Neuronal and hormonal control of Ca2+ signalling in exocrine glands: insight from in vivo studies.

Fluid and enzyme secretion from exocrine glands is initiated by Ca2+ signalling in acinar cells and is activated by external neural or hormonal signals. A wealth of information has been derived from studies in acutely isolated exocrine cells but Ca2+ signalling has until recently not been studied in undisrupted intact tissue in live mice. Our in vivo observations using animals expressing genetically encoded Ca2+ indicators in specific cell types in exocrine glands revealed both similarities to and differences from the spatiotemporal characteristics previously reported in isolated cells. These in vivo studies facilitate further understanding of how both neuronal and hormonal input shapes Ca2+ signalling events in a physiological setting and how these signals are translated into the stimulation of fluid secretion and exocytosis.

The role of hormones in the regulation of lactogenic immunity in porcine and bovine species.

Colostrum and milk offer a complete diet and vital immune protection for newborn mammals with developing immune systems. High immunoglobulin levels in colostrum serve as the primary antibody source for newborn piglets and calves. Subsequent milk feeding support continued local antibody protection against enteric pathogens, as well as maturation of the developing immune system and provide nutrients for newborn growth. Mammals have evolved hormonal strategies that modulate the levels of immunoglobulins in colostrum and milk to facilitate effective lactational immunity. In addition, hormones regulate the gut-mammary gland-secretory immunoglobulin A (sIgA) axis in pregnant mammals, controlling the levels of sIgA in milk, which serves as the primary source of IgA for piglets and helps them resist pathogens such as PEDV and TGEV. In the present study, we review the existing studies on the interactions between hormones and the gut-mammary-sIgA axis/lactogenic immunity in mammals and explore the potential mechanisms of hormonal regulation that have not been studied in detail, to draw attention to the role of hormones in influencing the immune response of pregnant and lactating mammals and their offspring, and highlight the effect of hormones in regulating sIgA-mediated anti-infection processes in colostrum and milk. Discussion of the relationship between hormones and lactogenic immunity may lead to a better way of improving lactogenic immunity by determining a better injection time and developing new vaccines.

The neuroendocrine and endocrine systems in insect - Historical perspective and overview.

A complex cascade of events leads to the initiation and maintenance of a behavioral act in response to both internally and externally derived stimuli. These events are part of a transition of the animal into a new behavioral state, coordinated by chemicals that bias tissues and organs towards a new functional state of the animal. This form of integration is defined by the neuroendocrine (or neurosecretory) system and the endocrine system that release neurohormones or hormones, respectively. Here we describe the classical neuroendocrine and endocrine systems in insects to provide an historic perspective and overview of how neurohormones and hormones support plasticity in behavioral expression. Additionally, we describe peripheral tissues such as the midgut, epitracheal glands, and ovaries, which, whilst not necessarily being endocrine glands in the pure sense of the term, do produce and release hormones, thereby providing even more flexibility for inter-organ communication and regulation.

The hormonal physiology of immune components in breast milk and their impact on the infant immune response.

During pregnancy, the maternal body undergoes a considerable transformation regarding the anatomy, metabolism, and immune profile that, after delivery, allows for protection and nourishment of the offspring via lactation. Pregnancy hormones are responsible for the development and functionality of the mammary gland for breast milk production, but little is known about how hormones control its immune properties. Breast milk composition is highly dynamic, adapting to the nutritional and immunological needs that the infant requires in the first months of life and is responsible for the main immune modeling of breastfed newborns. Therefore, alterations in the mechanisms that control the endocrinology of mammary gland adaptation for lactation could disturb the properties of breast milk that prepare the neonatal immune system to respond to the first immunologic challenges. In modern life, humans are chronically exposed to endocrine disruptors (EDs), which alter the endocrine physiology of mammals, affecting the composition of breast milk and hence the neonatal immune response. In this review, we provide a landscape of the possible role of hormones in the control of passive immunity transferred by breast milk and the possible effect of maternal exposure to EDs on lactation, as well as their impacts on the development of neonatal immunity.

