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  • Toward a better understanding of the effects of endocrine disrupting compounds on health: Human-relevant case studies from sheep models
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2020-01-16
    Catherine Viguié; Elodie Chaillou; Véronique Gayrard; Nicole Picard-Hagen; Paul A. Fowler

    There are many challenges to overcome in order to properly understand both the exposure to, and effects of, endocrine disruptors (EDs). This is particularly true with respect to fetal life where ED exposures are a major issue requiring toxicokinetic studies of materno-fetal exchange and identification of pathophysiological consequences. The sheep, a monotocous large size species is very suitable for in utero fetal catheterization allowing a modelling approach predictive of human fetal exposure. Predicting adverse effects of EDs on human health is frequently impeded by the wide interspecies differences in the regulation of endocrine functions and their effect on biological processes. Because of its similarity to humans as regards gestational and thyroid physiologies and brain ontogeny, the sheep constitutes a highly appropriate model to move one step further on thyroid disruptor hazard assessment. As a grazing animal, sheep has also been proven to be useful in the evaluation of the consequences of chronic environmental exposure to “real-life” complex mixtures at different stages of the reproductive life cycle.

    更新日期:2020-01-17
  • Trends in neurodevelopmental disability burden due to early life chemical exposure in the USA from 2001 to 2016: A population-based disease burden and cost analysis
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2020-01-14
    Abigail Gaylord; Gwendolyn Osborne; Akhgar Ghassabian; Julia Malits; Teresa Attina; Leonardo Trasande

    Endocrine disrupting chemicals are known to cause neurodevelopmental toxicity through direct and indirect pathways. In this study we used data from the National Health and Nutrition Examination Surveys, along with known exposure-disease relationships, to quantify the intellectual disability burden attributable to in utero exposure to polybrominated diphenyl ethers (PBDEs), organophosphates, and methylmercury and early life exposure to lead. We also estimated the cost of the IQ points lost and cases of intellectual disability. PBDE exposure was the greatest contributor to intellectual disability burden, resulting in a total of 162 million IQ points lost and over 738,000 cases of intellectual disability. This was followed by lead, organophosphates, and methylmercury. From 2001 to 2016, IQ loss from PBDEs, methylmercury, and lead have decreased or remained stagnant. Organophosphate exposure measurements were only available up to 2008 but did show an increase in organophosphate-attributable IQ loss. Although most of these trends show benefit for children's neurodevelopmental health, they may also point towards the use of potentially harmful substitutions for chemicals that are being phased out.

    更新日期:2020-01-14
  • Sex-specific estrogen regulation of hypothalamic astrocyte estrogen receptor expression and glycogen metabolism in rats
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2020-01-11
    Mostafa M.H. Ibrahim; Khaggeswar Bheemanapally; Paul W. Sylvester; Karen P. Briski

    Brain astrocytes are implicated in estrogenic neuroprotection against bio-energetic insults, which may involve their glycogen energy reserve. Forebrain estrogen receptors (ER)-alpha (ERα) and -beta (ERβ) exert differential control of glycogen metabolic enzyme [glycogen synthase (GS); phosphorylase (GP)] expression in hypoglycemic male versus female rats. Studies were conducted using a rat hypothalamic astrocyte primary culture model along with selective ER agonists to investigate the premise that estradiol (E2) exerts sex-dimorphic control over astrocyte glycogen mass and metabolism. Female astrocyte GS and GP profiles are more sensitive to E2 stimulation than the male. E2 did not regulate expression of phospho-GS (inactive enzyme form) in either sex. Data also show that transmembrane G protein-coupled ER-1 (GPER) signaling is implicated in E2 control of GS profiles in each sex and alongside ERα, GP expression in females. E2 increases total 5′-AMK-activated protein kinase (AMPK) protein in female astrocytes, but stimulated pAMPK (active form) expression with equivalent potency via GPER in females and ERα in males. In female astrocytes, ERα protein was up-regulated at a lower E2 concentration and over a broader dosage range compared to males, whereas ERβ was increased after exposure to 1–10 nM versus 100 pM E2 levels in females and males, respectively. GPER profiles were stimulated by E2 in female, but not male astrocytes. E2 increased astrocyte glycogen content in female, but not male astrocytes; selective ERβ or ERα stimulation elevated glycogen levels in the female and male, respectively. Outcomes imply that dimorphic astrocyte ER and glycogen metabolic responses to E2 may reflect, in part, differential steroid induction of ER variant expression and/or regulation of post-receptor signaling in each sex.

    更新日期:2020-01-11
  • The START-domain proteins in intracellular lipid transport and beyond
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2020-01-10
    Barbara J. Clark

    The Steroidogenic Acute Regulatory Protein-related Lipid Transfer (START) domain is a ∼210 amino acid sequence that folds into an α/β helix-grip structure forming a hydrophobic pocket for lipid binding. The helix-grip fold structure defines a large superfamily of proteins, and this review focuses on the mammalian START domain family members that include single START domain proteins with identified ligands, and larger multi-domain proteins that may have novel roles in metabolism. Much of our understanding of the mammalian START domain proteins in lipid transport and changes in metabolism has advanced through studies using knockout mouse models, although for some of these proteins the identity and/or physiological role of ligand binding remains unknown. The findings that helped define START domain lipid-binding specificity, lipid transport, and changes in metabolism are presented to highlight that fundamental questions remain regarding the biological function(s) for START domain-containing proteins.

    更新日期:2020-01-11
  • Transcriptional regulation of retinol binding protein 4 by Interleukin-6 via peroxisome proliferator-activated receptor α and CCAAT/Enhancer binding proteins
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2020-01-09
    Muzaida Aminah Mohd; Nur Adelina Ahmad Norudin; Tengku Sifzizul Tengku Muhammad

    Interleukin-6 (IL-6) is a major mediator of the acute phase response (APR) that regulates the transcription of acute phase proteins (APPs) in the liver. During APR, the plasma levels of negative APPs including retinol binding protein 4 (RBP4) are reduced. Activation of the IL-6 receptor and subsequent signaling pathways leads to the activation of transcription factors, including peroxisome proliferator-activated receptor alpha (PPARα) and CCAAT/enhancer binding protein (C/EBP), which then modulate APP gene expression. The transcriptional regulation of RBP4 by IL-6 is not fully understood. Therefore, this study aimed to elucidate the molecular mechanisms of PPARα and C/EBP isoforms in mediating IL-6 regulation of RBP4 gene expression. IL-6 was shown to reduce the transcriptional activity of RBP4, and functional dissection of the RBP4 promoter further identified the cis-acting regulatory elements that are responsible in mediating the inhibitory effect of IL-6. The binding sites for PPARα and C/EBP present in the RBP4 promoter were predicted at −1079 bp to −1057 bp and −1460 bp to −1439 bp, respectively. The binding of PPARα and C/EBPs to their respective cis-acting elements may lead to antagonistic interactions that modulate the IL-6 regulation of RBP4 promoter activity. Therefore, this study proposed a new mechanism of interaction involving PPARα and different C/EBP isoforms. This interaction is necessary for the regulation of RBP4 gene expression in response to external stimuli, particularly IL-6, during physiological changes.

    更新日期:2020-01-09
  • Interplay of ERα binding and DNA methylation in the intron-2 determines the expression and estrogen regulation of cystatin A in breast cancer cells
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2020-01-08
    Dixcy Jaba Sheeba John Mary; Girija Sikarwar; Ajay Kumar; Anil Mukund Limaye

    Despite advances in early detection and treatment, invasion and metastasis of breast tumors remains a major hurdle. Cystatin A (CSTA, also called stefin A), an estrogen-regulated gene in breast cancer cells, is an inhibitor of cysteine cathepsins, and a purported tumor suppressor. Loss of CSTA expression in breast tumors evidently shifts the balance in favor of cysteine cathepsins, thereby promoting extracellular matrix remodeling, tumor invasion and metastasis. However, the underlying mechanism behind the loss of CSTA expression in breast tumors is not known. Here, we have analyzed CSTA expression, and methylation of upstream and intron-2 CpG sites within the CSTA locus in human breast cancer cell lines and breast tumors of the TCGA cohort. Results showed an inverse relationship between expression and methylation. Sequence analysis revealed a potential estrogen response element (ERE) in the intron-2. Analysis of ChIP-seq data (ERP000380) and our own ChIP experiments showed that 17β-estradiol (E2) enhanced ERα binding to this ERE in MCF-7 cells. This ERE was located amidst the differentially methylated intron-2 CpG sites, which provoked us to examine the possible conflict between estrogen-regulation of CSTA and DNA methylation in the intron-2. We analyzed the expression of CSTA and its regulation by estrogen in MDA-MB-231 and T47D cells subjected to global demethylation by 5-azacytidine (5-aza). 5-aza significantly demethylated intron-2 CpGs, and enhanced estrogen-induced ERα occupancy at the intron-2 ERE, leading to restoration of estrogen-regulation. Taken together, our results indicate that DNA methylation-dependent silencing could play a significant role in the loss of CSTA expression in breast tumors. The potential of DNA methylation as an indicator of CSTA expression or as a marker of tumor progression can be explored in future investigations. Furthermore, our results indicate the convergence of ERα-mediated estrogen regulation and DNA methylation in the intron-2, thereby offering a novel context to understand the role of estrogen-ERα signaling axis in breast tumor invasion and metastasis.

    更新日期:2020-01-08
  • 更新日期:2020-01-04
  • Ultrastructure characterization of pancreatic β-cells is accompanied by modulatory effects of the HDAC inhibitor sodium butyrate on the PI3/AKT insulin signaling pathway in juvenile diabetic rats
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2020-01-02
    Dalia A. Elgamal; Amal T. Abou-Elghait; Asmaa Y. Ali; Maha Ali; Marwa H. Bakr

    Genetic and epigenetic factors contribute equally to the pathogenesis of type 1 diabetes mellitus. Sodium butyrate (NaB) has been reported to improve glucose homeostasis by modulation of the p38/ERK MAPK pathway. This work aims to evaluate the effect of NaB on the ultrastructure of pancreatic β-cells and the PI3/AKT pathway. Juvenile albino male rats were used to establish a type 1 diabetes model using streptozotocin injection and NaB in a pre- and post-treatment schedule. Plasma glucose, insulin levels, and glucose tolerance were evaluated. Light and electron microscopy and immunohistochemistry were performed using Ki-67, caspase-3, and insulin. NaB treatment resulted in a significant improvement in plasma glucose levels, plasma insulin levels/expression, and ameliorated diabetes-induced histological alternations. Additionally, it increased the expression of phosphorylated AKT. These findings provide evidence that NaB may be useful in the treatment of juvenile diabetes.

