulation. These results highlight that THs are crucial for both morphological remodelling and CNS plasticity during flatfish metamorphosis, underscoring their conserved role in vertebrate brain development.
Growth hormone enhances mitochondria biogenesis and endows mitochondrial thermogenesis in murine adipocytes.
Sadiq E, Liu Y, Li N … +9 more , Zong C, Li X, Yu T, Pu Z, Alameri L, Li Z, Li S, Wang X, Zhao R
Mol Cell Endocrinol · 2026 Jun · PMID 41679690 · Publisher ↗
Growth hormone (GH) can reduce the size of white adipocytes in vivo and in vitro. This catabolic effect was previously believed to be related to the breakdown of stored triglycerides into free fatty acids. However, littl...
Growth hormone (GH) can reduce the size of white adipocytes in vivo and in vitro. This catabolic effect was previously believed to be related to the breakdown of stored triglycerides into free fatty acids. However, little is known about its effects on mitochondria in adipose or adipocytes. We thus examined effects of GH on mitochondrial number change and metabolic changes in fat of diet induced obese mice as well as 3T3-L1 adipocytes. We first found in vitro GH increase the density of mitochondria in 3T3-L1 adipocytes. We figured out that GH enhanced the expression of mitochondria biogenesis related genes, such as peroxisome proliferative activated receptor gamma coactivator 1 alpha (Pgc1α), DNA polymerase gamma (Polg) and transcription factor A of mitochondria (Tfam) in vitro and in vivo. To explore the underlying mechanism, we further confirmed that the enhanced expression of these proteins was dependent on the three pathways of GH signaling transduction and that GH enhanced the promoter transactivation of Pgc1α or Polg. We also found that GH increased the cell death-inducing DNA fragmentation factor alpha subunit-like effector A (CIDEA) and uncoupling protein 1 (UCP1) expression by enhancing the promoter transactivation of Cidea. We further elucidated that GH induced UCP1 expression was dependent on CIDEA using CRISPR-Cas9 technique. We therefore conclude that GH has effects on reducing adipocyte size via promoting PGC1α and POLG mediated mitochondrial biogenesis, and also on increasing UCP1 expression via CIDEA. Making adipocytes browning by GH or its analogs may provide a therapeutic strategy for metabolic diseases.
Estradiol promotes trophoblasts syncytization by upregulating ESR2/SP1 transcription factor-mediated poFUT2 expression.
Li Y, Lei Y, Chen Y … +5 more , Wang L, Wang Y, Wang W, Wang J, Liu S
Mol Cell Endocrinol · 2026 Jun · PMID 41672297 · Publisher ↗
The multinucleated syncytiotrophoblast (STB) at the maternal-fetal interface is formed through the continuous fusion of mononucleated cytotrophoblasts (CTBs). Estradiol and protein glycosylation are known to participate...
The multinucleated syncytiotrophoblast (STB) at the maternal-fetal interface is formed through the continuous fusion of mononucleated cytotrophoblasts (CTBs). Estradiol and protein glycosylation are known to participate in trophoblast syncytialization. O-fucosyltransferase 2 (poFUT2), which catalyzes protein O-fucosylation, has been implicated in placental development. However, the exact role of poFUT2 in trophoblast syncytialization remains unclear. The aim of the present study is to investigate the function of the estradiol-poFUT2 axis in trophoblast syncytialization. Here, by applying immunohistochemistry, we found that poFUT2 expression was decreased in syncytiotrophoblast of placental tissues from preeclampsia patients. Employing a cell-model to induce trophoblast syncytialization in vitro, we demonstrated that poFUT2 promotes trophoblast cell fusion. Mechanistically, during pregnancy, elevated estradiol upregulated the expression of poFUT2 and enhanced syncytium formation. Chromatin immunoprecipitation and co-immunoprecipitation assays indicated that the regulation depends on the participation of SP1 in the estrogen receptor 2 (ESR2)-mediated regulation of the poFUT2 gene. Conclusively, our findings demonstrated that estradiol upregulated poFUT2 expression via the ESR2/SP1 complex, increasing trophoblast cell differentiation and fusion.
Citrate silver nanoparticles modulate estrogen signaling in estradiol-supplemented ER-positive breast cancer cells.