Future directions in urban endocrinology - The effects of endocrine plasticity on urban tolerance.

After twenty years of studies of endocrine traits in animals living in cities, the field of urban endocrinology has built a robust literature including numerous studies looking for signatures of the effects of urban living, usually in mean circulating hormone concentrations. The findings of this past research have primarily demonstrated the absence of any generalizable endocrine responses to city life. In this opinion paper, I suggest that a strong route forward would include investigations of the role of variation in endocrine plasticity in determining the degree to which organisms tolerate urban challenges (i.e., urban tolerance). Achieving this research aim will require creative experimental and comparative studies, consideration of alternative study systems, and teasing apart of sources of variation in plastic phenotypes (plasticity, sorting, and contemporary evolution). Insight into the role of endocrine plasticity in influencing urban tolerance could help us better understand and predict impacts of expanding urbanization on biodiversity across the globe.

A nonparametric test of group distributional differences for hierarchically clustered functional data.

Biological sex and gender are critical variables in biomedical research, but are complicated by the presence of sex-specific natural hormone cycles, such as the estrous cycle in female rodents, typically divided into phases. A common feature of these cycles are fluctuating hormone levels that induce sex differences in many behaviors controlled by the electrophysiology of neurons, such as neuronal membrane potential in response to electrical stimulus, typically summarized using a priori defined metrics. In this paper, we propose a method to test for differences in the electrophysiological properties across estrous cycle phase without first defining a metric of interest. We do this by modeling membrane potential data in the frequency domain as realizations of a bivariate process, also depending on the electrical stimulus, by adopting existing methods for longitudinal functional data. We are then able to extract the main features of the bivariate signals through a set of basis function coefficients. We use these coefficients for testing, adapting methods for multivariate data to account for an induced hierarchical structure that is a product of the experimental design. We illustrate the performance of the proposed approach in simulations and then apply the method to experimental data.

Mechanosensitive Steroid Hormone Signaling and Cell Fate.

Mechanical forces collaborate across length scales to coordinate cell fate during development and the dynamic homeostasis of adult tissues. Similarly, steroid hormones interact with their nuclear and nonnuclear receptors to regulate diverse physiological processes necessary for the appropriate development and function of complex multicellular tissues. Aberrant steroid hormone action is associated with tumors originating in hormone-sensitive tissues and its disruption forms the basis of several therapeutic interventions. Prolonged perturbations to mechanical forces may further foster tumor initiation and the evolution of aggressive metastatic disease. Recent evidence suggests that steroid hormone and mechanical signaling intersect to direct cell fate during development and tumor progression. Potential mechanosensitive steroid hormone signaling pathways along with their molecular effectors will be discussed in this context.

Cell Networks in Endocrine/Neuroendocrine Gland Function.

Reproduction, growth, stress, and metabolism are determined by endocrine/neuroendocrine systems that regulate circulating hormone concentrations. All these systems generate rhythms and changes in hormone pulsatility observed in a variety of pathophysiological states. Thus, the output of endocrine/neuroendocrine systems must be regulated within a narrow window of effective hormone concentrations but must also maintain a capacity for plasticity to respond to changing physiological demands. Remarkably most endocrinologists still have a "textbook" view of endocrine gland organization which has emanated from 20th century histological studies on thin 2D tissue sections. However, 21st -century technological advances, including in-depth 3D imaging of specific cell types have vastly changed our knowledge. We now know that various levels of multicellular organization can be found across different glands, that organizational motifs can vary between species and can be modified to enhance or decrease hormonal release. This article focuses on how the organization of cells regulates hormone output using three endocrine/neuroendocrine glands that present different levels of organization and complexity: the adrenal medulla, with a single neuroendocrine cell type; the anterior pituitary, with multiple intermingled cell types; and the pancreas with multiple intermingled cell types organized into distinct functional units. We give an overview of recent methodologies that allow the study of the different components within endocrine systems, particularly their temporal and spatial relationships. We believe the emerging findings about network organization, and its impact on hormone secretion, are crucial to understanding how homeostatic regulation of endocrine axes is carried out within endocrine organs themselves. © 2022 American Physiological Society. Compr Physiol 12:3371-3415, 2022.