    更新日期:2020-01-02
  • Endovascular trophoblast and spiral artery remodeling
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-31
    Yukiyasu Sato

    Spiral artery remodeling, which is indispensable for successful pregnancy, is accomplished by endovascular trophoblasts that move upstream along the arterial wall, replace the endothelium, and disrupt the muscular lining. This review outlines the possible factors that could regulate endovascular trophoblast differentiation and invasion. First, high oxygen tension in the spiral artery could initiate endovascular trophoblast invasion. Second, activation of maternal decidual natural killer (dNK) cells could support perivascular invasion of interstitial trophoblasts and consequently could facilitate the endovascular trophoblast invasion. Third, maternal platelets trapped by the endovascular trophoblasts could enhance endovascular trophoblast invasion, which is in part mediated by chemokine CCL5 (C–C motif ligand 5) released from the activated platelets and chemokine receptor CCR1 (C–C chemokine receptor type 1) expressed specifically on the endovascular trophoblasts. The rat, in which trophoblast cells exhibit extensive interstitial and endovascular invasion, could be a suitable model animal for the study of human spiral artery remodeling. Apparently paradoxical results came from the rat study, i.e., exposure to hypoxia or depletion of dNK cells resulted in acceleration of the endovascular trophoblast invasion. This implies the presence of as-yet-undetermined regulator(s) whose effects on endovascular trophoblast invasion surpass the effects of surrounding oxygen tension or maternal dNK cells. In the future, clarification of the molecular differences between human interstitial and endovascular trophoblasts as well as establishment of the pregnant rat model exhibiting shallow endovascular trophoblast invasion and preeclamptic symptoms will contribute to elucidating the mechanism of spiral artery remodeling.

    更新日期:2019-12-31
  • Direct effects of glucagon on glucose uptake and lipolysis in human adipocytes
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-28
    Maria J. Pereira; Ketan Thombare; Assel Sarsenbayeva; Prasad G. Kamble; Kristina Almby; Martin Lundqvist; Jan W. Eriksson

    We aim to investigate the expression of the glucagon receptor (GCGR) in human adipose tissue, and the impact of glucagon in glucose uptake and lipolysis in human adipocytes. GCGR gene expression in human subcutaneous and visceral adipose tissue was demonstrated, albeit at low levels and with an inter-individual variation. Furthermore, GCGR expression was not significantly different between subjects with T2D and matched controls, and we found no significant association with BMI. Glucagon only at a supra-physiological concentration (10–100 nM) significantly increased basal and insulin-stimulated glucose uptake by up to 1.5-fold. Also, glucagon (0.01 and 1 nM) dose-dependently increased basal and isoproterenol-stimulated lipolysis up to 3.7- and 1.7-fold, respectively, compared to control. In addition, glucagon did not change insulin sensitivity to stimulate glucose uptake or inhibit lipolysis. In conclusion, we show that the GCGR gene is expressed at low levels in human adipose tissue, and glucagon at high concentrations can increase both glucose uptake and lipolysis in human adipocytes. Taken together, our data suggest that glucagon at physiological levels has minor direct effects on the regulation of adipocyte metabolism, but does not antagonize the insulin effect to stimulate glucose uptake and inhibit lipolysis in human adipocytes.

    更新日期:2019-12-29
  • LncRNA HCP5 promotes cell proliferation and inhibits apoptosis via miR-27a-3p/IGF-1 axis in human granulosa-like tumor cell line KGN
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-28
    Yongqian Chen; Xiaolei Zhang; Yuan An; Bin Liu; Meisong Lu

    This study aimed to reveal the potential roles of long non-coding RNA HCP5 (lncRNA HCP5) and its potential molecular mechanism in polycystic ovarian syndrome (PCOS). The human granulosa-like tumor cell line KGN was used for assessing the effects of HCP5 in the proliferation and apoptosis of granulosa cells (GCs). The results showed that downregulation of HCP5 suppressed cell proliferation through arresting cell cycle progression at G1 phase, and induced the apoptosis via activating mitochondrial pathway, while overexpression of HCP5 played the opposite effects in KGN cells. We predicted and confirmed miR-27a-3p was a directly target to HCP5 and it could directly bind with insulin-like growth factor-1 (IGF-1). Next, we performed gain- and loss-of-functions approaches by transfecting miR-27a-3p inhibitor into HCP5 knocking down cells and transfecting miR-27a-3p mimics into HCP5 overexpressing cells. The results demonstrated that downregulation and upregulation of miR-27a-3p could block the effects on the proliferation and apoptosis mediated by silencing and overexpressing HCP5 in KGN cells. Additionally, miR-27a-3p inhibitor remarkably reversed the IGF-1 decrease regulated by knocking down HCP5 and miR-27a-3p mimics inhibited the IGF-1 increase modulated by overexpressing HCP5 in KGN cells. Furthermore, we observed that the promoted cell vitality and reduced apoptosis mediated by enforced expression of HCP5 could be alleviated when the KGN cells transfected with IGF-1 siRNA. Our findings indicate that HCP5 might be a potential regulatory factor for development of PCOS through regulating the miR-27a-3p/IGF-1 axis.

    更新日期:2019-12-29
  • Disruption of 17β-estradiol secretion by persistent organic pollutants present in human follicular fluid is dependent on the potential of ovarian granulosa tumor cell lines to metabolize estrogen
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-28
    Justyna Gogola; Marta Hoffmann; Samantha Nimpsz; Anna Ptak

    Endocrine-disrupting chemicals (EDCs), such as perfluorooctanoate, perfluorooctane sulfonate, 2,2-dichlorodiphenyldichloroethylene, hexachlorobenzene, and polychlorinated biphenyl 153 are persistent pollutants that are found in human follicular fluid (FF). These compounds may affect endocrine function, disrupt steroid secretion by granulosa cells, and play a role in granulosa cell tumor (GCT) development. GCTs demonstrate endocrine activity, expressing aromatase and secreting 17β-estradiol (E2). We aimed to determine the effects of a mixture of EDCs, similar to that found in human FF, on human granulosa tumor cell lines representing the juvenile (JGCT) and adult (AGCT) forms (COV434 and KGN cells, respectively). We found that all the individual compounds and mixtures tested altered granulosa tumor cell function by disrupting E2 secretion. In KGN cells, which possess significantly higher basal aromatase gene expression, and therefore secrete more E2 than JGCT cells, EDC mixtures activated estrogen receptors (ERs) and G protein-coupled receptor-30 signaling, thereby stimulating E2 secretion, without affecting aromatase expression. By contrast, in COV434 cells, which demonstrate higher CYP1A1 expression, a key mediator of estrogen metabolism, than KGN cells, EDC mixtures reduced E2 secretion in parallel with increases in the 2-hydroxyestrogen 1/E2 ratio and CYP1A1 expression, implying an upregulation of E2 metabolism. These results indicate that the EDC mixture present in FF disrupts E2 secretion in JGCT and AGCT cells according to the estrogen metabolic potential of the cell type, involving both classical and non-classical ER pathways.

    更新日期:2019-12-29
  • An estradiol-17β/miRNA-26a/cyp19a1a regulatory feedback loop in the protogynous hermaphroditic fish, Epinephelus coioides
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-28
    Qi Yu; Cheng Peng; Zhifeng Ye; Zhujing Tang; Shuisheng Li; Ling Xiao; Su Liu; Yuqing Yang; Mi Zhao; Yong Zhang; Haoran Lin
    更新日期:2019-12-29
  • Severe hypoglycemia exacerbates myocardial dysfunction and metabolic remodeling in diabetic mice
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-27
    Lishan Huang; Yu Zhou; Zhou Chen; Meilian Zhang; Zhidong Zhan; Linxi Wang; Libin Liu

    Although several studies have revealed that adverse cardiovascular events in diabetic patients are closely associated with severe hypoglycemia (SH), the causal relationship and related mechanisms remain unclear. This study aims to investigate whether SH promotes myocardial injury and further explores the potential mechanisms with focus on disturbances in lipid metabolism. SH promoted myocardial dysfunction and structural disorders in the diabetic mice but not in the controls. SH also enhanced the production of myocardial proinflammatory cytokines and oxidative stress. Moreover, myocardial lipid deposition developed in diabetic mice after SH, which was closely related to myocardial dysfunction and the inflammatory response. We further found that myocardial metabolic remodeling was associated with changes in PPAR-β/δ and its target molecules in diabetic mice exposed to SH. These findings demonstrate that SH exacerbates myocardial dysfunction and the inflammatory response in diabetic mice, which may be induced by myocardial metabolic remodeling via PPAR-β/δ.

    更新日期:2019-12-27
  • Rapamycin treatment maintains developmental potential of oocytes in mice and follicle reserve in human cortical fragments grafted into immune-deficient mice
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-27
    Yorino sato; Kazuhiro Kawamura

    The ovarian follicle pool size is limited; it decreases with age and following germ cell-damaging chemo- or radiation therapies. Due to a trend of delaying child-bearing age in the modern society, it is important to investigate the possibility to maintain the follicle reserve for middle-aged women and cancer-bearing patients subject to therapies. Earlier studies demonstrated the important role of the mammalian targets of the rapamycin (MTOR) signaling pathway in the activation of primordial follicles and suggested that treatment with the MTOR inhibitor rapamycin could maintain the follicle pool in rodents. Here, we confirmed the ability of rapamycin treatment for 3 weeks to suppress primordial follicle development and to maintain follicle pool size in mice. We further demonstrated that the developmental potential of oocytes was not affected by rapamycin treatment and the effect of rapamycin to decrease initial follicle recruitment is reversible. Using human ovarian cortical fragments grafted into immune-deficient mice, we demonstrated the ability of rapamycin to suppress follicle growth from the primordial stage. Our studies provide the basis for further studies on the possibility of using MTOR inhibitors to maintain follicle reserve in middle-aged women and cancer patients before/during germ cell-damaging therapies.

