From liver to hormones: The endocrine consequences of cirrhosis.

Hepatocrinology explores the intricate relationship between liver function and the endocrine system. Chronic liver diseases such as liver cirrhosis can cause endocrine disorders due to toxin accumulation and protein synthesis disruption. Despite its importance, assessing endocrine issues in cirrhotic patients is frequently neglected. This article provides a comprehensive review of the epidemiology, pathophysiology, diagnosis, and treatment of endocrine disturbances in liver cirrhosis. The review was conducted using the PubMed/Medline, EMBASE, and Scielo databases, encompassing 172 articles. Liver cirrhosis is associated with endocrine disturbances, including diabetes, hypoglycemia, sarcopenia, thyroid dysfunction, hypogonadotropic hypogonadism, bone disease, adrenal insufficiency, growth hormone dysfunction, and secondary hyperaldosteronism. The optimal tools for diagnosing diabetes and detecting hypoglycemia are the oral glucose tolerance test and continuous glucose monitoring system, respectively. Sarcopenia can be assessed through imaging and functional tests, while other endocrine disorders are evaluated using hormonal assays and imaging studies. Treatment options include metformin, glucagon-like peptide-1 analogs, sodium-glucose co-transporter-2 inhibitors, and insulin, which are effective and safe for diabetes control. Established standards are followed for managing hypoglycemia, and hormone replacement therapy is often necessary for other endocrine dysfunctions. Liver transplantation can address some of these problems.

Endocrine factors modulating vitellogenesis and oogenesis in insects: An update.

The endocrine system plays a pivotal role in shaping the mechanisms that ensure successful reproduction. With over a million known insect species, understanding the endocrine control of reproduction has become increasingly complex. Some of the key players include the classic insect lipid hormones juvenile hormone (JH) and ecdysteroids, and neuropeptides such as insulin-like peptides (ILPs). Individual endocrine factors not only modulate their own target tissue but also play crucial roles in crosstalk among themselves, ensuring successful vitellogenesis and oogenesis. Recent advances in omics, gene silencing, and genome editing approaches have accelerated research, offering both fundamental insights and practical applications for studying in-depth endocrine signaling pathways. This review provides an updated and integrated view of endocrine factors modulating vitellogenesis and oogenesis in insect females.

The Role of the Endocrine System in the Regulation of Acid-Base Balance by the Kidney and the Progression of Chronic Kidney Disease.

Systemic acid-base status is primarily determined by the interplay of net acid production (NEAP) arising from metabolism of ingested food stuffs, buffering of NEAP in tissues, generation of bicarbonate by the kidney, and capture of any bicarbonate filtered by the kidney. In chronic kidney disease (CKD), acid retention may occur when dietary acid production is not balanced by bicarbonate generation by the diseased kidney. Hormones including aldosterone, angiotensin II, endothelin, PTH, glucocorticoids, insulin, thyroid hormone, and growth hormone can affect acid-base balance in different ways. The levels of some hormones such as aldosterone, angiotensin II and endothelin are increased with acid accumulation and contribute to an adaptive increase in renal acid excretion and bicarbonate generation. However, the persistent elevated levels of these hormones can damage the kidney and accelerate progression of CKD. Measures to slow the progression of CKD have included administration of medications which inhibit the production or action of deleterious hormones. However, since metabolic acidosis accompanying CKD stimulates the secretion of several of these hormones, treatment of CKD should also include administration of base to correct the metabolic acidosis.

Paracrine and endocrine pathways of natriuretic peptides assessed by ligand-receptor mapping in the Japanese eel brain.

The natriuretic peptide (NP) family consists of cardiac NPs (ANP, BNP, and VNP) and brain NPs (CNPs) in teleosts. In addition to CNP1-4, a paralogue of CNP4 (named CNP4b) was recently discovered in basal teleosts including Japanese eel. Mammals have lost most Cnps during the evolution, but teleost cnps were conserved and diversified, suggesting that CNPs are important hormones for maintaining brain functions in teleost. The present study evaluated the potency of each Japanese eel CNP to their NP receptors (NPR-A, NPR-B, NPR-C, and NPR-D) overexpressed in CHO cells. A comprehensive brain map of cnps- and nprs-expressing neurons in Japanese eel was constructed by integrating the localization results obtained by in situ hybridization. The result showed that CHO cells expressing NPR-A and NPR-B induced strong cGMP productions after stimulation by cardiac and brain NPs, respectively. Regarding brain distribution of cnps, cnp1 is engaged in the ventral telencephalic area and periventricular area including the parvocellular preoptic nucleus (Pp), anterior/posterior tuberal nuclei, and periventricular gray zone of the optic tectum. cnp3 is found in the habenular nucleus and prolactin cells in the pituitary. cnp4 is expressed in the ventral telencephalic area, while cnp4b is expressed in the motoneurons in the medullary area. Such CNP isoform-specific localizations suggest that function of each CNP has diverged in the eel brain. Furthermore, the Pp lacking the blood-brain barrier expressed both npra and nprb, suggesting that endocrine and paracrine NPs interplay for regulating the Pp functions in Japanese eels.