The effect of reproductive, hormonal, nutritional and lifestyle on breast cancer risk among black Tanzanian women: A case control study.

PURPOSE: This study aimed to determine the effect of reproductive, hormonal, lifestyle and nutritional factors on breast cancer development among Tanzanian black women. METHODOLOGY: We undertook a case-control study age-matched to ±5years in 2018 at Muhimbili National Hospital. The study recruited 105 BC patients and 190 controls giving it 80% power to detect an odds ratio of ≥2 at the alpha error of <5% for exposure with a prevalence of 30% in the control group with 95% confidence. Controls were recruited from in patients being treated for non-cancer related conditions. Information regarding hormonal, reproductive, nutritional and lifestyle risk for breast cancer and demography was collected by interviews using a predefined data set. Conditional multinomial logistic regression used to determine the adjusted odds ratio for variables that had significant p-value in the binomial logistic regression model with 5% allowed error at 95% confidence interval. RESULTS: The study recruited 105 cases and 190 controls. Only old age at menopause had a significant risk, a 2.6 fold increase. Adolescent obesity, family history of breast cancer, cigarette smoking and alcohol intake had increased odds for breast cancer but failed to reach significant levels. The rural residency had 61% reduced odds for developing breast cancer though it failed to reach significant levels. CONCLUSION: Older age at menopause is a significant risk factor for the development of breast cancer among Tanzanian women. This study has shed light on the potential role of modifiable risk factors for breast cancer which need to be studied further for appropriate preventive strategies in similar settings.

Neuroendocrine-immune Interface: Interactions of Two Complex Systems in Health and Disease.

The relationship between the neuroendocrine and the immune systems is essential to maintain homeostasis. Their complex interactions are present in many physiological or pathological states whereby hormones exert different actions in immune system cells and vice versa. Hormones such as prolactin, growth hormone, cortisol and sex hormones are known to regulate the differentiation and function of immune system cells and the production of cytokines. Many of these cells express hormone receptors leading to the tempering of several autoimmune and neoplastic diseases. The pituitary gland is susceptible to autoimmune damage, be it because of primary lymphocytic hypophysitis, as part of IgG4-related disease or as an adverse event of treatment with immune checkpoint inhibitors (ICi). Finally, pituitary adenomas, like many other neoplasms, are frequently infiltrated by different cells of the immune system, a phenomenon that can be related to the degree of invasiveness of these lesions. The purpose of the present work is to critically analyze the neuroendocrine-immune interphase, from both a biological and a clinical perspective.

[The pituitary gland unveiled: from the stimulation-secretion coupling to cellular networks wiring]. / L'hypophyse dévoilée : du couplage stimulation-sécrétion aux réseaux cellulaires câblant la glande.

The year 2021 ended with an event of great sadness: the death of Andrée Tixier-Vidal. She was not only a pioneer in cell biology but also the charismatic promoter of stimulating and successful multidisciplinary collaborations. Her achievements led to subsequent major discoveries on both the stimulation-secretion coupling of pituitary endocrine cells and the hitherto unknown organization of these cells into multicellular 3D networks which build-up highly organized pulses of pituitary hormones controlling basic body functions such as growth and reproduction.

