Endocrinology最新文献

Pericytes are mural cells distributed in the basement membrane of precapillary arterioles, capillaries, and postcapillary venules and are indispensable parts of the vascular microenvironment. To date, pericytes have been found to play a crucial role in vascular homeostasis in several organs. The pituitary gland has a complex network of blood vessels that support endocrine function; thus, pericytes also have irreplaceable functions in the pituitary vascular microenvironment, including angiogenesis, vascular regulation, neuroendocrine, extracellular matrix regulation, and mesenchymal-like differentiation potential. Notably, emerging evidence suggests potential functional heterogeneity between anterior and posterior pituitary pericytes, which may underlie their specialized roles in regulating lobe-specific vascular and neuroendocrine activities. Additionally, the underlying impact of pericytes on pituitary lesions, such as tumors, apoplexy, and fibrosis, has been revealed in the past decade. In this review, we introduce the fundamental characteristics of pituitary pericytes on the basis of their morphological characteristics, molecular markers, and origin; emphasize their multiple functions under physiological conditions; and explore their latent role in pituitary diseases. This review is the first to provide a comprehensive overview of the physiological functions and pathological mechanisms of pituitary pericytes, in an attempt to develop new ideas for future research.

Endometriosis is a pathological condition characterized by the ectopic growth of endometrial cells, leading to chronic pelvic pain and infertility. Epidemiological studies have associated exposure to dioxin-like polychlorinated biphenyls, particularly PCB126, with an increased risk of endometriosis. However, the underlying mechanisms of this association remain poorly understood. We utilized a surgically induced endometriosis mouse model and human endometrial cell lines to assess the impact of PCB126 on endometriosis progression. Mice were exposed to environmentally relevant doses of PCB126. Endometriotic lesion growth, estrogen receptor signaling, receptor tyrosine kinase activity, and gene expression changes induced by PCB126-mediated elevation of DNA methyltransferase 3A (DNMT3A) were evaluated using histology, bioluminescent imaging, immunoblotting, and RNA sequencing. Functional validation was conducted using a pharmacologic AXL inhibitor and tissue-specific Dnmt3a knockout mice. PCB126 significantly promoted the growth of ectopic lesions and humanized models of endometriosis. Mechanistically, PCB126 enhanced estrogen receptor β (ESR2) activity by upregulating AXL and its ligand, growth arrest-specific 6, and elevating DNMT3A expression. The inhibition of AXL signaling suppressed the growth of endometriotic lesions. ESR2 directly regulated Dnmt3a expression, and loss of Dnmt3a reduced lesion growth and inflammatory cytokine production, thereby reversing immune dysregulation. These findings establish a mechanistic link between PCB126 exposure and epigenetic and immune reprogramming in endometriotic lesions. Our findings establish a mechanistic connection between environmental PCB126 exposure and endometriosis progression via the AXL/ESR2/DNMT3A axis. This study provides new insight into how endocrine-disrupting chemicals promote hormone-sensitive diseases through epigenetic and immunological pathways, offering potential targets for therapeutic intervention.

Selective pressures have led to the development of innumerable unique strategies to maximize fitness-an organism's ability to survive and reproduce. One strategy is the ability to reversibly enter a regulated state of hypometabolism, known as torpor, to temporarily halt or slow important metabolic processes to conserve energy and avoid a lethal energy shortage. While torpor can be highly adaptive, it can also interfere with reproduction. As a result of this tradeoff, organisms have developed adaptations that balance energy homeostasis needs with the metabolic demands of reproduction, thereby maximizing their fitness. In mammals, numerous studies have described a bidirectional relationship between torpor and reproduction, with reproductive state influencing the pattern and frequency of torpor use and, conversely, the reproductive axis undergoing dramatic changes during periods of frequent torpor use. Here, we review the current knowledge of the signaling networks underlying this bidirectional relationship, weigh hypotheses on unresolved questions in the field, and discuss the value and larger implications of these studies.