Methyltransferase-like 3 modifications of RNAs: Implications for the pathology in the endocrine system.

Methyltransferase-like 3 (METTL3) is the most well-known element of N6-methyladenosine modification on RNAs. METTL3 deposits a methyl group onto target RNAs to modify their expression, ultimately regulating various physiological and pathological events. Numerous studies have suggested the significant role of METTL3 in endocrine dysfunction and related disorders. However, reviews that summarize and interpret these studies are lacking. In this review, we systematically analyze such studies, including obesity, type 2 diabetes mellitus (T2DM), T2DM-induced diseases, pancreatic cancer, and thyroid carcinoma. This review indicates that METTL3 contributes remarkably to the endocrine dysfunction and progression of obesity, T2DM, T2DM-induced diseases, pancreatic cancer, and thyroid carcinoma. In conclusion, this review provides a comprehensive interpretation of the mechanism via which METTL3 functions on RNAs and regulates various endocrine dysfunction events and suggest potential associated correlations. Our review, thus, provides a valuable reference for further fundamental studies and clinical applications.

A battery of in silico models application for pesticides exerting reproductive health effects: Assessment of performance and prioritization of mechanistic studies.

Given the high attention to endocrine disrupting chemicals (EDC), there is an urgent need for the development of rapid and reliable approaches for the screening of large numbers of chemicals with respect to their endocrine disruption potential. This study aimed at the assessment of the correlation between the predicted results of a battery of in silico tools and the reported observed adverse effects from in vivo reproductive toxicity studies. We used VirtualToxLab (VTL) software and the EndocrineDisruptome (ED) online tool to evaluate the binding affinities to nuclear receptors of 17 pesticides, 7 of which were classified as reprotoxic substances under Regulation (EC) No 1272/2008 on the classification, labelling and packaging of substances and mixtures (CLP). Then, we aligned the results of the in silico modelling with data from ToxCast assays and in vivo reproductive toxicity studies. We combined results from different in silico tools in two different ways to improve the characteristics of their predictive performance. Reproductive toxicity can be caused by various mechanisms; however, in this study, we demonstrated that the use of a battery of in silico tools for assessing the binding to nuclear receptors can be useful for identifying hazardous compounds and for prioritizing further studies.

Integrating single-cell imaging and RNA sequencing datasets links differentiation and morphogenetic dynamics of human pancreatic endocrine progenitors.

Basic helix-loop-helix genes, particularly proneural genes, are well-described triggers of cell differentiation, yet information on their dynamics is limited, notably in human development. Here, we focus on Neurogenin 3 (NEUROG3), which is crucial for pancreatic endocrine lineage initiation. By monitoring both NEUROG3 gene expression and protein in single cells using a knockin dual reporter in 2D and 3D models of human pancreas development, we show an approximately 2-fold slower expression of human NEUROG3 than that of the mouse. We observe heterogeneous peak levels of NEUROG3 expression and reveal through long-term live imaging that both low and high NEUROG3 peak levels can trigger differentiation into hormone-expressing cells. Based on fluorescence intensity, we statistically integrate single-cell transcriptome with dynamic behaviors of live cells and propose a data-mapping methodology applicable to other contexts. Using this methodology, we identify a role for KLK12 in motility at the onset of NEUROG3 expression.

Insight into the Potential Mechanisms of Endocrine Disruption by Dietary Phytoestrogens in the Context of the Etiopathogenesis of Endometriosis.

