- Elucidating the Role of the Maternal Embryonic Leucine Zipper Kinase (MELK) in Adrenocortical Carcinoma. [Journal Article]
- EEndocrinology 2018 May 21
- Adrenocortical carcinoma (ACC) is an aggressive cancer with a five-year survival less than 35%. Mortality remains high due to lack of targeted therapies. Using bioinformatic analyses, we identified M...
Adrenocortical carcinoma (ACC) is an aggressive cancer with a five-year survival less than 35%. Mortality remains high due to lack of targeted therapies. Using bioinformatic analyses, we identified Maternal Embryonic Leucine Zipper Kinase (MELK) as 4.1-fold overexpressed in ACC compared to normal adrenal samples. High MELK expression in human tumors correlated with shorter survival and with increased expression of genes involved in cell division and growth. We investigated the functional effects of MELK inhibition using newly developed ACC cell lines with variable MELK expression, CU-ACC1 and CU-ACC2, compared with H295R cells. In vitro treatment with the MELK inhibitor, OTSSP167, resulted in a dose dependent decrease in rates of cell proliferation, colony formation and cell survival, with relative sensitivity of each ACC cell line based upon the level of MELK overexpression. To confirm a MELK specific anti-tumorigenic effect, MELK was inhibited in H295R cells via multiple shRNAs. MELK silencing resulted in 1.9-fold decrease in proliferation, and 3 to 10-fold decrease in colony formation in soft agar and clonogenicity assays, respectively. In addition, while MELK silencing had no effect on survival in normoxia, exposure to a hypoxia resulted in a 6- and 8-fold increase in apoptosis as assessed by caspase-3 activation and TUNEL, respectively. Together these data suggest that MELK is a modulator of tumor cell growth and survival in a hypoxic microenvironment in adrenal cancer cells, and support future investigation of its role as a novel therapeutic kinase target in patients with adrenocortical carcinoma.
- Changes in corticotrope gene expression upon increased expression of peptidylglycine α-amidating monooxygenase. [Journal Article]
- EEndocrinology 2018 May 16
- Throughout evolution, secretion has played an essential role in the ability of organisms and single cells to survive in the face of a changing environment. PAM (peptidylglycine α-amidating monooxygen...
Throughout evolution, secretion has played an essential role in the ability of organisms and single cells to survive in the face of a changing environment. PAM (peptidylglycine α-amidating monooxygenase) is an integral membrane monooxygenase, first identified for its role in the biosynthesis of neuroendocrine peptides released by the regulated secretory pathway. PAM was subsequently identified in Chlamydomonas reinhardtii, a unicellular green alga, where it plays an essential role in constitutive secretion and in ciliogenesis. Reduced expression of C.reinhardtii PAM resulted in significant changes in secretion and ciliogenesis. Hence, a screen was performed for transcripts and proteins whose expression responded to changes in PAM levels in a mammalian corticotrope tumor cell line. The goal was to identify genes not previously known to play a role in secretion. The screen identified transcription factors, peptidyl prolyl isomerases, endosomal/lysosomal proteins and proteins involved in tissue-specific responses to glucose and amino acid availability that had not previously been recognized as relevant to the secretory pathway. Perhaps reflecting the dependence of PAM on molecular oxygen, many PAM-responsive genes are known to be hypoxia-responsive. The data highlight the extent to which the performance of the secretory pathway may be integrated into a wide diversity of signaling pathways.
- Reproductive, physiological, and molecular outcomes in female mice deficient in Dhh and Ihh. [Journal Article]
- EEndocrinology 2018 May 16
- Ovarian development requires coordinate communications between oocytes, granulosa cells, and theca cells. Two Hedgehog (Hh) pathway ligands, desert (Dhh) and indian hedgehog (Ihh), are produced by th...
Ovarian development requires coordinate communications between oocytes, granulosa cells, and theca cells. Two Hedgehog (Hh) pathway ligands, desert (Dhh) and indian hedgehog (Ihh), are produced by the granulosa cells and work together to regulate theca cell specification and development. Mice lacking both Dhh and Ihh resulted in the loss of normal ovarian function and raised the question of which biological actions are specifically controlled by each ligand during folliculogenesis. By comparing the reproductive fitness, hormonal profiles, and ovarian transcriptomes between control, Dhh single knockout, Ihh single knockout, and Dhh/Ihh double knockout mice, we examined the specific roles of Dhh and Ihh in these processes. Dhh/Ihh double knockout females were infertile due to a lack of theca cells and their steroid product androgen. Although both Dhh and Ihh single knockout mice were fertile with normal folliculogenesis, they had decreased androgen production and alterations in their ovarian transcriptomes. Absence of Ihh led to aberrant steroidogenesis and elevated inflammation responses, which were not found in Dhh single KO ovaries, implicating that IHH has a greater impact than DHH on the activation of the Hh signaling pathway in the ovary. Our findings provide insight into not only how the Hedgehog pathway influences folliculogenesis, but also the distinct and overlapping roles of Dhh and Ihh in supporting ovarian development.