    更新日期:2019-12-27
  • Identification of a novel C-terminally truncated estrogen receptor α variant (ERαi34) with constitutive transactivation and estrogen receptor antagonist resistance
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-24
    Hirotaka Ishii; Yujiro Hattori; Hitoshi Ozawa

    Constitutively active estrogen receptor α (ERα) variants with C-terminal truncation are candidate molecules for gain of both endocrine- and chemotherapy-resistance in estrogen-sensitive tumors. Our previous reports using artificially truncated ERα constructs demonstrated that ERα variants encoded in 1-2-3-cryptic exon- and 1-2-3-4-cryptic exon-types of transcripts have potentials to display constitutive transactivation of an estrogen response element reporter. However, naturally occurring 1-2-3-cryptic exon-type ERα variants have not been cloned yet. Therefore, the present study was designed to identify naturally occurring ERα variants encoded in 1-2-3-cryptic exon-type ERα transcripts. We cloned a novel C-terminally truncated ERα variant (ERαi34) encoded in a 1-2-3-i34 transcript from MCF-7 cells and characterized its constitutive and ER antagonist-resistant transactivation in transfected cells. Stable transfection of the variant into MCF-7 cells augmented basal cell proliferation insensitive to fulvestrant. Collectively, we validated the structure-based mechanisms underlying constitutive and ER antagonist-resistant transactivation by C-terminally truncated ERα variants. (146 words).

    更新日期:2019-12-25
  • Triiodothyronine activated extranuclear pathways upregulate adiponectin and leptin in murine adipocytes
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-23
    Mathias Lucas Solla; Rodrigues Bruna Moretto; Gonçalves Bianca Mariani; Moretto Fernanda Cristina Fontes; Olimpio Regiane Marques Castro; Deprá Igor; De Sibio Maria Teresa; Tilli Helena Paim; Nogueira Célia Regina; de Oliveira Miriane

    Adiponectin and leptin, important for metabolic regulation, are synthesized and secreted by adipose tissue and are influenced by triiodothyronine (T3) that activates the MAPK/ERK and integrin αVβ3 pathways, modulating gene expression. Adipocytes were treated with T3 (10 nM), for 1 h, in the absence or presence of PD98059 (PD) and tetraiodothyroacetic acid (Tetrac), which are pathways inhibitors. The cells were incubated with Adipo Red/Oil Red O reagents, and intracellular lipid accumulation [glycerol and triacylglycerol (TAG)], MTT, 8-hydroxideoxyguanosine, and mRNA and protein expression were assessed. T3 increased leptin mRNA and protein expression, and, in contrast, there was a decrease in the Tetrac + T3 group. Adiponectin mRNA expression was not altered by T3, though it had increased its protein expression, which was terminated by inhibitors PD + T3 and Tetrac + T3. However, T3 did not alter PPARγ protein expression, lipid accumulation, TAG, glycerol, and DNA damage, but PD + T3 and Tetrac + T3 reduced these parameters. T3 activated the MAPK/ERK pathway on adipocytes to modulate the adiponectin protein expression and integrin αvβ3 to alter the leptin gene expression.

    更新日期:2019-12-23
  • Temporal organization of pineal melatonin signaling in mammals
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-19
    Michael R. Gorman

    In mammals, the pineal gland is the sole endocrine source of melatonin, which is secreted according to daily and seasonal patterns. This mini-review synthesizes the established endocrine actions of melatonin in the following temporal contexts. Melatonin is a strictly regulated output of the circadian timing system, but under certain conditions, may also entrain the circadian pacemaker and clocks in peripheral tissues. As the waveform of nightly melatonin secretion varies seasonally, melatonin provides a hormonal representation of the time of year. The duration of elevated melatonin secretion regulates reproductive physiology and other seasonal adaptations either by entraining a circannual rhythm or by inducing seasonal responses directly. An entrainment action of nightly melatonin on clock gene expression in the pars tuberalis of the anterior pituitary partly may underly its mechanistic role as a photoperiodic switch. Melatonin has important functions developmentally to regulate multiple physiological systems and program timing of puberty. Endogenous melatonergic systems are disrupted by modern lifestyles of humans through altered circadian entrainment, acute suppression by light and self-administration of pharmacological melatonin. Non-endocrine actions of locally synthesized melatonin fall outside of the scope of this mini-review.

    更新日期:2019-12-19
  • Molecular determinants of ACTH receptor for ligand selectivity
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-19
    Yingkui Yang; Carroll M. Harmon

    The adrenocorticotropic hormone (ACTH) receptor, known as the melanocortin-2 receptor (MC2R), plays a key role in regulating adrenocortical function. ACTH receptor is a subtype of the melanocortin receptor family which is a member of the G-protein coupled receptor (GPCR) superfamily. ACTH receptor has unique characteristics among MCRs. α-MSH, β-MSH, γ-MSH and ACTH are agonists for MCRs but only ACTH is the agonist for ACTH receptor. In addition, the melanocortin receptor accessory protein (MRAP) is required for ACTH receptor expression at cell surface and function. In this review, we summarized the information available on the relationship between ACTH and ACTH receptor and provide the latest understanding of the molecular basis of the ACTH receptor responsible for ligand selectivity and function.

    更新日期:2019-12-19
  • Developmental programming: Adipose depot-specific changes and thermogenic adipocyte distribution in the female sheep
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-19
    Muraly Puttabyatappa; Joseph N. Ciarelli; Adam G. Chatoff; Kanakadurga Singer; Vasantha Padmanabhan

    Prenatal testosterone (T)-treated female sheep exhibit an enhanced inflammatory and oxidative stress state in the visceral adipose tissue (VAT) but not in the subcutaneous (SAT), while surprisingly maintaining insulin sensitivity in both depots. In adult sheep adipose tissue is predominantly composed of white adipocytes which favor lipid storage. Brown/beige adipocytes that make up the brown adipose tissue (BAT) favor lipid utilization due to thermogenic uncoupled protein 1 expression and are interspersed amidst white adipocytes, more so in epicardiac (ECAT) and perirenal (PRAT) depots. The impact of prenatal T-treatment on ECAT and PRAT depots are unknown. As BAT imparts a metabolically healthy phenotype, the depot-specific impact of prenatal T-treatment on inflammation, oxidative stress, differentiation and insulin sensitivity could be dictated by the distribution of brown adipocytes. This hypothesis was tested by assessing markers of oxidative stress, inflammation, adipocyte differentiation, fibrosis and thermogenesis in adipose depots from control and prenatal T (100 mg T propionate twice a week from days 30–90 of gestation) -treated female sheep at 21 months of age. Our results show prenatal T-treatment induces depot-specific changes in inflammation, oxidative stress state, collagen accumulation, and differentiation with changes being more pronounced in the VAT. Prenatal T-treatment also increased thermogenic gene expression in all depots indicative of increased browning with effects being more prominent in VAT and SAT. Considering that inflammatory and oxidative stress are also elevated, the increased brown adipocyte distribution is likely a compensatory response to maintain insulin sensitivity and function of organs in the proximity of respective depots.

    更新日期:2019-12-19
  • Patterns of prolactin secretion
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-13
    Hollian R. Phillipps; Siew H. Yip; David R. Grattan

    Prolactin is pleotropic in nature affecting multiple tissues throughout the body. As a consequence of the broad range of functions, regulation of anterior pituitary prolactin secretion is complex and atypical as compared to other pituitary hormones. Many studies have provided insight into the complex hypothalamic-pituitary networks controlling prolactin secretion patterns in different species using a range of techniques. Here, we review prolactin secretion in both males and females; and consider the different patterns of prolactin secretion across the reproductive cycle in representative female mammals with short versus long luteal phases and in seasonal breeders. Additionally, we highlight changes in the pattern of secretion during pregnancy and lactation, and discuss the wide range of adaptive functions that prolactin may have in these important physiological states.

    更新日期:2019-12-13
  • Mechanisms of action of agrochemicals acting as endocrine disrupting chemicals
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-12
    Genoa R. Warner; Vasiliki E. Mourikes; Alison M. Neff; Emily Brehm; Jodi A. Flaws

    Agrochemicals represent a significant class of endocrine disrupting chemicals that humans and animals around the world are exposed to constantly. Agrochemicals can act as endocrine disrupting chemicals through a variety of mechanisms. Recent studies have shown that several mechanisms of action involve the ability of agrochemicals to mimic the interaction of endogenous hormones with nuclear receptors such as estrogen receptors, androgen receptors, peroxisome proliferator activated receptors, the aryl hydrocarbon receptor, and thyroid hormone receptors. Further, studies indicate that agrochemicals can exert toxicity through non-nuclear receptor-mediated mechanisms of action. Such non-genomic mechanisms of action include interference with peptide, steroid, or amino acid hormone response, synthesis and degradation as well as epigenetic changes (DNA methylation and histone modifications). This review summarizes the major mechanisms of action by which agrochemicals target the endocrine system.

    更新日期:2019-12-13
  • OECD approaches and considerations for regulatory evaluation of endocrine disruptors
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-09
    Patience Browne, Leon Van Der Wal, Anne Gourmelon

    Identifying the potential endocrine disruptor hazard of environmental chemicals is a regulatory mandate for many countries. However, due to the adaptive nature of the endocrine system, absence of a single method capable of identifying endocrine disruption, and the latency between exposure to endocrine disrupting chemical during sensitive life stages and the manifestation of adverse responses, satisfying the regulatory requirement needed to identify a chemical as an endocrine disruptor is a challenge. There are now a variety of validated regulatory tests that can be used in combination to provide evidence that a chemical affects the oestrogen, androgen, thyroid, and steroidogenic pathways of vertebrates, but most rely (at least to some extent) on animal testing and require considerable cost and time to produce the necessary data. Emerging research methods are able to evaluate other endocrine pathways, incorporate more sensitive endpoints, and combine multiple alternative methods to predict in vivo outcomes. Some research approaches may also bridge gaps that have been identified in current endocrine regulatory testing. For the near term, considering new endpoints in a regulatory context may require adding them to existing test methods in order to establish relationships between the traditional and the innovative. From the outset, endocrine testing has always required integration of multiple methods that provide data on different levels of biological organisation, thus, the area of endocrine disruption is particularly adaptable to adverse outcome pathway (AOP) frameworks and integrated test methods built around AOPs. Herein, we provide a review of the status of endocrine disruptors in the OECD context, examples where innovation from research is needed to improve or bridge gaps in endocrine testing, and suggestions for regulators and research to facilitate uptake of innovate methods for endocrine disruptor regulatory testing. The increase in several human complex human disorders that include an endocrine component and the alarming decrease in wildlife biodiversity are commanding directives to include the best, most informative, innovative approaches to accelerate the rate and throughput of chemical evaluation for endocrine disruption.