Title: L'hypophyse dévoilée : du couplage stimulation-sécrétion aux réseaux cellulaires câblant la glande. Abstract: L'année 2021 s'est terminée par un événement de grande tristesse : le décès d'Andrée Tixier-Vidal. Elle fut non seulement une pionnière en biologie cellulaire mais également la promotrice charismatique de fédérations collaboratives multidisciplinaires particulièrement stimulantes et fructueuses. Cette note en retrace les succès en termes de découvertes à la fois sur le couplage stimulation-sécrétion des cellules endocrines de l'hypophyse et sur l'organisation de ces cellules hypophysaires en réseaux 3D multicellulaires à l'origine des sécrétions pulsées des hormones hypophysaires qui contrôlent des fonctions de base de l'organisme comme la croissance corporelle et la reproduction.

Changes of lipoprotein(a) levels with endogenous steroid hormones.

BACKGROUND: Lipoprotein(a) [Lp(a)] is an LDL-like molecule that is likely causal for cardiovascular events and Lp(a) variability has been shown to be mostly of genetic origin. Exogenous hormones (hormone replacement therapy) seem to influence Lp(a) levels, but the impact of endogenous hormone levels on Lp(a) is still unknown. The aim of the study was to assess the effect of endogenous steroid hormone metabolites on Lp(a). METHODS: Lipoprotein(a) levels were measured in 1,021 participants from the Swiss Kidney Project on Genes in Hypertension, a family-based, multicentre, population-based prospective cohort study. Endogenous levels of 28 steroid hormone precursors were measured in 24-h urine collections from 883 individuals. Of the participants with Lp(a) data, 1,011 participants had also genotypes available. RESULTS: The participants had an average age of 51 years and 53% were female. Median Lp(a) levels were 62 mg/L, and the 90th percentile was 616 mg/L. The prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. Forty-three per cent of Lp(a) variability was explained respectively by: age (2%, p < .001), LDL-C (1%, p = .001), and two SNPs (39%, p value<2⋅10-16 ). Of the 28 endogenous steroid hormones assessed, androstenetriol, androsterone, 16α-OH-DHEA and estriol were nominatively associated with serum Lp(a) levels in univariable analyses and explained 0.4%-1% of Lp(a) variability, but none of them reached significance in multivariable models. CONCLUSIONS: In this contemporary population-based study, the prevalence of a Lp(a) elevation ≥700 mg/L was 3.2%. The effect of endogenous steroid hormone levels of Lp(a) variability was small at best, suggesting a negligible impact on the wide range of Lp(a) variability.

Seasonal reproduction and gonadal function: a focus on humans starting from animal studies.

Photoperiod impacts reproduction in many species of mammals. Mating occurs at specific seasons to achieve reproductive advantages, such as optimization of offspring survival. Light is the main regulator of these changes during the photoperiod. Seasonally breeding mammals detect and transduce light signals through extraocular photoreceptor, regulating downstream melatonin-dependent peripheral circadian events. In rodents, hormonal reduction and gonadal atrophy occur quickly and consensually with short-day periods. It remains unclear whether photoperiod influences human reproduction. Seasonal fluctuations of sex hormones have been described in humans, although they seem to not imply adaptative seasonal pattern in human gonads. This review discusses current knowledge about seasonal changes in the gonadal function of vertebrates, including humans. The photoperiod-dependent regulation of hypothalamic-pituitary-gonadal axis, as well as morphological and functional changes of the gonads is evaluated herein. Endocrine and morphological variations of reproductive functions, in response to photoperiod, are of interest as they may reflect the nature of past population selection for adaptative mechanisms that occurred during evolution.

Hormonal Regulation of the MHC Class I Gene in Thyroid Cells: Role of the Promoter "Tissue-Specific" Region.

