Sex-specific effects of fluoride and lead on thyroid endocrine function in zebrafish (Danio rerio).

Fluoride (F) and lead (Pb) are widespread pollutants in the environment. F and Pb affect the thyroid endocrine system, but the mechanism of action between F and Pb is still unclear. In this study, in order to evaluate the effects of F or/and Pb on histopathological changes, antioxidant indices, the levels of thyroid hormones (THs), and the expression of endocrine-related genes in zebrafish thyroid. One thousand and two hundred zebrafish (female:male = 1:1) were randomly divided into four groups: control group (C group), 80 mg/L F group (F group), 60 mg/L Pb group (Pb group), and 80 mg/L F + 60 mg/L Pb group (F + Pb group) for 45 d and 90 d. Histopathological sections showed a loss of glia and follicular epithelial hyperplasia in the thyroid gland after exposure to F and Pb. Oxidative stress in the thyroid was induced after F and Pb exposure. And each oxidation index was increased after F + Pb exposure. Combined F and Pb exposure aggravated the downregulation of thyroid hormones T3 and T4 compared to exposure alone. Furthermore, F and Pb exposure altered the expression of thyroid endocrine-related genes in a time-dependent manner. These results indicate that F and Pb can affect the endocrine system of thyroid by changing the tissue structure, antioxidant capacity, thyroid hormone secretion and the levels of endocrine-related genes in thyroid. F and Pb can also produce toxic effects on thyroid, but the degree of poisoning is different in different indicators, mainly for the additive effect between them. Additionally, males are more sensitive than females to F or Pb toxicity. However, the specific molecular mechanism of the effects of F and Pb on thyroid endocrine system needs to be further studied.

Endocrine risk factors for COVID-19 in context of aging.

Aged people are the most susceptible group to COVID-19 infection. Immunosenescence characterized by impairment of immune function with inflamm-aging contributes to pathophysiological alterations, among which endocrine and metabolic diseases are not exception. Diabetes, obesity along with impairment of disorders of thyroid functions are the most frequent ones, the common feature of which is failure of immune system including autoimmune processes. In the minireview we discussed how COVID-19 and aging impact innate and adaptive immunity, diabetes and selected neuroendocrine processes. Mentioned is also beneficial effect of vitamin D for attenuation of these diseases and related epigenetic issues. Particular attention is devoted to the role of ACE2 protein in the light of its intimate link with renin-angiotensin regulating system.

Placental Endocrine Activity: Adaptation and Disruption of Maternal Glucose Metabolism in Pregnancy and the Influence of Fetal Sex.

The placenta is an endocrine fetal organ, which secretes a plethora of steroid- and proteo-hormones, metabolic proteins, growth factors, and cytokines in order to adapt maternal physiology to pregnancy. Central to the growth of the fetus is the supply with nutrients, foremost with glucose. Therefore, during pregnancy, maternal insulin resistance arises, which elevates maternal blood glucose levels, and consequently ensures an adequate glucose supply for the developing fetus. At the same time, maternal ß-cell mass and function increase to compensate for the higher insulin demand. These adaptations are also regulated by the endocrine function of the placenta. Excessive insulin resistance or the inability to increase insulin production accordingly disrupts physiological modulation of pregnancy mediated glucose metabolism and may cause maternal gestational diabetes (GDM). A growing body of evidence suggests that this adaptation of maternal glucose metabolism differs between pregnancies carrying a girl vs. pregnancies carrying a boy. Moreover, the risk of developing GDM differs depending on the sex of the fetus. Sex differences in placenta derived hormones and bioactive proteins, which adapt and modulate maternal glucose metabolism, are likely to contribute to this sexual dimorphism. This review provides an overview on the adaptation and maladaptation of maternal glucose metabolism by placenta-derived factors, and highlights sex differences in this regulatory network.

Autonomic, endocrine, and psychological stress responses to different forms of blood draw.