Phytoestrogens (PEs) are estrogen-like nonsteroidal compounds derived from plants (e.g., nuts, seeds, fruits, and vegetables) and fungi that are structurally similar to 17ß-estradiol. PEs bind to all types of estrogen receptors, including ERα and ERß receptors, nuclear receptors, and a membrane-bound estrogen receptor known as the G protein-coupled estrogen receptor (GPER). As endocrine-disrupting chemicals (EDCs) with pro- or antiestrogenic properties, PEs can potentially disrupt the hormonal regulation of homeostasis, resulting in developmental and reproductive abnormalities. However, a lack of PEs in the diet does not result in the development of deficiency symptoms. To properly assess the benefits and risks associated with the use of a PE-rich diet, it is necessary to distinguish between endocrine disruption (endocrine-mediated adverse effects) and nonspecific effects on the endocrine system. Endometriosis is an estrogen-dependent disease of unknown etiopathogenesis, in which tissue similar to the lining of the uterus (the endometrium) grows outside of the uterus with subsequent complications being manifested as a result of local inflammatory reactions. Endometriosis affects 10-15% of women of reproductive age and is associated with chronic pelvic pain, dysmenorrhea, dyspareunia, and infertility. In this review, the endocrine-disruptive actions of PEs are reviewed in the context of endometriosis to determine whether a PE-rich diet has a positive or negative effect on the risk and course of endometriosis.

Targeting aging with the healthy skeletal system: The endocrine role of bone.

Aging is an inevitable biological process, and longevity may be related to bone health. Maintaining strong bone health can extend one's lifespan, but the exact mechanism is unclear. Bone and extraosseous organs, including the heart and brain, have complex and precise communication mechanisms. In addition to its load bearing capacity, the skeletal system secretes cytokines, which play a role in bone regulation of extraosseous organs. FGF23, OCN, and LCN2 are three representative bone-derived cytokines involved in energy metabolism, endocrine homeostasis and systemic chronic inflammation levels. Today, advanced research methods provide new understandings of bone as a crucial endocrine organ. For example, gene editing technology enables bone-specific conditional gene knockout models, which allows the study of bone-derived cytokines to be more precise. We systematically evaluated the various effects of bone-derived cytokines on extraosseous organs and their possible antiaging mechanism. Targeting aging with the current knowledge of the healthy skeletal system is a potential therapeutic strategy. Therefore, we present a comprehensive review that summarizes the current knowledge and provides insights for futures studies.

Psychological, endocrine and polygenic predictors of emotional well-being during the COVID-19 pandemic in a longitudinal birth cohort.

The COVID-19 pandemic severely affected the lives of families and the well-being of both parents and their children. Various factors, including prenatal stress, dysregulated stress response systems, and genetics may have influenced how the stress caused by the pandemic impacted the well-being of different family members. The present work investigated if emotional well-being during the COVID-19 pandemic could be predicted by developmental stress-related and genetic factors. Emotional well-being of 7-10 year-old children (n = 263) and mothers (n = 241) (participants in a longitudinal German birth cohort (POSEIDON)) was assessed during the COVID-19 pandemic using the CRISIS questionnaire at two time periods (July 2020-October 2020; November 2020-February 2021). Associations of the children's and mothers' well-being with maternal perceived stress, of the children's well-being with their salivary and morning urine cortisol at 45 months, and polygenic risk scores (PRSs) for depression, schizophrenia, loneliness were investigated. Lower emotional well-being was observed in both children and mothers during compared to before the pandemic, with the children's but not the mothers' emotional well-being improving over the course of the pandemic. A positive association between the child and maternal emotional well-being was found. Prenatally assessed maternal perceived stress was associated with a lower well-being in children, but not in mothers. Cortisol measures and PRSs were not significantly associated with the children's emotional well-being. The present study confirms that emotional well-being of children and mothers are linked, and were negatively affected by the COVID-19 pandemic, with differences in development over time.

RISING STARS: Endocrine regulation of metabolic homeostasis via the intestine and gut microbiome.

The gastrointestinal system is now considered the largest endocrine organ, highlighting the importance of gut-derived peptides and metabolites in metabolic homeostasis. Gut peptides are secreted from intestinal enteroendocrine cells in response to nutrients, microbial metabolites, and neural and hormonal factors, and they regulate systemic metabolism via multiple mechanisms. While extensive research is focused on the neuroendocrine effects of gut peptides, evidence suggests that several of these hormones act as endocrine signaling molecules with direct effects on the target organ, especially in a therapeutic setting. Additionally, the gut microbiota metabolizes ingested nutrients and fiber to produce compounds that impact host metabolism indirectly, through gut peptide secretion, and directly, acting as endocrine factors. This review will provide an overview of the role of endogenous gut peptides in metabolic homeostasis and disease, as well as the potential endocrine impact of microbial metabolites on host metabolic tissue function.

Growth differentiation factor 15 (GDF-15) in endocrinology.

