Single-cell and spatial transcriptomics in endocrine research.

Accumulating evidence suggests that cellular heterogeneity in organs and cell-cell and tissue-tissue interactions are crucial for maintaining physical homeostasis and disease progression. Endocrine organs also exhibit cellular heterogeneity and comprise multiple cell types. For instance, the pituitary gland comprises five types of pituitary hormone-producing cells as well as non-hormone-producing supporting cells, such as fibroblasts, endothelial cells, and folliculostellate cells. However, the functional roles of the interactions between hormone-producing and non-producing cells in the pituitary gland remain incompletely understood. Over the past decade, emerging technologies such as single-cell and spatial transcriptomics have provided excellent tools for studying cellular heterogeneity and their interactions; however, the application of these technologies in endocrine research remains limited. This review provides an overview of these technologies and discusses their strengths and limitations. Additionally, we also summarize the potential future applications of single-cell and spatial transcriptomics in the study of endocrine organs and their disorders.

Endocrinology of Taste with Aging.

Taste is one of our five primary senses, and taste impairment has been shown to increase with aging. The ability to taste allows us to enjoy the food we eat and to avoid foods that are potentially spoiled or poisonous. Recent advances in our understanding of the molecular mechanisms of taste receptor cells located within taste buds help us decipher how taste works. The discoveries of "classic" endocrine hormones in taste receptor cells point toward taste buds being actual endocrine organs. A better understanding of how taste works may help in reversing taste impairment associated with aging.

Review of the endocrine organ-like tumor hypothesis of cancer cachexia in pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal types of solid tumors, associated with a high prevalence of cachexia (~80%). PDAC-derived cachexia (PDAC-CC) is a systemic disease involving the complex interplay between the tumor and multiple organs. The endocrine organ-like tumor (EOLT) hypothesis may explain the systemic crosstalk underlying the deleterious homeostatic shifts that occur in PDAC-CC. Several studies have reported a markedly heterogeneous collection of cachectic mediators, signaling mechanisms, and metabolic pathways, including exocrine pancreatic insufficiency, hormonal disturbance, pro-inflammatory cytokine storm, digestive and tumor-derived factors, and PDAC progression. The complexities of PDAC-CC necessitate a careful review of recent literature summarizing cachectic mediators, corresponding metabolic functions, and the collateral impacts on wasting organs. The EOLT hypothesis suggests that metabolites, genetic instability, and epigenetic changes (microRNAs) are involved in cachexia development. Both tumors and host tissues can secrete multiple cachectic factors (beyond only inflammatory mediators). Some regulatory molecules, metabolites, and microRNAs are tissue-specific, resulting in insufficient energy production to support tumor/cachexia development. Due to these complexities, changes in a single factor can trigger bi-directional feedback circuits that exacerbate PDAC and result in the development of irreversible cachexia. We provide an integrated review based on 267 papers and 20 clinical trials from PubMed and ClinicalTrials.gov database proposed under the EOLT hypothesis that may provide a fundamental understanding of cachexia development and response to current treatments.

Skin as an endocrine organ: A narrative review.

Skin being the largest organ of the body, is equipped with numerous functional properties. Over the past few years, intricate research into the biology of skin has led to a gamut of discoveries. Skin is now regarded as one of the most vital endocrine organs. The skin contains equivalents of the hypothalamo-pituitary-adrenal axis, hypothalamo-pituitary-thyroid axis and the appendages produce multiple hormones such as Vitamin D, sex steroids, retinoids and opioids. In this article, we will explore the role of skin as a target and source of some of the hormones of the human body, and briefly touch on the clinical applications.

Impact of adipose tissue in chronic kidney disease development (Review).

Obesity is a worldwide pandemic health issue. Obesity is associated with the pathogenesis of type 2 diabetes, hypertension, dyslipidemia, cardiovascular diseases, cancer, and kidney diseases. This systemic disease can affect the kidneys by two mechanisms: Indirectly through diabetes mellitus (DM) and hypertension and directly through adipokines secreted by adipose tissue. Obesity is a risk factor for chronic kidney disease (CKD), which is associated with an increased risk of morbidity and mortality among the adult population. Increased visceral adipose tissue leads to renal glomerular hyperfiltration and hyperperfusion, which may lead to glomerular hypertrophy, proteinuria, and CKD development. Adipokines are hormones produced by fat tissue. They are involved in energy homeostasis, sugar and fat metabolism, reproduction, immunity, and thermogenesis control. Hormones and cytokines secreted by adipose tissue contribute to the development and progression of CKD. Decreased serum or urinary adiponectin levels are specific in diabetic and non-diabetic CKD patients, while leptin presents increased levels, and both are associated with the development of glomerulopathy. Excessive adipose tissue is associated with inflammation, oxidative stress (OS), insulin resistance and activation of the renin angiotensin-aldosterone system (RAAS). Therefore, adipose tissue dysfunction plays an important role in the development of CKD.