Liquid crystal monomers (LCMs) are ubiquitous environmental contaminants released from electronic devices' liquid crystal display (LCD) panels, which have led to the contamination of food, breast milk, and serum. As the toxicity of individual LCMs, not to mention their myriad mixtures, is currently very poorly characterized, there is a crucial need for investigations into the health hazards posed by exposure. In this study, 10 nonfluorinated (NF) and fluorinated (F) LCMs and 3 fluorination-based LCM mixtures were screened for metabolism and endocrine-disrupting potential in vitro at exposure-relevant concentrations using adipogenesis assays and luciferase reporter gene assays. Both NF-LCMs, F-LCMs, and their mixtures were found to alter the transcriptional activity of one or more nuclear receptors. Notably, 6 LCMs and all LCM mixtures were able to antagonize the progesterone receptor, with several displaying non-monotonic concentration-response curves. Multiple LCMs and their mixtures also increased triglyceride accumulation in murine preadipocytes and human mesenchymal stem cells in a concentration-dependent manner. The concentration addition principle underestimated the adipogenic potencies of LCM mixtures when compared with those derived from benchmark concentration analyses of empirical adipogenesis assay results, suggesting synergistic interactions. While no mechanistic pattern emerged between the bioactivities, results confirmed the metabolism and endocrine-disrupting potential of both NF-LCMs, F-LCMs, and their mixtures. This emphasizes the need to further investigate the metabolic and reproductive health impacts of LCM exposure in vivo, as well as the necessity of exploring alternative models to predict the toxicity of LCM mixtures.

The central subdivision of the bed nucleus of the stria terminalis (BNSTc) of humans is innervated by vasoactive intestinal polypeptide (VIP) neurons with a male-biased sex difference in VIP neuronal fibers. The oval nucleus of the bed nucleus of the stria terminalis (BNSTov) of mice is in the same anatomical position as the BNSTc, but no evidence for such a sex difference exists. Immunohistochemical analysis of the BNSTov in prepubertal, postpubertal, and adult mice revealed that a male-biased sex difference in the volume containing VIP neuronal fibers appears by the end of puberty, and this difference becomes significant in adulthood. Additionally, analysis of hormonally manipulated mice revealed that the volume of the BNSTov containing VIP neuronal fibers decreased in adult males with neonatal castration and increased in adult females with neonatal testosterone treatment. However, gonadectomy before and after puberty had no effect on the BNSTov volume that contained VIP neuronal fibers in both sexes. VIP neuron-specific retrograde tracing showed that VIP neurons innervating the BNSTov were localized in the basolateral amygdalar nucleus and basomedial amygdalar nucleus and that males had more VIP neurons in the basolateral amygdalar nucleus than did females. These findings suggest that the mouse BNSTov has the same traits regarding morphological sex differences as the human BNSTc. This study further showed that neonatal testicular androgens are required to establish the sex difference in VIP neuronal fibers, which may be attributed to a male-biased sex difference in VIP neurons projecting from the amygdala to the BNSTov.

The rising global incidence of type 2 diabetes mellitus and obesity underscores a critical public health challenge, with obesity serving as a primary contributor to insulin resistance. Current treatment modalities, including SGLT2 inhibitors and GLP-1 receptor agonists, have shown efficacy in glycemic control and weight management but remain insufficient for all patients. This review focuses on novel dual and triple agonists targeting glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon, and growth differentiation factor 15 (GDF15) due to their emerging clinical importance and recent preclinical progress. Other peptide-based therapies, such as amylin analogs, are beyond the scope of this work and will be addressed in future reviews. Evidence suggests that these novel agents not only improve metabolic parameters but may also offer cardioprotective and anti-inflammatory benefits. While advancements in understanding their mechanisms of action are promising, the safety profiles of these treatments warrant careful evaluation due to potential adverse effects. This review aims to provide a comprehensive overview of the evolving landscape of antidiabetic pharmacotherapy, emphasizing the unique benefits and challenges of emerging agents to optimize clinical outcomes in type 2 diabetes mellitus management.