Rakowski M, Lekki-Porębski S, Sikorska K … +2 more , Kruszewski M, Grzelak A
Mol Cell Endocrinol · 2026 Jun · PMID 41654166 · Publisher ↗
BACKGROUND: Breast cancer remains the most common type of cancer affecting women. The estrogen receptor status of a tumor defines the therapeutic approach, which often includes endocrine treatment. Therefore, identifying...
BACKGROUND: Breast cancer remains the most common type of cancer affecting women. The estrogen receptor status of a tumor defines the therapeutic approach, which often includes endocrine treatment. Therefore, identifying potential endocrine-disrupting chemicals is of great importance. METHODS: In this study, we cultured MCF-7 cells supplemented with 17β-estradiol and treated them with silver and polystyrene nanoparticles. We measured the impact of nanoplastics on silver nanoparticle-induced modulation of basic cellular processes. Additionally, we assessed the significance of estrogen signaling in the observed changes induced by these nanomaterials and compared our observations with results obtained on estrogen-deprived MCF-7 cells and ER-negative SK-BR-3 cell line. RESULTS: We observed an induction of proliferation in cells treated with silver nanoparticles (AgNPs). In contrast, treatment with citrate silver nanoparticles (AgNPcit) at the same concentration induced cytotoxicity. Polystyrene nanoparticles (PSNPs) modulated the observed effects of silver nanoparticles in a size-dependent manner. Both AgNPs and AgNPcit downregulated the expression of GPER1. Treatment with nanomaterials also led to the modulation of genes linked to estrogen signaling, such as FOS, MYC, CAV1, and EGR3. CONCLUSIONS: Our results suggest that the surface chemistry of silver nanoparticles may facilitate their ability to modulate estrogen signaling and interact with the estrogen receptor. Furthermore, the nanoplastics pollution may influence the cytotoxicity of silver nanoparticles. This paper highlights the importance of endocrine research in breast cancer, particularly within the context of nanoplastics pollution and the use of nanotechnology in breast cancer treatment.
Adiponectin upregulates irisin expression through the APPL1/p38MAPK/PGC-1α signalling pathway in murine skeletal muscle.
Huang R, Xu S, Guo Q … +3 more , Cao S, Tang D, Yi X
Mol Cell Endocrinol · 2026 Jun · PMID 41654165 · Publisher ↗
Adiponectin and irisin regulate energy homeostasis and interact with peroxisome proliferator-activated receptor coactivator 1α (PGC-1α). However, whether they establish a signal connection via PGC-1α is unclear. In the c...
Adiponectin and irisin regulate energy homeostasis and interact with peroxisome proliferator-activated receptor coactivator 1α (PGC-1α). However, whether they establish a signal connection via PGC-1α is unclear. In the current study, the expression of irisin was significantly decreased in the skeletal muscle of adiponectin knockout (KO) mice, accompanied by a de crease in APPL1/p38 mitogen-activated protein kinase (MAPK)/PGC-1α. However, adiponectin administration reversed this effect. In vitro, the p38 MAPK/PGC-1α signalling pathway mediated adiponectin-induced FNDC5 expression and irisin release in mouse-derived C2C12 myotube cells. Moreover, obesity caused dysregulation of the adiponectin/APPL1/p38 MAPK/PGC-1α signalling pathway in murine skeletal muscle, ultimately inhibiting irisin synthesis and secretion; meanwhile, prolonged exercise or exogenous recombinant adiponectin intervention activated this pathway in mouse skeletal muscle. This corresponded with an apparent improvement in high-fat diet-induced insulin resistance. The effect of mechanically stretching C2C12 myotube cells was consistent with in vivo findings. Hence, adiponectin upregulates irisin through the APPL1/p38MAPK/PGC-1α signalling pathway in murine skeletal muscle, which may enhance insulin sensitivity.
Special issue: An endocrinological perspective on metabolic diseases.
Rodrigues AC, Masi LN, Nunes MT
Mol Cell Endocrinol · 2026 May · PMID 41651104 · Publisher ↗
Abstract loading — click title to view on PubMed.
HIF-2α expression is controlled by the progesterone receptor and regulates hCG-induced gene expression in granulosa cells during ovulation in mice.