    更新日期:2019-12-11
  • Hormones, developmental plasticity, and adaptive evolution: Endocrine flexibility as a catalyst for ‘plasticity-first’ phenotypic divergence
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-09
    Sean C. Lema

    Explaining how populations adapt to environments is among the foremost objectives of evolutionary theory. Over generations, natural selection impels the phenotypic distribution of a population based on individual variation in phenotype and fitness. However, environmental conditions can also shape how individuals develop within their lifetime to influence which phenotypes are expressed in a population. It has been proposed that such environmentally-initiated phenotypic variation – also termed developmental plasticity – may enable adaptive evolution under some scenarios. As dynamic regulators of development and phenotypic expression, hormones are important physiological mediators of developmental plasticity. Patterns of hormone secretion, hormone transport, and the sensitivity of tissues to hormones can each be altered by environmental conditions, and understanding how endocrine regulation shapes phenotypic development in an ecologically-relevant context has much to contribute toward clarifying the role of plasticity in evolutionary adaptation. This article explores how the environmental sensitivity of endocrine regulation may facilitate ‘plasticity-first’ evolution by generating phenotypic variants that precede adaptation to altered or novel environments. Predictions arising from ‘plasticity-first’ evolution are examined in the context of thyroid hormone mediation of morphological plasticity in Cyprinodon pupfishes from the Death Valley region of California and Nevada, USA. This clade of extremophile fishes diversified morphologically over the last ∼20,000 years, and observations that some populations experienced contemporary phenotypic differentiation under recent habitat change provide evidence for hormone-mediate plasticity preceded genetic assimilation of morphology in one of the region's species: the Devils Hole pupfish, Cyprinodon diabolis. This example illustrates how conceptualizing hormones not only as regulators of homeostasis, but also as developmental intermediaries between environment conditions and phenotypic variation at the individual-, population-, and species-levels can enrich our understanding of endocrine regulation both as a facilitator of phenotypic change under shifting environments, and as important proximate mechanisms that may initiate ‘plasticity-first’ evolutionary adaptation.

    更新日期:2019-12-11
  • Sex steroids as mediators of phenotypic integration, genetic correlations, and evolutionary transitions
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-09
    Robert M. Cox

    In recent decades, endocrinologists have increasingly adopted evolutionary methods and perspectives to characterize the evolution of the vertebrate endocrine system and leverage it as a model for developing and testing evolutionary theories. This review summarizes recent research on sex steroids (androgens and estrogens) to illustrate three ways in which a detailed understanding of the molecular and cellular architecture of hormonally mediated gene expression can enhance our understanding of general evolutionary principles. By virtue of their massively pleiotropic effects on the expression of genes and phenotypes, sex steroids and their receptors can (1) structure the patterns of phenotypic variance and covariance that are available to natural selection, (2) alter the underlying genetic correlations that determine a population's evolutionary response to selection, and (3) facilitate evolutionary transitions in fitness-related phenotypes via subtle regulatory shifts in underlying tissues and genes. These principles are illustrated by the author's research on testosterone and sexual dimorphism in lizards, and by recent examples drawn from other vertebrate systems. Mechanistically, these examples call attention to the importance of evolutionary changes in (1) androgen- and estrogen-mediated gene expression, (2) androgen and estrogen receptor expression, and (3) the distribution of androgen and estrogen response elements in target genes throughout the genome. A central theme to emerge from this review is that the rapidly increasing availability of genomic and transcriptomic data from non-model organisms places evolutionary endocrinologist in an excellent position to address the hormonal regulation of the key evolutionary interface between genes and phenotypes.

    更新日期:2019-12-09
  • Relevant dose of the environmental contaminant, tributyltin, promotes histomorphological changes in the thyroid gland of male rats
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-09
    Paula Rodrigues-Pereira, Sofia Macedo, Tiago Bordeira Gaspar, Sule Canberk, Samia Selmi-Ruby, Valdemar Máximo, Paula Soares, Leandro Miranda-Alves

    Organotin compounds, such as tributyltin (TBT), are common environmental contaminants and suspected endocrine-disrupting chemicals. Tributyltin is found in antifouling paints, widely used in ships and other vessels. The present study evaluated whether a 15-day treatment with TBT at a dose of 100 ng/kg/day could induce histomorphological changes in the thyroid gland of rats. TBT promoted relevant alterations in the thyroid architecture, being the most relevant histological findings the presence of increased number of small-size follicles in the treated group. In qualitative analyses, colloid vacuolization, papillary budging structures, cystic degeneration and chronic thyroiditis, were observed in thyroid. Moreover, histomorphometric analysis showed statistically significant changes in the follicular architecture of TBT-treated rats, mainly a decrease in the follicle area (colloid) and an increased epithelial height that resulted in an increased epithelial height/colloid ratio. Augmented collagen deposition was also seen in the thyroids of treated groups. In immunohistochemical (IHC) analyses, the localization of NIS protein was described and a significant increased proliferation index (evaluated by Ki67 positive cells) in the treated group was reported. As an indirect measurement of oxidative stress, mitochondrial protein SDHA was also analyzed by IHC analysis. Although the cytoplasmic expression of SDHA was observed in both groups, the staining intensity score was higher in TBT-treated group. Our results suggest that besides causing histomorphological changes, environmental relevant dose of TBT treatment can also induce oxidative alterations.

    更新日期:2019-12-09
  • Pharmacological chaperones of ATP-sensitive potassium channels: Mechanistic insight from cryoEM structures
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-09
    Gregory M. Martin, Min Woo Sung, Show-Ling Shyng

    ATP-sensitive potassium (KATP) channels are uniquely evolved protein complexes that couple cell energy levels to cell excitability. They govern a wide range of physiological processes including hormone secretion, neuronal transmission, vascular dilation, and cardiac and neuronal preconditioning against ischemic injuries. In pancreatic β-cells, KATP channels composed of Kir6.2 and SUR1, encoded by KCNJ11 and ABCC8, respectively, play a key role in coupling blood glucose concentration to insulin secretion. Mutations in ABCC8 or KCNJ11 that diminish channel function result in congenital hyperinsulinism. Many of these mutations principally hamper channel biogenesis and hence trafficking to the cell surface. Several small molecules have been shown to correct channel biogenesis and trafficking defects. Here, we review studies aimed at understanding how mutations impair channel biogenesis and trafficking and how pharmacological ligands overcome channel trafficking defects, particularly highlighting recent cryo-EM structural studies which have revealed the mechanisms of channel assembly and pharmacological chaperones.

    更新日期:2019-12-09
  • Stanniocalcin-1 protein expression profile and mechanisms in proliferation and cell death pathways in prostate cancer
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-07
    Bruna Pasqualotto Costa, Vanessa Schein, Zhao Rafael, Andressa Schneiders Santos, Lucia Maria Kliemann, Fernanda Bordignon Nunes, João Carlos dos Reis Cardoso, Rute Castelo Félix, Adelino Vicente Mendonça Canário, Ilma Simoni Brum, Gisele Branchini

    Prostate cancer (PCa) is one of the most prevalent male tumours. Stanniocalcin-1 (STC1) is a glycoprotein and, although the role of STC1 in human cancer is poorly understood, it is suggested to be involved in the development and progression of different neoplasms. This study investigated the protein expression profile of STC1 in PCa and benign prostatic hyperplasia (BPH) samples and STC1 signalling during cell proliferation and cell death in vitro using cell lines. We found higher levels of STC1 in PCa when compared to BPH tissue and that STC1 inhibited forskolin stimulation of cAMP in PC-3 cells. A monoclonal antibody against STC1 was effective in reducing cell proliferation, in promoting cell cycle arrest, and in increasing apoptosis in the same cells. Since STC1 acts as a regulator of prostatic tissue signalling, we suggest that this protein is a novel candidate biomarker for prostrate tumour clinical progression and a potential therapeutic target.

    更新日期:2019-12-07
  • Heat shock proteins in thyroid malignancies: Potential therapeutic targets for poorly-differentiated and anaplastic tumours?
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-06
    Giacomo Lettini, Michele Pietrafesa, Silvia Lepore, Francesca Maddalena, Fabiana Crispo, Alessandro Sgambato, Franca Esposito, Matteo Landriscina
    更新日期:2019-12-06
  • Silencing DAPK3 blocks the autophagosome-lysosome fusion by mediating SNAP29 in trophoblast cells under high glucose treatment
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-05
    Yanling Wang, Lulu Ji, Zhihong Peng, Rujie Lai, Xiaoli Zhang, Yating Xu, Zhiguo Chen, Rui Liu, Yu Zhong, Hanyang Hu, Lin Wang

    Autophagy plays an essential role in gestational diabetes mellitus (GDM). Death-associated protein kinase-3 (DAPK3) regulates a variety of cellular functions; however, the relationship between DAPK3 and autophagy is unknown. In this study, we aim to investigate whether DAPK3 is associated with autophagy in GDM, and we found that DAPK3 was upregulated in the placenta of GDM patients and extravillous trophoblast cells under high-glucose conditions. Silencing DAPK3 decreased the assembly of the STX17-SNAP29-VAMP8 complex, leading to the blockade of autophagosome-lysosome fusion by mediating synaptosomal-associated protein 29 (SNAP29). Moreover, knockdown of DAPK3 ameliorates cell invasion and mediates autophagy in high glucose, and does not alter the expression of autophagy-related genes in normal glucose. Our study demonstrates the significance of DAPK3 in autophagy and GDM, which may provide new insights into the molecular mechanisms regulating trophoblast invasion.