- CHRONIC VARIABLE STRESS INDUCES SEX-SPECIFIC ALTERATIONS IN SOCIAL BEHAVIOR AND NEUROPEPTIDE EXPRESSION IN THE MOUSE. [Journal Article]
- EEndocrinology 2018 May 16
- Chronic exposure to stressors impairs the function of multiple organ systems and is implicated in increased disease risk. In the rodent, the chronic variable stress (CVS) paradigm has successfully mo...
Chronic exposure to stressors impairs the function of multiple organ systems and is implicated in increased disease risk. In the rodent, the chronic variable stress (CVS) paradigm has successfully modeled several stress-related illnesses. Despite striking disparities between men and women in the prevalence and etiology of disorders associated with chronic stress, most preclinical research examining chronic stressor exposure has focused on male subjects. One potential mediator of the consequences of CVS is oxytocin (OT), a known regulator of stress neurocircuitry and behaviors. To ascertain sex-specific effects of CVS in the C57BL/6 mouse on OT and the structurally similar neuropeptide arginine vasopressin (AVP), numbers of immunoreactive (-ir) and mRNA-containing neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) were determined using immunohistochemistry and in situ hybridization, respectively. In addition, subjects underwent a battery of behavioral tests to determine whether CVS affects social behaviors known to be regulated by OT and AVP. Six weeks of CVS increased sociability in the female mouse and decreased PVN OT-ir and AVP mRNA. In male subjects, CVS decreased PVN OT mRNA, but had no effect on social behavior, AVP, or OT-ir. CVS also increased soma volume for PVN OT neurons. In contrast, OT and AVP neurons in the SON were unaffected by CVS treatment. These findings demonstrate clear sex differences in the effects of CVS on neuropeptides in the mouse, suggest a pathway through which CVS alters sociability and stress-coping responses in females, and reveal a novel vulnerability to CVS in the C57BL/6 mouse strain.
- Obstructive Sleep Apnea Syndrome and Metabolic Diseases. [Journal Article]
- EEndocrinology 2018 May 18
- With the rapid changes of lifestyle in modern society, including high nutritional intake and reduced physical activity, the incidence of metabolic diseases is increasing year by year. Obstructive sle...
With the rapid changes of lifestyle in modern society, including high nutritional intake and reduced physical activity, the incidence of metabolic diseases is increasing year by year. Obstructive sleep apnea syndrome (OSAS) is a sleep disorder, usually characterized by sudden pauses of breathing during sleep with interrupted sleep rhythm. Although the pathological mechanism remains poorly understood, it is strongly associated with metabolic diseases, including obesity, insulin resistance, type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). In this mini-review, we briefly summarizes the connections between OSAS, obesity, T2DM and NAFLD, which may help to better understand the pathogenesis of human diseases.
- The hepatic glucocorticoid receptor is crucial for cortisol homeostasis and sepsis survival in humans and male mice. [Journal Article]
- EEndocrinology 2018 May 17
- Sepsis is hallmarked by hypercortisolemia, a stress response that is essential for survival. This elevation in plasma cortisol is partially brought about by suppressed hepatic cortisol breakdown. We ...