BACKGROUND: Although fingerstick is often favorably compared to venipuncture as a less invasive method of drawing blood for clinical labs, there is little empirical research that compares physical and psychological stress responses to fingerstick vs. venipuncture (blood draw using a needle in the arm) within the same person. METHODS AND FINDINGS: We assessed changes in cortisol (a stress hormone), heart rate variability (a marker of autonomic stress), and psychological stress in 40 healthy women who completed both venipuncture and fingerstick. Contrary to our predictions, there was a significant decline in cortisol across conditions, with greater decline from pre- to post-draw in response to venipuncture than fingerstick. There were similar patterns of rise and fall in heart rate variability in both types of blood draw, suggestive of mild vasovagal responses. Psychological measures of stress (such as negative emotion and perceived stress) were generally stronger predictors of participant's reported pain and blood draw preferences than physical stress measures. CONCLUSIONS: These findings challenge the characterization of fingerstick as necessarily "less invasive" than venipuncture, as participant's stress responses to fingerstick were equivalent to (and for some measures greater than) their response to venipuncture. Heart rate variability response to fingerstick significantly predicted that individual's vasovagal-like responses to venipuncture, suggesting that measuring heart rate variability during pre-donation hemoglobin testing may identify donors at risk for adverse events during venipuncture.

Targeting the gut to treat multiple sclerosis.

The gut-brain axis (GBA) refers to the complex interactions between the gut microbiota and the nervous, immune, and endocrine systems, together linking brain and gut functions. Perturbations of the GBA have been reported in people with multiple sclerosis (pwMS), suggesting a possible role in disease pathogenesis and making it a potential therapeutic target. While research in the area is still in its infancy, a number of studies revealed that pwMS are more likely to exhibit altered microbiota, altered levels of short chain fatty acids and secondary bile products, and increased intestinal permeability. However, specific microbes and metabolites identified across studies and cohorts vary greatly. Small clinical and preclinical trials in pwMS and mouse models, in which microbial composition was manipulated through the use of antibiotics, fecal microbiota transplantation, and probiotic supplements, have provided promising outcomes in preventing CNS inflammation. However, results are not always consistent, and large-scale randomized controlled trials are lacking. Herein, we give an overview of how the GBA could contribute to MS pathogenesis, examine the different approaches tested to modulate the GBA, and discuss how they may impact neuroinflammation and demyelination in the CNS.

Endocrine Dysfunction in Patients With Myotonic Dystrophy.

Myotonic dystrophy is a dominantly inherited multisystem disorder that results from increased CTG repeats in the 3' region of the myotonic dystrophy protein kinase gene (DMPK). The mutant DMPK mRNA remains in the nucleus and sequesters RNA-binding proteins, including regulators of mRNA splicing. Myotonic dystrophy is characterized by a highly variable phenotype that includes muscle weakness and myotonia, and the disorder may affect the function of many endocrine glands. DMPK mRNA is expressed in muscle, testis, liver, pituitary, thyroid, and bone; the mutated form leads to disruption of meiosis and an increase in fetal insulin receptor-A relative to adult insulin receptor-B, resulting in adult primary testicular failure and insulin resistance predisposing to diabetes, respectively. Patients with myotonic dystrophy are also at increased risk for hyperlipidemia, nonalcoholic fatty liver disease, erectile dysfunction, benign and malignant thyroid nodules, bone fractures, miscarriage, preterm delivery, and failed labor during delivery. Circulating parathyroid hormone and adrenocorticotropic hormone levels may be elevated, but the mechanisms for these associations are unclear. This review summarizes what is known about endocrine dysfunction in individuals with myotonic dystrophy.

Tumors modulate fenestrated vascular beds and host endocrine status.

Allograft and xenograft transplantation into a mouse host is frequently utilized to study cancer biology, tumor behavior, and response to treatment. Preclinical studies employing these models often focus solely upon the intra-tumoral effects of a given treatment, without consideration of systemic toxicity or tumor-host interaction, nor whether this latter relationship could modulate the toxicologic response to therapy. Here it is demonstrated that the implantation and growth of a range of human- and mouse-derived cell lines leads to structural vascular and, potentially, functional changes within peripheral endocrine tissues, a process that could conceivably ameliorate the severity of anti-angiogenic-induced fenestrated vessel attenuation. Observations suggest a multifactorial process, which may involve host- and tumor-derived cytokines/growth factors, and the liberation of myeloid-derived suppressor cells. Further investigation revealed a structurally comparable response to the administration of exogenous estrogen. These findings, in addition to providing insight into the development of clinical anti-angiogenic "adaptation," may be of significance within the "cancer-cachexia" and cancer-related anemia syndromes in man.