Roennfeldt AE, Dinh DT, McPhee TR … +8 more , Rose RD, Smith KM, Jayapal M, Allen TP, Robker RL, Bersten DC, Peet DJ, Russell DL
Mol Cell Endocrinol · 2026 May · PMID 41643762 · Publisher ↗
Ovulation is induced via a surge in gonadotrophin hormones, which increases the expression of the essential ovulatory transcription factor progesterone receptor (PGR) and its target genes. The importance of PGR in ovulat...
Ovulation is induced via a surge in gonadotrophin hormones, which increases the expression of the essential ovulatory transcription factor progesterone receptor (PGR) and its target genes. The importance of PGR in ovulation is well defined; however, the role of its many downstream genes largely remains unknown. Using mouse models of ovulation, we show that the Epas1 gene, which encodes the hypoxia inducible transcription factor 2α (HIF-2α), is expressed in a PGR-dependent manner during ovulation. Numerous HIF target genes increase in expression upon gonadotrophin stimulation in mouse granulosa cells, with expression of Epas1, but not its related isoform, Hif1a, increasing in a PGR-dependent manner. PGR directly binds introns of the Epas1 locus to enhance chromatin accessibility in ovarian granulosa cells in vivo, yet no evidence of PGR-dependent Epas1 expression was observed in PGR-expressing breast cancer cell lines, suggesting ovary-specific mechanisms of PGR-dependent Epas1 regulation. PGR activation in response to hormonal stimulation induced expression of a HIF reporter system in primary human granulosa cells, with HIF-2 inhibition with the small molecule PT-2385 confirming a HIF-2 contribution to this response. Upon HIF-2 inhibition with PT-2385 in mice, no change in ovulation counts were observed. However, gonadotrophin-induced ovary gene expression was significantly disrupted, supporting a model where HIF-2α contributes to the control of periovulatory gene expression downstream of PGR. In particular, inflammatory gene expression was dysregulated and a cohort of gonadotrophin-dependent genes, including Pgr, were elevated, suggesting impaired downregulation post-ovulation. These findings provide an important insight into regulation of the hypoxia inducible transcription factors during ovulation and how targeting HIF-2α may be of benefit in future fertility treatments.
The impact of maternal vitamin D deficiency during pregnancy and lactation on autism-like behavior in offspring.
Song XY, He HN, Tuo LJ … +3 more , Wang B, Zhang H, Xu DX
Mol Cell Endocrinol · 2026 May · PMID 41620169 · Publisher ↗
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments and stereotyped behaviors. Many epidemiological studies have found a potential relationship between vitamin D deficiency...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments and stereotyped behaviors. Many epidemiological studies have found a potential relationship between vitamin D deficiency (VDD) and ASD. However, the mechanism remains unclear. In this study, a VDD model was established by feeding a vitamin D-depleted diet to 5-week-old female mice, from their adulthood through pregnancy to end of lactation. Social deficits, repetitive stereotyped behaviors and anxiety-like behaviors were evaluated in the offspring. The results showed the number of buried marbles was increased in the female offspring of the VDD group. Social defects were observed in both male and female offspring in the VDD group. Mechanistically, several markers of cell proliferation, such as Pcna and Ki67, were upregulated. And the number of TBR2 cell, an intermediate progenitor cell, was increased in cerebral cortex of VDD-fed fetuses. Moreover, DKK1, a WNT/β-catenin pathway repressor, was elevated in cerebral cortex of VDD-fed fetuses. By contrast, β-catenin, a critical effector of the WNT/β-catenin pathway, was reduced in cerebral cortex of GD14 VDD fetuses. These results provide partial evidence that maternal vitamin D deficiency during pregnancy and lactation induces autism-like behaviors partly by suppressing WNT/β-catenin pathway in the cerebral cortex.
Metabolite profiling of the effect of prenatal stimuli across postnatal treatments in the liver.
Southey BR, Gomez AN, Sunderland GR … +3 more , Riggins CW, Villamil MB, Rodriguez-Zas SL
Mol Cell Endocrinol · 2026 May · PMID 41616834 · Full text
Hepatic molecular mechanisms can be modulated by pro- and anti-inflammatory signals associated with infections and nutritional changes that can, in turn, affect the endocrine system. The sex-specific interplay between st...