Sepsis is hallmarked by hypercortisolemia, a stress response that is essential for survival. This elevation in plasma cortisol is partially brought about by suppressed hepatic cortisol breakdown. We now demonstrated that a controlled downregulation of the hepatic glucocorticoid receptor (hepatic GR) is crucial herein. In a mouse model of fluid-resuscitated, antibiotic-treated abdominal sepsis and in human ICU patients, sepsis reduced hepatic GR expression and signaling, but increased (free) plasma cortisol/corticosterone, explained by suppressed cortisol/corticosterone binding proteins and A-ring-reductases. However, further experimental inhibition of hepatic GR with shRNA in septic mice increased mortality five-fold. Acutely, this further hepatic GR suppression prevented the rise in total corticosterone, but further reduced binding proteins, resulting in elevated free corticosterone. After 3 days of shRNA-GR-inhibition in sepsis, both total and free corticosterone were elevated, now explained by an additional reduction in A-ring-reductase expression. Hepatic GR inhibition blunted the hyperglycemic stress response without causing hypoglycemia, but also markedly increased circulating and hepatic inflammation markers and caused liver destruction, the severity of which explained increased mortality. In human sepsis, glucocorticoid treatment further suppressed hepatic GR expression, which could directly predispose to worse outcomes. In conclusion, sepsis partially suppressed hepatic GR expression, which appeared crucial to upregulate free cortisol/corticosterone availability. However, further sustained hepatic GR suppression evoked lethal excessive liver and systemic inflammation, independent of systemic cortisol/corticosterone availability.
- Proteomic Characterization Of The Extracellular Matrix Of Human Uterine Fibroids. [Journal Article]
- EEndocrinology 2018 May 16
- Uterine leiomyomas (fibroids) are the most common benign tumors that are associated with increased production of extracellular matrix (ECM). The excessive ECM deposition plays a major role in the enl...
Uterine leiomyomas (fibroids) are the most common benign tumors that are associated with increased production of extracellular matrix (ECM). The excessive ECM deposition plays a major role in the enlargement and stiffness of these tumors and contributes to clinical symptoms, such as abnormal bleeding and abdominal pain. However, no study so far has explored the global composition of the ECM of fibroids and normal myometrium. In this study, we performed systematic ECM enrichment procedure and comparative proteomic analyses to profile the ECM composition of genetically annotated different size fibroids (small, medium and large) and adjacent normal myometrium (ANM). Our matrisome analysis identified a combined total of 108, 126, 126, and 130 unique ECM and ECM-associated proteins with a confidence corresponding to a false discovery rate (FDR) < 1% in ANM, small, medium, and large fibroids, respectively. The majority of fibroid ECM proteins belong to the core matrisome that includes glycoproteins, collagens, and proteoglycans. Considering that the small-sized fibroids represent the initial stages of leiomyogenesis, we highlighted some of the most abundant and significant upregulated ECM proteins in small fibroids are POSTN, TNC, COL3A1, COL24A1, and ASPN. Furthermore, we revealed the list of 30 unique ECM proteins that exist only in fibroids but not present in ANM regardless of MED12 mutation. We propose that some of the proteins identified represent potential novel ECM drug targets that may potentially change the paradigm of fibroid treatment.
- Structure-Function Relationships in Endocrinology. [Journal Article]
- EEndocrinology 2018 Jun 01; 159(6):2376-2377
- The somatostatin-secreting pancreatic δ-cell in health and disease. [Review]
- NRNat Rev Endocrinol 2018 May 17
- The somatostatin-secreting δ-cells comprise ~5% of the cells of the pancreatic islets. The δ-cells have complex morphology and might interact with many more islet cells than suggested by their low nu...
The somatostatin-secreting δ-cells comprise ~5% of the cells of the pancreatic islets. The δ-cells have complex morphology and might interact with many more islet cells than suggested by their low numbers. δ-Cells contain ATP-sensitive potassium channels, which open at low levels of glucose but close when glucose is elevated. This closure initiates membrane depolarization and electrical activity and increased somatostatin secretion. Factors released by neighbouring α-cells or β-cells amplify the glucose-induced effects on somatostatin secretion from δ-cells, which act locally within the islets as paracrine or autocrine inhibitors of insulin, glucagon and somatostatin secretion. The effects of somatostatin are mediated by activation of somatostatin receptors coupled to the inhibitory G protein, which culminates in suppression of the electrical activity and exocytosis in α-cells and β-cells. Somatostatin secretion is perturbed in animal models of diabetes mellitus, which might explain the loss of appropriate hypoglycaemia-induced glucagon secretion, a defect that could be mitigated by somatostatin receptor 2 antagonists. Somatostatin antagonists or agents that suppress somatostatin secretion have been proposed as an adjunct to insulin therapy. In this Review, we summarize the cell physiology of somatostatin secretion, what might go wrong in diabetes mellitus and the therapeutic potential of agents targeting somatostatin secretion or action.
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- An update in the treatment preference for hyperthyroidism. [Letter]
- NRNat Rev Endocrinol 2018 May 17