New aspects of endocrine control of atrial fibrillation and possibilities for clinical translation.

Hormones are potent endo-, para-, and autocrine endogenous regulators of the function of multiple organs, including the heart. Endocrine dysfunction promotes a number of cardiovascular diseases, including atrial fibrillation (AF). While the heart is a target for endocrine regulation, it is also an active endocrine organ itself, secreting a number of important bioactive hormones that convey significant endocrine effects, but also through para-/autocrine actions, actively participate in cardiac self-regulation. The hormones regulating heart-function work in concert to support myocardial performance. AF is a serious clinical problem associated with increased morbidity and mortality, mainly due to stroke and heart failure. Current therapies for AF remain inadequate. AF is characterized by altered atrial function and structure, including electrical and profibrotic remodelling in the atria and ventricles, which facilitates AF progression and hampers its treatment. Although features of this remodelling are well-established and its mechanisms are partly understood, important pathways pertinent to AF arrhythmogenesis are still unidentified. The discovery of these missing pathways has the potential to lead to therapeutic breakthroughs. Endocrine dysfunction is well-recognized to lead to AF. In this review, we discuss endocrine and cardiocrine signalling systems that directly, or as a consequence of an underlying cardiac pathology, contribute to AF pathogenesis. More specifically, we consider the roles of products from the hypothalamic-pituitary axis, the adrenal glands, adipose tissue, the renin-angiotensin system, atrial cardiomyocytes, and the thyroid gland in controlling atrial electrical and structural properties. The influence of endocrine/paracrine dysfunction on AF risk and mechanisms is evaluated and discussed. We focus on the most recent findings and reflect on the potential of translating them into clinical application.

Backstage of Eating Disorder-About the Biological Mechanisms behind the Symptoms of Anorexia Nervosa.

Anorexia nervosa (AN) represents a disorder with the highest mortality rate among all psychiatric diseases, yet our understanding of its pathophysiological components continues to be fragmentary. This article reviews the current concepts regarding AN pathomechanisms that focus on the main biological aspects involving central and peripheral neurohormonal pathways, endocrine function, as well as the microbiome-gut-brain axis. It emerged from the unique complexity of constantly accumulating new discoveries, which hamper the ability to look at the disease in a more comprehensive way. The emphasis is placed on the mechanisms underlying the main symptoms and potential new directions that require further investigation in clinical settings.

Neonatal overnutrition programming impairs cholecystokinin effects in adultmale rats.

Overfeeding and rapid weight gain during early life are risk factors for the development of obesity in adulthood. This metabolic malprogramming may be mediated by endocrine disturbances during critical periods of development. Cholecystokinin (CCK) acts on the central nervous system by elevating thermogenesis and the activity of anorectic neurons, modulating overall energy balance. Therefore, we tested the hypothesis that postnatal overfeeding impaired CCK effects. Pups were raised in either a litter of three (neonatal overnutrition/small litter group) or 12 (controls/normal litter group) pups per dam to study the effects of postnatal overfeeding on the central and peripheral CCK systems in adulthood. Rats raised in small litters became overweight during lactation and remained overweight as adults, with increased adiposity and plasma levels of lipids, glucose, insulin, and leptin. Neonatally over-nourished rats showed attenuation of gastric emptying and anorexigenic response to CCK, suggesting that offspring from the SL group may present CCK resistance as adult male rats. Consistent with this idea, overweight rats displayed impaired central response in c-Fos immunoreactivity on the nucleus tractus solitarius, area postrema, paraventricular nucleus, central amygdala, arcuate nucleus, and dorsomedial hypothalamus in response to peripheral CCK at adulthood. The small litter group of adult male rats also exhibited reduced norepinephrine- and CCK-stimulated thermogenesis. Unresponsiveness to the effects of CCK may contribute to overweight and metabolic dysfunctions observed in postnatally over-nourished adult rats. Thus, the involvement of an impaired CCK system, among other neurohormonal failures, may contribute to the development of obesity.