Hepatic molecular mechanisms can be modulated by pro- and anti-inflammatory signals associated with infections and nutritional changes that can, in turn, affect the endocrine system. The sex-specific interplay between stimuli on hepatic pathways was studied using a biomedical model. The liver metabolome of pigs exposed to a prenatal immune activation from maternal infection was compared to that of matching female and male controls. Within prenatal treatment and sex group, the postnatal treatments were synthetic inflammatory factor, feeding deprivation (fasting), or saline. Liquid chromatography mass spectrometry enabled the detection of 2554 metabolites with significant (False Discovery Rate-adjusted p-value <0.05) sex, prenatal, and postnatal treatment effects. The glycine, serine, and threonine metabolism, RNA metabolism, and neurotransmitter transporters pathways included metabolites with prenatal-by-postnatal treatment interaction effects, such as alanine, arginine, and ketobutyric acid. These disruptions can impact hepatic detoxification, protein synthesis, and methylation. The synergistic interaction for adenosylhomocysteine was characterized by higher levels in the postnatal fasted relative to the saline-treated group, whereas this trend was 4.5-fold higher in the prenatal immune-activated group compared to controls. The antagonistic interaction for chenodeoxycholyltaurine was characterized by higher levels in prenatal-activated relative to controls under saline conditions, whereas this trend declined 2.2-fold in the postnatal-stimulated groups. Sex-specific effects were observed for glutamic acid, with differences between prenatal groups 4.7 times higher in males than in females. These findings offer insights into the interplay between sex, prenatal, and postnatal stimuli across pathways that must be considered in the development of therapies to optimize liver function.
2-Hydroxyestradiol regulates extracellular matrix deposition through estrogen receptor beta activation in airway smooth muscle cells.
Kumar A, Reza MI, Banerjee A … +8 more , Ambhore NS, Balraj P, Layek B, Thompson MA, Hawse JR, Pabelick CM, Prakash YS, Sathish V
Mol Cell Endocrinol · 2026 May · PMID 41616833 · Full text
Airway remodeling in asthma is characterized by increased extracellular matrix (ECM) production and deposition by airway smooth muscle (ASM) cells. Existing studies have shown contrasting effects of 17β-estradiol (E) in...
Airway remodeling in asthma is characterized by increased extracellular matrix (ECM) production and deposition by airway smooth muscle (ASM) cells. Existing studies have shown contrasting effects of 17β-estradiol (E) in regulating ASM cellular remodeling via differential activation of estrogen receptors (ERs: α and β). Even though downstream metabolites of E (2-hydroxyestradiol: 2-HE and 16-hydroxyestradiol: 16αHE) are gaining recognition for their biological roles in various cellular systems, their role in ASM remodeling remains largely unexplored. Here, we explore the effects of 2-HE and 16αHE, a highly potent metabolites, on ECM remodeling in ASM. ECM mRNA's/proteins expression and deposition were determined by Western blotting, qRT-PCR, and In-Cell Western analysis. Interaction of metabolites with ERs was performed using a docking study and their impact on regulation of an estrogen response element (ERE) was monitored via a luciferase reporter assay. Further, the ER-specific effect of metabolites was validated using shRNA-mediated ERα and ERβ knockdown ASM cells. 16αHE exposure showed no notable changes in transforming growth factor-β (TGF-β)-induced ECM proteins expression and deposition, whereas 2-HE exposure blunted the TGF-β effects. Molecular docking unveiled the binding of 16αHE with ERα, while 2-HE more strongly bound to ERβ, which was also confirmed by ERE-luciferase assay. In ERβ knockdown ASM cells, 2-HE inhibited the TGF-β-induced phosphorylation of SMAD2/3, AKT, and ERK1/2. However, 16αHE failed to elicit any of these effects. Furthermore, 2-HE significantly decreased the TGF-β-induced transcriptional activities of AP-1 and NF-κB. Overall, our findings suggest 2-HE blunts TGF-β-induced ECM through ERβ; therefore, it may serve as a novel therapeutic target for airway remodeling and asthma.
Plasma proteome mendelian randomization and network pharmacology reveal therapeutic targets for thyroid disorders.