The ED/TEG Indicator for the Identification of Endocrine Disrupting or Toxic Effects on Endocrine Glands of Crop Protection Products Used in Organic and Conventional Agriculture in France.

Studying the human health impacts of pesticides and their endocrine disruptor (ED) effects is a public health concern. The aim of this study is to identify phytopharmaceutical active substances (PAS) that are an ED or are toxic on endocrine glands (TEG), and to propose an ED/TEG effect indicator. Five international official databases were analyzed to identify the occurrence of health outcomes for 458 PAS. Health outcomes targeting seven endocrine systems were selected. For each substance, the level of evidence of the collected information and the number of outcomes were used to affect a level of concern about ED/TEG effects. Among the substances studied, 10% had a global ED/TEG effect classified as 'high concern', 55% as 'medium concern', 9% as 'low concern', and 26% as 'unknown'. Ten of the high ED/TEG concern substances and 170 medium or low concern substances were licensed in 2018 in France. The outcomes were mainly on the reproductive organs, thyroid, and adrenal glands. Eight of the 41 biocontrol products studied were classified: 5 were 'high' or 'medium concern' and 3 had 'unknown effect'. Although the proposed ED/TEG indicator is not an official classification, it can be used as an epidemiological tool for classifying the occupational and environmental risks of substances in retrospective population studies and be useful for occupational health physicians.

Adipose tissue in health and disease.

Adipose, or fat, tissue (AT) was once considered an inert tissue that primarily existed to store lipids, and was not historically recognized as an important organ in the regulation and maintenance of health. With the rise of obesity and more rigorous research, AT is now recognized as a highly complex metabolic organ involved in a host of important physiological functions, including glucose homeostasis and a multitude of endocrine capabilities. AT dysfunction has been implicated in several disease states, most notably obesity, metabolic syndrome and type 2 diabetes. The study of AT has provided useful insight in developing strategies to combat these highly prevalent metabolic diseases. This review highlights the major functions of adipose tissue and the consequences that can occur when disruption of these functions leads to systemic metabolic dysfunction.

PHOSPHO1 is a skeletal regulator of insulin resistance and obesity.

BACKGROUND: The classical functions of the skeleton encompass locomotion, protection and mineral homeostasis. However, cell-specific gene deletions in the mouse and human genetic studies have identified the skeleton as a key endocrine regulator of metabolism. The bone-specific phosphatase, Phosphatase, Orphan 1 (PHOSPHO1), which is indispensable for bone mineralisation, has been recently implicated in the regulation of energy metabolism in humans, but its role in systemic metabolism remains unclear. Here, we probe the mechanism underlying metabolic regulation by analysing Phospho1 mutant mice. RESULTS: Phospho1-/- mice exhibited improved basal glucose homeostasis and resisted high-fat-diet-induced weight gain and diabetes. The metabolic protection in Phospho1-/- mice was manifested in the absence of altered levels of osteocalcin. Osteoblasts isolated from Phospho1-/- mice were enriched for genes associated with energy metabolism and diabetes; Phospho1 both directly and indirectly interacted with genes associated with glucose transport and insulin receptor signalling. Canonical thermogenesis via brown adipose tissue did not underlie the metabolic protection observed in adult Phospho1-/- mice. However, the decreased serum choline levels in Phospho1-/- mice were normalised by feeding a 2% choline rich diet resulting in a normalisation in insulin sensitivity and fat mass. CONCLUSION: We show that mice lacking the bone mineralisation enzyme PHOSPHO1 exhibit improved basal glucose homeostasis and resist high-fat-diet-induced weight gain and diabetes. This study identifies PHOSPHO1 as a potential bone-derived therapeutic target for the treatment of obesity and diabetes.

Secretory glands and microvascular systems imaged in aqueous solution by atmospheric scanning electron microscopy (ASEM).

Exocrine glands, e.g., salivary and pancreatic glands, play an important role in digestive enzyme secretion, while endocrine glands, e.g., pancreatic islets, secrete hormones that regulate blood glucose levels. The dysfunction of these secretory organs immediately leads to various diseases, such as diabetes or Sjögren's syndrome, by poorly understood mechanisms. Gland-related diseases have been studied by optical microscopy (OM), and at higher resolution by transmission electron microscopy (TEM) of Epon embedded samples, which necessitates hydrophobic sample pretreatment. Here, we report the direct observation of tissue in aqueous solution by atmospheric scanning electron microscopy (ASEM). Salivary glands, lacrimal glands, and pancreas were fixed, sectioned into slabs, stained with phosphotungstic acid (PTA), and inspected in radical scavenger d-glucose solution from below by an inverted scanning electron microscopy (SEM), guided by optical microscopy from above to target the tissue substructures. A 2- to 3-µm specimen thickness was visualized by the SEM. In secretory cells, cytoplasmic vesicles and other organelles were clearly imaged at high resolution, and the former could be classified according to the degree of PTA staining. In islets of Langerhans, the microvascular system used as an outlet by the secretory cells was also clearly observed. Microvascular system is also critically involved in the onset of diabetic complications and was clearly visible in subcutaneous tissue imaged by ASEM. The results suggest the use of in-solution ASEM for histology and to study vesicle secretion systems. Further, the high-throughput of ASEM makes it a potential tool for the diagnosis of exocrine and endocrine-related diseases.