Metabolic Syndrome and COVID 19: Endocrine-Immune-Vascular Interactions Shapes Clinical Course.

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Individuals with metabolic syndrome are at increased risk for poor disease outcomes and mortality from COVID-19. The pathophysiologic mechanisms for these observations have not been fully elucidated. A critical interaction between SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2) facilitates viral entry into the host cell. ACE2 is expressed in pancreatic islets, vascular endothelium, and adipose tissue, and the SARS-CoV-2 -ACE2 interaction in these tissues, along with other factors, governs the spectrum and the severity of clinical manifestations among COVID-19 patients with metabolic syndrome. Moreover, the pro-inflammatory milieu observed in patients with metabolic syndrome may contribute toward COVID-19-mediated host immune dysregulation, including suboptimal immune responses, hyperinflammation, microvascular dysfunction, and thrombosis. This review describes the spectrum of clinical features, the likely pathophysiologic mechanisms, and potential implications for the management of metabolic syndrome in COVID-19 patients.

Endocrine fibroblast growth factors as potential biomarkers for chronic kidney disease.

INTRODUCTION: Among the family of fibroblast growth factors (FGFs), FGF19, FGF21, and FGF23 act as circulating hormones and are called endocrine FGFs. FGF19 and FGF21 regulate bile acid and energy homeostasis, respectively, whereas FGF23 regulates vitamin D and phosphate homeostasis. Accumulating evidence suggests that FGF23 plays a critical role in disturbed mineral metabolisms, left ventricular hypertrophy, immunosuppression, inflammation, among others in patients with chronic kidney disease (CKD), highlighting the potential both as a biomarker and a therapeutic target. Several studies have also examined the potential role of FGF19 and FGF21 in CKD patients. AREAS COVERED: In this review, we present a brief overview of the biology of FGF19, FGF21, and FGF23, and summarize recent clinical and experimental studies on the pathophysiological roles of endocrine FGFs, mainly FGF23, in CKD patients. EXPERT OPINION: Among the endocrine FGFs, FGF23 represents the most promising biomarker in CKD patients. If future studies confirm that FGF23 is directly toxic in CKD patients, FGF23 could be regarded as a therapeutic target and its measurement would be valuable if applied in clinical practice. Despite their potentially important roles, the clinical relevance of FGF19 and FGF21 in CKD patients is unclear, and much more studies are required.

Human exposure to synthetic endocrine disrupting chemicals (S-EDCs) is generally negligible as compared to natural compounds with higher or comparable endocrine activity: how to evaluate the risk of the S-EDCs?

Theoretically, both synthetic endocrine disrupting chemicals (S-EDCs) and natural (exogenous and endogenous) endocrine disrupting chemicals (N-EDCs) can interact with endocrine receptors and disturb hormonal balance. However, compared to endogenous hormones, S-EDCs are only weak partial agonists with receptor affinities several orders of magnitude lower. Thus, to elicit observable effects, S-EDCs require considerably higher concentrations to attain sufficient receptor occupancy or to displace natural hormones and other endogenous ligands. Significant exposures to exogenous N-EDCs may result from ingestion of foods such as soy-based diets, green tea and sweet mustard. While their potencies are lower as compared to natural endogenous hormones, they usually are considerably more potent than S-EDCs. Effects of exogenous N-EDCs on the endocrine system were observed at high dietary intakes. A causal relation between their mechanism of action and these effects is established and biologically plausible. In contrast, the assumption that the much lower human exposures to S-EDCs may induce observable endocrine effects is not plausible. Hence, it is not surprising that epidemiological studies searching for an association between S-EDC exposure and health effects have failed. Regarding testing for potential endocrine effects, a scientifically justified screen should use in vitro tests to compare potencies of S-EDCs with those of reference N-EDCs. When the potency of the S-EDC is similar or smaller than that of the N-EDC, further testing in laboratory animals and regulatory consequences are not warranted.

Prenatal over- and undernutrition differentially program small intestinal growth, angiogenesis, absorptive capacity, and endocrine function in sheep.