Human growth differentiation factor 15 (GDF-15) is a widely distributed protein that has shown to play multiple roles in both physiological and pathological conditions. In healthy individuals, GDF-15 is mainly expressed in the placenta, followed by the prostate, although low levels of expression have also been detected in different organs. GDF-15 acts through a recently identified receptor called glial-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) which signals through the rearranged during transfection (RET) tyrosine kinase receptor. The effects of GDF-15 are pleiotropic and include appetite regulation, and actions on metabolism, pregnancy, cell survival, immune response, and inflammation. GDF-15 also plays different roles in the pathophysiology of cardiovascular disease, autoimmunity, cancer-associated anorexia/cachexia, and diabetes. In recent years, several studies have reported a link between GDF-15 and the endocrine system. In this review, we up-date and summarize the relevant investigations of the relationships between GDF-15 and different endocrine conditions. We also assess the potential pathogenic role and potential therapeutic applications of GDF-15 in the field of endocrinology.

Weight of evidence for cross-species conservation of androgen receptor-based biological activity.

The U.S. Environmental Protection Agency's Endocrine Disruptor Screening Program (EDSP) is tasked with assessing chemicals for their potential to perturb endocrine pathways, including those controlled by androgen receptor (AR). To address challenges associated with traditional testing strategies, EDSP is considering in vitro high-throughput screening assays to screen and prioritize chemicals more efficiently. The ability of these assays to accurately reflect chemical interactions in nonmammalian species remains uncertain. Therefore, a goal of the EDSP is to evaluate how broadly results can be extrapolated across taxa. To assess the cross-species conservation of AR-modulated pathways, computational analyses and systematic literature review approaches were used to conduct a comprehensive analysis of existing in silico, in vitro, and in vivo data. First, molecular target conservation was assessed across 585 diverse species based on the structural similarity of ARs. These results indicate that ARs are conserved across vertebrates and are predicted to share similarly susceptibility to chemicals that interact with the human AR. Systematic analysis of over 5000 published manuscripts was used to compile in vitro and in vivo cross-species toxicity data. Assessment of in vitro data indicates conservation of responses occurs across vertebrate ARs, with potential differences in sensitivity. Similarly, in vivo data indicate strong conservation of the AR signaling pathways across vertebrate species, although sensitivity may vary. Overall, this study demonstrates a framework for utilizing bioinformatics and existing data to build weight of evidence for cross-species extrapolation and provides a technical basis for extrapolating hAR-based data to prioritize hazard in nonmammalian vertebrate species.

Short-Term Exposure to Benzo(a)Pyrene Causes Disruption of GnRH Network in Zebrafish Embryos.

Benzo(a)pyrene (BaP), a polycyclic aromatic hydrocarbon, is considered a common endocrine disrupting chemical (EDC) with mutagenic and carcinogenic effects. In this work, we evaluated the effects of BaP on the hypothalamo-pituitary-gonadal axis (HPG) of zebrafish embryos. The embryos were treated with 5 and 50 nM BaP from 2.5 to 72 hours post-fertilization (hpf) and obtained data were compared with those from controls. We followed the entire development of gonadotropin releasing hormone (GnRH3) neurons that start to proliferate from the olfactory region at 36 hpf, migrate at 48 hpf and then reach the pre-optic area and the hypothalamus at 72 hpf. Interestingly, we observed a compromised neuronal architecture of the GnRH3 network after the administration of 5 and 50 nM BaP. Given the toxicity of this compound, we evaluated the expression of genes involved in antioxidant activity, oxidative DNA damage and apoptosis and we found an upregulation of these pathways. Consequently, we performed a TUNEL assay and we confirmed an increment of cell death in brain of embryos treated with BaP. In conclusion our data reveal that short-term exposure of zebrafish embryos to BaP affects GnRH3 development likely through a neurotoxic mechanism.

Chromogranin A: An Endocrine Factor of Pregnancy.

Pregnancy is a state of physiological and hormonal changes. One of the endocrine factors involved in these processes is chromogranin A, an acidic protein produced, among others, by the placenta. Although it has been previously linked to pregnancy, no existing articles have ever managed to clarify the role of this protein regarding this subject. Therefore, the aim of the present study is to gather knowledge of chromogranin A's function with reference to gestation and parturition, clarify elusive information, and, most importantly, to formulate hypotheses for the future studies to verify.

Lead acetate induces cartilage defects and bone loss in zebrafish embryos by disrupting the GH/IGF-1 axis.