Precise long-range migration results from short-range stepwise migration during ring gland organogenesis.

Many organs are specified far from the location they occupy when functional, having to migrate long distances through the heterogeneous and dynamic environment of the early embryo. We study the formation of the main Drosophila endocrine organ, the ring gland, as a new model to investigate in vivo the genetic regulation of collective cell migration. The ring gland results from the fusion of three independent gland primordia that migrate from the head towards the anterior aorta as the embryo is experiencing major morphogenetic movements. To complete their long-range migration, the glands extend filopodia moving sequentially towards a nearby intermediate target and from there to more distal ones. Thus, the apparent long-range migration is composed of several short-range migratory steps that facilitate reaching the final destination. We find that the target tissues react to the gland's proximity by sending filopodia towards it. Our finding of a succession of independent migration stages is consistent with the stepwise evolution of ring gland assembly and fits with the observed gland locations found in extant crustaceans, basal insects and flies.

Hypothesis: solid tumours behave as systemic metabolic dictators.

Current knowledge regarding mechanisms of carcinogenesis in human beings centres around the accumulation of genetic instability, amplified cellular signalling, disturbed cellular energy metabolism and microenvironmental regulation governed by complicated cell-cell interactions. In this article, we provide an alternative view of cancer biology. We propose that cancer behaves as a systemic dictator that interacts with tissues throughout the body to control their metabolism and eventually homeostasis. The mechanism of development of this endocrine organ-like tumour (EOLT) tissue might be the driving force for cancer progression. Here, we review the literature that led to the development of this hypothesis. The EOLT phenotype can be defined as a tumour that alters systemic homeostasis. The literature indicates that the EOLT phenotype is present throughout cancer progression. The feedback mechanism that governs the interaction between tumours and various organs is unknown. We believe that investigating the mechanism of EOLT development may advance the current knowledge of regulation within the tumour macroenvironment and consequently lead to new diagnostic methods and therapy.

Translational research into species differences of endocrine toxicity via steroidogenesis inhibition by SMP-028--for human safety in clinical study.

SMP-028 is a drug candidate developed for the treatment of asthma. In a 13-week repeated dose toxicity study of SMP-028 in rats and monkeys, differences of endocrine toxicological events between rats and monkeys were observed. In rats, these toxicological events mainly consisted of pathological changes in the adrenal, testis, ovary, and the other endocrine-related organs. On the other hand, in monkeys, no toxicological events were observed. The goal of this study is to try to understand the reason why only rats, but not monkeys, showed toxicological events following treatment with SMP-028 and to eventually predict the possible toxicological effect of this compound on human endocrine organs. Our results show that SMP-028 inhibits neutral cholesterol esterase more strongly than other steroidogenic enzymes in rats. Although SMP-028 also inhibits monkeys and human neutral cholesterol esterase, this inhibition is much weaker than that of rat neutral cholesterol esterase. These results indicate (1) that the difference in endocrine toxicological events between rats and monkeys is mainly due to inhibition of steroidogenesis by SMP-028 in rats, not in monkeys, and (2) that SMP-028 may not affect steroidogenesis in humans and therefore might cause no endocrine toxicological events in clinical studies.

Effect of SMP-028 on steroidogenesis in rats; mechanism of toxicological events on endocrine organs of rats.

SMP-028 is a new compound for treatment of asthma. Oral administration of SMP-028 to rats was associated with toxicological events in endocrine organs. These events mainly consisted of pathological changes in the adrenal gland, testis, prostate, seminal vesicle, ovaries, and uterus. In this study, we set to clarify whether SMP-028 inhibits steroidogenesis in primary culture cells obtained from rat endocrine organs in vitro. Adrenal cells, testicular cells, and ovarian cells were treated with SMP-028 and the production of steroid hormones, i.e., progesterone, aldosterone, corticosterone, total testosterone, and estradiol from these cells was measured by radioimmunoassay. We found that the production of progesterone from these cells treated with SMP-028 at 1 µM decreased to 16-67% that of the control. These findings indicate that SMP-028 inhibits steroidogenesis in rat endocrine organs in vitro. Considering that free maximum concentration in rats treated with SMP-028 are higher than the IC50 values for the inhibition of steroidogenesis in vitro, it is therefore believed that the toxicological events seen in rats following treatment with SMP-028 are due to inhibition of steroidogenesis in vivo.