Wang C, Cai Y, Yang X … +1 more , Jie J
Mol Cell Endocrinol · 2026 May · PMID 41616832 · Publisher ↗
INTRODUCTION: Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroid cancer, impose a substantial global health burden. Existing treatments face limitations due to adverse effects and incomplete effica...
INTRODUCTION: Thyroid disorders, including hypothyroidism, hyperthyroidism, and thyroid cancer, impose a substantial global health burden. Existing treatments face limitations due to adverse effects and incomplete efficacy, highlighting the need for innovative therapeutic strategies informed by genetic and molecular insights. METHODS: We integrated Mendelian randomization (MR) with network pharmacology to systematically prioritize druggable targets. Genetic correlations between different thyroid disorders were evaluated using linkage disequilibrium score regression analysis. Plasma protein quantitative trait loci from 4907 plasma proteins were leveraged as instrumental variables in MR analyses across two independent cohorts. Bayesian colocalization validated shared causal variants. Network pharmacology methods encompassed constructing protein-protein interaction networks, conducting functional enrichment analyses, and identifying potential therapeutic compounds via the DSigDB database. Docking and dynamics simulations assessed binding and stability, while PheWAS assessed off-target effects. RESULTS: The LDSC analysis identified notable genetic correlations of hypothyroidism with hyperthyroidism (Rg = 0.167, P = 0.017), as well as hyperthyroidism with thyroid cancer (Rg = 0.286, P = 0.033). MR and colocalization identified seven causal proteins: IL2RB, CDH1, FGF19 (hypothyroidism); PSAPL1 (hyperthyroidism); DCP1B, SPRN, RPS6KA6 (thyroid cancer). Drug prediction prioritized compounds such as BI-2536 (binding energy: -9.5 kcal/mol with RPS6KA6) and deoxycholic acid. PheWAS confirmed minimal pleiotropic risks. CONCLUSIONS: By synergizing genetic epidemiology with network pharmacology, this study delineates shared genetic architecture among thyroid disorders and nominates seven high-confidence targets with therapeutic potential. The integrative framework advances precision medicine by bridging causal plasma protein identification, mechanistic pathway mapping, and drug repurposing, offering a blueprint for multi-omics-driven drug discovery in endocrine pathologies.
FNDC4 regulates M2 polarization of tumor-associated macrophages to affect colorectal cancer metastasis.
Liu S, Huang F, Wang J … +1 more , Liu J
Mol Cell Endocrinol · 2026 May · PMID 41616831 · Publisher ↗
A very dangerous tumor, colon cancer has the potential to spread and come back. Investigating FNDC4's function in colon cancer and its molecular mechanism is the goal of this study. The expression of FNDC4 and M2 macroph...
A very dangerous tumor, colon cancer has the potential to spread and come back. Investigating FNDC4's function in colon cancer and its molecular mechanism is the goal of this study. The expression of FNDC4 and M2 macrophage-related genes (CD163 and CD206) in tumor tissues was found using immunohistochemistry. After transfecting colorectal cancer cells with the FNDC4 knockdown plasmid, CCK8, clone formation, scratch assay, and Transwell test were used to determine cell proliferation, migration, and invasion. Using flow cytometry, the amount of CD163, CD206, and the rate of cell death were found. Western blot was utilized to identify the expression of proteins associated with the Akt/STAT3 pathway, M2 macrophages, and epithelial-mesenchymal cells. To see how sh-FNDC4 affected tumor growth, a xenograft tumor model was created, and H&E staining was used to look at liver tissue metastases. The findings demonstrated that FNDC4 was favorably connected with the expression of CD206 and CD163 and that it was substantially expressed in colorectal cancer. Tumor cell proliferation, migration, invasion, EMT, and M2 macrophage polarization were all reduced by FNDC4 knockdown. Furthermore, FNDC4 knockdown suppressed tumor growth and liver metastasis in vivo by blocking the Akt/STAT3 pathway. In conclusion, FNDC4's modulation of the Akt/STAT3 pathway may be the reason why its knockdown prevented colorectal cancer cell proliferation, metastasis, and M2 macrophage polarization.
Glial activation and increased blood brain barrier permeability in the medial preoptic area of male mice lacking neural androgen receptor.
