Molecular and Cellular Endocrinology最新文献

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.

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.

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.

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.

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.

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.