Skeletal system toxicity due to lead exposure has attracted extensive attention in recent years, but few studies focus on the skeletal toxicity of lead in the early life stages of zebrafish. The endocrine system, especially the GH/IGF-1 axis, plays an important role in bone development and bone health of zebrafish in the early life. In the present study, we investigated whether lead acetate (PbAc) affected the GH/IGF-1 axis, thereby causing skeletal toxicity in zebrafish embryos. Zebrafish embryos were exposed to lead PbAc between 2 and 120 h post fertilization (hpf). At 120 hpf, we measured developmental indices, such as survival, deformity, heart rate, and body length, and assessed skeletal development by Alcian Blue and Alizarin Red staining and the expression levels of bone-related genes. The levels of GH and IGF-1 and the expression levels of GH/IGF-1 axis-related genes were also detected. Our data showed that the LC50 of PbAc for 120 h was 41 mg/L. Compared with the control group (0 mg/L PbAc), after PbAc exposure, the deformity rate increased, the heart rate decreased, and the body length was shortened at various time periods, in the 20-mg/L group at 120 hpf, the deformity rate increased by 50 fold, the heart rate decreased by 34%, and the body length shortened by 17%. PbAc altered cartilage structures and exacerbated bone loss in zebrafish embryos; in addition, PbAc exposure down-regulated the expression of chondrocyte (sox9a, sox9b), osteoblast (bmp2, runx2) and bone mineralization-related genes (sparc, bglap), and up-regulated the expression of osteoclast marker genes (rankl, mcsf). The GH level increased and the IGF-1 level declined significantly. The GH/IGF-1 axis related genes (ghra, ghrb, igf1ra, igf1rb, igf2r, igfbp2a, igfbp3, igfbp5b) were all decreased. These results suggested that PbAc inhibited the differentiation and maturation of osteoblasts and cartilage matrix, promoted the formation of osteoclasts, and ultimately induced cartilage defects and bone loss by disrupting the GH/IGF-1 axis.

Prediction of the Endocrine disruption profile of fluorinated biphenyls and analogues: An in silico study.

Fluorinated biphenyls and their analogues (FBAs) are considered new persistent organic pollutants, but their endocrine-disrupting effects are still unknown. To fill this gap, the binding probability of 44 FBAs to different nuclear hormone receptors (NHRs) was predicted using Endocrine Disruptome. And molecular similarity and network toxicology analysis were used to strengthen the docking screening. The docking results showed that FBAs could have high binding potential for various NHRs, such as estrogen receptors ß antagonism (ERß an), liver X receptors α (LXRα), estrogen receptors α (ERα), and liver X receptors ß (LXRß). The similarity analysis found that the degree of overlap of the NHR repertoire was related to the Tanimoto coefficient of FBAs. Network toxicology verified a part of docking screening results and identified endocrine-disrupting pathways worthy of attention. This study found out potential endocrine-disrupting FBAs and their vulnerable, and developed a workflow that would leverage in silico approaches including molecular docking, similarity, and network toxicology for risk prioritization of potential endocrine-disrupting compounds.

Evolving roles of activins and inhibins in ovarian cancer pathophysiology.

Activins and inhibins are unique members of the transforming growth factor-ß (TGFß) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.

Bisphenol A-Induced Endocrine Dysfunction and its Associated Metabolic Disorders.

Bisphenol A (BPA) is an endocrine-disrupting chemical widely present in many consumer goods that poses a significant threat to our health upon exposure. Humans are exposed to BPA, which directly or indirectly causes endocrine dysfunctions that lead to metabolic disorders like obesity, fatty liver diseases, insulin resistance, polycystic ovarian syndrome, and other endocrine- related imbalances. The duration, quantity, and period of exposure to BPA, especially during the critical stage of development, determine its impact on reproductive and non-reproductive health. Because of its endocrine-disrupting effects, the European Chemical Agency has added BPA to the candidate list of chemicals of very serious concern. Due to its estrogenic properties and structural similarities with thyroid hormones, BPA disrupts the endocrine system at different levels. It interacts with estrogen receptors at the molecular level and acts as an antagonist or agonist via an estrogen receptor-dependent signaling pathway. In particular, BPA binds to G-protein coupled receptors and estrogen receptors, activating signaling pathways that influence cellular apoptosis, proliferation, differentiation, and inflammation. BPA acts as an obesogen that promotes adipogenesis and correlates with increased lipid accumulation and elevated expression of adipogenic markers. As a metabolic and endocrine disruptor, BPA impairs cellular homeostasis by increasing oxidative mediators and decreasing antioxidant enzymes, resulting in mitochondrial dysfunction. Due to its endocrine-disrupting properties, BPA exposure induces endocrine dysfunctions, causing metabolic syndrome. This review article gives recent development and novel insights into the cellular and molecular mechanisms of BPA-induced endocrine dysfunctions and their associated metabolic disorders.