Karameh N, Atallah A, Nuzzaci D … +2 more , Grange-Messent V, Mhaouty-Kodja S
Mol Cell Endocrinol · 2026 May · PMID 41611119 · Publisher ↗
We have previously shown that testosterone depletion in adult male mice induced neural androgen receptor (Ar) down-regulation and led to neuroinflammation and increased blood brain barrier (BBB) permeability in the media...
We have previously shown that testosterone depletion in adult male mice induced neural androgen receptor (Ar) down-regulation and led to neuroinflammation and increased blood brain barrier (BBB) permeability in the medial preoptic area. In the present study, we investigated the effects of neural Ar deletion on glial function and BBB integrity in male mice. For this purpose, we used control and mutant littermates obtained from a mouse line deleted for the Ar in neural progenitors by Cre-loxP technology. Neural Ar deletion induced glial activation evidenced by increased immunoreactivity against markers of astrocytes (glial fibrillary acidic protein -GFAP- and N-myc downstream-regulated gene 2) and microglia (ionized calcium binding adaptor molecule 1). Fluoro-Jade® C fluorescent labeling was increased and inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX2) were detected in the vicinity of capillaries in the male medial preoptic area of neural Ar knockout mice. Analysis of BBB integrity showed enhanced permeability for Evans Blue tracer and endogenous immunoglobulins in mutant animals compared to their control littermates. In addition, modifications in the ultrastructural organization of capillary endothelial tight junctions were observed by electron tomography. These effects were specific to neural Ar deletion since no changes were observed for GFAP-immunoreactivity, BBB permeability or Fluoro-Jade® C labeling in male mice expressing the wild type Ar allele and carrying the Cre transgene. Altogether, these data indicate the key role of the neural AR in testosterone-induced regulation of astrocyte, microglial and BBB functions in the medial preoptic area of male mice.
Triploidy alters hormonal and paracrine signaling to promote male development in zebrafish.
Torres-Martínez A, Tichopád T, Pšenička M … +1 more , Franěk R
Mol Cell Endocrinol · 2026 May · PMID 41611118 · Publisher ↗
Sex differentiation in zebrafish is governed by a complex interplay of genetic and endocrine signals. Triploid zebrafish, which are largely sterile, consistently develop as males, but the underlying mechanisms remain elu...
Sex differentiation in zebrafish is governed by a complex interplay of genetic and endocrine signals. Triploid zebrafish, which are largely sterile, consistently develop as males, but the underlying mechanisms remain elusive. Here, we combined histological and transcriptomic analyses to examine how triploidy and exposure to 17α-ethinylestradiol (EE2) modulate sex differentiation in zebrafish. Triploidy disrupted hormonal and paracrine signaling, with downregulation of fshr and amh, upregulation of igf3, potential activation of β-catenin pathway, and suppression of ptger2a and dio1, resulting in complete masculinization. In diploids, EE2 exposure resulted in a wide range of gonadal phenotypes, from testes and ovotestes to fully developed ovaries, reflecting the complexity and variable sensitivity of zebrafish sex differentiation to hormonal stimuli. Potential mechanistic insights underlying these outcomes are provided. By contrast, long exposure of triploid zebrafish to EE2 promoted the expansion of early germ cells, but failed to induce ovarian differentiation, suggesting a fixed male trajectory induced by triploidy. Triploids also showed a distinct endocrine state, lacking the EE2-induced suppression of cyp11c1 observed in diploids, suggesting altered corticosteroid homeostasis that may reinforce masculinization. Both triploidy and EE2 administration altered meiosis and spermiogenesis, consistent with the downregulation of klhl10 and constrained retinoic acid signaling through dhrs3a and/or cyp26b1. At the molecular level, both triploidy and EE2 converged on suppression of early steroidogenic genes, including star and cyp11a1, indicating limited androgen and estrogen biosynthesis. Together, these findings reveal how triploidy reshapes endocrine regulation and responsiveness and reveal shared and unique molecular pathways by which EE2 influences zebrafish gonadal fate.
Hyperglycemia differentially regulates osteoblast and osteoclast autophagy via AMPK/mTOR/p70 S6K signaling in diabetic osteoporosis.