The aim was to test the hypothesis that prenatal under- and overnutrition in late gestation can program small intestinal (SI) growth, angiogenesis, and endocrine function to predispose for a hyperabsorptive state, thereby increasing the susceptibility to the adverse effects of an early postnatal obesogenic diet. Twin-pregnant ewes were exposed to adequate (NORM), LOW (50% of NORM), or HIGH (150% energy and 110% protein of NORM) diets through the last trimester (term ~147 days). From 3 days to 6 months of age, their lambs were fed either a moderate (CONV) or a high-carbohydrate high-fat (HCHF) diet. At 6 months of age, responses in plasma metabolites and insulin to refeeding after fasting were determined and then different segments of the SI were sampled at autopsy. Prenatal overnutrition impacts were most abundant in the duodenum where HIGH had increased villus amplification factor and lowered villi thickness with increased IRS-1 and reduced GH-R expressions. In jejunum, HIGH lambs had an increased expression of Lactate gene and amplified when exposed to HCHF postnatally. Specifically, in LOW, sensitivity to HCHF was affected in ileum. Thus, the mismatching LOW-HCHF nutrition increased expressions of angiogenic genes (VEGF, VEGF-R1, ANGPT1, RTK) and increased mucosa layer (tunica mucosa) thickness but reduced muscle layer (Tunica muscularis) thickness. The SI is a target of prenatal nutritional programming, where late gestation overnutrition increased and shifted digestive capacity for carbohydrates toward the jejunum, whereas late gestation undernutrition predisposed for ileal angiogenesis and carbohydrate and fat hyperabsorptive capacity upon subsequent exposure to postnatal obesogenic diet.

Evidence for a More Disrupted Immune-Endocrine Relation and Cortisol Immunologic Influences in the Context of Tuberculosis and Type 2 Diabetes Comorbidity.

Pulmonary tuberculosis (PTB), caused by Mycobacterium tuberculosis (Mtb), is a major health problem worldwide, further aggravated by the convergence of type 2 diabetes mellitus (DM) which constitutes an important risk factor for TB development. The worse scenario of patients with PTB and DM may be partly related to a more unbalanced defensive response. As such, newly diagnosed PTB patients with DM (TB+DM, n = 11) or not (TB, n = 21), as well as DM (n = 18) patients and pair matched controls (Co, n = 22), were investigated for the circulating immuno-endocrine-metabolic profile (ELISA), along with studies in peripheral blood mononuclear cells (PBMC) analyzing transcript expression (RT-qPCR) of mediators involved in glucocorticoid functionality. Given the hyperglycemic/hypercortisolemic scenario of TB+DM patients, PBMC were also exposed to stress-related cortisol concentrations (0.1 and 1 µM) and supraphysiologic glucose doses (10, 20, and 40 mM) and assessed for the specific response against Mtb stimulation (lymphoproliferation, -thymidine incorporation-, and cytokine production -bead-cytometry). All TB patients displayed increased plasma amounts of cortisol, growth hormone -hGH-, and proinflammatory mediators. In turn, TB+DM showed even higher levels of interferon gamma -IFN-γ- and hGH (vs. TB), or IL-6, C reactive protein, cortisol and hGH (vs. DM). Both DM groups had equally augmented values of IL-10. All TB patients showed decreased dehydroepiandrosterone- sulfate concentrations, even more in TB+DM cases. Leptin was also decreased in both TB cases, particularly in the TB group, revealing a lower body mass index, as well. Unlike PBMC from TB cases showing a decreased relationship between the glucocorticoids receptor (GR) isoforms (GRα/GRß; functional isoform/negative isoform), cells from TB+DM patients had no changes in this regard, along with an increased expression of 11-beta hydroxysteroid dehydrogenase type-1, the enzyme facilitating intracellular cortisone to cortisol conversion. TB+DM patients also showed an increased Mtb antigen-driven lymphoproliferation. Compared to TB, DM and HCo counterparts, PBMC from TB+DM patients had a biased Th1 response to Mtb stimulation (increased IL-2 and IFN-γ production), even when exposed to inhibitory cortisol doses. TB+DM patients show a more unbalanced immuno-endocrine relationship, respect the non-diabetic counterparts, with a relative deficiency of cortisol immunomodulatory influences, despite their more favorable microenvironment for cortisol-mediated immune effects.