Previous studies show that orphan nuclear receptor 4A1 (NR4A1) regulates endometriotic cell growth, survival, estrogen receptor β (ERβ), mechanistic target of rapamycin signaling and fibrosis. NR4A2 is also expressed in epithelial and stromal derived endometriotic cells, and in this study the effects of 1,1-bis(3'-indolyl)-(3,5-disubstitutedphenyl)methane (DIM-3,5) dual NR4A1/nuclear receptor 4A2 (NR4A2) ligands and knockdown of NR4A1 and NR4A2 were investigated. The dual NR4A1/2 DIM-3,5 analogs inhibited previously identified proendometriotic pathways and gene products, and they also inhibited TWIST1 and multiple markers associated with epithelial-to-mesenchymal transition (EMT). The results show that both NR4A1 and NR4A2 regulate the same pathways, including endometriotic cell growth, survival, and migration and also some of the same genes in endometriotic epithelial and stromal cells. For example, DIM-3,5 compounds downregulate ERβ in stromal but not epithelial endometriotic cells, and this response is NR4A1- and not NR4A2-dependent. Among the EMT-related markers, claudin-1 is induced by DIM-3,5 ligands and after knockdown of NR4A1 or NR4A2 in both epithelial and stromal cells. Most of the EMT markers are downregulated by DIM-3,5 ligands and are coregulated by NR4A1 and NR4A2. In vivo studies showed that DIM-3,5-Cl2 significantly reduced the growth of endometriotic lesions in a mouse model without inducing cytotoxicity during treatment. Thus, DIM-3,5 derivatives simultaneously suppress NR4A1- and NR4A2-dependent endometriosis progression effectively and represent a promising nonhormonal therapeutic strategy to replace current hormone-based treatments that can be associated with adverse effects.

Milk ejection is the final process in maternal milk transfer from mothers to offspring and is regulated by oxytocin (OT) released from the neurohypophysis in response to the milk ejection reflex. Arginine vasopressin (AVP), another neurohypophyseal hormone well known for its antidiuretic and vasoconstrictive effects, shares structural similarity with OT, and intravenous AVP injection can also induce milk ejection. Nonetheless, AVP has also been reported to inhibit OT-induced milk ejection in rabbits. In this study, we examined the roles of OT and AVP receptors in these opposing effects of AVP on milk ejection using an in vivo assay model in mice. AVP induced milk ejection, and this effect was inhibited by an OT receptor antagonist. Intravenous pretreatment with AVP suppressed the following transient milk ejection induced by intravenous OT injection. Furthermore, AVP treatment interrupted the continuous milk ejection induced by intraperitoneal OT. These inhibitory effects of AVP were ameliorated by pretreatment with a selective Avpr1a antagonist. We further examined the role of AVP receptors using Avpr1a and Avpr1b knockout mice. The AVP-dependent inhibition of OT-induced milk ejection was abolished in Avpr1a knockout mice, but not in Avpr1b knockout mice. Our findings suggest that AVP induces milk ejection through the OT receptor while inhibiting OT-induced milk ejection via Avpr1a. This duality might reflect a physiological mechanism for restricting milk transfer under severe stress or hyperosmotic conditions and could provide insights into breastfeeding difficulties in humans, including the perception of insufficient milk and infant failure to thrive.

SALL1 is a critical regulator of embryonic development across a wide swath of tissues, including vital organs, but little is known about its function in adult tissues. Recent work from our group demonstrates that SALL1 is involved in urogenital development. This study delineates the role of SALL1 transcription factor in the adult reproductive system by demonstrating its requirement at multiple levels of uterine function during the implantation phase of early pregnancy. By generating a conditional knockout mouse model of Sall1 exclusively in female reproductive organs, it is demonstrated here that SALL1 is independently required both in the uterine luminal epithelium for the attachment of competent blastocysts to the uterine wall and in the uterine stroma for the process of decidualization, another prerequisite for pregnancy success. This robust, multitissue-layer requirement for SALL1 across multiple stages in the process of implantation makes it a newly identified regulator of early pregnancy. Here, it is shown that loss of SALL1 causes misexpression of estrogen receptor α during the window of implantation, and subsequent pathological deregulation of multiple estrogen response genes whose tight titrations are prerequisites of pregnancy. RNA sequencing of independent knockout uterine compartments at multiple timepoints, and chromatin immunoprecipitation sequencing to identify direct transcriptional targets, elucidated multiple powerful regulatory pathways downstream of SALL1. Importantly, the use of a selective estrogen receptor antagonist, fulvestrant, at a precise timepoint and dose, offers a partial rescue of embryo attachment to the uterine luminal epithelium, further demonstrating that SALL1 is upstream of estrogen receptor α during implantation phase signaling.