    更新日期:2019-12-05
  • Selective estrogen receptor (ER)β activation provokes a redistribution of fat mass and modifies hepatic triglyceride composition in obese male mice
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-05
    Marcela González-Granillo, Christina Savva, Xidan Li, Moumita Ghosh Laskar, Bo Angelin, Jan-Åke Gustafsson, Marion Korach-André

    Estrogen exerts its action through the binding to two major receptors, estrogen receptor (ER)α and β. Recently, the beneficial role of selective ERβ activation in the regulation of metabolic homeostasis in obesity has been demonstrated, but its importance is still controversial. However, no data are available regarding possible gender differences in response to pharmaceutical activation of ERβ. Male mice were fed a control diet (CD) or a high fat diet (HFD) before being treated with the ERβ selective ligand, 4-(2-(3-5-dimethylisoxazol-4-yl)-1H-indol-3yl)phenol (DIP) in the same conditions as in our recently published paper in female mice. Magnetic resonance imaging and spectroscopy were performed repeatedly in vivo after 6 weeks of diet and after 2 weeks of DIP. Adipose tissue distribution and hepatic triglycerides composition were quantified. HFD-treated males showed a feminization of their fat distribution towards more subcutaneous fat depots and increase total fat content and visceral adipose tissue showed clear browning sites after DIP. Hepatic lipid composition was modified by DIP, with less saturated and more unsaturated lipids and an improved insulin sensitivity. Finally, brown adipose tissue size expended after DIP, due to an increase of the size of the lipid droplets. Our data demonstrate that selective activation of ERβ exerts a tissue-specific and sex-dependent response to metabolic adaptation to overfeeding. Most importantly, together with our previously published results in females, the current findings support the concept that sex should be considered in the future development of obesity-moderating drugs.

    更新日期:2019-12-05
  • The TCF7L2-dependent high-voltage activated calcium channel subunit α2δ-1 controls calcium signaling in rodent pancreatic beta-cells
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-02
    Yingying Ye, Mohammad Barghouth, Cheng Luan, Abdulla Kazim, Yuedan Zhou, Lena Eliasson, Enming Zhang, Ola Hansson, Thomas Thevenin, Erik Renström
    更新日期:2019-12-03
  • Testosterone modulates structural synaptic plasticity of primary cultured hippocampal neurons through ERK - CREB signalling pathways
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-02
    Guoxin Guo, Lin Kang, Dan Geng, Shuo Han, Sha Li, Juan Du, Chang Wang, Huixian Cui

    Although hippocampus-derived androgens play an important role in hippocampal synaptic plasticity, studies at the cellular level have received relatively less attention. Furthermore, the underlying signalling pathways associated with synaptic plasticity remain unclear. Results of the present study demonstrated that testosterone treatment of primary cultured rat hippocampal neurons resulted in a rapid increase in spine density, accompanied by the elevation of protein and messenger RNA levels of synaptophysin, developmentally regulated brain protein (Drebrin), and the N-methyl-D-aspartate receptor NR1 subunit. Testosterone treatment also increased the phosphorylation levels of extracellular-regulated protein kinase (ERK)1/2 and cAMP-responsive element binding protein (CREB), rather than p38 and Jun N-terminal kinase (JNK). U0126 significantly reversed the testosterone-mediated phosphorylation of CREB. Importantly, the increase in spine density was not induced by testosterone under U0126 treatment. These findings suggest that the ERK1/2-CREB signalling pathway plays an important role in testosterone-mediated rapid spinogenesis of cultured rat hippocampal neurons. Results of this study will be helpful in further clarifying the physiological function of testosterone and related signalling pathways in vitro.

    更新日期:2019-12-02
  • Irisin is expressed by undifferentiated spermatogonia and modulates gene expression in organotypic primate testis cultures
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-12-01
    Fazal Wahab, Charis Drummer, Kerstin Mätz-Rensing, Eberhard Fuchs, Rüdiger Behr

    The molecular mechanisms regulating undifferentiated spermatogonial cell proliferation and differentiation are still not fully understood. Irisin is an exercise-induced hormone, which is a cleaved and secreted fragment of the fibronectin type III repeat containing 5 (FNDC5) transmembrane protein. Recent studies have demonstrated the role of irisin in cell proliferation and differentiation in various tissues. However, testicular irisin expression and its potential action have not been analyzed. Here, we demonstrate expression of irisin in undifferentiated spermatogonia of primates and in the tree shrew, a bridging species between primates and insectivores. Rhesus monkeys are seasonal breeders with annual phases of high and low testicular activity and germ cell proliferation. Interestingly, expression of both FNDC5 mRNA and irisin is altered between breeding (high spermatogenesis) and nonbreeding seasons (low spermatogenesis). Organotypic testis culture in the presence of irisin increased the expression levels of the Sertoli cell (GDNF) and spermatogonial transcripts Kruppel-like factor 4 (KLF4), Inhibitor of differentiation 4 (ID4), Cluster of differentiation 117 (cKIT), and SALL4, compared to untreated controls, while irisin suppressed its own FNDC5 mRNA. Our data suggest that irisin is a novel endocrine factor involved in the regulation of spermatogonial activities in the testes of primates.

    更新日期:2019-12-02
  • Zinc-α2-glycoprotein promotes browning of white adipose tissue in cold-exposed male mice
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-29
    Guoqiang Fan, Xiaobo Dang, Yanfei Li, Jinglong Chen, Ruqian Zhao, Xiaojing Yang

    The promotion of white adipose tissue (WAT) browning has emerged as a promising therapeutic target to increase energy expenditure and decrease weight gain. Zinc-α2-glycoprotein (ZAG) is a newly identified adipokine that regulates lipid metabolism. It shows high expression in brown adipose tissue (BAT), but whether ZAG plays a key role in the browning of white adipose tissue is still largely unclear. In the present study, we explored the relationship between ZAG and the browning of WAT in cold-exposed ZAG knockout (KO) mice and 3T3-L1 adipocytes with overexpressed ZAG. The results showed that cold stress induced marked accumulation of ZAG in wild type (WT) mice. Additionally, ZAG deficiency inhibited the loss of body weight and adipose tissue weight in cold stressed mice. ZAG KO mice were resistant to cold-induced expression of browning markers and energy metabolism in WAT. Furthermore, replenishment ZAG plasmid improved the reduction in cold-induced browning of WAT in ZAG KO mice. In vitro, ZAG overexpression promoted browning and mitochondrial biogenesis and increased the expression of β3-AR and P–P38 in 3T3-L1 adipocytes. These findings demonstrate that ZAG can promote the browning of white adipose tissue and can serve as a potential therapeutic target for treating metabolic diseases such as obesity.

    更新日期:2019-11-30
  • Role of protein aggregation and degradation in autosomal dominant neurohypophyseal diabetes insipidus
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-27
    Martin Spiess, Michael Friberg, Nicole Beuret, Cristina Prescianotto-Baschong, Jonas Rutishauser

    This review focuses on the cellular and molecular aspects underlying familial neurohypophyseal diabetes insipidus (DI), a rare disorder that is usually transmitted in an autosomal-dominant fashion. The disease, manifesting in infancy or early childhood and gradually progressing in severity, is caused by fully penetrant heterozygous mutations in the gene encoding prepro-vasopressin-neurophysin II, the precursor of the antidiuretic hormone arginine vasopressin (AVP). Post mortem studies in affected adults have shown cell degeneration in vasopressinergic hypothalamic nuclei. Studies in cells expressing pathogenic mutants and knock-in rodent models have shown that the mutant precursors are folding incompetent and fail to exit the endoplasmic reticulum (ER), as occurs normally with proteins that have entered the regulated secretory pathway. A portion of these mutants is eliminated via ER-associated degradation (ERAD) by proteasomes after retrotranslocation to the cytosol. Another portion forms large disulfide-linked fibrillar aggregates within the ER, in which wild-type precursor is trapped. Aggregation capacity is independently conferred by two domains of the prohormone, namely the AVP moiety and the C-terminal glycopeptide (copeptin). The same domains are also required for packaging into dense-core secretory granules and regulated secretion, suggesting a disturbed balance between the physiological self-aggregation at the trans-Golgi network and avoiding premature aggregate formation at the ER in the disease. The critical role of ERAD in maintaining physiological water balance has been underscored by experiments in mice expressing wild-type AVP but lacking critical components of the ERAD machinery. These animals also develop DI and show amyloid-like aggregates in the ER lumen. Thus, the capacity of the ERAD is exceeded in autosomal dominant DI, which can be viewed as a neurodegenerative disorder associated with the formation of amyloid ER aggregates. While DI symptoms develop prior to detectable cell death in transgenic DI mice, the eventual loss of vasopressinergic neurons is accompanied by autophagy, but the mechanism leading to cell degeneration in autosomal dominant neurohypophyseal DI still remains unknown.

    更新日期:2019-11-28
  • MicroRNA miR-222 mediates pioglitazone beneficial effects on skeletal muscle of diet-induced obese mice
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-23
    Mariana de Mendonça, Érica de Sousa, Ailma O. da Paixão, Bruna Araújo dos Santos, Alexandre Roveratti Spagnol, Gilson M. Murata, Hygor N. Araújo, Tanes Imamura de Lima, Dimitrius Santiago Passos Simões Fróes Guimarães, Leonardo R. Silveira, Alice C. Rodrigues

    Pioglitazone belongs to the class of drugs thiazolidinediones (TZDs) and is an oral hypoglycemic drug, used in the treatment of type 2 diabetes, which improves insulin sensitivity in target tissues. Adipose tissue is the main target of pioglitazone, a PPARg and PPARa agonist; however, studies also point to skeletal muscle as a target. Non-PPAR targets of TZDs have been described, thus we aimed to study the direct effects of pioglitazone on skeletal muscle and the possible role of microRNAs as targets of this drug. Pioglitazone treatment of obese mice increased insulin-mediated glucose transport as a result of increased fatty acid oxidation and mitochondrial activity. PPARg blockage by treatment with GW9662 nullified pioglitazone's effect on systemic and muscle insulin sensitivity and citrate synthase activity of obese mice. After eight weeks of high-fat diet, miR-221–3p expression in soleus muscle was similar among the groups and miR-23b-3p and miR-222–3p were up-regulated in obese mice compared to the control group, and treatment with pioglitazone was able to reverse this condition. In vitro studies in C2C12 cells suggest that inhibition of miR-222–3p protects C2C12 cells from insulin resistance and increased non-mitochondrial respiration induced by palmitate. Together, these data demonstrate a role of pioglitazone in the downregulation of microRNAs that is not dependent on PPARg. Moreover, miR-222 may be a novel PPARg-independent mechanism through which pioglitazone improves insulin sensitivity in skeletal muscle.