The Psilocybin-Telomere Hypothesis: An empirically falsifiable prediction concerning the beneficial neuropsychopharmacological effects of psilocybin on genetic aging.

We introduce a novel hypothesis which states that the therapeutic utilisation of psilocybin has beneficial effects on genetic aging. Ex hypothesi, we predict a priori that controlled psilocybin interventions exert quantifiable positive impact on leucocyte telomere length (telomeres are a robust predictor of mortality and multifarious aging-related diseases). Our hypothesising follows the Popperian logic of scientific discovery, viz., bold (and refutable) conjectures form the very foundation of scientific progress. The 'psilocybin-telomere hypothesis' is formalised as a logically valid deductive (syllogistic) argument and we provide substantial evidence to support the underlying premises. Impetus for our theorising derives from a plurality of converging empirical sources indicating that psilocybin has persistent beneficial effects on various aspects of mental health (e.g., in the context of depression, anxiety, PTSD, OCD, addiction, etc.). Additional support is based on a large corpus of studies that establish reliable correlations between mental health and telomere attrition (improved mental health is generally correlated with longer telomeres). Another pertinent component of our argument is based on recent studies which demonstrate that "meditative states of consciousness" provide beneficial effects on genetic aging. Similarly, psilocybin can induce states of consciousness that are neurophysiologically and phenomenologically significantly congruent with meditative states. Furthermore, prior research has demonstrated that a single dose of psilocybin can occasion life-changing transformative experiences (≈ 70% of healthy volunteers rate their experience with psilocybin amongst the five personally most meaningful lifetime events, viz., ranked next to giving birth to a child or losing a loved one). We postulate that these profound psychological events leave quantifiable marks at the molecular genetic/epigenetic level. Given the ubiquitous availability and cost effectiveness of telomere length assays, we suggest that quantitative telomere analysis should be regularly included in future psilocybin studies as an adjunctive biological marker (i.e., to facilitate scientific consilience via methodological triangulation). In order to substantiate the 'psilocybin-telomere hypothesis' potential neuropsychopharmacological, endocrinological, and genetic mechanisms of action are discussed (e.g., HPA-axis reactivity, hippocampal neurogenesis, neurotropic growth factors such as BDNF, 5-HT2A receptor agonism, neuroplasticity/synaptoplasticity, brain-wide alterations in neuronal functional connectivity density, involvement of the SLC6A4 serotonin transporter gene, inter alia). The proposed research agenda is thus intrinsically highly interdisciplinary, and it has deep ramifications from a philosophy of science perspective as it connects the epistemic level (qualitative experiential phenomenology) with the ontic level (quantitative molecular genetics) of analysis. In the long term, multidisciplinary and innovative investigations of the 'psilocybin-telomere hypothesis' could contribute to the improvement of senotherapeutic psychological interventions and the identification of novel geroprotective and neuroprotective/restorative pharmaceutical targets to decelerate genetic aging and improve well-being and quality of life during the aging process.

Prader Willi syndrome: endocrine updates and new medical therapies.

PURPOSE OF REVIEW: Prader Willi syndrome is characterized not only by hyperphagia frequently resulting in obesity, but also by endocrine dysfunction across a variety of axes. This article reviews the most recent literature regarding possible causes of hyperphagia and the nature of endocrinopathies seen in Prader Willi syndrome, as well as current research into possible therapies. RECENT FINDINGS: Investigation into neurologic, metabolic and hormonal drivers of hyperphagia and obesity has revealed new insights and clarified underlying pathophysiology. Additional studies continue to elucidate the hormonal deficiencies seen in the syndrome, allowing for improvements in clinical care. SUMMARY: The underlying causes of the hyperphagia and progressive obesity frequently seen in Prader Willi Syndrome are largely unknown and likely multifactorial. Understanding the hormonal and metabolic drivers at work in PWS, as well as the nature of other hormonal dysfunction seen in the syndrome is necessary to guide current management and future research directions.