Long-term survival of a patient with pulmonary artery intimal sarcoma after sequential metastasectomies of the thyroid and adrenal glands.

Cancer metastases to the thyroid or adrenal gland are uncommon. Furthermore, cases showing long-term survival after surgical resection of those metastatic tumors are rare. We report a case of pulmonary artery intimal sarcoma with metastases to the thyroid and adrenal glands sequentially that was successfully treated with sequential metastasectomies. A 62-year-old woman presented with a 4-week history of dyspnea on exertion and facial edema in November 1999. Echocardiography and chest computed tomography (CT) revealed an embolism-like mass in the pulmonary trunk. Pulmonary artery endarterectomy with pulmonary valve replacement was performed, and histopathology revealed pulmonary artery intimal sarcoma. A thyroid nodule was found by chest CT in November 2001 (2 years after initial surgery). During follow-up, this lesion showed no change, but we decided to obtain fine needle aspiration cytology (FNAC) in August 2004 (4.7 years after initial surgery). FNAC revealed atypical spindle cells suggestive of metastatic intimal sarcoma. She underwent total thyroidectomy. During follow-up, a right adrenal gland mass was detected by chest CT in March 2006 (6.3 years after initial surgery), and adrenalectomy was done, which also revealed metastatic sarcoma. She has been followed up without any evidence of recurrent disease until May 2012 (12.5 years after initial surgery).

Long-Term Survival of a Patient with Pulmonary Artery Intimal Sarcoma after Sequential Metastasectomies of the Thyroid and Adrenal Glands

Cancer metastases to the thyroid or adrenal gland are uncommon. Furthermore, cases showing long-term survival after surgical resection of those metastatic tumors are rare. We report a case of pulmonary artery intimal sarcoma with metastases to the thyroid and adrenal glands sequentially that was successfully treated with sequential metastasectomies. A 62-year-old woman presented with a 4-week history of dyspnea on exertion and facial edema in November 1999. Echocardiography and chest computed tomography (CT) revealed an embolism-like mass in the pulmonary trunk. Pulmonary artery endarterectomy with pulmonary valve replacement was performed, and histopathology revealed pulmonary artery intimal sarcoma. A thyroid nodule was found by chest CT in November 2001 (2 years after initial surgery). During follow-up, this lesion showed no change, but we decided to obtain fine needle aspiration cytology (FNAC) in August 2004 (4.7 years after initial surgery). FNAC revealed atypical spindle cells suggestive of metastatic intimal sarcoma. She underwent total thyroidectomy. During follow-up, a right adrenal gland mass was detected by chest CT in March 2006 (6.3 years after initial surgery), and adrenalectomy was done, which also revealed metastatic sarcoma. She has been followed up without any evidence of recurrent disease until May 2012 (12.5 years after initial surgery).

Funciones endocrinas del tejido adiposo

El tejido adiposo se considera en la actualidad como un órgano con función endocrina, capaz de secretar diversas sustancias que están relacionadas directamente en la aparición de la obesidad. Es la principal reserva energética del organismo y su unidad funcional es el adipocito. Se distinguen dos tipos de tejido adiposo, el blanco y el pardo o marrón; el primero, es donde tiene lugar su función endocrina y se encuentra ampliamente distribuido en el cuerpo, dividido en dos compartimientos: subcutáneo y visceral. Entre el grupo de sustancias secretadas por el tejido adiposo se encuentran moléculas implicadas en la regulación del peso corporal: leptina y adiponectina; en el sistema inmune: factor de necrosis tumoral alfa, interleuquina 1 y 6; en la función vascular: angiotensina e inhibidor del activador del plasminógeno tipo 1; en el desarrollo de la resistencia a la insulina: resistina. El conocimiento de estas sustancias abre una nueva ventana para la explicación de la génesis de la obesidad y para la efectividad en la búsqueda del tratamiento futuro.

Adipose tissue has been considered as an endocrine organ which is able to secreting several peptides directly involved with obesity. Adipose tissue is also the main body energetic storage and its functional unit is the adipocite. Two types of adipose tissue are known: white and brown adipose tissue; the first one has an endocrine function and it is widely spread in whole body including two compartments: subcutaneous and visceral. Peptides secreted by adipose tissue are involved in different systems: body weight regulation: leptin, adiponectin; immune system: alpha tumour necrosis factor, interleukin 1 and 6; vascular function: angiotensin and plasminogen activator inhibitor-l; and insulin resistance pathogenesis: resistin. The knowledge of these substances open a new door for understanding of obesity and its treatment.