    更新日期:2019-11-26
  • Courtship vocalizations: A potential biomarker of adult exposure to endocrine disrupting compounds?
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-22
    Sakina Mhaouty-Kodja

    In rodents, male courtship is stimulated by pheromones emitted by the sexually receptive female. In response, the male produces ultrasonic vocalizations, which appear to play a role in female attraction and facilitate copulation. The present review summarizes the main findings on courtship vocalizations and their tight regulation by sex steroid hormones. It describes studies that address the effects of exposure to endocrine disrupting compounds (EDC) on ultrasound production, as changes in hormone levels or their signaling pathways may interfere with the emission of ultrasonic vocalizations. It also discusses the potential use of this behavior as a noninvasive biomarker of adult exposure to EDC.

    更新日期:2019-11-22
  • Thyroid disrupting chemicals and developmental neurotoxicity – New tools and approaches to evaluate hormone action
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-21
    Katherine L. O'Shaughnessy, Mary E. Gilbert

    It is well documented that thyroid hormone (TH) action is critical for normal brain development, which is mediated by both nuclear and extranuclear pathways. Given this dependence, the impact of environmental endocrine disrupting chemicals that interfere with thyroid signaling is a major concern with direct children's health implications. However, identification of thyroid disrupting chemicals in vivo is primarily reliant on serum T4 measurements within greater developmental and reproductive toxicity assessments. These studies do not often measure known TH-dependent neurodevelopmental phenotypes in parallel, which complicates chemical assessment. Additionally, there exist no recommendations regarding what degree of serum T4 dysfunction is adverse, and little consideration is given to quantifying TH action within the developing brain. This review summarizes current chemical testing strategies in rodent models and discusses new approaches for evaluating developmental neurotoxicity of thyroid disrupting chemicals. This includes assays for identifying adverse cellular effects of the brain by both immunohistochemistry and gene expression to compliment standard measures of serum T4. While additional experiments are needed to test the full utility of these approaches, incorporation of such complimentary cellular and molecular assays could enhance chemical evaluation within the regulatory arena.

    更新日期:2019-11-22
  • Nuclear receptors are important targets of environmental disrupting compounds
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-21
    Lucia Toporova, Patrick Balaguer

    Environmental disrupting compounds (EDCs) are exogenous substances that are suspected to cause adverse effects in the endocrine system mainly by acting through their interaction with nuclear receptors like the estrogen receptors α and β (ERα and ERβ), the androgen receptor (AR), the pregnan X receptor (PXR), the peroxysome proliferator activated receptor α and γ (PPARα, PPARγ) and the thyroid receptors α and β (TRα and β). More recently, the retinoid X receptors (RXR α, β and γ), the constitutive androstane receptor (CAR) and the estrogen related receptor γ (ERRγ) have also been identified as targets of EDCs. Finally, nuclear receptors still poorly studied for their interaction with environmental ligands like the progesterone receptor (PR), the mineralocorticoid receptor (MR), the glucocorticoid receptor (GR), the retinoic acid receptors (RAR α, β and γ), the farnesoid X receptor (FXR) and the liver X receptors α and β (LXRα and β) are other suspected targets of EDCs. Humans are generally exposed to low doses of pollutants, therefore current researches aim to identify the targets of EDCs at environmental concentrations. In this review, we analyze recent works refering that nuclear receptors are targets of EDCs and we highlight which EDCs are able to act at low concentrations.

    更新日期:2019-11-21
  • Downregulation of microR-147b represses the proliferation and invasion of thyroid carcinoma cells by inhibiting Wnt/β-catenin signaling via targeting SOX15
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-21
    Chongwen Xu, Junsong Liu, Xiaobao Yao, Yanxia Bai, Qian Zhao, Ruimin Zhao, Bo Kou, Honghui Li, Peng Han, Xuan Wang, Longwei Guo, Zhiwei Zheng, Shaoqiang Zhang
    更新日期:2019-11-21
  • Empagliflozin attenuates ischemia and reperfusion injury through LKB1/AMPK signaling pathway
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-21
    Qingguo Lu, Jia Liu, Xuan Li, Xiaodong Sun, Jingwen Zhang, Di Ren, Nanwei Tong, Ji Li
    更新日期:2019-11-21
  • Hepatic insulin resistance induced by mitochondrial oxidative stress can be ameliorated by sphingosine 1-phosphate
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-20
    Hongjuan Fang, Qiong Feng, Yunxiang Shi, Jiping Zhou, Qiang Wang, Liyong Zhong

    The bioactive lipid mediator sphingosine 1-phosphate (S1P) is considered to be involved in the development of insulin resistance (IR) via effects on oxidative stress; the mechanism however is not yet fully revealed. To this end, we investigated the role and mechanism of S1P on hepatic IR. We found that treatment of the normal human liver cell LO2 with 1000 nM insulin for 48 h reduced glucose uptake and increased serine phosphorylation of insulin receptor substrate-1, indicating a reduction in insulin receptor signaling. Moreover, the same concentration of insulin caused accumulation of reactive oxygen species (ROS) in the cytosol and mitochondria, and enhanced expression of the antioxidant transcription factor (Nrf2) and upregulated Nrf2 nuclear translocation. Using known inhibitors and donors of ROS (H2O2, ·O2−, ·OH), the results demonstrated the differential roles for the specific ROS in regulating IR in LO2 cells, with H2O2 having a more significant inhibitory role compared with ·O2− and ·OH. Cell treatment with S1P at 0.1–5.0 μM reversed the effects of high insulin concentrations on ROS generation, glucose uptake, and insulin signaling. H2O2 also reversed the beneficial effects of S1P in alleviating IR. These results show that H2O2 signaling plays a key determinant in hepatic IR induced by insulin. S1P can ameliorate hepatic IR by reducing mitochondrial ROS generation, and the possible anti-IR effect mechanism may be involved in H2O2 signaling.

    更新日期:2019-11-20
  • Role of core circadian clock genes in hormone release and target tissue sensitivity in the reproductive axis
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-19
    Aritro Sen, Hanne M. Hoffmann

    Precise timing in hormone release from the hypothalamus, the pituitary and ovary is critical for fertility. Hormonal release patterns of the reproductive axis are regulated by a feedback loop within the hypothalamic-pituitary-gonadal (HPG) axis. The timing and rhythmicity of hormone release and tissue sensitivity in the HPG axis is regulated by circadian clocks located in the hypothalamus (suprachiasmatic nucleus, kisspeptin and GnRH neurons), the pituitary (gonadotrophs), the ovary (theca and granulosa cells), the testis (Leydig cells), as well as the uterus (endometrium and myometrium). The circadian clocks integrate environmental and physiological signals to produce cell endogenous rhythms generated by a transcriptional-translational feedback loop of transcription factors that are collectively called the “molecular clock”. This review specifically focuses on the contribution of molecular clock transcription factors in regulating hormone release patterns in the reproductive axis, with an emphasis on the female reproductive system. Specifically, we discuss the contributions of circadian rhythms in distinct neuronal populations of the female hypothalamus, the molecular clock in the pituitary and its overall impact on female and male fertility.

    更新日期:2019-11-20
  • Longitudinal evaluation of glucocorticoid receptor alpha/beta expression and signalling, adrenocortical function and cytokines in critically ill steroid-free patients
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-19
    Alice G. Vassiliou, Georgios Stamogiannos, Edison Jahaj, Efi Botoula, Georgios Floros, Dimitra A. Vassiliadi, Ioannis Ilias, Stylianos Tsagarakis, Marinella Tzanela, Stylianos E. Orfanos, Anastasia Kotanidou, Ioanna Dimopoulou

    Purpose Glucocorticoid actions are mediated by the glucocorticoid receptor (GCR) whose dysfunction leads to glucocorticoid tissue resistance. Our objective was to evaluate GCR-α and GCR-β expression and key steps in the GCR signalling cascade in critical illness. Methods Expression of GCR and major GCR-target genes, cortisol, adrenocorticotropin (ACTH) and cytokines was measured in 42 patients on ICU admission and on days 4, 8, and 13. Twenty-five age- and sex-matched subjects were used as controls. Results Acutely, mRNA expression of GCR-α was 10-fold and of GCR-β 3-fold the expression of controls, while during the sub-acute phase expression of both isoforms was lower compared to controls. Expression of FKBP5 and GILZ decreased significantly. Cortisol levels remained elevated and ACTH increased during the 13-day period. Conclusions GCR expression and hypothalamic-pituitary-adrenal axis function undergo a biphasic response during critical illness. The dissociation between low GCR expression and high cortisol implies an abnormal stress response.

    更新日期:2019-11-20
  • Glyphosate-based herbicide induces hyperplastic ducts in the mammary gland of aging Wistar rats
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-19
    María V. Zanardi, Marlise Guerrero Schimpf, María P. Gastiazoro, María M. Milesi, Mónica Muñoz-de-Toro, Jorgelina Varayoud, Milena Durando

    Glyphosate-based herbicide (GBH) exposure is known to have adverse effects on endocrine-related tissues. Here, we aimed to determine whether early postnatal exposure to a GBH induces long-term effects on the rat mammary gland. Thus, female Wistar pups were injected with saline solution (Control) or GBH (2 mg glyphosate/kg/day) on postnatal days (PND) 1, 3, 5 and 7. At 20 months of age, mammary gland samples were collected to determine histomorphological features, proliferation index and the expression of steroid hormone receptors expression, by immunohistochemistry, and serum samples were collected to assess 17β-estradiol (E2) and progesterone (P4) levels. GBH exposure induced morphological changes evidenced by a higher percentage of hyperplastic ducts and a fibroblastic-like stroma in the mammary gland. GBH-treated rats also showed a high expression of steroid hormone receptors in hyperplastic ducts. The results indicate that early postnatal exposure to GBH induces long-term alterations in the mammary gland morphology of aging female rats.