In previous studies we have demonstrated that the expression of the Major Histocompatibility Complex (MHC) class I gene in thyrocytes is controlled by several hormones, growth factors, and drugs. These substances mainly act on two regions of the MHC class I promoter a "tissue-specific" region (-800 to -676 bp) and a "hormone/cytokines-sensitive" region (-500 to -68 bp). In a previous study, we have shown that the role of the "tissue-specific" region in the MHC class I gene expression is dominant compared to that of the "hormone/cytokines-sensitive" region. In the present report we further investigate the dominant role of the "tissue-specific" region evaluating the effect of thyroid stimulating hormone (TSH), methimazole (MMI), phenylmethimazole (C10), glucose and thymosin-α1. By performing experiments of electrophoretic mobility shift assays (EMSAs) we show that TSH, MMI and C10, which inhibit MHC class I expression, act on the "tissue-specific" region increasing the formation of a silencer complex. Glucose and thymosin-α1, which stimulate MHC class I expression, act decreasing the formation of this complex. We further show that the silencer complex is formed by two distinct members of the transcription factors families activator protein-1 (AP-1) and nuclear factor-kB (NF-kB), c-jun and p65, respectively. These observations are important in order to understand the regulation of MHC class I gene expression in thyroid cells and its involvement in the development of thyroid autoimmunity.

The involvement of JAK/STAT signaling pathway in the treatment of Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder in which inflammation and oxidative stress play key etiopathological role. The pathology of PD brain is characterized by inclusions of aggregated α-synuclein (α-SYN) in the cytoplasmic region of neurons. Clinical evidence suggests that stimulation of pro-inflammatory cytokines leads to neuroinflammation in the affected brain regions. Upon neuroinflammation, the Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) signaling pathway, and other transcription factors such as nuclear factor κB (NF-κB), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), mammalian target of rapamycin (mTOR), and toll-like receptors (TLRs) are upregulated and induce the microglial activation, contributing to PD via dopaminergic neuron autophagy. Aberrant activation or phosphorylation of the components of JAK/STAT signaling pathway has been implicated in increased transcription of the inflammation-associated genes and many neurodegenerative disorders such as PD. Interferon gamma (IFN-γ), and interleukine (IL)-6 are two of the most potent activators of the JAK/STAT pathway, and it was shown to be elevated in PD. Stimulation of microglial cell with aggregated α-SYN results in production of nitric oxide (NO), tumor necrosis factor (TNF)-α, and IL-1ß in PD. Dysregulation of the JAK/STAT in PD and its involvement in various inflammatory pathways make it a promising PD therapy approach. So far, a variety of synthetic or natural small-molecule JAK inhibitors (Jakinibs) have been found promising in managing a spectrum of ailments, many of which are in preclinical research or clinical trials. Herein, we provided a perspective on the function of the JAK/STAT signaling pathway in PD progression and gathered data that describe the rationale evidence on the potential application of Jakinibs to improve neuroinflammation in PD.

Complex combined steroid mix of the female tract modulates human sperm.

Human spermatozoa interact with a complex biochemical environment in the female reproductive tract en route to the site of fertilisation. Ovarian follicular fluid contributes to this complex milieu and is known to contain steroids such as progesterone, whose effects on sperm physiology have been widely characterised. We have previously reported that progesterone stimulates intracellular calcium concentration ([Ca2+]i) signalling and acrosome reaction in human spermatozoa. To characterise the effects of the unified complete follicular fluid steroid hormone complement on human spermatozoa, a comprehensive, data-based, 'physiological standard' steroid hormone balance of follicular fluid (shFF) was created from individual constituents. shFF induced a rapid biphasic [Ca2+]i elevation in human spermatozoa. Using population fluorimetry, we compared [Ca2+]i signal amplitude in cells exposed to serial applications of shFF (6 steps from 10-5X up to 1X shFF) with responses to the equivalent progesterone component alone (6 steps from 135 pM - 13.5µM). Threshold for the response to shFF was right-shifted (≈10-fold) compared to progesterone alone, but the maximum response to shFF was greatly enhanced. An acrosome reaction assay was used to assess functional effects of shFF-induced sperm calcium signalling. shFF as well as progesterone-treated spermatozoa showed a significant increase in % acrosome reaction (P < 0.01). All of this evidence suggests the modulation of progesterone-mediated responses by other follicular fluid steroids.