Zhou B, Feng F, Zhou C … +2 more , Yao K, Huang P
Mol Cell Endocrinol · 2026 May · PMID 41611117 · Publisher ↗
Type 2 diabetes mellitus (T2DM) often induces diabetic osteoporosis (DOP) with impaired bone remodeling, yet its underlying mechanism remains elusive. This study identified the differential regulatory role of the AMPK/mT...
Type 2 diabetes mellitus (T2DM) often induces diabetic osteoporosis (DOP) with impaired bone remodeling, yet its underlying mechanism remains elusive. This study identified the differential regulatory role of the AMPK/mTOR/p70 S6K signaling axis in bone cell function. In vivo, diabetes reduced AMPK phosphorylation, enhanced mTOR/p70 S6K activation, and diminished autophagy in rat femoral tissue. In vitro, HG exerted cell-type-specific effects via the AMPK signaling pathway: in osteoblasts, HG inhibited AMPK phosphorylation, activated mTOR/p70 S6K, suppressed autophagy, and impaired mineralization as well as alkaline phosphatase (ALP) activity; conversely, in osteoclasts, HG enhanced autophagy through the inverse regulatory pathway and accelerated osteoclast differentiation and bone resorption. Collectively, these findings illustrate that hyperglycemia disrupts bone homeostasis via cell-type-specific regulation of AMPK, suggesting that AMPK-mediated autophagy serves as a potential critical therapeutic target for diabetes-related bone diseases.
The implementation of small molecule agonists and antagonists to elucidate gonadotropin receptor structure, function and physiology.
Dias JA, Newton CL, Ulloa-Aguirre A
Mol Cell Endocrinol · 2026 May · PMID 41571224 · Publisher ↗
Pursuant to patient desires of alternatives to injectable gonadotropins, a plethora of attempts have identified, characterized, and demonstrated efficacy of small molecules that activate (agonists) gonadotropin receptors...
Pursuant to patient desires of alternatives to injectable gonadotropins, a plethora of attempts have identified, characterized, and demonstrated efficacy of small molecules that activate (agonists) gonadotropin receptors. Discoveries have also been made of small molecule gonadotropin receptor inhibitors (antagonists), which have potential as useful alternatives to steroid hormone-based contraception. Implementation of these small molecules in advanced testing systems not necessarily used in screening, which identified lead compounds, has yielded a bounty of wonders. It is likely that a richer understanding of the role of signaling platforms and conformation-dependent molecular assemblies are likely to emerge. Several small molecule agonists have been observed to function as conformational boosters that can rescue receptor trafficking defects, or initiate internalization of receptors without bound hormone. Still others have revealed insights into the role of molecular platforms in persistent signaling. Unexpectedly, such antagonists, like molecular scalpels, can ablate certain signaling pathways and not others leading to discovery of biased signaling in gonadotropin receptors. That seminal observation has led to studies of nuanced signaling and, consequently, nuanced gene expression. Gonadotropin receptor structure-based design for better specificity and potency of agonists and antagonists has been provided by new cryo-EM structures of the gonadotropin receptors, demonstrating proof of concept. Structural determination of downstream supramolecular assemblies will be necessary to validate and fully understand these complicated receptors and how their interaction with other proteins and when occupied by hormone and allosteric modulators, nuances their actions and, ultimately, fertility.
Exploring recent insights on intermittent fasting in regulating glucocorticoid levels and diet-induced metabolic disorders with focus on MAFLD and hepatic outcomes.
Elechi JOG, de Mendonça CR, Bandeira VCA … +6 more , Da Silva MSP, de Melo APR, Guedes RCA, Hirabara SM, Cione E, de Vasconcelos DAA
Mol Cell Endocrinol · 2026 Apr · PMID 41554431 · Publisher ↗
Consumers' risky eating behaviours aided by the current food environment have led to an increase in diet-related metabolic disorders. Metabolic (dysfunction)-associated fatty liver disease origin represents a major globa...