    更新日期:2019-11-19
  • Regulation of the KCNJ5 gene by SF-1 in the adrenal cortex: Complete genomic organization and promoter function
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-18
    Ayaka Nishikido, Takashi Okamura, Yasuyo Nakajima, Emi Ishida, Tomoko Miyamoto, Akiko-Katano Toki, Shunichi Matsumoto, Satoshi Yoshino, Kazuhiko Horiguchi, Tsugumichi Saito, Eijiro Yamada, Atsushi Ozawa, Yuki Shimoda, Tetsunari Oyama, Masanobu Yamada

    Activating mutations in the KCNJ5 gene are responsible for the significant number of aldosterone-producing adenomas. To elucidate the molecular mechanisms underlying KCNJ5 expression, we characterized the entire human KCNJ5 gene. The gene spanned approximately 29.8 kb and contained three exons and two introns. The strongest expression of KCNJ5 mRNA was observed in the adrenal gland. The promoter region contained a putative binding site for SF-1 at −1782 bp. A construct containing −2444 bp of the promoter region exhibited the strongest promoter activity in adrenal H295R cells, and the introduction of a mutation in the SF-1 binding site almost completely abolished promoter activity. Furthermore, deletion mutation, EMSA, and knockdown analyses revealed that SF-1 bound to this element and was functional. Immunochemistry showed that KCNJ5 was predominantly expressed in the zona glomerulosa, while SF-1 was ubiquitously expressed in the adrenal cortex. These results demonstrated that SF-1 mediates the expression of human KCNJ5 in the adrenal cortex.

    更新日期:2019-11-18
  • Defects in protein folding in congenital hypothyroidism
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-18
    Héctor M. Targovnik, Karen G. Scheps, Carina M. Rivolta

    Primary congenital hypothyroidism (CH) is the most common endocrine disease in children and one of the most common preventable causes of both cognitive and motor deficits. CH is a heterogeneous group of thyroid disorders in which inadequate production of thyroid hormone occurs due to defects in proteins involved in the gland organogenesis (dysembryogenesis) or in multiple steps of thyroid hormone biosynthesis (dyshormonogenesis). Dysembryogenesis is associated with genes responsible for the development or growth of thyroid cells: such as NKX2-1, FOXE1, PAX8, NKX2-5, TSHR, TBX1, CDCA8, HOXD3 and HOXB3 resulting in agenesis, hypoplasia or ectopia of thyroid gland. Nevertheless, the etiology of the dysembryogenesis remains unknown for most cases. In contrast, the majority of patients with dyshormonogenesis has been linked to mutations in the SLC5A5, SLC26A4, SLC26A7, TPO, DUOX1, DUOX2, DUOXA1, DUOXA2, IYD or TG genes, which usually originate goiter. About 800 genetic mutations have been reported to cause CH in patients so far, including missense, nonsense, in-frame deletion and splice-site variations. Many of these mutations are implicated in specific domains, cysteine residues or glycosylation sites, affecting the maturation of nascent proteins that go through the secretory pathway. Consequently, misfolded proteins are permanently entrapped in the endoplasmic reticulum (ER) and are translocated to the cytosol for proteasomal degradation by the ER-associated degradation (ERAD) machinery. Despite of all these remarkable advances in the field of the CH pathogenesis, several points on the development of this disease remain to be elucidated. The continuous study of thyroid gene mutations with the application of new technologies will be useful for the understanding of the intrinsic mechanisms related to CH. In this review we summarize the present status of knowledge on the disorders in the protein folding caused by thyroid genes mutations.

    更新日期:2019-11-18
  • Calcium sensing receptor activation in THP-1 macrophages triggers NLRP3 inflammasome and human preadipose cell inflammation
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-15
    Amanda D'Espessailles, Natalia Santillana, Sofía Sanhueza, Cecilia Fuentes, Mariana Cifuentes

    Excess adipose tissue (AT) associates with inflammation and obesity-related diseases. We studied whether calcium-sensing receptor (CaSR)-mediated NLRP3 inflammasome activation in THP-1 macrophages elevates inflammation in LS14 preadipocytes, modeling deleterious AT cell crosstalk. THP-1 macrophages exposed to Cinacalcet (CaSR activator, 2 μM, 4 h) showed elevated proinflammatory marker and NLRP3 inflammasome mRNA, pro-IL-1β protein and caspase-1 activity, whereas preincubation with CaSR negative modulators prevented these effects. The key NLRP3 inflammasome component ASC was silenced (siRNA) in THP-1 cells, and inflammasome activation was evaluated (qPCR, Western blot, caspase-1 activity) or they were further cultured to obtain conditioned medium (CoM). Exposure of LS14 preadipocytes to CoM from cinacalcet-treated THP-1 elevated LS14 proinflammatory cytokine expression, which was abrogated by THP-1 inflammasome silencing. Thus, CaSR activation elevates THP-1-induced inflammation in LS14 preadipocytes, via macrophage NLRP3 inflammasome activation. Modulating CaSR activation may prevent deleterious proinflammatory cell crosstalk in AT, a promising approach in obesity-related metabolic disorders.

    更新日期:2019-11-15
  • Rhythmicity matters: Circadian and ultradian patterns of HPA axis activity
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-15
    Caroline M.B. Focke, Karl J. Iremonger

    Oscillations are a fundamental feature of neural and endocrine systems. The hypothalamic-pituitary-adrenal (HPA) axis dynamically controls corticosteroid secretion in basal conditions and in response to stress. Across the 24-h day, HPA axis activity oscillates with both an ultradian and circadian rhythm. These rhythms have been shown to be important for regulating metabolism, inflammation, mood, cognition and stress responsiveness. Here we will discuss the neural and endocrine mechanisms driving these rhythms, the physiological importance of these rhythms and health consequences when they are disrupted.

    更新日期:2019-11-15
  • Pinopodes: Recent advancements, current perspectives, and future directions
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-15
    Kelsey E. Quinn, Brooke C. Matson, Margeaux Wetendorf, Kathleen M. Caron
    更新日期:2019-11-15
  • Do hormone manipulations reduce fitness? A meta-analytic test of the Optimal Endocrine Phenotype Hypothesis
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-09
    Frances Bonier, Robert M. Cox

    Endocrine traits (e.g., circulating hormone concentrations, receptor expression) can vary considerably among individuals within populations. Here, we develop two evolutionary hypotheses to explain this variation. Under the Optimal Endocrine Phenotype Hypothesis, adaptive plastic responses to environmental variation generate individual variation in endocrine traits and allow individuals to express near-optimal endocrine phenotypes. In contrast, under the Ongoing Selection Hypothesis, individual variation in endocrine traits reflects varying adaptive value, with some individuals expressing suboptimal phenotypes that are selected against. These two hypotheses generate distinct predictions for the effects of hormone manipulations on fitness. Under the Optimal Endocrine Phenotype Hypothesis, all hormone manipulations should incur fitness costs, whereas under the Ongoing Selection Hypothesis, manipulating endocrine phenotypes toward a putative optimum should increase fitness. Using a meta-analysis of findings from experimental field studies that involved manipulation of circulating glucocorticoids or androgens and measurement of fitness effects, we test and find some support for the Optimal Endocrine Phenotype Hypothesis. On average, fitness was reduced across 97 estimates of the effects of experimental hormone manipulations on fitness. However, the fitness effects of glucocorticoid manipulations varied with the sex of the individuals being studied. Fitness was more uniformly reduced by glucocorticoid manipulations in males and when both sexes were considered together. In females, effects on fitness varied from highly positive to highly negative. The effects of androgen manipulations varied across males and females, and depending upon whether fitness was estimated using measures of reproductive success or survival. Reproductive success was consistently decreased by androgen manipulation in females, but was increased almost as often as it was decreased across experiments in males. When survival was estimated as a component of fitness, it was fairly uniformly compromised by exogenous androgens in males. This variation in fitness effects of hormone manipulations across sexes and fitness metrics is consistent with the expectation that hormones differentially regulate life-history investment and that optimal endocrine phenotypes differ between males and females. Overall, our meta-analysis provides some support for the Optimal Endocrine Phenotype Hypothesis, but we await direct tests of the Ongoing Selection Hypothesis to determine the degree to which individual variation in endocrine traits continues to be shaped by natural selection.

    更新日期:2019-11-11
  • Effects of starvation and refeeding cycles on spermatogenesis and sex steroids in the Nile tilapia Oreochromis niloticus
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-08
    Camila Ferreira Sales, Ana Paula Barbosa Pinheiro, Yves Moreira Ribeiro, André Alberto Weber, Fabíola de Oliveira Paes-Leme, Ronald Kennedy Luz, Nilo Bazzoli, Elizete Rizzo, Rafael Magno Costa Melo

    Food restriction is part of the life cycle of many fish species; however, nutritional deficiency may negatively influence gametogenesis and gonadal maturation. The aim of this study was to evaluate the effects of food restriction on the spermatogenesis of Nile tilapia. For this, adult males were submitted to starvation and refeeding cycles (alternating periods of starvation and feeding) for 7, 14, 21, and 28 days. After 7 days of starvation, glycaemic and lipid levels were significantly reduced, followed by reduction of plasma testosterone (T) and 11-ketotestosterone (11-KT). In addition, reduced proliferation of spermatogonia and increased apoptosis of spermatocytes, spermatids, and spermatozoa was observed in starvation groups. In the refeeding groups, the sex steroids and the proportion of germ cells had no significant alterations compared to the control group, except for spermatozoa. In this sense, the present study suggests that starvation after 7 days progressively reduces T and 11-TK, resulting in damage to the production of spermatogenic cells, while refeeding may delay spermatogenesis but does not lead to testicular impairment.

    更新日期:2019-11-08
  • The NF-κB/miR-425-5p/MCT4 axis: A novel insight into diabetes-induced endothelial dysfunction
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-08
    Erfei Luo, Dong Wang, Gaoliang Yan, Yong Qiao, Boqian Zhu, Bo Liu, Jiantong Hou, Chengchun Tang

    Endothelial cells (ECs) primarily rely on glycolysis for their energy metabolism, and the final product of glycolysis—lactate—is transferred out of cells via monocarboxylate transporter 4 (MCT4). We previously showed that MCT4 downregulation is involved in diabetic endothelial injury. However, the underlying regulatory mechanisms of MCT4 in diabetes remain unclear. This study showed that miR-425-5p was significantly upregulated in diabetic patients and human umbilical vein endothelial cells (HUVECs) treated with high glucose (HG) and interleukin-1β (IL-1β). MCT4 was shown to be a direct target gene of miR‐425‐5p, and miR-425-5p expression led to MCT4 downregulation, lactate accumulation and increased apoptosis in HUVECs. Furthermore, the results indicated that NF-κB signaling activation increased miR-425-5p levels and induced MCT4 downregulation, lactate accumulation and apoptosis in HUVECs. In conclusion, NF-κB/miR-425-5p/MCT4 axis activation plays a crucial role in the EC injury induced by HG and IL-1β.

    更新日期:2019-11-08
  • High ambient temperature disrupted the circadian rhythm of reproductive hormones and changed the testicular expression of steroidogenesis genes and clock genes in male mice
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-06
    Zhaojian Li, Yansen Li, Yu Ren, Chunmei Li

    High ambient temperature-related male reproduction disruptions are well illustrated across species, the effects on circadian oscillation in reproduction hormones and testicular steroidogenesis remain unclear. Here, we showed the changes in circadian behaviour in rectal temperature, ingestion and serum hormones as well as the testicular oscillations of steroidogenesis genes and clock genes in heat-treated male mice. We observed that daily heat exposure from 11:00 (ZT4) to 15:00 (ZT8) increased the rectal temperature at ZT8 and water intake from ZT4 to ZT8 and decreased the feed consumption from ZT4 to ZT12 (19:00). Serum testosterone levels were arrhythmic after heat exposure, with an increase at ZT4 and a reduce at ZT8. Heat exposure enhanced testicular StAR and AR mRNA transcription at ZT4 and Cyp11a1 protein levels at ZT16. A much higher Clock mRNA level was observed at ZT4 in the testis of heat-treated mice, and the Clock protein content was reduced at ZT4. The Bmal1 protein level in the testis at ZT16 was increased in heat-treated mice. These results suggest that high external environmental temperature changes the circadian rhythms of body temperature and serum reproduction hormones and the testicular oscillations of clock genes and steroidogenesis genes, supporting the hypothesis that high temperatures arrest spermatogenesis by a disrupted reproductive rhythm.

    更新日期:2019-11-06
  • Neuroendocrine, Autocrine, and Paracrine control of follicle-stimulating hormone secretion
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-11-02
    Vasantha Padmanabhan, Rodolfo C. Cardoso

    Follicle-stimulating hormone (FSH) is a glycoprotein hormone produced by gonadotropes in the anterior pituitary that plays a central role in controlling ovarian folliculogenesis and steroidogenesis in females. Moreover, recent studies strongly suggest that FSH exerts extragonadal actions, particularly regulating bone mass and adiposity. Despite its crucial role, the mechanisms regulating FSH secretion are not completely understood. It is evident that hypothalamic, ovarian, and pituitary factors are involved in the neuroendocrine, paracrine, and autocrine regulation of FSH production. Large animal models, such as the female sheep, represent valuable research models to investigate specific aspects of FSH secretory processes. This review: (i) summarizes the role of FSH controlling reproduction and other biological processes; (ii) discusses the hypothalamic, gonadal, and pituitary regulation of FSH secretion; (iii) considers the biological relevance of the different FSH isoforms; and (iv) summarizes the distinct patterns of FSH secretion under different physiological conditions.

    更新日期:2019-11-04
  • Curcumin-activated autophagy plays a negative role in its anti-osteoclastogenic effect
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-10-31
    Dianshan Ke, Yu Wang, Yunlong Yu, Yongxuan Wang, Wang Zheng, Xiaomin Fu, Junyong Han, Guoyou Zhang, Jie Xu

    Background/purpose It remains unclear what role curcumin plays in the autophagy of osteoclast precursors (OCPs) during osteoclastogenesis, since some researchers found that curcumin has the ability to inhibit osteoclastogenesis. While others have considered it as an autophagy activator. This study aimed to determine the effect of curcumin-regulated autophagy on osteoclastogenesis. Results The results revealed that direct administration of curcumin enhanced the OCP autophagy response in bone marrow-derived macrophages (BMMs). Curcumin could also abate RANKL's stimulatory effect on OCP autophagy and osteoclastogenesis. Autophagic suppression related to pharmacological inhibitors or gene silencing could further enhance the inhibitory effect of curcumin on osteoclastogenesis. As expected, curcumin ameliorated ovariectomy (OVX)-induced bone loss and its effect could be promoted by an autophagy inhibitor (chloroquine). Conclusions In conclusion, curcumin can directly enhance the autophagic activity of OCPs, which inhibits its anti-osteoclastogeneic effects. Autophagy inhibition-based drugs are expected to enhance curcumin's efficacy in treating osteoporosis.

    更新日期:2019-11-01
  • Multifactorial control of reproductive and growth axis in male goldfish: Influences of GnRH, GnIH and thyroid hormone
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-10-31
    Y. Ma, C. Ladisa, J.P. Chang, H.R. Habibi

    Reproduction and growth are under multifactorial control of neurohormones and peripheral hormones. This study investigated seasonally related effects of GnIH, GnRH, and T3 on the reproductive and growth axis in male goldfish at three stages of gonadal recrudescence. The effects of injection treatments with GnRH, GnIH and/or T3 were examined by measuring serum LH and GH levels, as well as peripheral transcript levels, using a factorial design. As expected, GnRH elevated serum LH and GH levels in a seasonally dependant manner, with maximal elevations of LH in late stages of gonadal recrudescence (Spring) and maximal increases in GH in the regressed gonadal stage (Summer). GnIH injection increased serum LH and GH levels only in fish at the regressed stage but exerted both stimulatory and inhibitory effects on GnRH-induced LH responses depending on season. T3 treatment mainly had stimulatory effects on circulating LH levels and inhibitory effects on serum GH concentrations. In the liver and testes, we observed seasonal differences in thyroid receptors, estrogen receptors, vitellogenin, follicle-stimulating hormone receptor, aromatase and IGF-I transcript levels that were tissue- and sex-specific. Generally, there were no clear correlation between circulating LH and GH levels and peripheral transcript levels, presumably due to time-related response and possible direct interaction of GnRH and GnIH at the level of liver and testis. The results support the hypothesis that GnRH and GnIH are important components of multifactorial mechanisms that work in concert with T3 to regulate reciprocal control of reproduction and growth in goldfish.

    更新日期:2019-11-01
  • Link between steroidogenesis, the cell cycle, and PKA in adrenocortical tumor cells
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-10-31
    Marthe Rizk-Rabin, Sabrina Chaoui-Ibadioune, Anna Vaczlavik, Christopher Ribes, Michel Polak, Bruno Ragazzon, Jerôme Bertherat

    Adrenocortical tumors (ACTs) frequently cause steroid excess and present cell-cycle dysregulation. cAMP/PKA signaling is involved in steroid synthesis and play a role in cell-cycle regulation. We investigated, by cell synchronization in the different phases of the cell-cycle, the control of steroidogenesis and the contribution of PKA in adrenocortical cells (H295R and culture of primary pigmented nodular adrenocortical disease cells). Cells showed increased steroidogenesis and a maximal PKA activity at G2 phase, and a reduction at G1 phase. PRKACA overexpression, or cAMP stimulation, enhanced PKA activity and induced steroidogenesis in all synchronized groups but is not sufficient to drive cell-cycle progression. PRKAR1A inactivation enhanced PKA activity and induced STAR gene expression, only in cells in G1, and triggered cell-cycle progression in all groups. These findings provide evidence for a tight association between steroidogenesis and cell-cycle in ACTs. Moreover, PRKAR1A is essential for mediating the function of PKA activity on both steroidogenesis and cell-cycle progression in adrenocortical cells.

    更新日期:2019-11-01
  • Inhibition of LncRNA FOXD3-AS1 suppresses the aggressive biological behaviors of thyroid cancer via elevating miR-296-5p and inactivating TGF-β1/Smads signaling pathway
    Mol. Cell. Endocrinol. (IF 3.693) Pub Date : 2019-10-31
    Yonghui Chen, Hongbo Gao, Yaomei Li

    Background Thyroid cancer is the most common malignant tumor with relatively high incidence and mortality in endocrine system. Research about thyroid cancer-related targets is the basis for the diagnosis of thyroid cancer and the development of new drugs. However, the predictive value of long non-coding RNA (lncRNA) for the diagnosis and prognosis of thyroid cancer is still in the preliminary stage of exploration. Thus, we for the first time investigated the effects and associated regulatory mechanism of lncRNA Forkhead box D3 antisense RNA 1 (FOXD3-AS1) in thyroid cancer in vitro and in vivo. Methods Quantitative real-time polymerase chain reaction (qRT-PCR) was used to measure the expression of lncRNA FOXD3-AS1 and miR-296-5p. Cell proliferation was detected through colony formation assay. Cell cycle was analyzed through flow cytometry. Cell mobility was valued through transwell invasion assay and wound healing assay. Western blotting was used to examine the expression of proteins related to cell proliferation and cell migration and TGF-β1/Smads signaling pathway. Luciferase reporter assay was used to verify the targeting relationship between FOXD3-AS1 and miR-296-5p. Tumor xenograft model was established and immunohistochemistry (IHC) was used to examine the expression of Ki67 and VEGF. Results We found that the expression of lncRNA FOXD3-AS1was upregulated and it had negative correlation with the level of miR-296-5p in thyroid cancer tissues and cells. LncRNA FOXD3-AS1 knockdown effectively suppressed cell proliferation and cell invasion in vitro. Further study revealed that miR-296-5p was a target of lncRNA FOXD3-AS1 and FOXD3-AS1 exerted anti-tumor effect through up-regulating miR-296-5p. Moreover, we found that FOXD3-AS1 knockdown suppressed the aggressive biological behaviors of thyroid cancer through inactivating the TGF-β1/Smads signaling pathway. Subsequently, the in vivo experiments further verified that the FOXD3-AS1/miR-296-5p axis exerted obvious anti-tumor effect through inhibiting tumor growth and metastasis and the TGF-β1/Smads signaling pathway was also inactivated in vivo by the inhibition of FOXD3-AS1. Conclusion Inhibition of LncRNA FOXD3-AS1 suppresses the aggressive biological behaviors of thyroid cancer via elevating miR-296-5p and inactivating TGF-β1/Smads signaling pathway.

    更新日期:2019-11-01
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