Consumers' risky eating behaviours aided by the current food environment have led to an increase in diet-related metabolic disorders. Metabolic (dysfunction)-associated fatty liver disease origin represents a major global health burden that is increasing at an alarming rate on an annual basis. Modifying the timing of calorie consumption, dietary composition, or caloric intake offers a promising therapeutic approach for the management of this condition. The aim of this review was to provide a concise analysis of the impact of intermittent fasting on the regulation of glucocorticoid levels and diet-induced metabolic disorders with a focus on non-alcoholic fatty liver diseases. We found that intermittent fasting primarily regulates hepatic autophagy via nutritional and hormonal pathways, aiding in the maintenance of energy equilibrium, enhancement of mitochondrial function, regulation of liver quality, preservation of cellular homeostasis, protection of cells from harmful factors, mitigation of liver metabolic disorders, and improvement of liver inflammation. Also, the physiological changes induced by intermittent fasting and their metabolic consequences arise through multiple mechanisms, including alterations in hepatic metabolism, hepatic autophagy, inflammatory responses, liver functional enzymes, hepatic steatosis, fibroblast growth factor signalling, White adipoe tissue browning, adipokines, circadian rhythms, lipid profiles, body composition, the adipose tissue-gut microbiome axis, skeletal muscle, and the autophagy process. Interestingly, we identified the complex interplay among glucocorticoids, intermittent fasting, and non-alcoholic fatty liver diseases highlighting the hepatic macrophage glucocorticoid receptor as a pivotal mediator of fasting-induced reprogramming of the macrophage secretome, including fasting-suppressed cytokines. In conclusion, existing data indicates that intermittent fasting in patients with non-alcoholic fatty liver diseases is a viable, safe, and successful strategy for weight reduction, demonstrating notable trends in the amelioration of dyslipidaemia and non-alcoholic fatty liver diseases.
Corrigendum to "The local corticotropin-releasing hormone receptor 2 signalling pathway partly mediates hypoxia-induced increases in lipolysis via the cAMP-protein kinase A signalling pathway in white adipose tissue" [Mol. Cellul. Endocrinol. 392/1-2 (2014) 106-114].
Xiong Y, Qu Z, Chen N … +5 more , Gong H, Song M, Chen X, Du J, Xu C
Mol Cell Endocrinol · 2026 Apr · PMID 41548835 · Publisher ↗
Abstract loading — click title to view on PubMed.
circPTPRM can encode a functional polypeptide circPTPRM-187aa to promote papillary thyroid carcinoma progression.
Lv C, Huang J, Ji X … +2 more , Sun W, Zhang H
Mol Cell Endocrinol · 2026 Apr · PMID 41539369 · Publisher ↗
AIMS: Papillary thyroid carcinoma (PTC) is the most common thyroid tumor, usually with a good prognosis, though some cases show early invasion, metastasis, and may become iodine-refractory. circRNAs can interact with miR...
AIMS: Papillary thyroid carcinoma (PTC) is the most common thyroid tumor, usually with a good prognosis, though some cases show early invasion, metastasis, and may become iodine-refractory. circRNAs can interact with miRNAs, bind proteins, regulate transcription, and encode polypeptides, but their translation function in thyroid cancer remains unexplored. METHODS: Quantitative real-time PCR (qRT-PCR), agarose gel electrophoresis, circRNA stability assessment, fluorescence in situ hybridization (FISH) were performed to explore the expression profile of circPTPRM in PTC tissues and adjacent non-cancerous thyroid tissues. We performed molecular biological and cell function experiments by constructing knockdown and various overexpression vectors. Effects of circPTPRM on PTC tumorigenesis were investigated through in vitro and in vivo experiments. The mechanism of circPTPRM-mediated tumor promotion was explored through immunofluorescence (IF), LC-MS/MS, immunoprecipitation (IP) and Co-immunoprecipitation (Co-IP), protein stability assessment, and ubiquitination assay. RESULTS: We confirmed that circPTPRM influenced PTC cell proliferation, migration, invasion through its translated polypeptides. In vivo experiments with nude mouse tumors also demonstrated that overexpression of circPTPRM contributed to the tumor's increased volume and weight. Subsequently, in the mechanistic analysis we found that circPTPRM-187aa polypeptide could bind IQGAP1 and induce TGF-β pathway activation by elevating RAC1 and CDC42. CONCLUSION: CircPTPRM can encode circPTPRM-187aa polypeptide. circPTPRM-187aa, regulates the expression of IQGAP1 protein, and up-regulates RAC1 and CDC42 proteins in TGF-β signaling pathway, enhancing the PTC cells proliferation, migration, and invasion.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe